Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]1[C@H:7]([OH:8])[C@H:6]([OH:9])[C@H:5]([CH3:10])[O:4][C@H:3]1[O:11][CH2:12][CH2:13][NH:14][C:15]([C@@H:17]1[C@H:22]([C:23]([NH:25][CH2:26][CH2:27][O:28][C@H:29]2[C@@H:34]([OH:35])[C@H:33]([OH:36])[C@H:32]([OH:37])[C@H:31]([CH3:38])[O:30]2)=[O:24])[CH2:21][CH2:20][NH:19][CH2:18]1)=[O:16].O=[CH:40][CH2:41][CH2:42][CH2:43][CH2:44][C:45]([O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:46].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C1COCC1.O>[OH:1][C@H:2]1[C@H:7]([OH:8])[C@H:6]([OH:9])[C@H:5]([CH3:10])[O:4][C@H:3]1[O:11][CH2:12][CH2:13][NH:14][C:15]([C@@H:17]1[C@H:22]([C:23](=[O:24])[NH:25][CH2:26][CH2:27][O:28][C@H:29]2[C@@H:34]([OH:35])[C@H:33]([OH:36])[C@H:32]([OH:37])[C@H:31]([CH3:38])[O:30]2)[CH2:21][CH2:20][N:19]([CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][C:45]([O:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[O:46])[CH2:18]1)=[O:16]
Reactant: O=CCCCCC(=O)OCc1ccccc1
Reactant: C[C@@H]1O[C@@H](OCCNC(=O)[C@H]2CNCC[C@H]2C(=O)NCCO[C@@H]2O[C@@H](C)[C@@H](O)[C@@H](O)[C@@H]2O)[C@@H](O)[C@H](O)[C@@H]1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C[C@@H]1O[C@@H](OCCNC(=O)[C@H]2CN(CCCCCC(=O)OCc3ccccc3)CC[C@H]2C(=O)NCCO[C@@H]2O[C@@H](C)[C@@H](O)[C@@H](O)[C@@H]2O)[C@@H](O)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(3R,4R)—N3,N4-bis(2-(((2R,3S,4R,5S,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)ethyl)piperidine-3,4-dicarboxamide (118 mg, 0.214 mmol) was dissolved in THF (2 mL), to which benzyl 6-oxohexanoate (70.7 mg, 0.321 mmol) in THF (0.5 mL) was added, followed by sodium triacetoxyborohydride (136 mg, 0.642 mmol) and acetic acid (3.67 μL, 0.064 mmol) were added, and the mixture was stirred at room temperature for 3 h. The product was isolated by preparative reverse-phase chromatography on C-18 column, using a gradient of 0-30% of AcN in water. UPLC Method F: m/e=756.4241 [M+1]; Rt=3.05 min
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:3]12[CH3:4])[C@:16]1([CH3:17])[C:11](=[CH:12][C:13](=[O:21])[CH2:14][CH2:15]1)[C@@H:10]([CH3:22])[CH2:9]3.[CH:23](OC)=[O:24].C[O-].[Na+].O[C@@]1(C)CC[C@H]2[C@H]3[C@H](CC[C@]12C)[C@]1(C)C(=C(C)C(=O)C(=CO)C1)CC3>O1CCCC1.CO>[OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:3]12[CH3:4])[C@:16]1([CH3:17])[C:11](=[CH:12][C:13](=[O:21])[C:14](=[CH:23][OH:24])[CH2:15]1)[C@@H:10]([CH3:22])[CH2:9]3
Reactant: C[C@H]1C[C@H]2[C@@H]3CC[C@H](O)[C@@]3(C)CC[C@@H]2[C@@]2(C)CCC(=O)C=C12
Reactant: COC=O
Agent: CC1=C2CC[C@@H]3[C@H](CC[C@@]4(C)[C@H]3CC[C@]4(C)O)[C@@]2(C)CC(=CO)C1=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H]1C[C@H]2[C@@H]3CC[C@H](O)[C@@]3(C)CC[C@@H]2[C@@]2(C)CC(=CO)C(=O)C=C12

Procedure:
17β-Hydroxy-2-hydroxymethylene-6α-methylandrost-4-en-3-one was prepared from 286 g. of 17β-hydroxy-6α-methylandrost-4-en-3-one (6α-methyltestosterone), 410 ml. of methyl formate, 140 g. of sodium methoxide, 40 ml. of methanol and 3 l. of tetrahydrofuran according to the procedure of Example 1, part (c). The total product, obtained nearly quantitative yield as an amber glass was used directly in the next reaction.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]([N:13]=[C:14]=[S:15])[C:10]([CH3:16])=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[N:8]2)#[N:2].[CH2:17]([NH2:20])[CH2:18][NH2:19]>C1(C)C=CC=CC=1>[NH2:19][CH2:18][CH2:17][NH:20][C:14](=[S:15])[NH:13][C:11]1[C:10]([CH3:16])=[C:9]2[C:4]([CH:5]=[CH:6][CH:7]=[N:8]2)=[C:3]([C:1]#[N:2])[CH:12]=1
Reactant: NCCN
Reactant: Cc1c(N=C=S)cc(C#N)c2cccnc12
Solvent: Cc1ccccc1
Product: Cc1c(NC(=S)NCCN)cc(C#N)c2cccnc12
Reaction time: 0.17 h

Procedure:
A solution of 5-cyano-7-isothiocyanato-8-methylquinoline (0.85 g) in toluene (100 mL) is added dropwise to a solution of ethylenediamine (1.94 g) in toluene (100 mL). A yellow-white precipitate is observed after the reaction stirs at room temperature for 10 minutes. The precipitate is filtered and dried in vacuo to afford 7-[N'-(2-aminoethyl)thioureido]-5-cyano-8-methylquinoline as a yellow-white solid.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:19]([CH2:20][CH2:21][C@:4]12[CH3:5])[C@:17]1([CH3:18])[C@H:12]([CH2:13][C:14](=[O:22])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3.[OH-].[K+].[CH:25](=O)[CH3:26].C(O)(=O)C>C(O)C>[CH:25](=[C:15]1[CH2:16][C@@:17]2([CH3:18])[C@@H:12]([CH2:11][CH2:10][C@@H:9]3[C@@H:19]2[CH2:20][CH2:21][C@@:4]2([CH3:5])[C@H:6]3[CH2:7][CH2:8][C@@H:3]2[O:2][CH3:1])[CH2:13][C:14]1=[O:22])[CH3:26]
Reactant: CC=O
Reactant: CO[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: CC=C1C[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](OC)CC[C@@H]32)CC1=O

Procedure:
A mixture of 17β-methoxy-5α-androstan-3-one (U.S. Pat. No. 3,301,850, Example 14, 8 g.), potassium hydroxide (2.1 g.) and acetaldehyde (5 ml.) in absolute ethanol (500 ml.) is stirred for 16 hours under nitrogen. The potassium hydroxide is then neutralized with acetic acid and the mixture concentrated to about 100 ml. Water is added and the product is extracted with diethyl ether. After the diethyl ether is removed the steroid is chromatographed over silica gel and then alumina. The appropriate fractions are pooled and concentrated to give both isomers of the product, IR (neat) 1720 and 1690 cm-1 ; MS (m/e) 330; NMR (CDCl3) 0.79, 0.78, 0.83, 1.72, 3.22, 3.35 and 6.75 δ; and UV (ethanol) λ=246 nm (ε=4,300).
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:37])=[C:7]2[C:12](=[C:13]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[N:14]=1)[N:11]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:10](=[O:28])[C:9]([CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[CH:8]2)=[O:4].[NH2:38][CH2:39][CH2:40][C:41]([OH:43])=[O:42].C[O-].[Na+]>C([O-])(O)=O.[Na+]>[CH2:21]([N:11]1[C:12]2[C:7](=[C:6]([OH:37])[C:5]([C:3]([NH:38][CH2:39][CH2:40][C:41]([OH:43])=[O:42])=[O:4])=[N:14][C:13]=2[C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:8]=[C:9]([CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:10]1=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCCC(=O)O
Reactant: COC(=O)c1nc(-c2cccnc2)c2c(cc(CCc3ccccc3)c(=O)n2Cc2ccccc2)c1O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1nc(-c2cccnc2)c2c(cc(CCc3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 50.9 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-phenethyl-8-pyridin-3-yl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (42 mg, 0.086 mmol), β-alanine (610 mg, 6.8 mmol) and NaOMe solution (10 mL, 5.1 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 3. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography (10-100% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3, and the resulting precipitate was isolated by filtration to give 24 mg of the title compound as a light yellow solid. MS: (+) m/z 549.50 (M+1).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[S:12][C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:14](Br)[N:15]=2)[CH:8]=[CH:7][N:6]=1)(=[O:3])[CH3:2].[Br-].[CH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[CH2:33][Zn+].C1COCC1>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[S:12][C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:14]([CH2:33][C:24]3[CH:25]=[CH:26][C:27]4[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:23]=3)[N:15]=2)[CH:8]=[CH:7][N:6]=1)(=[O:3])[CH3:2]
Reactant: [Zn+]Cc1ccc2ccccc2c1
Reactant: CCOC(=O)c1sc(-c2ccnc(NC(C)=O)c2)nc1Br
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Br-]
Solvent: C1CCOC1
Product: CCOC(=O)c1sc(-c2ccnc(NC(C)=O)c2)nc1Cc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 40 %

Procedure:
To a mixture of ethyl 2-(2-acetamidopyridin-4-yl)-4-bromothiazole-5-carboxylate (190 mg, 0.510 mmol) and bis(tri-t-butylphosphine)palladium(0) (65.6 mg, 0.128 mmol) under nitrogen was added a 0.500 M solution of 2-napthylmethylzinc bromide in THF (3.60 mL, 1.80 mmol). The reaction was stirred at room temperature for 5 minutes, then at 60 degrees for 1 hour. Another portion of bis(tri-t-butylphosphine)palladium(0) (60.0 mg, 0.117 mmol) was added, followed by another portion of 0.500 M solution of 2-napthylmethylzinc bromide in THF (3.00 mL, 1.50 mmol), and the reaction was heated at 60 degrees for an additional 45 minutes. The reaction was cooled to room temperature and quenched with saturated ammonium chloride (10 mL). The mixture was extracted with ethyl acetate (2×20 mL) and the combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate/hexane=0/100→100/0) to give 100 mg of the title compound. (40% yield). LC/MS (FA) ES+ 432.
Reaction SMILES: [CH3:1][C@@:2]12[C@@:10]([OH:15])([C:11]([CH2:13][OH:14])=[O:12])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:16][CH2:17][C:18]3[C@@:24]([CH3:25])([C@H:5]1[C@@H:4]([OH:26])[CH2:3]2)[CH:23]=[CH:22][C:20](=[O:21])[CH:19]=3.[CH:27]1[C:32]([CH2:33][CH2:34][CH2:35][C:36](O)=[O:37])=[CH:31][CH:30]=[C:29]([N:39]([CH2:43][CH2:44][Cl:45])[CH2:40][CH2:41][Cl:42])[CH:28]=1.CC1C=CC(S(O)(=O)=O)=CC=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl.C(O)(=O)C>[CH3:1][C@@:2]12[C@@:10]([OH:15])([C:11]([CH2:13][O:14][C:36]([CH2:35][CH2:34][CH2:33][C:32]3[CH:27]=[CH:28][C:29]([N:39]([CH2:40][CH2:41][Cl:42])[CH2:43][CH2:44][Cl:45])=[CH:30][CH:31]=3)=[O:37])=[O:12])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:16][CH2:17][C:18]3[C@@:24]([CH3:25])([C@H:5]1[C@@H:4]([OH:26])[CH2:3]2)[CH:23]=[CH:22][C:20](=[O:21])[CH:19]=3
Reactant: O=C(O)CCCc1ccc(N(CCCl)CCCl)cc1
Reactant: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)CO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CC(=O)O
Product: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)COC(=O)CCCc1ccc(N(CCCl)CCCl)cc1
Temperature: 0 °C
Reaction time: 20 h
Yield: 91 %

Procedure:
To 250 ml CH2Cl2 is added with stirring 36 g prednisolone (0.10 mol), 31.3 g chlorambucil (0,103 mol), 1.2 g DMAP (0,01 mol) and 1.1 g pTSA (0,06 mol). The reaction mixture is cooled to 0° C. and with continued stirring at this temperature a solution of 22.7 g DCC (0,11 mol) in 50 ml CH2Cl2 is slowly added. The reaction mixture is then kept at 0° C. with stirring for 20 h. 3 ml acetic acid is added and precipitated urea filtered off. The filtrate is evaporated in vacuo and the residue recrystallized from ethanol to give 58.9 g of TLC pure prednimustine (91% yield) without any discolouration. M.P. 165°-166° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].Cl[CH2:11][C:12]([N:14]=[C:15]=[O:16])=[O:13].C1CCN2C(=NCCC2)CC1>O1CCOCC1>[O:16]=[C:15]1[NH:14][C:12](=[O:13])[CH2:11][N:1]1[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6]
Reactant: N#Cc1cccc(N)c1
Reactant: O=C=NC(=O)CCl
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1cccc(N2CC(=O)NC2=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
g of 3-Aminobenzonitril were dissolved in 60 ml Dioxan and 0.8 ml of Chloro-acetyl isocyanate added. The reaction mixture was stirred at rt for 2 h. 2.5 ml of DBU were added and the reaction mixture stirred at rt for 40 h. The product was extracted with DCM. MS(ISO): 202.2 (MH+)
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:15]2[C:19]([C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[N:18][N:17]=[C:16]2[CH2:26][O:27][CH3:28])=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[NH:8][C:7](=[O:13])[C:6](=[O:14])[NH:5]2.[OH:29]OS([O-])=O.[K+].S([O-])([O-])(=O)=S.[Na+].[Na+]>O>[Cl:1][C:2]1[C:3]([N:15]2[C:19]([C:20]3[CH:21]=[N+:22]([O-:29])[CH:23]=[CH:24][CH:25]=3)=[N:18][N:17]=[C:16]2[CH2:26][O:27][CH3:28])=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[NH:8][C:7](=[O:13])[C:6](=[O:14])[NH:5]2
Reactant: COCc1nnc(-c2cccnc2)n1-c1c(Cl)c(Cl)cc2[nH]c(=O)c(=O)[nH]c12
Reactant: O=S([O-])OO
Agent: O=S([O-])([O-])=S
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: COCc1nnc(-c2ccc[n+]([O-])c2)n1-c1c(Cl)c(Cl)cc2[nH]c(=O)c(=O)[nH]c12
Temperature: 25 °C
Reaction time: 60 h
Yield: 85.8 %

Procedure:
(−)-6,7-Dichloro-5-[3-methoxymethyl-5-(3-pyridyl)-4H-1,2,4-triazol-4-yl]-2,3(1H,4H)-quinoxalinedione (see Preparation 1) (412.2 g, 0.98 mol) and OXONE (trade mark) (1.44 kg, 2.3 mol) were slurried in water (4.13 L) and the mixture stirred at ambient temperature for 60 hours. Saturated aqueous sodium thiosulphate solution (2.2 L) was added and the slurry stirred for 1 hour before being filtered under reduced pressure. The filter cake was slurried at ambient temperature for 4 hours in 1:1, by volume, isopropyl alcohol: dichloromethane (111 L) and the solid collected by filtration. The filtrate was vaporated under reduced pressure to give the title compound as a colourless solid (366 g).
Reaction SMILES: [C:1]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1Cl)=[CH:16][CH:15]=[CH:14][C:13]=2[O:20][CH3:21])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:22][C:23]1[C:24]([CH3:29])=[CH:25][CH:26]=[CH:27][CH:28]=1>O1CCOCC1>[C:1]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29])=[CH:16][CH:15]=[CH:14][C:13]=2[O:20][CH3:21])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccccc1N
Reactant: COc1cccc2c(Cl)c(C(=O)c3ccccc3)cnc12
Solvent: C1COCCO1
Product: COc1cccc2c(Nc3ccccc3C)c(C(=O)c3ccccc3)cnc12

Procedure:
3-Benzoyl-4-chloro-8-methoxyquinoline (3.0 g, 0.01 mol) was heated under reflux in 1,4-dioxan (100 ml) with o-toluidine (5.0 ml) for 1 hour. The solvent was evaporated and the residue was dissovled in dichloromethane, and washed with dilute hydrochloric acid, sodium hydrogen carbonate solution, water and brine. The organic solution was dried and evaporated to an oil which was chromatographed (silica gel, 1% methanolic ammonia in dichloromethane). 3-Benzoyl-4-(2-methylphenylamino)-8-methoxyquinoline was isolated as crystals (0.95 g, 25.8%) from ether/hexane, m.p. 128-130.
Reaction SMILES: [SH2:1].[CH2:2]([S:4][C:5](=N)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:7]=1[CH2:13][CH2:14][C:15]1[CH:20]=[C:19]([Br:21])[CH:18]=[CH:17][C:16]=1[O:22][CH3:23])[CH3:3].Cl.CCOCC>O1CCCC1.O>[CH2:2]([S:4][C:5](=[S:1])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:7]=1[CH2:13][CH2:14][C:15]1[CH:20]=[C:19]([Br:21])[CH:18]=[CH:17][C:16]=1[O:22][CH3:23])[CH3:3]
Reactant: CCSC(=N)c1cccc(Cl)c1CCc1cc(Br)ccc1OC
Reactant: S
Agent: Cl
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCSC(=S)c1cccc(Cl)c1CCc1cc(Br)ccc1OC
Temperature: 45 °C
Reaction time: 8 h

Procedure:
As shown in Scheme 11, hydrogen sulfide gas (˜2 mL) was condensed into a cooled (−78° C.) solution of 2.8 grams (6.8 mmol) of 2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-thiobenzimidic acid ethyl ester and 13.6 mL (13.6 mmol) of 1.0 M HCl/ether in 100 mL of tetrahydrofuran. The reaction was heated to 45° C. and stirred overnight in a sealed tube. The reaction mixture was diluted with water and extracted with methylene chloride once. The organic layer was washed with brine, dried (MgSO4), filtered and evaporated to give a crude orange oil. The oil was partially purified by chromatography through a short column of silica gel (eluting with 5:95 ethyl acetate/hexanes) which resulted in 1.8 g of an orange powder which was used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([O:9][CH3:10])[C:3]=1[C@H:11]([C:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19]([C:22]3[CH:23]=[N:24][N:25]([CH:28]4[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]4)[C:26]=3[CH3:27])[CH:20]=2)[NH:15][CH:14]=1)[CH3:12].[N:35]1(C(OC(C)(C)C)=O)[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].ClCCCl.O1CCOCC1.Cl>>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([O:9][CH3:10])[C:3]=1[C@H:11]([C:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19]([C:22]3[CH:23]=[N:24][N:25]([C@H:28]4[CH2:33][CH2:32][C@@H:31]([N:35]5[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]5)[CH2:30][CH2:29]4)[C:26]=3[CH3:27])[CH:20]=2)[NH:15][CH:14]=1)[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1ccc(F)c(Cl)c1[C@@H](C)c1c[nH]c2ncc(-c3cnn(C4CCC(=O)CC4)c3C)cc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCCl
Product: COc1ccc(F)c(Cl)c1[C@@H](C)c1c[nH]c2ncc(-c3cnn([C@H]4CC[C@@H](N5CCNCC5)CC4)c3C)cc12
Temperature: 60 °C
Reaction time: 4 h

Procedure:
A mixture of 4-(4-{3-[(1S)-1-(2-chloro-3-fluoro-6-methoxyphenyl)ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-5-methyl-1H-pyrazol-1-yl)cyclohexanone (12.0 mg, 0.0250 mmol), tert-butyl 1-piperazinecarboxylate (46.47 mg, 0.2495 mmol), sodium triacetoxyborohydride (10.58 mg, 0.04990 mmol) and 1,2-dichloroethane (3 mL, 40 mmol) was heated to 60° C. in a sealed tube for 1 h. The solution was extracted with DCM and sat. NaHCO3, and the organic layer was concentrated in vacuo. The material was dissolved in 1,4-dioxane (35 mL, 450 mmol), 4 M of HCl in 1,4-dioxane (1 mL, 4 mmol) was added, and the solution was allowed to stir at rt for 4 h. The material was concentrated in vacuo, loaded onto silica gel for column chromatography, and eluted with 5-10% (7N NH3 in MeOH)/DCM. The fractions containing the cis product were concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ=1.59-1.77 (m, 4H), 1.82 (d, J=7.3 Hz, 3H), 2.16-2.36 (m, 8H), 2.57 (br. s., 4H), 2.95 (t, J=4.9 Hz, 4H), 3.66 (br. s., 3H), 4.28-4.38 (m, 1H), 5.12 (q, J=7.1 Hz, 1H), 6.90 (dd, J=9.1, 4.3 Hz, 1H), 7.10 (t, J=8.8 Hz, 1H), 7.36 (d, J=1.3 Hz, 1H), 7.42 (s, 1H), 7.46 (s, 1H), 8.12 (d, J=2.0 Hz, 1H). MS (ES+): m/z=551.27/553.27 (100/50) [MH+]. HPLC: tR=1.15 min (polar—3 min, UPLC-ACQUITY).
Reaction SMILES: C(OC(=O)[N:7]([CH2:32][CH:33]=[CH2:34])[C@H:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N:18]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH:29]([CH3:31])[CH3:30])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[CH3:19])[CH:14]=2)[CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl.C(OCC)(=O)C>[CH2:32]([NH:7][C@H:8]1[CH2:17][CH2:16][C:15]2[CH:14]=[C:13]([N:18]([CH3:19])[S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH:29]([CH3:30])[CH3:31])=[CH:25][CH:24]=3)(=[O:21])=[O:22])[CH:12]=[CH:11][C:10]=2[CH2:9]1)[CH:33]=[CH2:34]
Reactant: C=CCN(C(=O)OC(C)(C)C)[C@H]1CCc2cc(N(C)S(=O)(=O)c3ccc(C(C)C)cc3)ccc2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C=CCN[C@H]1CCc2cc(N(C)S(=O)(=O)c3ccc(C(C)C)cc3)ccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.2 %

Procedure:
Allyl-{(S)-6-[(4-isopropyl-benzenesulfonyl)-methyl-amino]-1,2,3,4-tetrahydronaphthalen-2-yl}-carbamic acid tert-butyl ester (672 mg, 1.35 mmol) was dissolved in dichloromethane (30 ml). Trifluoroacetic acid (1 ml) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was evaporated to dryness. Ethyl acetate (100 ml) was added and extracted with NaOH (2M). The organic layer was dried over magnesium sulfate, filtered, and evaporated to dryness to yield 1.05 g of crude product. The crude product was dissolved in ethyl acetate (20 ml) and the precipitate was collected to yield the desired compound (270 mg, 50%). The mother liquid was reduced in vacuo to yield an oil (840 mg, 54% purity).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][NH:3]1.[OH-].[Na+].Br[CH2:10][CH2:11][CH2:12][Cl:13]>CC(C)=O>[Cl:13][CH2:12][CH2:11][CH2:10][N:3]1[CH2:4][CH2:5][CH2:6][CH:2]1[CH3:1]
Reactant: CC1CCCN1
Reactant: ClCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CC1CCCN1CCCCl
Yield: 58.4 %

Procedure:
2-Methylpyrrolidine (0.9 g, 10.6 mmol), acetone (18 ml, 20 vol), 5M NaOH solution (2.50 ml) and 1-bromo-3-chloropropane (5 g, 31.8 mmol, 3 eq) were reacted together according to general procedure A to give the title compound (1 g, 59%) as a pale yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[C:12]1([CH2:18][CH2:19][CH2:20][CH2:21]O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C(OCC)C>[C:12]1([CH2:18][CH2:19][CH2:20][CH2:21][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: OCCCCc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCCCCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 36 h
Yield: 68.8 %

Procedure:
A mixture of methyl 4-hydroxybenzoate (3 g, 19.7 mmol), 4-phenylbutanol (3.04 ml, 19.7 mmol) and triphenylphosphine (7.74 g, 29.6 mmol) in anhydrous tetrahydrofuran (110 ml) was added with diethyl azodicarboxylate (4.65 ml, 29.6 mmol). The resulting mixture was left under stirring at room temperature for 36 h, then was added with ethyl ether (500 ml) and left to crystallize for 24 hours at 0° C. After that the solid was filtered and the filtrate was washed successively with 0.2M hydrochloric acid, 5% sodium bicarbonate and a sodium chloride saturated solution. After drying and removing the solvent under reduced pressure, a residue was obtained which was purified by chromatography through a silica gel column, eluting with petroleum ether:chloroform mixtures of increasing polarity, thereby recovering 3.856 g of the title compound (70% yield).
Reaction SMILES: C(OC(N1CCNCC1)=O)(C)(C)C.[Cl:14]CC(Cl)=O.[C:19]([NH2:23])([CH3:22])([CH3:21])[CH3:20].[ClH:24].Cl.COCC(N[C:32](=[O:40])[CH2:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)C>>[ClH:14].[ClH:24].[C:19]([NH:23][C:32](=[O:40])[CH2:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)([CH3:22])([CH3:21])[CH3:20]
Reactant: COCC(C)NC(=O)CN1CCNCC1
Reactant: CC(C)(C)N
Reactant: O=C(Cl)CCl
Agent: CC(C)(C)OC(=O)N1CCNCC1
Agent: Cl
Product: CC(C)(C)NC(=O)CN1CCNCC1

Procedure:
N-tert-butyl-2-piperazin-1-yl-acetamide dihydrochloride was prepared from 1-tert-butyloxycarbonyl-piperazine, chloroacetylchloride and N-tert-butylamine in an analogous manner as described for the preparation of N-(2-methoxy-1-methyl-ethyl)-2-piperazin-1-yl-acetamide dihydrochloride (example 40).
Reaction SMILES: [C:1]1([C:7]2([C:12]([OH:14])=O)[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:17])=O>>[C:1]1([C:7]2([C:12]([Cl:17])=[O:14])[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C1(c2ccccc2)CCCC1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)C1(c2ccccc2)CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The carboxylic acid chlorides used in the synthesis of the parent amides were all synthesized as described below. In a 1-liter 3-neck flask, 200 gm (1.05 mole) of 1-phenylcyclopentanecarboxylic acid (ACROS ORGANICS) was added drop-wise to stirring excess of thionyl chloride (Aldrich) under nitrogen. The resulting mixture was heated at reflux for two hrs. The reaction was further stirred at room temperature overnight. The resulting brown-red solution was concentrated at reduced pressure and heat on a rotary evaporator to remove excess thionyl chloride. The reaction yielded 216 gm of a lachrymator substance whose 1H-NMR and 13C-NMR spectra were ideal for the desired acid chloride.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:13][CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16].[CH3:19][C:20]1[CH:24]=[C:23]([CH3:25])[NH:22][N:21]=1>>[ClH:1].[CH3:19][C:20]1[CH:24]=[C:23]([CH3:25])[N:22]([C:2]2[N:11]=[C:10]([NH:13][CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[N:21]=1
Reactant: CCC(N)CC
Reactant: Cc1cc(C)[nH]n1
Reactant: Clc1nc(Cl)c2ccccc2n1
Product: CCC(CC)Nc1nc(-n2nc(C)cc2C)nc2ccccc12
Product: Cl

Procedure:
Was prepared according to Method A from 2,4-dichloroquinazoline, 3-aminopentane and 3,5-dimethylpyrazole. Mp. 96.4° C.