Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si](C)(C)CCOC[N:7](COCC[Si](C)(C)C)[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[C:12]2[N:11]=[C:10]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[C:9]=1[C:33]#[N:34].Cl>CCO>[NH2:7][C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[C:12]2[N:11]=[C:10]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[C:9]=1[C:33]#[N:34]
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1c(C#N)c(N2CCOCC2)nc2c(-c3cnc4ccccc4c3)cnn12
Agent: Cl
Solvent: CCO
Product: N#Cc1c(N2CCOCC2)nc2c(-c3cnc4ccccc4c3)cnn2c1N
Temperature: 60 °C

Procedure:
A mixture of 7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-5-morpholino-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidine-6-carbonitrile (5 mg), EtOH (1 mL) and 3N HCl (1 mL) was heated at 60° C. until LCMS indicated the completed reaction. The mixture was cooled to room temperature and the solvent was evaporated in vacuo. Purification by prep-LC afforded the desired compound. LCMS tR=3.12 Min (UV254nm). Mass calculated for, M+ 371.1, observed LC/MS m/z 372.2 (M+H).
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][O:13][CH:14]2[C:20]3[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=3[N:18]([C:26](=[O:45])[C:27]3[CH:32]=[CH:31][C:30]([NH:33][C:34](=[O:42])[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=4[CH3:41])=[CH:29][C:28]=3[O:43][CH3:44])[CH2:17][CH2:16][CH2:15]2)(=O)=O)=CC=1.[CH3:47][N:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1.[I-].[Na+]>CN(C)C=O>[CH3:47][N:48]1[CH2:53][CH2:52][N:51]([CH2:11][CH2:12][O:13][CH:14]2[C:20]3[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=3[N:18]([C:26](=[O:45])[C:27]3[CH:32]=[CH:31][C:30]([NH:33][C:34](=[O:42])[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=4[CH3:41])=[CH:29][C:28]=3[O:43][CH3:44])[CH2:17][CH2:16][CH2:15]2)[CH2:50][CH2:49]1
Reactant: COc1cc(NC(=O)c2ccccc2C)ccc1C(=O)N1CCCC(OCCOS(=O)(=O)c2ccc(C)cc2)c2cc(F)ccc21
Reactant: CN1CCNCC1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(NC(=O)c2ccccc2C)ccc1C(=O)N1CCCC(OCCN2CCN(C)CC2)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
In 10 ml of dimethylformamide were dispersed 0.4 g of 5-[2-(p-toluenesulfonyloxy)ethoxy]-7-fluoro-1-[2-methoxy-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine, 0.38 ml of N-methylpiperazine and 0.3 g of sodium iodide. The dispersion was stirred at room temperature for 3 days. The reaction mixture was concentrated. The residue was mixed with water and the mixture was subjected to extraction with ethyl acetate. The extract was dried over sodium carbonate and purified by silica gel column chromatography (elutant: dichloromethane/-methanol=10/1) to obtain 1.15 g of 5-[2-(4-methyl-1-piperazinyl)ethoxy]-7-fluoro-1-[2-methoxy-4-(2-methyl-benzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine. Colorless and amorphous
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][O:8][C:7]([CH3:18])([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[C:6]=2[CH:19]=1.Br[C:21]1[S:25][C:24]([C:26]#[N:27])=[CH:23][C:22]=1[CH3:28]>>[CH3:28][C:22]1[CH:23]=[C:24]([C:26]#[N:27])[S:25][C:21]=1[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][O:8][C:7]([CH3:18])([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[C:6]=2[CH:19]=1
Reactant: CC1(c2cccs2)OCC(=O)Nc2ccc(Br)cc21
Reactant: Cc1cc(C#N)sc1Br
Product: Cc1cc(C#N)sc1-c1ccc2c(c1)C(C)(c1cccs1)OCC(=O)N2

Procedure:
Prepared from 7-bromo-5-methyl-5-thien-2-yl-1,5-dihydro-4,1-benzoxazepin-2(3H)-one and 5-bromo-4-methylthiophene-2-carbonitrile generally according to the coupling procedure described in examples 82 and 1. 1H-NMR (DMSO-d6) δ 10.26 (s, 1H), 7.83 (s, 1H), 7.56 (dd, J=4.9, 1.1 Hz, 1H), 7.47 (dd, J=8.5, 2.2 Hz, 1H), 7.32 (d, J=2.2 Hz, 1H), 7.29 (d, J=8.5 Hz, 1H), 7.00 (m, 1H), 6.96 (m, 1H), 4.23 (d, J=15.9 Hz, 1H), 4.13 (d, J=15.9 Hz, 1H), 2.19 (s, 3H), 2.03 (s, 3H); MS (ES) m/z 381 (M+H)+; Anal. Calc. For C20H16N2O2S2: C, 63.14, H, 4.24; N, 7.36. Found: C, 62.85, H, 4.16; N, 7.09.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:11]([O:13][C:14]1[CH:15]=[C:16]([C:22]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([N+:32]([O-:34])=[O:33])[CH:25]=2)=O)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH3:12].[CH2:35]1COC[CH2:36]1>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C>[CH2:11]([O:13][C:14]1[CH:15]=[C:16]([C:22]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([N+:32]([O-:34])=[O:33])[CH:25]=2)=[CH:35][CH3:36])[CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH3:12]
Reactant: CCOc1cc(C(=O)c2ccc(OC)c([N+](=O)[O-])c2)ccc1OC
Reactant: C1CCOC1
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Product: CC=C(c1ccc(OC)c(OCC)c1)c1ccc(OC)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 77 %

Procedure:
Lithium bis(trimethylsilyl)amide (8.5 mL, 8.5 mmol) was added dropwise to a stirred suspension of (ethyl)triphenylphosphonium bromide (3.14 g, 8.5 mmol) in anhydrous THF (30 mL) at 0° C. After 10 min at cold, the reaction mixture was stirred at room temperature for 40 min. The Wittig reagent was then added dropwise to a stirred suspension of (3-ethoxy-4-methoxy-phenyl)-(4-methoxy-3-nitro-phenyl) -methanone (1.40 g, 4.2 mmol) in THF (30 mL) at 0° C. The reaction mixture was stirred at room temperature for 2 h. The solution was poured into ice water (100 mL) and extracted with CH2Cl2 (4×40 mL). The combined organic layers were washed with water (2×40 mL), brine (40 mL) and dried (MgSO4). Removal of solvent and chromatography (Silica Gel) gave a mixture of (E/Z) 4-[1-(3-ethoxy-4-methoxy-phenyl)-propenyl]-1-methoxy-2-nitro-benzene as a solid (1.12 g, 77% yield): 1H NMR (CDCl3) δ 1.41-1.46 (m, 6H, 2CH3), 1.75-1.80 (m, 6H, 2CH3), 3.86-4.08 (m, 16H, 4OCH3+2CH2), 6.06-6.15 (q, J=7.0 and 14.0 Hz, 2H, 2CH), 6.64-7.74 (m, 12H, Ar).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:49]=[CH:48][C:12]([O:13][CH2:14][C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]4[CH:30]=[CH:29][C:28]([CH2:31][C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)=[C:27]([OH:38])[CH:26]=4)=[CH:20][C:19]=3[N:39](C)[C:40](=O)OC(C)(C)C)=O)=[CH:11][CH:10]=2)[S:3]1.[ClH:50].O1CCOCC1.C(OCC)(=O)C>CCCCCC>[ClH:50].[CH2:31]([C:28]1[CH:29]=[CH:30][C:25]([O:24][C:21]2[CH:22]=[CH:23][C:18]3[N:17]=[C:15]([CH2:14][O:13][C:12]4[CH:48]=[CH:49][C:9]([CH2:8][CH:4]5[S:3][C:2](=[O:1])[NH:6][C:5]5=[O:7])=[CH:10][CH:11]=4)[N:39]([CH3:40])[C:19]=3[CH:20]=2)=[CH:26][C:27]=1[OH:38])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(Cc3ccccc3)c(O)c2)ccc1NC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: Cl
Solvent: CCCCCC
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(Cc4ccccc4)c(O)c3)cc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of t-butyl N-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]-5-(4-benzyl-3-hydroxyphenoxy)phenyl}-N-methylcarbamate (1.4 g) and 4N hydrogen chloride/dioxane (20 ml) was stirred at ambient temperature for 3 days. On addition of ethyl acetate and n-hexane insoluble product was formed and isolated by filtration to give the title compound (1.5 g)
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]>CN(C=O)C>[N:1]1([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
To a solution of pyrrolidine (1.2 g, 16.3 mmol, 1.0 eq) in DMF were added K2CO3 (5.63 g, 40.7 mmol, 2.5 eq.) and ethyl 2-bromoacetate (1.73 g, 24.4 mmol, 1.5 eq.). The mixture was stirred at RT for 16 h and quenched and extracted as in Intermediate Example 5(a). The solvent was distilled off to afford the product in 80% yield (2 g). LC-MS (ESI): Calculated mass: 157.2; Observed mass 158.1 [M+H]+ (rt: 0.2 min).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3]C.C([C:10]([OH:18])([CH2:15][CH:16]=[CH2:17])[C:11]([CH3:14])([CH3:13])C)(C)(C)C.C(=O)C1C=CC=CC=1.[NH4+].[Cl-]>CCCCC.C1COCC1.[Zn+2].[Br-].[Br-].C(OCC)C>[C:11]1([CH:10]([OH:18])[CH2:15][CH:16]=[CH2:17])[CH:13]=[CH:3][CH:2]=[CH:1][CH:14]=1
Reactant: C=CCC(O)(C(C)(C)C)C(C)(C)C
Reactant: [Li]CCCC
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CCC(O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1.94 ml of a 1.4-molar solution of n-butyllithium (2.71 mmol) in pentane were added dropwise at 0° C. under argon for 2 min to a stirred solution of 500 mg (2.71 mmol) 3-tert-butyl-2,2-dimethylhex-5-en-3-ol in 4 ml THF. The solution obtained was stirred for 15 minutes, and then a solution of 610 mg (2.71 mmol) ZnBr2 in 2 ml THF and subsequently 275 μl (2.71 mmol) benzaldehyde were added. The reaction mixture was stirred for 1 hour and heated to room temperature. Subsequently, 15 ml NH4Cl solution were added. The organic components were extracted three times with 15 ml Et2O each, the combined organic phases were washed with 10 ml brine, then dried and concentrated under reduced pressure. The raw product obtained was cleaned by means of a silica column with 15% diethyl ether/light gasoline. There was obtained the alcohol as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)=O)=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1.[C:21](OCC)(=[O:28])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].[O-]CC.[Na+]>C(O)C>[OH:28][C:21]1[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[C:11]2[CH:10]=[C:9]3[CH2:8][CH2:7][CH2:6][CH2:5][C:4]3=[N:3][C:2]=2[N:1]=1
Reactant: Cc1ccc(C(=O)c2cc3c(nc2N)CCCC3)cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1c(O)nc2nc3c(cc2c1-c1ccc(C)cc1)CCCC3
Temperature: 100 °C
Yield: 25.7 %

Procedure:
To a solution of (2-amino-5,6,7,8-tetrahydroquinolin-3-yl)(p-tolyl)methanone (0.533 g; 2 mmol) and diethyl malonate (1.22 mL; 8 mmol) in ethanol (10 mL) under nitrogen atmosphere was added a solution of sodium ethoxide 21% (w/w) in ethanol (2.24 mL; 6 mmol). The mixture was stirred in a sealed tube and heated to 100° C. for 48 h. The volatiles were removed under reduced pressure and the remaining residue was purified by flash-chromatography on silica gel column using a gradient of ethyl acetate (1 to 60%) in dichloromethane as eluent to furnish 0.186 g (25%) of ethyl 2-hydroxy-4-(p-tolyl)-6,7,8,9-tetrahydrobenzo[b][1,8]naphthyridine-3-carboxylate as a white solid. ESI/APCI(+): 363 (M+H). NMR 1H (DMSO-d6) (ppm): δ 12.37 (s, 1H, NH); 7.35-7.19 (m, 5H, 5×Harom.); 4.00 (q, 2H, OCH2CH3); 2.88 (m, 2H, CH2); 2.66 (m, 2H, CH2); 2.35 (s, 3H, CH3); 1.86-1.79 (m, 2H, CH2); 1.74-1.69 (m, 2H, CH2); 0.90 (t, 3H, OCH2CH3).
Reaction SMILES: [CH2:1]([N:8]1[CH2:11][C:10]([CH2:14][CH2:15][CH2:16][Cl:17])([C:12]#N)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)[OH:19].N.[C:24]([OH:29])(=[O:28])[C:25]([OH:27])=[O:26]>CO.CCOCC>[C:24]([OH:29])(=[O:28])[C:25]([OH:27])=[O:26].[CH2:1]([N:8]1[CH2:11][C:10]([CH2:14][CH2:15][CH2:16][Cl:17])([C:12]([O:26][CH3:25])=[O:19])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CC1(CCCCl)CN(Cc2ccccc2)C1
Reactant: O=S(=O)(O)O
Agent: N
Agent: O=C(O)C(=O)O
Solvent: CCOCC
Solvent: CO
Product: COC(=O)C1(CCCCl)CN(Cc2ccccc2)C1
Temperature: 80 °C

Procedure:
A stirred solution of 1-benzyl-3-(3-chloropropyl)-azetidine-3-carbonitrile (D1, 5.35 g, 0.022 mole) in methanol (75 ml) was treated cautiously with 18 concentrated sulphuric acid (15 ml) and then heated at 80° C. for 20 h. The solution was cooled in an ice bath and a further 12 ml of concentrated sulphuric acid added. The solution was heated at 80° C. for a further 9 hours, then allowed to cool, before pouring cautiously into ice/water (400 ml) with vigorous stirring. The aqueous mixture was basified by the addition of 0.88 ammonia solution, then extracted with ethyl acetate (2×200 ml). The combined extracts were dried (Na2SO4) and concentrated in vacuo to leave an orange oil, which was filtered through a basic alumina column eluting with ether. The colourless oil obtained was dissolved in ether (150 ml) and treated with a solution of oxalic acid (2.0 g, 0.022 mole) in methanol (10 ml). The title compound (D2) was filtered off as a white crystalline solid (7.25 g, 91%).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[C:9]([CH2:11][CH:12]([CH3:14])[CH3:13])[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1>>[CH2:11]([C:9]1[S:8][C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH:15][CH:16]3[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH2:21]3)[C:3]=2[CH:10]=1)[CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)Cc1cc2c(Cl)ncnc2s1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Product: CC(C)Cc1cc2c(NC3CCN(C(=O)OC(C)(C)C)CC3)ncnc2s1

Procedure:
The title compound was prepared (337 mg, 65%) from 4-chloro-6-isobutylthieno[2,3-d]pyrimidine (300 mg, 1.32 m. mol) and tert-butyl 4-aminopiperidine-1-carboxylate (400 mg, 1.99 m. mol) by following the general procedure described for Preparation 9. 1H NMR (400 MHz, CDCl3): δ 8.45 (s, 1H), 6.80 (s, 1H), 4.95 (m, 1H), 4.35 (m, 1H), 4.15 (m, 2H), 2.95 (m, 2H), 2.75 9d, 2H), 2.15 (m, 2H), 1.95 (m, 1H), 1.45 (s, 9H), 1.40-1.50 (m, 2H), 0.95 (d, 6H).
Reaction SMILES: [C:1]([O:7][C:8]1[CH:9]=[N:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]34[CH2:27][CH2:26][C:23]([CH2:28][CH2:29][CH3:30])([CH2:24][CH2:25]3)[CH2:22][CH2:21]4)=[CH:16][CH:15]=2)=[N:12][CH:13]=1)(=[O:6])/[CH:2]=[CH:3]/[CH2:4]C.C(OC1C=NC(C2C=CC(C34CCC(CCC)(CC3)CC4)=CC=2)=NC=1)(=O)/C=C/CCC.C(OC1C=NC(C2C=CC(C34CCC(CCC)(CC3)CC4)=CC=2)=NC=1)(=O)/C=C/CCCC.C(OC1C=NC(C2C=CC(C34CCC(CCC)(CC3)CC4)=CC=2)=NC=1)(=O)/C=C/CCCCC.C(OC1C=NC(C2C=CC(C34CCC(CCCCC)(CC3)CC4)=CC=2)=NC=1)(=O)/C=C/C.C(OC1C=NC(C2C=CC(C34CCC(CCCCC)(CC3)CC4)=CC=2)=NC=1)(=O)/C=C/CC.C(OC1C=NC(C2C=CC(C34CCC(CCCCC)(CC3)CC4)=CC=2)=NC=1)(=O)/C=C/CCCC.C(OC1C=NC(C2C=CC(C34CCC(CCCCC)(CC3)CC4)=CC=2)=NC=1)(=O)/C=C/CCCCC.C(OC1C=NC(C2C=CC(C34CCC(CCCCCCC)(CC3)CC4)=CC=2)=NC=1)(=O)/C=C/C.C(OC1C=NC(C2C=CC(C34CCC(CCCCCCC)(CC3)CC4)=CC=2)=NC=1)(=O)/C=C/CC.C(OC1C=NC(C2C=CC(C34CCC(CCCCCCC)(CC3)CC4)=CC=2)=NC=1)(=O)/C=C/CCC.C(OC1C=NC(C2C=CC(C34CCC(CCCCCCC)(CC3)CC4)=CC=2)=NC=1)(=O)/C=C/CCCC.C(OC1C=NC(C2C=CC(C34CCC(CCCCCCC)(CC3)CC4)=CC=2)=NC=1)(=O)/C=C/CCCCC>>[C:1]([O:7][C:8]1[CH:13]=[N:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]([C:20]34[CH2:25][CH2:24][C:23]([CH2:28][CH2:29][CH3:30])([CH2:22][CH2:21]3)[CH2:26][CH2:27]4)=[CH:18][CH:19]=2)=[N:10][CH:9]=1)(=[O:6])/[CH:2]=[CH:3]/[CH3:4]
Reactant: CC/C=C/C(=O)Oc1cnc(-c2ccc(C34CCC(CCC)(CC3)CC4)cc2)nc1
Agent: C/C=C/C(=O)Oc1cnc(-c2ccc(C34CCC(CCCCC)(CC3)CC4)cc2)nc1
Agent: C/C=C/C(=O)Oc1cnc(-c2ccc(C34CCC(CCCCCCC)(CC3)CC4)cc2)nc1
Agent: CC/C=C/C(=O)Oc1cnc(-c2ccc(C34CCC(CCCCC)(CC3)CC4)cc2)nc1
Product: C/C=C/C(=O)Oc1cnc(-c2ccc(C34CCC(CCC)(CC3)CC4)cc2)nc1

Procedure:
2-[4-(4-Propylbicyclo[2.2.2]octyl)phenyl]pyrimidin-5-yl (E)-pent-2-enoate. 2-[4-(4-Propylbicyclo[2.2.2]octyl)phenyl]pyrimidin-5-yl (E)-hex-2-enoate. 2-[4-(4-Propylbicyclo[2.2.2]octyl)phenyl]pyrimidin-5-yl (E)-hept-2-enoate. 2-[4-(4-Propylbicyclo[2.2.2]octyl)phenyl]pyrimidin-5-yl (E)-oct-2-enoate. 2-[4-(4-Pentylbicyclo[2.2.2]octyl)phenyl]pyrimidin-5-yl (E)-but-2-enoate. 2-[4-(4-Pentylbicyclo[2.2.2]octyl)phenyl]pyrimidin-5-yl (E)-pent-2-enoate. 2-[4-(4-Pentylbicyclo[2.2.2]octyl)phenyl]pyrimidin-5-yl (E)-hept-2-enoate. 2-[4-(4-Pentylbicyclo[2.2.2]octyl)phenyl]pyrimidin-5-yl (E)-oct-2-enoate. 2-[4-(4-Heptylbicyclo[2.2.2]octyl)phenyl]pyrimidin-5-yl (E)-but-2-enoate. 2-[4-(4-Heptylbicyclo[2.2.2]octyl)phenyl]pyrimidin-5-yl (E)-pent-2-enoate. 2-[4-(4-Heptylbicyclo[2.2.2]octyl)phenyl]pyrimidin-5-yl (E)-hex-2-enoate. 2-[4-(4-Heptylbicyclo[2.2.2]octyl)phenyl]pyrimidin-5-yl (E)-hept-2-enoate. 2-[4-(4-Heptylbicyclo[2.2.2]octyl)phenyl]pyrimidin-5-yl (E)-oct-2-enoate.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[S:10])[S-:9].C([NH+](CC)CC)C.[C:18]1([C:24](=[O:27])[CH:25]=[CH2:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(#N)C.C(Cl)(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[S:9])[S:10][CH2:26][CH2:25][C:24](=[O:27])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: S=C([S-])Nc1ccccn1
Reactant: C=CC(=O)c1ccccc1
Agent: CC[NH+](CC)CC
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: O=C(CCSC(=S)Nc1ccccn1)c1ccccc1
Reaction time: 4 h
Yield: 28.3 %

Procedure:
The procedure of Example 4 is followed but a suspension of triethylammonium pyrid-2-yldithiocarbamate (81 g) in acetonitrile (400 cc) and a solution of 1-phenylprop-2-en-1-one (40 g) in acetonitrile (100 cc) are used as the starting materials at a maximum temperature of 25° C. The reaction is allowed to proceed for 4 hours at between 20° and 25° C. Triethylammonium pyrid-2-yldithiocarbamate (21 g) is filtered off. The acetonitrile is evaporated off under reduced pressure (20 mmHg) at 45° C. The residue is dissolved in chloroform (500 cc) and the chloroform solution is washed three times with distilled water (total 300 cc), dried over sodium sulphate and evaporated to dryness. The product obtained (60 g) is dissolved in chloroform (400 cc); the solution is chromatographed on silica (0.063-0.2 mm; 600 g) distributed in a column of diameter 6 cm. Elution is carried out with chloroform (1,600 cc), this eluate being discarded, and then with chloroform (3,000 cc), this eluate being collected and evaporated to dryness under reduced pressure (20 mmHg) at 40° C. The chromatographed product (35.2 g) is purified by recrystallisation from diisopropyl ether (105 cc). 3-Oxo-3-phenylpropyl pyrid-2-yldithiocarbamate (25.5 g) (structure determined by IR spectroscopy in petroleum jelly), which melts at 120° C., is obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:29]=1)[N:7]=[C:8]([NH:21]C(=O)OC(C)(C)C)[CH2:9][C:10]([C:12](=[O:20])[N:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])=[CH:11]2.[CH2:30]([O:32][C:33]([C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1)=[O:34])[CH3:31]>>[NH2:21][C:8]1[CH2:9][C:10]([C:12](=[O:20])[N:13]([CH2:14][CH2:15][CH3:16])[CH2:17][CH2:18][CH3:19])=[CH:11][C:5]2[CH:4]=[CH:3][C:2]([C:38]3[CH:39]=[CH:40][C:35]([C:33]([O:32][CH2:30][CH3:31])=[O:34])=[CH:36][CH:37]=3)=[CH:29][C:6]=2[N:7]=1
Reactant: CCCN(CCC)C(=O)C1=Cc2ccc(Br)cc2N=C(NC(=O)OC(C)(C)C)C1
Reactant: CCOC(=O)c1ccc(B(O)O)cc1
Product: CCCN(CCC)C(=O)C1=Cc2ccc(-c3ccc(C(=O)OCC)cc3)cc2N=C(N)C1

Procedure:
The title compound was prepared by the procedures as described in Example 124 (Step F) and Example 101 (Step I) using tert-butyl (1E,4E)-8-bromo-4-(dipropylcarbamoyl)-3H-benzo[b]azepin-2-ylcarbamate and 4-(ethoxycarbonyl)phenylboronic acid. MS APCI (+) m/z 434 (M+1) detected; 1H-NMR (400 MHz, CDCl3) δ 8.11 (d, 2H), 7.72 (d, 2H), 7.54 (d, 1H), 7.38 (d, 1H), 7.34 (dd, 1H), 6.84 (s, 1H), 4.40 (q, 2H), 3.47 (br s, 4H), 2.83 (s, 2H), 1.62-1.72 (m, 4H), 1.42 (t, 3H), 0.94 (t, 6H).
Reaction SMILES: [CH:1]1([N:5]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([CH3:14])[CH:12]=3)[C:7]([C:16]#[N:17])=[CH:6]2)[CH2:4][CH2:3][CH2:2]1.[B:18](OC(C)C)([O:23]C(C)C)[O:19]C(C)C.[Li+].CC([N-]C(C)C)C>C1COCC1>[C:16]([C:7]1[C:8]2[C:13](=[CH:12][C:11]([CH3:14])=[C:10]([F:15])[CH:9]=2)[N:5]([CH:1]2[CH2:2][CH2:3][CH2:4]2)[C:6]=1[B:18]([OH:23])[OH:19])#[N:17]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Cc1cc2c(cc1F)c(C#N)cn2C1CCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc2c(cc1F)c(C#N)c(B(O)O)n2C1CCC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Into a solution of 1-cyclobutyl-5-fluoro-6-methyl-1H-indole-3-carbonitrile (1.2 g, 5.3 mmol) and triisopropyl borate (2.18 mL, 9.47 mmol) in THF (20 mL) at −78° C. was added LDA (1.5 M in cyclohexane, 4.6 mL, 6.84 mmol). The mixture was stirred at −78° C. for 30 min and quenched with ice water (60 mL) and stirred for 15 min without cooling. The mixture was extracted with ethyl acetate 1:1 in hexane (20 mL). The aqueous layer was acidified with 2 N aq. HCl to pH 5 and then extracted with CH2Cl2 (60 mL). The organic layer was dried over Na2SO4 and concentrated to give 3-cyano-1-cyclobutyl-5-fluoro-6-methyl-1H-indol-2-ylboronic acid as a solid (1.44 g, 98% pure by LCMS) that was used in the next step without further purification.
Reaction SMILES: C1(S([N:10]2[CH2:17][CH:16]3[N:18]([CH3:19])[CH:12]([CH2:13][O:14][CH2:15]3)[CH2:11]2)(=O)=O)C=CC=CC=1.C1(C)C=CC=CC=1.[ClH:27]>C1(C)C(C)=CC=CC=1>[ClH:27].[CH3:19][N:18]1[CH:12]2[CH2:11][NH:10][CH2:17][CH:16]1[CH2:15][O:14][CH2:13]2
Reactant: CN1C2COCC1CN(S(=O)(=O)c1ccccc1)C2
Agent: Cl
Solvent: Cc1ccccc1C
Solvent: Cc1ccccc1
Product: CN1C2CNCC1COC2
Temperature: 140 °C
Reaction time: 18 h
Yield: 43 %

Procedure:
To a mixture of the above described 7-benzenesulfonyl-9-methyl-3-oxa-7,9-diaza-bicyclo[3.3.1]nonane (880 mg, 3.177 mmol) in xylene (20 ml) was added sodium dihydro-bis(2-methoxyethoxy)aluminate in toluene (2.423 ml, 7.947 mmol) and the mixture was stirred at 140° C. for 18 h. Cooled to 23° C., poured into 2 M HCl, extracted twice with tert-butyl methyl ether, the aqueous layer was made alkaline with 10 M NaOH-sol., extracted twice with tert-butyl methyl ether, the combined organic layer was dried over sodium sulfate, filtered, to the filtrate was added ethanol (5 ml) and chlorotrimethylsilane (ca. 0.5 ml) and all volatiles were removed in vacuum to give the title compound as a colorless oil (190 mg, 43%), MS (ISP) m/e=143.2 [(M+H)+].
Reaction SMILES: N#N.[F:3][C:4]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([N+:18]([O-])=O)[CH:15]=[N:14]2)=[CH:9][CH:8]=1)([F:6])[CH3:5].[NH4+].[Cl-]>CCO.O.[Fe]>[F:6][C:4]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)([F:3])[CH3:5]
Reactant: CC(F)(F)c1ccc(Cn2cc([N+](=O)[O-])cn2)o1
Agent: [Fe]
Agent: N#N
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: CC(F)(F)c1ccc(Cn2cc(N)cn2)o1
Temperature: 75 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a mixture of 1-[5-(1,1-difluoro-ethyl)-furan-2-ylmethyl]-4-nitro-1H-pyrazole (234 mg, 0.91 mmol), iron powder (154 mg, 2.73 mmol) and NH4Cl (246 mg, 4.55 mmol) in a mixture of EtOH (4.0 mL) and water (2.0 mL) was stirred at 75° C. for 1 h. The reaction mixture was filtered while hot and concentrated under reduced pressure. CH2Cl2 (20 mL) was added followed by 1M NaOH (20 mL). The aq. layer was extracted with CH2Cl2 (2×20 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give the title compound as an orange oil. LC-MS-conditions 02: tR=0.65 min; [M+AcCN+H]+=269.07.