Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].[CH3:11][C:12]1([CH3:19])[O:16][C@H:15]([CH2:17]O)[CH2:14][O:13]1.C(P(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:17][C@@H:15]1[CH2:14][O:13][C:12]([CH3:19])([CH3:11])[O:16]1)[CH:5]=[O:6]
Reactant: CC1(C)OC[C@@H](CO)O1
Reactant: O=Cc1ccc(O)c(Cl)c1
Agent: CCCCP(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CC1(C)OC[C@@H](COc2ccc(C=O)cc2Cl)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.8 %

Procedure:
To a solution of 3-chloro-4-hydroxybenzaldehyde (4.21 g, 27 mmol) in degassed toluene (100 mL) is added ((4R)-2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol (5.35 g, 40.5 mmol), 1,1′-(azodicarbonyl)dipiperidide (13.63 g, 54 mmol) followed by tributylphosphine (10.93 g, 54 mmol). The mixture becomes slightly warm and a precipitate forms. The reaction mixture is diluted with degassed toluene (500 mL) and is stirred at rt for 2 h, then at 60° C. for further 18 h before it is washed with 1 N aq. NaOH (3×150 mL) and water (150 mL). The organic phase is dried over MgSO4, filtered and concentrated to leave a dark brown oil which is chromatographed on silica gel eluting with hexane/EA 4:1 to give the title compound (4.30 g) as yellow oil. 1H NMR (CDC3): δ 9.82 (s, 1H), 7.89 (d, J=1.8 Hz, 1H), 7.74 (dd, J=1.8, 8.2 Hz, 1H), 7.05 (d, J=8.2 Hz, 1H), 4.56-4.43 (m, 1H), 4.23-4.17 (m, 2H), 4.14-4.08 (m, 1H), 4.06-4.00 (m, 1H), 1.47 (s, 3H), 1.41 (s, 3H).
Reaction SMILES: C(N1C=CN=C1)([N:3]1C=CN=C1)=O.[CH:13]1([NH:19][C:20]2[CH:29]=[C:28]3[C:23]([C:24](=[O:38])[C:25]([C:35]([OH:37])=O)=[CH:26][N:27]3[CH:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)=[CH:22][C:21]=2[F:39])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.N>CN(C=O)C>[CH:13]1([NH:19][C:20]2[CH:29]=[C:28]3[C:23]([C:24](=[O:38])[C:25]([C:35]([NH2:3])=[O:37])=[CH:26][N:27]3[CH:30]3[CH2:31][CH2:32][CH2:33][CH2:34]3)=[CH:22][C:21]=2[F:39])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc2c1=O
Agent: N
Solvent: CN(C)C=O
Product: NC(=O)c1cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc2c1=O
Temperature: 100 °C
Reaction time: 13.5 h
Yield: 92.7 %

Procedure:
2.6 g of 1,1′-carbonyldiimidazole was added to a 30 ml DMF suspension of 4.0 g 7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, followed by stirring at 100° C. for 13.5 hours. 10 ml of 28% aqueous ammonia was added thereto under ice-cooling, followed by stirring under ice-cooling for 75 minutes and at room temperature for 5 hours. After evaporation of the solvent under a reduced pressure, ethanol was added, and heating under reflux was carried out. After cooling to room temperature, the insoluble materials were collected by filtration and dried to obtain 3.7 g of 7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxamide.
Reaction SMILES: [CH2:1]([O:8][CH2:9][O:10][CH2:11][C@H:12]([CH3:15])[CH2:13][OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[S:23](Cl)([C:26]1[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=1)(=[O:25])=[O:24]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:1]([O:8][CH2:9][O:10][CH2:11][C@@H:12]([CH3:15])[CH2:13][O:14][S:23]([C:26]1[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=1)(=[O:25])=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C[C@H](CO)COCOCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@H](C)COCOCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.8 %

Procedure:
To a mixture of diol 3 (29.2 mmol, 6.13 g), DMAP (0.82 mmol, 100 mg) and triethylamine (116.7 mmol, 16.2 mL, 11.8 g) in anhydrous CH2Cl2 (60 mL) was added tosyl chloride (37.9 mmol, 7.23 g) at 0° C. The reaction mixture was allowed to warm to room temperature and stirring was continued overnight. The mixture was then diluted with CH2Cl2 (100 mL) and was then washed with a saturated aqueous solution of NaHCO3, dried over Na2SO4, and concentrated under reduced pressure. The residue was chromatographed on a silica gel using hexane/EtOAc (7:3) as an eluent to give the oily tosylate 4 (10.2 g, 97%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=2/[CH:14]=[CH:15]/[C:16]2[N:17]=[C:18]3[N:22]([C:23]=2[C:24](O)=[O:25])[CH:21]=[CH:20][S:19]3)[CH2:3][CH2:2]1.[F:27][C:28]([F:42])([F:41])[C:29]1[CH:30]=[CH:31][C:32]([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)=[N:33][CH:34]=1.C(N(CC)CC)C>ClCCl>[CH:1]1([CH2:4][O:5][C:6]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=2/[CH:14]=[CH:15]/[C:16]2[N:17]=[C:18]3[N:22]([C:23]=2[C:24]([N:38]2[CH2:39][CH2:40][N:35]([C:32]4[CH:31]=[CH:30][C:29]([C:28]([F:42])([F:27])[F:41])=[CH:34][N:33]=4)[CH2:36][CH2:37]2)=[O:25])[CH:21]=[CH:20][S:19]3)[CH2:3][CH2:2]1
Reactant: COc1cccc(/C=C/c2nc3sccn3c2C(=O)O)c1OCC1CC1
Reactant: FC(F)(F)c1ccc(N2CCNCC2)nc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(/C=C/c2nc3sccn3c2C(=O)N2CCN(c3ccc(C(F)(F)F)cn3)CC2)c1OCC1CC1

Procedure:
The title compound was prepared according to the general procedure (Method A) by coupling Intermediate 1 (50 mg, 0.134 mmol) with 1-[5-(trifluoromethyl)pyridin-2-yl]piperazine in the presence of triethylamine (34 mg, 0.337 mmol) in dichloromethane (5 mL) gave 46 mg of the product as an off-white solid; 1H NMR (300 MHz, CDCl3) δ 0.25-0.29 (m, 2H), 0.52-0.58 (m, 2H), 1.25-1.28 (m, 1H), 3.72-3.74 (m, 4H), 3.78-3.82 (m, 6H), 3.83 (s, 3H), 6.61 (d, J=9.0 Hz, 1H), 6.79-6.82 (m, 1H), 6.87-6.88 (m, 1H), 7.00 (t, J=7.8 Hz, 1H), 7.09-7.12 (m, 1H), 7.19-7.22 (m, 1H), 7.61-7.63 (m, 1H), 7.74 (d, J=3.9 Hz, 1H), 7.80 (d, J=15.9 Hz, 1H), 8.36 (br s, 1H); ESI-MS (m/z) 584.35 (MH)+.
Reaction SMILES: CC(C)([O:4][C:5]1[N:10]=[C:9]([O:11]C(C)(C)C)[C:8]([C:16]2([OH:33])[C:22]3[N:23]=[C:24]([CH3:26])[S:25][C:21]=3[CH2:20][CH2:19][C:18]3[CH:27]=[C:28]([CH2:31][CH3:32])[CH:29]=[CH:30][C:17]2=3)=[CH:7][N:6]=1)C>C(O)(=O)C>[CH2:31]([C:28]1[CH:29]=[CH:30][C:17]2[C:16]([C:8]3[C:9](=[O:11])[NH:10][C:5](=[O:4])[NH:6][CH:7]=3)([OH:33])[C:22]3[N:23]=[C:24]([CH3:26])[S:25][C:21]=3[CH2:20][CH2:19][C:18]=2[CH:27]=1)[CH3:32]
Reactant: CCc1ccc2c(c1)CCc1sc(C)nc1C2(O)c1cnc(OC(C)(C)C)nc1OC(C)(C)C
Solvent: CC(=O)O
Product: CCc1ccc2c(c1)CCc1sc(C)nc1C2(O)c1c[nH]c(=O)[nH]c1=O

Procedure:
A solution of the product from step (ii) (0.44 g) in glacial acetic acid (10 ml) was stirred at room temperature overnight. The reaction mixture was evaporated to dryness (azeotroped twice with toluene) and the residue triturated with diethyl ether to give a pink solid.
Reaction SMILES: Cl[C:2]1[N:7]2[CH:8]=[C:9]([CH3:11])[N:10]=[C:6]2[CH:5]=[N:4][C:3]=1[C:12]#[C:13][Si](C)(C)C.O.O.O.O.O.O.O.O.O.[S-2:27].[Na+].[Na+]>CN(C)C=O>[CH3:11][C:9]1[N:10]=[C:6]2[CH:5]=[N:4][C:3]3[CH:12]=[CH:13][S:27][C:2]=3[N:7]2[CH:8]=1
Reactant: [S-2]
Reactant: Cc1cn2c(Cl)c(C#C[Si](C)(C)C)ncc2n1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cn2c(cnc3ccsc32)n1
Temperature: 100 °C
Reaction time: 1 h
Yield: 52.1 %

Procedure:
A mixture of 5-chloro-2-methyl-6-[(trimethylsilyl)ethynyl]imidazo[1,2-a]pyrazine (0.400 g, 1.52 mmol), and sodium sulfide nonahydrate (1.09 g, 4.55 mmol) in N,N-dimethylformamide (6.0 mL) was heated in a preheated oil bath at 100° C. with stirring for 1 h. The reaction was cooled and partitioned between EtOAc and water. The organic layer was washed with water, brine, dried and the solvent was removed in vacuo. The residue was chromatographed on silica gel eluting with EtOAc and 3% MeOH in EtOAc to give the desired product (0.15 g, 52%). LCMS calculated for C9H8N3S (M+H)+: m/z=190.0. Found: 190.0.
Reaction SMILES: [N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C:4]3=O)[CH2:2]1)[CH2:8]2.C1(C)C=CC(S([CH2:21][N+:22]#[C-])(=O)=O)=CC=1.CC(C)([O-])C.[K+]>COCCOC.C(O)C>[N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@H:4]3[C:21]#[N:22])[CH2:2]1)[CH2:8]2
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=C1C2CC3CC1CN(C3)C2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCO
Product: N#CC1C2CC3CC1CN(C3)C2
Temperature: -78 °C
Reaction time: 5 h

Procedure:
Azaadamantan-4-one (3.76 g, 24.9 mmol; see Becker, D. P.; Flynn, D. L. Synthesis 1992, 1080-1082.) and p-toluenesulfonylmethyl isocyanide (TOSMIC, 6.38 g, 32.3 mmol) were dissolved in a mixture of 1,2-dimethoxyethane (87 mL) and ethanol (3.2 mL) and chilled to −78° C. To the reaction mixture was added potassium tert-butoxide (6.70 g, 59.7 mmol) over a period of 1 minute. The cooling bath was removed and the reaction mixture was stirred at 25° C. for 5 hours and then heated at 40° C. for 0.5 hour. The reaction mixture was cooled and filtered through a glass frit. The filtrate was concentrated, and the residue was purified by silica gel chromatography (10% concentrated NH4OH in acetonitrile, Rf=0.25) to afford the title compound. An aliquot of the solid was then dissolved in 10:1 ether/methanol and treated with fumaric acid (10 mg/mL solution in 10:1 ether/methanol). The precipitate was filtered and dried under vacuum to afford the title compound as a fumarate for characterization: 1H NMR (500 MHz, methanol-d4) δ 2.07-2.14 (m, 2H), 2.22-2.32 (m, 3H), 2.47 (s, 2H), 3.49-3.56 (m, 5 H), 3.59-3.66 (m, 2 H), 6.70 ppm (s, 2.8 H; C4H4O4); MS (DCI/NH3) m/z 163 (M+H)+; Anal. Calcd. for C10H14N2.1.45C4H4O4: C, 57.41; H, 6.04; N, 8.48. Found: C, 57.26; H, 6.04; N, 8.87.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][CH:23]=[C:22]4[CH2:26][CH2:27][NH:28][CH2:29][C:30]([O:32]CC)=[O:31])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+]>O1CCCC1.CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][CH:23]=[C:22]4[CH2:26][CH2:27][NH:28][CH2:29][C:30]([OH:32])=[O:31])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CCOC(=O)CNCCc1c[nH]c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CCNCC(=O)O)c[nH]c34)no2)cc1Cl
Temperature: 20 °C
Reaction time: 8 h
Yield: 64.3 %

Procedure:
To a solution of ethyl N-{2-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]ethyl}glycinate (D86) (132 mg) in tetrahydrofuran (5 mL) and methanol (5 mL) stirred at 20° C. was added a solution of sodium hydroxide (40 mg) in water (5 mL) in one charge. The reaction mixture was stirred at 20° C. overnight. The reaction mixture was concentrated to about 5 mL and then HCl aquous solution was added dropwise until no further white precipitate was formed. The solid was filtered and washed with EtOAc. The solid was collected and then was suspended in methanol (5 mL) and water (5 mL). The mixture was acidified with HCl (1 M) solution to pH around 1 to form a clear solution. After most of the solvent was evaporated off, the residue was freeze-dried to afford N-{2-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]ethyl}glycine (E63) (80 mg) as a hydrochloride salt. δH (DMSO-d6, 400 MHz): 1.37 (6H, d), 3.11-3.38 (4H, m), 3.61 (2H, s), 4.88-4.94 (1H, m), 7.26 (1H, t), 7.38 (1H, d), 7.47 (1H, d), 7.86 (1H, d), 7.97 (1H, d), 8.21 (1H, dd), 8.38 (1H, d), 11.00 (1H, br s). MS (ES): C23H23ClN4O4 requires 454; found 455.2 (M+H+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C@@H:8]([NH:18][C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[CH2:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=2)[C:5]([C:25]2[CH:26]=[CH:27][C:28]([Cl:40])=[C:29]3[C:33]=2[N:32]([CH3:34])[N:31]=[C:30]3[NH:35][S:36]([CH3:39])(=[O:38])=[O:37])=[CH:4][CH:3]=1.[CH3:41][NH:42][CH2:43][CH2:44][OH:45]>CC(N(C)C)=O>[Cl:40][C:28]1[CH:27]=[CH:26][C:25]([C:5]2[C:6]([C@@H:8]([NH:18][C:19](=[O:24])[C:20]([F:21])([F:22])[F:23])[CH2:9][C:10]3[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=3)=[N:7][C:2]([N:42]([CH2:43][CH2:44][OH:45])[CH3:41])=[CH:3][CH:4]=2)=[C:33]2[C:29]=1[C:30]([NH:35][S:36]([CH3:39])(=[O:37])=[O:38])=[N:31][N:32]2[CH3:34]
Reactant: CNCCO
Reactant: Cn1nc(NS(C)(=O)=O)c2c(Cl)ccc(-c3ccc(Cl)nc3[C@H](Cc3cc(F)cc(F)c3)NC(=O)C(F)(F)F)c21
Solvent: CC(=O)N(C)C
Product: CN(CCO)c1ccc(-c2ccc(Cl)c3c(NS(C)(=O)=O)nn(C)c23)c([C@H](Cc2cc(F)cc(F)c2)NC(=O)C(F)(F)F)n1
Temperature: 150 °C

Procedure:
To a solution of (S)—N-(1-(6-chloro-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2,2,2-trifluoroacetamide (57D, 50 mg, 0.08 mmol) in DMA (1 mL) was added 2-(methylamino)ethanol (64.5 μL, 0.803 mmol). The reaction mixture was heated to 150° C. for 2 hours. The crude mixture was concentrated in vacuo and used without further purification. MS (m/z) 661.16 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH:7]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=3[F:19])[N:10]=[C:9]([CH:20]=[O:21])[CH2:8]2)=[CH:4][CH:3]=1.[C:22]([Si](C)(C)C)([F:25])([F:24])[F:23].Cl>O1CCCC1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>[Br:1][C:2]1[S:6][C:5]([CH:7]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=3[F:19])[N:10]=[C:9]([CH:20]([OH:21])[C:22]([F:25])([F:24])[F:23])[CH2:8]2)=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=CC1=NN(c2ccc(F)cc2F)C(c2ccc(Br)s2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: OC(C1=NN(c2ccc(F)cc2F)C(c2ccc(Br)s2)C1)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.2 %

Procedure:
To a solution of 5-(5-bromo-thiophen-2-yl)-1-(2,4-difluoro-phenyl)-4,5-dihydro-1H-pyrazole-3-carbaldehyde (9.1 g, 22.4 mmol) prepared in Step 5 and CF3TMS (5.7 mL, 38.1 mmol) in tetrahydrofuran (100.0 mL), was slowly added a solution of TBAF (1.0 M, in tetrahydrofuran 0.5 mL, 0.5 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1 hour and then a 6N hydrochloric acid solution was added thereto. The reaction mixture was stirred at room temperature for 1 hour and then extracted with ethyl acetate. The extract was washed distilled water and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give 9.9 g of the titled compound as a yellow liquid.
Reaction SMILES: C(Cl)(Cl)Cl.[C:5]([OH:33])(=[O:32])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[C:15][C:16]#[C:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].[Cl-].[Cd+2:35].[Cl-].C(=O)(O)[O-].[K+]>O>[C:5]([O-:33])(=[O:32])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[C:15][C:16]#[C:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].[Cd+2:35].[C:5]([O-:33])(=[O:32])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[C:15][C:16]#[C:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCCCCCCCCCC#CC#CCCCCCCCCC(=O)O
Agent: O=C([O-])O
Agent: [Cd+2]
Agent: [Cl-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCC#CC#CCCCCCCCCC(=O)[O-]

Procedure:
A chloroform solution of heptacosa-10,12-diynoic acid was allowed to spread over the surface of a water solution of 4×10-4M cadmium chloride and 5×10-5M potassium bicarbonate; the solvent was then evaporated and the surface pressure is raised to 10 mN/m, thus forming a film of cadmium heptacosa-10,12-diynoate on the surface of the water. The Langmuir-Blodgett method was used to laminate 11 layers of this film onto a glass substrate, the surface of which had been treated to be hydrophilic.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:7][O:8][C:9]1[CH:10]=[N+:11]([O-])[CH:12]=[C:13]([Br:15])[CH:14]=1.[H][H]>[Ni]>[CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:7][O:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([Br:15])[CH:14]=1
Reactant: CN1CCC[C@H]1COc1cc(Br)c[n+]([O-])c1
Reactant: [H][H]
Agent: [Ni]
Product: CN1CCC[C@H]1COc1cncc(Br)c1

Procedure:
A sample of 3-((1-methyl-2-(S)-pyrrolidinyl)methoxy)-5-bromo-pyridine-N-oxide, from Example 98a above, is reacted with hydrogen in the presence of Raney nickel according to the method of Y. Tamura et al., Heterocycles, 15:871-874 (1981). The solvents are removed, and the product is extracted, then purified by chromatography on silica gel.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:10]2[CH2:11][NH:12][CH2:13][CH2:14][CH:15]=2)[CH:7]=[CH:8][CH:9]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:22](Br)[CH:23]=[CH2:24]>CN(C)C=O>[CH2:24]([N:12]1[CH2:13][CH2:14][CH:15]=[C:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH3:2])[CH:5]=2)[CH2:11]1)[CH:23]=[CH2:22]
Reactant: COc1cccc(C2=CCCNC2)c1
Reactant: C=CCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCN1CCC=C(c2cccc(OC)c2)C1
Reaction time: 6 h
Yield: 83 %

Procedure:
A mixture of 7 g of 3-(3-methoxyphenyl)-1,2,5,6-tetrahydropyridine hydrochloride, 100 ml of dimethylformamide, 9.8 g of sodium carbonate and 3.75 g of allyl bromide was stirred for 6 hours and was then filtered. The filtrate was evaporated to dryness and the residue was chromatographed over silica gel. Elution with a 7-3 benzene-ethyl acetate mixture yielded 5.9 g of 1-allyl-3-(3-methoxyphenyl)-1,2,5,6-tetrahydropyridine.
Reaction SMILES: Br[CH:2]([CH2:28][CH2:29][CH3:30])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([S:20][C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1)[C:8]#[N:9].[CH3:31][O:32][C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][C:42]=1[O:43][CH3:44])[CH2:39][NH:38][CH2:37][CH2:36]2>>[CH3:19][O:18][C:12]1[CH:11]=[C:10]([C:7]([S:20][C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:28][CH2:29][CH2:30][N:38]2[CH2:37][CH2:36][C:35]3[C:40](=[CH:41][C:42]([O:43][CH3:44])=[C:33]([O:32][CH3:31])[CH:34]=3)[CH2:39]2)[C:8]#[N:9])[CH:15]=[CH:14][C:13]=1[O:16][CH3:17]
Reactant: COc1cc2c(cc1OC)CNCC2
Reactant: CCCC(Br)CCCCC(C#N)(Sc1ccc(C)cc1)c1ccc(OC)c(OC)c1
Product: COc1ccc(C(C#N)(CCCCCCCCN2CCc3cc(OC)c(OC)cc3C2)Sc2ccc(C)cc2)cc1OC
Yield: 20041 %

Procedure:
The procedure of Example 3 is repeated using 0,836 g of α-(5-bromooctyl)-3,4-dimethoxy-α-[(4-methylphenyl)thio]benzeneacetonitrile and 0.675 g of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline. This affords 0,422 g of the desired product as a brown gum.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[N:6]=[N:7]2.[Se](=O)=[O:19]>C1C2C(=CC=CC=2)C=CC=1>[C:12]1([C:5]2[N:6]=[N:7][C:8]3[CH:9]=[CH:10][CH:11]=[C:2]([CH:1]=[O:19])[C:3]=3[CH:4]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=[Se]=O
Reactant: Cc1cccc2nnc(-c3ccccc3)cc12
Solvent: c1ccc2ccccc2c1
Product: O=Cc1cccc2nnc(-c3ccccc3)cc12
Yield: 42.7 %

Procedure:
1.65 g (7.5 mmol) of the compound from Example VIII are stirred for 6 h at 200° C. with 1.85 g of selenium dioxide in 17 g of naphthalene. After chromatography on silica gel, 0.75 g (43%) of the title compound is obtained. In some batches, it is necessary to stop the reaction before complete conversion of the starting material, since byproducts increasingly occur. M.p.: 156°-157° C.
Reaction SMILES: [O:1]([CH2:8][CH:9]1[O:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:12][N:13]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:15]2([CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[C:14]1=[O:27]>C(O)C>[OH:11][CH:9]([CH2:8][O:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:10][N:18]1[CH2:19][CH2:20][C:15]2([C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:13]([CH3:12])[C:14]2=[O:27])[CH2:16][CH2:17]1
Reactant: c1ccc(OCC2CO2)cc1
Reactant: CN1C(=O)C2(CCNCC2)c2ccccc21
Solvent: CCO
Product: CN1C(=O)C2(CCN(CC(O)COc3ccccc3)CC2)c2ccccc21

Procedure:
A mixture of 1.7 g of 1-phenoxy-2,3-epoxypropane, 2 g of 1-methyl-2-oxo-indoline-3-spiro-4'-piperidine and 120 ml of ethanol was refluxed for 3 hours. The resulting mixture was concentrated and crystallized from diisopropylether to give 1'-(2-hydroxy-3-phenoxypropyl)-1-methyl-2-oxo-indoline-3-spiro-4'-piperidine
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:11]2[C:6](=[CH:7][C:8]([C:12](=[O:14])[CH3:13])=[CH:9][CH:10]=2)[C:5](=O)[CH2:4][CH2:3]1.C[C:18]1(C)[C:27]2[C:22](=CC(Br)=CC=2)[C:21]([S:29]C2C=CC=CC=2)=[CH:20][CH2:19]1>>[CH3:1][C:2]1([CH3:16])[C:11]2[C:6](=[CH:7][C:8]([C:12](=[O:14])[CH3:13])=[CH:9][CH:10]=2)[C:5]([S:29][C:21]2[CH:22]=[CH:27][CH:18]=[CH:19][CH:20]=2)=[CH:4][CH2:3]1
Reactant: CC1(C)CC=C(Sc2ccccc2)c2cc(Br)ccc21
Reactant: CC(=O)c1ccc2c(c1)C(=O)CCC2(C)C
Product: CC(=O)c1ccc2c(c1)C(Sc1ccccc1)=CCC2(C)C

Procedure:
Employing the procedure used for the preparation of 4,4-dimethyl-7-acetyl-3,4-dihydronaphthalen-1(2H)-one (Compound C1) 1.2 g, (3.5 mmol) of 4,4-dimethyl-7-Bromo-1-phenylthio-3,4-dihydronaphthalene (Compound A35) was converted to the title compound.
Reaction SMILES: [N:1]1([C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[C:8]([NH2:10])=O)[CH:5]=[N:4][N:3]=[N:2]1.[OH-].COC(NS([NH3+])(=O)=O)=O.O>O1CCCC1>[N:1]1([C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[C:8]#[N:10])[CH:5]=[N:4][N:3]=[N:2]1
Reactant: NC(=O)c1ccccc1-n1cnnn1
Agent: COC(=O)NS([NH3+])(=O)=O
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccccc1-n1cnnn1

Procedure:
To a solution of 2-Tetrazol-1-yl-benzamide (1.5 g, 7.9 mmol) in tetrahydrofuran (50 ml) was added (methoxycarbonylsulfamoyl)ammonium hydroxide, inner salt (2.8 g, 11.8 mmol) in three portions over 1.5 h. Water was added and the reaction mixture was extracted with ethyl acetate. The combined organic layers were washed with brine. Drying and solvent evaporation gave 2-Tetrazol-1-yl-benzonitrile; 1H NMR (CDCl3, 400 MHz) δ 9.27 (s, 1H), 7.90 (m, 3H), 7.72 (m, 1H).
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22]O)[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].CS(Cl)(=O)=O.[SH:29][C:30]1[NH:31][C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[N:34]=1.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>O1CCCC1>[N:31]1[C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[NH:34][C:30]=1[S:29][CH2:22][CH2:21][N:18]1[CH2:19][CH2:20][N:15]([C:13]([O:12][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:14])[CH2:16][CH2:17]1
Reactant: Sc1nc2ccccc2[nH]1
Reactant: CC(C)(C)OC(=O)N1CCN(CCO)CC1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(CCSc2nc3ccccc3[nH]2)CC1
Temperature: 0 °C
Yield: 65.3 %

Procedure:
Triethylamine (1.04 g, 10.3 mmol) and 4-dimethyl aminopyridine (104 mg, 0.854 mmol) were added to a solution of 1-tert-butoxycarbonyl-4-(2-hydroxyethyl)piperazine (2.00 g, 8.54 mmol) in tetrahydrofuran (THF) (30 mL) in an ice bath, and the solutes were dissolved by stirring. Methanesulfonyl chloride (1.37 g, 12.0 mmol) was added dropwise to the solution in the ice bath over a period of 5 minutes with stirring, and the mixture was stirred for 1 hour in an ice bath. After the completion of the reaction, the insoluble content was removed by filtration, and the thus removed insoluble content was washed with THF (10 mL×2). The filtrate and the washing solution were combined and concentrated under reduced pressure to such degree that substantially no solvent was left. The concentrate was diluted with DMF (20 mL). To the solution was added 2-mercaptobenzimidazole (1.41 g, 9.39 mmol), potassium carbonate (1.77 g, 12.8 mmol), and 18-crown-6 (226 mg, 0.854 mmol), and the mixture was stirred at 80° C. for 3 hours. The reaction solution was concentrated under reduced pressure, and the resulting concentrate was diluted and separated with ethyl acetate (10 mL) and water (50 mL). The aqueous layer was further extracted with ethyl acetate (10 mL×2), and the extract was combined with the organic layer, washed with saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate. It was then purified by silica gel column chromatography (chloroform/methanol saturated with ammonia=40/1) to give 1-[2-(benzimidazol-2-ylthio)ethyl]-4-tert-butoxycarbonyl piperazine 2.02 g (64%) as colorless powdery crystals.