Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH3:16])[C:6]=2[CH:17]=1.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[CH:28][C:27]=2[S:38]([N:41]([CH3:43])[CH3:42])(=[O:40])=[O:39])[C:22]([Cl:44])=[CH:21][N:20]=1>>[Cl:44][C:22]1[C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[CH:28][C:27]=2[S:38]([N:41]([CH3:43])[CH3:42])(=[O:39])=[O:40])=[N:24][C:19]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[C:11]([CH3:12])([CH3:13])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH3:16])[C:6]=3[CH:17]=2)=[N:20][CH:21]=1
Reactant: CCN1C(=O)CCC(C)(C)c2ccc(N)cc21
Reactant: CN(C)S(=O)(=O)c1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Product: CCN1C(=O)CCC(C)(C)c2ccc(Nc3ncc(Cl)c(Nc4ccc(N5CCOCC5)cc4S(=O)(=O)N(C)C)n3)cc21

Procedure:
The title compound was prepared from 8-Amino-1-ethyl-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N,N-dimethyl-5-morpholin-4-yl-benzenesulfonamide in an analogous manner to Example 61e. Product isolated as tan foam (0.076 g, 52%). MP: 130-151° C. 1HNMR (400 MHz, CDCl3, δ, ppm): 9.06 (s, 1H), 8.28 (d, J=9.1 Hz, 1H), 8.10 (s, 1H), 7.68 (d, J=2.3 Hz, 1H), 7.35 (d, J=3.0 Hz, 1H), 7.29-7.26 (m, 1H), 7.18 (dd, J=8.7 Hz and 2.1 Hz, 1H), 7.04 (dd, J=9.2 Hz and 2.9 Hz, 1H), 6.94 (br s, 1H), 3.92-3.88 (m, 4H), 3.76-3.62 (m, 2H), 3.23-3.17 (m, 4H), 2.73 (s, 6H), 2.35-2.26 (m, 2H), 2.15-1.95 (m, 2H), 1.33 (s, 6H), 1.18 (t, J=7.2 Hz, 3H). MS: 628.25 (MH)+.
Reaction SMILES: [C:1]([Br:4])(=[O:3])C.[C:5]([O:8][CH2:9][C@@H:10]1[C@@H:14]([CH2:15][O:16][C:17](=[O:19])[CH3:18])[O:13][CH2:12][O:11]1)(=[O:7])[CH3:6].[CH:20]1C=CC=CC=1>[Cl-].[Zn+2].[Cl-]>[Br:4][CH2:1][O:3][C@@H:10]([C@H:14]([O:13][C:12](=[O:11])[CH3:20])[CH2:15][O:16][C:17](=[O:19])[CH3:18])[CH2:9][O:8][C:5](=[O:7])[CH3:6]
Reactant: c1ccccc1
Reactant: CC(=O)Br
Reactant: CC(=O)OC[C@H]1OCO[C@@H]1COC(C)=O
Agent: [Cl-]
Agent: [Zn+2]
Product: CC(=O)OC[C@@H](OCBr)[C@@H](COC(C)=O)OC(C)=O
Temperature: 0 °C

Procedure:
A mixture of 25.0 g of acetyl bromide and 42.0 g of (4R,5R)-4,5-bis(acetoxymethyl)-1,3-dioxolane obtained in Example 4 was stirred under cooling with ice, and 1.0 g of anhydrous zinc chloride was added to it. After the reaction for 30 minutes, the ice water bath was dismantled and the mixture was stirred for a further one hour while stirring at room temperature. After the reaction, 50 ml of benzene was added to separate insoluble matters by filtration, and the benzene was evaporated at a low temperature (below room temperature). No peaks for the raw material were observed at all by NMR analysis of the reaction product, indicating that the decylization occurred quantitatively and the title compound was produced.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[CH3:15])[N:5]=[C:4]([CH3:16])[N:3]=1.[Br:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1>>[Cl:14][C:12]1[CH:11]=[CH:10][C:9]([CH3:15])=[C:8]([C:6]2[N:5]=[C:4]([CH3:16])[N:3]=[C:2]([NH:22][C:21]3[CH:23]=[CH:24][C:18]([Br:17])=[CH:19][CH:20]=3)[CH:7]=2)[CH:13]=1
Reactant: Cc1nc(Cl)cc(-c2cc(Cl)ccc2C)n1
Reactant: Nc1ccc(Br)cc1
Product: Cc1nc(Nc2ccc(Br)cc2)cc(-c2cc(Cl)ccc2C)n1
Yield: 21 %

Procedure:
Following the method described in Example 38, 4-chloro-6-(5-chloro-2-methyl-phenyl)-2-methyl-pyrimidine and 4-bromoaniline provided the title compound (21% yield). 1H NMR (DMSO-d6) δ 2.48 (s, 3H, CH3), 2.54 (s, 3H, CH3), 6.71 (s, 1H, Ar), 7.36 (d, 1H, J=8.2 Hz, Ar), 7.42 (dd, 1H, J=8.2 Hz, J=2.2 Hz, Ar), 7.47 (d, 1H, J=2.1 Hz, Ar), 7.52 (d, 2H, J=8.8 Hz, Ar), 7.73 (d, 2H, J=8.8 Hz, Ar), 9.72 (s, 1H, NH).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[CH:10]([OH:14])[C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22][Si](C=[N+]=[N-])(C)C>C1C=CC=CC=1.CO>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:15][CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1)[CH:10]([OH:14])[C:11]([O:13][CH3:22])=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H](CC1CCCCC1)C(O)C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)C(O)[C@@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of Example 3C (10.234 g, 34 mmol), and trimethylsilyldiazomethane (2.0M in hexanes, 25 mL) in 3.5:1 benzene/methanol (232 mL) at room temperature was stirred at 0° C. for 1 hour, warmed to ambient temperature, stirred for 1 hour, quenched by the dropwise addition of acetic acid, concentrated to provide the desired product. MS (ESI) m/e 316 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[CH2:18][S:17][C:16]3=[O:21])[N:5]2[CH:22]=1.[CH:23](=O)[CH2:24][CH2:25][CH3:26].N1CCCCC1>C(O)C>[CH:23](=[C:18]1[S:17][C:16](=[O:21])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][S:10][C:6]2[N:5]3[CH:22]=[C:2]([CH3:1])[N:3]=[C:4]3[CH:9]=[CH:8][CH:7]=2)[C:19]1=[O:20])[CH2:24][CH2:25][CH3:26]
Reactant: Cc1cn2c(SCCCCN3C(=O)CSC3=O)cccc2n1
Reactant: CCCC=O
Solvent: CCO
Solvent: C1CCNCC1
Product: CCCC=C1SC(=O)N(CCCCSc2cccc3nc(C)cn23)C1=O

Procedure:
To a solution of 0.67 g (2.0 mmol) of 3-[4-(2-methylimidazo[1,2-a]pyridin-5-ylthio)butyl]thiazolidine-2,4-dione and 0.18 ml (2.0 mmol) of n-butyraldehyde in 10 ml of ethanol, 0.02 ml (0.2 mmol) of piperidine was added, followed by refluxing for 2 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, n-hexane/ethyl acetate=1/4) to yield 0.794 g (quant, light yellow oily substance) of the desired product.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][CH:7]([OH:10])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[CH2:11]([Br:14])[CH:12]=[CH2:13]>C(OCC)C>[Br-:14].[CH2:1]([N+:4]1([CH2:13][CH:12]=[CH2:11])[CH2:9][CH2:8][CH:7]([OH:10])[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCN1CCC(O)CC1
Reactant: C=CCBr
Solvent: CCOCC
Product: C=CC[N+]1(CC=C)CCC(O)CC1
Product: [Br-]
Temperature: 5 °C
Reaction time: 24 h

Procedure:
To a 500 mL 3-necked round-bottomed flask, was added 24.0 g of 4-hydroxypiperidine dissolved in 140 mL of acetone. To this mixture was added 40.9 g of powdered anhydrous potassium carbonate. The reaction mixture was cooled to 5° C. with an ice bath. While stirring, 28.7 9 of allyl bromide in 60 mL acetone was added slowly to the reaction mixture. After addition was complete, the reaction mixture was allowed to stir at room temperature for 18 hours. The solid residue was removed by filtration, and acetone was removed from the filtrate using a rotary evaporator yielding 25.0 g of N-allyl(4-hydroxy)piperidine as viscous liquid. To a 500 mL 3-necked round-bottomed flask was added 20 g of N-allyl(4-hydroxy)piperidine dissolved in 75 mL diethyl ether. After cooling to 5° C. with an ice bath, 21.4 g of allyl bromide dissolved in 30 mL of diethyl ether was added slowly. After completion of addition of allyl bromide, the reaction mixture was allowed to warm to room temperature and stirred at room temperature for 24 hours. The solid residue thus formed was collected by filtration and was washed with diethyl ether (2×1.5 L). The washed solid was recrystallized from acetonitrile. After removal of acetonitrile by filtration, the residue was dried under vacuum yielding 22 9 of N,N-diallyl(4-hydroxy)piperidinium bromide as a white solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:22][CH3:23])=O)C.[N:24]([C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=1)=[C:25]=[O:26]>>[CH:17]1([N:16]2[C:15]3[C:14]4[CH:13]=[CH:12][CH:11]=[C:10]([O:22][CH3:23])[C:9]=4[N:8]=[CH:7][C:6]=3[C:4](=[O:3])[N:24]([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)[C:25]2=[O:26])[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: Cc1ccc(N=C=O)cc1
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCCC1
Product: COc1cccc2c1ncc1c(=O)n(-c3ccc(C)cc3)c(=O)n(C3CCCC3)c12
Yield: 64.8 %

Procedure:
1-Cyclopentyl-7-methoxy-3-p-tolyl-1H-pyrimido[5,4-c]quinoline-2,4-dione (26 mg) was prepared from 4-cyclopentylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (0.1 mmol) and 1-isocyanato-4-methyl-benzene (0.5 mmol) following general procedure C. LCMS: m/z 402 [M+1]+. 1H NMR (400 MHz, CDCl3): δ 9.49 (s, 1H), 7.84 (d, 1H), 7.61 (t, 1H), 7.38 (m, 1H), 7.34 (m, 1H), 7.32 (m, 1H), 7.24 (d, 1H), 7.08 (d, 1H), 5.03 (p, 1H), 4.16 (s, 3H), 2.43 (m, 2H), 2.29 (s, 3H), 2.08 (m, 4H), and 1.24 (m, 2H) ppm.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19]C)=[C:15]([CH2:21]C1C=CC(Cl)=CC=1)[CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2].[Cl:29][C:30]1[CH:45]=[CH:44][C:33](CC2C=C3C(=CC=2)NC=C3)=[CH:32][CH:31]=1.[CH2:46]([O:48]C(=O)C([N+]([O-])=O)C(O)CC)C>C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][O:48][CH3:46])=[C:15]([CH2:21][C:31]1[CH:32]=[CH:33][CH:44]=[CH:45][C:30]=1[Cl:29])[CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: Clc1ccc(Cc2ccc3[nH]ccc3c2)cc1
Reactant: CCOC(=O)C(C(O)CC)[N+](=O)[O-]
Reactant: CCOC(=O)c1ncc2[nH]c3cccc(Cc4ccc(Cl)cc4)c3c2c1CC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ncc2[nH]c3cccc(Cc4ccccc4Cl)c3c2c1COC

Procedure:
5-(4-chlorobenzyl)-4-ethyl-β-carboline-3-carboxylic acid ethyl ester from 5-(4-chlorobenzyl)-indole and 3-hydroxy-2-nitrovaleric acid ethyl ester, melting point 265° C. (ethyl acetate);
Reaction SMILES: [OH:1][CH:2]1[O:10][CH2:9][C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].F[C:12](F)(F)S(O)(=O)=O.C(N([CH2:24][CH3:25])CC)C>C(O)C=C>[CH2:12]([C:2]1([O:10][CH2:9][C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4])[OH:1])[CH:24]=[CH2:25]
Reactant: CCN(CC)CC
Reactant: OC1OC[C@@H](O)[C@H](O)[C@H]1O
Reactant: O=S(=O)(O)C(F)(F)F
Solvent: C=CCO
Product: C=CCC1(O)OC[C@@H](O)[C@H](O)[C@H]1O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Xylopyranose (15.0 g) was dissolved in allyl alcohol (150 mL) and trifluoromethane sulfonic acid (235 μL) was dropwise added 0° C. The reaction was stirred at 0° C. for 15 minutes and then heated at 80° C. for 4 hours. The reaction solution was then neutralized with triethylamine and evaporated to dryness. Chromatography of the material of silica gel using dichloromethne-methanol (19:1) as eluent provided allyl-xylopyranose (14.9 g).
Reaction SMILES: [OH:1][CH:2]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:6][CH2:5]1)[CH3:3].CCN(CC)CC.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl>[CH3:27][S:28]([O:1][CH:2]([CH:4]1[CH2:5][CH2:6][N:7]([C:10]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:11])[CH2:8][CH2:9]1)[CH3:3])(=[O:30])=[O:29]
Reactant: CC(O)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(OS(C)(=O)=O)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
A mixture of (±)-phenylmethyl 4-(1-hydroxyethyl)-1-piperidinecarboxylate (0.64 g, 2.43 mmol), Et3N (1.03 mL, 7.29 mmol) in CH2Cl2 (50 mL) at 0° C. was treated dropwise with methanesulfonyl chloride (0.38 mL, 4.86 mmol). The reaction mixture was stirred at 0° C. for 1 h, then at ambient temperature for 1.5 h, diluted with CH2Cl2 (100 mL) and washed with 1M NaH2PO4 (50 mL×2) and brine (25 mL). The CH2Cl2 layer was dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as a light brown oil. The crude product was purified by flash chromatography on an ISCO silica gel column using 0 to 45% EtOAc/hexanes to give 0.73 g (88%) of (±)-phenylmethyl 4-{1-[(methylsulfonyl)oxy]ethyl}-1-piperidinecarboxylate as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.40-7.25 (m, 5H), 5.12 (s, 2H), 4.70-4.60 (m, 1H), 4.25 (bs, 2H), 2.99 (s, 3H), 2.80-2.65 (m, 2H), 1.85-1.60 (m, 3H), 1.40 (d, 3H, J=6.4 Hz), 1.35-1.20 (m, 2H).
Reaction SMILES: [CH:1]1[C:11]2[C:10]3=[CH:12][C:13]4[CH:14]=[CH:15][C:16]([C:19](O)=[O:20])=[CH:17][C:18]=4[N:9]3[CH2:8][CH:7]=[CH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C[N:23](C)S(N)(=O)=O.N=C=N.C[N:33](C)[CH:34]=[O:35]>CN(C1C=CN=CC=1)C>[CH:1]1[C:11]2[C:10]3=[CH:12][C:13]4[CH:14]=[CH:15][C:16]([C:19]([NH2:23])=[O:20])=[CH:17][C:18]=4[N:9]3[CH2:8][C:7]([C:34]([NH2:33])=[O:35])=[CH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CN(C)C=O
Reactant: CN(C)S(N)(=O)=O
Reactant: O=C(O)c1ccc2cc3n(c2c1)CC=Cc1ccccc1-3
Agent: CN(C)c1ccncc1
Agent: N=C=N
Product: NC(=O)C1=Cc2ccccc2-c2cc3ccc(C(N)=O)cc3n2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-3-methoxy-6-[[[2-(methylamino)-2-oxoethyl]amino]carbonyl]- (110 mg, 0.22 mmol), N,N-dimethylsulfamide (136 mg, 1.10 mmol) and DMAP (134 mg, 1.10 mmol) in dimethylformamide (2 mL) was added PS-carbodiimide (576 mg, 1.3 mmol/g, 0.88 mmol). The reaction solution was shaken at rt overnight, filtered, concentrated and purified by preparative HPLC (MeOH/H2O with an NH4OAc buffer) to yield 7H-indolo[2,1-a][2]benzazepine-6,10-dicarboxamide, 13-cyclohexyl-N10-[(dimethylamino)sulfonyl]-3-methoxy-N6-[2-(methylamino)-2-oxoethyl]- (40 mg, 0.07 mmol, 30%) as a yellow solid. 1HNMR (500 MHz, CD3OD) δ 8.13 (s. 1H), 7.85 (d, J=8.6 Hz, 1H), 7.60-7.52 (m, 3H), 7.15 (dd, J=2.8, 8.8 Hz, 1H), 7.10 (d, J=2.8 Hz, 1H), 5.64-5.53 (m, 1H), 4.19-4.07 (m, 1H), 3.96-3.86 (m, 2H), 3.91 (s, 3H), 2.99 (s, 6H), 2.89-2.80 (m, 1H), 2.71 (s, 3H), 2.16-1.70 (m, 6H), 1.54-1.16 (m, 4H). LCMS: m/e 606 (M−H)−, ret time 1.57 min, column A, 3 minute gradient.
Reaction SMILES: C(C1OC1)Cl.B(F)(F)F.[CH3:10][CH2:11][O:12][CH2:13][CH3:14].[F:15][B-:16]([F:19])([F:18])[F:17].[CH2:20]([O+:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[CH3:21].[CH3:27][N:28]1C=C[CH:31]=[CH:30][C:29]1=O>CCOCC.C(Cl)Cl>[F:15][B-:16]([F:19])([F:18])[F:17].[CH2:20]([O+:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[CH3:21].[F:15][B-:16]([F:19])([F:18])[F:17].[CH2:11]([O:12][C:13]1[CH:14]=[CH:31][CH:30]=[CH:29][N+:28]=1[CH3:27])[CH3:10]
Reactant: CCOCC
Reactant: Cn1ccccc1=O
Agent: CC[O+](CC)CC
Agent: FB(F)F
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: ClCC1CO1
Product: CCOc1cccc[n+]1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 71 %

Procedure:
Triethyloxonium fluoroborate is prepared from 3.70 g (0.040 mole) of epichlorohydrin in 14 ml of ether and 7.58 g (0.054 mole) of boron trifluoride etherate in 6 ml of ether. The resulting solid triethyloxonium tetrafluoroborate is dissolved in 20 ml of dry methylene chloride and treated under nitrogen with 4.36 g (0.040 mole) of 1-methyl-2-pyridone in 15 ml of methylene chloride. The reaction mixture is stirred under nitrogen at room temperature overnight (about 16 hours). The solvent is evaporated at room temperature, in vacuo and the quaternary salt obtained is recrystallized from methanol-ether (1:1) to give 8.0 g (71%) of 2-ethoxy-1-methylpyridinium fluoroborate, m.p. 58°-60° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9](Cl)[N:8]=[N:7][C:6]=1[Cl:12])([CH3:4])([CH3:3])[CH3:2].O.[NH2:14][NH2:15]>C(O)C>[C:1]([C:5]1[CH:10]=[C:9]([NH:14][NH2:15])[N:8]=[N:7][C:6]=1[Cl:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(Cl)nnc1Cl
Reactant: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1cc(NN)nnc1Cl
Yield: 60.7 %

Procedure:
4-t-Butyl-3,6-dichloropyridazine (Samaritoni, J. G.; Org. Prep. & Proc. Intl., 1988, 20(2), 117-121) (16 g, 78 mmol) and hydrazine monohydrate (24.7 mL, 780 mmol) in ethanol (250 mL) were heated at reflux for 16 hours. The solvent was removed and hydrochloric acid (5M) was added and the resulting mixture was washed with dichloromethane. The aqueous layer was poured onto ice and ammonium hydroxide was added until the mixture was basic. The mixture was extracted with dichoromethane, dried (MgSO4) filtered and evaporated to give a yellow solid (9.5 g, 61%) 1HNMR (360 MHz, CDCl3) δ 1.46 (9H, s, t Bu), 378 (2H, br s, NH2), 6.84 (1H, br s, NH), 7.10 (1H, s, ArH); MS (ES+) m/e 201 [MH+].
Reaction SMILES: S(Cl)(Cl)=O.ClC1C=CC=CC=1OC(C)C(O)=O.ClC1C=CC=CC=1OC(C)C(Cl)=O.[CH3:31][O:32][C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][C:42]=1[O:43][CH3:44])[N:39]=[CH:38][N:37]=[C:36]2[O:45][C:46]1[CH:52]=[CH:51][C:49]([NH2:50])=[CH:48][CH:47]=1.[Cl:53][C:54]1[CH:67]=[CH:66][CH:65]=[CH:64][C:55]=1[O:56][CH:57]([CH3:63])[C:58]([N:60]=[C:61]=[S:62])=[O:59]>C1(C)C=CC=CC=1.C(O)C>[Cl:53][C:54]1[CH:67]=[CH:66][CH:65]=[CH:64][C:55]=1[O:56][CH:57]([CH3:63])[C:58]([NH:60][C:61]([NH:50][C:49]1[CH:51]=[CH:52][C:46]([O:45][C:36]2[C:35]3[C:40](=[CH:41][C:42]([O:43][CH3:44])=[C:33]([O:32][CH3:31])[CH:34]=3)[N:39]=[CH:38][N:37]=2)=[CH:47][CH:48]=1)=[S:62])=[O:59]
Reactant: CC(Oc1ccccc1Cl)C(=O)N=C=S
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Agent: CC(Oc1ccccc1Cl)C(=O)Cl
Agent: CC(Oc1ccccc1Cl)C(=O)O
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O=S(Cl)Cl
Product: COc1cc2ncnc(Oc3ccc(NC(=S)NC(=O)C(C)Oc4ccccc4Cl)cc3)c2cc1OC
Temperature: 100 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
Toluene (20 ml) and thionyl chloride (1 ml) were added to commercially available 2-(2-chlorophenoxy)propanoic acid (80 mg), and the mixture was heated at 100° C. for one hr. The solvent was removed by distillation, and 2-(2-chlorophenoxy)propanoyl isothiocyanate was prepared using the resultant 2-(2-chlorophenoxy)propanoyl chloride as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 2-(2-chlorophenoxy)propanoyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (45 mg, yield 50%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:9][CH2:10][C@@H:11]2[CH2:14][CH2:13][N:12]2C(OC(C)(C)C)=O)[CH:5]=[N:6][C:7]=1[Cl:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[ClH:8].[Br:1][C:2]1[CH:3]=[C:4]([O:9][CH2:10][C@@H:11]2[CH2:14][CH2:13][NH:12]2)[CH:5]=[N:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cnc(Cl)c(Br)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cl
Product: Clc1ncc(OC[C@@H]2CCN2)cc1Br
Reaction time: 0.5 h

Procedure:
To 5-bromo-6-chloro-3-(1-BOC-2-(S)-azetidinylmethoxy)pyridine from step 66a (360 mg, 0.95 mmol) was added TFA in methylene chloride at 0° C., and the mixture was stirred for 30 minutes. The volatiles were then removed under vacuum. The residue was neutralized with NaHCO3 to pH 8, then extracted with methylene chloride, which was dried over MgSO4 and concentrated. The residue was chromatographed on a silica gel column, eluting with methylene chloride:methanol:NH4OH 10:1:0.1 to afford to give the free base of the title compound. The base was converted to the salt by treatment with hydrogen chloride saturated ethanol to give the title compound (224 mg). mp 168°-169° C. MS (DCI/NH3) m/z 277, 279 (M+H)+. 1H NMR (D2O, 300 MHz) δ: 2.69 (dd, J=7.0, 8.5, 2H), 4.06-4.20 (m, 3H), 4.43 (d, J=4.5, 2H), 4.91-4.99 (m, 1H), 7.94 (d, J=3.0, 1H), 8.17 (d, J=3.0, 1H). Anal. Calcd for C9H10N2OBrCl·0.9 HCl: C, 34.83; H, 3.54; N, 9.03. Found: C, 34.85; H, 3.56; N, 8.82. [α]25D =-4.81° (c 0.13, MeOH).
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.CNC(=O)[O-].[CH3:14][O:15][C:16]1[CH:17]=[CH:18][C:19]2[CH:20]([CH3:28])[CH:21]3[CH2:25][NH:24][CH2:23][CH:22]3[C:26]=2[CH:27]=1>CC#N.O.CCOC(C)=O>[CH3:14][O:15][C:16]1[C:17]([Br:8])=[CH:18][C:19]2[CH:20]([CH3:28])[CH:21]3[CH2:25][NH:24][CH2:23][CH:22]3[C:26]=2[CH:27]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc2c(c1)C1CNCC1C2C
Agent: CNC(=O)[O-]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1Br)C(C)C1CNCC21
Temperature: 25 °C
Reaction time: 8 h
Yield: 118.1 %

Procedure:
NBS (70 mg, 0.4 mmol) was added to a solution of N-methylcarbamate-5-methoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 2, step A) (0.1 g, 0.36 mmol) in CH3CN (3.6 mL), and stirred overnight at room temperature. The reaction was diluted with H2O and EtOAc and filtered through an Extrelut column. The column was washed with EtOAc and the filtrate was concentrated to afford 120 mg (94%) of the subtitle compound. MS calculated for C16H20BrNO3+H: 342, observed: 342.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+].Cl[CH2:14][CH2:15][CH2:16][C:17](Cl)=[O:18].Cl>O.C1(C)C=CC=CC=1>[N:1]1([C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)[CH2:14][CH2:15][CH2:16][C:17]1=[O:18]
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: O=C(Cl)CCCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(O)c1ccc(N2CCCC2=O)cc1
Temperature: 17.5 °C
Reaction time: 1 h
Yield: 96.1 %

Procedure:
4-Aminobenzoic acid (100 g, 0.73 mol) is suspended in water (400 mL) and toluene (200 mL), and thereto is added dropwise 30% aqueous sodium hydroxide solution (97 g, 0.73 mol) under ice-cooling. After confirming that pH is basic enough, 4-chlorobutyric chloride (103 g, 0.73 mol) and 30% aqueous sodium hydroxide solution (290 g, 2.2 mol) are added dropwise simultaneously while maintaining the pH range of 9-12 and temperature range of 15-20° C. over 1 hour. After stirring at room temperature for 1 hour, sodium hydroxide (88 g, 2.2 mol) is added to the mixture under ice-cooling. To the reaction solution is added conc. hydrochloric acid (370 g) at 30° C. or below and precipitated crystals are collected by filtration. The resulting crystals are washed with water and air-dried at 40° C. to give 4-(2-pyrrolidon-1-yl)benzoic acid (144 g, yield: 96.0%, purity: 98.3%). The purity was determined by HPLC analysis.
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:45]=[CH:44][C:43]([NH2:46])=[CH:42][CH:41]=2)=[N:8]1.Cl.[C:48](Cl)(=O)[C:49]1[CH:54]=[CH:53][CH:52]=[N:51][CH:50]=1.C(N(CC)CC)C.[O:64]1CCC[CH2:65]1>>[NH:18]1[CH:19]=[N:20][C:16]([C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[NH:7][N:8]=[C:9]3[C:40]2[CH:45]=[CH:44][C:43]([NH:46][C:65](=[O:64])[CH2:48][C:49]3[CH:50]=[N:51][CH:52]=[CH:53][CH:54]=3)=[CH:42][CH:41]=2)=[N:17]1
Reactant: C1CCOC1
Reactant: O=C(Cl)c1cccnc1
Reactant: Nc1ccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)cc1
Agent: Cl
Solvent: CCN(CC)CC
Product: O=C(Cc1cccnc1)Nc1ccc(-c2n[nH]c3ccc(-c4nc[nH]n4)cc23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
To a solution of 4-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.306 g, 0.51 mmol) in tetrahydrofuran (4.5 mL) was added nicotinoyl chloride hydrochloride (0.409 g, 0.79 mmol) and triethylamine (0.35 mL, 2.52 mmol). The reaction mixture was stirred overnight at room temperature, and quenched with methanol (0.20 mL). This mixture was washed with sodium bicarbonate (aqueous) and extracted with ethyl acetate (3×). The organic fractions were combined, dried with magnesium sulfate, filtered, and condensed resulting in a crude solid (0.346 g) that was used without further purification. This solid was dissolved in 6 N hydrochloride solution (aqueous) (5 mL) and 1,4-dioxane (5 mL) and allowed to stir at room temperature overnight. The reaction was quenched by adding the reaction mixture dropwise to a solution of sodium bicarbonate (saturated aqueous) to form a precipitate, which was filtered and dried in a vacuum oven overnight. (0.109 g, 56% yield): 1H NMR (DMSO-d6) δ 9.12 (d, 1H), 8.78 (dd, 1H), 8.72 (s, 1H), 8.34 (dt,1H), 8.29 (s, 1H), 8.04 (m, 5H), 7.68 (d, 1H), 7.60 (ddd, 1H); ES-MS (m/z) 382 [M+1]+.