Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:9]=1)([O-])=O>C(OCC)(=O)C.C(O)(=O)C.ClCCl.[Pd]>[N:16]1([C:6]2[CH:5]=[C:4]([NH2:1])[CH:9]=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:7]=2)[CH2:17][CH2:18][O:19][CH2:20][CH2:21]1
Reactant: O=[N+]([O-])c1cc(-c2ccccc2)cc(N2CCOCC2)c1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Nc1cc(-c2ccccc2)cc(N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Pd/C (53.9 mg, 0.051 mmol) was added to a solution of 4-(5-nitrobiphenyl-3-yl)morpholine (144 mg, 0.506 mmol) in ethyl acetate (5 mL) and acetic acid (0.5 mL). The reaction mixture was stirred under H2 atmosphere (1 atm) for 2 hours at room temperature. The reaction mixture was diluted with dichloromethane and filtered through CELITE and washed with ethyl acetate. The resultant solution was concentrated in vacuo to provide 5-(morpholin-4-yl)biphenyl-3-amine as a grey solid which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 7.57 (d, J=5.7 Hz, 2H), 7.36 (dd, J=32.4, 26.2 Hz, 3H), 6.58 (s, 1H), 6.49 (s, 1H), 6.27 (s, 1H), 5.13 (s, 2H), 3.89 (s, 4H), 3.21 (s, 4H).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]([CH:16]([CH2:25][CH2:26][OH:27])[CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C=O)C.N1C=CN=C1.[C:38]([Si:42](Cl)([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([CH3:41])([CH3:40])[CH3:39]>O>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]([CH:16]([CH2:25][CH2:26][O:27][Si:42]([C:38]([CH3:41])([CH3:40])[CH3:39])([C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:17][C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CC(CCO)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CC(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl 3-((S)-4-benzyl-2-oxooxazolidine-3-carbonyl)-5-hydroxyvalerate (401 g) and DMF (2000 mL) were mixed. To the mixture were added imidazole (160 g) and tert-butylchlorodiphenylsilane (287 mL) at ice temperature. The mixture was stirred at RT for 1 hr. After pouring water (1.2 L) into the reaction, the mixture was extracted with toluene (2.3 L). The organic layer was washed with aqueous 20 w/v % citric acid (1.6 L), water (2 L) and 10 w/v % brine (1.6 L), then dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated in vacuo to give the title compound (744.2 g) as a crude product.
Reaction SMILES: O[CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10](=[O:24])[CH:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6][CH2:5]1.P(Br)(Br)[Br:26]>ClCCl>[Br:26][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10](=[O:24])[CH:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6][CH2:5]1
Reactant: O=C(C(c1ccccc1)c1ccccc1)N1CCC(CCO)CC1
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: O=C(C(c1ccccc1)c1ccccc1)N1CCC(CCBr)CC1
Yield: 26.3 %

Procedure:
1-[4-(2-Hydroxyethyl)piperidin-1-yl]-2,2-diphenylethanone (2.39 g; 8.11 mmol) was dissolved in dichloromethane (20 ml). At room temperature, phosphorous tribromide (1.6 ml; 8.92 mmol) was slowly added dropwise. The reaction mixture was heated under reflux for 4 h. Cooling was followed by washing with saturated NaHCO3 solution, 2N HCl and saturated NaCl solution, and the organic phase was separated off and dried over Na2SO4. The solvent was removed under reduced pressure. Purification of the residue through a cartridge (silica gel) resulted in 1-[4-(2-bromoethyl)-piperidin-1-yl]-2,2-diphenylethanone (0.75 g; 2.13 mmol).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:19])[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[CH:5][CH:4]=1)#[N:2].[BH4-].[Na+].Cl>CO>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]([OH:19])[CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1ccc(C(=O)CCc2ccc(F)cc2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1ccc(C(O)CCc2ccc(F)cc2)cc1
Temperature: 30 °C
Reaction time: 1 h

Procedure:
1-(4-cyanophenyl)-3-(4-fluorophenyl)-1-propanone (6.35 g, 25 mmol) is dissolved in methanol (50 ml). Sodium borohydride (0.48 g, 12.6 mmol) is added and the mixture is stirred in 30° C. for 1 h. The mixture is rendered acidic with 2M hydrochloric acid and the solvent is evaporated. The residue is dissolved into ethyl acetate. The solution is washed with dilute sodium hydroxide and water, dried and the solvent is evaporated. The product is used for the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].[N+:13]([O-])([O-:15])=[O:14].[K+].S(=O)(=O)(O)O>ClCCl>[Br:1][C:2]1[C:3]([C:9]([F:12])([F:10])[F:11])=[CH:4][C:5]([F:8])=[CH:6][C:7]=1[N+:13]([O-:15])=[O:14]
Reactant: O=[N+]([O-])[O-]
Reactant: Fc1ccc(Br)c(C(F)(F)F)c1
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(F)cc(C(F)(F)F)c1Br

Procedure:
2-Bromo-5-fluoro-benzotrifluoride (XVII) (50 g, purchased from ABCR, F01421) is dissolved in 750 mL of dichloromethane. Potassium-nitrate (60.54 g) is added under stirring, followed by slow addition of sulfuric acid (587.3 g, 20% SO3, Riedel de Haen 30736). The temperature of the reaction mixture is kept at 25-30° C. by gentle cooling during the addition of the sulfuric acid. The reaction mixture is stirred for additional 25 hours at room temperature, after which time an IPC indicated >97% conversion. For work-up, the layers are separated and the acid layer is extracted by stirring with dichloromethane (2×300 mL). The dichloromethane phases are combined and washed sequentially with 1,000 mL of saturated aqueous NaHCO3 solution, 1,000 mL of aqueous sulfamic acid solution (5% m/m), 1,000 mL of saturated aqueous NaHCO3 solution and 1,000 mL of water. The dichloromethane solution is dried on anhydrous MgSO4 and the solvent is evaporated under reduced pressure to obtain 2-bromo-5-fluoro-1-nitro-3-trifluoromethyl-benzene (XVIII) as a yellow liquid. GC-MS: m/z: 287, 268, 257, 241, 229. These mass peaks are accompanied by the corresponding isotope peaks characteristic for bromine containing compounds. IR (film): 3101, 1618, 1591, 1554, 1454, 1423, 1365, 1319, 1232, 1186, 1153, 1113, 883 cm−1.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]([NH2:13])=[S:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Br[CH2:15][C:16](=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18]>CN(C=O)C>[OH:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[S:12][CH:15]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: CCOC(=O)C(=O)CBr
Reactant: COc1ccc(NC(N)=S)cc1O
Solvent: CN(C)C=O
Product: CCOC(=O)c1csc(Nc2ccc(OC)c(O)c2)n1
Yield: 63 %

Procedure:
Following the general procedure for the synthesis of derivatives 6 and 7, a solution of 1-(3-hydroxy-4-methoxyphenyl)thiourea (150 mg, 0.76 mmol) and ethyl 3-bromopyruvate (0.095 mL, 0.76 mmol) in dry DMF (3.0 mL) was heated at 60° C. for 6 h. The title compound was obtained after purification by flash chromatography on silica gel (hexane:EtOAc 6/4) in 63% yield (139 mg).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)([C:8]#[N:9])[CH2:4][CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:1][N:2]1[CH2:7][CH2:6][C:5]([CH2:8][NH2:9])([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[CH2:4][CH2:3]1
Reactant: CN1CCC(C#N)(c2ccccn2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCC(CN)(c2ccccn2)CC1
Reaction time: 8 h
Yield: 93.4 %

Procedure:
A solution of 1-methyl-4-(pyridin-2-yl)piperidine-4-carbonitrile (0.544 g, 2.70 mmol) in tetrahydrofuran (10 mL) was slowly added to a suspension of lithium aluminum hydride (0.205 g, 5.41 mmol) in tetrahydrofuran (10 mL) at 23° C. The reaction was stirred overnight, then quenched with sodium sulfate decehydrate. This was stirred for 1 hour, then ethyl acetate was added and the slurry was stirred for 2 more hours. Celite was added and the paste was filtered on Celite. The filtrate was concentrated to afford an oil (0.518 g, 93%) which was used as such for the next reaction. 1H NMR (400 MHz, CDCl3) δ ppm: 1.76-1.88 (2H, m), 2.07-2.19 (2H, m), 2.23 (3H, s), 2.43 (2H, br d, J=14.6 Hz), 2.58-2.69 (2H, m), 2.87 (2H, s), 7.16 (1H, ddd, J=7.52, 4.86 and 1.01 Hz), 7.33 (1H, d, J=8.08 Hz), 7.69 (1H, td, J=7.77 and 1.89 Hz), 8.65 (1H, d, J=4.80 and 1.01 Hz).
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[C:7]1[CH:12]=[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:10]([CH2:21][CH:22]=[CH2:23])=[C:9]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:41])C=1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:32])[C:7]1[CH:8]=[C:9]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:10]([CH2:21][CH:22]2[CH2:23][O:41]2)=[C:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:12]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C=CCc1c(OCc2ccccc2)cc(C(=O)OC(C)(C)C)cc1OCc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1cc(OCc2ccccc2)c(CC2CO2)c(OCc2ccccc2)c1
Yield: 57.9 %

Procedure:
To a solution of 4-allyl-3,5-bis-benzyloxy-benzoic acid tert-butyl ester (200d) (125 g, 0.29 mol) in CH2Cl2 was added m-CPBA (100 g, 0.58 mol) in several portions. The mixture was refluxed overnight. The solid was filtered and washed with CH2Cl2. The combined filtrates were washed with saturated aqueous Na2S2O4 (250 mL) and brine (250 mL). The organic layer was dried over Na2SO4 and concentrated to give a yellow oil. The crude oil was purified by flash column chromatography (EtOAc/petroleum ether=1/20) to give the title compound (75 g, 57.8%) as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.40 (m, 12H), 5.09(s, 4H), 3.53 (dd, 1H), 3.17 (m, 1H), 2.80 (dd, H), 2.63 (t, 1H), 2.51 (dd, 1H), 1.60 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2I.[N:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[C:16]1[CH:17]=[CH:18][N:13]=[CH:14][CH:15]=1
Reactant: OB(O)c1ccncc1
Reactant: Brc1ccc2nccc(I)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Brc1ccc2nccc(-c3ccncc3)c2c1
Temperature: 100 °C
Reaction time: 28 h
Yield: 92.3 %

Procedure:
A 1 L sealed tube charged with 6-bromo-4-iodoquinoline (11.58 g, 0.0347 mol), 4-pyridineboronic acid (5.97 g, 0.0486 mol), tetrakis(triphenyphosphine)palladium[0] (2.0 g, 0.00173 mol), 2 M aqueous potassium carbonate (152 mL) and 1,4-dioxane (152 mL) was stirred at 100° C. for 28 hrs. After cooling to rt, the organic layer was separated and the aqueous portion extracted with EtOAc (200 mL×3). The combined organic extracts were dried (Na2SO4), filtered and partially concentrated in vacuo. The resultant mixture was filtered to give the title compound (9.13 g) as a tan solid. The residual supernatant was concentrated to dryness and purified by silica gel chromatography (100% ethyl acetate to 2% methanol in ethyl acetate) to provide an additional 0.036 g of the title compound as a tan solid (combined 9.166 g, 92% yield).
Reaction SMILES: Cl[C:2]([C:4]([CH2:11][CH3:12])([CH2:9][CH3:10])[C:5]([O:7][CH3:8])=[O:6])=[O:3].C(N(CC)CC)C.[CH3:20][O:21][C:22](=[O:27])[CH2:23][CH2:24][NH:25][CH3:26]>CCOCC>[CH2:9]([C:4]([CH2:11][CH3:12])([C:2](=[O:3])[N:25]([CH3:26])[CH2:24][CH2:23][C:22]([O:21][CH3:20])=[O:27])[C:5]([O:7][CH3:8])=[O:6])[CH3:10]
Reactant: CCC(CC)(C(=O)Cl)C(=O)OC
Reactant: CNCCC(=O)OC
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCC(CC)(C(=O)OC)C(=O)N(C)CCC(=O)OC
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
To a solution of 19.2 g of methyl 2-chloroformyl-2-ethyl-butyrate and 20 g of triethylamine in 100 ml of dry ether, which is mechanically stirred and cooled at -10° C, there is added dropwise 12.8 g of N-methyl-β-alanine methyl ester dissolved in 50 ml of dry ether. After the addition, which takes 30 minutes, the mixture is stirred during 18 hours at room temperature. After filtration of the separated triethylamine hydrochloride, the solvent is evaporated leaving the desired product as an oil, boiling at 118° C (0.2 mm). Yield 93%. nD19 1.4646.
Reaction SMILES: [CH2:1]([N:3]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[F:22])[C:4](=[O:14])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].Br[CH2:24][C:25]1[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=1[C:27]([O:29][CH3:30])=[O:28].C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>C(#N)C>[CH2:1]([N:3]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[F:22])[C:4](=[O:14])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:24][C:25]2[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=2[C:27]([O:29][CH3:30])=[O:28])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCN(Cc1ccccc1F)C(=O)COc1ccc(O)cc1
Reactant: COC(=O)c1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCN(Cc1ccccc1F)C(=O)COc1ccc(OCc2ccccc2C(=O)OC)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 91.5 %

Procedure:
N-Ethyl-N-(2-fluorobenzyl)-2-(4-hydroxyphenoxy)acetamide (0.177 g, 0.586 mmol) was dissolved in acetonitrile (10 ml), methyl 2-(bromomethyl)benzoate (0.147 g, 0.642 mmol) and dipotassium carbonate (0.161 g, 1.167 mmol) were added. The solution was stirred for 2 hours at 60° C. EtOAc (20 ml) was added and the organic phase was washed with two portions of brine (2×20 ml, aq). The organic layer was dried (MgSO4) and the solvent was removed by evaporation. The crude was purified by preparative HPLC (started with isocratic acetonitrile/buffer 60/40 and then the acetonitrile concentration was increased to 100%, the buffer was a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KR-100-7-C8, 50 mm×250 mm, flow 40 ml/min). The product containing fractions were pooled and the acetonitrile was removed by evaporation. EtOAc (10 ml) was added and the organic phase was washed with two portions of brine and dried (MgSO4) and the solvent was removed by evaporation to give 0.242 g of methyl 2-[(4-{2-[ethyl(2-fluorobenzyl)amino]-2-oxoethoxy}phenoxy)methyl]benzoate (yield 91.9%).
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][CH2:6][NH:7][C:8]([C:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[C:19]([O:21][C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][C:32]4[CH:37]=[C:36]([CH3:38])[CH:35]=[CH:34][C:33]=4[F:39])=[O:30])=[C:24]([F:40])[CH:23]=3)[CH:18]=[CH:17][N:16]=2)[NH:12][CH:11]=1)=[O:9])C.Cl.O>C1COCC1>[F:40][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][C:25]=1[NH:28][C:29]([NH:31][C:32]1[CH:37]=[C:36]([CH3:38])[CH:35]=[CH:34][C:33]=1[F:39])=[O:30])[O:21][C:19]1[CH:18]=[CH:17][N:16]=[C:15]([C:13]2[NH:12][CH:11]=[C:10]([C:8]([NH:7][CH2:6][CH2:5][CH:4]=[O:3])=[O:9])[CH:14]=2)[CH:20]=1
Reactant: CCOC(CCNC(=O)c1c[nH]c(-c2cc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)c(F)c3)ccn2)c1)OCC
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)NCCC=O)c[nH]4)c3)cc2F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of N-(3,3-diethoxypropyl)-5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide (240 mg, 0.40 mmol) in 10 ml of THF, was added 2M HCl (1 ml, 2 mmol). The mixture was stirred at room temperature for 1 hour, and poured into 100 ml of water with vigorous stirring. The precipitates were filtered, washed with water and dried in vacuo to give 5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N-(3-oxopropyl)-1H-pyrrole-3-carboxamide as brown solid. Yield: 186 mg, 89%.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([C:13]#[N:14])[C:7]2[CH:8]=[N:9][NH:10][C:11]=2[CH:12]=1.I[CH3:16]>O1CCCC1>[Br:3][C:4]1[CH:5]=[C:6]([C:13]#[N:14])[C:7]2[CH:8]=[N:9][N:10]([CH3:16])[C:11]=2[CH:12]=1
Reactant: N#Cc1cc(Br)cc2[nH]ncc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1ncc2c(C#N)cc(Br)cc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 25 %

Procedure:
Tetrahydrofuran (27 ml) was added to a flask containing sodium hydride (0.275 g, 6.89 mmol) and the mixture was stirred for 10 minutes at 0° C. 6-Bromo-1H-indazole-4-carbonitrile (1.39 g, 6.26 mmol) was added portionwise and the mixture was stirred for 10 mins until no further effervescence was seen. Iodomethane (0.431 ml, 6.89 mmol) was added and the mixture stirred at 0° C. for 1 h. The ice bath was removed and the flask was placed in a water bath at room temperature. The reaction remained stirring for 19 h and the mixture was then evaporated in vacuo. The residual solid purified by silica (100 g) cartridge using a gradient of ethyl acetate and cyclohexane to give the title compound as a white solid (370 mg).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10]([C:12]1([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11])[CH2:2]2.[Br:25][CH2:26][C:27]([NH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[F:36])=[O:28]>C(#N)C>[Br-:25].[F:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[NH:29][C:27]([CH2:26][N+:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10]([C:12]1([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11])[CH2:2]2)=[O:28]
Reactant: O=C(CBr)Nc1ccccc1F
Reactant: O=C(O[C@H]1CN2CCC1CC2)C1(c2ccccc2)CCCCCC1
Solvent: CC#N
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)C1(c3ccccc3)CCCCCC1)C2)Nc1ccccc1F
Product: [Br-]
Temperature: 25 °C
Reaction time: 30 h

Procedure:
A mixture of 1-phenyl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl) ester (Example 14e) (56 mg) and 2-bromo-N-(2-fluoro-phenyl)-acetamide (Example 23a (44 mg) in acetonitrile (1 mL) was stirred at room temperature for 30 h. The resulting precipitate was collected by filtration, washed with ether and dried under vacuum at 50° C. to give the title compound (52 mg) as a colourless solid.
Reaction SMILES: [Br:1][CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=1)=[O:4].[CH2:14]([NH2:18])[CH:15]([CH3:17])[CH3:16]>ClCCl>[BrH:1].[Cl:13][C:8]1[CH:7]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][NH:18][CH2:14][CH:15]([CH3:17])[CH3:16])[CH:11]=[CH:10][C:9]=1[Cl:12]
Reactant: CC(C)CN
Reactant: O=C(CBr)Nc1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Product: Br
Product: CC(C)CNCC(=O)Nc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 79.5 %

Procedure:
To a solution of 2-bromo-N-(3,4-dichloro-phenyl)-acetamide (0.1 g) in dichloromethane (80 mL) at 0° C. was slowly added of isobutylamine (52 mg) in dichloromethane. The reaction mixture was allowed to warm up to room temperature and then stirred for another 24 hours. Then the salt was filtered off and the filtrate was concentrated in vacuo. The residue was then purified by column chromatography to yield the title compound as a white solid (0.1 g). MS (m/e): 357.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[C:14](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:14])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 88.9 %

Procedure:
To a suspension of 4-chloro-3-nitrobenzoic acid (10 g) and potassium carbonate (7.54 g) in N,N-dimethylformamide (100 mL) was added methyl iodide (3.24 mL) at room temperature under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 3.5 hours. The reaction mixture was diluted with ethyl acetate and washed successively with 1 N-hydrochloric acid, water, an aqueous saturated sodium hydrogencarbonate solution and brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The residual solid was washed with diisopropyl ether to give methyl 4-chloro-3-nitrobenzoate (9.51 g) as a yellow solid.
Reaction SMILES: C1([CH2:4][O:5][C:6]2[C:11]([C:12]3[N:16]([CH2:17][C:18]4[CH:23]=[CH:22][C:21](CCC(O)=O)=[CH:20][CH:19]=4)[C:15]4[CH:29]=[C:30]([F:34])[C:31]([F:33])=[CH:32][C:14]=4[N:13]=3)=[CH:10]C=CN=2)CC1.F[C:36]1[C:52](F)=CC2NC(C3C=CC=CC=3OC)=NC=2[CH:37]=1.BrCC1CCCCC1>>[CH:18]1([CH2:17][N:16]2[C:15]3[CH:29]=[C:30]([F:34])[C:31]([F:33])=[CH:32][C:14]=3[N:13]=[C:12]2[C:11]2[CH:10]=[CH:52][CH:36]=[CH:37][C:6]=2[O:5][CH3:4])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: COc1ccccc1-c1nc2cc(F)c(F)cc2[nH]1
Reactant: O=C(O)CCc1ccc(Cn2c(-c3cccnc3OCC3CC3)nc3cc(F)c(F)cc32)cc1
Agent: BrCC1CCCCC1
Product: COc1ccccc1-c1nc2cc(F)c(F)cc2n1CC1CCCCC1

Procedure:
The title compound was prepared in analogy to Example 19, intermediate b, from 5,6-difluoro-2-(2-methoxy-phenyl)-1H-benzoimidazole and bromomethyl-cyclohexane (2550-36-9). Brown sticky solid (42%). MS (Turbo Spray): m/z=357.4 (M+H).
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][C@@:7]12[C:15]([OH:18])([C:16]#[N:17])[CH2:14][CH2:13][C@H:12]1[C@@H:11]1[CH2:19][CH2:20][C:21]3[C@@:27]([CH3:28])([C:10]1(O)[CH2:9][CH2:8]2)[CH2:26][CH2:25][C:23](=[O:24])[CH:22]=3>O>[C:16]([C@@:15]1([OH:18])[CH2:14][CH2:13][C@H:12]2[C@H:11]3[C:10](=[CH:9][CH2:8][C@:7]12[CH3:6])[C@:27]1([CH3:28])[C:21](=[CH:22][C:23](=[O:24])[CH2:25][CH2:26]1)[CH2:20][CH2:19]3)#[N:17]
Reactant: C[C@]12CCC(=O)C=C1CC[C@H]1[C@@H]3CCC(O)(C#N)[C@@]3(C)CCC12O
Agent: O=S(=O)(O)O
Solvent: O
Product: C[C@]12CCC(=O)C=C1CC[C@@H]1C2=CC[C@@]2(C)[C@H]1CC[C@]2(O)C#N
Reaction time: 19 h

Procedure:
A mixture of sulfuric acid (37 ml) and water (32.1 ml) is added to 17β-cyano-9α,17α-dihydroxyandrost-4-en-3-one (I, EXAMPLE 87, 13.28 g). The mixture is stirred at 20°-25° for 19 hr, stirred at 30° for 4 hr, then cooled to 10°. Sulfuric acid (11.2 ml) is added, the mixture is stirred at 20°-25° for 45 min, then cooled to 0° and water (55 ml) is added, maintaining the temperature at <5°. The product is collected by vacuum filtration and washed with water (80 ml), aqueous ammonium acetate (1M, 80 ml) and water (80 ml). The solid is dried in an air stream for 24 hr to give the title compound, mp 225°-228°.
Reaction SMILES: [CH2:1]1[O:30][C:4]2=[CH:5][C:6]3[C:12]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[N:11][N:10]([C:19]4[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=4)[C:9](=[O:28])[CH2:8][C:7]=3[CH:29]=[C:3]2[O:2]1.O.NN>C(O)C.Cl.[Ni]>[NH2:25][C:22]1[CH:23]=[CH:24][C:19]([N:10]2[C:9](=[O:28])[CH2:8][C:7]3[CH:29]=[C:3]4[O:2][CH2:1][O:30][C:4]4=[CH:5][C:6]=3[C:12]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[N:11]2)=[CH:20][CH:21]=1
Reactant: O=C1Cc2cc3c(cc2C(c2ccccc2)=NN1c1ccc([N+](=O)[O-])cc1)OCO3
Agent: [Ni]
Agent: Cl
Agent: NN
Solvent: CCO
Solvent: O
Product: Nc1ccc(N2N=C(c3ccccc3)c3cc4c(cc3CC2=O)OCO4)cc1
Reaction time: 0.67 h
Yield: 65.5 %

Procedure:
To a solution of 7,8-methylenedioxy-3-(4-nitrophenyl)-1-phenyl-3,5-dihydro-2,3-benzodiazepin-4(4H)-one (15 mg, 0.037 mmol) in ethanol (5 mL) was added HCl (conc. 2 drops), hydrazine hydrate (0.3 mL) and Raney Ni (excess) and the reaction was stirred for 40 min. The excess Raney Ni was removed by filtration and the pure product (9 mg, 66%) was obtained by flash chromatography (12.5% acetone in CH2Cl2). 1H NMR (CDCl3) 7.60 (m, 2H), 7.42 (m, 3H), 7.20 (d, J=8.6, 2H), 6.92 (s, 1H), 6.71 (d, J=8.6, 2H), 6.68 (s, 1H), 6.07 (s, 1H), 6.03 (s, 1H), 3.80-3.45 (m, 4H).