Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([S:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)=[CH:20][CH:19]=2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.CO.[ClH:35].CCOCC>>[ClH:35].[F:32][C:29]1[CH:28]=[CH:27][C:26]([CH2:25][O:24][C:21]2[CH:22]=[CH:23][C:18]([CH2:17][S:16][C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[O:15])=[CH:19][CH:20]=2)=[CH:31][CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)SCc2ccc(OCc3ccc(F)cc3)cc2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: O=C(SCc1ccc(OCc2ccc(F)cc2)cc1)N1CCNCC1

Procedure:
A solution of 4.89 g (10.6 mmol) 4-[4-(4-fluoro-benzyloxy)-benzylsulfanylcarbonyl]-piperazine-1-carboxylic acid tert-butyl ester in 120.6 ml 1.5M HCl/Et2O and 24.1 ml abs. MeOH was stirred at rt for 6 h. Evaporation of the reaction mixture provided 3.96 g piperazine-1-carbothioic acid S-[4-(4-fluoro-benzyloxy)-benzyl] ester hydrochloride as colourless powder, mp. 169–169.5° C. 1H-NMR(d6-DMSO): 3.05 m, 4H and 3.58–3.75 m, 4H; 4.09 s, 2H; 5.06 s, 2H; 6.94 d, 2H, 7.17–7.30 m, 4H and 7.43–7.55 m, 2H; 9.2 br, 2H. MS (ISP): 361.2 (M+H)+.
Reaction SMILES: C(N1C2C=CC=CC=2C([N+]([O-])=[O:15])=CC2C=CC=CC1=2)#N.B(F)(F)F.[C:25]([N:28]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[C:32]([N+]([O-])=O)=[CH:31][C:30]2[CH:42]=[CH:43][CH:44]=[CH:45][C:29]1=2)(=[O:27])[NH2:26]>ClC1C=CC=CC=1.C(O)(=O)C>[C:25]([N:28]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[C:32](=[O:15])[CH2:31][C:30]2[CH:42]=[CH:43][CH:44]=[CH:45][C:29]1=2)(=[O:27])[NH2:26]
Reactant: NC(=O)N1c2ccccc2C=C([N+](=O)[O-])c2ccccc21
Reactant: N#CN1c2ccccc2C=C([N+](=O)[O-])c2ccccc21
Agent: FB(F)F
Solvent: CC(=O)O
Solvent: Clc1ccccc1
Product: NC(=O)N1c2ccccc2CC(=O)c2ccccc21

Procedure:
31.5 g (0.12 mole) of 5-cyano-10-nitro-5H-dibenz[b,f]azepine are suspended in 340 ml of chlorobenzene and 98 ml of a solution of 10% by weight of BF3 in acetic acid are quickly added. By heating to 30° dissolution occurs and shortly after that the BF3 adduct of 5-carbamoyl-10-nitro-5H-dibenz[b,f]azepine begins to precipitate. The mixture is left to crystallise for 2 hours in an ice-bath, suction-filtered and washed with benzine. The dry intermediate is dissolved in a mixture of 200 ml of acetic acid and 35 ml of water. 50 g of iron powder are added in portions over a period of 30 minutes and the temperature is maintained at approximately 60° by cooling. The mixture is stirred for a further hour at 50°, filtered and then washed with acetic acid. The filtrate is concentrated by evaporation in vacuo and the residue is taken up in 500 ml of water. The precipitated product is suction-filtered, washed neutral with water and dried in vacuo at 50°. 5-Carbamoyl-10-oxo-10,11-dihydro-5H-dibenz[b,f]azepine is obtained, which according to the IR spectrum is identical to authentic material.
Reaction SMILES: [C:1]1([C@H:7]([N:9]2[CH2:13][CH2:12][C@@H:11]([CH2:14]O)[CH2:10]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(CC)CC.[CH3:23][S:24](Cl)(=[O:26])=[O:25].O>C(Cl)Cl>[C:1]1([C@H:7]([N:9]2[CH2:13][CH2:12][C@@H:11]([CH2:14][S:24]([CH3:23])(=[O:26])=[O:25])[CH2:10]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)Cl
Reactant: C[C@H](c1ccccc1)N1CC[C@@H](CO)C1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](c1ccccc1)N1CC[C@@H](CS(C)(=O)=O)C1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 103.5 %

Procedure:
To a solution of (3R)-1-[(R)-1-phenylethyl]-3-(hydroxymethyl)pyrrolidine (25.2 g, 0.12 mol) in CH2Cl2 (250 mL) was added Et3N (18.8 mL, 0.13 mol). The mixture was cooled to 0° C. and treated dropwise with methanesulfonyl chloride (10.63 mL, 0.13 mol) dissolved in CH2Cl2 (125 mL). The mixture was stirred at 0° for 1.5 hours and then at 25° C. for 4 hours. Water was added and the organic layer was separated, washed with NaHCO3 (2×), dried (MgSO4) and concentrated to provide (3R)-1-[(R)-1-phenylethyl]-3-(methanesulfonyl methyl)pyrrolidine (2a, 33.2 g); NMR (CDCl3) δ 1.39 (m, 3H), 1.54 (m, 1H), 2.0 (m, 1H), 2.3-2.8 (m, 5H), 2.98 (d, 3H), 3.29 (q, 1H), 4.14 (t, 2H), 7.31 (m, 5H). The material was used directly in the next step.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.Br[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1>>[C:24]1([C:22]([C:9]2[CH:10]=[N:11][C:12]3[C:17]([C:8]=2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([O:1][CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=4)[CH:3]=2)=[CH:16][CH:15]=[CH:14][C:13]=3[C:18]([F:21])([F:19])[F:20])=[O:23])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: BrCc1ccccn1
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(O)c1
Product: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(OCc2ccccn2)c1

Procedure:
The title compound was prepared from [4-(3-hydroxyphenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and 2-Bromomethyl-pyridine following the procedure of Example 478: MS (ESI) m/z 485.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=2)[C:9]([OH:11])=O)[CH:5]=[CH:4][CH:3]=[CH:2]1.[N:15]1([CH2:21][CH2:22][O:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]([NH2:34])=[CH:26][CH:25]=2)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>>[N:15]1([CH2:21][CH2:22][O:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]([NH:34][C:9](=[O:11])[C:8]3[CH:12]=[CH:13][CH:14]=[C:6]([N:1]4[CH:2]=[CH:3][CH:4]=[CH:5]4)[CH:7]=3)=[CH:26][CH:25]=2)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: Nc1ccc(OCCN2CCOCC2)c2ccccc12
Reactant: O=C(O)c1cccc(-n2cccc2)c1
Product: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1cccc(-n2cccc2)c1

Procedure:
Compound is prepared from 3-pyrrol-1-yl-benzoic acid and 4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-ylamine according to conditions described in general procedure G. (96 mg) (40%). Mp: 142-143° C. 1H NMR (300 MHz, DMSO-d6) δ 10.38 (s, 1H), 8.25 (m, 2H), 7.90 (m, 2H), 7.83 (d, J=8.1, 1H), 7.66-7.47 (m, 6H), 7.06 (d, J=8.4 Hz, 1H), 6.32 (brs, 2H), 4.33 (t, J=5.4, 2H), 3.62 (brt, 4H), 2.93 (brs, 2H), 2.62 (brs, 4H). MS: 442 (M+1).
Reaction SMILES: [O:1]=[C:2]1[CH:6]([N:7]2[C:15](=[O:16])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]2=[O:17])[CH2:5][CH2:4][NH:3]1.[C:18]1(=O)N(C2CCCNC2=O)C(=O)C2=CC=CC=C12>>[CH3:18][O:1][C:2]1[CH:6]([N:7]2[C:15](=[O:16])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]2=[O:17])[CH2:5][CH2:4][N:3]=1
Reactant: O=C1NCCCC1N1C(=O)c2ccccc2C1=O
Reactant: O=C1NCCC1N1C(=O)c2ccccc2C1=O
Product: COC1=NCCC1N1C(=O)c2ccccc2C1=O

Procedure:
By analogy with the method described in example 1 (step 1.1), using 2-(2-Oxo-pyrrolidin-3-yl)-isoindole-1,3-dione (prepared by analogy to the method described in (Heterocycles (1996), 42(2), 537-42, Enantiomer (2001), 6(5), 275-279, Synthesis (1991), (5), 417-20)) in place of 3-phtalimidopiperidin-2-one, the compound was obtained as a white powder.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[C:9]([Br:11])[CH:8]=[C:7]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[C:6]=1[Cl:21])C=C.C(N(CC)[C:25]1[CH:30]=CC=C[CH:26]=1)C>>[CH2:30]([C:10]1[C:9]([Br:11])=[CH:8][C:7]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)=[C:6]([Cl:21])[C:5]=1[OH:4])[CH:25]=[CH2:26]
Reactant: CCN(CC)c1ccccc1
Reactant: C=CCOc1cc(Br)cc(Cc2ccc(OC)cc2)c1Cl
Product: C=CCc1c(Br)cc(Cc2ccc(OC)cc2)c(Cl)c1O
Temperature: 200 °C
Reaction time: 45 h
Yield: 91 %

Procedure:
The mixture of bromide 184 (2.52 g, 6.85 mmol) in N,N-diethylaniline (8 mL) was stirred at 200° C. for 45 hours. The mixture was cooled to rt and extracted with EtOAc/aq. 1N HCl solution (100 mL/100 mL). The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography to provide the desired product 185 (2.3 g, 91%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:30]2[S:34][C:33]([C:35]3([O:39][CH2:40][O:41][CH3:42])[CH2:38][CH2:37][CH2:36]3)=[N:32][CH:31]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:18]=[CH:17][C:14]([CH:15]=O)=[C:13]([F:19])[CH:12]=3)[N:8]([S:20]([C:23]3[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:5]2=[N:6][CH:7]=1.[F:43][CH:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1.Cl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.ClCCl.CO>[Cl:1][C:2]1[C:3]([C:30]2[S:34][C:33]([C:35]3([O:39][CH2:40][O:41][CH3:42])[CH2:36][CH2:37][CH2:38]3)=[N:32][CH:31]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:18]=[CH:17][C:14]([CH2:15][N:47]4[CH2:48][CH2:49][CH:44]([F:43])[CH2:45][CH2:46]4)=[C:13]([F:19])[CH:12]=3)[N:8]([S:20]([C:23]3[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:5]2=[N:6][CH:7]=1
Reactant: COCOC1(c2ncc(-c3c(Cl)cnc4c3cc(-c3ccc(C=O)c(F)c3)n4S(=O)(=O)c3ccc(C)cc3)s2)CCC1
Reactant: FC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CO
Product: COCOC1(c2ncc(-c3c(Cl)cnc4c3cc(-c3ccc(CN5CCC(F)CC5)c(F)c3)n4S(=O)(=O)c3ccc(C)cc3)s2)CCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a 4 mL reaction vial was added 4-(5-chloro-4-(2-(1-(methoxymethoxy)cyclobutyl)thiazol-5-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-fluorobenzaldehyde (Example 30A) (53 mg, 0.085 mmol), 4-fluoropiperidine, hydrochloric acid (35.46 mg, 0.255 mmol), methanol (0.5 ml), dichloromethane (0.5 ml), and a few drops of acetic acid. The reaction mixture was stirred at room temperature for 30 minutes, and sodium triacetoxyborohydride (53.82 mg, 0.255 mmol) was added. The reaction was stirred at room temperature overnight and then carefully quenched by addition of saturated sodium bicarbonate solution (about 400 μL) and dichloromethane (about 1 mL). The organic layer was collected, and the aqueous layer extracted with dichloromethane (2×1 mL). The combined organics were concentrated to give the title compound, which was used without further purification. MS APCI(+) m/z 713.42 [M+H]+.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:14]([OH:16])=O)[CH3:13])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC.[NH2:39][CH2:40][CH2:41][CH:42]([O:46][CH2:47][CH3:48])[O:43][CH2:44][CH3:45].C(N(CC)C(C)C)(C)C>O1CCCC1>[CH2:44]([O:43][CH:42]([O:46][CH2:47][CH3:48])[CH2:41][CH2:40][NH:39][C:14](=[O:16])[C@@H:12]([NH:11][C:1](=[O:2])[O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[CH3:13])[CH3:45]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CCOC(CCN)OCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(CCNC(=O)[C@H](C)NC(=O)OCc1ccccc1)OCC
Yield: 84.8 %

Procedure:
By using an analogous procedure to that described for Reference Example 13, carbobenzyloxy-L-alanine (2 g, 8.99 mmol), hydroxybenzotriazole (1.2 g, 8.99 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.72 g, 8.99 mmol), 1-amino-3,3-diethoxypropane (1.25 g, 8.53 mmol) and N,N-diisopropylethylamine (1.56 ml, 8.99 mmol) were reacted in anhydrous tetrahydrofuran (40 ml) at room temperature for 16 h, to provide benzyl (1S)-2-[(3,3-diethoxypropyl)amino]-1-methyl-2-oxoethylcarbamate (2.55 g, 85%) as a pale yellow solid.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[CH:13]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]([O:17]C(Cl)=O)[CH3:16].[N-:21]=[N+:22]=[N-:23].[Na+]>CC(C)=O.O>[CH2:1]([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1/[CH:13]=[CH:16]/[C:15]([N:21]=[N+:22]=[N-:23])=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cl
Reactant: O=Cc1cccn1Cc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: [N-]=[N+]=NC(=O)/C=C/c1cccn1Cc1ccccc1
Reaction time: 2 h
Yield: 67.9 %

Procedure:
To a mixture of 1-benzyl-1H-pyrrole-2-carbaldehyde (28.4 g, 0.125 mol) and TEA (13.5 mL, 0.187 mol) in acetone (300 mL) was added ethylchloroformate (17.9 mL, 0.87 mol) dropwise. The reaction was stirred for 1.5 h after which NaN3 (13 g, 0.200 mol) in H2O (100 mL) was added. After 2 h, the reaction was diluted with water and left overnight. The acetone was removed and the product was filtered off to afford 21.4 g of a light brown solid. This compound was taken to the next step.
Reaction SMILES: [CH3:1][C:2]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[C:10]([OH:15])[CH:11]=3)[C:6]=2[CH:5]=[CH:4][N:3]=1.Br[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH3:1][C:2]1[C:14]2[N:13]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH2:6][C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)[CH:11]=3)[C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: Cc1nccc2c1[nH]c1cc(O)ccc12
Reactant: BrCc1ccccc1
Product: Cc1nccc2c3ccc(OCc4ccccc4)cc3n(Cc3ccccc3)c12
Yield: 66 %

Procedure:
The title compound was synthesized from 1-methyl-7-hydroxy-β-carboline (1 g, 3.173 mmol) in presence of 1-bromomethylbenzene (1.085 g, 6.346 mmol) as described here above.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[N:12](S(C3C=CC=CC=3)(=O)=O)[CH:11]=[C:10]([CH:22]=[O:23])[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[OH-].[Na+]>CO.O1CCCC1.[Cl-].[Na+].O>[F:1][C:2]1[C:7]([C:8]2[NH:12][CH:11]=[C:10]([CH:22]=[O:23])[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=Cc1cc(-c2cccnc2F)n(S(=O)(=O)c2ccccc2)c1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1c[nH]c(-c2cccnc2F)c1
Reaction time: 1 h
Yield: 79.5 %

Procedure:
5-(2-Fluoropyridin-3-yl)-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde (2.25 g) was dissolved in methanol (20 mL) and tetrahydrofuran (20 mL), a 8 mol/L aqueous sodium hydroxide solution (20 mL) was added dropwise at room temperature and the mixture was stirred for 1 hr. The reaction mixture was diluted with saturated brine, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Ethyl acetate was added to the residue and insoluble crystals were collected by filtration to give the title compound as pale-brown crystals (yield 1.03 g, 79%).
Reaction SMILES: C(C1C=C(C(C)C)C=C(C(C)C)C=1S(NN=[C:21]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])(=O)=O)(C)C.[CH:33](=[O:42])[C:34]1[C:35](OC)=[CH:36][CH:37]=[CH:38][CH:39]=1>>[CH:34]1([CH:33]([OH:42])[C:21]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:22][CH2:23][N:24]([CH3:25])[CH3:26])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]1
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)NN=C(CCN(C)C)c2ccccc2)c(C(C)C)c1
Reactant: COc1ccccc1C=O
Product: CN(C)CC=C(c1ccccc1)C(O)C1CCCCC1
Yield: 60.3 %

Procedure:
By using a method similar to that described in Example 22, but starting from β-dimethylaminopropiophenone 2,4,6-triisopropylbenzenesulphonylhydrazone (20 g) and from o-anisaldehyde (6.5 g), 4-dimethylamino-1-(2-methoxyphenyl)-2-phenyl-2-buten-1-ol (Z) (7.2 g) is obtained in the form of a white powder melting at 77° C. after recrystallisation from a mixture (85 cc) of petroleum ether and isopropyl ether (70/30 by volume).
Reaction SMILES: CC1N[C:5]2[N:6]=[CH:7][CH:8]=[C:9](O)[C:4]=2C=1.[F:12][C:13]1[CH:14]=[C:15]([N+:20]([O-:22])=[O:21])[CH:16]=[CH:17]C=1F.[C:23](=[O:26])([O-])[O-].[K+].[K+]>CN(C=O)C.O>[F:12][C:13]1[CH:14]=[C:15]([N+:20]([O-:22])=[O:21])[CH:16]=[CH:17][C:23]=1[O:26][N:6]1[C:5]2=[CH:14][CH:15]([CH3:16])[NH:20][C:4]2=[CH:9][CH:8]=[CH:7]1
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: Cc1cc2c(O)ccnc2[nH]1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1C=C2C(=CC=CN2Oc2ccc([N+](=O)[O-])cc2F)N1
Temperature: 50 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
A mixture of 2-methyl-1H-pyrrolo[2,3-b]pyridin-4-ol (90 mg, TFA salt, 0.34 mmol), 3,4-difluoronitrobenzene (0.05 mL) and potassium carbonate (100 mg, 0.72 mmol) in DMF (1 mL) was stirred at 50° C. for 2 h. The mixture was diluted with water and extracted with ethyl acetate (3×5 mL). The combined extracts were washed with water, dried (MgSO4) and concentrated in vacuo to afford the crude product, which was purified by preparative HPLC to give the title compound (45 mg, 46%). 1H NMR (CD3OD) δ 8.25 (dd, 2H, J=10.4, 2.6 Hz), 8.12 (m, 1H), 8.04 (d, 1H, J=5.5 Hz), 7.30 (t, 1H, J=8.3 Hz), 6.67 (d, 1H, J=5.5 Hz), 5.95 (s, 1H), 2.41 (s, 3H); MS(ESI+) m/z 288 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:19]([F:20])=[CH:18][CH:17]=[C:16]([F:21])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13](I)=[CH:14][C:6]1=2.[Cl:22][C:23]1[CH:28]=[CH:27][C:26](B2OC(C)(C)C(C)(C)O2)=[CH:25][N:24]=1>>[Cl:1][C:2]1[C:19]([F:20])=[CH:18][CH:17]=[C:16]([F:21])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13]([C:27]3[CH:26]=[CH:25][N:24]=[C:23]([Cl:22])[CH:28]=3)=[CH:14][C:6]1=2
Reactant: CC1(C)OB(c2ccc(Cl)nc2)OC1(C)C
Reactant: Fc1ccc(F)c(CN2CCNc3ncc(I)cc32)c1Cl
Product: Fc1ccc(F)c(CN2CCNc3ncc(-c4ccnc(Cl)c4)cc32)c1Cl
Yield: 50 %

Procedure:
1-(2-Chloro-3,6-difluorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (308 mg) was coupled to 2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine as in General Procedure 4B to give the title compound (50% yield). LCMS: m/z=407.32 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 3.30 (2H, t, J=4.8 Hz), 3.56 (2H, m), 4.34 (2H, s), 5.35 (1H, bs), 7.06 (2H, m), 7.15 (1H, m), 7.33 (1H, dd, J=5.3, 1.5 Hz), 5.46 (1H, m), 7.80 (1H, d, J=1.5 Hz), 8.34 (1H, d, J=5.3 Hz).
Reaction SMILES: Cl.[CH3:2][NH:3][C:4]1([C:13]#[N:14])[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1.[O-:15][C:16]#N.[K+].CC(O)=[O:21]>O>[CH3:2][N:3]1[C:4]2([CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:5]2)[C:13](=[O:21])[NH:14][C:16]1=[O:15]
Reactant: N#C[O-]
Reactant: CC(=O)O
Reactant: CNC1(C#N)Cc2ccccc2C1
Agent: Cl
Agent: [K+]
Solvent: O
Product: CN1C(=O)NC(=O)C12Cc1ccccc1C2
Reaction time: 1 h

Procedure:
To a stirred mixture of 2-(methylamino)indane-2-carbonitrile hydrochloride from Step A (6.0 g, 28.8 mmol) in AcOH (45 mL) was added a solution of potassium cyanate (4.65 g, 57 mmol) in H2O (6 mL) and the reaction mixture was stirred for 1 h. The mixture was poured into cold H2O (150 mL) and the precipitate was isolated by filtration, washed with H2O and air dried. The crude solid was suspended in 1 N HCl (30 mL) and stirred to 50° C. for 2 h. The reaction mixture was cooled, filtered, and the isolated solid washed with H2O and dried in vacuo to yield the title compound. MS: m/z=217 (M+1).
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[CH2:9][N:10]2[CH2:15][CH2:14][N:13]([CH:16]3[C:26]4[C:21](=[N:22][CH:23]=[CH:24][CH:25]=4)[CH2:20][CH2:19][C:18]4[CH:27]=[CH:28][C:29]([O:31][Si](C(C)(C)C)(C)C)=[CH:30][C:17]3=4)[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[OH-].[Na+]>C(O)C>[C:1]1(/[CH:7]=[CH:8]/[CH2:9][N:10]2[CH2:15][CH2:14][N:13]([CH:16]3[C:26]4[C:21](=[N:22][CH:23]=[CH:24][CH:25]=4)[CH2:20][CH2:19][C:18]4[CH:27]=[CH:28][C:29]([OH:31])=[CH:30][C:17]3=4)[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)C(N1CCN(C/C=C/c3ccccc3)CC1)c1cccnc1CC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Oc1ccc2c(c1)C(N1CCN(C/C=C/c3ccccc3)CC1)c1cccnc1CC2
Temperature: 25 °C
Reaction time: 12 h
Yield: 73 %

Procedure:
In 20 ml of ethanol was dissolved 1.05 g of 5-[4-{(E)-3-phenylallyl}piperazin-1-yl]-7-tert-butyldimethylsilyloxy-10,11-dihydro-5H-benzo[4,5]cyclohepta[1,2-b]pyridine. The solution was adjusted to pH 0.5 with 6 N hydrochloric acid and then stirred for 12 hours at room temperature. The reaction mixture was adjusted to pH 8.0 with a 10% aqueous sodium hydroxide solution. The solvent was removed by distillation under reduced pressure. To the residue were added 20 ml of water and 20 ml of ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by a column chromatography (eluant: n-hexane/acetone=2/1) to obtain 600 mg of 5-[4-{(E)-3-phenylallyl}piperazin-1-yl]-7-hydroxy-10,11-dihydro-5H-benzo[4,5]cyclohepta[1,2-b]pyridine. It was recrystallized from ethanol to obtain 510 mg of colorless crystals having a melting point of 136°-140° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:16])[C:11]1[CH2:10][CH2:9]/[C:8](=[CH:17]\[C:18]3[N:19]=[CH:20][NH:21][C:22]=3[CH3:23])/[C:7](=[O:24])[C:6]2=1>C(O)C.[Pd]=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:16])[C:11]1[CH2:10][CH2:9][CH:8]([CH2:17][C:18]3[N:19]=[CH:20][NH:21][C:22]=3[CH3:23])[C:7](=[O:24])[C:6]2=1
Reactant: COc1ccc2c(c1)c1c(n2C)CC/C(=C\c2nc[nH]c2C)C1=O
Agent: O=[Pd]
Solvent: CCO
Product: COc1ccc2c(c1)c1c(n2C)CCC(Cc2nc[nH]c2C)C1=O
Yield: 99.4 %

Procedure:
A solution of (E)-1,2,3,9-tetrahydro-6-methoxy-9-methyl-3-[(5-methyl-1H-imidazol-4-yl)methylene]-4H-carbazol-4-one (200 mg) in absolute ethanol (15 ml) was hydrogenated at room temperature and atmospheric pressure over a stirred suspension of 10% palladium oxide on carbon catalyst (50% aqueous paste; 100 mg) in absolute ethanol (5 ml). The mixture was filtered and evaporated to give a foam (ca. 200 mg) which was purified by FCC eluting with System A (200:10:1) to give the title compound (154 mg) as a solid, m.p. 227°-229°, t.l.c. (System A 200:10:1) Rf 0.26.
Reaction SMILES: C([O:4][C@@H:5]1[C@H:9]([O:10]C(=O)C)[C@@H:8]([CH2:14][O:15]C(=O)C)[O:7][C@H:6]1[N:19]1[C:34]2[N:33]=[CH:32][N:31]=[C:23]([NH:24][C@H:25]3[CH2:29][CH2:28][CH2:27][C@@H:26]3[OH:30])[C:22]=2[N:21]=[CH:20]1)(=O)C.C(N)(C)(C)C>CO>[OH:30][C@H:26]1[CH2:27][CH2:28][CH2:29][C@@H:25]1[NH:24][C:23]1[C:22]2[N:21]=[CH:20][N:19]([C:34]=2[N:33]=[CH:32][N:31]=1)[C@@H:6]1[O:7][C@H:8]([CH2:14][OH:15])[C@@H:9]([OH:10])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(N[C@H]4CCC[C@@H]4O)ncnc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: CC(C)(C)N
Solvent: CO
Product: OC[C@H]1O[C@@H](n2cnc3c(N[C@H]4CCC[C@@H]4O)ncnc32)[C@H](O)[C@@H]1O
Reaction time: 16 h
Yield: 60 %

Procedure:
A solution of 2',3',5'-tri-O-acetyl-N-[(1S,trans)-2-hydroxycyclopentyl]adenosine (0.34 g) in methanol (7 ml) containing t-butylamine (3 ml) was allowed to stand at 23° for 16 h. The solution was evaporated to dryness and residual t-butylamine was removed azeotropically with methanol to leave a glass. Crystallisation of a sample of this glass (0.19 g) from a mixture of methanol and ethyl acetate (1:20) gave the title compound (0.15 g), m.p. 160°-163°. Its chromatographic behaviour resembled that of authentic material.
Reaction SMILES: C(Cl)Cl.[CH2:4]([O:11][C:12]1[CH:13]=[C:14]([S:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]([NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])([CH2:30][O:31][CH2:32][O:33][CH3:34])[CH2:28][OH:29])=[C:21]([Cl:43])[CH:20]=2)[CH:15]=[CH:16][CH:17]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(Br)(Br)(Br)Br.[P:49]([O:54]C)([O:52][CH3:53])[O:50][CH3:51]>O.N1C=CC=CC=1>[CH2:4]([O:11][C:12]1[CH:13]=[C:14]([S:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]([NH:35][C:36]([O:38][C:39]([CH3:40])([CH3:42])[CH3:41])=[O:37])([CH2:30][O:31][CH2:32][O:33][CH3:34])[CH2:28][O:29][P:49]([O:52][CH3:53])([O:50][CH3:51])=[O:54])=[C:21]([Cl:43])[CH:20]=2)[CH:15]=[CH:16][CH:17]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: COCOCC(CO)(CCc1ccc(Sc2cccc(OCc3ccccc3)c2)cc1Cl)NC(=O)OC(C)(C)C
Reactant: COP(OC)OC
Agent: BrC(Br)(Br)Br
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: COCOCC(CCc1ccc(Sc2cccc(OCc3ccccc3)c2)cc1Cl)(COP(=O)(OC)OC)NC(=O)OC(C)(C)C
Temperature: 0 °C

Procedure:
To a methylene chloride solution (2 mL) containing the compound of Example 219 (860 mg), carbon tetrabromide (533 mg) and pyridine (2 mL), trimethyl phosphite (0.19 mL) was added while the mixture was stirred at 0° C. and the mixture was stirred for 5 hours until room temperature. Subsequently, water was added and the mixture was extracted with ethyl acetate. The extract was washed sequentially with water and a saturated aqueous solution of sodium chloride. The organic phase was then dried over anhydrous sodium sulfate. The solvent was removed by distillation and the residue was purified on a silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain the desired product as a colorless oil (830 mg).