Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([OH:11])=O)[CH:2]=1.ON1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:35][CH2:36][CH2:37][CH2:38][OH:39]>O1CCCC1.O1CCOCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([NH:35][CH2:36][CH2:37][CH2:38][OH:39])=[O:11])[CH:2]=1
Reactant: NCCCO
Reactant: O=C(O)C=Cc1cccnc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: O=C(C=Cc1cccnc1)NCCCO
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.5 %

Procedure:
A mixture of 4.5 g of 3-(3-pyridyl)acrylic acid, 3.5 g of N-hydroxysuccinimide, 6.8 g of dicyclohexylcarbodiimide, and 80 ml of dioxane is stirred at room temperature overnight. The reaction mixture is filtered, and the filtrate is concentrated to give a brown oil. The product is dissolved in 100 ml of tetrahydrofuran, and 2.3 g of 3-amino-1-propanol is added. The mixture is stirred at room temperature overnight and concentrated. The residue is chromatographed on silica gel with chloroform-methanol (30:1) to give 4.2 g of N-[3-(3-pyridyl)acryloyl]-3-amino-1-propanol. The product is converted into the hydrochloride with 35 w/v % ethanolic hydrogen chloride. To the hydrochloride is added 4.6 g of thionyl chloride, and the mixture is stirred at 100° C. for 2 hours. The remaining thionyl chloride is distilled off, and 50 ml of water is added. The resulting solution is neutralized with 10% aqueous sodium carbonate solution and extracted with three 50-ml portions of chloroform. The combined extracts are dried over magnesium sulfate, and the chlorofom is distilled off. The residue is chromatographed on silica gel with chloroform-methanol (30:1) to give 3.2 g of N-[3-(3-pyridyl)acryloyl]-3-amino-1-chloropropane.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH2:16])=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Cl:8][C:4]1[N:3]=[C:2]([NH:16][CH2:15][C:14]2[CH:17]=[CH:18][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)[CH:7]=[N:6][CH:5]=1
Reactant: Clc1cncc(Cl)n1
Reactant: COc1ccc(CN)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CNc2cncc(Cl)n2)cc1
Reaction time: 12 h
Yield: 74.7 %

Procedure:
To a solution of 2,6-dichloropyrazine (4.00 g, 26.8 mmol) and 4-methoxybenzylamine (7.02 mL, 53.7 mmol) in DMF (30 mL) was added K2CO3 (7.42 g, 53.7 mmol) at RT and the reaction mixture was stirred for 12 h. The reaction mixture was diluted with cold water (100 mL) and extracted into ethyl acetate (2×50 mL). The combined organic layer was dried over sodium sulfate, filtered and evaporated under reduced pressure to give a residue that was purified by CombiFlash (REDISEP®, silica gel, 24 g, 25% EtOAc/petroleum ether) to give 6-chloro-N-(4-methoxybenzyl)pyrazin-2-amine (5.00 g, 74.6%). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.31 (s, 3H), 4.37 (d, J=6.0 Hz, 2H), 6.87-6.93 (m, 2H), 7.24-7.31 (m, 2H), 7.70 (s, 1H), 7.90 (s, 1H), 7.95 (t, J=5.5 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:10][C@@H:11]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].I[CH2:41][CH2:42][CH2:43][F:44]>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:10][C@@H:11]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:41][CH2:42][CH2:43][F:44])=[CH:22][CH:21]=1)[C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: FCCCI
Reactant: CC(C)(C)OC(=O)N[C@H](C[C@@H](Cc1ccc(O)cc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](C[C@@H](Cc1ccc(OCCCF)cc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 100 °C

Procedure:
To 140 mg (0.30 mmol) of di-tert-butyl (4R)—N-(tert-butoxycarbonyl)-4-(4-hydroxy-benzyl)-D-glutamate in 5 mL N,N-dimethylformamide were added 42 mg (0.3 mmol) of powdered potassium carbonate and 56 mg (0.30 mmol) of 1-iodo-3-fluoropropane (ABCR GmbH, Germany) and the resulting suspension was heated for 2 h at 100° C. in a microwave oven. The reaction mixture was then filtered, the solvent evaporated and the residue was taken up in ethyl acetate and water. The organic phase was separated off, washed with water until neutral, dried over sodium sulfate and filtered, and the filtrate was concentrated in vacuo. The crude product obtained in this manner was chromatographed on silica gel using a dichloromethane/methanol gradient, and the appropriate fractions were combined and concentrated.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13]C)[CH:8]=2)[S:4][C:3]=1[C:15]([NH2:17])=[O:16].C[Si]([N:22]=[C:23]=[O:24])(C)C.CN(C)C=O>ClCCl>[NH2:22][C:23]([NH:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([OH:13])[CH:8]=2)[S:4][C:3]=1[C:15]([NH2:17])=[O:16])=[O:24]
Reactant: C[Si](C)(C)N=C=O
Reactant: COc1cccc(-c2cc(N)c(C(N)=O)s2)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: NC(=O)Nc1cc(-c2cccc(O)c2)sc1C(N)=O
Reaction time: 72 h

Procedure:
3-Amino-5-(3-methoxyphenyl)-2-thiophenecarboxamide (0.5 g), trimethylsilylisocyanate (2 mL), dimethylformamide (2 mL) and dichloromethane were heated at reflux for 3 days. After cooling the solid was filtered off, suspended in dichloromethane (100 mL) and treated with boron tribromide (5 mL of a 1M solution in dichloromethane). After 3 days. methanol (50 mL) was added. After 1 h, the solvent was evaporated and the residue was triturated with 2M hydrochloric acid. The title urea was filtered off (0.35 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][NH:14][CH:15]([CH3:17])[CH3:16])[C@H:10]([C:18]([CH3:26])([CH3:25])[O:19][SiH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][O:28][CH2:29][CH2:30][CH2:31][N:32]1[C:40]2[C:35](=[CH:36][CH:37]=[C:38]([C:41](O)=[O:42])[CH:39]=2)[C:34]([CH3:44])=[CH:33]1.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:15]([CH3:16])[CH3:17])[C:41]([C:38]2[CH:39]=[C:40]3[C:35]([C:34]([CH3:44])=[CH:33][N:32]3[CH2:31][CH2:30][CH2:29][O:28][CH3:27])=[CH:36][CH:37]=2)=[O:42])[C@H:10]([C:18]([CH3:26])([CH3:25])[O:19][SiH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCCn1cc(C)c2ccc(C(=O)O)cc21
Reactant: CC(C)NC[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1C(C)(C)O[SiH2]C(C)(C)C
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCCn1cc(C)c2ccc(C(=O)N(C[C@@H]3CN(C(=O)OC(C)(C)C)C[C@H]3C(C)(C)O[SiH2]C(C)(C)C)C(C)C)cc21
Reaction time: 3 h

Procedure:
A mixture of (3S,4R)-3-(tert-butyl-dimethyl-silanyloxymethyl)-4-(isopropylamino-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (8.5 g, 22 mmol), 1-(3-methoxy-propyl)-3-methyl-1H-indole-6-carboxylic acid (7.6 g, 30.8 mmol), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (7.84 g, 30.8 mmol) and triethylamine (12.3 mL, 88 mmol) in CH2Cl2 (425 mL) is refluxed overnight under a nitrogen atmosphere and then quenched by the addition of an aqueous saturated solution of NaHCO3. The organic layer is separated, and the aqueous phase is extracted 3 times with AcOEt. The combined organic extracts are concentrated in vacuo. The residual oil is taken up in a mixture of THF and MeOH, NaOH 1N is added to cleave the anhydride side product and the mixture stirred for 3 h. The solvents are concentrated, CH2Cl2 is added and the layers are separated. The aqueous one is then back extracted twice with CH2Cl2 and the combined organic extracts are washed with brine, dried over Na2SO4, filtered and concentrated. The crude product is used in the next step without further purification. TLC, Rf (AcOEt)=0.6. MS (LC-MS): 516.3 [M-Boc+H]+; tR (HPLC, Macherey-Nagel Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN an H2O containing 0.1% TFA, flow: 1.5 mL/min): 8.60 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[C:16]([CH2:17][OH:18])=[N:15][O:14][N:13]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[F:8].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(Cl)Cl>C(=O)(O)[O-].[Na+]>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[C:16]([CH:17]=[O:18])=[N:15][O:14][N:13]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(Nc1ccc(F)c(Cl)c1)c1nonc1CO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=Cc1nonc1C(=O)Nc1ccc(F)c(Cl)c1

Procedure:
A solution of N-(3-chloro-4-fluorophenyl)-4-(hydroxymethyl)-1,2,5-oxadiazole-3-carboxamide (8.50 g, 31.3 mmol), Dess-Martin periodinane (14.6 g, 34.4 mmol) and DCM (400 mL) was stirred at 25° C. for 3 h. The reaction was diluted with a saturated sodium bicarbonate solution and extracted with ethyl acetate three times, dried with sodium sulfate, filtered, and concentrated in vacuo.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][OH:12])[N:6]=1)=[O:4].O>ClCCCl.[O-2].[O-2].[Mn+4]>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]=[O:12])[N:6]=1)=[O:4]
Reactant: COC(=O)c1cccc(CO)n1
Agent: [Mn+4]
Agent: [O-2]
Solvent: O
Solvent: ClCCCl
Product: COC(=O)c1cccc(C=O)n1
Yield: 79 %

Procedure:
A solution of 3 g of 6-hydroxymethylpyridine-2-carboxylic acid methyl ester (16.5 mmol) in 70 ml of 1,2-dichloroethane containing 15 g of manganese dioxide (165 mmol) is heated under reflux for 4 hours with removal of the water formed continuously. The solid is removed by filtration on celite and then the dichloromethane is evaporated off. The title product is isolated by chromatography on a silica column (eluent: dichloromethane/ethyl acetate; 70:30). 2.33 g of a yellow oil are recovered.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[CH:4][CH:3]=1.C1C(=O)N([Br:28])C(=O)C1.CCOC(C)=O>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[CH:4][C:3]=1[Br:28]
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](c2ccc(N)cc2)C1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCO[C@H](c2ccc(N)c(Br)c2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.3 %

Procedure:
To a stirred solution of tert-butyl (R)-2-(4-aminophenyl)morpholine-4-carboxylate (3.2 g, CAS 1260220-42-5) in DMF (25 ml) was added NBS (2.05 g) and the mixture was stirred at room temperature for 30 min. The reaction mixture was then poured into EtOAc and extracted sequentially with water and with saturated brine. The organic layer was dried over Na2SO4 and then concentrated in vacuo. The residue was purified by column chromatography (SiO2, gradient: 0% to 70% EtOAc in heptanes) to give tert-butyl (R)-2-(4-amino-3-bromophenyl)morpholine-4-carboxylate (3.71 g, 90%) as an off-white solid. MS (ISP): 359.1 ([{81Br}M+H]+), 357.0 ([{79Br}M+H]+), 303.0 ([{81Br}M+H—C4H8]+), 301.0 ([{79Br}M+H—C4H8]+).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:17])=O>>[F:1][C:2]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:17])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c(F)c1
Product: CS(=O)(=O)c1ccc(C(=O)Cl)c(F)c1

Procedure:
A mixture of 2-fluoro-4-methylsulphonylbenzoic acid (6.0 g) and thionyl chloride were stirred and heated at reflux for 2 hours. The mixture was cooled and evaporated to dryness. Toluene was added and the solvent re-evaporated to 1.5 give 2-fluoro4-methylsulphonylbenzoyl chloride (6.5 g) as a brown solid which was not further purified.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:19]=[CH:18][C:7]([CH2:8][CH:9]([C:14]([O:16][CH3:17])=[O:15])[C:10]([O:12][CH3:13])=[O:11])=[CH:6][C:5]=1[CH2:20][OH:21])[CH3:2].[F:22][C:23]([F:34])([F:33])[C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1>>[CH2:1]([O:3][C:4]1[CH:19]=[CH:18][C:7]([CH2:8][CH:9]([C:14]([O:16][CH3:17])=[O:15])[C:10]([O:12][CH3:13])=[O:11])=[CH:6][C:5]=1[CH2:20][O:21][C:31]([NH:30][C:27]1[CH:26]=[CH:25][C:24]([C:23]([F:22])([F:33])[F:34])=[CH:29][CH:28]=1)=[O:32])[CH3:2]
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: CCOc1ccc(CC(C(=O)OC)C(=O)OC)cc1CO
Product: CCOc1ccc(CC(C(=O)OC)C(=O)OC)cc1COC(=O)Nc1ccc(C(F)(F)F)cc1

Procedure:
Using dimethyl 2-[4-ethoxy-3-(hydroxymethyl)benzyl]-malonate and α,α,α-trifluoro-p-tolylisocyanate, the title compound was obtained in the same manner as described in Example 192b).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11]Cl)=[CH:7][N:6]=1)[CH3:3].[NH2:13][CH2:14][CH2:15][CH2:16][NH2:17].[OH-].[Na+]>O>[CH2:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:13][CH2:14][CH2:15][CH2:16][NH2:17])=[CH:7][N:6]=1)[CH3:3]
Reactant: NCCCN
Reactant: CCOc1ccc(CCl)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOc1ccc(CNCCCN)cn1
Yield: 65.2 %

Procedure:
2-Ethoxy-5-pyridylmethyl chloride hydrochloride (9.6 g) in an aqueous solution was added dropwise to the mixed solution of trimethylenediamine (11.1 g) and 20% aqueous solution (22 g) of sodium hydroxide at 0°-5° C. After the reaction mixture was stirred at room temperature for some time, water and excess trimethylenediamine were distilled off under reduced pressure from the contents and after the inorganic salts were filtered off, the produced viscous and oily substance was evaporated in vaccum to give N-(2-ethoxy-5-pyridylmethyl) trimethylenediamine (6.3 g). b.p. 134°-135° C./0.08 mmHg ##STR23##
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11](=O)[CH3:12])[C:8]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.C([O-])(=O)C.[NH4+].C([BH3-])#[N:27].[Na+]>CO.C(#N)C>[Cl:1][C:2]1[CH:10]=[C:9]([CH:11]([NH2:27])[CH3:12])[C:8]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2
Reactant: CC(=O)c1cc(Cl)c2cn[nH]c2c1-c1cccc(F)c1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: CC(N)c1cc(Cl)c2cn[nH]c2c1-c1cccc(F)c1
Temperature: 65 °C
Yield: 99.9 %

Procedure:
A mixture of 1-[4-chloro-7-(3-fluorophenyl)-1H-indazol-6-yl]ethanone (2.365 g, 8.192 mmol), ammonium acetate (6.31 g, 81.9 mmol) and sodium cyanoborohydride (1.03 g, 16.4 mmol) in methanol (30 mL) and acetonitrile (30 mL) was heated at 65° C. overnight, in a sealed tube. The mixture was then cooled to room temperature and quenched with sat. sodium bicarbonate and then extracted with dichloromethane. The combined extracts were dried over magnesium sulfate and evaporated to dryness to give the crude product (2.37 g). LCMS calculated for C15H11ClFN2 (M−NH2)+: m/z=273.1; Found: 273.0.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[H][H]>C(OCC)(=O)C.[Pd]>[NH2:11][C:8]1[CH:9]=[CH:10][C:2]([F:1])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1F
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(F)c(C(=O)O)c1
Yield: 102.3 %

Procedure:
111 g of 2-fluoro-5-nitrobenzoic acid was dissolved in 1 liter of ethyl acetate. To this solution was added 5 g of 5 percent palladium on charcoal. The mixture was hydrogenated on a Parr apparatus for 24 hours at 20° C. at 50 psi of hydrogen. The theoretical amount of hydrogen was absorbed. The solution was filtered, then evaporated to dryness to provide a tan residue of 95.2 g of 5-amino-2-fluorobenzoic acid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]#[N:9])[CH:2]=1.Br[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]>>[CH2:15]([O:14][C:12](=[O:13])[CH2:11][C:7]([C:8]#[N:9])([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH3:16]
Reactant: CCOC(=O)CBr
Reactant: N#CCc1cccnc1
Product: CCOC(=O)CC(C#N)(CC(=O)OCC)c1cccnc1

Procedure:
Prepare by the method of example 1.1.2 using pyridin-3-yl-acetonitrile (0.161 mol) and ethyl bromoacetate (0.325 mol). Chromatograph on silica gel to give the title compound.
Reaction SMILES: [OH:1][C@H:2]1[CH2:5][C@H:4]([CH:6]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[C:28]5[C:23](=[CH:24][C:25]([F:29])=[CH:26][CH:27]=5)[N:22]([CH3:30])[N:21]=4)[N:18]=3)[N:13]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:12]=2)=[O:10])[CH3:7])[CH2:3]1.C(N(CC)CC)C.[CH3:46][S:47](Cl)(=[O:49])=[O:48]>C(Cl)Cl>[F:29][C:25]1[CH:24]=[C:23]2[C:28]([C:20]([C:17]3[N:18]=[C:19]4[C:11]([C:9]([NH:8][CH:6]([C@H:4]5[CH2:3][C@H:2]([O:1][S:47]([CH3:46])(=[O:49])=[O:48])[CH2:5]5)[CH3:7])=[O:10])=[CH:12][N:13]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:37])([CH3:36])[CH3:38])[C:14]4=[N:15][CH:16]=3)=[N:21][N:22]2[CH3:30])=[CH:27][CH:26]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)[C@H]1C[C@H](O)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)[C@H]1C[C@H](OS(C)(=O)=O)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a partial suspension of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [1-(trans-3-hydroxy-cyclobutyl)-ethyl]-amide (85 mg, 0.16 mmol) in CH2Cl2 (3 mL) at 0° C. was added triethylamine (33 μL, 0.24 mmol) followed by methanesulfonyl chloride (14 μL, 0.18 mmol). The reaction mixture was stirred at 0° C. for 1 h then quenched with water and extracted with CH2Cl2. The organics were dried over MgSO4 and concentrated to give methanesulfonic acid trans-3-(1-{[2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbonyl]-amino}-ethyl)-cyclobutyl ester as an off-white foam which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C1C(=O)N([Br:18])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>ClC1C=CC=CC=1>[Br:18][CH2:10][C:9]1[C:2]([Cl:1])=[C:3]([CH:6]=[CH:7][CH:8]=1)[C:4]#[N:5]
Reactant: Cc1cccc(C#N)c1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: Clc1ccccc1
Product: N#Cc1cccc(CBr)c1Cl
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A soln. of 2-chloro-3-methylbenzonitrile (6.6 mmol) in 25 mL chlorobenzene was heated to 50° C. when NBS (7.9 mmol) was added. The flask was purged with Ar before AIBN (0.66 mmol) was added at once still at 50° C. The reaction mixture was stirred at 80° C. for 2 h. The solvent was evaporated off, the resulting residue was redissolved in Et2O and washed 3 times with 1N HCl soln. and brine. It was dried over MgSO4 and conc. in vacuo. Purification with CC (0-15% EtOAc/Hept) gives the desired compound as white solid.
Reaction SMILES: C([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH:13]([CH3:15])[CH3:14])[CH:11]=2)[C:6](=[O:16])[CH:5]=[C:4]1[C:17]([OH:19])=[O:18])C.[OH-].[Na+]>>[CH3:15][CH:13]([C:10]1[CH:11]=[C:12]2[C:7]([C:6](=[O:16])[CH:5]=[C:4]([C:17]([OH:19])=[O:18])[NH:3]2)=[CH:8][CH:9]=1)[CH3:14]
Reactant: CCn1c(C(=O)O)cc(=O)c2ccc(C(C)C)cc21
Agent: [Na+]
Agent: [OH-]
Product: CC(C)c1ccc2c(=O)cc(C(=O)O)[nH]c2c1
Yield: 84.8 %

Procedure:
Treatment of ethyl 7-(1-methylethyl)-4-oxo-1,4-dihydroquinoline-2-carboxylic acid (0.5 g) with sodium hydroxide (0.308 g), as described in Example 1c, gave 7-(1-methylethyl)-4-oxo-1,4-dihydroquinoline-2-carboxylic acid (0.378 g), mp>240° C., δ (360 MHz, DMSO-d6) 1.25 (6H, d, (CH3)2), 2.98 (1H, m, CH), 6.58 (1H, s, 3-H), 7.27 (1H, dd, 6-H), 7.82 (1H, s, 8-H) and 8.00 (1H, d, 5-H), (Found: C, 67.40; H, 5.63; N, 6.44%. C13H13NO3 requires C, 67.52; H, 5.67; N, 6.06%).
Reaction SMILES: [C:1]([N:9]1[CH2:21][CH2:20][C:19]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11]=2[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:24]([O:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36]Cl)=[CH:34][CH:33]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>CN(C=O)C>[C:1]([N:9]1[CH2:21][CH2:20][C:19]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([CH2:36][C:35]3[CH:38]=[CH:39][C:32]([O:31][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:33][CH:34]=3)[C:11]=2[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)N1CCc2c([nH]c3ccccc23)C1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1ccccc1)N1CCc2c(n(Cc3ccc(OCc4ccccc4)cc3)c3ccccc23)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97.1 %

Procedure:
To a stirred solution of 2-benzoyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole (17.75 g, 58.0 mmole) in dry DMF (75 mL) at 5° C. was added 60% NaH (2.78 g, 69.6 mmole). After 10 min, 4-benzyloxybenzyl chloride (14.85 g, 63.8 mmole) was added and the reaction was allowed to warm to RT and stir for 12 hr. The reaction contents were poured into H2O (150 mL) and extracted with EtOAc (2×150 mL). The combined organic phases were washed sequentially with H2O and brine, then were dried over Na2SO4. Concentration under reduced pressure and purification on silica (hexanes/EtOAc, 1:1) afforded the title compound (26.61 g, 97%) as a white solid: MS (ES) m/e 473 (M+H)+.
Reaction SMILES: FC(F)(F)S(OC1C=CC2[C:31]3[C:19](=[CH:20][C:21]4[N:22]([CH2:32][CH3:33])[C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:28]=5[C:29]=4[CH:30]=3)C3C(=CC=CC=3)C=2C=1)(=O)=O.[C:36]1(B(O)O)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C([O-])([O-])=O.[Na+].[Na+].O>C1(C)C=CC=CC=1.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>[CH2:32]([N:22]1[C:21]2[CH:20]=[C:19]3[C:37]4[C:36]([C:20]5[CH:21]=[C:29]([C:28]6[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=6)[CH:30]=[CH:31][C:19]=5[C:31]3=[CH:30][C:29]=2[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]1=2)=[CH:41][CH:40]=[CH:39][CH:38]=4)[CH3:33]
Reactant: CCn1c2ccccc2c2cc3c4ccc(OS(=O)(=O)C(F)(F)F)cc4c4ccccc4c3cc21
Reactant: OB(O)c1ccccc1
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: Cc1ccccc1
Product: CCn1c2ccccc2c2cc3c4ccc(-c5ccccc5)cc4c4ccccc4c3cc21
Reaction time: 5 h
Yield: 135.9 %

Procedure:
10.0 g (20.28 mmol) of 10-ethyl-10H-phenanthro[9,10-b]carbazol-3-yl trifluoromethanesulfonate synthesized in Synthetic Example 9, 3.71 g (30.42 mmol) of phenylboronic acid, and 0.23 g (0.20 mmol) of Pd(PPh3)4 were dissolved in 150 ml of toluene, and 4.30 g (40.56 mmol) of Na2CO3 was put into 50 ml of distilled water, and then refluxed and agitated for 5 hours. After the reaction was finished, extraction was performed by dichloromethane, filtering was performed by silica gel, and the column was used at a ratio of Hexane:MC=7:3 (v/v) to obtain 5.81 g of 10-ethyl-3-phenyl-10H-phenanthro[9,10-b]carbazole (yield 68%).
Reaction SMILES: Cl.[C:2]([N:5]([CH2:37][C:38]1[CH:43]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:41]=[C:40]([C:48]([F:51])([F:50])[F:49])[CH:39]=1)[CH:6]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][CH:16]([CH3:18])[CH3:17])=[O:14])[C:8]2[CH:19]=[C:20]([N:23]=C(C3C=CC=CC=3)C3C=CC=CC=3)[CH:21]=[CH:22][C:7]1=2)(=[O:4])[CH3:3]>O1CCCC1.C(OCC)(=O)C>[C:2]([N:5]([CH2:37][C:38]1[CH:39]=[C:40]([C:48]([F:51])([F:50])[F:49])[CH:41]=[C:42]([C:44]([F:47])([F:45])[F:46])[CH:43]=1)[CH:6]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][CH:16]([CH3:18])[CH3:17])=[O:14])[C:8]2[CH:19]=[C:20]([NH2:23])[CH:21]=[CH:22][C:7]1=2)(=[O:4])[CH3:3]
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc(N=C(c3ccccc3)c3ccccc3)ccc21
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc(N)ccc21
Reaction time: 3 h
Yield: 74.8 %

Procedure:
Add 2 N hydrochloric acid (0.19 mL) to a solution of isopropyl 5-[acetyl-(3,5-bistrifluoromethylbenzyl)amino]-8-(benzhydrylideneamino)-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (0.520 g, 0.747 mmol) in tetrahydrofuran (5 mL) at room temperature and stir for 3 h. Dilute the mixture with ethyl acetate (20 mL) and wash with saturated sodium bicarbonate solution and brine (10 mL each), then dry the organic layer over sodium sulfate, filter and remove the solvent under reduced pressure. Purify the residue using chromatography on silica gel, eluting with hexanes/ethyl acetate (1:1), to provide the title compound as an off-white solid (0.297 g, 75%): 530 (M−H).