Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]([N:11]2[CH2:16][CH:15]3[CH:13]([CH:14]3[C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[CH2:12]2)=[O:10])[CH:5]=[CH:6][C:7]=1[CH3:8].CCN(CC)CC.[Cl:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[CH:35][N:34]=1>C(Cl)Cl>[Cl:32][C:33]1[CH:41]=[CH:40][C:36]([C:37]([NH:1][C:2]2[CH:3]=[C:4]([C:9]([N:11]3[CH2:16][CH:15]4[CH:13]([CH:14]4[C:17]4[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=4)[CH2:12]3)=[O:10])[CH:5]=[CH:6][C:7]=2[CH3:8])=[O:38])=[CH:35][N:34]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: COc1ccc(C2C3CN(C(=O)c4ccc(C)c(N)c4)CC32)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C2C3CN(C(=O)c4ccc(C)c(NC(=O)c5ccc(Cl)nc5)c4)CC32)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 79.2 %

Procedure:
To a solution of (3-Amino-4-methylphenyl)(6-(4-methoxyphenyl)-3-azabicyclo[3.1.0]hexan-3-yl)methanone (150 mg, 0.47 mmol) and Et3N (0.25 mL, 1.8 mmol) in CH2Cl2 (4 mL) at 0° C. was added 6-chloronicotinoyl chloride (106 mg, 0.6 mmol). The ice bath was removed after the addition. The reaction mixture was stirred at room temperature for 1.5 h and then purified by flash column chromatography with EtOAc in hexane (60%, then 100%) to give the title compound as a white foam (0.172 g, 80% yield). MS [M+H]+: 462, 464.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[CH2:14][C@H:13]([NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])[CH2:12]3)O1.Br[C:27]1[C:28]([F:34])=[N:29][C:30]([CH3:33])=[CH:31][CH:32]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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:34][C:28]1[C:27]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[CH2:14][C@H:13]([NH:18][S:19]([CH:22]([CH3:23])[CH3:24])(=[O:20])=[O:21])[CH2:12]3)=[CH:32][CH:31]=[C:30]([CH3:33])[N:29]=1
Reactant: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2C1
Reactant: Cc1ccc(Br)c(F)n1
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: C1COCCO1
Product: Cc1ccc(-c2ccc3c(c2)C[C@@H](NS(=O)(=O)C(C)C)C3)c(F)n1

Procedure:
To a solution of N-[(2S)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfonamide (250 mg, 0.68 mmol) in dry 1,4 dioxane (5 ml), polymer supported Pd(PPh3)4 (14 mg, 0.5 mmol/g, 0.007 mmol) was added along with 3-bromo-2-fluoro-6-methylpyridine (194 mg, 1.02 mmol) and 680 μl of a 2M Na2CO3 solution in water. The resulting mixture was heated at 90° degrees for 3 hours. Then after cooling the resin was removed by filtration and then the solvent was removed under reduced pressure. The residue was taken up with DCM, washed with water and loaded on a 25M+ silica cartridge eluating with a cyclohexane/AcOEt 75/25 mixture. 175 mg of title compound were recovered as white solid (74%). Due to the use of chiral Intermediate 7, the final compound is believed to be N-[(2S)-5-(2-fluoro-6-methyl-3-pyridinyl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfonamide.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([O:17][CH3:18])=[C:14]([NH2:16])[CH:15]=1.[C:19](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([O:17][CH3:18])=[C:14]([NH:16][CH3:19])[CH:15]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(-c2cc3ccccc3[nH]2)cc1N
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CNc1cc(-c2cc3ccccc3[nH]2)ccc1OC
Temperature: 40 °C
Reaction time: 48 h
Yield: 27 %

Procedure:
In acetone (50 mL) was placed 5-(1H-indol-2-yl)-2-methoxy-phenylamine (2.38 g, 10 mmol). To this was added potassium carbonate (5.53 g, 40 mmol), and to the vigorously stirred mixture was added methyl iodide (1.55 g, 11 mmol). The mixture warmed to 40° C. and stirred for 48 hours. The mixture cooled to room temperature and was filtered free of inorganics. The resulting solution was evaporated in vacuo to give a solid which was partitioned between ethyl acetate (50 mL) and water (50 mL). The organic phase was separated, dried over magnesium sulfate, and evaporated in vacuo to give a tan solid. This solid was purified by flash chromatography over silica gel (5% ethyl acetate/methylene chloride). Evaporation of the appropriate fractions gave 0.68 g of pure compound. MS: M+1=253.1. 1H NMR (DMSO-d6) δ 2.79 (d, J=5.3 Hz, 3H), 3.80 (s, 3H), 5.08-5.12 (m, 1H), 6.69 (s, 1H), 6.83-7.05 (m, 5H), 7.33 (d, J=7.9 Hz, 1H), 7.44 (d, J=8.0 Hz, 1H), 11.28 (s, 1H) ppm.
Reaction SMILES: [NH2:1][CH:2]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1)[CH:3]([C:5]1[CH:9]=[CH:8][O:7][CH:6]=1)[OH:4].[F:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([C:32](O)=[O:33])=[CH:24][CH:23]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([C:32]([NH:1][CH:2]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:13][CH:12]=2)[CH:3]([C:5]2[CH:9]=[CH:8][O:7][CH:6]=2)[OH:4])=[O:33])=[CH:24][CH:23]=1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccoc1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: O=C(NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccoc1)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.6 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(3-furanyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (500 mg, 1.75 mmol) in acetonitrile (30 ml) were added 4-fluoronaphthalenecarboxylic acid (333 mg, 1.75 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (504 mg, 2.63 mmol) and 1-hydroxy-1H-benzotriazole (268 mg, 1.75 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1). Recrystallization from ethyl acetate-hexane gave the title compound (573 mg, 71%).
Reaction SMILES: [CH3:1][C:2]1([CH2:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[Cl:10][C:11]1[C:12](F)=[CH:13][C:14]([F:24])=[C:15]([CH:23]=1)[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[Cl:10][C:11]1[C:12]([O:9][CH2:8][C:2]2([CH3:1])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)=[CH:13][C:14]([F:24])=[C:15]([CH:23]=1)[C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17]
Reactant: CC1(CO)CCCCC1
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CC1(COc2cc(F)c(C(=O)OC(C)(C)C)cc2Cl)CCCCC1
Temperature: 70 °C
Reaction time: 16 h
Yield: 45.2 %

Procedure:
To a solution of (1-methylcyclohexyl)methanol (4.98 g, 38.80 mmol) and tert-butyl 5-chloro-2,4-difluorobenzoate (20.67 g, 83.10 mmol) in anhydrous dimethylsulfoxide (80 mL) was added cesium carbonate (25.14 g, 77.20 mmol). The mixture was heated to 70° C. and stirred for 16 hours. The mixture was then cooled to ambient temperature, filtered through a pad of diatomaceous earth and the solid was washed with ethyl acetate. The combined organic layers were washed with water and brine; dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (0% to 10% ethyl acetate in hexanes) to afford the title compound (6.26 g, 44%): 1H NMR (300 MHz, CDCl3) δ 7.87 (d, J=7.7 Hz, 1H), 6.62 (d, J=12.2 Hz, 1H), 3.70 (s, 2H), 1.57 (s, 9 H), 1.52-1.31 (m, 10H), 1.08 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH3:15])([CH3:14])[CH2:8][CH2:9][C:10]2=O)=[CH:5][C:4]=1[CH3:16].[C:17]([Mg]Cl)([CH3:20])([CH3:19])[CH3:18]>>[C:17]([C:10]1[C:11]2[C:6](=[CH:5][C:4]([CH3:16])=[C:3]([O:2][CH3:1])[CH:12]=2)[C:7]([CH3:15])([CH3:14])[CH2:8][CH:9]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Mg]Cl
Reactant: COc1cc2c(cc1C)C(C)(C)CCC2=O
Product: COc1cc2c(cc1C)C(C)(C)CC=C2C(C)(C)C
Yield: 35.3 %

Procedure:
Following General Procedure A, 7-methoxy-4,4,6-trimethyl-3,4-dihydro-2H-naphthalen-1-one (Compound 6, 1.5 g, 6.9 mmol) was reacted with a solution of 2M tert-butylmagnesium chloride (12 mL, 23 mmol), and the crude product was purified by flash column (hexane:ethyl acetate=4:1) to give 0.63 g (36%) of the title product as a clear oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([NH:23][C@@H:24]1[CH2:28][NH:27][CH2:26][C@@H:25]1[NH:29][C:30](=[O:33])[CH:31]=[CH2:32])[N:17]=[CH:16]2.CCN(C(C)C)C(C)C.[C:43](Cl)(=[O:45])[CH3:44]>ClCCl>[C:43]([N:27]1[CH2:28][C@@H:24]([NH:23][C:18]2[N:17]=[CH:16][C:15]3[C:20](=[CH:21][CH:22]=[C:13]([C:3]4[C:2]([Cl:1])=[C:7]([O:8][CH3:9])[CH:6]=[C:5]([O:10][CH3:11])[C:4]=4[Cl:12])[CH:14]=3)[N:19]=2)[C@@H:25]([NH:29][C:30](=[O:33])[CH:31]=[CH2:32])[CH2:26]1)(=[O:45])[CH3:44]
Reactant: C=CC(=O)N[C@H]1CNC[C@H]1Nc1ncc2cc(-c3c(Cl)c(OC)cc(OC)c3Cl)ccc2n1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)N[C@H]1CN(C(C)=O)C[C@H]1Nc1ncc2cc(-c3c(Cl)c(OC)cc(OC)c3Cl)ccc2n1
Reaction time: 1 h
Yield: 51.4 %

Procedure:
To a solution of N-((3S,4R)-4-((6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)amino)pyrrolidin-3-yl)acrylamide (0.37 g, 0.76 mmol) in dichloromethane (15 mL) at 0° C. was added DIEA (0.16 mL, 0.92 mmol) and acetyl chloride (0.054 mL, 0.76 mmol) and the reaction was stirred for 60 mins. LC-MS indicated complete consumption of SM. The reaction mixture was purified by silica gel chromatography to yield N-((3S,4R)-1-acetyl-4-((6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)amino)pyrrolidin-3-yl)acrylamide (0.207 g, 51%). MS (ES+) C25H25Cl2N5O4 requires: 529, found: 530.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:33])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][C:25](O)=[O:26])[CH:11]3[C:28]([CH2:31][CH3:32])=[CH:29][CH3:30])[C:5]2=[CH:4][CH:3]=1.N1C(F)=NC(F)=NC=1[F:36].N1C=CC=CC=1>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:33])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][C:25]([F:36])=[O:26])[CH:11]3[C:28]([CH2:31][CH3:32])=[CH:29][CH3:30])[C:5]2=[CH:4][CH:3]=1
Reactant: CC=C(CC)C1N(CC(=O)O)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Reactant: Fc1nc(F)nc(F)n1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC=C(CC)C1N(CC(=O)F)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Yield: 74.3 %

Procedure:
In a manner similar to the method described in example 34a, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-ethyl-propenyl)-1-hydroxycarbonyl-methylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.16 g, 0.33 mmol) prepared in example 81c was reacted with cyanuric fluoride (0.044 mL, 1.64 mmol) (Alfa) and pyridine (0.13 g, 1.64 mmol) in dichloromethane to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-ethyl-propenyl)-1′-fluorocarbonylmethyl-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (yield: 0.12 g, 75%).
Reaction SMILES: [OH-:1].[K+:2].O=C[C@@H:5]([C@H:7]([C@H:9]([C@@H:11]([CH2:13][OH:14])[OH:12])[OH:10])[OH:8])[OH:6]>CO.O>[O:1]=[C:5]([O-:6])[C@H:7]([C@H:9]([C@@H:11]([CH2:13][OH:14])[OH:12])[OH:10])[OH:8].[K+:2]
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Reactant: [OH-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=C([O-])[C@@H](O)[C@@H](O)[C@H](O)CO
Yield: 573.9 %

Procedure:
Air was sparged at 100 mL/min through a rapidly stirred solution of potassium hydroxide (41.9 g, 65.5 mmol) and D-galactose (45.0 g, 25.0 mmol) in a mixture of methanol/water (375 mL/180 mL) at 60 psi in a Parr bomb (1 L). The temperature was maintained at 35°-36° C. throughout the reaction. After sparging for 24 hours (h), methanol (50 mL) was added and sparging continued for a total of 45 h. The reaction mixture was cooled and vented. The bomb was opened and the light yellow mixture was filtered to remove a small amount of solids. The bomb and filter were rinsed with water (5 mL) in which most of the solids dissolved. The filtrate was stirred and diluted with methanol (850 mL). Crystallization occurred after approximately 500 mL of methanol had been added. After stirring for 4 h, the crystals were collected by filtration and vacuum dried to provide 29.3 g (57% yield) of potassium D-lyxonate 1 as a white solid: DISC mp 171.25° C.; Analysis calculated for C5H9O6K: C, 29.41; H, 4.44. Found: C, 28.86; H, 4.16. This white solid material was used in Example 2 without further purification.
Reaction SMILES: [N:1]1[NH:2][N:3]=[N:4][C:5]=1/[CH:6]=[CH:7]/[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH:15]2[C:24]3[C:19](=[CH:20][C:21]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:22][CH:23]=3)[CH2:18][CH2:17][N:16]2[C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)=[CH:10][CH:9]=1.[C:40](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C)C=O>[CH3:40][N:3]1[N:2]=[N:1][C:5](/[CH:6]=[CH:7]/[C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH:15]3[C:24]4[C:19](=[CH:20][C:21]([O:25][CH2:26][C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)=[CH:22][CH:23]=4)[CH2:18][CH2:17][N:16]3[C:33]3[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=3)=[CH:10][CH:9]=2)=[N:4]1
Reactant: O=C([O-])[O-]
Reactant: Fc1ccc(N2CCc3cc(OCc4ccccc4)ccc3C2Cc2ccc(/C=C/c3nn[nH]n3)cc2)cc1
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1nnc(/C=C/c2ccc(CC3c4ccc(OCc5ccccc5)cc4CCN3c3ccc(F)cc3)cc2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 22.6 %

Procedure:
To a solution containing 1-{[4-((1E)-2-(2H-1,2,3,4,-tetrazol-5-yl)vinyl)phenyl]methyl}-2-(4-fluorophenyl)-6-(phenylmethoxy)-1,2,3,4,-tetrahydroisoquinoline (430 mg, 0.831 mmol) in dimethyl formamide (12 mL) was added cesium carbonate (812 mg, 2.493 mmol) and methyl iodide (0.06 mL, 1.0 mmol). The mixture was allowed to stir at ambient temperature for 18 hours. The solvent was removed and the resulting oil was extracted with ethyl acetate and distilled water. The organic layer was dried over sodium sulfate, filtered and concentrated to afford a brown oil. The brown oil was purified by column chromatography (SiO2, 30% ethyl acetate/hexanes), to afford the title compound (100 mg, 23% yield): ES-MS (m/z) 532 [M+H]+.
Reaction SMILES: C(#N)C.[Na].[CH2:5]([C:12]1[O:13][C:14](=O)[C:15](=[CH:17][OH:18])[N:16]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl.[C:21]([NH2:29])(=[NH:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O>[C:22]1([C:21]2[NH:29][C:17](=[O:18])[C:15]([NH:16][C:12](=[O:13])[CH2:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=3)=[CH:14][N:28]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: N=C(N)c1ccccc1
Reactant: O=C1OC(Cc2ccccc2)=NC1=CO
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CC#N
Product: O=C(Cc1ccccc1)Nc1cnc(-c2ccccc2)[nH]c1=O
Temperature: 80 °C
Reaction time: 8 h
Yield: 75.2 %

Procedure:
Acetonitrile (6 ml) was added to 2-benzyl-4-hydroxymethylene-5-oxazolone sodium salt (0.50 g, 2.22 mmol) and benzamidine hydrochloride (0.35 g, 2.22 mmol), and the mixture was stirred overnight at 80° C. Water (3 ml) was added, and the mixture was stirred. The precipitate was collected by filtration, and the obtained crystals were washed with water and vacuum dried to give 2-phenyl-6-oxo-5-phenylacetylamino-1,6-dihydropyrimidine (0.51 g, 1.67 mmol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:19](OC)=O)[C:11](=[O:18])[N:12]([CH2:14][CH:15]([CH3:17])[CH3:16])[N:13]=2)=[CH:4][C:3]=1[CH3:23].FC1C=CC(C2C=[C:33](COS(C)(=O)=O)[C:34](=O)[N:35]([CH2:37][CH:38](C)C)N=2)=CC=1C.C(NCC)C>>[CH2:34]([N:35]([CH2:19][C:10]1[C:11](=[O:18])[N:12]([CH2:14][CH:15]([CH3:17])[CH3:16])[N:13]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH3:23])[CH:4]=2)[CH:9]=1)[CH2:37][CH3:38])[CH3:33]
Reactant: COC(=O)c1cc(-c2ccc(F)c(C)c2)nn(CC(C)C)c1=O
Reactant: Cc1cc(-c2cc(COS(C)(=O)=O)c(=O)n(CC(C)C)n2)ccc1F
Solvent: CCNCC
Product: CCN(CC)Cc1cc(-c2ccc(F)c(C)c2)nn(CC(C)C)c1=O

Procedure:
Following the procedure of Example 9 (4), 6-(4-fluoro-3-methylphenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and diethylamine were reacted to yield the title compound as a slightly yellow oil (yield: 94.7%).
Reaction SMILES: [Li+].[CH3:2]CC[CH2-].[Cl:6][C:7]1[CH:15]=[C:14]([CH:16]([O:19][CH2:20][C:21]2([C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)[CH:17]=O)[C:13]2[C:9](=[CH:10][N:11]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[N:12]=2)[CH:8]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.CCOCC>[Cl:6][C:7]1[CH:15]=[C:14]([CH:16]([O:19][CH2:20][C:21]2([C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[CH2:23][CH2:22]2)[CH:17]=[CH2:2])[C:13]2[C:9](=[CH:10][N:11]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[N:12]=2)[CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COC(C=O)c2cc(Cl)cc3cn(COCC[Si](C)(C)C)nc23)(c2ccc(F)cc2)CC1
Reactant: [CH2-]CCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CC(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Cl)cc2cn(COCC[Si](C)(C)C)nc12
Reaction time: 0.17 h
Yield: 30.4 %

Procedure:
To a suspension of methyltriphenylphosphoniumbromide (470 mg, 1.314 mmol) in THF (17 ml) was added N-BUTYLLITHIUM (0.526 ml, 1.314 mmol). The ice bath was removed and the suspension was stirred for 10 min. To this was added tert-butyl 4-((1-(5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)-2-oxoethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (277 mg, 0.438 mmol) in 2.5 mL THF. The reaction was allowed to stir 1 hour before diluted with ether (100 mL) and filtered out the solid, the ether layer was washed with water, brine and dried over magnesium sulfate, filtered and concentrated. It was then purified by Biotage LC (20-25% EtOAc/Hex) to give title compound (84 mg, 0.133 mmol, 30.4% yield) as light yellow foam solid. 1H-NMR (CDCl3, 500 MHz) δ 7.98 (s, 1H), 7.49 (d, J=1.8 Hz, 1H), 7.29 (m, 2H), 7.00 T, J=8.8 Hz, 2H), 6.85 (s, 1H), 5.88 (ddd, J=17.2, 10.6, 5.9 Hz, 1H), 5.63(d, J=4.0 Hz, 1H), 5.60 (d, J=3.7 Hz, 1H), 5.30 (d, J=5.5 Hz, 1H), 5.23 (d, J=17.2 Hz, 1H), 5.02 (d, J=10.3 Hz, 1H), 3.69 (m, 2H), 3.58 (t, J=8.4 Hz, 2H), 3.42 (AB, Δν=28.5 Hz, J=8.8 Hz, 2H), 3.04 (m, 2H), 1.80-2.25 (m,4H), 1.41 (s, 9H), 0.88 (t, J=9.2 Hz, 2H), −0.07 (s, 9H). LC/MS (HPLC method 3): tR=4.43 min, 630.3(MH)+.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[C:8]([Cl:13])=[N:9][CH:10]=[CH:11][CH:12]=1)=[O:5].S(=O)(=O)(O)O>O.C(O)(=O)C>[Cl:13][C:8]1[C:7]([NH:6][C:4](=[O:5])[C:3]2[CH:14]=[CH:15][CH:16]=[CH:17][C:2]=2[F:1])=[C:12]([C:4](=[O:5])[CH2:3][CH2:2][CH3:17])[CH:11]=[CH:10][N:9]=1
Reactant: O=C(Nc1cccnc1Cl)c1ccccc1F
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: CCCC(=O)c1ccnc(Cl)c1NC(=O)c1ccccc1F
Yield: 25 %

Procedure:
Using the procedure described in Examples 1 and 2, but replacing 2-phenyloxazolo[4,5-b]pyridine by 3-(2-fluorobenzoylamino)-2-chloropyridine and using 1.5 ml of concentrated sulfuric acid in 7.5 ml of water and 25 ml of acetic acid, and after the separation of 2-chloro-3-(2-fluorobenzoylamino)-6-butyrylpyridine, the expected product is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([NH:17][C:18]2[CH2:22][CH2:21][CH2:20][C:19]=2[C:23]([O:25]CC)=O)=[S:16])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[Na]>C(O)(C)C.CN(C)C=O>[Cl:1][C:2]1[CH:13]=[CH:12][C:11]([N:14]2[C:23](=[O:25])[C:19]3[CH2:20][CH2:21][CH2:22][C:18]=3[NH:17][C:15]2=[S:16])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: CCOC(=O)C1=C(NC(=S)Nc2ccc(Cl)c(C(=O)OC(C)C)c2)CCC1
Agent: [Na]
Solvent: CC(C)O
Solvent: CN(C)C=O
Product: CC(C)OC(=O)c1cc(-n2c(=S)[nH]c3c(c2=O)CCC3)ccc1Cl

Procedure:
using isopropyl 2-chloro-5-{3-[2-(ethoxycarbonyl)-1-cyclopenten-1-yl]thioureido}-benzoate with sodium isopropylate in an isopropanol/dimethylformamide mixture there is obtained isopropyl 2-chloro-5-(1,2,4,5,6,7-hexahydro-4-oxo-2-thioxo-3H-cyclopenta[d]pyrimidin-3-yl)benzoate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][NH2:10])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Br:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>C(Cl)Cl>[C:1]([O:5][C:6]([NH:7][CH2:8][CH2:9][NH:10][S:26]([C:23]1[CH:24]=[CH:25][C:20]([Br:19])=[CH:21][CH:22]=1)(=[O:28])=[O:27])=[O:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCNS(=O)(=O)c1ccc(Br)cc1
Reaction time: 3 h
Yield: 87.1 %

Procedure:
To a solution of N-(2-Aminoethyl)carbamic acid tert-butyl ester (1.86 g, 11.5 mmol) and triethyl amine (3 mL) in CH2Cl2 (100 mL) at 0° C., was added (4-bromophenyl)chlorosulfone (2.93 g, 11.5 mmol). The mixture was stirred for 3 hours, before the solvent was removed. The residue was dissolved in EtOAc (150 mL), washed with sat. NaHCO3 (50 mL), sat. NaCl (50 mL), 1N HCl (50 mL), sat. NaCl (2×50 mL), dried over MgSO4, and evaporated to give 3.8 g of the title compound as a white solid in 100% yield.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[C:10]2[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]1=2.[N:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:22][N:19]1[CH2:20][CH2:21][C:9]2[N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[C:26]3[CH:27]=[CH:28][N:23]=[CH:24][CH:25]=3)[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]=2[CH2:18]1
Reactant: OB(O)c1ccncc1
Reactant: Cc1ccc2c(c1)c1c(n2-c2ccccc2Br)CCN(C)C1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2-c2ccccc2-c2ccncc2)CCN(C)C1
Temperature: 95 °C
Yield: 7.8 %

Procedure:
To a de-aerated solution of 5-(2-bromo-phenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (180 mg, 0.508 mmol), 4-pyridinylboronic acid (93.8 mg, 0.762 mmol) and K3PO4 (270 mg, 1.27 mmol) in DMF-water (9:1 mL) was added PdCl2(PPh3)2 (18 mg, 5 mol %). The reaction mixture was heated at 95° C. for 30 min under nitrogen atmosphere. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 2,8-dimethyl-5-(2-pyridin-4-yl-phenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole as semisolid (14 mg). 1H NMR (Freebase, CDCl3) d (ppm): 8.38 (d, 2H), 7.58 (m, 3H), 7.40 (d, 1H), 7.20 (s, 1H), 6.90 (m, 4H), 3.75 (m, 2H), 2.76 (m, 1H), 2.60 (m, 1H), 2.50 (m, 1H), 2.48 (s, 3H), 2.42 (s, 3H), 2.20 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17](C)[CH:18]=3)[N:13]([CH2:21][C:22]([OH:24])=[O:23])[C:12]=2[CH3:25])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(OC(=O)CN1C2C(=CC(C)=CC=2)C(S(C2C=CC([Cl:50])=CC=2)(=O)=O)=C1C)C>>[Cl:50][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:14]=1[N:13]([CH2:21][C:22]([OH:24])=[O:23])[C:12]([CH3:25])=[C:11]2[S:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)(=[O:10])=[O:9]
Reactant: Cc1ccc2c(c1)c(S(=O)(=O)c1ccc(Cl)cc1)c(C)n2CC(=O)O
Reactant: CCOC(=O)Cn1c(C)c(S(=O)(=O)c2ccc(Cl)cc2)c2cc(C)ccc21
Product: Cc1c(S(=O)(=O)c2ccc(Cl)cc2)c2cccc(Cl)c2n1CC(=O)O

Procedure:
The title compound was prepared by the method of example 2 part (d) using the product from part (c).