Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3](=[CH:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]2[N:28]=[C:29]3[C:35]([C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:34][N:33](COCC[Si](C)(C)C)[C:30]3=[N:31][CH:32]=2)=[CH:22][CH:21]=1)[C:4]([N:6]1[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]1)=[O:5])#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:6]1([C:4]([C:3](=[CH:19][C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27]3[N:28]=[C:29]4[C:35]([C:36](=[O:41])[C:37]([CH3:39])([CH3:38])[CH3:40])=[CH:34][NH:33][C:30]4=[N:31][CH:32]=3)=[CH:22][CH:21]=2)[C:1]#[N:2])=[O:5])[CH2:7][CH2:8][NH:9][CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)C(C#N)=Cc2ccc(Nc3cnc4c(n3)c(C(=O)C(C)(C)C)cn4COCC[Si](C)(C)C)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)C(=O)c1c[nH]c2ncc(Nc3ccc(C=C(C#N)C(=O)N4CCNCC4)cc3)nc12
Reaction time: 8 h
Yield: 38.2 %

Procedure:
Tert-butyl 4-[2-cyano-3-[4-[[7-(2,2-dimethylpropanoyl)-5-(2-trimethylsilylethoxy-methyl)-pyrrolo[2,3-b]pyrazin-2-yl]amino]phenyl]prop-2-enoyl]piperazine-1-carboxylate (80 mg, 0.12 mmol) was dissolved in DCM (3 mL), cooled in an ice bath, and TFA (3 mL, 0.12 mmol) was added. The reaction mixture was stirred overnight, and then most of the solvent was removed in vacuo. The mixture was neutralized by Na2HCO3 to pH 7-8, extracted by EtOAc, combined organic layer was evaporated. The residue was dissolved in methanol (15 mL), adding HCl (0.05 mL, 0.12 mmol, and a few of drops water, and the mixtured was stirred overnight. When the reaction was deemed complete by LCMS analysis, the solvent was removed, and the product precipitated from EtOAc/MeOH to get 21 mg of 2-(piperazine-1-carbonyl)-3-(4-((7-pivaloyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)amino)phenyl)acrylonitrile.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([CH:8]=1)[NH2:7].[CH3:10][C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[C:15]([CH3:17])[CH:16]=1>>[CH3:10][C:11]1[CH:12]=[C:13]([C:2]2[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([NH2:7])[CH:8]=2)[CH:14]=[C:15]([CH3:17])[CH:16]=1
Reactant: Cc1ccc(Br)cc1N
Reactant: Cc1cc(C)cc(B(O)O)c1
Product: Cc1cc(C)cc(-c2ccc(C)c(N)c2)c1
Yield: 94 %

Procedure:
Using the same method as in Example 5-(i), 5-bromo-2-methylaniline was reacted with 3,5-dimethylphenyl boronic acid to give 3′,4,5′-trimethylbiphenyl-3-amine (yield: 94%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][CH:6]1[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]1.FC(F)(F)C(O)=O>ClCCl>[NH:9]1[CH2:10][CH2:11][CH:6]([CH2:5][C:4]2[CH:3]=[C:2]([CH:21]=[CH:20][CH:19]=2)[NH2:1])[CH2:7][CH2:8]1
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2cccc(N)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1cccc(CC2CCNCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 109.6 %

Procedure:
tert-Butyl 4-(3-aminobenzyl)piperidine-1-carboxylate (6.09 mmol, 1.77 g) was dissolved in dichloromethane (10 mL). Trifluoroacetic acid (5 mL) was added and the reaction mixture stirred at room temperature for 1 hour. The reaction mixture was concentrated under vacuum and purified by SCX chromatography to afford the intermediate 3-(piperidin-4-ylmethyl)aniline (1.27 g).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.[Cl:7][CH2:8][CH:9]=O.C([O-])(O)=O.[Na+]>CO.CC(O)=O.Cl>[Cl:7][CH2:8][CH2:9][N:4]1[CH2:5][CH2:6][C@@H:2]([OH:1])[CH2:3]1
Reactant: O=CCCl
Reactant: O[C@@H]1CCNC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O[C@@H]1CCN(CCCl)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23.1 %

Procedure:
To a solution of (R)-3-hydroxypyrrolidine (0.47 g, 5.5 mmol) in MeOH (14.4 mL) and AcOH (1.44 mL) was added chloroacetaldehyde (0.86 mL, 5.5 mmol, 50% in H2O solution) and picolineborane complex (0.58 g, 5.5 mmol). The reaction mixture was stirred at ambient temperature for 0.5 h. Then additional picoline borane complex (0.29 g, 2.7 mmol) was added. The reaction mixture was stirred for an additional 0.5 h. Then the reaction mixture was diluted with HCl (30 mL, 10% in H2O) and stirred for 0.5 h at ambient temperature. The mixture was slowly basified with solid NaHCO3 (7.85 g) and extracted with EtOAc (3×20 mL). The organics extracts were dried (Na2SO4) and concentrated to yield the title compound (0.19 g, 23%) as a light yellow oil. 1H NMR (300 MHz, CD3OD) δ 4.36-4.32 (m, 1H), 3.63 (t, J=6.6 Hz, 2H), 2.91-2.76 (m, 4H), 2.66-2.52 (m, 3H), 2.16-2.09 (m, 1H), 1.74-1.70 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[C:8]2[N:10]([CH2:14][CH3:15])[N:11]=[C:12]([CH3:13])[C:7]2=[N:6][C:5]=1[C:16]([OH:18])=O)[CH3:2].S(Cl)([Cl:21])=O>>[CH2:1]([O:3][C:4]1[N:9]=[C:8]2[N:10]([CH2:14][CH3:15])[N:11]=[C:12]([CH3:13])[C:7]2=[N:6][C:5]=1[C:16]([Cl:21])=[O:18])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCOc1nc2c(nc1C(=O)O)c(C)nn2CC
Product: CCOc1nc2c(nc1C(=O)Cl)c(C)nn2CC

Procedure:
22.7 g. of 6-ethoxy-1-ethyl-3-methyl-1H-pyrazolo-[3,4-b]pyrazine-5-carboxylic acid (0.09 mol.) and 250 ml. of thionyl chloride are heated at reflux temperature for two hours. After vacuum removal of excess thionyl chloride, the residual 6-ethoxy-1-ethyl-3-methyl-1H-pyrazolo[3,4-b]pyrazine-5-carbonyl chloride is recrystallized from hexane, yield 20.5 g. (85%), m.p. 109°-111°.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]2.[C:18]([C:22]1[CH:27]=[CH:26][C:25]([SH:28])=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19]>>[C:18]([C:22]1[CH:23]=[CH:24][C:25]([S:28][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]3)=[CH:26][CH:27]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)c1ccc(S)cc1
Reactant: O=c1ccc2cc(OCCCCBr)ccc2[nH]1
Product: CC(C)(C)c1ccc(SCCCCOc2ccc3[nH]c(=O)ccc3c2)cc1

Procedure:
Prepared analogous to Example 122 from 6-(4-bromobutoxy)-carbostyril (m.p. 198°-199° C.) and 4-tert. butylthiophenol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[CH2:18]([C:21]1[N:25]([C:26]([CH3:29])([CH3:28])[CH3:27])[N:24]=[C:23]([CH:30]=O)[CH:22]=1)[CH2:19][CH3:20]>>[C:26]([N:25]1[C:21]([CH2:18][CH2:19][CH3:20])=[CH:22][C:23]([CH2:30][NH:17][CH2:16][CH2:15][N:12]2[CH2:11][CH2:10][N:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[CH2:14][CH2:13]2)=[N:24]1)([CH3:29])([CH3:28])[CH3:27]
Reactant: CCCc1cc(C=O)nn1C(C)(C)C
Reactant: COc1ccc(N2CCN(CCN)CC2)cc1
Product: CCCc1cc(CNCCN2CCN(c3ccc(OC)cc3)CC2)nn1C(C)(C)C
Yield: 34.2 %

Procedure:
Compound 38 was prepared using the same method as that of Example 1 except that 4-(4-methoxyphenyl)piperazin-1-ylethylamine and 5-propyl-1-t-butylpyrazole-3-carbaldehyde were used.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][N:9]2[C:17]3[CH:16]=[CH:15][C:14]([C:18]#[N:19])=[CH:13][C:12]=3[C:11]3[CH2:20][C@H:21]([NH:23][C:24](=[O:29])[O:25][CH:26]([CH3:28])[CH3:27])[CH2:22][C:10]2=3)[C:3]=1[O:30][CH3:31]>[Pd].CO.O>[CH:26]([O:25][C:24](=[O:29])[NH:23][C@@H:21]1[CH2:22][C:10]2[N:9]([CH2:8][C:4]3[C:3]([O:30][CH3:31])=[CH:2][CH:7]=[CH:6][N:5]=3)[C:17]3[CH:16]=[CH:15][C:14]([C:18]#[N:19])=[CH:13][C:12]=3[C:11]=2[CH2:20]1)([CH3:28])[CH3:27]
Reactant: COc1c(Cl)ccnc1Cn1c2c(c3cc(C#N)ccc31)C[C@H](NC(=O)OC(C)C)C2
Agent: [Pd]
Solvent: O
Solvent: CO
Product: COc1cccnc1Cn1c2c(c3cc(C#N)ccc31)C[C@H](NC(=O)OC(C)C)C2
Reaction time: 8 h
Yield: 93.5 %

Procedure:
A mixture of (S)-isopropyl 4-((4-chloro-3-methoxypyridin-2-yl)methyl)-7-cyano-1,2,3,4-tetrahydrocyclopenta[b]indol-2-ylcarbamate (12.53 g, 28.55 mmol) and 10% palladium on carbon (1.00 g) in methanol (150 mL) is hydrogenated at 50 psi at room temperature overnight. A fresh batch of 10% palladium on carbon (1.2 g) is slurried in water (˜2 mL) and added to the reaction mixture, which is hydrogenated (50 psi) at room temperature overnight. The catalyst is filtered off and the solution is concentrated under reduced pressure to obtain a pale yellow solid. The solid is triturated with ether twice and dried under high vacuum to afford a yellow solid (10.80 g, 94%). LC-ES/MS m/z 405.2 [M+H]+
Reaction SMILES: C([O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:10]([C:20]#[N:21])=[C:9]2[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[F:28])(C)(C)C.FC(F)(F)C(O)=O>O1CCCC1>[F:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:9]1[C:8]2[C:13](=[CH:14][CH:15]=[C:6]([OH:5])[CH:7]=2)[N:12]=[C:11]([CH2:16][CH:17]([CH3:18])[CH3:19])[C:10]=1[C:20]#[N:21]
Reactant: CC(C)Cc1nc2ccc(OC(C)(C)C)cc2c(-c2ccccc2F)c1C#N
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Cc1nc2ccc(O)cc2c(-c2ccccc2F)c1C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.5 %

Procedure:
To a solution of 6-tert-butoxy-4-(2-fluorophenyl)-2-isobutylquinoline-3-carbonitrile (0.22 g, 0.58 mmol) in tetrahydrofuran (1 ml) was added trifluoroacetic acid (5 ml), and the mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated and the obtained crude crystals were recrystallized from n-hexane-ethyl acetate to give 4(2-fluorophenyl)-6-hydroxy-2-isobutylquinoline-3-carbonitrile (0.17 g, yield 92%) as pale-yellow crystals.
Reaction SMILES: [C:1]([OH:5])([CH3:4])([CH3:3])[CH3:2].Cl[C:7]([O:9][CH:10]([Cl:12])[CH3:11])=[O:8].N1C=CC=CC=1>ClCCl>[C:7](=[O:8])([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[O:9][CH:10]([Cl:12])[CH3:11]
Reactant: CC(C)(C)O
Reactant: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(Cl)OC(=O)OC(C)(C)C

Procedure:
In a reactor cooled to +5° C., there are introduced 600 ml of dicloromethane, 43.7 g (0.59 mole) of tert-butanol and 94.7 g (0.66 mole) of α-chloroethyl chloroformate. 57 g (0.72 mole) of pyridine are then added dropwise and with stirring while the temperature is maintained at between 10° and 20° C. The mixture is stirred for 4 hours at room temperature.
Reaction SMILES: [Mg].II.[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH2:9]Cl.CN(C)[C:16]([CH:18]1[CH2:20][CH2:19]1)=[O:17]>O1CCCC1.C(OCC)C>[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH2:9][C:16]([CH:18]1[CH2:20][CH2:19]1)=[O:17]
Reactant: COc1cccc(CCl)c1
Reactant: CN(C)C(=O)C1CC1
Agent: II
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1cccc(CC(=O)C2CC2)c1
Reaction time: 1 h

Procedure:
A 250 ml round-bottomed flask is filled with magnesium (4.9 g, 0.20 mol) and iodine (0.1 g) is sublimated to the magnesium, then diethyl ether (100 ml) is added and under boiling a solution of 3-methoxybenzyl chloride (11.9 ml, 0.1 mol) and diethyl ether (40 ml) are added to the reaction mixture. The mixture is boiled for one hour and at this temperature a solution of cyclopropanecarboxylic acid dimethylamide (16.6 g, 0.15 mol) and tetrahydrofuran (70 ml) are added. The reaction mixture is stirred for half an hour and under cooling aqueous hydrogen chloride (80 ml, 1:1) is added dropwise to the mixture. The organic layer is dried and the residue (32 g) is fractionated in vacuo.
Reaction SMILES: Br[C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:23])[C:8]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:9]=4[C:10]([CH3:16])([CH3:15])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.[Cu][C:25]#[N:26]>CN1C(=O)CCC1.C(OCC)(=O)C>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:8]2[C:7](=[O:23])[C:6]3[C:5]4[C:13](=[CH:14][C:2]([C:25]#[N:26])=[CH:3][CH:4]=4)[NH:12][C:11]=3[C:10]([CH3:16])([CH3:15])[C:9]=2[CH:17]=1
Reactant: N#C[Cu]
Reactant: COc1ccc2c(c1)C(C)(C)c1[nH]c3cc(Br)ccc3c1C2=O
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O
Temperature: 170 °C
Reaction time: 17 h
Yield: 73.8 %

Procedure:
(Method 1) 3-Bromo-8-methoxy-6,6-dimethyl-5,6-dihydrobenzo[b]carbazol-11-one (Compound A4, 10.45 g, 28.2 mmol) and copper (I) cyanide (5.0 g, 50.2 mmol) were dissolved in NMP (100 ml), followed by stirring at 170° C. for 17 hr. The reaction mixture was suspended in ethyl acetate (500 mL) and distilled water (200 mL). The insoluble matters were removed by Celite filtration and washed twice with ethyl acetate (300 mL×2). The organic layer was washed once with an aqueous solution of disodium EDTA (200 mL) and twice with saturated brine (200 mL) in order, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure to yield a product, which was suspended and washed with a small amount of CPME to obtain the title compound as a colorless crystal (6.58 g, 73%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C@H:14]([OH:19])[C:15]([F:18])([F:17])[F:16])[C:11](=[O:20])[N:10]([CH2:21][C:22]([NH:24][CH:25]([C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([C:43]([F:46])([F:45])[F:44])[CH:38]=3)[C:26]([NH:28][C:29]3([C:32]([O:34]CC)=[O:33])[CH2:31][CH2:30]3)=[O:27])=[O:23])[N:9]=2)=[CH:4][CH:3]=1.[OH-].[Li+].Cl>CO.CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C@H:14]([OH:19])[C:15]([F:16])([F:17])[F:18])[C:11](=[O:20])[N:10]([CH2:21][C:22]([NH:24][CH:25]([C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([C:43]([F:46])([F:44])[F:45])[CH:38]=3)[C:26]([NH:28][C:29]3([C:32]([OH:34])=[O:33])[CH2:31][CH2:30]3)=[O:27])=[O:23])[N:9]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1(NC(=O)C(NC(=O)Cn2nc(-c3ccc(Cl)cc3)n(C[C@H](O)C(F)(F)F)c2=O)c2cccc(C(F)(F)F)c2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: CS(C)=O
Product: O=C(Cn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O)NC(C(=O)NC1(C(=O)O)CC1)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
78 mg (0.115 mmol) of the compound of Example 1 were dissolved in 2.2 ml of methanol, and 460 μl of a 1M aqueous lithium hydroxide solution (0.46 mmol) were added. The mixture was stirred at RT overnight and then adjusted to pH 2 by addition of 1N hydrochloric acid, diluted with a little DMSO and separated by preparative HPLC [Method 6]. This gave 64 mg (86% of theory) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N+:3]=1[O-:9].C([O-])(C)(C)C.[K+].[CH:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH3:1][C:2]1[CH:7]=[C:6](/[CH:8]=[CH:16]/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:5]=[CH:4][N+:3]=1[O-:9]
Reactant: O=Cc1ccccc1
Reactant: Cc1cc[n+]([O-])c(C)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: Cc1cc(/C=C/c2ccccc2)cc[n+]1[O-]
Yield: 7 %

Procedure:
Following the general method described in example 2a, 2,4-dimethylpyridine 1-oxide was reacted with potassium tert.-butanolate and benzaldehyde. After extraction and chromatography (SiO2 with CH2Cl2/MeOH=97/3) the title compound was obtained as a yellow solid material (yield 7%)). NMR (250 MHz, DMSO): 2.37 (s, 3H, CH3), 7.20 (d, J=16.5 Hz, 1H, CH═CH), 7.25-7.75 (m, 8H, arom-H, CH═CH), 8.22 (d, J=6.8 Hz, 1H, arom-H).
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([CH3:34])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[CH3:37][CH:38]([NH2:47])[CH2:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>>[CH3:34][C:23]1[CH:22]=[C:21]([C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([NH:47][CH:38]([CH3:37])[CH2:39][CH2:40][C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:20])[CH:26]=[CH:25][C:24]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH3:33]
Reactant: CC(N)CCc1ccccc1
Reactant: Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)cc1C
Product: Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NC(C)CCc4ccccc4)n3Cc3ccccc32)cc1C

Procedure:
The title compound was synthesized in the manner of Example 13 from 2,2,2-trichloro-1-{10-[(2,2′-dimethyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 6 and 1-methyl-3-phenylpropylamine, m.p. 152-154° C. MS [(+)ESI, m/z]: 566 [M+H]+ Anal. Calcd for C36H37N3O2: C, 80.39; H, 6.57; N, 7.40. Found: C, 80.27; H, 6.70; N, 7.27.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([F:16])([F:15])[F:14])=[C:11]([C:17](Cl)=[O:18])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:22]=[C:23]([S:27]([F:30])(=[O:29])=[O:28])[CH:24]=[CH:25][CH:26]=1.N1C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([F:16])([F:15])[F:14])=[C:11]([C:17]([NH:20][C:21]3[CH:22]=[C:23]([S:27]([F:30])(=[O:29])=[O:28])[CH:24]=[CH:25][CH:26]=3)=[O:18])[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Nc1cccc(S(=O)(=O)F)c1
Reactant: O=C(Cl)c1cnn(-c2ccc(Cl)cc2)c1C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1cccc(S(=O)(=O)F)c1)c1cnn(-c2ccc(Cl)cc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.4 %

Procedure:
1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carbonyl chloride (3.00 g, 9.70 mmol) was added to 3-amino-benzenesulfonyl fluoride (1.87 g, 10.6 mmol) in CH2Cl2 (50 ml) containing pyridine (2.35 ml, 29.1 mmol). Reaction mixture stirred overnight at room temperature, concentrated under reduced pressure and crude product purified by column chromatography to give 3-{[1-(4-chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carbonyl]-amino}-benzenesulfonyl fluoride (3.23 g, 74%).
Reaction SMILES: C[C:2]1[C:3](C)=[C:4]([C:12]#[C:13]CO)[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[OH-].[Na+].C1(C)C=CC=CC=1>C(OCC)C>[C:4]1([C:12]#[CH:13])[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[CH:2][CH:3]=1
Reactant: Cc1cc2ccccc2c(C#CCO)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: C#Cc1cccc2ccccc12
Temperature: 120 °C
Yield: 88.8 %

Procedure:
Dimethylhydroxymethyl-1-naphthylacetylene (898 mg, 4.27 mmol) and NaOH (239 mg, KISHIDA CHEMICAL CO., Ltd., 0.7 mm granular, 98% article, 5.98 mmol) were placed in a 30 mL two-neck flask equipped with a reflux condenser and the air inside the flask was replaced with Ar. 20 mL of toluene was added thereto and the mixture was refluxed at 120° C. for 30 minutes. Diethyl ether was added to the reaction mixture and the mixture was washed with a saturated aqueous ammonium chloride solution and dried over magnesium sulfate. The solvent was distilled off under reduced pressure by an evaporator. The crude reaction product was purified by column chromatography (Hexane/AcOEt=100/0→1/10) using silica gel to give 577 mg of the desired compound as a yellow solid (yield: 88.8%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][O:15][C:16](=[O:23])[NH:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:4][CH:3]=1.[CH2:24]([O:26][C:27]([C:29]1([C:32]2[CH:37]=[CH:36][C:35](B3OC(C)(C)C(C)(C)O3)=[CH:34][CH:33]=2)[CH2:31][CH2:30]1)=[O:28])[CH3:25]>>[CH2:24]([O:26][C:27]([C:29]1([C:32]2[CH:37]=[CH:36][C:35]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH2:14][O:15][C:16](=[O:23])[NH:17][CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)=[CH:4][CH:3]=3)=[CH:34][CH:33]=2)[CH2:30][CH2:31]1)=[O:28])[CH3:25]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1COC(=O)NC1CCCC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4COC(=O)NC4CCCC4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using cyclopentyl-carbamic acid 5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylmethyl ester and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH:4]([N:7]([C:14]#[N:15])[NH:8][C:9]([O:11]CC)=O)([CH3:6])[CH3:5]>C(O)C>[CH3:1][N:2]([CH3:3])[C:14]1[N:7]([CH:4]([CH3:5])[CH3:6])[NH:8][C:9](=[O:11])[N:15]=1
Reactant: CCOC(=O)NN(C#N)C(C)C
Reactant: CNC
Solvent: CCO
Product: CC(C)n1[nH]c(=O)nc1N(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a solution of 100 ml of 33 % strength dimethylamine in absolute ethanol are added dropwise 35 g (0.2 mol) of ethyl 2-isopropyl-2-cyano-hydrazinecarboxylate. The solution is first stirred for 8 hours at room temperature and then for 1.5 hours at the reflux temperature. Concentration in a rotary evaporator gives an oily residue which slowly crystallizes on standing. Recrystallization from cyclohexane/ethyl acetate (4:1 by vol.) gives 30 g (88 % of theory) of 5-dimethylamino-1-isopropyl-1,2-dihydro-3H-1,2,4-triazol -3-one having a melting point of 111° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].[Cl:13][C:14]1[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[S:22](Cl)(=[O:24])=[O:23])=[C:16]([O:26][CH3:27])[CH:15]=1>N1C=CC=CC=1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:22](/[CH:21]=[CH:20]/[C:17]2[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][C:16]=2[O:26][CH3:27])(=[O:23])=[O:24])=[C:3]([S:9]([NH2:12])(=[O:11])=[O:10])[CH:4]=1
Reactant: COc1cc(Cl)ccc1/C=C/S(=O)(=O)Cl
Reactant: Nc1ccc(Cl)cc1S(N)(=O)=O
Solvent: c1ccncc1
Product: COc1cc(Cl)ccc1/C=C/S(=O)(=O)Nc1ccc(Cl)cc1S(N)(=O)=O
Yield: 99.5 %

Procedure:
A solution of 2-amino-5-chlorobenzenesulfonamide (0.041 g, 0.20 mmol) and (E)-2-(4-chloro-2-methoxyphenyl)ethenesulfonyl chloride (0.053 g, 0.20 mmol) in pyridine (2 mL) was stirred at room temperature over night. The reaction mixture was concentrated, 1 M hydrochloric acid was added and the mixture was extracted with dichloromethane. The organic phase was dried over magnesium sulfate and the solvent was evaporated to give 0.087 g (99% yield) of the title compound.
Reaction SMILES: [CH:1]1([CH:6]([OH:10])[C:7]([OH:9])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.N[C@H](C([NH:17][CH:18]1[C:24](=[O:25])[N:23]([CH2:26][CH:27]2[CH2:29][CH2:28]2)[C:22]2[CH:30]=[CH:31][CH:32]=[CH:33][C:21]=2[N:20]([CH2:34][CH:35]2[CH2:37][CH2:36]2)[C:19]1=[O:38])=O)C>>[CH:1]1([CH:6]([OH:10])[C:7]([NH:17][C@H:18]([C:24]([C:18]2([NH2:17])[C:24](=[O:25])[N:23]([CH2:26][CH:27]3[CH2:29][CH2:28]3)[C:22]3[CH:30]=[CH:31][CH:32]=[CH:33][C:21]=3[N:20]([CH2:34][CH:35]3[CH2:37][CH2:36]3)[C:19]2=[O:38])=[O:25])[CH3:19])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C[C@H](N)C(=O)NC1C(=O)N(CC2CC2)c2ccccc2N(CC2CC2)C1=O
Reactant: O=C(O)C(O)C1CCCC1
Agent: Cl
Product: C[C@H](NC(=O)C(O)C1CCCC1)C(=O)C1(N)C(=O)N(CC2CC2)c2ccccc2N(CC2CC2)C1=O

Procedure:
Following General Procedure I above using cyclopentyl-α-hydroxyacetic acid (Example P) and 3-(L-alaninyl)-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine hydrochloride (Example 8-U), the title compound was prepared as a white foam. Purification was by L.C. 2000 eluting with CH2Cl2/EtOAc (1:1 gradient to 1:2) then flash chromatography eluting with 2:1 EtOAc/CH2Cl2. Rf=0.47 and 0.37 (CH2Cl2/EtOAc, 1:2).
Reaction SMILES: C([C:5]1([O:11][CH2:12][CH2:13][CH2:14]Br)[CH2:10][CH2:9][CH2:8][CH2:7][O:6]1)(C)(C)C.[OH:16][CH2:17][C:18]1[S:19][CH:20]=[CH:21][CH:22]=1>CN(C=O)C>[S:19]1[CH:20]=[CH:21][CH:22]=[C:18]1[CH2:17][O:16][CH2:14][CH2:13][CH2:12][O:11][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][O:6]1
Reactant: OCc1cccs1
Reactant: CC(C)(C)C1(OCCCBr)CCCCO1
Solvent: CN(C)C=O
Product: c1csc(COCCCOC2CCCCO2)c1

Procedure:
In an analogous manner to that described in Example 1(g), by alkylating tert-butyl (RS)-2-(3-bromo-propoxy)-tetrahydro-pyran with 2-hydroxymethyl-thiophene in DMF there was obtained (RS)-2-[3-(thiophen-2-ylmethoxy)-propoxy]-tetrahydro-pyran, which after cleavage of the THP group analogously to Example 53(c), yielded 3-(thiophen-2-ylmethoxy)-propan-1-ol. Subsequent conversion into the mesylate according to a procedure known from the literature and alkylation effected with the latter analogously to Example 44(e) of tert-butyl (3RS,4RS)-3-hydroxy-4-(4-hydroxy-phenyl)-piperidine-1-carboxylate gave tert-butyl (3RS,4RS)-3-hydroxy-4-[4-[3-(thiophen-2-ylmethoxy)-propoxy]-phenyl]-piperidine-1-carboxylate. By alkylation with 2-chloromethyl-1,4-dimethoxy-naphthalene analogously to Example 1(g) there was obtained (3RS,4RS)-3-(1,4-dimethoxy-naphthalen-2-ylmethoxy)-4-{4-[3-(thiophen-2-ylmethoxy)-propoxy]-phenyl}-piperidine-1-carboxylate as a pale yellow resin; MS: 648 (M+H)+.