Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li]CCCC.[CH2:6]([O:8][C:9]1[CH:14]=[C:13](I)[C:12]([F:16])=[CH:11][C:10]=1[CH3:17])[CH3:7].[B:18](OC)([O:21]C)[O:19]C>C1COCC1>[CH2:6]([O:8][C:9]1[C:10]([CH3:17])=[CH:11][C:12]([F:16])=[C:13]([B:18]([OH:21])[OH:19])[CH:14]=1)[CH3:7]
Reactant: COB(OC)OC
Reactant: CCOc1cc(I)c(F)cc1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOc1cc(B(O)O)c(F)cc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.3 %

Procedure:
In dried glassware, 2.5M n-BuLi in hexanes (18.01 mL, 45.02 mmol) was added over 15 minutes to a stirred solution of 1-ethoxy-4-fluoro-5-iodo-2-methyl-benzene [CAS: 918813-06-6](9.7 g, 34.63 mmol) in dry THF (100 mL) at −78° C. under N2. After stirring for 30 mins, trimethyl borate (7.72 mL, 69.27 mmol) was added over 10 mins. The mixture was stirred for 3.25 h at −78° C. then quenched by slow addition of 1M HCl (115 ml). The mixture was warmed to ambient temperature, diluted with water (115 ml) and extracted with EtOAc (2×100 ml). The combined organic extracts were washed with saturated sodium metabisulfite soln (250 ml), brine (100 ml) and dried (MgSO4). The almost colourless solution was evaporated to a cream solid, dried rt/vac/1 h (wt=6.2 g). This solid was stirred with Et2O/iso-hexane (1:1) (40 ml) and filtered under suction and washed with the mixture then iso-hexane, dried rt/vac/overnight to give (5-ethoxy-2-fluoro-4-methyl-phenyl)boronic acid (D94) (4.0 g);
Reaction SMILES: C([N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][C:17]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=O)[CH2:11][CH2:10]1)(=O)C1C=CC=CC=1.Cl>>[F:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:17][CH2:16][CH2:15][CH:12]2[CH2:11][CH2:10][NH:9][CH2:14][CH2:13]2)=[CH:24][CH:23]=1
Reactant: O=C(CCC1CCN(C(=O)c2ccccc2)CC1)c1ccc(F)cc1
Agent: Cl
Product: Fc1ccc(CCCC2CCNCC2)cc1
Yield: 55.1 %

Procedure:
The procedure is as in Example 6 starting from 24.2 g of 3-(1-benzoyl 4-piperidyl) 1-(4-fluorophenyl) 1-propanone. 8.7 g of 4-[3-(4-fluorophenyl)1-propyl]piperidine are obtained in the form of the hydrochloride melting at 142° C.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:11][C:12]2[CH:21]=[C:20]3[C:15]([CH:16]=[CH:17][CH:18]=[C:19]3[N:22]3[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]3)=[CH:14][CH:13]=2)=[N+:6]([O-])[CH:7]=[CH:8][CH:9]=1)([O-])=O.C([O-])=O.[NH4+]>[Pd].C(O)C>[NH2:1][C:4]1[C:5]([NH:11][C:12]2[CH:21]=[C:20]3[C:15]([CH:16]=[CH:17][CH:18]=[C:19]3[N:22]3[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]3)=[CH:14][CH:13]=2)=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3ccc(Nc4c([N+](=O)[O-])ccc[n+]4[O-])cc23)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2cccc3ccc(Nc4ncccc4N)cc23)CC1
Yield: 30 %

Procedure:
A mixture of 7-(3-nitro-1-oxido-2-pyridylamino)-1-(4-tert-butoxycarbonyl-1-piperazinyl)-naphthalene (0.40 g, 0.86 mmol, product of the above reaction), ammonium formate (1.0 g, 17.2 mmol), and 10% palladium on carbon (0.15 g)in ethanol (30 mL) was refluxed 4 hour while continually returning sublimed ammonium formate back into the reaction. The solvent was removed at reduced pressure and the residue was taken up in methylene chloride. The organic solution was washed with water and brine, dried over calcium sulfate, and concentrated. The residue was flash chromatographed on silica gel (1×3 inches), Elution proceeded as follows: 25% ethyl acetate/hexane (100 mL), nil; 35% ethyl acetate/hexane (250 mL), 0.25 g of product. The product was treated with activated carbon, filtered, and concentrated. The residue was recrystallized from ethyl acetate/ether to give 0.11 g (30%) of 7-(3-amino-2-pyridylamino)-1-(4-tert-butoxycarbonyl-1-piperazinyl)-naphthalene as white crystals which were sensitive to air (turn brown on air exposure) and had mp 183°-184° C. Analysis calculated for C24H29N5O2 : C, 68.71; H, 6.97; N, 16.69. Found: C, 68.76; H, 6.58; N, 16.56.
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=2)=[O:17])[CH:12]([CH3:28])[CH2:11]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C:20]2[CH:21]=[C:22]([Cl:27])[CH:23]=[C:24]([Cl:26])[CH:25]=2)=[O:17])[CH:12]([CH3:28])[CH2:11]1
Reactant: CC1CC(CNC(=O)OC(C)(C)C)CCN1C(=O)OCc1cc(Cl)cc(Cl)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1CC(CN)CCN1C(=O)OCc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture comprising of 3,5-dichlorobenzyl 4-(((tert-butoxycarbonyl)amino)methyl)-2-methylpiperidine-1-carboxylate (step 3) (970 mg, 2.249 mmol) and trifluoroacetic acid (173 μl, 2.249 mmol) in DCM (7.5 ml) was left stirring at room temperature 18 hours. The resulting mixture was loaded on to a 10 g Isolute® SCX-2 cartridge and washed with MeOH. The product was eluted with 2M ammonia in MeOH and the product fractions were concentrated under reduced pressure to afford the title compound;
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[C:4](C(O)=O)[C:3]=1[C:14]([OH:16])=[O:15].CS(C)=O.C(OCCCC)CCC.S(=O)(=O)(O)O>C1(C)C=CC=CC=1.O.C(N(CC)CC)C>[F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[CH:4][C:3]=1[C:14]([OH:16])=[O:15]
Reactant: O=C(O)c1c(F)c(F)c(F)c(F)c1C(=O)O
Agent: O=S(=O)(O)O
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(O)c1cc(F)c(F)c(F)c1F
Reaction time: 0.62 h
Yield: 93.7 %

Procedure:
3,4,5,6-Tetrafluorophthalic acid (58 g) was added to a two liter flask. Dimethyl sulfoxide (230 ml) followed by triethylamine (11.5 ml) were then added and the mixture heated over a 20 minute period to 115°-120° C. The solution was heated with stirring at 115°-120° C. for another 35-40 minutes and then cooled with an ice bath. Demineralized water (580 ml) followed by n-butyl ether (250 ml) and toluene (350 ml) were added. Sulfuric acid (99%, 3.5 ml) was then cautiously added with stirring and cooling. The layers were separated and the aqueous layer extracted with two portions of toluene (580 ml and 290 ml). The combined organic layers were extracted with 2% aqueous sulfuric acid (3×150 ml). The organic layer was dried over anhydrous sodium sulfate (60 g) and Darco S-51 (11.5 g) was added. After filtering the mixture was concentrated under reduced pressure and the resulting solid dried under vacuum at 50°-60° C. for seven hours to give 2,3,4,5-tetrafluorobenzoic acid (44.3 g, 94%); mp 77°-80° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH2:8]Cl)[CH:5]=[C:4]([O:10][CH3:11])[N:3]=1.[F-:12].[Cs+]>CN(C)C=O>[NH2:1][C:2]1[N:7]=[C:6]([CH2:8][F:12])[CH:5]=[C:4]([O:10][CH3:11])[N:3]=1
Reactant: [F-]
Reactant: COc1cc(CCl)nc(N)n1
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cc(CF)nc(N)n1

Procedure:
A mixture of 17.0 parts of 2-amino-4-chloromethyl-6-methoxypyrimidine, 59.5 parts of caesium fluoride and 130 parts of dry dimethylformamide was stirred under reflux for 2 hours. The mixture was cooled and evaporated in vacuo. The residue was taken up in ethyl acetate and the solution was washed four times with water. The organic phase was dried with anhydrous magnesium sulphate, stirred with decolourising charcoal, filtered and evaporated. The crude product was purified by chromatography on silica, eluted with ethyl acetate to give 2-amino-4-fluoromethyl-6-methoxypyrimidine m.p. 119°-121° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:47]=[C:46]([O:48][CH3:49])[CH:45]=[CH:44][C:4]=1[CH2:5][N:6]1[CH:11]=[C:10]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([F:21])=[C:17]([CH:20]=2)[C:18]#[N:19])[N:9]2[CH:22]=[C:23]([C:25]3[C:33]4[C:28](=[N:29][CH:30]=[CH:31][CH:32]=4)[N:27](S(C4C=CC=CC=4)(=O)=O)[CH:26]=3)[CH:24]=[C:8]2[C:7]1=[O:43].[OH-].[Na+]>O1CCOCC1.O>[CH3:1][O:2][C:3]1[CH:47]=[C:46]([O:48][CH3:49])[CH:45]=[CH:44][C:4]=1[CH2:5][N:6]1[CH:11]=[C:10]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([F:21])=[C:17]([CH:20]=2)[C:18]#[N:19])[N:9]2[CH:22]=[C:23]([C:25]3[C:33]4[C:28](=[N:29][CH:30]=[CH:31][CH:32]=4)[NH:27][CH:26]=3)[CH:24]=[C:8]2[C:7]1=[O:43]
Reactant: COc1ccc(Cn2cc(Cc3ccc(F)c(C#N)c3)n3cc(-c4cn(S(=O)(=O)c5ccccc5)c5ncccc45)cc3c2=O)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(Cn2cc(Cc3ccc(F)c(C#N)c3)n3cc(-c4c[nH]c5ncccc45)cc3c2=O)c(OC)c1
Temperature: 50 °C

Procedure:
To a solution of EXAMPLE 2A (90 mg, 0.13 mmol) in dioxane (10 ml) was added NaOH (52 mg, 1.3 mmol) in water (1 ml). The mixture was heated at 50° C. overnight, and partitioned between ethyl acetate and water. The organic phase was concentrated to afford the title compound. MS (DCI/NH3) m/z 534 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=[O:6].[C:13]1([CH2:19]O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(Cl)CCl>CN(C1C=CN=CC=1)C.CN(C=O)C>[NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([O:7][CH2:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:6]
Reactant: OCc1ccccc1
Reactant: COc1ccc(C(=O)O)cc1N
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COc1ccc(C(=O)OCc2ccccc2)cc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
3-amino-4-methoxybenzoic acid (20 g, 120 mmol), phenylmethanol (12.94 g, 120 mmol), DMAP (14.62 g, 120 mmol), and EDC (22.94 g, 120 mmol) were dissolved in DMF (100 ml). The reaction was stirred at RT for 2 hours. The reaction mixture was filtered, and the mother liquor was diluted with water and extracted with EtOAc. The organic phase was extracted with water, dried over Na2SO4 and evaporated under vacuum. The crude product was crystallized in EtOAc. The mother liquor are purified by flash chromatography (Petroleum Ether/EtOAc 80/20). The overall amount of the desired product was 16 g (Yield: 52%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([OH:12])[C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].[CH3:13]C1C=CC(S(O)(=O)=O)=CC=1>CO>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([OH:12])[C:10]=1[CH3:11])[C:5]([O:7][CH3:13])=[O:6]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Cc1c(O)cc(C(=O)O)cc1O
Solvent: CO
Product: COC(=O)c1cc(O)c(C)c(O)c1

Procedure:
3,5-dihydroxy-4-methylbenzoic acid (5.0 g, 29.79 mmol, 1.0 eq) and PTSA (1.13 g, 5.94 mmol, 0.2 eq) were dissolved in 50 ml of methanol, and the mixture was heated to reflux for 6 h. Methanol was evaporated. The resultant solid was washed with 10% sodium bicarbonate solution. The aqueous solution was extracted thrice with ethyl acetate. The combined organic layer was dried over sodium sulphate and evaporated under vacuum. Yield: 5.25 g (96%). 1H NMR (400 MHz, DMSO-d6): δ 1.98 (s, 3H), 3.78 (s, 3H), 6.93 (s, 2H), 9.53 (s, 2H). LCMS: (ES+) m/z=183 (M+H) Method: Column: Phenomenex Luna C18 (4.6×30) mm, 5 micron Mphase A: 10% MeOH-90% H2O-10 mM NH4OAc Mphase B: 90% MeOH-10% H2O-10 mM NH4OAc
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][C@@H:10]3[N:16]([CH:17]=2)[C:15](=[O:18])[C:14]2[CH:19]=[C:20]([O:61][CH3:62])[C:21]([O:23][CH2:24][CH2:25][CH2:26][O:27][C:28]4[C:58]([O:59][CH3:60])=[CH:57][C:31]5[C:32](=[O:56])[N:33]6[CH:48]=[C:47](S(C(F)(F)F)(=O)=O)[CH2:46][C@H:34]6[C:35](=[O:45])[N:36]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[C:30]=5[CH:29]=4)=[CH:22][C:13]=2[N:12]([CH2:63][O:64][CH2:65][CH2:66][Si:67]([CH3:70])([CH3:69])[CH3:68])[C:11]3=[O:71])=[CH:4][CH:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:91]([Si:93]([CH3:96])([CH3:95])[CH3:94])#[CH:92]>N1CCCCC1.[Cu]I.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>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][C@@H:10]3[N:16]([CH:17]=2)[C:15](=[O:18])[C:14]2[CH:19]=[C:20]([O:61][CH3:62])[C:21]([O:23][CH2:24][CH2:25][CH2:26][O:27][C:28]4[C:58]([O:59][CH3:60])=[CH:57][C:31]5[C:32](=[O:56])[N:33]6[CH:48]=[C:47]([C:92]#[C:91][Si:93]([CH3:96])([CH3:95])[CH3:94])[CH2:46][C@H:34]6[C:35](=[O:45])[N:36]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[C:30]=5[CH:29]=4)=[CH:22][C:13]=2[N:12]([CH2:63][O:64][CH2:65][CH2:66][Si:67]([CH3:70])([CH3:69])[CH3:68])[C:11]3=[O:71])=[CH:4][CH:3]=1
Reactant: COc1cc2c(cc1OCCCOc1cc3c(cc1OC)C(=O)N1C=C(S(=O)(=O)C(F)(F)F)C[C@H]1C(=O)N3COCC[Si](C)(C)C)N(COCC[Si](C)(C)C)C(=O)[C@@H]1CC(c3ccc(N)cc3)=CN1C2=O
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: COc1cc2c(cc1OCCCOc1cc3c(cc1OC)C(=O)N1C=C(c4ccc(N)cc4)C[C@H]1C(=O)N3COCC[Si](C)(C)C)N(COCC[Si](C)(C)C)C(=O)[C@@H]1CC(C#C[Si](C)(C)C)=CN1C2=O
Reaction time: 8 h

Procedure:
A mixture of 9 (0.150 g, 0.14 mmol), CuI (0.003 g, 0.014 mmol, 0.1 eq), Pd(PPh3)4 (0.0162 g, 0.014 mmol, 0.1 eq) and PPh3 (0.007 g, 0.028 mmol, 0.2 eq) was dissolved in piperidine (9 mL) in presence of molecular sieves under an argon atmosphere. Ethynyltrimethylsilane (0.06 ml, 0.42 mmol, 3 eq) was added to the mixture at 70° C. and the reaction mixture was allowed to stir overnight. The solvent was removed by rotary evaporation under reduced pressure and the resulting brown solid purified by flash column chromatography (silica gel, 90% EtOAc, 10% hexane). Compound 27 was obtained as an orange solid (0.043 g, 30%); Rf 0.69 [EtOAc]; LC-MS (5 min) 4.28 min, ES+1008.28.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[NH:17][C:16]([CH3:18])=[C:15]([C:19]([OH:21])=O)[C:14]=1[CH3:22].[NH2:23][CH2:24][CH:25]([OH:32])[CH2:26][N:27]1[CH:31]=[CH:30][N:29]=[N:28]1>>[OH:32][CH:25]([CH2:26][N:27]1[CH:31]=[CH:30][N:29]=[N:28]1)[CH2:24][NH:23][C:19]([C:15]1[C:14]([CH3:22])=[C:13](/[CH:12]=[C:5]2\[C:6](=[O:11])[NH:7][C:8]3[C:4]\2=[CH:3][C:2]([F:1])=[CH:10][CH:9]=3)[NH:17][C:16]=1[CH3:18])=[O:21]
Reactant: NCC(O)Cn1ccnn1
Reactant: Cc1[nH]c(C=C2C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)NCC(O)Cn1ccnn1

Procedure:
5-(5-Fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (120 mg, 0.4 mmol) was condensed with 1-amino-3(1,2,3)triazol-1-yl-propan-2-ol (85 mg, 0.48 mmol) to precipitate 5-[5-fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-hydroxy-3-[1,2,3]triazol-1-yl-propyl)-amide (100 mg, 62%). 1H NMR (DMSO-d6) δ 2.42, 2.44 (2×s, 6H, 2×CH3), 3.27 (m, 2H), 3.98 (m, 1H), 4.27 (dd, J=7.6, 14 Hz, 1H), 4.50 (dd, J=3.4, 13.6 Hz, 1H), 5.38 (d, J=5.6 Hz, 1H, OH), 6.82 (dd, J=4.4, 8.4 Hz, 1H), 6.91 (td, 2J=2.4, 3J=9.0 Hz, 1H), 7.70 (m, 3H), 7.75 (dd, J=2.4, 9.2 Hz, 1H), 8.11 (s. 1H), 10.93 (s, 1H, CONH), 13.73 (s, 1H, NH). LC-MS (m/z) 423.4 (M−1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[C:6]([NH:13][CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:5]=1>CO.C1COCC1.[Ni]>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([NH:13][CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:5]=1
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(NCCN2CCCC2)c1
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccc(N)c(NCCN2CCCC2)c1

Procedure:
4-Nitro-3-(2-pyrrolidin-1-yl-ethylamino)-benzoic acid methyl ester (xiii) (1.30 g, 4.42 mmol) was shaken in MeOH/THF 1:1 (40 mL) in presence of Raney nickel under 1.1 bar H2 at rt for 40 min. The catalyst was filtered off and washed with MeOH. The filtrate was evaporated to give the title compound as an oil (tR 2.05 min (conditions 8), MH+=264).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH3:10][NH2:11]>C1COCC1>[Br:1][C:2]1[C:3]([NH:11][CH3:10])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: CN
Solvent: C1CCOC1
Product: CNc1nc(Cl)ncc1Br
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
5-Bromo-2,4-dichloro-pyrimidine (2.41 g, 10.6 mmol) is slowly treated with methylamine (8 M in EtOH, 3.3 mL) in THF (15 mL) at about −20° C. After stirring for 30 minutes at about −20° C., the reaction mixture is partitioned between CHCl3 and saturated NaHCO3. The aqueous layer is extracted with additional CHCl3 twice and the combined organic layer is dried over MgSO4, filtered and concentrated. The crude product is purified by column chromatography (SiO2, EtOAc/Hexane=3/7) to give 1.76 g (75%) of (5-bromo-2-chloro-pyrimidin-4-yl)-methylamine as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[O:14][CH:15]=[C:16]([CH3:18])[CH:17]=2)[N:3]=1.[OH:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([C:13]2[O:14][CH:15]=[C:16]([CH3:18])[CH:17]=2)[C:5]([C:11]#[N:12])=[C:6]([O:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[N:7]=1
Reactant: OCCc1ccccn1
Reactant: Cc1coc(-c2nc(N)nc(S(C)=O)c2C#N)c1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1coc(-c2nc(N)nc(OCCc3ccccn3)c2C#N)c1

Procedure:
From 2-amino-4-methanesulfinyl-6-(4-methyl-furan-2-yl)-pyrimidine-5-carbonitrile, 2-(2-hydroxyethyl)pyridine and DBU in DME. ES-MS m/e (%): 322 (M+H+, 100).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.CC(C)CC(Cl)=O.[Cl-].[F:32][C:33]1[CH:38]=[CH:37][C:36]([C:39](=[O:42])[CH2:40][NH3+:41])=[CH:35][C:34]=1[C:43]([F:46])([F:45])[F:44]>C1COCC1>[F:32][C:33]1[CH:38]=[CH:37][C:36]([C:39](=[O:42])[CH2:40][NH:41][C:14]([CH:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]2)=[O:16])=[CH:35][C:34]=1[C:43]([F:44])([F:45])[F:46]
Reactant: [NH3+]CC(=O)c1ccc(F)c(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CC(C)CC(=O)Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NCC(=O)c2ccc(F)c(C(F)(F)F)c2)CC1
Temperature: -10 °C
Reaction time: 0.33 h
Yield: 71.5 %

Procedure:
To a solution of piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (9611.92 mg; 41.92 mmol; 1.08 eq.) in THF 100 ml, added 4-methyl-morpholine (14.51 ml; 131.98 mmol; 3.40 eq.), The reaction mixture was cooled to −10° C., 3-methyl-butyryl chloride (5.03 ml; 38.82 mmol; 1.00 eq.) was add dropwise and maintaining the temperature below −5° C. after stirring for 30 mins at from −5° C. to 10° C., 2-(4-Fluoro-3-trifluoromethyl-phenyl)-2-oxo-ethyl-ammonium chloride (10.00 g; 38.82 mmol; 1.00 eq.) was added at −5° C. and stirred the mixture for 20 mins and then RT for 1 h. Added brine, extracted with EA, washed with brine, dried and concentrated. The crude oil was treated with ether. The white solid was collected as the title compound (12 g, yield 71.5%).
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[C:13]([Si:15]([CH3:18])([CH3:17])[CH3:16])#[CH:14].C(NC(C)C)(C)C>C1COCC1.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:16][Si:15]([C:13]#[C:14][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1)([CH3:18])[CH3:17]
Reactant: CCOC(=O)c1ccc(Br)cc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(C#C[Si](C)(C)C)cc1
Yield: 73 %

Procedure:
A mixture of ethyl 4-bromobenzoate (1.5 g, 6.55 mmol), ethynyl trimethylsilane (965 mg, 9.82 mmol), diisopropylamine (1.39 g, 13.7 mmol), cuprous iodide(25 mg, 0.131 mmol), and bis(triphenylphosphine) palladium(II) chloride (184 mg, 0.262 mmol) was heated at 45° C. for 4 h in dry THF (10 ml) under argon atmosphere. The reaction was quenched by the addition of water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel flash column chromatography (eluent: hexane/ethyl acetate=100/1) to give ethyl 4-[(trimethylsilyl)ethynyl]benzoate (73%).
Reaction SMILES: Cl.Cl.[C:3]([O:11][CH2:12][CH2:13][NH2:14])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.ClC1C=C(Cl)C(Cl)=CC=1[CH:24]([Cl:32])[CH2:25][N:26]([N:30]=[O:31])[C:27](=O)[O-:28].C(Cl)(Cl)Cl.C(OCC)(=O)C>N1C=CC=CC=1>[Cl:32][CH2:24][CH2:25][N:26]([N:30]=[O:31])[C:27]([NH:14][CH2:13][CH2:12][O:11][C:3]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)=[O:10])=[O:28]
Reactant: O=NN(CC(Cl)c1cc(Cl)c(Cl)cc1Cl)C(=O)[O-]
Reactant: NCCOC(=O)c1cccnc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: O=NN(CCCl)C(=O)NCCOC(=O)c1cccnc1

Procedure:
A solution of 2-aminoethyl nicotinate dihydrochloride (1.25 g, 52 mmol) and 2,4,5-trichlorophenyl-N-(2-chloroethyl)-N-nitrosocarbamate (2 g, 6 mmol) in 40 mL of pyridine was stirred under nitrogen at room temperature for 24 hours. The reaction was monitored by thin layer chromatography (silica, 1:1 chloroform/ethyl acetate, Rf 0.26). The solvent was removed in vacuo and the residue was chromatographed on a silica gel column by eluting, first with benzene to remove unreacted nitrosocarbamate and trichlorophenol by-product, and then with chloroform, to qive the desired product. The resultant oil solidified in the freezer. It melted at 63°-64° C. and had the formula ##STR151##
Reaction SMILES: [C:1]([C:5]1[CH:24]=[CH:23][C:8]([O:9][C:10]2[CH:19]=[C:18]3[C:13]([CH:14]=[C:15]([C:20](O)=[O:21])[N:16]=[CH:17]3)=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:25][O:26][C:27](=[O:38])[C@@H:28]([NH2:37])[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([Br:36])=[CH:32][CH:31]=1>>[CH3:25][O:26][C:27](=[O:38])[C@@H:28]([NH:37][C:20]([C:15]1[N:16]=[CH:17][C:18]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([O:9][C:8]1[CH:23]=[CH:24][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=1)[CH:19]=2)=[O:21])[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([Br:36])=[CH:32][CH:31]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(Br)cc1
Reactant: CC(C)(C)c1ccc(Oc2ccc3cc(C(=O)O)ncc3c2)cc1
Product: COC(=O)[C@H](Cc1ccc(Br)cc1)NC(=O)c1cc2ccc(Oc3ccc(C(C)(C)C)cc3)cc2cn1
Yield: 95.4 %

Procedure:
500 mg (1.55 mmol) of 7-(4-tert-butylphenoxy)-isoquinoline-3-carboxylic acid (Example 371) was reacted with 441 mg (1.7 mmol) of (2S)-amino-3-(4-bromo-phenyl)-propionic acid methyl ester as described in general procedure A. The crude product was purified by flash column chromatography on silica using 8:2 hexane/ethyl acetate as eluent, to afford 830 mg of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]([F:44])([F:43])[C:3]1[CH:4]=[C:5]([CH:40]=[CH:41][CH:42]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[C:20]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:19]=[CH:18][C:17]=2[NH:28][C:29]([C:31]2[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=2)[C:34](O)=[O:35])=[O:30])[CH:11]=1)=[O:9].CN(CCN1CCOCC1)C(=O)C1C=CC=[C:50]([C:51]([NH:53][C:54]2C=CC(N3CCCCC3)=C[C:55]=2[C:66]2C=C(C(=O)NCC3C=CC=C(C(F)(F)F)C=3)C=[CH:68][N:67]=2)=[O:52])C=1.CC#N.N1CC[C@H](NC(=O)C)C1>CN(C=O)C>[C:51]([NH:53][C@H:54]1[CH2:55][CH2:66][N:67]([C:34]([C:33]2[CH:32]=[C:31]([CH:39]=[CH:38][CH:37]=2)[C:29]([NH:28][C:17]2[CH:18]=[CH:19][C:20]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:21][C:16]=2[C:12]2[CH:11]=[C:10]([CH:15]=[CH:14][N:13]=2)[C:8]([NH:7][CH2:6][C:5]2[CH:40]=[CH:41][CH:42]=[C:3]([C:2]([F:1])([F:44])[F:43])[CH:4]=2)=[O:9])=[O:30])=[O:35])[CH2:68]1)(=[O:52])[CH3:50]
Reactant: CN(CCN1CCOCC1)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reactant: O=C(O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Agent: CC(=O)N[C@H]1CCNC1
Solvent: CC#N
Solvent: CN(C)C=O
Product: CC(=O)N[C@H]1CCN(C(=O)c2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3-c3cc(C(=O)NCc4cccc(C(F)(F)F)c4)ccn3)c2)C1

Procedure:
This compound was prepared from 3-((2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-4-(piperidin-1-yl)phenyl)carbamoyl)benzoic acid 4.1e using the procedure described for the preparation of N1-methyl-N1-(2-morpholinoethyl)-N3-(4-(piperidin-1-yl)-2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)phenyl)isophthalamide 4.8, except that CH3CN was substituted for DMF as the reaction solvent and (S)—N-(pyrrolidin-3-yl)acetamide was used as the amine component. 1H-NMR (300 MHz, CD3OD, ppm): δ 8.88 (d, J=3.5 Hz, 1H), 8.69˜8.663 (m, 1H), 8.33 (s, 1H), 8.10˜8.05 (m, 2H), 8.00˜7.97 (m, 1H), 7.76 (d, J=5.2 Hz, 1H), 7.71˜7.66 (m, 1H), 7.60˜7.43 (m, 6H), 4.60 (s, 2H), 4.40˜4.16 (m, 1H), 3.71˜3.21 (m, 8H), 2.22˜1.71 (m, 11H). MS (ES, m/z): 713 [M+H]+.