Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[C:9](/[CH3:13])=[CH:10]/[CH:11]=O)=[CH:5][CH:4]=1.[C:14]([CH:18]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:16][CH3:17])=[O:15]>C(Cl)(Cl)(Cl)Cl.ClCCl>[CH3:17][O:16][C:14](=[O:15])/[CH:18]=[CH:11]/[CH:10]=[C:9](/[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)\[CH3:13]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(/C(C)=C/C=O)cc1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)/C=C/C=C(\C)c1ccc(OC)cc1

Procedure:
As described in Example 99, (E)-3-(4-methoxyphenyl)-2-butenal (8 g) was treated with (carbomethoxymethylene)triphenylphosphorane (17 g) in carbon tetrachloride (70 mL) and dichloromethane (15 mL) overnight at room temperature. The ester was isolated in the normal fashion and crystallized from hexane to afford 7.2 g of (E,E)-5-(4-methoxyphenyl)-2,4-hexadienoic acid methyl ester, mp 84°-86° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[C:11]1[N:15]([C:16]2[CH:21]=[CH:20][C:19]([C:22](=[O:31])[N:23]([CH3:30])[CH2:24][CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])=[CH:18][C:17]=2[CH:32]([CH3:34])[CH3:33])[N:14]=[C:13]([C:35]([NH:37][C:38]2([C:48]([OH:50])=[O:49])[CH:45]3[CH2:46][CH:41]4[CH2:42][CH:43]([CH2:47][CH:39]2[CH2:40]4)[CH2:44]3)=[O:36])[CH:12]=1.CC([O-])(C)C.[K+:56]>CC(O)C>[K+:56].[CH3:10][O:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]=1[C:11]1[N:15]([C:16]2[CH:21]=[CH:20][C:19]([C:22](=[O:31])[N:23]([CH3:30])[CH2:24][CH2:25][CH2:26][N:27]([CH3:28])[CH3:29])=[CH:18][C:17]=2[CH:32]([CH3:34])[CH3:33])[N:14]=[C:13]([C:35]([NH:37][C:38]2([C:48]([O-:50])=[O:49])[CH:39]3[CH2:40][CH:41]4[CH2:42][CH:43]([CH2:44][CH:45]2[CH2:46]4)[CH2:47]3)=[O:36])[CH:12]=1
Reactant: COc1cccc(OC)c1-c1cc(C(=O)NC2(C(=O)O)C3CC4CC(C3)CC2C4)nn1-c1ccc(C(=O)N(C)CCCN(C)C)cc1C(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)O
Product: COc1cccc(OC)c1-c1cc(C(=O)NC2(C(=O)[O-])C3CC4CC(C3)CC2C4)nn1-c1ccc(C(=O)N(C)CCCN(C)C)cc1C(C)C
Temperature: -20 °C
Yield: 56.8 %

Procedure:
A solution of 0.15 g of the compound obtained in EXAMPLE 1' and 0.03 g of potassium tert-butylate in 6.5 ml of 2-propanol is left overnight at RT and then concentrated under vacuum. The residue is dissolved in 0. 5 ml of MeOH, and this solution is poured into 25 ml of isopropyl ether cooled to -20° C. The precipitate formed is drained and dried over P2O5 at 80° C. 0.09 g of the expected product is obtained, m.p.=222° C.
Reaction SMILES: [CH3:1][N:2](S(C1C=CC=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11].[F:22][C:23]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:27][C:24]=1[C:25]#[N:26].[Cl-].[Al+3].[Cl-].[Cl-].ClC1C=CC=CC=1Cl>C(Cl)(Cl)Cl>[Cl:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:4]1[N:26]=[C:25]([C:24]2[CH:27]=[C:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH:29]=[CH:30][C:23]=2[F:22])[N:2]([CH3:1])[N:3]=1
Reactant: CCCCCCCCCCCc1ccc(F)c(C#N)c1
Reactant: CN(N=C(Cl)c1ccccc1Cl)S(=O)(=O)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1Cl
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCc1ccc(F)c(-c2nc(-c3ccccc3Cl)nn2C)c1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
A mixture of N-methyl-N-(benzenesulfonyl)-2-chlorobenzohydrazonoyl chloride (1.27 g), 2-fluoro-5-undecylbenzonitrile (1.09 g), anhydrous aluminum chloride (0.55 g) and o-dichlorobenzene (5 ml) is stirred at an oil bath temperature of 140° C. for 30 minutes. After cooling, the reaction mixture is dissolved in chloroform (200 ml), washed with dilute hydrochloric acid, dilute aqueous solution of sodium hydroxide and saline in this order, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography using mixed solvent of hexane-ethyl acetate as eluent to give 0.85 g of desired compound (melting point: 35.0°-37.0° C.).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][C:6]=1[C:13]([F:16])([F:15])[F:14])(=[O:4])=[O:3]>N.CO.[Ni]>[CH3:1][S:2]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][C:6]=1[C:13]([F:14])([F:15])[F:16])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(C#N)cc1C(F)(F)F
Agent: [Ni]
Agent: N
Solvent: CO
Product: CS(=O)(=O)c1ccc(CN)cc1C(F)(F)F

Procedure:
A mixture of 4-fluoro-3-trifluoromethylbenzonitrile (75 mg, 0.40 mmol), sodium sulfinate (44.5 mg, 0.44 mmol) in N,N-dimethylformamide (1.5 mL) was heated at 100° C. for 2 h. The reaction mixture was cooled to room temperature, quenched with water. The resulting white solid was collected via filtration, washed with cold water, dried in a vacuum oven to give 4-methanesulfonyl-3-trifluoromethyl-benzonitrile (90 mg, 90% yield). This benzonitrile was hydrogenated in 2N NH3 in methanol with 35 mg of Raney Ni under a hydrogen balloon for 2 h. The reaction mixture was filtered through a celite plug, washed with methanol, evaporated in vacuo to give the titled compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([CH3:10])[C:3]=1[CH3:11].[CH:12](O)=[O:13]>>[CH:12]([NH:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([CH3:10])[C:3]=1[CH3:11])=[O:13]
Reactant: Cc1cc(O)c(C)c(C)c1N
Reactant: O=CO
Product: Cc1cc(O)c(C)c(C)c1NC=O
Yield: 72.5 %

Procedure:
4-Amino-2,3,5-trimethylphenol (100 g, 662 mmol) was dissolved in formic acid (500 ml). The mixture was heated under reflux for 36 hours. The reaction mixture was poured into ice-cold water. The precipitated crystals were filtered, washed with water and dried. The crude crystals obtained were recrystallized from ethanol to obtain the desired compound (85.9 g, yield: 72.5%), m.p. 219°-220° C.
Reaction SMILES: O.O.Cl[Sn]Cl.[N:6]1([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([N+:20]([O-])=O)[CH:18]=3)[NH:13][N:12]=2)[CH:10]=[CH:9][N:8]=[CH:7]1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[N:6]1([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([NH2:20])[CH:18]=3)[NH:13][N:12]=2)[CH:10]=[CH:9][N:8]=[CH:7]1
Reactant: O=[N+]([O-])c1cnc2[nH]nc(-n3ccnc3)c2c1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1cnc2[nH]nc(-n3ccnc3)c2c1
Reaction time: 0.5 h
Yield: 49.3 %

Procedure:
SnCl2.2H2O (1.03 g, 4.56 mmol) was added to 3-(1H-imidazol-1-yl)-5-nitro-1H-pyrazolo[3,4-b]pyridine (210 mg, 0.912 mmol) in ethyl acetate (100 mL). The mixture was heated to reflux for 1 hour. The cooled reaction mixture was diluted with ethyl acetate and treated dropwise with saturated aqueous sodium bicarbonate. The slurry was stirred for 30 minutes and then filtered through celite. The filtrate was washed with saturated aqueous sodium bicarbonate, brine, dried over magnesium sulfate, filtered, and evaporated to yield 3-(1H-imidazol-1-yl)-1H-pyrazolo[3,4-b]pyridin-5-amine (90 mg, 49% yield) as a solid.
Reaction SMILES: [CH3:1][CH:2]([CH3:35])[CH:3]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:4][C:5]1[N:6]=[CH:7][N:8](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:9]=1.Cl.[OH-].[Na+]>C(O)C.O>[CH3:1][CH:2]([CH3:35])[CH:3]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:4][C:5]1[N:6]=[CH:7][NH:8][CH:9]=1
Reactant: CC(C)C(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)C(Cc1c[nH]cn1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 21.3 %

Procedure:
To a stirred suspension of 4-(3-methyl-2-phenyl-butyl)-1-trityl-1H-imidazole (80 mg) at r.t. in ethanol (2 ml) under an argon atmosphere was added 2 N HCl (3 ml). The mixture (suspension) was heated to reflux (turning to a clear light yellow solution when reaching 90° C.) and stirred for 2 hours and 30 minutes, then cooled to r.t. and concentrated to leave a light brown sticky solid. This was taken up in H2O and basified to pH>12 by the addition of 4 N NaOH. The product was extracted with CH2Cl2/MeOH 9:1. The combined organics were dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (silica gel; gradient: CH2Cl2→CH2Cl2/MeOH 85:15) to give 4-(3-methyl-2-phenyl-butyl)-1H-imidazole (8 mg) as colorless gum. MS (ISP): 215.4 ([M+H]+)
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:11])[CH:3]=1.[CH3:12][C:13]1[C:14]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[N:15][CH:16]=[C:17]([CH:20]=1)[C:18]#[N:19]>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:24]2[CH2:25][CH2:26][N:21]([C:14]3[C:13]([CH3:12])=[CH:20][C:17]([C:18]#[N:19])=[CH:16][N:15]=3)[CH2:22][CH2:23]2)=[O:8])=[C:4]([F:11])[CH:3]=1
Reactant: Cc1cc(C#N)cnc1N1CCNCC1
Reactant: O=C(O)c1ccc(Br)cc1F
Product: Cc1cc(C#N)cnc1N1CCN(C(=O)c2ccc(Br)cc2F)CC1
Yield: 109.4 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 60 and using 4-bromo-2-fluorobenzoic acid (215 mg) and 5-methyl-6-piperazin-1-ylnicotinonitrile (202 mg), the title compound (433 mg) was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH3:25])=[CH:21][CH:22]=3)[CH:17]=[CH:16][N:15]=2)[CH2:10][CH:9]1[C:26](=[O:36])[NH:27][C:28]1([C:33](O)=[O:34])[CH2:30][CH:29]1[CH2:31][CH3:32])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:37]([C:39]1([O:42][S:43](=[O:46])(=[O:45])[NH2:44])[CH2:41][CH2:40]1)[CH3:38]>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH3:25])=[CH:21][CH:22]=3)[CH:17]=[CH:16][N:15]=2)[CH2:10][CH:9]1[C:26](=[O:36])[NH:27][C:28]1([C:33]([NH:44][S:43]([O:42][C:39]2([CH2:37][CH3:38])[CH2:41][CH2:40]2)(=[O:46])=[O:45])=[O:34])[CH2:30][CH:29]1[CH2:31][CH3:32])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCC1(OS(N)(=O)=O)CC1
Reactant: CCC1CC1(NC(=O)C1CC(Oc2nccc3cc(OC)ccc23)CN1C(=O)OC(C)(C)C)C(=O)O
Product: CCC1CC1(NC(=O)C1CC(Oc2nccc3cc(OC)ccc23)CN1C(=O)OC(C)(C)C)C(=O)NS(=O)(=O)OC1(CC)CC1

Procedure:
2-[2-Ethyl-1-(1-ethyl-cyclopropoxysulfonylaminocarbonyl)-cyclopropylcarbamoyl]-4-(6-methoxy-isoquinolin-1-yloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester was prepared according to the method presented in Example 27. Treatment of 2-(1-carboxy-2-ethyl-cyclopropylcarbamoyl)-4-(6-methoxy-isoquinolin-1-yloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.70 mmol) occurred under the same conditions, adjusted for scale with the exception of utilizing sulfamic acid 1-ethyl-cyclopropyl ester to afford the desired acylsulfamate (230 mg, 51%): LCMS found 647.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]([Cl:15])=[C:3]1[CH:7]2[C:8]3[C:13]([CH:4]1[CH2:5][CH2:6]2)=[CH:12][CH:11]=[CH:10][C:9]=3[NH2:14].C(N(CC)CC)C.[F:23][CH:24]([F:34])[C:25]1[C:29]([C:30](Cl)=[O:31])=[CH:28][N:27]([CH3:33])[N:26]=1>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]([Cl:15])=[C:3]1[CH:7]2[C:8]3[C:13]([CH:4]1[CH2:5][CH2:6]2)=[CH:12][CH:11]=[CH:10][C:9]=3[NH:14][C:30]([C:29]1[C:25]([CH:24]([F:34])[F:23])=[N:26][N:27]([CH3:33])[CH:28]=1)=[O:31]
Reactant: Nc1cccc2c1C1CCC2C1=C(Cl)Cl
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Solvent: Cc1ccccc1C
Solvent: CCN(CC)CC
Product: Cn1cc(C(=O)Nc2cccc3c2C2CCC3C2=C(Cl)Cl)c(C(F)F)n1
Temperature: 80 °C
Yield: 83.4 %

Procedure:
9-Dichloromethylene-1,2,3,4-tetrahydro-1,4-methano-naphthalen-5-ylamine (166 g, 35% xylene solution, 0.25 mol), triethylamine (28 g, 0.275 mol) and xylene (13 g) were charged in a reactor and the mixture was heated to 80° C. 3-Difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride (182 g, 26% xylene solution, 0.25 mol) was added over 2 hours. After conversion, the product was extracted, concentrated and crystallized in a mixture of xylene/methycyclohexane. 83 g of pure product were isolated. (Purity: 97%, Yield: 82%)
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]([NH:13][CH2:14][C:15]3[CH:16]=[C:17]4[C:22](=[CH:23][CH:24]=3)[N:21]=[CH:20][CH:19]=[CH:18]4)[C:10]([N+:25]([O-])=O)=[C:9](N)[CH:8]=2)[CH:4]=[N:3]1.C[OH:30]>[Pd]>[NH2:25][C:10]1[C:11]([NH:13][CH2:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]=[CH:20][CH:19]=[CH:18]3)=[N:12][C:7]([C:5]2[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=2)=[CH:8][C:9]=1[OH:30]
Reactant: Cn1cc(-c2cc(N)c([N+](=O)[O-])c(NCc3ccc4ncccc4c3)n2)cn1
Reactant: CO
Agent: [Pd]
Product: Cn1cc(-c2cc(O)c(N)c(NCc3ccc4ncccc4c3)n2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 6-(1-methyl-1H-pyrazol-4-yl)-3-nitro-N2-(quinolin-6-ylmethyl)pyridine-2,4-diamine (200 mg, 0.53 mmol) in methanol (10 mL) was added 10% Pd/C (20 mg, 0.1 eq). The reaction mixture was stirred at room temperature under 1 atm of H2 for 2 h, then filtered. The filtrate was concentrated to afford the title compound (170 mg), which was used for the next step without further purification. MS (m/z): 347 (M+1)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].[H-].[Na+].Cl[C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([N+:16]([O-:18])=[O:17])=[CH:11][N:10]=1.O>COC(C)(C)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([N+:16]([O-:18])=[O:17])=[CH:11][N:10]=1
Reactant: Cc1cc(Cl)ncc1[N+](=O)[O-]
Reactant: COCCO
Agent: [H-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: O
Product: COCCOc1cc(C)c([N+](=O)[O-])cn1
Reaction time: 0.25 h

Procedure:
To 20 mL of 2-Methoxy-ethanol 243 mg of NaH (6.09 mmol, 60% suspension in oil) were added and the mixture was stirred for 15 min. in an argon atmosphere. 1 g (5.8 mmol) 2-Chloro-4-methyl-5-nitro-pyridine were added and the reaction mixture was stirred for 3 h at room temperature. After addition of 40 mL water and methyl-tertbutyl ether, the phases were separated and the organic phase was washed with saturated NaHCO3 solution and water and was dried over Na2SO4. After filtration, the solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel using heptane/ethyl acetate=8/2. 2-(2-Methoxy-ethoxy)-4-methyl-5-nitro-pyridine was isolated as colourless oil. Yield: 0.73 g.
Reaction SMILES: C[O:2][C:3](=[O:36])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([N:13]([CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[C:14]2[N:15]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:16]=[C:17]3[C:22]=2[CH:21]=[CH:20][CH:19]=[CH:18]3)=[O:12])=[C:6]([Cl:35])[CH:5]=1.[OH-].[Li+]>C1COCC1.CO>[Cl:35][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[NH:10][C:11]([N:13]([CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[C:14]1[N:15]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:16]=[C:17]2[C:22]=1[CH:21]=[CH:20][CH:19]=[CH:18]2)=[O:12])[C:3]([OH:36])=[O:2]
Reactant: COC(=O)c1ccc(NC(=O)N(c2c3ccccc3nn2-c2ccccc2)C2CCCCC2)c(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(NC(=O)N(c2c3ccccc3nn2-c2ccccc2)C2CCCCC2)c(Cl)c1

Procedure:
In analogy to the procedure described in example 2.2, 3-chloro-4-[3-cyclohexyl-3-(2-phenyl-2H-indazol-3-yl)-ureido]-benzoic acid methyl ester was treated with 1 N aqueous lithium hydroxide solution in THF/MeOH 1/1 for 16 h at ambient temperature to give the title compound as off-white solid. MS: m/e=489.3 [M+H+].
Reaction SMILES: CC(C[AlH]CC(C)C)C.C([O:12][C:13](=O)/[C:14](/[C:22]1[S:23][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][CH:26]=1)=[CH:15]/[CH2:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)C.CO>C1COCC1>[CH:17]1([CH2:16]/[CH:15]=[C:14](\[C:22]2[S:23][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][CH:26]=2)/[CH2:13][OH:12])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CCOC(=O)/C(=C/CC1CCCC1)c1ccc(S(C)(=O)=O)s1
Agent: CC(C)C[AlH]CC(C)C
Solvent: CO
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(/C(=C\CC2CCCC2)CO)s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 104.4 %

Procedure:
Add a solution of DIBAL (5.41 mL, 1.2 M in toluene, 6.48 mmol) dropwise over one h to a solution of (Z)-4-cyclopentyl-2-(5-methanesulfonyl-thiophen-2-yl)-but-2-enoic acid ethyl ester (939 mg, max. 2.59 mmol) in THF (5 mL) at to −78 ° C. Then allow the reaction mixture to warm slowly to r.t., and stir for 18 h. Add methanol (1.5 mL) at −78° C. and allow the reaction mixture to warm to r.t. Partition the residue between ethyl acetate (15 mL) and sodium potassium tartrate (15 mL). Then extract the aqueous layer with ethyl acetate. Combine the organic layers, wash them with saturated aqueous sodium chloride solution, dry over sodium sulfate and remove solvent under vacuum to give 812 mg crude product. MS (m/e): 323.0 (M+Na).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[C:21]([O:22][CH3:23])=[N:20][CH:19]=[CH:18][N:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>>[CH3:23][O:22][C:21]1[C:16]([NH:15][CH2:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[N:17][CH:18]=[CH:19][N:20]=1
Reactant: COc1nccnc1NCC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Product: COc1nccnc1NCC1CCNCC1
Reaction time: 0.5 h

Procedure:
4-[(3-Methoxy-pyrazin-2-ylamino)-methyl]-piperidine-1-carboxylic acid tert-butyl ester (0.5 g, 0.0015 mol) and trifluoroacetic acid (5 mL) were allowed to stir under nitrogen for 0.5 h. The reaction was concentrated in vacuo, and chromatographed on silica using methylene chloride/methanol/ammonium hydroxide (90/10/2) to give the title compound. M.S.(M+1): 223.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:15])[N:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].[Br:22]Br>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:15])[N:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:10]=1[Br:22])=[O:5])[CH3:2]
Reactant: BrBr
Reactant: CCOC(=O)c1cc(C(C)(C)C)nn1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCOC(=O)c1c(Br)c(C(C)(C)C)nn1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 5-tert-butyl-2-methyl-pyrazole-3-carboxylic acid ethyl ester (2.00 g, 9.51 mmol) and K2CO3 (3.94 g, 28.5 mmol) in DCM (120 mL), in the dark, was added Br2 (1.46 mL, 28.5 mmol) slowly under Ar. After stirring at room temperature for 3 h under Ar, the resulting mixture was quenched with saturated aqueous Na2S2O3 (50 mL). The organic layer was separated and washed with H2O (50 mL) and brine (50 mL), then dried with Na2SO4. Removal of the solvent under reduced pressure yielded a white solid. 1H-NMR (400 MHz, CDCl3) δ: 4.40 (q, J=7.1 Hz, 2H), 4.08 (s, 3H), 1.43 (t, J=7.1 Hz, 3H), 1.42 (m, 9H). Mass Spectrum (LCMS, ESI pos.) Calculated For C11H17BrN2O2: 289.1 (M+H), Measured: 289.1.
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[C:9]2=[N:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:8]2[C:7](=[O:17])[N:6]([CH3:18])[CH2:5]1.[C:19]1([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1(C)C=CC=CC=1>[CH3:18][N:6]1[CH2:5][CH:4]([CH2:3][CH2:2][N:28]2[CH2:29][CH2:30][N:25]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:26][CH2:27]2)[C:9]2=[N:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:8]2[C:7]1=[O:17]
Reactant: CN1CC(CCCl)c2nc3ccccc3n2C1=O
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: Cc1ccccc1
Product: CN1CC(CCN2CCN(c3ccccc3)CC2)c2nc3ccccc3n2C1=O

Procedure:
To 4.0 g (0.015 mol) of 4-(2-chloroethyl)-3,4-dihydro-2-methylpyrimido[1,6-a]benzimidazol-1(2H)-one in 35 mL of toluene was added 6.5 g (0.04 mol) of N-phenylpiperazine. The reaction mixture was heated to reflux for 2 days. The entire reaction mixture was washed with 3×50 mL of 1N NaOH, dried over Na2SO4, filtered, and concentrated by rotary evaporation. The residue was subjected to preparative HPLC using acetone as the eluent and silica gel as the stationary phase. Like fractions were combined, concentrated and the residue crystallized from isopropyl alcohol to give 3.7 g (64%) of analytically pure, crystalline material, mp 143.5°-145.5° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:12])=[CH:5][C:6](=O)[C:7]=1[N+:8]([O-:10])=[O:9].P(Cl)(Cl)([Cl:15])=O>>[Cl:15][C:6]1[CH:5]=[C:4]([CH3:12])[N:3]=[C:2]([CH3:1])[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(=O)c([N+](=O)[O-])c(C)[nH]1
Product: Cc1cc(Cl)c([N+](=O)[O-])c(C)n1
Yield: 79 %

Procedure:
By the method of Yakugaku Zasshi, 87, 387 (1967), 2,6-dimethyl-3-nitro-4(1H)-pyridone (see part (a)) (11.23 g, 66.8 mmol) and phosphorus oxychloride (57 ml) were heated together at reflux for 1.5 hours. The excess reagent was removed under reduced pressure, and the residue dissolved in dichloromethane (150 ml). This solution was treated with dilute aqueous sodium bicarbonate until the aqueous layer was at pH7, then the organic phase was separated, dried (MgSO4) and concentrated under reduced pressure to give the title compound as a pale yellow solid, (9.8 g, 79%). Caution: this compound is a potential skin irritant.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH:9]=[C:8]([N+:10]([O-])=O)[N:7]=[C:6]2[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:3][CH2:2]1.[H][H]>C1COCC1.[Ni]>[NH2:10][C:8]1[N:7]=[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:5]([CH2:4][CH:1]2[CH2:2][CH2:3]2)[CH:9]=1
Reactant: CCOC(=O)c1nc([N+](=O)[O-])cn1CC1CC1
Reactant: [H][H]
Agent: [Ni]
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(N)cn1CC1CC1

Procedure:
3.89 g (16.26 mmol) of ethyl 1-(cyclopropylmethyl)-4-nitro-1H-imidazole-2-carboxylate are dissolved in 50 ml of THF, and a spatula tip of Raney nickel is added. The reaction mixture is hydrogenated with hydrogen in the hydrogenation apparatus at room temperature. The catalyst is filtered off and the filtrate is evaporated in vacuo. The residue from evaporation is further used directly for the next reaction.
Reaction SMILES: [H-].[Na+].[Cl:3][CH2:4][CH2:5][CH2:6][CH2:7]Cl.[NH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=[O:15]>CN(C)C=O>[Cl:3][CH2:4][CH2:5][CH2:6][CH2:7][N:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=[O:15]
Reactant: ClCCCCCl
Reactant: O=C1CCCCN1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCCCN1CCCCCl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Sodium hydride (3.87 g of 50% dispersion in oil, 0.0807 mole) was suspended and stirred in 80 ml of dry dimethylformamide. A solution of 1,4-dichlorobutane (44 ml, 0.404 mole) and 2-piperidone (8 g, 0.0807 mole) in 100 ml of dimethylformamide was added dropwise over 1 hour, maintaining the temperature at 25°-30° C. by use of a water bath. The reaction mixture was stirred for 16 hours at room temperature, then byproduct salt removed by filtration and the mother liquor evaporated in vacuo to one-tenth volume. The resulting concentrate was distributed between 100 ml of water and 100 ml of hexane. The lower, oily phase of three phases was separated, diluted with 50 ml of methylene chloride, dried over magnesium sulfate, filtered and evaporated to yield 1-(4-chloro-1-butyl)-2-piperidone as an oil [14.3 g; pnmr(CDCl3) delta 1.4-1.83 (4H, m), 3.03-3.72 (6H, m), 4.10-4.43 (2H, t, J=7)].
Reaction SMILES: [CH2:1]([N:3]([CH2:9][CH3:10])[CH2:4][CH2:5][CH2:6][CH2:7][NH2:8])[CH3:2].[C:11]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([CH2:22][CH2:23][NH:24][C:25](=[O:39])[C:26]3[CH:31]=[CH:30][C:29]([C:32]4[CH:37]=[CH:36][N:35]=[C:34](Cl)[N:33]=4)=[CH:28][CH:27]=3)[CH:20]=2)[NH:15][CH:14]=1)#[N:12]>>[C:11]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([CH2:22][CH2:23][NH:24][C:25](=[O:39])[C:26]3[CH:31]=[CH:30][C:29]([C:32]4[CH:37]=[CH:36][N:35]=[C:34]([NH:8][CH2:7][CH2:6][CH2:5][CH2:4][N:3]([CH2:9][CH3:10])[CH2:1][CH3:2])[N:33]=4)=[CH:28][CH:27]=3)[CH:20]=2)[NH:15][CH:14]=1)#[N:12]
Reactant: CCN(CC)CCCCN
Reactant: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(Cl)n4)cc3)cc12
Product: CCN(CC)CCCCNc1nccc(-c2ccc(C(=O)NCCc3ccc4[nH]cc(C#N)c4c3)cc2)n1

Procedure:
Using 4-diethylaminobutylamine (reference example 93h) and N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide (reference example 1az) as substrates. MS (ion spray) m/z 510 (M+H)+.