Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9]C=2OC)[N:5]=[CH:4][C:3]=1[C:15]([NH2:17])=[O:16].N[C:19]1N(C2CCCC2)N=C(C)C=1C#N>>[NH2:1][C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[N:5]=[C:4]([CH3:19])[C:3]=1[C:15]([NH2:17])=[O:16]
Reactant: Cc1nn(C2CCCC2)c(N)c1C#N
Reactant: COc1ccccc1-n1ncc(C(N)=O)c1N
Product: Cc1nn(C2CCCC2)c(N)c1C(N)=O

Procedure:
Following the procedure for the preparation of 5-amino-1-(2-methoxyphenyl)-1H-pyrazole-4-carboxamide but substituting 5-amino-1-cyclopentyl-3-methyl-1H-pyrazole-4-carbonitrile provided the title compound. 1H NMR (300 MHz, CDCl3): δ 5.39 (br, 2H), 5.32 (br, 2H), 4.26 (m, 1H), 2.38 (s, 3H), 2.04 (m, 4H), 1.9 (m, 2H), 1.66 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([NH:10][CH3:11])[C:7]([F:12])=[CH:6][C:3]=1[C:4]#N.[H-].C([Al+]CC(C)C)C(C)C.C[OH:24].Cl>C(OCC)C>[F:1][C:2]1[CH:9]=[C:8]([NH:10][CH3:11])[C:7]([F:12])=[CH:6][C:3]=1[CH:4]=[O:24]
Reactant: CNc1cc(F)c(C#N)cc1F
Reactant: CO
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: CCOCC
Product: CNc1cc(F)c(C=O)cc1F
Reaction time: 16 h

Procedure:
To a solution of 2,5-difluoro-4-methylaminobenzonitrile (0.509 g, 3.03 mmol) in dry diethyl ether (40 ml) stirred at room temperature under nitrogen, was added dropwise by syringe diisobutylaluminium hydride (5.5 ml, 1.0 M in toluene, 5.5 mmol) and stirring continued for 16 h. The solution was chilled in an ice-bath and methanol (2.8 ml) was added dropwise and the mixture stirred for 1 h before 1.0 M HCl (17 ml) was added and stirring continued for a further 1 h. The reaction mixture was then partitioned between ether (50 ml) and water (50 ml) and the aqueous layer re-extracted with ether (50 ml). The combined ether extract was washed with 5% sodium bicarbonate solution (34 ml), then brine, dried (MgSO4) and evaporated to give a mixture of the desired aldehyde and unhydrolysed imine (0.511 g). The material was filtered through a plug of silica gel using 100% dichloromethane to give pure 2,5-difluoro-4-methylaminobenzaldehyde (x).
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6]([C:8]([O:10]CC)=O)[C:5](=[O:13])[C:4]2[CH:14]=[CH:15][O:16][C:3]1=2.[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH2:23])=[CH:20][CH:19]=1>C1(C)C=CC=CC=1>[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH:23][C:8]([C:6]2[C:5](=[O:13])[C:4]3[CH:14]=[CH:15][O:16][C:3]=3[N:2]([CH3:1])[CH:7]=2)=[O:10])=[CH:20][CH:19]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cn(C)c2occc2c1=O
Solvent: Cc1ccccc1
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2ccoc21
Temperature: 190 °C
Yield: 68 %

Procedure:
A mixture of ethyl 7-methyl-4-oxo-4,7-dihydrofuro[2,3-b]pyridine-5-carboxylate (Preparation 9, 1.00 g) and 4-chlorobenzylamine (5.5 mL) was heated to 190° C. for 1 h. The reaction mixture was allowed to cool for several minutes and toluene (50 mL) was added. The resulting off-white solid was filtered and recrystallized from ethyl acetate to yield 0.979 g (68%) of the title compound as a pale yellow solid. Physical characteristics. M.p. 197-205° C.; 1H NMR (400 MHz, DMSO-d6) δ 10.62, 8.59, 7.92, 7.41-7.33, 7.06, 4.55, 3.94; 13C NMR (100 MHz, CDCl3) δ 174.0, 164.8, 153.4, 141.4, 140.5, 137.3, 132.8, 128.9, 128.7, 116.7, 114.2, 107.9, 42.6, 37.7; MS (ESI+) m/z 317 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[N:12][C:11]3=[N:21][N:22]([CH3:24])[CH:23]=[C:10]3[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH2:35])(=[O:34])=[O:33])=[CH:28][CH:27]=1>>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]2[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([S:32]([NH2:35])(=[O:33])=[O:34])=[CH:28][CH:27]=4)[CH:7]=3)=[CH:9][C:10]3[C:11](=[N:21][N:22]([CH3:24])[CH:23]=3)[N:12]=2)=[CH:15][CH:16]=1
Reactant: Cn1cc2cc(-c3ccnc(Cl)c3)c(-c3ccc(F)cc3)nc2n1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Product: Cn1cc2cc(-c3ccnc(Nc4ccc(S(N)(=O)=O)cc4)c3)c(-c3ccc(F)cc3)nc2n1

Procedure:
Following a similar procedure to that described in example 214, but starting from 5-(2-chloropyridin-4-yl)-6-(4-fluorophenyl)-2-methylpyrazolo[3,4-b]pyridine (obtained in example 263) and 4-aminobenzenesulfonamide, the title compound was obtained.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[NH:6][CH:5](SC)[N:4]([NH2:11])[C:3]1=[O:12].C(O)(=O)C.[CH3:17][NH2:18]>C(O)(C)C>[CH3:1][N:2]1[C:7](=[O:8])[NH:6][CH:5]([NH:18][CH3:17])[N:4]([NH2:11])[C:3]1=[O:12]
Reactant: CN
Reactant: CSC1NC(=O)N(C)C(=O)N1N
Solvent: CC(=O)O
Solvent: CC(C)O
Product: CNC1NC(=O)N(C)C(=O)N1N
Reaction time: 10 h
Yield: 88 %

Procedure:
18.8 g (0.1 mole) of 1-methyl-3-amino-4-methylmercaptotetrahydro-1,3,5-triazine-2,6-dione (prepared according to Example 2) were idssolved in 200 ml of isopropanol with addition of 6 g of glacial acetic acid and a pinch of ptoluenesulphonic acid and the mixture was saturated with methylamine gas at room temperature. The batch was left to stand for about 10 hours and was evaporated in vacuo, and the resudue was recrystallized from isopropanol. 15 g (88%) of 1-methyl-3-amino-4-methylamino-tetrahydro-1,3,5-triazine2,6-dione were obtained as a colorless powder; melting point 225°-227° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][CH2:13][NH2:14])[CH2:7][CH2:6]1.[N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([CH:25]=O)=[CH:17][CH:16]=1.[BH4-].[Na+].O>C(O)C>[N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([CH2:25][NH:14][CH2:13][CH2:12][CH2:11][N:8]2[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][CH2:2][NH:1][CH2:25][C:18]3[C:19]4[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=4)[N:15]=[CH:16][CH:17]=3)[CH2:10][CH2:9]2)=[CH:17][CH:16]=1
Reactant: O=Cc1ccnc2ccccc12
Reactant: NCCCN1CCN(CCCN)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: c1ccc2c(CNCCCN3CCN(CCCNCc4ccnc5ccccc45)CC3)ccnc2c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 1,4-bis(3-aminopropyl)piperazine (0.51 mL, 2.5 mmol) and 4-quinolinecarboxaldehyde (824 mg, 5.24 mmol) in absolute ethanol (20 mL), 3 Å molecular sieves are added. After stirring the mixture at room temperature for 12 h, NaBH4 (1.9 g, 249.92 mmol) was added portionwise and the mixture was stirred for 12 h at room temperature. The reaction was quentched by dropwise addition of water (20 mL) and ethanol was removed under reduced pressure. The aqueous residue was extracted with CH2Cl2 (3×30 mL). Combined organic layers were extracted with HCl 1M. The combined aqueous layers were neutralized with NaOH 1M and extracted with CH2Cl2. Combined organic layers were dried over MgSO4. Crude compound is purified by flash chromatography on neutral aluminium oxide (CH2Cl2/MeOH).
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][CH:19]=[CH:18][C:5]=1[O:6][C:7]1[CH:8]=[C:9]([C:13]2[NH:17][N:16]=[N:15][N:14]=2)[CH:10]=[CH:11][CH:12]=1)([O-])=O>C(O)C.CN(C)C=O.[C].[Pd]>[NH:17]1[C:13]([C:9]2[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=2)[O:6][C:5]2[CH:18]=[CH:19][CH:20]=[CH:21][C:4]=2[NH2:1])=[N:14][N:15]=[N:16]1
Reactant: O=[N+]([O-])c1ccccc1Oc1cccc(-c2nnn[nH]2)c1
Agent: [Pd]
Solvent: CCO
Solvent: CN(C)C=O
Product: Nc1ccccc1Oc1cccc(-c2nnn[nH]2)c1
Yield: 96.9 %

Procedure:
In a mixture of 18 ml of ethanol and 9 ml of N,N-dimethylformamide was dissolved 1.5 g of 5-[3-(2-nitrophenoxy)phenyl]-1H-tetrazole and catalytic hydrogenation was carried out in the presence of 0.3 g of palladium-carbon at atmospheric temperature and pressure. After this reaction, the catalyst was filtered off and the filtrate was concentrated to give 1.3 g of the title compound as a colorless oil.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:11][OH:12])[C@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4].N1C=CN=C1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>CN(C=O)C.[Cl-].[Na+].O>[NH2:1][C@@H:2]([CH2:11][O:12][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[C@H:3]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[OH:4]
Reactant: N[C@@H](CO)[C@@H](O)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Cl-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC[C@H](N)[C@@H](O)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of (1S,2S)-2-amino-1-phenyl-1,3-propanediol (2.07 g, 12.4 mmol) in DMF (10 mL) was added imidazole (1.0 g, 14.7 mmol) and tert-butyldimethylsilyl chloride (20.30 g, 15.3 mmol). After stirring at rt for 12 h the mixture was added to diluted brine (150 mL, water/brine: 1/1). Extraction with ethyl acetate (4×30 mL), washing of the combined extracts with brine (30 mL) and drying (MgSO4) gave after concentration a residue which was purified by flash chromatography on silica gel (eluent: ethyl acetate). The title compound was obtained as colourless oil. δH (CDCl3): 0.24, 0.26 (6H, 2s), 1.12 (9H, s), 2.50-2.78 (3H, br s), 3.16 (1H, ddd), 3.78 (1H, dd), 3.85 (1H, dd), 4.84 (1H, d), 7.49-7.55 (5H, m); m/z (ES+)=282.32 [M+H]+; RT=2.87 min.
Reaction SMILES: [NH3:1].[C:2]1([S:8]([C:11]2[C:12]([S:29][CH3:30])=[N:13][N:14]3[C:19](Cl)=[CH:18][C:17]([CH2:21][N:22]4[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]4)=[N:16][C:15]=23)(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.CN(C=O)C>[C:2]1([S:8]([C:11]2[C:12]([S:29][CH3:30])=[N:13][N:14]3[C:19]([NH2:1])=[CH:18][C:17]([CH2:21][N:22]4[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]4)=[N:16][C:15]=23)(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N
Reactant: CSc1nn2c(Cl)cc(CN3CCN(C)CC3)nc2c1S(=O)(=O)c1ccccc1
Solvent: CN(C)C=O
Solvent: CO
Product: CSc1nn2c(N)cc(CN3CCN(C)CC3)nc2c1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77 %

Procedure:
10 ml of a 50% solution of NH3 in MeOH were added to a solution of 0.8 g (1.77 mmol) of 3-benzenesulphonyl-7-chloro-5-(4-methyl-piperazin-1-ylmethyl)-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidine in 20 ml of DMF and stirred at RT for 4 hrs. The reaction solution was evaporated and the residue was partitioned between 2N NaOH and CH2Cl2. The aqueous phase was extracted three times with CH2Cl2, and the combined organic phases were dried (MgSO4), filtered and evaporated. Subsequent chromatography (SiO2, CH2Cl2/MeOH/NH40H 90:10:1) yielded 0.59 g (77%) of 3-benzenesulphonyl-5-(4-methyl-piperazin-1-ylmethyl)-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidin-7-ylamine as colorless crystals, m.p. 203-205°.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:13][C@@H:14]2[CH2:18][C@H:17]([O:19][CH2:20][CH2:21][OH:22])[C@@H:16]([OH:23])[C@H:15]2[OH:24])=[N:4][C:5]([S:9][CH2:10][CH2:11][CH3:12])=[N:6][C:7]=1[Cl:8].[N:25](OCCC(C)C)=O>C(OCC)(=O)C>[Cl:8][C:7]1[C:2]2[N:1]=[N:25][N:13]([C@@H:14]3[CH2:18][C@H:17]([O:19][CH2:20][CH2:21][OH:22])[C@@H:16]([OH:23])[C@H:15]3[OH:24])[C:3]=2[N:4]=[C:5]([S:9][CH2:10][CH2:11][CH3:12])[N:6]=1
Reactant: CCCSc1nc(Cl)c(N)c(N[C@@H]2C[C@H](OCCO)[C@@H](O)[C@H]2O)n1
Reactant: CC(C)CCON=O
Solvent: CCOC(C)=O
Product: CCCSc1nc(Cl)c2nnn([C@@H]3C[C@H](OCCO)[C@@H](O)[C@H]3O)c2n1
Temperature: 65 °C
Reaction time: 1 h
Yield: 79.5 %

Procedure:
To a stirring solution of (1S,2S,3R,5S)-3-((5-amino-6-chloro-2-(propylthio)pyrimidin-4-yl)amino)-5-(2-hydroxyethoxy)cyclopentane-1,2-diol (OLACINA; 0.38 g, 1 mmol) in ethyl acetate (7 mL) was added isopentyl nitrite (0.16 mL, 1.2 mmol). The reaction mixture was stirred for 1 h at 65° C. and then evaporated under reduced pressure to give a reddish powder which was recrystallized from a mixture of methyl tert-butyl ether/n-hexane to give CLTOL as a crystalline product (0.31 g, 80% yield): 99 area % by HPLC.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([O:18]CC)=O)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH3:24].[Cl-].[NH4+]>CO>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([NH2:24])=[O:18])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: N
Reactant: CCCc1nc2c(N)nc3ccccc3c2n1CC(=O)OCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: CCCc1nc2c(N)nc3ccccc3c2n1CC(N)=O

Procedure:
Ethyl (4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)acetate (0.80 g), a solution of ammonia in methanol (35 mL of 7 N), and ammonium chloride (0.50 g) were heated in a sealed pressure vessel at 150° C. for 20 hours. The volatiles were removed under reduced pressure, and the solid residue was triturated with saturated aqueous sodium bicarbonate for one hour, isolated by filtration, and washed with water. The solid was recrystallized from methanol/water, and the crystals were washed sequentially with 25% aqueous sodium hydroxide (2×25 mL) and water (2×25 mL) and dried overnight in a vacuum oven at 70° C. to provide 0.120 g of 2-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)acetamide as light tan crystals, mp>300° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:11]([NH:13][C:14]2[O:15][C:16]([C:19]3[O:20][CH:21]=[CH:22][CH:23]=3)=[N:17][N:18]=2)=[O:12])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[CH2:24]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=2)=[CH:28][CH:27]=1)[CH3:25]>>[CH2:24]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][C:35]([C:2]3[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([C:11]([NH:13][C:14]4[O:15][C:16]([C:19]5[O:20][CH:21]=[CH:22][CH:23]=5)=[N:17][N:18]=4)=[O:12])[CH:3]=3)=[CH:34][CH:33]=2)=[CH:28][CH:27]=1)[CH3:25]
Reactant: CCc1ccc(-c2ccc(B(O)O)cc2)cc1
Reactant: O=C(Nc1nnc(-c2ccco2)o1)c1cc(Br)cc([N+](=O)[O-])c1
Product: CCc1ccc(-c2ccc(-c3cc(C(=O)Nc4nnc(-c5ccco5)o4)cc([N+](=O)[O-])c3)cc2)cc1

Procedure:
The title compound was synthesized in accordance with the synthesis method of compound Ia-50, using 3-bromo-N-[5-(2-furyl)-1,3,4-oxadiazol-2-yl]-5-nitrobenzenecarboxamide prepared in Reference Example 37 instead of compound Ia-50 and using commercially available 4′-ethyl-4-biphenylboronic acid instead of 1-methyl-5-indoleboronic acid pinacol ester.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[F:16][C:17]([F:30])([F:29])[O:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([S:25]([C:22]3[CH:21]=[CH:20][C:19]([O:18][C:17]([F:16])([F:29])[F:30])=[CH:24][CH:23]=3)(=[O:27])=[O:26])[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)N2CCNCC2)cn1
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)N2CCN(S(=O)(=O)c3ccc(OC(F)(F)F)cc3)CC2)cn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 20.1 %

Procedure:
To a solution of 1-[(6-methyl-3-pyridinyl)carbonyl]piperazine (may be prepared as described in Description 14) (100 mg, 0.487 mmol) in DMF (10 ml) was added 4-[(trifluoromethyl)oxy]benzenesulfonyl chloride (152 mg, 0.585 mmol). Finally DIPEA (0.255 ml, 1.462 mmol) was added and the reaction mixture was stirred at room temperature for 20 h. Solvent was removed by evaporation, the residue was dissolved in ethyl acetate and the solution extracted with saturated aqueous NaHCO3. The organic layer was dried over MgSO4, filtered and evaporated to dryness and the residue was purified by MDAP to yield the title compound (42 mg) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH2:8][CH2:9][C:10]3[CH:11]=[CH:12][N:13]([CH2:15][CH2:16][NH:17][C:18](=O)[CH3:19])[C:14]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.[OH-].[Na+].[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32]>C(O)C>[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32].[Cl:1][C:2]1[C:7]2[CH2:8][CH2:9][C:10]3[CH:11]=[C:12]4[C:18]([CH3:19])=[N:17][CH2:16][CH2:15][N:13]4[C:14]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)NCCn1ccc2c1-c1cccc(Cl)c1CC2
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O=P(Cl)(Cl)Cl
Product: CC1=NCCn2c1cc1c2-c2cccc(Cl)c2CC1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
N-[2-(6-Chloro-4,5-dihydro-1H-benz[g]indol-1-yl)ethyl]acetamide (6.0 g) was treated with 30 ml of phosphorus oxychloride and the mixture was stirred at 100° C. for 30 minutes. The cooled mixture was added to 2500 g of ice-water and treated with 100 ml of 2N sodium hydroxide solution and 200 ml of 28% sodium hydroxide solution. The mixture was extracted once with 300 ml of methylene chloride and twice with 100 ml of methylene chloride each time, the organic phases were combined, dried with MgSO4 and freed from solvent. 5.7 g of residue were dissolved in a 20-fold amount of hot ethanol and treated while hot with 1.1 equivalents of a saturated solution of fumaric acid in ethanol. There were obtained 6.6 g (82%) of 4-chloro-5,6,10,11-tetrahydro-8-methylbenz[g]pyrazino[1,2-a]indole fumarate (1:1); m.pt.: 191°-192° C. (dec.).
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)[CH:7]=[C:6]([CH3:17])[C:3]=1[C:4]#[N:5].Cl.[CH3:19][C:20]1[N:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][NH2:29])=[CH:22][CH:21]=1.C(=O)([O-])O.[Na+].CS(C)=O>O>[CH3:19][C:20]1[N:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][NH:29][C:2]2[N:9]=[C:8]([NH:10][C:11]3[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=3)[CH:7]=[C:6]([CH3:17])[C:3]=2[C:4]#[N:5])=[CH:22][CH:21]=1
Reactant: Cc1ccc(OCCN)cn1
Reactant: Cc1cc(Nc2cc(C)c(C#N)c(Cl)n2)n[nH]1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc(OCCNc2nc(Nc3cc(C)[nH]n3)cc(C)c2C#N)cn1
Temperature: 100 °C
Reaction time: 27 h
Yield: 19.8 %

Procedure:
Compound A (300 mg, 1.22 mmol), 2-(6-methylpyridin-3-yloxy)ethylamine hydrochloride (549 mg) and sodium hydrogencarbonate (1.02 g) were added to DMSO (10 ml), and the mixture was stirred at 100° C. for 27 hr. After stirring, the reaction mixture was added to cold water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and concentrated, and the residue was washed by suspending in ethyl acetate to give the object compound of 2-(2-(6-methylpyridin-3-yloxy)ethylamino)-6-(5-methyl-1H-pyrazol-3-ylamino)-4-methylnicotinonitrile (88 mg).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11](Cl)=[O:12].[NH2:14][C:15]1[CH:16]=[C:17]([CH:30]=[CH:31][C:32]=1[CH3:33])[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([N:27]([CH3:29])[CH3:28])[CH:22]=1)=[O:19]>>[CH3:29][N:27]([CH3:28])[C:23]1[CH:22]=[C:21]([NH:20][C:18](=[O:19])[C:17]2[CH:30]=[CH:31][C:32]([CH3:33])=[C:15]([NH:14][C:11]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)=[O:12])[CH:16]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: Cc1ccc(C(=O)Nc2cccc(N(C)C)c2)cc1N
Reactant: O=C(Cl)c1ccc2ccccc2c1
Product: Cc1ccc(C(=O)Nc2cccc(N(C)C)c2)cc1NC(=O)c1ccc2ccccc2c1

Procedure:
Using an analogous procedure to that described in Example 1, 2-naphthoyl chloride was reacted with 3-amino-N-(3-dimethylaminophenyl)-4-methylbenzamide to give the title compound; Mass Spectrum: M+H+ 424.
Reaction SMILES: [Cl-].[CH:2]([O:5][C:6]1[CH:7]=[C:8]([C@@H:12]([NH3+:14])[CH3:13])[CH:9]=[CH:10][CH:11]=1)([CH3:4])[CH3:3].C([O:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]1[CH:33]=[CH:32][C:31]([CH2:34][N:35]2[C:43]3[C:38](=[CH:39][C:40]([C:44](O)=[O:45])=[CH:41][CH:42]=3)[C:37]([CH3:47])=[C:36]2[CH3:48])=[CH:30][CH:29]=1)=[O:21])(C)(C)C>>[CH:2]([O:5][C:6]1[CH:7]=[C:8]([C@@H:12]([NH:14][C:44]([C:40]2[CH:39]=[C:38]3[C:43](=[CH:42][CH:41]=2)[N:35]([CH2:34][C:31]2[CH:30]=[CH:29][C:28]([C:23]4[C:22]([C:20]([OH:21])=[O:19])=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:33][CH:32]=2)[C:36]([CH3:48])=[C:37]3[CH3:47])=[O:45])[CH3:13])[CH:9]=[CH:10][CH:11]=1)([CH3:4])[CH3:3]
Reactant: CC(C)Oc1cccc([C@H](C)[NH3+])c1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Agent: [Cl-]
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@@H](C)c3cccc(OC(C)C)c3)cc12

Procedure:
The title compound was prepared following the same general synthetic procedure as described in Steps 3-4, Example 2, starting with (S)-1-(3-isopropoxyphenyl)ethanaminium chloride and 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of (S)-1-(4-(tert-butyl)phenyl)ethanaminium chloride and 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 560 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:17])=[C:6]([CH:8]=[N:9][C:10]([O:12][Si](C)(C)C)=[CH2:11])[CH:7]=1.C(OC([N:25]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([Cl:34])[CH:32]=2)/[C:27](=[CH:35]/[C:36]2[CH:41]=[C:40]([Cl:42])[CH:39]=[CH:38][C:37]=2[O:43][CH:44]2[CH2:49][CH2:48][N:47]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:46][CH2:45]2)/[C:26]1=[O:57])=O)(C)(C)C>C1(C)C=CC=CC=1>[C:53]([O:52][C:50]([N:47]1[CH2:48][CH2:49][CH:44]([O:43][C:37]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:36]=2[CH:35]2[CH2:12][C:10](=[O:11])[NH:9][CH:8]([C:6]3[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[CH3:17])[C:27]32[C:28]2[C:33](=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)[NH:25][C:26]3=[O:57])[CH2:45][CH2:46]1)=[O:51])([CH3:56])([CH3:54])[CH3:55]
Reactant: C=C(N=Cc1cc(F)ccc1C)O[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)cc2/C=C2\C(=O)N(C(=O)OC(C)(C)C)c3cc(Cl)ccc32)CC1
Solvent: Cc1ccccc1
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OC2CCN(C(=O)OC(C)(C)C)CC2)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 65 °C
Reaction time: 3 h
Yield: 24.9 %

Procedure:
To a solution of 1-(5-fluoro-2-methyl-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (15 mL, 30 mmol) in toluene (50 mL) was added E/Z-3-[2-(1-tert-Butoxycarbonyl-piperidin-4-yloxy)-5-chloro-benzylidene]-6-chloro-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (3.6 g, 6 mmol). The reaction mixture was stirred under argon at 65° C. for 3 h and then heated at 130° C. for 4 h. After cooled to room temperature, the mixture was concentrated. The residue was purified by chromatography to give the title compound as a white solid (Yield: 1 g).
Reaction SMILES: [O:1]=[C:2]1[C:10]2([CH2:14][CH2:13][CH2:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[C:15]([NH:17][CH2:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:16].[CH3:25][C:26]([CH3:33])([CH:31]=O)[C:27]([O:29][CH3:30])=[O:28].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:25][C:26]([CH3:33])([CH2:31][N:22]1[CH2:21][CH2:20][CH:19]([CH2:18][NH:17][C:15]([N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]3([CH2:14][CH2:13][CH2:12][CH2:11]3)[C:2]2=[O:1])=[O:16])[CH2:24][CH2:23]1)[C:27]([O:29][CH3:30])=[O:28]
Reactant: COC(=O)C(C)(C)C=O
Reactant: O=C(NCC1CCNCC1)N1C(=O)C2(CCCC2)c2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)C(C)(C)CN1CCC(CNC(=O)N2C(=O)C3(CCCC3)c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 22.6 %

Procedure:
To a stirred solution of 2′-oxo-N-(piperidin-4-ylmethyl)spiro[cyclopentane-1,3′-indole]-1′(2′H)-carboxamide (480 mg, 1.5 mmol, step 2 of Example 2) and methyl 2,2-dimethyl-3-oxopropanoate (248 mg, 1.7 mmol, Kim, Hwa-Ok et al., Synth. Commun., 1997, 27, 2505) in CH2Cl2 (40 mL) was added sodium triacetoxyborohydride (623 mg, 2.9 mmol) in one portion at room temperature. The mixture was stirred for 20 h at ambient temperature. To the mixture was added sat. NaHCO3 aq. (10 mL), extracted with CH2Cl2 (30 mL×2), dried over MgSO4, filtered and concentrated gave yellow oil. The residue was chromatographed on a column of aminopropyl-silica gel eluting with hexane/ethyl acetate (9:1) to give 150 mg (23%) of the title compound as clear colorless oil.