Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].Cl.C(C1C=CC(OC)=C(C=1)C[NH:12][C@@H:13]1[C@H:18]([CH:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:17]2[CH2:32][CH2:33][C@H:14]1[C@@H:15]([C:34]([OH:36])=[O:35])[CH2:16]2)(C)C>O.[Pd]>[ClH:1].[ClH:1].[NH2:12][C@@H:13]1[C@H:18]([CH:19]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:17]2[CH2:32][CH2:33][C@H:14]1[C@@H:15]([C:34]([OH:36])=[O:35])[CH2:16]2
Reactant: COc1ccc(C(C)C)cc1CN[C@H]1[C@H]2CCN(C[C@@H]2C(=O)O)[C@H]1C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: O
Product: N[C@H]1[C@H]2CCN(C[C@@H]2C(=O)O)[C@H]1C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 111.4 %

Procedure:
A mixture of (3R,4S,5S,6S)-5-(5-isopropyl-2-methoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxylic acid dihydrochloride (500 mg, 0.88 mmol) and Pd-C (10%, 500 mg) in water (20 mL) was stirred under H2 atmosphere (50 atm) at rt for 20 h. The catalyst was filtered off by filtration, and the filtrate was concentrated to give the title compound as a pale yellow solid (200 mg, 0.49 mmol, 54%).
Reaction SMILES: [CH2:1]([C:4]1[N:5]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[N:30](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:29]=[N:28][N:27]=3)=[CH:16][CH:15]=2)[C:6]([CH:11]=[O:12])=[C:7]([CH:9]=[CH2:10])[N:8]=1)[CH2:2][CH3:3].FC(F)(F)C(O)=O.O.[OH-].[Na+]>C1COCC1>[CH2:1]([C:4]1[N:5]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[NH:30][N:29]=[N:28][N:27]=3)=[CH:16][CH:15]=2)[C:6]([CH:11]=[O:12])=[C:7]([CH:9]=[CH2:10])[N:8]=1)[CH2:2][CH3:3]
Reactant: C=Cc1nc(CCC)n(Cc2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)c1C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: O
Product: C=Cc1nc(CCC)n(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 131.6 %

Procedure:
2-n-propyl-1-[(2'-(N-triphenylmethyl-(1H-tetrazol-5-yl))biphenyl-4-yl)methyl]-4-vinyl-imidazole-5-carboxaldehyde (330 mg), trifluoroacetic acid (1.65 mL), water (1.65 mL), and THF (1.65 mL) were mixed and stirred at room temperature. After 8 h, the mixture was neutralized to pH=7 with 10N NaOH and the solvents removed in vacuo. The residue was flash chromatographed in 1:1 hexane/ethyl acetate to 100% ethanol to yield 270 mg of a white glass. NMR (DMSO-d6) δ 9.92 (s,1H); 7.65-7.50 (m,1H); 7.50-7.12 (m,3H); 7.09 (d,2H,J=9Hz); 6.89 (d,2H,J=9Hz); 6.11 (d of d1H,J=17,3Hz); 5.55 (s,2H); 5.45 (d of d, 1H,J=12,3 Hz); 2.63 (t,2H,J=7Hz); 1.64 (t of q,2H,J=7,7Hz); 0.90 (t,3H,J= 7Hz). IR (Nujol) 1680 cm-1.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:7]=[C:6]([C:8]([OH:10])=O)[NH:5][N:4]=1.[CH3:13][O:14][CH:15]([O:18][CH3:19])[CH2:16][NH2:17].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>ClCCl>[CH3:13][O:14][CH:15]([O:18][CH3:19])[CH2:16][NH:17][C:8]([C:6]1[NH:5][N:4]=[C:3]([C:2]([F:1])([F:12])[F:11])[CH:7]=1)=[O:10]
Reactant: COC(CN)OC
Reactant: O=C(O)c1cc(C(F)(F)F)n[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(CNC(=O)c1cc(C(F)(F)F)n[nH]1)OC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 500 mg (2.78 mmol) of 3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid, 0.333 mL (3.05 mmol) of aminoacetaldehyde dimethyl acetal, 588 mg (3.05 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC), 510 mg (3.33 mmol) of 1-hydroxybenzotriazole (HOBT), 1.92 mL (11.1 mmol) of N,N-diisopropylethylamine, and 20 mL of dichloromethane was stirred at room temperature for 20 h and then concentrated. Purification of the residue by flash chromatography on silica gel (0-10% methanol in dichloromethane) afforded the title compound as a white solid. LC-MS 268 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5]>C1COCC1.O>[Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1Cl
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1cccc(CO)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
10.0 g (49.61 mmol) of 2-chloro-3-nitrobenzoic acid are initially charged in 50 ml of THF. With ice cooling, 104 ml of 1M borane/THF complex are added, and the mixture is stirred at RT overnight. At 0° C., the mixture is carefully hydrolyzed using water. After the evolution of gas has ceased, the mixture is diluted with 500 ml of water and the aqueous phase is extracted three times with in total 500 ml of ethyl acetate. The organic phase is washed with saturated sodium chloride solution and dried over magnesium sulfate. The solvent is then removed under reduced pressure using a rotary evaporator. This gives 9.20 g (98% of theory) of the title compound.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:37])[NH:27][C:28]4[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=4)=[CH:21][CH:20]=3)[N:8]=2)[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:71]1([CH:77]2[CH2:82][CH2:81][NH:80][CH2:79][CH2:78]2)[CH2:76][CH2:75][CH2:74][CH2:73][CH2:72]1>CN1C(=O)CCC1>[N:71]1([CH:77]2[CH2:82][CH2:81][N:80]([C:32]([C:31]3[CH:30]=[CH:29][C:28]([NH:27][C:26]([NH:25][C:22]4[CH:21]=[CH:20][C:19]([C:9]5[N:10]=[C:11]([N:13]6[CH2:14][CH2:15][O:16][CH2:17][CH2:18]6)[N:12]=[C:7]([N:4]6[CH2:3][CH2:2][O:1][CH2:6][CH2:5]6)[N:8]=5)=[CH:24][CH:23]=4)=[O:37])=[CH:36][CH:35]=3)=[O:33])[CH2:79][CH2:78]2)[CH2:76][CH2:75][CH2:74][CH2:73][CH2:72]1
Reactant: O=C(Nc1ccc(C(=O)O)cc1)Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Reactant: C1CCN(C2CCNCC2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: O=C(Nc1ccc(C(=O)N2CCC(N3CCCCC3)CC2)cc1)Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Yield: 60.1 %

Procedure:
To the solution of 4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2yl)phenyl)ureido)benzoic acid (50 mg; 0.099 mmol), Hunig's base (103 μL, 0.594 mmol), HBTU (188 mg, 0.495 mmol) in 2 mL of NMP was reacted according to example 68 with 1,4′-bipiperidine (67 mg, 0.396 mmol). Evaporated the solvent and purified by HPLC to give the product as a white solid (39 mg, 60% yield); MS (ESI) m/z=656.8.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:10]=[C:11]([NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31](Br)[N:30]=3)[C:12]3[N:13]([C:15]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][N:24]=[CH:23][C:22]=4[F:27])=[O:19])=[CH:16][N:17]=3)[N:14]=2)[CH2:4][CH2:3]1.[CH3:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>CN1C(=O)CCC1>[NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:10]=[C:11]([NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([N:40]4[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]4)[N:30]=3)[C:12]3[N:13]([C:15]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][N:24]=[CH:23][C:22]=4[F:27])=[O:19])=[CH:16][N:17]=3)[N:14]=2)[CH2:4][CH2:3]1
Reactant: CN1CCNCC1
Reactant: N[C@H]1CC[C@H](Nc2cc(Nc3cccc(Br)n3)c3ncc(C(=O)Nc4ccncc4F)n3n2)CC1
Solvent: CN1CCCC1=O
Product: CN1CCN(c2cccc(Nc3cc(N[C@H]4CC[C@H](N)CC4)nn4c(C(=O)Nc5ccncc5F)cnc34)n2)CC1
Temperature: 120 °C

Procedure:
A mixture of 6-((trans-4-aminocyclohexylamino)-8-(6-bromopyridin-2-ylamino)-N-(3-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide 17B (35.0 mg, 0.065 mmol) and 1-methylpiperazine (32.4 mg, 0.324 mmol) in NMP (0.4 mL) was heated to 120° C. overnight. The reaction mixture was cooled to room temperature and purified by preparative HPLC. The desired fraction was concentrated and lyophilized to give 17C (23.9 mg, 40%) as light yellow solid. [M+H]=560. HPLC Peak Rt=2.313 minutes. (Chromolith column 4.6×50 mm eluting with 10-90% aqueous methanol over 4 minutes containing 0.1% TFA, 4 mL/min, monitoring at 220 nm.)
Reaction SMILES: C(O)(=O)C.[NH2:5][NH2:6].F[C:8]1[CH:9]=[C:10]([N:20]2[CH2:24][CH2:23][N:22]([C:25]3[CH:26]=[N:27][CH:28]=[CH:29][C:30]=3[CH3:31])[C:21]2=[O:32])[CH:11]=[CH:12][C:13]=1[C:14](=O)[C:15]([F:18])([F:17])[F:16].CO>C1COCC1.C(Cl)(Cl)Cl>[CH3:31][C:30]1[CH:29]=[CH:28][N:27]=[CH:26][C:25]=1[N:22]1[CH2:23][CH2:24][N:20]([C:10]2[CH:9]=[C:8]3[C:13]([C:14]([C:15]([F:18])([F:17])[F:16])=[N:5][NH:6]3)=[CH:12][CH:11]=2)[C:21]1=[O:32]
Reactant: NN
Reactant: Cc1ccncc1N1CCN(c2ccc(C(=O)C(F)(F)F)c(F)c2)C1=O
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1ccncc1N1CCN(c2ccc3c(C(F)(F)F)n[nH]c3c2)C1=O
Temperature: 150 °C
Reaction time: 8 h
Yield: 23.46 %

Procedure:
Acetic acid (0.1 mL, 1.36 mmol) and 1M hydrazine in THF (4 mL, 2.72 mmol) were added to 1-[3-fluoro-4-(2,2,2-trifluoro-acetyl)-phenyl]-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-160b: 100 mg, 0.272 mmol) in dry THF (2 mL). The resulting mixture was stirred at 150° C. overnight. The reaction was monitored by TLC (5% MeOH in CHCl3). The reaction mixture was partitioned between water and chloroform. The organic layer was dried over Na2SO4 and concentrated. Purification by column chromatography on silica gel (4% MeOH in CHCl3), followed by preparative HPLC afforded 23 mg of the product (23.46% yield).
Reaction SMILES: [Na+].CS([CH2-])=O.[H-].[Na+].[C:8]([N:11]1[CH2:16][CH2:15][C:14]([C:18]#[CH:19])([OH:17])[CH2:13][CH2:12]1)(=[O:10])[CH3:9].F[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N+:27]([O-:29])=[O:28]>O.CS(C)=O>[C:8]([N:11]1[CH2:16][CH2:15][C:14]([C:18]#[CH:19])([O:17][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N+:27]([O-:29])=[O:28])[CH2:13][CH2:12]1)(=[O:10])[CH3:9]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: C#CC1(O)CCN(C(C)=O)CC1
Agent: [CH2-]S(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: C#CC1(Oc2ccccc2[N+](=O)[O-])CCN(C(C)=O)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 23.7 %

Procedure:
To a stirred solution of dimsyl sodium, prepared from 16.5 g of sodium hydride (50% in oil, washed three times with hexanes) and 400 ml of dimethylsulfoxide at 17°-25° was added, in aliquots, 57.7 g of 1-acetyl-4-ethynyl-4-piperidinol. Upon completion of the addition, 55.3 g of 2-fluoronitrobenzene was added dropwise at a rate such that the temperature remained below 25°. The mixture was stirred at room temperature for 20 min, poured into cold water, extracted three times with ether, washed with saturated sodium chloride solution and dried over anhydrous potassium carbonate. Filtration followed by evaporation of solvent provided an oil, which crystallized on standing. Recrystallization from ethyl acetate/cyclohexane provided 23.6 g (24%) of product, mp 112°-115°.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]([C:19](=O)[CH3:20])=[C:17]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[N:16]=[CH:15]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC(OC)N(C)C.NC(N)=N.Cl.C[O-].[Na+].[CH3:45][NH:46][C:47]([NH2:49])=[NH:48].Cl>CCO.O>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]([C:19]3[CH:20]=[CH:45][N:46]=[C:47]([NH2:49])[N:48]=3)=[C:17]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[N:16]=[CH:15]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)c1c(-c2ccc(F)cc2)ncn1C1CCN(Cc2ccccc2)CC1
Reactant: CNC(=N)N
Agent: COC(OC)N(C)C
Agent: C[O-]
Agent: Cl
Solvent: O
Solvent: CCO
Product: Nc1nccc(-c2c(-c3ccc(F)cc3)ncn2C2CCN(Cc3ccccc3)CC2)n1
Temperature: 90 °C
Reaction time: 3 h
Yield: 47 %

Procedure:
To a solution of the ketoimidazole prepared in Example 13 above (0.38 g, 1.01 mmol) in 5 mL of EtOH was added N,N-dimethylformamide dimethyl acetal (0.4 mL, 0.36 g, 3.02 mmol) and the solution was heated at 90° C. for 3 h. After 3 h, an additional 1 mL of DMEFDMA was added and heated for 3 h. At this time, TLC indicated no starting material and the solution was cooled to 70° C. and guanidine•HCl (0.19 g, 2.02 mmol) and NaOMe (25% w/w solution, 0.46 mL, 0.44 g, 2.02 mmol) were added. After 15 hours, additional N-methylguanidine•HCl (0.19 g, 2.02 mmol) and NaOMe (25% w/w solution, 0.46 mL, 0.44 g, 2.02 mmol) were added and heated at 75° C. for 24 h. The solution was cooled to room temperature, diluted with 50 mL of water and extracted 2×50 mL of EtOAC. The combined organics were concentrated and the residue was recrystallized from EtOAc to give 0.2 g (47%) of the title compound: 1H NMR (CDCl3) δ 8.19 (1H, d, J=5.2 Hz), 7.76 (1H, s), 7.44 (2H, m), 7.33 (5H, m), 7.01 (2H, t, J=8.6 Hz), 6.50 (1H, d, J=5.2 Hz), 5.17 (2H, br s), 4.54 (1H, m), 3.53 (2H, s), 3.02 (2H, m), 2.09 (6H, m).
Reaction SMILES: [O:1]=[S:2]1(=[O:27])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]([CH2:25][CH3:26])[C:15]3[C:20]([C:21]=2[C:22]#[N:23])=[CH:19][CH:18]=[C:17]([OH:24])[CH:16]=3)=[CH:9][CH:8]=1.C([O-])([O-])=O.[K+].[K+].[I-].[Na+].Cl.Cl[CH2:38][CH2:39][N:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1>C(C(C)=O)C.O.CN(C=O)C>[O:27]=[S:2]1(=[O:1])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]([CH2:25][CH3:26])[C:15]3[C:20]([C:21]=2[C:22]#[N:23])=[CH:19][CH:18]=[C:17]([O:24][CH2:38][CH2:39][N:40]2[CH2:45][CH2:44][O:43][CH2:42][CH2:41]2)[CH:16]=3)=[CH:11][CH:12]=1
Reactant: CCn1c(-c2ccc(N3CCCS3(=O)=O)cc2)c(C#N)c2ccc(O)cc21
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: CCC(C)=O
Solvent: CN(C)C=O
Product: CCn1c(-c2ccc(N3CCCS3(=O)=O)cc2)c(C#N)c2ccc(OCCN3CCOCC3)cc21
Temperature: 100 °C
Reaction time: 13 h

Procedure:
A mixture of 2-[4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)phenyl]-1-ethyl-6-hydroxy-1H-indole-3-carbonitrile, prepared in example 1AT above (70 mg, 0.25 mmol), K2CO3 (75 mg, 0.51 mmol), sodium iodide (27 mg, 0.18 mmol), 4-(2-chloroethyl)morpholine hydrochloride (42 mg, 0.25 mmol) in methyl ethyl ketone (3 mL) is heated in a sealed tube at 100° C. After 13 hours, DMF (3 mL) is added and the reaction is heated for an additional 6 h. After this time, an additional 42 mg of 4-(2-chloroethyl)morpholine hydrochloride and 135 mg of K2CO3 is added and the reaction is heated for an additional 6 h to complete the reaction. The reaction mixture is cooled to room temperature, diluted with water, and extracted with EtOAc (3×). The combined organic phases are washed with water (2×) and saturated NaCl and dried and concentrated. Pure 2-[4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-phenyl]-1-ethyl-6-(2-morpholin-4-yl-ethoxy)-1H-indole-3-carbonitrile is obtained by flash chromatography (MeOH/CH2Cl2, 0-6%) to give 29 mg (34%) of a tan solid.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:4][CH:3]=1.O.[NH3:15]>>[N:7]1[C:2]([NH2:15])=[CH:3][CH:4]=[CH:5][C:6]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: Brc1cccc(-c2ccccn2)n1
Reactant: N
Solvent: O
Product: Nc1cccc(-c2ccccn2)n1
Temperature: 25 °C
Yield: 85 %

Procedure:
To a mixture of 6-bromo-2,2′-bipyridine (3.0 mmol, 705 mg) and Cu2O (0.01 mmol, 1.0 mg) in glycol in autoclave NH3 was feed. The reaction was maintained under 10 atm of NH3 at 110° C. for 24 h. After cooling to room temperature, water was added and the aqueous phase was extracted with DCM. The combined organic layers were washed with brine and dried over MgSO4. After solvent evaporation, the crude product was purified by column chromatography on silica gel (Hexanes:ethyl acetate=1:1 as eluent) to afford a white solid (437 mg, 85% yield). 1H NMR (500 MHz, CDCl3, ppm): 8.65 (s, 1H), 8.25 (d, 1H, J=7.9 Hz), 7.79-7.76 (m, 1H), 7.71-7.70 (m, 1H), 7.57 (t, 1H, J=7.1 Hz), 7.26 (t, 1H, J=7.1 Hz), 6.65 (d, 1H, J=7.9 Hz), 4.53 (br, 2H). 13C NMR (125 MHz, CDCl3, ppm): 157.97, 156.38, 154.57, 149.11, 138.58, 136.73, 123.31, 120.94, 111.59, 108.87.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8](=[O:10])[CH3:9])[C:3]=1[CH3:11].[BH4-].[Na+]>C(O)C>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([CH:8]([OH:10])[CH3:9])[C:3]=1[CH3:11]
Reactant: CC(=O)c1ncnc(Cl)c1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1c(Cl)ncnc1C(C)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-(6-Chloro-5-methyl-4-pyrimidinyl)ethanone (Intermediate 43, 500 mg, 2.93 mmol) was dissolved in ethanol (10.0 mL), treated with sodium borohydride (111 mg, 2.93 mmol) and the resulting mixture was stirred at room temperature under argon for 2 hours. The solvent was removed under reduced pressure and the residue was diluted with water and extracted with ethyl acetate (×3). The ethyl acetate layers were combined, dried under magnesium sulfate and evaporated under reduced pressure to give the title compound as a white crude solid (380 mg) which was used without further purification;
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([C:9]([OH:11])=[O:10])[CH:5]=[CH:4][N:3]=1.[C:12](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:4][N:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1c(C(=O)O)ccnc1Cl
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1ccnc(Cl)c1C
Temperature: 25 °C
Reaction time: 18.5 h
Yield: 70.8 %

Procedure:
To a stirred solution of 2-chloro-3-methylpyridine-4-carboxylic acid (780 mg, 4.5 mmol) in anhydrous DMF (5.0 ml), was added potassium carbonate (1.25 g, 9.1 mmol), followed by methyl iodide (0.42 ml, 6.8 mmol) dropwise. A further 4 ml of DMF was added and the reaction mixture was stirred at room temperature under nitrogen for 18.5 hours. The solvent was removed in-vacuo and the residue was then partitioned between CH2Cl2 (20 ml) and water (20 ml). The layers were separated and the aqueous layer was extracted with CH2Cl2 (3×15 ml). The combined organic layers were washed with water (2×30 ml), brine (40 ml), dried (MgSO4), filtered and concentrated in-vacuo. The residue was purified by column chromatography (10 g SNAP cartridge, Isolera, 0-6% ethyl acetate:heptanes) to give the title compound (591 mg, 59%) as a colourless oil. LC-MS 84%, m/z=185.9, 187.9; 1H NMR (500 MHz, Chloroform-d) δ ppm 8.33 (d, J=5.04 Hz, 1H) 7.54 (d, J=5.04 Hz, 1H) 3.95 (s, 3H) 2.60 (s, 3H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([CH3:21])([CH3:20])[CH2:5][C@H:6]1[CH2:10][O:9]C(C)(C)[N:7]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]>CC(O)=O>[OH:9][CH2:10][C@@H:6]([NH:7][C:13](=[O:14])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:5][C:4]([CH3:21])([CH3:20])[CH2:3][O:2][CH3:1]
Reactant: COCC(C)(C)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Solvent: CC(=O)O
Product: COCC(C)(C)C[C@@H](CO)NC(=O)OC(C)(C)C
Temperature: 55 °C
Reaction time: 2 h
Yield: 140.1 %

Procedure:
(S)-tert-butyl 4-(3-methoxy-2,2-dimethylpropyl)-2,2-dimethyloxazolidine-3-carboxylate (6.4 g, 21.3 mmol) was dissolved in 70% CH3COOH. The solution was heated to 50-60° C. and stirred for 2 h. The reaction solution was evaporated to give (S)-tert-butyl 1-hydroxy-5-methoxy-4,4-dimethylpentan-2-ylcarbamate (7.8 g, 100%) as an oil that was used in the next step without further purification. 1H NMR (CDCl3, 400 MHz) δ3.69 (m, 3H), 3.32 (s, 3H), 3.01 (m, 2H), 2.11 (s, 7H), 1.48 (m, 10H), 1.23 (m, 22H), 0.91 (m, 18H).
Reaction SMILES: Cl.[OH:2][CH:3]([CH:9]1[O:14][CH2:13][CH2:12][NH:11][CH2:10]1)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[S:15](Cl)([C:18]1[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=1)(=[O:17])=[O:16].S(Cl)(C)(=O)=O>>[OH:2][CH:3]([CH:9]1[O:14][CH2:13][CH2:12][N:11]([S:15]([C:18]2[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:10]1)[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(O)C1CNCCO1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CS(=O)(=O)Cl
Agent: Cl
Product: CCOC(=O)C(O)C1CN(S(=O)(=O)c2ccc(C)cc2)CCO1
Yield: 35.5 %

Procedure:
According to the Step 28-1 in synthetic method for EXAMPLE 28, compound 115-3 (0.2 g) and tosylchloride (203 mg) were used instead of 26-5 and mesyl chloride to obtain compound 116-1 (108 mg) as a pale yellow amorphous solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:19](=[N:21]O)[CH3:20])[CH:17]=[CH:18][C:13]=2[N:12]([CH3:23])[C:11](=[O:24])[CH:10]([CH3:25])[N:9]=1.[H][H]>N.[Ni]>[NH2:21][CH:19]([C:16]1[CH:17]=[CH:18][C:13]2[N:12]([CH3:23])[C:11](=[O:24])[CH:10]([CH3:25])[N:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[C:14]=2[CH:15]=1)[CH3:20]
Reactant: CC(=NO)c1ccc2c(c1)C(c1ccccc1F)=NC(C)C(=O)N2C
Reactant: [H][H]
Agent: [Ni]
Agent: N
Product: CC1N=C(c2ccccc2F)c2cc(C(C)N)ccc2N(C)C1=O

Procedure:
A solution of 4.1 g (12.08 mmol) of 5-(o-fluorophenyl)-1,3-dihydro-7-[1-(hydroxyimino)ethyl]-1,3-dimethyl-2H-1,4-benzodiazepin-2-one in 150 ml of 2 N methanolic ammonia is treated with 5 g of Raney-nickel paste and the suspension is stirred in a hydrogen atmosphere for 24 hours. After filtration of the catalyst and removal of the solvent in vacuo, there is obtained 7-(1-aminoethyl)-5-(o-fluorophenyl)-1,3-dihydro-1,3-dimethyl-2H-1,4-benzodiazepin-2-one as a foam of melting point 48°-50°.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:19]2[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=2)[C:13]([CH2:21]O)=[CH:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:25])=O.CCCCCC>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[C:19]2[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=2)[C:13]([CH2:21][Cl:25])=[CH:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)n1cc(CO)c2cc(Cl)ccc21
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCCCCC
Product: O=C(OCc1ccccc1)n1cc(CCl)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 1-benzyloxycarbonyl-5-chloro-3-hydroxymethylindole (1.45 g) in dichloromethane (23 ml) was added thionylchloride (0.797 μl) at −78° C. After the mixture was stirred for 1.5 hours at room temperature, the reaction mixture was concentrated under the reduced pressure to give a residue. Hexane was added to the residue. 1-benzyloxycarbonyl-5-chloro-3-chloromethylindole (1.43 g) was obtained as a crystal.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]#[N:14].[Cl:15][C:16]1[CH:22]=[C:21]([Cl:23])[C:20]([O:24][CH3:25])=[CH:19][C:17]=1[NH2:18].Cl.N1C=CC=CC=1>>[Cl:15][C:16]1[CH:22]=[C:21]([Cl:23])[C:20]([O:24][CH3:25])=[CH:19][C:17]=1[NH:18][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]#[N:14]
Reactant: COc1cc(N)c(Cl)cc1Cl
Reactant: N#Cc1cnc2cc(F)ccc2c1Cl
Agent: Cl
Solvent: c1ccncc1
Product: COc1cc(Nc2c(C#N)cnc3cc(F)ccc23)c(Cl)cc1Cl
Yield: 48.2 %

Procedure:
Following the procedure of Reference Example 8, a mixture of 4-chloro-7-fluoro-3-quinolinecarbonitrile (2.10 g, 10.2 mmol), 2,4-dichloro-5-methoxyaniline (2.15 g, 11.2 mmol) and pyridine hydrochloride (1.18 g, 10.2 mmol) provides 1.78 g of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-7-fluoro-3-quinolinecarbonitrile, mp 199-201° C.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1.[NH2:13][C:14]1[CH:19]=[C:18](Cl)[CH:17]=[CH:16][N:15]=1>CS(C)=O>[NH:10]1[C:11]2[C:7](=[CH:6][CH:5]=[C:4]([O:3][C:18]3[CH:17]=[CH:16][N:15]=[C:14]([NH2:13])[CH:19]=3)[CH:12]=2)[CH:8]=[CH:9]1
Reactant: Nc1cc(Cl)ccn1
Reactant: Oc1ccc2cc[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Nc1cc(Oc2ccc3cc[nH]c3c2)ccn1
Temperature: 160 °C
Reaction time: 8.5 h
Yield: 10.6 %

Procedure:
Sodium hydride (1.04 g, 26.0 mmol, 60% in oil) was suspended in dimethyl sulfoxide (2.5 ml); 6-hydroxyindole (3.46 g, 26.0 mmol) and 2-amino-4-chloropyridine (2.57 g, 20.0 mmol, WO 02/332872) were subsequently added thereto at room temperature under nitrogen stream; and the reaction mixture was stirred at 160° C. for 8.5 hours. After cooled down to room temperature, the reaction mixture was partitioned between ethyl acetate (150 ml) and a solvent mixture of aqueous ammonia:water=1:1 (50 ml); the organic layer was washed with a solvent mixture of aqueous ammonia:water=1:1, and with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (Fuji Silysia BW-300, ethyl acetate, or ethyl acetate:methanol=93:7); and the obtained crystals were suspended in diethyl ether, filtered off, washed with diethyl ether, and dried to yield the title compound (477 mg, 2.12 mmol, 10.6%) as pale yellow crystals.