Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[SH:11].[OH-].[Na+].Cl.Cl[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1>C1COCC1>[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[S:11][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1
Reactant: ClCc1ccccn1
Reactant: Cc1cc([N+](=O)[O-])ccc1S
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc([N+](=O)[O-])ccc1SCc1ccccn1
Yield: 73.7 %

Procedure:
2-methyl-4-nitrobenzenethiol (3.0 g) was dissolved in THF (60 ml), and to this solution was added aqueous solution of sodium hydroxide (2.1 g, 15 ml) and then, 2-(chloromethyl)pyridine hydrochloride (3.5 g), and the mixture was stirred for 30 minutes. The solvent was removed under reduced pressure, and the residue was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure and the obtained residue was washed with hexane/ethyl acetate, to give 2-[[(2-methyl-4-nitrophenyl)sulfanyl]methyl]pyridine (3.4 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[C:7](=[O:20])[C:8]3[C:13]([S:14](=[O:18])(=[O:17])[C:15]=2[CH:16]=1)=[CH:12][CH:11]=[C:10]([CH3:19])[CH:9]=3)#[N:2].[N-:21]=[N+:22]=[N-:23].[Na+].[Cl-].[NH4+].Cl>CN(C)C=O>[CH3:19][C:10]1[CH:9]=[C:8]2[C:13]([S:14](=[O:17])(=[O:18])[C:15]3[CH:16]=[C:3]([C:1]4[NH:23][N:22]=[N:21][N:2]=4)[CH:4]=[CH:5][C:6]=3[C:7]2=[O:20])=[CH:12][CH:11]=1
Reactant: Cc1ccc2c(c1)C(=O)c1ccc(C#N)cc1S2(=O)=O
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)C(=O)c1ccc(-c3nnn[nH]3)cc1S2(=O)=O

Procedure:
3-Cyano-7-methylthioxanthone-10,10dioxide (0.36 g), sodium azide (0.091 g), ammonium chloride (0.081 g) and dimethyl formamide (5.0 ml) were heated together on the steam bath for 7 hrs., poured on to ice and hydrochloric acid, and the precipitated tetrazole filtered off, washed with water and recrystallised from acetic acid, m.p. 267° C. (decomposes).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([F:35])=[C:8]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C@H:16]3[CH2:20][CH2:19][C@:18]4([CH2:24][CH2:23][N:22]([CH3:25])[C:21]4=[O:26])[N:17]3C(OC(C)(C)C)=O)[C:11]=2[CH3:34])[CH:9]=1)[CH3:2].O1CCOCC1>Cl>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([F:35])=[C:8]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C@H:16]3[CH2:20][CH2:19][C@:18]4([CH2:24][CH2:23][N:22]([CH3:25])[C:21]4=[O:26])[NH:17]3)[C:11]=2[CH3:34])[CH:9]=1)[CH3:2]
Reactant: CCOc1ccc(F)c(-c2ccnc([C@H]3CC[C@]4(CCN(C)C4=O)N3C(=O)OC(C)(C)C)c2C)c1
Agent: Cl
Solvent: C1COCCO1
Product: CCOc1ccc(F)c(-c2ccnc([C@H]3CC[C@]4(CCN(C)C4=O)N3)c2C)c1
Yield: 96.7 %

Procedure:
A solution of tert-butyl (2R,5R)-2-[4-(5-ethoxy-2-fluoro-phenyl)-3-methyl-2-pyridyl]-7-methyl-6-oxo-1,7-diazaspiro[4.4]nonane-1-carboxylate (which may be prepared as described in Description 100)(74.2 mg, 0.1500 mmol) in 4M HCl in dioxane (0.38 mL, 1.53 mmol) was stirred for 2 hours. The reaction was then concentrated in vacuo. The residue was loaded onto an SCX cartridge which was eluted with MeOH and 0.5 M methanolic ammonia. The basic fractions were combined and concentrated in vacuo to give (2R,5R)-2-[4-(5-ethoxy-2-fluoro-phenyl)-3-methyl-2-pyridyl]-7-methyl-1,7-diazaspiro[4.4]nonan-6-one (55.6 mg, 0.1450 mmol, 94.524% yield) as a colourless oil (5182RTS331-A1, >95% pure);
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:21])=[C:6]([C@:8]2([CH2:19][F:20])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.[C:22]([C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[N:28][CH:29]=1)#[N:23].C(=O)([O-])[O-].[Cs+].[Cs+].C(C1C=NC=C(B2OC(C)(C)C(C)(C)O2)C=1)#N>C1COCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:18][C:10]1[O:11][C@H:12]([C:14]([F:17])([F:16])[F:15])[CH2:13][C@:8]([C:6]2[CH:7]=[C:2]([C:26]3[CH:27]=[N:28][CH:29]=[C:24]([CH:25]=3)[C:22]#[N:23])[CH:3]=[CH:4][C:5]=2[F:21])([CH2:19][F:20])[N:9]=1
Reactant: NC1=N[C@](CF)(c2cc(Br)ccc2F)C[C@@H](C(F)(F)F)O1
Reactant: N#Cc1cncc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC1(C)OB(c2cncc(C#N)c2)OC1(C)C
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1cncc(-c2ccc(F)c([C@]3(CF)C[C@@H](C(F)(F)F)OC(N)=N3)c2)c1
Temperature: 80 °C
Reaction time: 6 h
Yield: 65.8 %

Procedure:
In a microwave vial a mixture of (4S,6S)-4-(5-bromo-2-fluorophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (8a, 110 mg, 0.295 mmol), 5-cyano-3-pyridinyl boronic acid (43.6 mg, 0.295 mmol), and cesium carbonate (384 mg, 1.179 mmol) in THF (2.0 mL) and water (983 μL) was purged with argon for 5 min. Dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (12.04 mg, 0.015 mmol) was added and the tube was sealed and the mixture was heated at 80° C. overnight. Additional 3-cyanopyridine-5-boronic acid pinacol ester (67.8 mg, 0.295 mmol) and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (12.04 mg, 0.015 mmol) were added. The reaction mixture was stirred at 80° C. for another 6 h. After cooling to room temperature, the reaction mixture was partitioned between EtOAc and water and brine. The aqueous layer was back extracted with EtOAc (2×) and the combined organics was washed with brine, dried (Na2SO4) and concentrated. The crude material was purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 0% to 0% EtOAc in hexane, to provide 5-(3-((4S,6S)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)nicotinonitrile (77 mg, 0.194 mmol, 65.9% yield) as off-white solid. MS m/z=397 [M]+. Calculated for C18H13F5N4O: 396.31.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[C:10]([C:18](O)=[O:19])[C:9]1=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C(Cl)(=O)OCC.[CH2:35]([NH:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]>O1CCCC1>[CH2:42]([N:41]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:18]([C:10]1[C:9](=[O:21])[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:17]2[C:12]([N:11]=1)=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:19])[CH2:43][CH2:44][CH2:45][CH2:46][CH3:47]
Reactant: O=C(O)c1nc2ccccc2n(Cc2ccccc2)c1=O
Reactant: CCCCCCNCCCCCC
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCN(CCCCCC)C(=O)c1nc2ccccc2n(Cc2ccccc2)c1=O
Temperature: -40 °C
Reaction time: 0.17 h

Procedure:
In 30 ml of tetrahydrofuran were dissolved 0.50 g of 1-benzyl-1,2-dihydro-2-oxoquinoxaline-3-carboxylic acid and 0.87 ml of triethylamine, and after cooling to −40° C., 0.19 ml of ethyl chlorocarbonate was added dropwise over 5 minutes. After stirring at −40° C. for 10 minutes, 0.46 ml of dihexylamine was added dropwise over 5 minutes. After stirring at −40° C. for an hour, the temperature was raised to room temperature over an hour, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue, after addition of ethyl acetate, was washed with water, 1N hydrochloric acid, a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (silica gel; Wakogel C200 (manufactured by Wako Pure Chemicals), developing solvent; chloroform) and recrystallized from hexane to give 0.53 g of N,N-dihexyl-1-benzyl-1,2-dihydro-2-oxoquinoxaline-3-carboxamide.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.Cl.[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[N:31][CH:30]=1>O1CCCC1>[CH:13]1([CH2:12][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:28]([C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)=[O:35])=[CH:7][CH:6]=2)[C:9]([OH:11])=[O:10])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C(Cl)c1cccnc1
Reactant: Nc1ccc(C(CC2CCCC2)C(=O)O)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(C(CC2CCCC2)C(=O)O)cc1)c1cccnc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 22.4 %

Procedure:
A solution of 2-(4-amino-phenyl)-3-cyclopentyl-propionic acid (130 mg, 0.56 mmol) in tetrahydrofuran (10 mL) at 25° C. was treated with N,N-diisopropylethylamine (0.23 mL, 1.34 mmol) and nicotinoyl chloride hydrochloride (99 mg, 0.54 mmol). The reaction mixture was stirred at 25° C. for 48 h. At this time, the reaction was concentrated in vacuo. High pressure liquid chromatography (Chromegasphere SI-60, 10 μM, 60 Å, 25 cm×23 cm ID, 90/10 ethyl acetate/heptane) afforded 3-cyclopentyl-2-{4-[(pyridine-3-carbonyl)-amino]-phenyl}-propionic acid (40.9 mg, 21.7%) as a yellow solid: mp 160-163° C.; EI-HRMS m/e calcd for C21H23NO3 (M+) 337.1677, found 337.1670.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[CH:12]2.[Cl:18][CH2:19][CH2:20][CH2:21][C:22](Cl)=[O:23].[OH-].[Na+]>O1CCCC1>[Cl:18][CH2:19][CH2:20][CH2:21][C:22]([NH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[CH:12]2)=[O:23]
Reactant: Nc1ccc2[nH]ncc2c1
Reactant: O=C(Cl)CCCCl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(CCCCl)Nc1ccc2[nH]ncc2c1
Yield: 32 %

Procedure:
Triethylamine (2.1 ml, 15 mmol) was added to a suspension of 5-aminoindazole (1.00 g, 7.51 mmol) in tetrahydrofuran (10 ml) at room temperature, followed by adding thereto a solution of 4-chlorobutyryl chloride (1.16 g, 8.26 mmol) in tetrahydrofuran (5 ml) at 0° C., and the resulting mixture was stirred at 0° C. for 1 hour. Then, a 1N-aqueous sodium hydroxide solution was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was suspended in ethanol and stirred, followed by filtration. The solid collected by the filtration was dried under reduced pressure to obtain 4-chloro-N-(1H-indazol-5-yl)butanamide (572 mg, 32%).
Reaction SMILES: [CH3:1][N:2]1[CH2:18][CH2:17][C:5]2[N:6]([CH2:14][C:15]#[CH:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.Br[C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1.C(N(CC)CC)C>C(#N)C.[Cu]I>[CH3:1][N:2]1[CH2:18][CH2:17][C:5]2[N:6]([CH2:14][C:15]#[C:16][C:21]3[CH:20]=[CH:25][CH:24]=[CH:23][N:22]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Brc1cccnc1
Reactant: C#CCn1c2c(c3cc(C)ccc31)CN(C)CC2
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1ccc2c(c1)c1c(n2CC#Cc2ccccn2)CCN(C)C1
Temperature: 80 °C
Yield: 57.1 %

Procedure:
A mixture of 2,3,4,5-tetrahydro-2,8-dimethyl-5-(prop-2-ynyl)-1H-pyrido[4,3-b]indole (150 mg, 0.6 mmol), 3-bromopyridine (0.6 ml, 0.6 mmol), dichlorobis(triphenyl-phosphine) palladium (8 mg, 0.012 mmol), CuI (1 mg, 0.006 mmol), and triethylamine (0.01 ml 0.071 mmol) in acetonitrile (5 ml) was heated at 80° C. to obtain 108 mg of 2,3,4,5-tetrahydro-2,8-dimethyl-5-(3-(pyridin-2-yl)prop-2-ynyl)-1H-pyrido[4,3-b]indole after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:19])OC2C=CC=CC=2)[N:7]([CH3:20])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH2:34][CH2:35][O:36][CH3:37])[N:29]=[CH:28][N:27]=[C:26]2[O:38][C:39]1[CH:40]=[C:41]([CH:43]=[CH:44][CH:45]=1)[NH2:42].C(N(C(C)C)CC)(C)C>CN(C1C=CN=CC=1)C>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:42][C:41]2[CH:43]=[CH:44][CH:45]=[C:39]([O:38][C:26]3[C:25]4[C:30](=[CH:31][C:32]([O:33][CH2:34][CH2:35][O:36][CH3:37])=[C:23]([O:22][CH3:21])[CH:24]=4)[N:29]=[CH:28][N:27]=3)[CH:40]=2)=[O:19])[N:7]([CH3:20])[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cn1nc(C(C)(C)C)cc1NC(=O)Oc1ccccc1
Reactant: COCCOc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: COCCOc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)nn4C)c3)c2cc1OC

Procedure:
The procedure in 138B was used to react the carbamate from Example 157A (123 mg, 0.45 mmol) with 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)aniline from Example 117B (103 mg, 0.30 mmol). To this solution was added diisopropylethyl amine (78 μL, 0.45 mmol) and DMAP (3.6 mg, 0.03 mmol). The reaction was concentrated to dryness. The resulting oil purified by silica gel chromatography eluting with ethyl acetate/dichloromethane 10-50% over 60 minutes. The main peak concentrated to a solid weighing 126 mg. 1H (DMSO-d6) 9.10 (s, 1H), 8.70 (s, 2H), 7.65 (m, 2H), 7.50 (m, 2H), 7.30 (m, 1H), 7.15 (s, 1H), 6.95 (m, 1H), 6.00 (s, 1H), 4.40 (s, 2H), 4.00 (s, 3H), 3.85 (s, 2H), 3.60 (s, 3H), 3.40 (s, 3H), 1.25 (s, 9H). LCMS (ESI) m/z 521 (M+H)
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=3[CH:25]=O)[CH:8]=2)[N:3]=1.Cl.[CH3:32][C@H:33]1[CH2:37][CH2:36][CH2:35][NH:34]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl.O1CCCC1>[NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:15][C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:22]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=3[CH2:25][N:34]3[CH2:35][CH2:36][CH2:37][C@@H:33]3[CH3:32])[CH:8]=2)[N:3]=1
Reactant: C[C@H]1CCCN1
Reactant: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3ccccc3C=O)ccc2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCCl
Product: C[C@H]1CCCN1Cc1ccccc1-c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Temperature: 40 °C
Reaction time: 6 h

Procedure:
100 mg of 2-[2-amino-4-(1,3-dihydroisoindole-2-carbonyl)quinazolin-6-yl]benzaldehyde are dissolved in 3 ml of 1,2-dichloroethane and 3 ml of tetrahydrofuran. 43 mg of (S)-2-methylpyrrolidine hydrochloride are added, and the mixture is stirred at 40° C. for 6 h. After cooling to 25° C., 113 mg of sodium triacetoxyborohydride are added and stirred at 25° C. for a further 12 h. The mixture is poured into water, extracted three times with dichloromethane, and the combined organic phases are dried over sodium sulfate. After filtration, the filtrate is evaporated to dryness and purified by chromatography (reversed phase HPLC).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][C:13]([O:20]C)=[C:14]([C:17]([OH:19])=[O:18])[CH:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.B(Br)(Br)Br.O>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][C:13]([OH:20])=[C:14]([C:17]([OH:19])=[O:18])[CH:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2[nH]nc(-c3cccc(F)c3)c2cc1C(=O)O
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: O=C(O)c1cc2c(-c3cccc(F)c3)n[nH]c2cc1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 91.9 %

Procedure:
A total of 96.2 mg of 3-(3-fluoro-phenyl)-6-methoxy-1H-indazole-5-carboxylic acid obtained in Production Example II-1-e was dissolved in 3.36 ml of dichloromethane, 4.0 ml of a 1.0 M solution of boron tribromide in dichloromethane was added under ice-cooling, and the mixture was stirred at room temperature for 1.5 hours. Water was added to the reaction mixture, followed by extracting with ethyl acetate. The resulting organic layer was washed brine, dried over magnesium sulfate and the solvent was evaporated, to give 84.1 mg of the crude product of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH:7]([NH2:28])[C@H:8]([C:22]([O:24][CH2:25][CH:26]=[CH2:27])=[O:23])[CH:9]([C:11]1[O:12][C:13]2[CH:19]=[C:18](Cl)[CH:17]=[C:16]([F:21])[C:14]=2[N:15]=1)[OH:10])([CH3:4])([CH3:3])[CH3:2].ClC1C=C([F:40])C2N=COC=2C=1.FC1C2N=COC=2C=C(F)C=1>>[C:1]([O:5][C:6](=[O:29])[CH:7]([NH2:28])[C@H:8]([C:22]([O:24][CH2:25][CH:26]=[CH2:27])=[O:23])[CH:9]([C:11]1[O:12][C:13]2[CH:19]=[C:18]([F:40])[CH:17]=[C:16]([F:21])[C:14]=2[N:15]=1)[OH:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCOC(=O)[C@@H](C(N)C(=O)OC(C)(C)C)C(O)c1nc2c(F)cc(Cl)cc2o1
Reactant: Fc1cc(Cl)cc2ocnc12
Agent: Fc1cc(F)c2ncoc2c1
Product: C=CCOC(=O)[C@@H](C(N)C(=O)OC(C)(C)C)C(O)c1nc2c(F)cc(F)cc2o1

Procedure:
Compound 717 was prepared as described for compound 714, except compound 713 was replaced with compound 716. ##STR96##
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:38])[N:5]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:6]([CH:12]([O:14][C:15]1[N:23]=[CH:22][N:21]=[C:20]3[C:16]=1[N:17]=[CH:18][N:19]3COCC[Si](C)(C)C)[CH3:13])=[N:7]2>CO.Cl>[CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:38])[N:5]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:6]([CH:12]([O:14][C:15]1[N:23]=[CH:22][N:21]=[C:20]3[C:16]=1[N:17]=[CH:18][NH:19]3)[CH3:13])=[N:7]2
Reactant: Cc1cccc2nc(C(C)Oc3ncnc4c3ncn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: Cl
Solvent: CO
Product: Cc1cccc2nc(C(C)Oc3ncnc4[nH]cnc34)n(-c3ccccc3)c(=O)c12
Temperature: 40 °C

Procedure:
Compound 182 (0.053 g, 0.1 mmol) was dissolved in a mixture of methanol (2 mL) and 4M HCl (2 mL). The mixture was stirred and heated to 40° C. for 3 h. The reaction mixture was removed from the heat source and allowed to cool. The reaction mixture was then filtered through a plug of GFA (glass fiber) filter paper and the filtrate concentrated to only remove the methanol. The residue was adjusted to pH 10 by addition of 10% potassium carbonate solution. The resulting solid was collected by filtration and purified by RP-HPLC (C18 Luna column, 10×250 mm, 4.7 mL/min, 10-90% CH3CN in water in 18 min, with all solvents containing 0.05% formic acid) to give compound 176 as a fluffy white solid after lyophilization. 1H NMR (400 MHz, d6-DMSO) δ 13.40, br s, 1H, 8.40, s, 1H, 8.35, s, 1H, 7.66, t, J=7.8 Hz, 1H, 7.48-7.58, m, 4H, 7.31-7.36, m, 2H, 7.20-7.23, m, 1H, 5.65, q, J=6.6 Hz, 1H, 2.73, s, 3H, 1.65, d, J=6.6 Hz, 3H. ESI-MS m/z=399 (MH+). The reaction described above and compound 176 are shown below.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([NH2:9])[N:3]=1.C(O)(=[O:12])C.OO>O1CCCC1>[NH2:9][C:4]1[N:3]([OH:12])[C:2](=[NH:1])[N:7]=[C:6]([Cl:8])[CH:5]=1
Reactant: Nc1cc(Cl)nc(N)n1
Reactant: CC(=O)O
Agent: OO
Solvent: C1CCOC1
Product: N=c1nc(Cl)cc(N)n1O
Reaction time: 4 h
Yield: 63 %

Procedure:
1.5 g (10 mmoles) of 2,6-diamino-4-chloropyrimidine are dissolved in 20 ml of anhydrous tetrahydrofuran. A mixture of 10 ml of acetic acid and 2 ml of a 70% aqueous hydrogen peroxide solution is added in 30 minutes under stirring and reflux. The reaction mixture is boiled for four hours, evaporated in vacuo to third of its volume, and a 40% aqueous sodium hydroxide solution is added to the residue until reaching a pH value of 8. The mixture is allowed to stand in refrigerator for a night. The crystals are filtered, washed with water and dried. In this way 1.0 g (63%) of the aimed compound is obtained.
Reaction SMILES: [C-:1]#[N:2].[K+].Br[CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)=[O:7].C(O)(=O)C>C(O)C.O.ClCCl>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:6](=[O:7])[CH2:5][C:1]#[N:2])=[CH:9][CH:10]=1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: N#CCC(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 5.58 g (86 mmole) of potassium cyanide and 1 mL of water was added in one portion to a solution of 8.0 g (34.3 mmole) of α-bromo-p-chloroacetophenone in 50 mL of 95% ethanol. The mixture was stirred at room temperature for 5 hours, then diluted with water and dichloromethane and acidified with acetic acid. The organic layer was washed with brine. The aqueous layers were extracted with dichloromethane. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give crude 3-(4-chloro-phenyl)-3-oxo-propionitrile which was used in next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17]CC3C=CC=CC=3)=[CH:14][CH:15]=2)[C:10]([NH:25][C:26](=[O:53])[C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]3)=[CH:29][C:28]=2[N:40]([CH:47]2[CH2:52][CH2:51][O:50][CH2:49][CH2:48]2)[C:41](=[O:46])[C:42]([F:45])([F:44])[F:43])=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1CCCCC=1>O1CCOCC1.[Pd]>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[C:10]([NH:25][C:26](=[O:53])[C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]3)=[CH:29][C:28]=2[N:40]([CH:47]2[CH2:52][CH2:51][O:50][CH2:49][CH2:48]2)[C:41](=[O:46])[C:42]([F:43])([F:44])[F:45])=[N:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1CCN(c2ccc(C(=O)Nc3nn(C(=O)OC(C)(C)C)c4ccc(OCc5ccccc5)cc34)c(N(C(=O)C(F)(F)F)C3CCOCC3)c2)CC1
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: C1COCCO1
Product: CN1CCN(c2ccc(C(=O)Nc3nn(C(=O)OC(C)(C)C)c4ccc(O)cc34)c(N(C(=O)C(F)(F)F)C3CCOCC3)c2)CC1
Yield: 95 %

Procedure:
5-Benzyloxy-3-{4-(4-methyl-piperazin-1-yl)-2-[(tetrahydro-pyran-4-yl)-(2,2,2-trifluoro-acetyl)-amino]-benzoylamino}-indazole-1-carboxylic acid tert-butyl ester (2.3 g, 3.13 mmol) in dioxane (46 mL) was treated with cyclohexene (18 mL) and 10% Pd/C (1.6 g). The mixture was stirred at reflux temperature. After 1.5 hs it was filtered over a celite funnel and washed with dioxane. Evaporation of the solvent left a solid that was washed with Et2O. After drying at 45° C. under vacuum, 1.92 g of title compound in 95% yield were obtained.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=2)[CH2:10][N:11]=[C:12]=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][N:18]([CH3:20])[NH2:19].C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH3:17][N:18]([CH3:20])[NH:19][C:12]([NH:11][CH2:10][C:9]1[CH:14]=[CH:15][CH:16]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]=1)=[O:13]
Reactant: O=C=NCc1cccc(-c2ccccc2)c1
Reactant: CN(C)N
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CN(C)NC(=O)NCc1cccc(-c2ccccc2)c1
Reaction time: 1.5 h
Yield: 42.5 %

Procedure:
To a solution of 2.56 g of this crude 3-phenylbenzylisocyanate in 8 ml of toluene was added dropwise 0.78 g (13 mmol) of N,N-dimethylhydrazine with ice-cooling. The mixture was removed from an ice bath and stirred for 1.5 hours. The reaction mixture was concentrated and the residue was subjected to silica gel column chromatography (eluted with n-hexane:ethyl acetate=1:1 and then 1:2) to obtain 1.40 g (5.20 mmol) of 1,1-dimethyl-4-(3-phenylbenzyl)semicarbazide.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]([C:10]2[CH:11]=[C:12]([CH3:16])[CH:13]=[CH:14][CH:15]=2)=O)=[CH:3][CH:2]=1.Cl.O([NH2:20])C>FC(F)(F)C(O)=O.[Pd]>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH:8]([NH2:20])[C:10]2[CH:11]=[C:12]([CH3:16])[CH:13]=[CH:14][CH:15]=2)=[CH:3][CH:2]=1
Reactant: Cc1cccc(C(=O)Cc2ccncc2)c1
Reactant: CON
Agent: [Pd]
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(C(N)Cc2ccncc2)c1
Reaction time: 14 h

Procedure:
The intermediate oxime was prepared from 2-pyridin-4-yl-1-m-tolyl-ethanone (crude) and methoxylamine hydrochloride (8.00 g, 95.78 mmol) according to the protocol described in general procedure B. The oxime was then dissolved in trifluoroacetic acid (30.00 mL) and Pd/C (0.80 g) was added. The reaction mixture was hydrogenated under 50 psi for 14 hours, then filtered and concentrated. The residue was basified with 5M sodium hydroxide and extracted with methylene chloride. The combined organic phases were dried over potassium carbonate and concentrated to yield the title compound. Spectroscopic data: 1H NMR (300 MHz, DMSO-d6) δ ppm 2.27 (s, 3H) 2.89 (d, J=7.04 Hz, 2 H) 4.12 (t, 1 H) 7.10-7.22 (m, 1 H) 7.39 (ddd, J=7.77, 4.25, 1.47 Hz, 2 H) 7.75-7.82 (m, 1H) 8.41 (td, J=4.98, 2.05 Hz, 2 H) 8.58 (dd, J=5.86, 1.76 Hz, 2 H).