Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.FC(F)(F)C(O)=O.[OH:17][CH:18]1[CH2:21][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:19]1>>[CH3:9][C:4]1[CH:5]=[C:6]([CH3:8])[N:7]=[C:2]([O:17][CH:18]2[CH2:19][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21]2)[N:3]=1
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Reactant: Cc1cc(C)nc(Cl)n1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)nc(OC2CN(C(=O)OC(C)(C)C)C2)n1

Procedure:
Compound P24 was prepared according to the general procedure described in the preparation of P21, except that 2-chloro-4,6-dimethylpyrimidine was used in place of 2-bromopyridine, to afford P24. LCMS (ESI) m/z 280.3 (M+1). 1H NMR (400 MHz, CDCl3) δ 1.39 (s, 9H), 2.34 (s, 6H), 3.96 (m, 2H), 4.25 (m, 2H), 5.26 (m, 1H), 6.66 (s, 1H). Compound P24 was deprotected with trifluoroacetic acid as described for tert-butyl 3-hydroxyazetidine-1-carboxylate in the preparation of C19, Example 3 before being used in the coupling step.
Reaction SMILES: [NH2:1][C@H:2]([C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[CH2:3][OH:4].C(N(CC)CC)C.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>C(Cl)Cl>[CH3:19][O:20][C:21]1[CH:22]=[CH:23][C:24]([S:27]([NH:1][C@H:2]([C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[CH2:3][OH:4])(=[O:29])=[O:28])=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)[C@@H](N)CO
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N[C@@H](CO)C(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 101.1 %

Procedure:
To a solution of 12.18 g (0.0756 mol) of L-serine, t-butyl ester, 26.52 ml of triethylamine in 160 ml of CH2Cl2 (cooled in an ice bath) was added, in small portions, 16.1 g (0.0771 mol) of 4-methoxybenzene-sulfonyl chloride. The mixture was stirred at 0° C. for 0.5 hours and at room temperature overnight. The mixture was washed with H2O, 2N citric acid, brine and dried with Na2SO4. The solvent was removed under vacuum to give 25.34 g of solid which was triturated with hexane. The solid was recrystallized from 120 ml of toluene to give 12.18 g (48.7%) of product as a white solid. The filtrate was concentrated and the residue chromatographed on silica gel with hexane-ethyl acetate (7:3) as eluent to give 5.71 g (22.8%) of white solid. m.p. 70-75° C. Anal. for C14H21NO6S: Calc'd: C. 50.7; H,6.4; N,4.2; Found: C, 50.4; H,6.3; N,4.4.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=2[F:19])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:20])[CH:8]=2)[N:3]=1.O.[NH2:22][NH2:23]>>[Cl:20][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:22][NH2:23])[CH:11]=[C:10]2[C:12]1[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=1[F:19]
Reactant: NN
Reactant: Fc1cccc(F)c1-c1cc(Cl)nc2ccc(Cl)cc12
Solvent: O
Product: NNc1cc(-c2c(F)cccc2F)c2cc(Cl)ccc2n1

Procedure:
In the manner given in Example 1, 2,6-dichloro-4-(2,6-difluorophenyl)quinoline is reacted at reflux with hydrazine hydrate to give 6-chloro-4-(2,6-difluorophenyl)-2-hydrazinoquinoline.
Reaction SMILES: C(N1CCN([NH:14][C:15](=[O:23])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)CC1)(OC(C)(C)C)=O.[CH2:24]([C:26]1[N:31]=[C:30]([N:32]2[CH2:37][CH2:36]N(C(OC(C)(C)C)=O)[CH2:34][CH2:33]2)[C:29]2[CH:45]=[C:46]([CH2:48][CH3:49])[S:47][C:28]=2[N:27]=1)[CH3:25]>>[CH2:24]([C:26]1[N:31]=[C:30]([N:32]2[CH2:37][CH2:36][N:14]([C:15](=[O:23])[CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:34][CH2:33]2)[C:29]2[CH:45]=[C:46]([CH2:48][CH3:49])[S:47][C:28]=2[N:27]=1)[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCN(NC(=O)Cc2ccccc2)CC1
Reactant: CCc1nc(N2CCN(C(=O)OC(C)(C)C)CC2)c2cc(CC)sc2n1
Product: CCc1nc(N2CCN(C(=O)Cc3ccccc3)CC2)c2cc(CC)sc2n1
Yield: 27 %

Procedure:
Phenylacetamidopiperazine hydrochloride (Example 141) was reacted 2-ethyl-4-chloro-6-ethylthienopyrimidine (Example 156) according to Example 87. Yield=27%, ES-MS: (M+H)+ 395.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH2:12][C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([F:22])[CH:21]=1)[C:16](O)=[O:17])=[N:9][NH:8][C:7]2=[O:23].[CH2:24]([O:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[CH3:25].CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH2:12][C:13]1[CH:21]=[C:20]([F:22])[CH:19]=[C:15]([C:16]([N:30]3[CH2:31][CH2:32][CH:27]([O:26][CH2:24][CH3:25])[CH2:28][CH2:29]3)=[O:17])[CH:14]=1)=[N:9][NH:8][C:7]2=[O:23]
Reactant: O=C(O)c1cc(F)cc(Cc2n[nH]c(=O)c3cccc(Cl)c23)c1
Reactant: CCOC1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC1CCN(C(=O)c2cc(F)cc(Cc3n[nH]c(=O)c4cccc(Cl)c34)c2)CC1
Reaction time: 1 h

Procedure:
3-((8-chloro-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)-5-fluorobenzoic acid (128), 4-ethoxypiperidine and 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium tetrafluoroborate were dissolved in DMF (10 mL), to this was added DIPEA and the reaction was stirred for 1 hour. The solvent was evaporated to dryness and the gum was dissolved in acetonitrile (4 mL) and purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired compound as a white foam (130 mg); 1H NMR (400.132 MHz, CDCl3) δ 1.20 (3H, t), 2.00-1.38 (4H, m), 3.29-3.05 (1H, m), 3.57-3.34 (5H, m), 4.08-3.91 (1H, m), 4.68 (2H, s), 6.90 (1H, d), 6.97-6.94 (2H, m), 7.67 (1H, t), 7.80 (1H, d), 8.50 (1H, dd); NH missing; m/z (LC-MS, ESI+), RT=2.06 (M+H 444).
Reaction SMILES: C([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=O)[C@H:10]([CH2:12][CH3:13])[CH3:11])=[O:7])(C)(C)C.[NH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl.CCN(C(C)C)C(C)C>[CH3:11][CH:10]([CH2:12][CH3:13])[CH:9]([NH:8][C:6](=[O:7])[OH:5])[C:14]([NH:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[O:16]
Reactant: NCc1ccccn1
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC(C)C(NC(=O)O)C(=O)NCc1ccccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 123.5 %

Procedure:
To a room temperature solution of 2.33 g of N-(tert-butoxycarbonyl)-L-isoleucine in 5 ml of methylene chloride is added, in the following order, 1.0 g of 2-(aminomethyl)pyridine in 5 ml of methylene chloride, 6.95 g of BOP in 5 ml of methylene chloride and 16 ml of Hunig's base. The reaction is stirred at room temperature for 2 hours, diluted with methylene chloride, and, washed with saturated sodium chloride. The organic layer is dried, filtered and concentrated in vacuo. Purification by chromatography (400 g Silica Gel; 90% ethyl acetate/hexane) gives 3.03 g of the desired product as an oil.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([NH2:13])[N:10]=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:14]N1C(=O)CCC1=O>>[Br:14][C:12]1[N:11]=[N:10][C:9]([NH2:13])=[N:8][C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1nncc(-c2ccccc2)n1
Product: Nc1nnc(Br)c(-c2ccccc2)n1
Yield: 64.1 %

Procedure:
6-Bromo-5-phenyl-1,2,4-triazin-3-amine (1.40 g, 64%) was prepared from 5-phenyl-1,2,4-triazin-3-amine (1.50 g, 8.70 mmol) and N-bromosuccinimide (4.50 g, 26.6 mmol) according to the general procedure of Preparation 3.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[CH:11][CH:10]=[C:9]2[CH3:23])=[CH:4][CH:3]=1.[Cl:24]N1C(=O)CCC1=O>C1COCC1>[Cl:24][C:10]1[CH:11]=[C:12]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:9]=1[CH3:23]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1ccc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(F)cc1
Solvent: C1CCOC1
Product: Cc1c(Cl)cc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(F)cc1
Temperature: 20 °C
Reaction time: 18 h
Yield: 9.7 %

Procedure:
To a solution of 1-(4-fluorophenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrole (Example 1) (1 g, 3.03 mmol) in THF (100 ml) at -70° C., N-chlorosuccinimide (488 mg, 3.65 mmol) was added over 10 minutes. The reaction mixture was warmed to 20° C. over 3 hours and stirred for 18 hours. More N-chlorosuccinimide (450 mg, 3.37 mmol) was added and the mixture was stirred for 6 hours. After dilution with aqueous potassium carbonate, the reaction mixture was extracted with ethyl acetate. The organic fractions were washed with water, dried (MgSO4), filtered and concentrated. The crude dark orange solid (1.3 g) was purified by chromatography (silica gel, hexane/ethyl acetate, 1/1) to give 3-chloro-1-(4-fluorophenyl)-2-methyl-5-[-4-(methylsulfonyl)phenyl]-1H-pyrrole (107 mg, 10%): mp (DSC) 172° C. Anal Calc'd. for C18H15NSClFO2 : C, 59.42; H, 4.16; N, 3.85. Found: C, 59.21; H, 4.10; N, 3.56.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([NH2:14])=[C:12]([C:15]2[C:16]([C:27]([F:30])([F:29])[F:28])=[N:17][N:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)[CH:19]=2)[O:11][N:10]=1.[C:31](O)(=[O:33])C>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([NH:14][CH:31]=[O:33])=[C:12]([C:15]2[C:16]([C:27]([F:29])([F:30])[F:28])=[N:17][N:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)[CH:19]=2)[O:11][N:10]=1
Reactant: CC(=O)O
Reactant: Nc1c(-c2c(F)cccc2Cl)noc1-c1cn(-c2cccc(F)c2)nc1C(F)(F)F
Product: O=CNc1c(-c2c(F)cccc2Cl)noc1-c1cn(-c2cccc(F)c2)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.2 %

Procedure:
A solution of 130 mg (0.295 mmol) 3-(2-chloro-6-fluorophenyl)-5-[1-(3-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl]isoxazol-4-amine (example 117) in a mixture of 1847 mg (17.4 mmol) trimethylorthoether and 1660 mg (27.7 mmol) acetic acid was stirred at r.t. for 1 h. The suspension was filtered, and the obtained white solid salts were washed on the filter with hexane. Filtrates were combined and evaporated to dryness. The residue was treated by hexane, and the extract was purified by CC on silica gel, (eluent EtOAc/hexane 1/1). The obtained fraction of the pure product (example 141) was evaporated to give 50 mg of a light greenish oil (yield 36%). Result of LC/MS MH+: 469.04; 1H NMR (400 MHz, methanol-d4): 7.29-7.35 (m, 1H) 7.44 (s, 3H) 7.46-7.50 (m, 1H) 7.57-7.67 (m, 2H) 7.72 (s, 1H) 8.26 (s, 1H)
Reaction SMILES: [OH-].[Na+].Cl.C([O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH2:19][C:18]([C:24]3[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[CH:25]=3)([C:20]([F:23])([F:22])[F:21])[O:17][N:16]=2)=[CH:11][C:10]=1[F:32])(=O)C>C(O)C.O>[Cl:31][C:26]1[CH:25]=[C:24]([C:18]2([C:20]([F:21])([F:23])[F:22])[O:17][N:16]=[C:15]([C:12]3[CH:13]=[CH:14][C:9]([CH2:8][OH:7])=[C:10]([F:32])[CH:11]=3)[CH2:19]2)[CH:29]=[C:28]([Cl:30])[CH:27]=1
Reactant: CC(=O)OCc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: OCc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1F
Yield: 69.9 %

Procedure:
In a solution of 1.50 g of crude 3-(4-acetoxymethyl-3-fluorophenyl)-5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole in 10 ml of ethanol, 2.00 g of sodium hydroxide dissolved in 20 ml of water was added, and stirred under reflux with heat for 4.5 hours. After the completion of the reaction, the reaction mixture was cooled with ice, and adjusted to pH 2-3 by carefully adding concentrated hydrochloric acid, and extracted with ethyl acetate (50 ml×1). The organic phase was dehydrated with saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with ethyl acetate-hexane (1:2) to obtain 0.95 g of the aimed product as pale yellow resinous substance.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[C:16]([C:17]3[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([N:24](CC4C=CC(OC)=CC=4)CC4C=CC(OC)=CC=4)[N:18]=3)=[CH:15][C:14]([CH2:43][N:44]3[CH2:49][CH2:48][N:47]([S:50]([CH3:53])(=[O:52])=[O:51])[CH2:46][C@H:45]3[CH3:54])=[CH:13][N:12]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9].FC(F)(F)C(O)=O.FC(F)(F)S(O)(=O)=O>>[F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[C:16]([C:17]3[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([NH2:24])[N:18]=3)=[CH:15][C:14]([CH2:43][N:44]3[CH2:49][CH2:48][N:47]([S:50]([CH3:53])(=[O:52])=[O:51])[CH2:46][C@H:45]3[CH3:54])=[CH:13][N:12]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(S(C)(=O)=O)C[C@H]4C)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: COc1ncc(Nc2ncc(CN3CCN(S(C)(=O)=O)C[C@H]3C)cc2-c2nc(C)nc(N)n2)cc1F

Procedure:
The title compound was prepared from (R)-4-(2-(5-fluoro-6-methoxypyridin-3-ylamino)-5-((2-methyl-4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine via a similar deprotection step as previously described in Example 178, Step 4, using trifluoroacetic acid and trifluoromethanesulfonic acid, and isolated as a yellow solid. m/z (ESI, +ve ion) 518 (M+H)+. 1H NMR (400 MHz, d6-DMSO) 811.95 (s, 1H) 8.71 (d, J=2.35 Hz, 1H) 8.41 (d, J=2.15 Hz, 1H) 8.33-8.40 (m, 1H) 8.27 (d, J=2.15 Hz, 1H) 7.90 (br. s., 1H) 7.76 (br. s., 1H) 3.93 (s, 3H) 3.91 (s, 1H) 3.13-3.30 (m, 3H) 2.87-2.95 (m, 1H) 2.85 (s, 3H) 2.53-2.79 (m, 3H) 2.44 (s, 3H) 2.14-2.28 (m, 1H) 1.16 (d, J=6.26 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]([NH:11][CH:12]=[O:13])([CH3:10])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl-].[Al+3].[Cl-].[Cl-].[Br:18]Br>C(Cl)Cl>[Br:18][C:7]1[CH:6]=[CH:5][C:4]([CH2:3][C:2]([NH:11][CH:12]=[O:13])([CH3:1])[CH3:10])=[CH:9][CH:8]=1
Reactant: CC(C)(Cc1ccccc1)NC=O
Reactant: BrBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C)(Cc1ccc(Br)cc1)NC=O
Temperature: -5 °C

Procedure:
1.00 g (5.64 mmol) N-(1,1-dimethyl-2-phenyl-ethyl)-formamide (I34) is added to 8 mL DCM and cooled down to −5° C. Then 1.50 g (11.3 mmol) aluminium chloride is added by several portions, stirred for 5 min, before 0.9 g (5.64) bromine is added over a period of 1 min. Having finished the addition, the mixture is stirred for two more minutes at 0° C., poured onto ice water and extracted with DCM. The organic layer is dried with MgSO4 and the solvent is removed in vacuo.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6])#[CH:2].[C:10]([NH:17][CH2:18][C:19](O)=[O:20])([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>ClCCl>[C:1]([C:3]1[CH:4]=[C:5]([NH:6][C:19](=[O:20])[CH2:18][NH:17][C:10](=[O:11])[O:12][C:13]([CH3:14])([CH3:15])[CH3:16])[CH:7]=[CH:8][CH:9]=1)#[CH:2]
Reactant: C#Cc1cccc(N)c1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C#Cc1cccc(NC(=O)CNC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
3-Ethynylaniline (1.0 g, 8.54 mmol), N-Boc glycine (2.7 g, 15.41 mmol) and PyBOP (8.1 g, 15.41 mmol) were combined in dichloromethane (25 mL). Diisopropylethylamine (3.3 g, 25.61 mmol) was added to the solution and the mixture was allowed to stir at room temperature under argon for 10 h. The reaction mixture was diluted with dichloromethane and then washed successively with water and brine. The organic solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography, on silica gel, eluting with 95:5 hexanes:ethyl acetate to yield tert-butyl 2-(3-ethynylphenylamino)-2-oxoethylcarbamate. 1H NMR (CDCl3): 8.45 (br s, 1H), 7.62 (m, 1H), 7.58 (m, 1H), 7.30 (m, 2H), 5.38 (br s, 1H), 3.95 (d, 2H), 3.08 (s, 1H), 1.48 ppm (s, 9H).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:47]1([C@H:53]([NH2:55])[CH3:54])[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:35][CH2:36][CH:37]([CH2:40][C:41]([NH:55][C@@H:53]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[CH3:54])=[O:43])[CH2:38][CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H](N)c1ccccc1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)N[C@H](C)c2ccccc2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with (R)-(+)-1-phenylethylamine (Aldrich) to give the title product. LC-MS (ES+) 768 [(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]([O:17]CC)=[O:16])=[CH:10][C:9]=2[CH3:20])=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:10][C:9]=2[CH3:20])=[O:7])=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1cc(C)c(C(=O)c2ccc(Cl)cc2)n1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(CC(=O)O)n(C)c1C(=O)c1ccc(Cl)cc1

Procedure:
A suspension of 4.0 g. (0.0125 mole) of ethyl 5-(p-chlorobenzoyl)-1,4-dimethylpyrrole-2-acetate in 26 ml. of 0.5 N sodium hydroxide (0.013 mole) is heated under reflux for 30 mins. The resulting solutions is acidified with dilute hydrochloric acid, and the precipitated solid is collected by filtration, air dried and recrystallized from 2-propanol to give 5-(p-chlorobenzoyl)-1,4-dimethylpyrrole-2-acetic acid as a white crystalline solid, m.p. 178°-179°C.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[O:7][C@@H:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@@H:5]([NH:14][C:15]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2I)=[O:16])[CH2:4][O:3]1.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28](B(O)O)[CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][C:2]1([CH3:25])[O:7][C@@H:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@@H:5]([NH:14][C:15]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:28]2[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=2)=[O:16])[CH2:4][O:3]1
Reactant: CC1(C)OC[C@H](NC(=O)Nc2ccccc2I)[C@H](c2ccccc2)O1
Reactant: OB(O)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: CC1(C)OC[C@H](NC(=O)Nc2ccccc2-c2cccnc2)[C@H](c2ccccc2)O1
Temperature: 80 °C
Yield: 36.1 %

Procedure:
To a reaction flask charged with 10.8 mg (0.0094 mmol) of tetrakis(triphenylphosphine)palladium(0) in ethylene glycol dimethyl ether (1.8 mL) under nitrogen was added 107 mg (0.24 mmol) of the product from Example 6. The resulting yellow solution was stirred for 15 min before the addition of 34.0 mg (0.28 mmol) of pyridine-3-boronic acid dissolved in ethanol (0.4 mL) and ethylene glycol dimethyl ether (0.2 mL), and the subsequent addition of 0.23 mL (0.47 mmol) of a 2 M sodium carbonate aqueous solution. The reaction mixture was heated at 80° C. for ˜20 h and then cooled to room temperature. The liquid was separated from the solid residue, and the residue was rinsed with dichloromethane, which was subsequently combined with the isolated liquid. The solvent was evaporated, and the crude product was partitioned between brine (˜4 mL) and dichloromethane (˜4 mL). The organic layer was washed with additional brine, dried over magnesium sulfate, and filtered. The solvent was evaporated, and the residue, an orange oil, was purified by column chromatography (hexane/ethyl acetate) to yield 35 mg (36%) of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]2[NH:8][C:9](=[O:12])[CH2:10][O:11][C:6]=2[CH:5]=1)([O-])=O.CO>[Pd].CCOC(C)=O>[NH2:1][C:4]1[CH:14]=[CH:13][C:7]2[NH:8][C:9](=[O:12])[CH2:10][O:11][C:6]=2[CH:5]=1
Reactant: O=C1COc2cc([N+](=O)[O-])ccc2N1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1ccc2c(c1)OCC(=O)N2
Yield: 92.3 %

Procedure:
7-Nitro-4H-benzo[1,4]oxazin-3-one (0.65 g, 3.3 mmol) and 10% palladium on carbon (0.13 g) were combined in EtOAc (15 mL) and MeOH (15 mL) and hydrogenated for 2 h at atmospheric pressure. The catalyst was removed by filtration through celite and the filtrate reduced in vacuo to yield the title compound as a colourless oil (0.50 g, 91%). δH (DMSO-d6) 4.42 (2H, s), 4.89 (2H, br s), 6.13-6.20 (2H, m), 6.56 (1H, d, J 8.1 Hz), 10.27 (1H, br s).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([CH:23]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[C:20](O)=[O:21])=[CH:15][CH:14]=1.C(N(CC)CC)C.S(Cl)(C)(=O)=O.[C:42]([NH2:45])(=[O:44])[CH3:43].CN(C1C=CC=CN=1)C>C1COCC1>[C:42]([NH:45][C:20](=[O:21])[CH:19]([C:16]1[CH:17]=[CH:18][C:13]([O:12][CH2:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)=[CH:14][CH:15]=1)[CH:23]1[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1)(=[O:44])[CH3:43]
Reactant: CC(N)=O
Reactant: O=C(O)C(c1ccc(OCc2ccc3ccccc3n2)cc1)C1CCCCCC1
Agent: CN(C)c1ccccn1
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)NC(=O)C(c1ccc(OCc2ccc3ccccc3n2)cc1)C1CCCCCC1
Temperature: 0 °C

Procedure:
8.0 g (0.02 mol) of 2-[4-(quinolin-2-yl-methoxy)phenyl]-2-cycloheptyl-acetic acid and 4.0 g (5.6 ml/0.04 mol) of triethylamine are dissolved in 80 ml of THF, the solution is cooled to 0° C., and 2.3 g (1.6 ml/0.02 mol) of mesyl chloride are added. 2.4 g (0.04 mol) of acetamide and 7.2 g (0.06 mol) of dimethylaminopyridine (DMAP), dissolved in 20 ml of THF, are added at 0° C. The mixture is allowed to react at room temperature for 48 hours (stirring) and is then concentrated to dryness in vacuo, and the residue is extracted by stirring with 50 ml of water and 50 ml of dichloromethane. The organic phase is separated off, dried and concentrated to a small volume, and the residue is separated by column chromatography (silica gel 60, mobile phase: toluene/ethyl acetate/ glacial acetic acid=8/1/1).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[S:10][CH:9]=[N:8][C:6]=2[N:7]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].CN([CH:30]=[O:31])C.Cl>O1CCCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)[C:5]2[S:10][C:9]([CH:30]=[O:31])=[N:8][C:6]=2[N:7]=1
Reactant: CN(C)C=O
Reactant: Clc1nc(N2CCOCC2)c2scnc2n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: O=Cc1nc2nc(Cl)nc(N3CCOCC3)c2s1
Temperature: -78 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
To a suspension of 5-chloro-7-morpholin-4-yl-thiazolo[4,5-d]pyrimidine (2 g, 7.79 mmol) in anhydrous tetrahydrofuran, cooled to −78° C. under nitrogen atmosphere, lithium bis(trimethylsilyl)amide (11.7 mL, 11.68 mmol) was added dropwise at −78° C. and the resulting reaction mixture stirred at −78° C. for 1 h. Subsequently DMF was slowly added and the mixture stirred for further 30 min. The temperature was allowed to rise to −5° C. over 10 min and then cooled again to −78° C. The resulting reaction mixture was transferred via cannula into ice-cold aqueous 1M HCl (400 mL) and stirred vigorously. The aqueous phase was extracted with ethyl acetate (2×150 mL). The organic layer was washed with water (1×125 mL), brine (2×125 mL), dried over Na2SO4 and filtered. The solvent was reduced in vacuo to afford the title compound as an orange-brown solid (1.82 g, 82%). 1H NMR (400 MHz, CDCl3): δ 10.19 (1 H, s), 4.03 (4 H, t, J=4.90 Hz), 3.87 (4 H, t, J=4.90 Hz).