Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[CH2:11][C:10]2[C:5](=[CH:6][C:7]([NH:12][C:13](=[O:26])[C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([C:22]([F:25])([F:24])[F:23])[CH:15]=3)=[CH:8][CH:9]=2)[CH2:4][N:3]1C(=O)C(F)(F)F.C(=O)([O-])[O-].[K+].[K+]>CO.O>[CH3:1][C:2]1([CH3:33])[CH2:11][C:10]2[C:5](=[CH:6][C:7]([NH:12][C:13](=[O:26])[C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([C:22]([F:24])([F:23])[F:25])[CH:15]=3)=[CH:8][CH:9]=2)[CH2:4][NH:3]1
Reactant: COc1ccc(C(=O)Nc2ccc3c(c2)CN(C(=O)C(F)(F)F)C(C)(C)C3)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1ccc(C(=O)Nc2ccc3c(c2)CNC(C)(C)C3)cc1C(F)(F)F
Yield: 86.1 %

Procedure:
To a stirred solution of N-(3,3-dimethyl-1,2,3,4-tetrahydro-2-trifluoroacetylisoquinolin-7-yl)-4-methoxy-3-trifluoromethyl benzamide (442 mg; 0.93 mmol) in methanol (50 ml) and water (25 ml) was added potassium carbonate (642 mg; 4.65 mmol) and the resultant mixture heated under reflux for I h. Evaporation in vacuo gave a residue which was partitioned between dichloromethane and water. The organic phase was dried over sodium sulfate, and evaporation in vacuo gave the title compound (303 mg).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1.[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[N:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:10][CH2:9][O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:24][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NCc1ccccc1
Reactant: BrCCCCCCOCCc1ccccn1
Product: c1ccc(CNCCCCCCOCCc2ccccn2)cc1

Procedure:
2-[2-[(6-Bromohexyl)oxy]ethyl]pyridine (6.3 g) was added to benzylamine (20 ml) at 140° under nitrogen. After 1 h at 140° the reaction mixture was cooled and partitioned between 2M sodium hydroxyde (100 ml) and ether (100 ml). The organic layer was washed with water and brine, dried and concentrated to a yellow oil. The excess benzylamine was removed by distillation under reduced pressure to leave the title compound as a yellow oil (6.8 g), t.l.c. (System A 80:20:2) Rf 0.44.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4][C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][NH:14][C:13](=[O:17])[CH:12]=2)[CH:8]=[CH:7][N:6]=1.Cl[CH:19]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([F:32])[CH:26]=1)[C:20]1[O:24][CH:23]=[N:22][CH:21]=1>CN(C=O)C.C(OCC)(=O)C>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([CH:19]([C:20]2[O:24][CH:23]=[N:22][CH:21]=2)[N:14]2[CH:15]=[CH:16][C:11]([C:9]3[CH:8]=[CH:7][N:6]=[C:5]([S:4][CH3:3])[N:10]=3)=[CH:12][C:13]2=[O:17])=[CH:26][C:27]=1[F:32]
Reactant: Fc1cc(C(Cl)c2cnco2)ccc1Cl
Reactant: CSc1nccc(-c2cc[nH]c(=O)c2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CSc1nccc(-c2ccn(C(c3ccc(Cl)c(F)c3)c3cnco3)c(=O)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.7 %

Procedure:
NaH (13.2 mg, 0.331 mmol; 60 wt % oil dispersion) neat as a solid was added to a stirred suspension of 4-(2-(methylthio)pyrimidin-4-yl)pyridin-2(1H)-one (65.9 mg, 0.301 mmol) in DMF (600 μL) at room temperature under nitrogen. After 30 minutes, the suspension had become a solution. A solution of 5-(chloro(4-chloro-3-fluorophenyl)methyl)oxazole (111 mg, 0.451 mmol) was then added as a solution in DMF (300 μL) dropwise by syringe. After stirring at room temperature overnight, TLC in ethyl acetate showed a new high rf spot, as well as a new mid rf spot (both bright blue under UV). The reaction was quenched with water (1 mL) and then partitioned between ethyl acetate (30 mL) and water with a little brine (30 mL). The organics were isolated and washed with water/brine (3×30 mL). The organics were isolated, dried (MgSO4), filtered and concentrated to an oil. The mixture was loaded onto a Biotage 12M column with 7/3 ethyl acetate/hexanes and eluted. Two main spots eluted and corresponding fractions were pooled and concentrated. The least polar fraction appears to be alkylated on the pyridone oxygen. The second eluting spot appears to be the desired N-alkylated pyridone, which was isolated as a foam, 1-((4-chloro-3-fluorophenyl)(oxazol-5-yl)methyl)-4-(2-(methylthio)pyrimidin-4-yl)pyridin-2(1H)-one (50 mg, 39%).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15](=O)[CH3:16])[C:10]=2[OH:18])=[CH:5][CH:4]=1.[NH:21]([C:23]([NH:25][C:26]1[S:30][C:29]([C:31]([OH:33])=[O:32])=[CH:28][CH:27]=1)=[S:24])[NH2:22]>>[F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15](=[N:22][NH:21][C:23]([NH:25][C:26]3[S:30][C:29]([C:31]([OH:33])=[O:32])=[CH:28][CH:27]=3)=[S:24])[CH3:16])[C:10]=2[OH:18])=[CH:5][CH:4]=1
Reactant: CC(=O)c1nn(C)c(-c2ccc(C(F)(F)F)cc2)c1O
Reactant: NNC(=S)Nc1ccc(C(=O)O)s1
Product: CC(=NNC(=S)Nc1ccc(C(=O)O)s1)c1nn(C)c(-c2ccc(C(F)(F)F)cc2)c1O

Procedure:
From 1-[5-(4-trifluoromethylphenyl)-4-hydroxy-1-methyl-1H-pyrazol-3-yl]ethanone (40.0 mg, 0.14 mmol) and 5-hydrazinocabonothioylamino-2-thiophenecarboxylic acid (34.0 mg, 0.14 mmol), the desired product was obtained in the same manner as in Synthetic Example 114 as a pale yellow solid (55.8 mg, yield 82%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[C:16]([NH:17][C:18](=[S:27])[C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=3[OH:26])=[CH:15][CH:14]=[CH:13][N:12]=2)=[O:10])=[N:6][CH:7]=1.[C:28]([O:32][C:33]([NH:35][CH2:36][C@@H:37]([CH3:40])[CH2:38]O)=[O:34])([CH3:31])([CH3:30])[CH3:29]>>[C:28]([O:32][C:33]([NH:35][CH2:36][C@@H:37]([CH3:40])[CH2:38][O:26][C:20]1[CH:21]=[C:22]([CH3:25])[CH:23]=[CH:24][C:19]=1[C:18]([NH:17][C:16]1[C:11]([C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)=[O:10])=[N:12][CH:13]=[CH:14][CH:15]=1)=[S:27])=[O:34])([CH3:31])([CH3:30])[CH3:29]
Reactant: C[C@@H](CO)CNC(=O)OC(C)(C)C
Reactant: Cc1ccc(C(=S)Nc2cccnc2C(=O)Nc2ccc(Cl)cn2)c(O)c1
Product: Cc1ccc(C(=S)Nc2cccnc2C(=O)Nc2ccc(Cl)cn2)c(OC[C@H](C)CNC(=O)OC(C)(C)C)c1
Yield: 81 %

Procedure:
Using a procedure analogous to Example 38-D, N-(5-chloropyridin-2-yl)-3-[2-hydroxy-4-methylthiobenzoyl-amino]pyridine-2-carboxamide and (2R)-3-(t-butoxycarbonyl-amino)-2-methylpropanol gave the desired product as a solid (850 mg, 81%).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:6]2[C:7]([O:11][C:12]3[N:17]=[CH:16][C:15]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[NH2:21])=[CH:14][CH:13]=3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1.C(N(CC)CC)C.Cl[C:34](Cl)([O:36]C(=O)OC(Cl)(Cl)Cl)Cl.C([O-])(O)=O.[Na+]>ClCCl>[CH3:1][C:2]1([CH3:25])[C:6]2[C:7]([O:11][C:12]3[N:17]=[CH:16][C:15]([N:18]4[C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[NH:21][C:34]4=[O:36])=[CH:14][CH:13]=3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(N)C(=O)Nc1ccc(Oc2cccc3c2C(C)(C)CO3)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)NC(=O)N(c2ccc(Oc3cccc4c3C(C)(C)CO4)nc2)C1=O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
N1-{6-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-3-pyridinyl}-2-methylalaninamide (Intermediate 75, 7.5 mg) was dissolved in dry dichloromethane (1 ml). The reaction mixture was cooled down in an ice bath. Triethylamine (18.37 μl, 0.132 mmol) was added at 0° C. Then 0.5 ml of a solution of triphosgene in dry dichloromethane (0.012 mmol) was added dropwise. The solution was prepared with 7.18 mg of triphosgene dissolved in 1 ml of dichloromethane). The reaction mixture was stirred under argon during 10 min at 0° C., then during 30 min at room temperature. A saturated aqueous solution of NaHCO3 was added and the aqueous layer was extracted with dichloromethane 4 times. After drying over sodium sulphate, the solvents were removed under vacuum.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH3:11])[CH:3]=1.ClC1C=CC=CC=1.[S:19](=[O:23])(=[O:22])([OH:21])N>CN1CCCC1=O>[NH2:1][C:2]1[C:7]([S:19]([OH:23])(=[O:22])=[O:21])=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH3:11])[CH:3]=1
Reactant: NS(=O)(=O)O
Reactant: Cc1cc(N)ccc1[N+](=O)[O-]
Solvent: Clc1ccccc1
Solvent: CN1CCCC1=O
Product: Cc1cc(N)c(S(=O)(=O)O)cc1[N+](=O)[O-]

Procedure:
18.3 g of 1-amino-3-methyl-4-nitrobenzene, 120 ml of chlorobenzene, 24 g of sulphamic acid and 12 ml of 1-methylpyrrolid-2-one are warmed to 120°C whilst stirring. The reaction mixture is stirred for 8 hours at this temperature. After cooling, the reaction mixture is filtered and the residue is washed with trichloroethylene and recrystallised from 200 ml of water. The crystals which have precipitated are filtered off, suspended in 100 ml of trichloroethylene, stirred for one hour at 75°C, separated from the organic solvent by filtration and dried at 80°C. 25 g (84% of theory) of yellow crystals, which according to thin layer chromatography are a single substance, of 1-amino-3-methyl-4-nitro-benzene-6 -sulphonic acid in the form of its ammonium salt [melting point 290° C (decomposition)]are obtained.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][C:14](O)=[O:15])=[CH:10][CH:9]=1>C1COCC1>[Cl:7][C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH2:14][OH:15])=[CH:10][CH:9]=1
Reactant: O=C(O)COc1ccc(Cl)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCOc1ccc(Cl)cc1
Reaction time: 0.5 h

Procedure:
A stirred mixture of dry THF (20 ml) and 1.0 M lithiumaluminiumhydride (9.0 ml, 9.0 mmol) was placed under an atmosphere of nitrogen. A solution of 4-chlorophenoxyacetic acid (1.9 g, 10 mmol) in dry THF (10 ml) is slowly added dropwise. When addition was complete the reaction mixture was stirred for 30 min and then heated at reflux temperature for 10 min. The cooled reaction mixture was quenched with small amounts of water and 4 N NaOH and ethyl acetate was added. The mixture was dried (MgSO4) and then concentrated. The residue was re-evaporated with DCM to give crude 2-(4-chlorophenoxy)ethanol as an oil.
Reaction SMILES: CN(C)C=O.Cl.Cl[CH:8]([C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[F:23])[C:9]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][N:10]=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([SH:31])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)C>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([S:31][CH:8]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[F:23])[C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:27][CH:26]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: Cc1cccnc1C(Cl)c1cc(F)ccc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cc1cccnc1C(Sc1ccc(Cl)cc1)c1cc(F)ccc1F
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a dimethylformamide (5 ml) solution of the 2-[chloro-(2,5-difluorophenyl)methyl]-3-methylpyridine hydrochloride (94 mg, 0.32 mmol) obtained in Referential Example 14 were added 4-chlorobenzenethiol (70 mg, 0.49 mmol) and potassium carbonate (265 mg, 1.92 mmol) under a nitrogen atmosphere. The resulting mixture was stirred at 50° C. for 1 hour. After cooling to room temperature, diethyl ether (50 ml) was added to the reaction mixture. The resulting mixture was washed with water and brine. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (hexane:ethyl acetate 10:1), whereby the title compound (103 mg, 89%) was obtained as an oil.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[C:8]([C:15]([F:18])([F:17])[F:16])[C:9]([C:13]#[N:14])=[CH:10][CH:11]=2)[CH:6]=[N:5]1)(=O)C.Cl.[OH-].[Na+].CCOC(C)=O>CCO>[F:17][C:15]([F:16])([F:18])[C:8]1[C:9]([C:13]#[N:14])=[CH:10][CH:11]=[C:12]2[C:7]=1[CH:6]=[N:5][NH:4]2
Reactant: CC(=O)n1ncc2c(C(F)(F)F)c(C#N)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: N#Cc1ccc2[nH]ncc2c1C(F)(F)F
Temperature: 70 °C
Yield: 28.1 %

Procedure:
The crude 1-acetyl-4-(trifluoromethyl)-1H-indazole-5-carbonitrile from Example 210A (ca. 1.28 mmol) was dissolved in EtOH (5 mL) and conc. HCl (5 mL). The resulting mixture was heated to 70° C. for 20 min. The cooled reaction's pH was adjusted to ca. 8 with 6 N NaOH. EtOAc (20 mL) was added and the isolated organic portion was dried (Na2SO4), filtered and concentrated. Purification by semipreparative HPLC afforded the title compound as a pale yellow solid (0.076 g, 28% overall): 1H NMR (DMSO-d6) δ 14.13 (s, 1H), 8.41 (s, 1H), 8.06 (d, J=6.0 Hz, 1H), 7.93 (d, J=6.0 Hz, 1H).
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[C:15]([NH2:16])=[N:14][CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:18]1[N:23]=[C:22]([NH:24][C@H:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH3:26])[C:21]([NH2:33])=[N:20][CH:19]=1.[CH:34](O)=[O:35]>[Pd]>[C:1]1([C@@H:7]([N:9]2[C:10]3=[N:11][CH:12]=[CH:13][N:14]=[C:15]3[NH:16][C:34]2=[O:35])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:27]1([C@@H:25]([NH:24][C:22]2[C:21]([NH2:33])=[N:20][CH:19]=[CH:18][N:23]=2)[CH3:26])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: C[C@H](Nc1nc(Br)cnc1N)c1ccccc1
Reactant: O=CO
Agent: [Pd]
Agent: C[C@H](Nc1nccnc1N)c1ccccc1
Product: C[C@@H](c1ccccc1)n1c(=O)[nH]c2nccnc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(S)—N2-(1-Phenylethyl)pyrazine-2,3-diamine. The title compound was prepared by dissolving (S)-6-bromo-N2-(1-phenylethyl)pyrazine-2,3-diamine (1.00 g, 3.37 mmol) in neat formic acid (15 mL), and adding 10% Pd/C (0.34 mmol). This solution was purged with hydrogen gas at 1 atm., and stirred for 4 hours at room temperature. Upon completion, the reaction was filtered through celite and concentrated. The crude material was purified using silica gel chromatography (0-10% methanol in dichloromethane). Clean fractions were combined and condensed to afford 0.47 g (2.19 mmol, 65%) of (S)—N2-(1-phenylethyl)pyrazine-2,3-diamine. MS (ESI) m/z 215.4 [M+1]+.
Reaction SMILES: [C:1]1([O:11][CH2:12][CH2:13][CH2:14][C:15]2[C:23]3[C:18](=[C:19](B4OC(C)(C)C(C)(C)O4)[CH:20]=[CH:21][CH:22]=3)[NH:17][C:16]=2[C:33]([O:35][CH2:36]C)=[O:34])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[F:38][C:39]1[CH:44]=[C:43](I)[C:42]([CH3:46])=[CH:41][N:40]=1.[F-].[Cs+]>C(COC)OC.CO.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>[F:38][C:39]1[CH:44]=[C:43]([C:19]2[CH:20]=[CH:21][CH:22]=[C:23]3[C:18]=2[NH:17][C:16]([C:33]([O:35][CH3:36])=[O:34])=[C:15]3[CH2:14][CH2:13][CH2:12][O:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[C:42]([CH3:46])=[CH:41][N:40]=1
Reactant: Cc1cnc(F)cc1I
Reactant: CCOC(=O)c1[nH]c2c(B3OC(C)(C)C(C)(C)O3)cccc2c1CCCOc1cccc2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CO
Solvent: COCCOC
Product: COC(=O)c1[nH]c2c(-c3cc(F)ncc3C)cccc2c1CCCOc1cccc2ccccc12
Temperature: 25 °C

Procedure:
A mixture of EXAMPLE 43A (0.40 g), 2-fluoro-4-iodo-5-methylpyridine (0.209 g), tetrakis(triphenylphosphine)palladium (46 mg) and cesium fluoride (0.365 g) in dimethoxyethane (3 mL) and methanol (1.5 mL) was heated at 120° C. for 20 minutes under microwave conditions (CEM Discovery). After cooling to room temperature, the reaction mixture was loaded onto a silica gel cartridge. The cartridge was dried in vacuum oven for 1 hour and eluted with 1:4 ethyl acetate/hexanes to give the desired product. 1H NMR (500 MHz, DMSO-d6): 11.33 (s, 1H), 8.23-8.25 (m, 1H), 8.17 (s, 1H), 7.86-7.88 (m, 1H), 7.79-7.81 (m, 1H), 7.45-7.56 (m, 3H), 7.39 (t, J=7.93 Hz, 1H), 7.12-7.14 (m, 2H), 7.04 (d, J=2.14 Hz, 1H), 6.91 (d, J=7.32 Hz, 1H), 4.20 (t, J=5.95 Hz, 2H), 3.78 (s, 3H), 3.37 (t, J=7.48 Hz, 2H), 2.20-2.26 (m, 2H), 2.00 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].O=S(Cl)Cl.[CH3:19]O>>[F:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:19])=[O:8]
Reactant: CO
Reactant: Cc1c(C(=O)O)cc(F)cc1[N+](=O)[O-]
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(F)cc([N+](=O)[O-])c1C
Yield: 25 %

Procedure:
To a solution of conc. H2SO4 (700 mL) was added portion-wise 5-fluoro-2-methylbenzoic acid (80 g, 520 mmol) at −5˜0° C. Then a mixture of conc. HNO3 (60.4 g, 624 mmol) in conc. H2SO4 (60 mL) was added drop-wise at −5˜0° C. in a period of about 1.5 hrs. After the addition, the mixture was stirred at this temperature for 2 hrs. TLC (petroleum ether/EtOAc=1:1) showed the reaction was complete. The mixture was poured into crash ice with vigorous stirring and the precipitate was collected by filtration. The precipitate was dissolved in EtOAc, washed with brine, dried over anhydrous Na2SO4, concentrated to give crude 5-fluoro-2-methyl-3-nitrobenzoic acid (54 g). A solution of this crude 5-fluoro-2-methyl-3-nitrobenzoic acid (54 g) in dry methanol (500 mL) was cooled to 0° C., SOCl2 (64.52 g, 542.3 mmol) was added drop-wise. After the addition, the mixture was heated to reflux for 16 hrs. TLC (petroleum ether/EtOAc=1:1) showed the reaction was complete. Solvent was removed under reduced pressure to give crude product. The crude product was purified by silica gel chromatography (petroleum ether to petroleum ether/EtOAc=50:1) to give methyl 5-fluoro-2-methyl-3-nitrobenzoate (28 g, yield 25% for two steps) as a white solid. 1H-NMR (400 MHz, CDCl3) δ (ppm): 2.59 (s, 3H), 3.95 (s, 3H), 7.60-7.63 (dd, 1H), 7.74-7.77 (dd, 1H); LC-MS (ESI) m/z: 214 (M+1)+, 216(M+3)+.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([C:7]1[CH:8]=[CH:9][C:10]2[O:14][CH:13](O)[C:12]([CH3:17])([CH3:16])[C:11]=2[CH:18]=1)#[N:6].N1C=CC=CC=1>ClCCl>[Cl:3][CH:13]1[C:12]([CH3:17])([CH3:16])[C:11]2[CH:18]=[C:7]([C:5]#[N:6])[CH:8]=[CH:9][C:10]=2[O:14]1
Reactant: O=S(Cl)Cl
Reactant: CC1(C)c2cc(C#N)ccc2OC1O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(C)c2cc(C#N)ccc2OC1Cl
Yield: 78.2 %

Procedure:
Thionyl chloride (9.3 g) in dichloromethane (10 ml) was added dropwise with stirring and cooling to 5-cyano-2,3-dihydro-3,3-dimethyl-2-hydroxybenzofuran (11.3 g) prepared as in Example 10 and pyridine (6.2 g) in dichloromethane (60 ml.) The mixture was stirred for 2 hours at room temperature prior to washing with water, dilute sodium hydroxide solution and water again, drying over magnesium sulphate and evaporating under vacuum. Recrystallisation from toluene and petroleum ether (bp 80°-100° C.) gave 9.7 g of the title compound, mp 105°-106° C.
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]([O:17][CH3:18])[C:6]([NH:9][CH2:10][CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[N:7][CH:8]=1)#[N:2].[CH2:19]([O:26][C:27](ON1C(=O)CCC1=O)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([O:26][C:27]([N:14]1[CH2:15][CH2:16][CH:11]([CH2:10][NH:9][C:6]2[C:5]([O:17][CH3:18])=[N:4][C:3]([C:1]#[N:2])=[CH:8][N:7]=2)[CH2:12][CH2:13]1)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COc1nc(C#N)cnc1NCC1CCNCC1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Product: COc1nc(C#N)cnc1NCC1CCN(C(=O)OCc2ccccc2)CC1

Procedure:
The above compound was prepared in a similar manner as described in EXAMPLE 130 from 4-[(5-cyano-3-methoxy-pyrazin-2-ylamino)-methyl]-piperidine using N-(benzyloxycarbonyloxy)succinimide (Sigma-Aldrich). M.S.(M+1): 382.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19][CH2:18][C@@H:17]([NH:26][C:27](=[O:40])[CH2:28][C:29]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])([CH3:31])[CH3:30])[C:16]2=[O:41])=[CH:10][CH:9]=1.C[Si]([N:46]=[C:47]=[O:48])(C)C>C(Cl)Cl>[NH2:46][C:47]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][C:11]([CH2:14][N:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19][CH2:18][C@@H:17]([NH:26][C:27](=[O:40])[CH2:28][C:29]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])([CH3:31])[CH3:30])[C:16]2=[O:41])=[CH:12][CH:13]=1)=[O:48]
Reactant: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3N)cc2)C1=O)NC(=O)OC(C)(C)C
Reactant: C[Si](C)(C)N=C=O
Solvent: ClCCl
Product: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3NC(N)=O)cc2)C1=O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 43.8 %

Procedure:
A solution of 445 mg (0.80 mmol) of N-[1-[[(2'-amino)[1,1'-biphenyl]-4-yl]methyl]-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl]-3-t-butoxycarbonylamino-3-methylbutanamide (Example 2, Step B) in 3 mL of methylene chloride under a nitrogen atmosphere was treated with 4 mL (29.5 mmol) of trimethylsilyl isocyanate. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was evaporated under vacuum and the residue was passed over silica gel. Elution with ethyl acetateexanes (4:1) yielded 211 mg (0.35 mmol, 44%) of product. FAB-MS: calculated for C34H41N5O5 599: found 622 (M+Na). 1H NMR (400 MHz, CDCl3): δ 1.31 (s, 3H), 1.38 (s, 3H), 1.39 (s, 9H), 1.90 (m, 1H), 2.48 (dd, 2H), 2.60 (m, 2H), 4.48 (m, 1H), 4.95 (d, 1H), 5.08 (d, 1H), 5.28 (br s, 1H), 6.66 (br s, 1H), 6.78 (d, 1H), 7.22 (m, 11H), 7.72 (d, 1H).
Reaction SMILES: [NH3:1].[N:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])=[C:3]=[O:4]>CO>[CH2:5]([NH:2][C:3]([NH2:1])=[O:4])[CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: N
Reactant: CCCCCN=C=O
Solvent: CO
Product: CCCCCNC(N)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 7.0 M solution of ammonia in methanol (32 mL) was dropwise added 1-isocyanatopentane (5.0 g, 0.044 mol). After the addition, the mixture was stirred at room temperature for 1 h and concentrated under reduced pressure to give a white solid, which was directly used for next step without further purification. LCMS calculated for C6H15N2O (M+H): 131.1; found 131.1.
Reaction SMILES: COS(O)(=O)=O.B(OC)(OC)OC.C(OC)(=O)C.C[C:20]([O:22][CH2:23][C:24]1[CH2:33][S:32][C@@H:27]2[C@H:28]([NH2:31])[C:29](=[O:30])[N:26]2[C:25]=1[C:34]([OH:36])=[O:35])=O>S1(CCCC1)(=O)=O>[NH2:31][CH:28]1[C:29](=[O:30])[N:26]2[C:25]([C:34]([OH:36])=[O:35])=[C:24]([CH2:23][O:22][CH3:20])[CH2:33][S:32][C@H:27]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: COB(OC)OC
Agent: COS(=O)(=O)O
Solvent: O=S1(=O)CCCC1
Solvent: COC(C)=O
Product: COCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: 20 °C
Reaction time: 1 h
Yield: 85.8 %

Procedure:
11.9 g of a methanolic solution of methoxysulfonic acid (prepared as described in Preparation 2) and 2.10 g of trimethyl borate were added to a solution containing 10 ml of sulfolane and 5 ml of methyl acetate. The mixture was cooled to 20° C., and 2.74 g of 7-ACA were added thereto, followed by stirring at 20° C. for 1 hour. After completion of the reaction, the reaction mixture was treated following the procedures described in Example 2 to give 2.11 g (yield 86%) of the desired compound with a high purity.
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=3)[N:6]2[N:5]=1)=O.C(N(CC)C(C)C)(C)C.[NH2:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[N:36]([CH3:40])[C:35](=[O:41])[CH2:34]2.COCC(O)C>>[CH3:20][O:19][C:16]1[N:15]=[CH:14][C:13]([C:12]2[N:6]3[C:7]([CH:8]=[N:9][C:4]([NH:30][C:31]4[CH:32]=[C:33]5[C:37](=[CH:38][CH:39]=4)[N:36]([CH3:40])[C:35](=[O:41])[CH2:34]5)=[N:5]3)=[CH:10][CH:11]=2)=[CH:18][CH:17]=1
Reactant: CN1C(=O)Cc2cc(N)ccc21
Reactant: COc1ccc(-c2ccc3cnc(S(C)=O)nn23)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: COCC(C)O
Product: COc1ccc(-c2ccc3cnc(Nc4ccc5c(c4)CC(=O)N5C)nn23)cn1
Yield: 8.3 %

Procedure:
2-Methanesulfinyl-7-(6-methoxy-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazine (125.0 mg, 0.0004335 mol), N,N-Diisopropylethylamine (0.249 mL, 0.00143 mol) and 5-Amino-1-methyl-1,3-dihydro-indol-2-one (0.141 g, 0.000867 mol) were dissolved in 1-Methoxy-2-propanol (0.498 mL, 0.00510 mol) and the reaction was irradiated at 300 watts, 180° C. for 40 minutes or until HPLC showed consumption of starting material. The reaction mixture was then reduced en vacuo and the product was isolated and purified by Gilson prep HPLC to afford 13.85 mg of 5-[7-(6-Methoxy-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-1-methyl-1,3-dihydro-indol-2-one as a lyophilized powder. (M+H)=387.1. 1H NMR (400 MHz, DMSO, d6) δ 9.40 (s, 1H), 8.96 (s, 2H), 8.47 (d, 1H, J=8.73 Hz), 7.82 (s, 1H), 7.51 (d, 1H, J=8.40 Hz), 7.16 (d, 1H, J=4.37 Hz), 7.04 (d, 1H, J=8.65 Hz), 6.91 (m, 2H), 3.95 (s, 3H), 3.59 (s, 2H), 3.12 (s, 3H).