Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C@H:10]([C@H:27]([OH:29])[CH3:28])[C:11]([NH:13][NH:14][C:15](=[O:26])[C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[O:12])=[CH:5][C:4]=1[C:30]([F:33])([F:32])[F:31])#[N:2].N1C=CN=C1.[CH3:39][C:40]([Si:43](Cl)([CH3:45])[CH3:44])([CH3:42])[CH3:41]>CN(C=O)C>[Si:43]([O:29][C@H:27]([CH3:28])[C@@H:10]([NH:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([C:30]([F:33])([F:32])[F:31])[CH:5]=1)[C:11]([NH:13][NH:14][C:15](=[O:26])[C:16]1[CH:17]=[CH:18][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][CH:21]=1)=[O:12])([C:40]([CH3:42])([CH3:41])[CH3:39])([CH3:45])[CH3:44]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@@H](O)[C@@H](Nc1ccc(C#N)c(C(F)(F)F)c1)C(=O)NNC(=O)c1ccc(S(C)(=O)=O)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](Nc1ccc(C#N)c(C(F)(F)F)c1)C(=O)NNC(=O)c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 82.6 %

Procedure:
To a pre-cooled (0° C.) solution of N′-((2R,3R)-2-(4-cyano-3-(trifluoromethyl)phenylamino)-3-hydroxybutanoyl)-4-(methylsulfonyl)benzohydrazide (5.16 g, 10.7 mmol) in DMF (150 mL) was added imidazole (4.36 g, 64.0 mmol) then TBSCl (4.81 g, 32.0 mmol). The reaction was warmed slowly to room temperature, stirred for 17 h, cooled to 0° C. and quenched with H2O (300 mL). The solution was extracted with EtOAc (250 mL). The organic extract was washed with brine (2×200 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide a brown oil, which was purified by flash chromatography over silica gel (50% EtOAc in hexanes) to provide the title compound (5.29 g, 83%): 1H NMR (400 MHz, acetone-d6, δ in ppm) 10.06 (s, 2H), 8.10 (dm, J=8.6 Hz, 2H), 8.03 (dm, J=8.6 Hz, 2H), 7.70 (d, J=8.6 Hz, 1H), 7.35 (d, J=2.4 Hz, 1H), 7.14 (dd, J=2.4, 8.6 Hz, 1H), 6.57 (d, J=7.4 Hz, 1H), 4.50-4.41 (m, 2H), 3.17 (s, 3H), 1.36 (d, J=5.9 Hz, 3H), 0.85 (s, 9H), 0.11 (s, 3H), 0.09 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[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:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:38][C:39]1[N:40]=[C:41]([CH2:44][C:45]([N:47]2[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]2)=[O:46])[S:42][CH:43]=1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:50]3[CH2:51][CH2:52][N:47]([C:45](=[O:46])[CH2:44][C:41]4[S:42][CH:43]=[C:39]([CH3:38])[N:40]=4)[CH2:48][CH2:49]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: Cc1csc(CC(=O)N2CCNCC2)n1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(C(=O)Cc2nc(C)cs2)CC1

Procedure:
In a manner analogous to the method described in examples 8, (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 chloride (example 51) was coupled with 2-(4-methyl-thiazol-2-yl)-1-piperazin-1-yl-ethanone (Enamine) to give the title compound. HR-MS (ES, m/z) calculated for C39H45Cl2N6O3S [(M+H)+] 747.2646, observed 747.2642.
Reaction SMILES: [C:1]1([CH:7]2[S:20][C:14]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]2=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:28](Cl)(=[O:30])[CH3:29]>C(Cl)(Cl)Cl>[C:28]([N:17]1[CH2:16][CH2:15][C:14]2([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[S:20]2)[CH2:19][CH2:18]1)(=[O:30])[CH3:29]
Reactant: c1ccc(C2SC3(CCNCC3)c3ccccc32)cc1
Reactant: CC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC2(CC1)SC(c1ccccc1)c1ccccc12

Procedure:
A cold stirred solution of 1,3-dihydro-3-phenylspiro[benzo(c)thiophene-1,4'-piperidine], Example 4, and triethylamine in 50 ml of chloroform is treated dropwise with a solution of acetyl chloride in chloroform to provide 1'-acetyl-1,3-dihydro-3-phenylspiro[benzo(c)thiophene-1,4'-piperidine].
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:14]=[C:15]([O:17][CH2:18][CH2:19][CH2:20][O:21]C2CCCCO2)[CH:16]=1)[C:8](N(OC)C)=[O:9])([CH3:4])([CH3:3])[CH3:2].[CH3:28][Si]([N-][Si](C)(C)C)(C)C.[Li+].C[Mg]Br>C1COCC1>[C:1]([C:5]1[CH:6]=[C:7]([C:8](=[O:9])[CH3:28])[CH:14]=[C:15]([O:17][CH2:18][CH2:19][CH2:20][OH:21])[CH:16]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CON(C)C(=O)c1cc(OCCCOC2CCCCO2)cc(C(C)(C)C)c1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: C[Mg]Br
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(=O)c1cc(OCCCO)cc(C(C)(C)C)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
3-tert-Butyl-N-methoxy-N-methyl-5-[3-(tetrahydropyran-2-yloxy)propoxy]benzamide (O3.059; 5.49 g) was dissolved in THF (100 ml), cooled to 0° C. and admixed with lithium bis(trimethylsilyl)amide (14.47 ml, 1 M in MTB ether). After stirring at 0° C. for 30 min, methylmagnesium bromide (9.65 ml, 3 M in ether) was added dropwise. The cooling bath was removed and, after stirring at RT for 2 h, the mixture was diluted with water and extracted by shaking with EA. The EA phase was dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was purified using silica gel (200 g, n-heptane/EA 4:1). 3.4 g of the title compound were obtained.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][N:6]([CH2:15][C:16]2[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:7][C:8]2[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:2]1.CCN(C(C)C)C(C)C.Br[CH2:33][C:34]([O:36][CH3:37])=[O:35].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:37][O:36][C:34](=[O:35])[CH2:33][N:1]1[CH2:4][CH:3]([CH2:5][N:6]([CH2:7][C:8]2[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:15][C:16]2[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:2]1
Reactant: COC(=O)CBr
Reactant: Cc1cccnc1CN(Cc1ncccc1C)CC1CNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)CN1CC(CN(Cc2ncccc2C)Cc2ncccc2C)C1
Temperature: 25 °C
Reaction time: 19 h
Yield: 23.9 %

Procedure:
To a solution of azetidin-3-ylmethyl-bis-(3-methyl-pyridin-2-ylmethyl)-amine (0.4739 g, 1.6 mmol) in CH2Cl2 (16 mL) were added DIPEA (0.56 mL, 3.2 mmol), and methyl bromoacetate (0.18 mL, 1.9 mmol). The mixture was stirred at room temperature for 19 hours, and then saturated NaHCO3 (15 mL) was added and extracted with CH2Cl2 (3×50 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated. Purification of the crude material by column chromatography on silica gel (100:1:1 CH2Cl2-MeOH—NH4OH) provided 0.1411 g (24%) of (3-{[bis-(3-methyl-pyridin-2-ylmethyl)-amino]-methyl}-azetidin-1-yl)-acetic acid methyl ester as a yellow sticky oil. 1H NMR (CDCl3) δ 2.09 (s, 6H), 2.53-2.58 (m, 2H), 2.65-2.78 (m, 3H), 3.10 (s, 2H), 3.51 (t, 2H, J=6.0 Hz), 3.65 (s, 3H), 3.68 (s, 4H), 7.06-7.10 (m, 2H), 7.38 (d, 2H, J=9.0 Hz), 8.35 (d, 2H, J=6.0 Hz).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)(OC(C)(C)C)=O.ClC1[N:16]=[C:17]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[Cl:34])[C:18]2[CH:24]=[CH:23][CH:22]=[N:21][C:19]=2[N:20]=1.C(N(CC)C(C)C)(C)C>C(O)CCC>[Cl:34][C:28]1[CH:29]=[C:30]([Cl:33])[CH:31]=[CH:32][C:27]=1[CH2:26][NH:25][C:17]1[C:18]2[CH:24]=[CH:23][CH:22]=[N:21][C:19]=2[N:20]=[C:1]([N:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)[N:16]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1ccc(CNc2nc(Cl)nc3ncccc23)c(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Clc1ccc(CNc2nc(N3CCNCC3)nc3ncccc23)c(Cl)c1
Reaction time: 10 h
Yield: 99.9 %

Procedure:
Boc-piperazine (122 mg, 0.65 mmol) was added to the solution of (2-Chloro-pyrido[2,3-d]pyrimidin-4-yl)-(2,4-dichloro-benzyl)-amine(185 mg, 0.54 mmol) and N,N-diisopropylethylamine (145 μL, 0.82 mmol) in n-butanol (2 mL). The reaction mixture was stirred at 85° for 10 h. All starting material was consumed as seen on HPLC. The reaction mixture was concentrated at room temperature under vacuo. The resulting residue was suspended in 2 mL of TFA-CH2Cl2 (1:1) mixture and stirred at room temperature for 45 minutes. The reaction mixture was concentrated in vacuo, diluted with saturated aqueous sodium bicarbonate solution. The aqueous layer was extracted with CH2Cl2 (2×10 mL), dried (Na2SO4) and concentratd to furnish (2,4-Dichloro-benzyl)-(2-piperazin-1-yl-pyrido[2,3-d]pyrimidin-4-yl)-amine(210 mg) as pale brown oil. The crude was carried forward as such in the next reaction.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[CH:11]([NH:19][C:20]1[CH:29]=[C:28]([F:30])[CH:27]=[C:26]2[C:21]=1[CH:22]=[CH:23][C:24](=[O:31])[NH:25]2)[C:12]1([C:15]([F:18])([F:17])[F:16])[CH2:14][O:13]1.C(=O)([O-])[O-].[Cs+].[Cs+].O.[CH2:39]([OH:41])[CH3:40]>>[Cl:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[CH:11]([NH:19][C:20]1[CH:29]=[C:28]([F:30])[CH:27]=[C:26]2[C:21]=1[CH:22]=[CH:23][C:24](=[O:31])[NH:25]2)[C:12]([CH2:14][O:41][CH2:39][CH3:40])([OH:13])[C:15]([F:17])([F:16])[F:18]
Reactant: CCO
Reactant: COc1ccc(C(Nc2cc(F)cc3[nH]c(=O)ccc23)C2(C(F)(F)F)CO2)c(Cl)c1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Product: CCOCC(O)(C(Nc1cc(F)cc2[nH]c(=O)ccc12)c1ccc(OC)c(F)c1Cl)C(F)(F)F

Procedure:
70 mg (0.15 mmol) 5-{[(2-chloro-3-fluoro-4-methoxyphenyl)(2-trifluoromethyl-oxiranyl)methyl]amino}-7-fluoro-1H-quinolin-2-on obtained in example 3 are stirred with 84 mg (0.26 mmol) Caesium carbonate in 0.67 ml ethanol. After 40 hours water is added and the aqueous phase is extracted with ethyl acetate. The combined organic phases are washed with brine and dried over sodium sulphate. After removal of the solvent preparative thin layer chromatography on silica gel (ethyl acetate) yields 22 mg of the title compound.
Reaction SMILES: C[O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([C:13]([OH:15])=[O:14])[N:7]2[CH3:12].B(Br)(Br)Br.[OH-].[Na+]>ClCCl>[OH:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([C:13]([OH:15])=[O:14])[N:7]2[CH3:12]
Reactant: COc1cccc2c1cc(C(=O)O)n2C
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cn1c(C(=O)O)cc2c(O)cccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 39.9 %

Procedure:
To 4-methoxy-1-methyl-1H-indole-2-carboxylic acid (2.92 mmol, 600 mg) in dichloromethane (30 ml) under a nitrogen atmosphere was added boron tribromide (6.96 mmol, 671 μl, 1745 mg) keeping the temperature at 0 to 5° C. After stirring the reaction mixture at room temperature for three hours it was treated with 2N aqueous sodium hydroxide (to give a pH of 9) and stirred for additional 10 minutes. The aqueous phase was separated and neutralized with 2 N hydrochloric acid at 0° C. (pH between 6 and 7). The precipitate thus obtained was collected by filtration and coevaporated with toluene twice to yield 4-hydroxy-1-methyl-1H-indole-2-carboxylic acid (223 mg).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([N:9]2[CH:13]=[N:12][N:11]=[N:10]2)[CH:6]=[CH:5][C:4]=1[CH2:14][C:15]([N:17]1[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]1)=[O:16])#[N:2].Cl.CCO.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[O:16]=[C:15]([N:17]1[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]1)[CH2:14][C:4]1[CH:5]=[CH:6][C:7]([N:9]2[CH:13]=[N:12][N:11]=[N:10]2)=[CH:8][C:3]=1[C:1]#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)Cc2ccc(-n3cnnn3)cc2C#N)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCO
Product: N#Cc1cc(-n2cnnn2)ccc1CC(=O)N1CCNCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl 4-{[2-cyano-4-(1H-tetrazol-1-yl)phenyl]acetyl}piperazine-1-carboxylate (160 mg, 0.4 mmol) in 10 mL of dioxane was added 10 mL of 5 M HCl/EtOH, then the mixture was stirred at room temperature for 3 h. The solvent was removed under reduce pressure. The crude compound was suspension in 20 mL of MeCN and added Na2CO3 (102 mg, 0.96 mmol), then the mixture was stirred at room temperature overnight. After filtration, the filtrate was concentrated in vacua to give crude 2-[2-oxo-2-(piperazin-1-yl)ethyl]-5-(1H-tetrazol-1-yl)benzonitrile, which was used for next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:37]=[CH:36][C:6]([C:7]([NH:9][NH:10][C:11]([C:13]2[CH:21]=[C:20]3[C:16]([CH:17]=[C:18]([C:22]4[C:27]([CH3:28])=[CH:26][C:25]([CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:24][C:23]=4[CH3:35])[NH:19]3)=[CH:15][CH:14]=2)=O)=[O:8])=[CH:5][CH:4]=1.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]2[O:8][C:11]([C:13]3[CH:21]=[C:20]4[C:16]([CH:17]=[C:18]([C:22]5[C:27]([CH3:28])=[CH:26][C:25]([CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:24][C:23]=5[CH3:35])[NH:19]4)=[CH:15][CH:14]=3)=[N:10][N:9]=2)=[CH:36][CH:37]=1
Reactant: COC(=O)CCc1cc(C)c(-c2cc3ccc(C(=O)NNC(=O)c4ccc(OC)cc4)cc3[nH]2)c(C)c1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: C1CCOC1
Product: COC(=O)CCc1cc(C)c(-c2cc3ccc(-c4nnc(-c5ccc(OC)cc5)o4)cc3[nH]2)c(C)c1
Temperature: 150 °C

Procedure:
A mixture of methyl 3-(4-{6-[N′-(4-methoxybenzoyl)-hydrazinocarbonyl]-1H-indol-2-yl}-3,5-dimethyl-phenyl)-propionate (220 mg, 440 μmol) and Burgess reagent (210 mg, 880 μmol) in THF (10 mL) was heated in a microwave apparatus at 150° C. for 30 min. The solvent was removed under reduced pressure, and the residue chromatographed using a 30-70% gradient of heptane/ethyl acetate to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:15](=[O:16])NC(=O)[NH:12]3)[CH2:10][CH2:9][O:8][C:5]2=[CH:6][CH:7]=1.[OH2:18].O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-]>O>[NH2:12][C:11]1([C:15]([OH:16])=[O:18])[C:4]2[C:5](=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[O:8][CH2:9][CH2:10]1
Reactant: O=C1NC(=O)C2(CCOc3ccc(F)cc32)N1
Reactant: O
Agent: [Ba+2]
Agent: [OH-]
Product: NC1(C(=O)O)CCOc2ccc(F)cc21
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
A stirred slurry of 78 g (0.33 mole) of (RS)-6-fluoro-spiro-[chroman-4,4'-imidazolidine]-2',5'-dione and 208.3 g (0.66 mole) of barium hydroxide octahydrate in 585 ml of water was slowly heated to reflux over 3 hours and refluxed 16 hours. The slurry was cooled to 80° C. and powdered NH4CO3 (78 g) added portionwise over 5 minutes. Moderate foaming was noted. After stirring 1.5 hours at 80° C., the mixture was cooled to 60° C., and filtered over diatomaceous earth with 2×100 ml hot water for wash. The combined filtrate and washes were stripped to 200 ml and allowed to stand overnight. 2-Propanol (600 ml) was added and the mixture heated to 70° C. to dissolve precipitated solids. The hot solution was treated with activated carbon, filtered over diatomaceous earth and washed with hot 1:1 water:2-propanol. The combined filtrate and washes were stripped to 200 ml, and water chased with 3×300 ml fresh 2-propanol. The resulting thick slurry was diluted with 200 ml additional 2-propanol, cooled to 5° C., granulated for 0.5 hour, filtered and air dried to yield title product, 63.5 g, 91.2%, mp 252°-253° C. (dec).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C:12]2[C:17]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH3:26])=[C:16]([O:27][CH2:28][CH2:29][NH2:30])[N:15]=[C:14]([C:31]3[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=3)[N:13]=2)(=[O:10])=[O:9])=[N:6][CH:7]=1.[S:37]1[CH:41]=[CH:40][CH:39]=[C:38]1[S:42](Cl)(=[O:44])=[O:43]>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C:12]2[C:17]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH3:26])=[C:16]([O:27][CH2:28][CH2:29][NH:30][S:42]([C:38]3[S:37][CH:41]=[CH:40][CH:39]=3)(=[O:44])=[O:43])[N:15]=[C:14]([C:31]3[CH:32]=[CH:33][N:34]=[CH:35][CH:36]=3)[N:13]=2)(=[O:10])=[O:9])=[N:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C)cn2)nc(-c2ccncc2)nc1OCCN
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C)cn2)nc(-c2ccncc2)nc1OCCNS(=O)(=O)c1cccs1

Procedure:
According to the procedure described in Example 4a) 107 mg 5-methyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide was reacted with thiophene-2-sulfonylchloride to give 135 mg 5-methyl-N-[6-(2-(2-thiophenesulfonylamino)-ethoxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide. LC-MS: tR=4.33 min, [M+1]+=655.46, [M−1]−=653.50.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:10]=[CH:11][C:12]([NH:22][C:23]2[CH:28]=[C:27]([Cl:29])[C:26]([C:30]([F:33])([F:32])[F:31])=[CH:25][C:24]=2[O:34][CH3:35])=[C:13](/[CH:15]=[CH:16]/[C:17]([O:19]CC)=O)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+]>CO>[CH2:1]([S:8][C:9]1[CH:14]=[C:13]2[C:12](=[CH:11][CH:10]=1)[N:22]([C:23]1[CH:28]=[C:27]([Cl:29])[C:26]([C:30]([F:32])([F:33])[F:31])=[CH:25][C:24]=1[O:34][CH3:35])[C:17](=[O:19])[CH:16]=[CH:15]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)/C=C/c1cc(SCc2ccccc2)ccc1Nc1cc(Cl)c(C(F)(F)F)cc1OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(C(F)(F)F)c(Cl)cc1-n1c(=O)ccc2cc(SCc3ccccc3)ccc21
Temperature: 25 °C
Yield: 67 %

Procedure:
A flask was charged with (E)-ethyl 3-(5-(benzylthio)-2-((5-chloro-2-methoxy-4-(trifluoromethyl)phenyl)amino)phenyl)acrylate (5.33 g, 10.21 mmol) and MeOH (102 mL), followed by sodium methoxide (8.17 ml, 4.08 mmol) under nitrogen atmosphere. A reflux condensor was added, and the flask was lowered into an oil bath at 75° C. At 18 h the reaction was cooled to RT and filtered through a silica plug to remove black particulates. The product was eluted with MeOH and concentrated down to about 50 mL, followed by filtration through a medium glass frit, washing the solid with MeOH. The solid precipitate was dried under high vac to provide 6-(benzylthio)-1-(5-chloro-2-methoxy-4-(trifluoromethyl)phenyl)quinolin-2(1H)-one (3.257 g, 6.84 mmol, 67.0% yield). m/z (ESI) 475.8 (M+H)+.
Reaction SMILES: [NH2:1][C@@H:2]([C:7]([OH:9])=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4].[C:10](O)(=O)[CH:11]([CH:13]([C:15]([OH:17])=O)O)[OH:12]>>[NH2:1][C@@H:2]([C:7]([OH:9])=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4].[CH:15](=[O:17])[C:13]1[C:11](=[CH:10][CH:3]=[CH:2][CH:7]=1)[OH:12]
Reactant: O=C(O)C(O)C(O)C(=O)O
Agent: CC[C@H](C)[C@@H](N)C(=O)O
Product: O=Cc1ccccc1O

Procedure:
More recently, Noda et al., in U.S. Pat. No. 6,310,242, have reported a method in which D-allo-isoleucine is separated from an epimeric mixture with L-isoleucine using a tartaric acid derivative by the formation of a complex, which is precipitated and decomposed in alcohol. An alternative uses a selective precipitation of the L-isoleucine derivative. Again, as a separation of stereoisomers, the maximum theoretical yield is 50%, and the actual yields were lower. It is also important to point out that the tartaric acid derivatives used were not readily available and relatively expensive to produce. In an improvement of this method, Noda and coworkers describe the use of the same tartaric acid to form a complex with D-allo-isoleucine in the presence of a C1 to C5 saturated fatty acid and salicylaldehyde. The reaction was carried out in an inert solvent that does not substantially dissolve amino acids. The reported optical purity was 94.6%. A method that achieves closer to 100% optical purity would be preferable and desirable.
Reaction SMILES: CN([CH:4]=[O:5])C.P(Cl)(Cl)(Cl)=O.[CH2:11]([C:15]1[O:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH:19]=1)[CH2:12][CH2:13][CH3:14]>C(Cl)Cl>[CH2:11]([C:15]1[O:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[C:19]=1[CH:4]=[O:5])[CH2:12][CH2:13][CH3:14]
Reactant: CCCCc1cc2ccccc2o1
Reactant: CN(C)C=O
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCc1oc2ccccc2c1C=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.6 %

Procedure:
To a solution of DMF (59 g, 0.805 mol) in anhydrous DCM (300 mL) was added slowly at 0° C. under N2 atmosphere phosphorous oxy-chloride (123 g, 0.84 mol). The mixture was stirred at rt for 2 h. To this was added slowly 2-butyl-1-benzofuran (35 g, 0.21 mol) in anhydrous DCM (100 mL). The reaction mixture was slowly heated to 60° C. for 72 h, cooled to rt and poured into ice and extracted with EtOAc. The organic layer was washed with water, brine and dried over MgSO4. The solvent was removed under vacuum and the crude product purified by column chromatography over silica gel (PetEther/EtOAc) to give 2-butyl-1-benzofuran-3-carbaldehyde (30 g, 74%) as a light brown liquid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][CH:3]=1.[F:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[Cl:18])[CH:13]=[O:14].ClC1C=CC(C(C2C=CC(OC)=CC=2)O)=CC=1>>[Cl:18][C:17]1[CH:16]=[CH:15][C:12]([CH:13]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[OH:14])=[CH:11][C:10]=1[F:9]
Reactant: O=Cc1ccc(Cl)c(F)c1
Reactant: Fc1ccc(Br)cc1
Agent: COc1ccc(C(O)c2ccc(Cl)cc2)cc1
Product: OC(c1ccc(F)cc1)c1ccc(Cl)c(F)c1

Procedure:
The title compound was prepared starting from 5.00 g (28.57 mmol) of 4-fluorobromobenzene and 5.44 g (34.29 mmol) of 3-fluoro-4-chlorobenzaldehyde in analogy to the synthesis of the compound from Example 175A. 5.01 g (69% of theory) of the title compound were obtained.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([C@@H:23]([CH3:26])[CH2:24][CH3:25])[C:20](O)=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.CCN(S(F)(F)[F:39])CC>C(Cl)Cl>[F:39][C:20](=[O:21])[C@@H:19]([NH:18][C:16](=[O:17])[O:15][CH2:14][CH:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)[C@@H:23]([CH3:26])[CH2:24][CH3:25]
Reactant: CC[C@H](C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: CCN(CC)S(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC[C@H](C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
To a solution of (2S,3S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methylpentanoic acid (Fmoc-Isoleucine) (7 g, 19.81 mmol) and pyridine (1.602 mL, 19.81 mmol) in DCM (120 mL) was added via cannula a solution of DAST (3.11 mL, 23.77 mmol) in DCM (20 mL) over 10 min. The reaction mixture was stirred at room temperature for 1 hour, diluted with DCM (80 mL), washed with ice-cold water (2×200 mL), the organic layer was dried over MgSO4, filtered, and evaporated in vacuo to give (9H-fluoren-9-yl)methyl (2S,3S)-1-fluoro-3-methyl-1-oxopentan-2-ylcarbamate (6.65 g, 94%) as a white solid. An esterification test was performed to assure quantitative acid fluoride formation by dissolving Fmoc-Ile-F (5 mg) in anhydrous MeOH (0.3 mL) and DIEA (0.030 mL) and allowing to react at room temperature for 15 min. The mixture was then evaporated in vacuo and analyzed by LCMS, showed less than 1% of Fmoc-Ile-OH present.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([OH:14])=O)[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH2:63]([N:67]([CH2:69][CH:70]1[CH2:75][CH2:74][CH2:73][CH2:72][NH:71]1)[CH3:68])[CH2:64][CH2:65][CH3:66]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:71]1[CH2:72][CH2:73][CH2:74][CH2:75][CH:70]1[CH2:69][N:67]([CH2:63][CH2:64][CH2:65][CH3:66])[CH3:68])=[O:14])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CCCCN(C)CC1CCCCN1
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN(C)CC1CCCCN1C(=O)c1cc2ncnc(NC(C)c3nc4cc(Cl)ccc4[nH]3)c2cc1Cl

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and N-butyl-N-methyl-C-(piperidin-2-yl)-methylamine in DMSO at ambient temperature.