Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C@H:7]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:10]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:9](SC)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:27]([NH2:35])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CO>[C:21]([O:20][C:18]([N:10]1[C@H:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=[C:9]1[NH:35][CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: CSC1=N[C@@H](c2ccccc2)[C@@H](c2ccccc2)N1C(=O)OC(C)(C)C
Reactant: NCCc1ccccc1
Solvent: CO
Product: CC(C)(C)OC(=O)N1C(NCCc2ccccc2)=N[C@@H](c2ccccc2)[C@H]1c1ccccc1
Temperature: 100 °C
Yield: 44.2 %

Procedure:
A mixture of intermediate 59 (2.0 g, 5.43 mmol), phenethylamine (2.04 mL, 16.3 mmol) and MeOH (0.5 mL) is heated at 100° C. for 2 days. The reaction mixture is cooled to RT, and is purified by chromatography on silica gel; gradient elution with heptane:EtOAc (75:25-60:40) gives 1.06 g of the product 93. 1H NMR (CDCl3) δ 7.40-7.30 (m, 4 H), 7.30-7.10 (m, 2 H), 7.10-6.90 (m, 8 H), 6.80-6.65 (m, 2 H), 5.45-5.25 (m, 2 H), 3.90-3.60 (m, 2 H), 3.05 (t, 2 H), 1.13 (s, 9 H); MS: m/z 442 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[CH2:12][C:11]([NH2:15])=[N:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.N1C=CC=CC=1.[N+](C1C=CC=CC=1)([O-])=O.[C:31](Cl)(=[O:34])[CH:32]=[CH2:33].[OH-].[Na+]>O.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[CH2:12][C:11]([NH:15][C:31](=[O:34])[CH:32]=[CH2:33])=[N:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: NC1=NN(c2cc(Cl)cc(Cl)c2)C(=O)C1
Reactant: C=CC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: O=[N+]([O-])c1ccccc1
Product: C=CC(=O)NC1=NN(c2cc(Cl)cc(Cl)c2)C(=O)C1

Procedure:
Fourteen-point-six grams (0.06 mole) of 1-(3,5-dichlorophenyl)-3-amino-2-pyrazoline-5-one, 11.4 ml (0.14 mole) of pyridine and 1.2 ml of nitrobenzene were added to 200 ml of tetrahydrofuran. To this mixture, cooled by ice, were added dropwise 12.7 g (0.14 mole) of acryloyl chloride. The liquid, after 30-minute stirring, was poured into 2 liters of water, extracted with use of ethyl acetate, and dried with use of anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure at a temperature of from 25° to 35° C. To the remaining oily substance were added 60 ml of ethanol and 60 ml of water, and further a solution of 8.4 g (0.21 mole) of sodium hydroxide dissolved in water. The liquid was stirred for 30 minutes at room temperature, and neutralized, and the thus deposited crystals were filtrated, and recrystallized from ethanol, whereby 8.6 g (48%) of Coupler Monomer (6) were obtained.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[SH3+].[Br:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[CH:15]1[CH2:17][O:16]1>CC(O)(C)C.CS(C)=O>[Br:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[CH:15]1[CH2:17][CH2:1][O:16]1
Reactant: Brc1cnccc1C1CO1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Agent: [SH3+]
Solvent: CS(C)=O
Solvent: CC(C)(C)O
Product: Brc1cnccc1C1CCO1
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 44.9 %

Procedure:
potassium tert-butoxide (561 mg, 5 mmol) was added to a solution of sulfonium salt (1100 mg, 5 mmol) in t-BuOH (20 mL) at room temperature. After 15 min, a solution of 3-Bromo-4-oxiranyl-pyridine (200 mg, obtained above) in DMSO (10 mL) was added dropwise at 50° C. The resulting mixture was stirred at 50° C. for 15 h. The reaction mixture was quenched with brine, and the resulting mixture was extracted with ethyl acetate twice. The combined extracts were dried over anhydrous Na2SO4. After filtration and concentration, the residue was purified by flash column and afforded the title compound (96 mg). ESI-MS m/z: 216.1 [M+1]+, Retention time 1.01 min; 1HNMR (CDCl3, 400.342 MHz) δ ppm 2.50-2.59 (m, 1H), 3.31-3.39 (m, 1H), 4.65-4.70 (m, 1H), 4.87-4.92 (m, 1H), 5.91 (t, J=8 Hz, 1H), 7.95 (d, J=8 Hz, 1H), 8.68 (d, J=8 Hz, 1H), 8.73 (s, 1H).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:5]=2[CH:6]=1.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.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.C(OCC)(=O)C>[Cl:11][C:8]1[CH:9]=[CH:10][C:4]2[S:3][C:2]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[Cl:12])=[CH:6][C:5]=2[CH:7]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: Clc1ccc2sc(Br)cc2c1
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: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Clc1ccc2sc(-c3ccccc3Cl)cc2c1
Temperature: 100 °C
Yield: 94.7 %

Procedure:
To a solution of 1.03 g (4.16 mmol) 2-bromo-5-chlorobenzothiophene in 12 ml DME under argon were added 1.0 g (6.4 mmol) 2-chlorobenzeneboronic acid, 88 mg Pd(PPh3)4, and 6.4 ml 1M aqueous sodium carbonate solution, and the mixture was heated overnight at 100° C. in a sealed tube. After cooling 20 ml water and 20 ml ethyl acetate were added followed by vigorous stirring. The organic layer was dried over sodium sulfate and concentrated in vacuo, and the title compound was purified by chromatography on silica gel with hexane/ethyl acetate 97:3 to give 1.1 g (95%) of a colorless oil, which slowly solidified; MS 278 (M+).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[O:3]1.[Cl:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](Cl)=[O:15]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([CH:5]1[C:6](=[O:8])[O:7][C:2]([CH3:10])([CH3:1])[O:3][C:4]1=[O:9])=[O:15]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC1(C)OC(=O)C(C(=O)c2ccccc2Cl)C(=O)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.9 %

Procedure:
A solution of 4-(dimethylamino)pyridine (33.96 g; 278 mmol) and 2,2-dimethyl-1,3-dioxane-4,6-dione (20.0 g, 139 mmol) in 50 mL of CH2Cl2 was cooled in an ice-salt bath to −10° C. A solution of 2-chlorobenzoyl chloride (29.2 g, 167 mmol) in 20 mL of CH2Cl2 was added dropwise via addition funnel over 1 h. After stirring cold for 1 h, the reaction was allowed to warm to rt and stirred for an additional 3 h. The resulting yellow-orange solution was then extracted with an aq. 10% HCl solution (200 mL) and 200 mL of brine. After drying with MgSO4, the mixture was filtered and the solvent was removed in vacuo. The resulting orange oil was triturated with hexanes (3×50 mL), affording the title compound (20 g) as a yellow solid.
Reaction SMILES: [C:1]([N:6]=[C:7]=[O:8])(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:9]1([OH:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>ClCCCl.C(Cl)(Cl)Cl>[C:1]([NH:6][C:7](=[O:8])[O:15][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: Oc1ccccc1
Reactant: C=C(C)C(=O)N=C=O
Solvent: ClCCCl
Solvent: ClC(Cl)Cl
Product: C=C(C)C(=O)NC(=O)Oc1ccccc1

Procedure:
A solution of methacryloyl isocyanate (11.1 g; 0.1 mol) in 1,2-dichloroethane (50 ml) was dropwise added to a solution of dry phenol (9.4 g; 0.1 mol) in chloroform (20 ml) under nitrogen stream while cooling with ice. After completion of the addition, chloroform and 1,2-dichloroethane were evaporated under reduced pressure. The residue (20.5 g) was recrystallized from a mixture of hexane and benzene to give phenyl N-methacryloylcarbamate as colorless needles. M.P., 94°-95° C.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:3]=1[NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1.[C:16](Cl)(=O)/[CH:17]=[CH:18]/[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1>>[CH3:15][C:12]1[CH:13]=[CH:14][C:2]2[N:1]=[C:16](/[CH:17]=[CH:18]/[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:4]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=3)[C:3]=2[CH:11]=1
Reactant: Cc1ccc(N)c(Nc2ccccn2)c1
Reactant: O=C(Cl)/C=C/c1ccccc1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Product: Cc1ccc2nc(/C=C/c3ccccc3)n(-c3ccccn3)c2c1

Procedure:
The titled compound was prepared from 2-amino-5-methyl-N-(2-pyridyl)aniline and (E)-cinnamoyl chloride according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH2:10])=[N:8][CH:9]=1)([O-:3])=[O:2].[Br:11]Br>C(O)(=O)C>[Br:11][C:6]1[C:7]([NH2:10])=[N:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: BrBr
Reactant: Nc1ccc([N+](=O)[O-])cn1
Solvent: CC(=O)O
Product: Nc1ncc([N+](=O)[O-])cc1Br
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 30.9 %

Procedure:
To a solution of 5-nitro-pyridin-2-ylamine (30 g, 0.22 mol) in acetic acid (200 mL) at 10° C. was added Br2 (38 g, 0.24 mol) dropwise. After addition, the mixture was stirred at 20° C. for 30 min. The solid was filtered and then dissolved in ethyl acetate (200 mL). The mixture was basified to pH 8-9 with saturated aqueous NaHCO3. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated under vacuum to afford 3-bromo-5-nitropyridin-2-amine (14.8 g, 32%). 1H-NMR (CDCl3, 400 MHz) δ 8.94 (d, J=2.4 Hz, 1H), 8.50 (d, J=2.4 Hz, 1H), 5.67 (brs, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9](=O)[CH3:10].C[O-].[Na+].Br[CH2:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[C:19]#[N:20]>CN(C=O)C.C(O)C.ClCCl.CO>[CH3:10][C:9]1[C:3]2[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=2[O:1][C:16]=1[C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[C:19]#[N:20]
Reactant: N#Cc1ccccc1CBr
Reactant: CC(=O)c1cc(C)ccc1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Solvent: ClCCl
Product: Cc1ccc2oc(-c3ccccc3C#N)c(C)c2c1
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 32.3 %

Procedure:
A solution of 1-(2-hydroxy-5-methylphenyl)ethanone (1 g) in DMF (7 ml) was added to a solution of sodium methoxide (0.39 g) in ethanol (7 ml). After about 10 min a solution of 2-(bromomethyl)benzonitrile (1.3 g) in DMF (7 ml) was added and the solution heated to 110° C. After 2 h further sodium methoxide (0.39 g) was added and heating at 110° C. continued. After a further 30 min, the reaction was cooled to room temperature and the ethanol evaporated. The solution was poured into water/ice (200 ml) and extracted into ethyl acetate (4×30 ml). The combined organic extracts were washed with water (4×20 ml) and dried. Filtration and evaporation gave a yellow oil which was then dissolved in dichloromethane (2 ml) and methanol (30 ml). Concentration gave a solid which was collected and washed with further methanol to give the title compound as a white solid (0.53 g).
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([CH:8]1[CH2:17][C:16](=[O:18])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[S:9]1)[CH:5]=CC>ClCCl.CO>[O:1]=[CH:5][CH2:4][CH:8]1[CH2:17][C:16](=[O:18])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[S:9]1
Reactant: CC=CCC1CC(=O)c2ccccc2S1
Reactant: O=[O+][O-]
Solvent: ClCCl
Solvent: CO
Product: O=CCC1CC(=O)c2ccccc2S1
Reaction time: 0.25 h
Yield: 99 %

Procedure:
An ozone stream (3 g ozone/hour) was conducted while stirring for 15 minutes through a solution, cooled to -70°, of 3 g of (RS)-2-(2-buten-1-yl)-4-thiochromanone in 100 ml of anhydrous dichloro-methane and 30 ml of anhydrous methanol. Subsequently, the solution was flushed with oxygen for 5 minutes and with argon for 10 minutes. After the addition of 2 ml of dimethyl sulfide, the mixture was stirred at room temperature for 16 hours. The reaction mixture was subsequently evaporated in a vacuum. The residue was treated with 50 ml of dichloromethane and, after the addition of 5 ml of water and 5 ml of trifluoroacetic acid, stirred at room temperature for 1 hour. The mixture was subsequently poured into 50 ml of water and neutralized by the spatula-wise addition of sodium hydrogen carbonate while stirring. An additional 50 ml of water were added, the phases were separated and the aqueous phase was extracted twice with 80 ml of dichloromethane each time. The combined organic phases were dried over magnesium sulfate and concentrated in a vacuum. There were obtained 2.8 g (99%) of 2-(2-oxoethyl)-4-thiochromanone as a yellow oil which was used in the next reaction without further recrystallization.
Reaction SMILES: C(N(C(C)C)C(C)C)C.[O:10]=[C:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:20]([OH:22])=O)[CH:17]=2)[NH:12]1.F[B-](F)(F)F.[N:28]1(OC(N(C)C)=[N+](C)C)[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[N:30]=N1.O.ON1C2C=CC=CC=2N=N1.NCC1C=CC=CN=1.C([O-])(O)=O.[Na+]>CN(C)C=O.C(#N)C>[O:10]=[C:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:20]([NH:30][CH2:31][C:36]3[CH:35]=[CH:34][CH:33]=[CH:32][N:28]=3)=[O:22])[CH:17]=2)[NH:12]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C1Cc2cc(C(=O)O)ccc2N1
Agent: F[B-](F)(F)F
Agent: NCc1ccccn1
Agent: O=C([O-])O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1Cc2cc(C(=O)NCc3ccccn3)ccc2N1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 68.1 %

Procedure:
To a N,N-dimethylformamide/acetonitrile, (2 mL: 10 mL), mixture containing ethyldiisopropylamine (0.52 mL, 3 mmol) was added 2-oxoindoline-5-carboxylic acid (0.354 g, 2.0 mmol; described in: Sun L. et al. J. Med. Chem. 2000, 43(14), 2655:), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (0.77 g, 2.4 mmol) and 1-hydroxybenzotriazole hydrate (0.324 g, 2.4 mmol) and stirred for 5 min at room temperature. Thereafter, 2-(aminomethyl)pyridine (0.562 g, 5.2 mmol) was added and the resulting reaction mixture was stirred for 90 min followed by addition of a saturated aqueous NaHCO3 solution (10 mL). The solvents were removed in vacuo and 0.364 g (68% yield) of the title product was obtained as a white solid after purification on a silica gel column using chloroform/methanol, (9:1), as the eluent: 1H NMR (DMSO-d6, 400 MHz) δ 10.66 (s, 1H), 8.96 (t, J=5.6 Hz, 1H), 8.55 (d, J=4.4 Hz, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.83 (s, 1H), 7.78 (t, J=7.6 Hz, 1H), 7.34 (d, J=8.0 Hz, 1H), 7.29 (t, J=6.4 Hz, 1H), 6.92 (d, J=8.0 Hz, 1H), 4.59 (d, J=6.0 Hz, 2H), 3.58 (s, 2H); MS (EI) m/z 268 (M++1).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:17][CH3:18])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[Br:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][C:21]=1[O:27][CH3:28].OS(O)(=O)=O.O>CN1C(=O)CCC1>[Br:19][C:20]1[CH:26]=[CH:25][C:23]([NH:24][C:2]2[N:3]=[C:4]([NH:17][CH3:18])[C:5]3[CH2:10][CH2:9][CH:8]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[C:6]=3[N:7]=2)=[CH:22][C:21]=1[O:27][CH3:28]
Reactant: CNc1nc(Cl)nc2c1CCC2c1ccccc1
Reactant: COc1cc(N)ccc1Br
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CN1CCCC1=O
Product: CNc1nc(Nc2ccc(Br)c(OC)c2)nc2c1CCC2c1ccccc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 91.6 %

Procedure:
A mixture of 2-chloro-N-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (Preparation Ga) (0.24 g, 0.924 mmol), 4-bromo-3-methoxyaniline (0.187 g, 0.924 mmol) and H2SO4 (0.064 mL, 1.201 mmol) in NMP (Volume: 2 mL) was stirred in a sealed microwave tube at 90° C. overnight. The reaction was poured into 20 mL of water. The precipitate was collected by filtering. The cake was air dried. The cake was triturated with a minmum amount of cold MeOH to get 0.36 g (84%) of product as an off-white solid. LC-MS (M+H)+=425.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.39 (1H, br. s.), 7.68 (1H, d, J=1.51 Hz), 7.53 (1H, d, J=8.53 Hz), 7.34-7.42 (2H, m), 7.24-7.34 (3H, m), 6.94 (1H, dd, J=8.66, 2.38 Hz), 4.36-4.51 (1H, m), 3.83 (3H, s), 3.05 (3H, d, J=4.52 Hz), 2.79-2.95 (1H, m), 2.59-2.77 (2H, m), 1.93-2.12 (1H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].C([O:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[CH:28]=[CH:27][C:26]([CH2:29][N:30]2[C:38]3[C:33](=[CH:34][C:35]([C:39](O)=[O:40])=[CH:36][CH:37]=3)[C:32]([CH3:42])=[C:31]2[CH3:43])=[CH:25][CH:24]=1)=[O:16])(C)(C)C>>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH:5][C:39]([C:35]1[CH:34]=[C:33]2[C:38](=[CH:37][CH:36]=1)[N:30]([CH2:29][C:26]1[CH:25]=[CH:24][C:23]([C:18]3[C:17]([C:15]([OH:16])=[O:14])=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:28][CH:27]=1)[C:31]([CH3:43])=[C:32]2[CH3:42])=[O:40]
Reactant: NCc1ccccc1Cl
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)NCc3ccccc3Cl)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Steps 8-9, Example 1, using 2-chlorobenzylamine and 1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15](Cl)[CH:14]=2)=[C:11]2[C:6]([N:7]([CH3:23])[C:8](=[O:22])[N:9]([CH3:21])[C:10]2=[O:20])=[CH:5]1.BrC1C=C(C=CC=1)[C:28]([O:30][CH3:31])=[O:29]>>[NH2:1][CH2:2][CH2:3][N:4]1[C:12]([C:13]2[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=2)[C:28]([O:30][CH3:31])=[O:29])=[C:11]2[C:6]([N:7]([CH3:23])[C:8](=[O:22])[N:9]([CH3:21])[C:10]2=[O:20])=[CH:5]1
Reactant: Cn1c(=O)c2c(-c3cccc(Cl)c3)n(CCN)cc2n(C)c1=O
Reactant: COC(=O)c1cccc(Br)c1
Product: COC(=O)c1cccc(-c2c3c(=O)n(C)c(=O)n(C)c3cn2CCN)c1

Procedure:
The title compound was prepared analogously to Intermediate B by replacing 1-bromo-3-chlorobenzene with methyl 3-bromobenzoate;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[NH2:32][CH2:33][C:34]1[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:30])([F:31])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[CH:20][C:21]([C:22]([NH:32][CH2:33][C:34]4[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=4)=[O:23])=[CH:25][CH:26]=3)=[CH:17][C:9]1=2
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Reactant: NCc1cccnc1
Product: O=C(NCc1cccnc1)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 3-(aminomethyl)pyridine as in General Procedure 10 to give the title compound. LCMS: m/z=537.95 (M+H+); retention time=0.57 minutes.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:4]([C:20]#[N:21])[N:3]=1.[CH2:22]([NH2:25])[CH:23]=[CH2:24]>C(O)CCC>[CH2:22]([NH:25][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:4]([C:20]#[N:21])[N:3]=1)[CH:23]=[CH2:24]
Reactant: COc1ccc2c(Cl)nc(C#N)c(-c3ccccc3)c2c1
Reactant: C=CCN
Solvent: CCCCO
Product: C=CCNc1nc(C#N)c(-c2ccccc2)c2cc(OC)ccc12

Procedure:
To a suspension of 104 mg of 1-chloro-6-methoxy-4-phenylisoquinoline-3-carbonitrile in nBuOH was added 252 uL of allylamine. The reaction was heated at 210 C in a microwave reactor for 1 h, then partitioned between EA and saturated aqueous sodium bicarbonate. The organic solution was washed with brine once, then dried (Na2SO4) and concentrated. Flash chromatography (540% EA/hex, Gilson, 40 g silica) gave a pink solid.
Reaction SMILES: [C:1]([N:5]([C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=1)[O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1.O.C(OCC)(=O)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:1]([N:5]([C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)=[O:19])=[CH:16][CH:15]=1)[O:6][Si:7]([C:10]([CH3:12])([CH3:11])[CH3:13])([CH3:9])[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: Nc1ccccn1
Reactant: CC(C)(C)N(O[Si](C)(C)C(C)(C)C)c1ccc(C(=O)O)cc1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)N(O[Si](C)(C)C(C)(C)C)c1ccc(C(=O)Nc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 186.3 %

Procedure:
To a solution of 1.0 g (3.09 mmol) of compound 2 in CH2Cl2 (5 mL) were added 0.733 g (3.71 mmol) of 1-(3-dimethylamino)propyl-3-ethylcarbodiimide hydrochloride, 0.189 g (1.545 mmol) of 4-dimethylaminopyridine, and 0.438 g (4.63 mmol) of 2-aminopyridine. After stirring for 12 hours at room temperature, H2O and ethyl acetate were added. The organic layer was separated, washed with sat'd NaHCO3 solution, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica, Hex:EtOAc=10:1) to give 2.3 g of compound 5 in 75% yield.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[C:17](Br)[CH:16]=[CH:15][C:14]=2[C:20]#[N:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:22][C:23]([F:34])([F:33])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O>>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[C:17]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[C:23]([F:34])([F:33])[F:22])[CH:16]=[CH:15][C:14]=2[C:20]#[N:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC(Oc2cc(Br)ccc2C#N)C1
Product: CC(C)(C)OC(=O)N1CC(Oc2cc(-c3ccccc3C(F)(F)F)ccc2C#N)C1

Procedure:
Prepared from the title compound of Step A according to Example 1 Step E using 2-trifluoromethylphenylboronic acid.
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.Cl.[C:28]1([CH2:34][C:35]([NH2:43])([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH3:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>ClCCl>[C:4]([O:3][C:1]([NH:8][CH2:9][C:10]([NH:43][C:35]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([CH3:36])[CH2:34][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:12])=[O:2])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(N)(Cc1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCC(=O)NC(C)(Cc1ccccc1)c1ccccc1
Reaction time: 2.25 h

Procedure:
A reaction vessel was charged with dichloromethane (360 l) and Boc-glycine (32.6 kg, 186.3 mol). Triethylamine (18.8 kg, 186.1 mol) was added cautiously keeping the temperature below 25° C. The mixture was cooled to below -5° C. and pivaloyl chloride (trimethylacetyl chloride, 22.4 kg, 185.9 mol) in dichloromethane (40 l) was added at such a rate as to keep the temperature below -5° C. This was washed in with dichloromethane (2 l). The mixture was then stirred at below -5° C. for 2-2.5 h and then 1,2-diphenyl-2-propylamine hydrochloride (40 kg, 161.1 mol, dry weight estimate, actual weight including moisture 42.94 kg) was added as a solid through the manway keeping the temperature below -5° C. Triethylamine (28.4 kg, 281.2 mol) was then added keeping the temperature below -5° C. This was washed in with dichloromethane (2 l). The mixture was stirred at below -5° C. for 2.75-3.25 h, water (400 l) was added and the mixture stirred for at least 15 min. The organic layer was separated and washed with dilute hydrochloric acid made up from concentrated hydrochloric acid (40 l) and water (400 l). The organic layer was again separated and then about 80% (360 l) of the dichloromethane was removed by distillation. Isopropyl alcohol (140 l) was then charged and distillation continued until the head temperature reached 80° C. The solution was then cooled and isopropyl alcohol added to make up to a total weight of 200 kg. This solution was then divided in two by weight and each half used directly in the next step.