Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Mg]Br.[Cl:4][C:5]1[C:6]([CH:20]=[O:21])=[C:7]2[C:12](=[CH:13][C:14]=1[Cl:15])[N:11]=[C:10]([O:16][CH3:17])[C:9]([O:18][CH3:19])=[N:8]2.[Cl-].[NH4+]>O1CCCC1>[Cl:4][C:5]1[C:6]([CH:20]([OH:21])[CH3:1])=[C:7]2[C:12](=[CH:13][C:14]=1[Cl:15])[N:11]=[C:10]([O:16][CH3:17])[C:9]([O:18][CH3:19])=[N:8]2
Reactant: C[Mg]Br
Reactant: COc1nc2cc(Cl)c(Cl)c(C=O)c2nc1OC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1nc2cc(Cl)c(Cl)c(C(C)O)c2nc1OC
Reaction time: 0.5 h
Yield: 91.1 %

Procedure:
Methylmagnesium bromide (2.3 mL, 1M in di-n-butylether, 2.3 mmol) was added to a suspension of 6,7-dichloro-2,3-dimethoxy-5-formylquinoxaline (600 mg, 2.09 mmol) in dry tetrahydrofuran (30 mL) under nitrogen at room temperature. After 30 minutes, saturated ammonium chloride (20 mL) was added, and the product was extracted into ethyl acetate (2×30 mL). The combined extracts were dried (MgSO4) and concentrated under reduced pressure to give 6,7-dichloro-2,3-dimethoxy-5-(1-hydroxyethyl)quinoxaline (577 mg, 91%), as a creamy coloured solid.
Reaction SMILES: NC1N(C2C=CC=CC=2[O:13]C)N=CC=1C(N)=O.[NH2:18][C:19]1[N:23]([CH:24]2[CH2:29][CH2:28][C:27]([F:31])([F:30])[CH2:26][CH2:25]2)[N:22]=[CH:21][C:20]=1[C:32]#[N:33]>>[NH2:18][C:19]1[N:23]([CH:24]2[CH2:29][CH2:28][C:27]([F:31])([F:30])[CH2:26][CH2:25]2)[N:22]=[CH:21][C:20]=1[C:32]([NH2:33])=[O:13]
Reactant: COc1ccccc1-n1ncc(C(N)=O)c1N
Reactant: N#Cc1cnn(C2CCC(F)(F)CC2)c1N
Product: NC(=O)c1cnn(C2CCC(F)(F)CC2)c1N

Procedure:
Following the procedure for the preparation of 5-amino-1-(2-methoxyphenyl)-1H-pyrazole-4-carboxamide but substituting 5-amino-1-(4,4-difluorocyclohexyl)-1H-pyrazole-4-carbonitrile provided the title compound. 400 MHz 1H NMR (CD3OD) δ 8.01 (s, 1H), 4.19 (m, 1H), 2.22-1.90 (m, 8H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([O:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:21][CH:22]([OH:35])[C:23]([O:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[CH:29][CH:28]=2)([CH3:25])[CH3:24])=[N+:18]([O-:20])[CH:19]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.N1C(C)=CC=CC=1C>ClCCl>[CH2:6]([O:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:21][CH:22]([O:35][S:2]([CH3:1])(=[O:4])=[O:3])[C:23]([O:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[CH:29][CH:28]=2)([CH3:25])[CH3:24])=[N+:18]([O-:20])[CH:19]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(Oc1ccc(C#N)cc1)C(O)Cc1ccc(OCc2ccccc2)c[n+]1[O-]
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(C)(Oc1ccc(C#N)cc1)C(Cc1ccc(OCc2ccccc2)c[n+]1[O-])OS(C)(=O)=O
Reaction time: 4.5 h
Yield: 32.4 %

Procedure:
0.7 g of methanesulphonyl chloride was added to a stirred solution of 2.3 g of 5-benzyloxy-2-[3-(4-cyanophenoxy)-2-hydroxy -3-methylbutyl]pyridine N-oxide and 1 ml of 2,6-lutidine in 10 ml of dichloromethane. The mixture was stirred for 4.5 hours and then a further 1 ml of 2,6-lutidine and 0.7 g of methanesulphonyl chloride were added. After 2.5 hours a further 1 ml of 2,6-lutidine and 0.7 g of methanesulphonyl chloride were added and the mixture was stirred for 16 hours. The mixture was then diluted with 50 ml of dichloromethane and washed in succession with 2M hydrochloric acid, water and 10% sodium bicarbonate solution The organic solution was evaporated and the residue was chromatographed on silica gel using diethyl ether/methanol (9:1) for the elution to give 0.89 g of 5-benzyloxy-2-[3-(4-cyanophenoxy)-3-methyl-2-(methylsulphonyloxy)butyl]pyridine N-oxide in the form of a cream solid of melting point 142° C. after recrystallization from ethyl acetate.
Reaction SMILES: [C:1](OCC(CO)O)(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[OH:16][CH2:17][C:18]([CH2:23][OH:24])([CH2:21][OH:22])[CH2:19][OH:20].C(OC)(=O)C1C(=CC=CC=1)O.C[O-].[Na+]>>[C:1]([O:16][CH2:17][C:18]([CH2:23][OH:24])([CH2:21][OH:22])[CH2:19][OH:20])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4]
Reactant: O=C(OCC(O)CO)c1ccccc1O
Reactant: OCC(CO)(CO)CO
Agent: C[O-]
Agent: [Na+]
Solvent: COC(=O)c1ccccc1O
Product: O=C(OCC(CO)(CO)CO)c1ccccc1O

Procedure:
Pentaerythritol salicylate was prepared by the method described in Example 1 for the preparation of glycerol salicylate except that the reactants were pentaerythritol (34.04 g; 0.25 moles), methyl salicylate (86.72 g; 0.57 moles) and sodium methoxide (0.41 g; 0.0075 moles). The final methyl salicylate level was 12.5%.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][C@@:20]2([CH3:21])[C@@H:16]([CH2:17][CH2:18][C@@H:19]2[OH:23])[C@H:15]2[C@@:6]1([F:26])[C@:7]1([CH3:25])[C:12]([CH2:13][CH2:14]2)=[CH:11][C:10](=[O:24])[CH:9]=[CH:8]1)(=[O:3])[CH3:2].[CH3:27][S:28](Cl)(=[O:30])=[O:29]>N1C=CC=CC=1>[C:1]([O:4][C@H:5]1[CH2:22][C@@:20]2([CH3:21])[C@@H:16]([CH2:17][CH2:18][C@@H:19]2[O:23][S:28]([CH3:27])(=[O:30])=[O:29])[C@H:15]2[C@@:6]1([F:26])[C@:7]1([CH3:25])[C:12]([CH2:13][CH2:14]2)=[CH:11][C:10](=[O:24])[CH:9]=[CH:8]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1C[C@]2(C)[C@@H](O)CC[C@H]2[C@@H]2CCC3=CC(=O)C=C[C@]3(C)[C@@]12F
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1C[C@]2(C)[C@@H](OS(C)(=O)=O)CC[C@H]2[C@@H]2CCC3=CC(=O)C=C[C@]3(C)[C@@]12F
Temperature: 0 °C
Reaction time: 20 h
Yield: 93.9 %

Procedure:
A solution of (11β,17β)-11-(acetyloxy)-9-fluoro-17-hydroxyandrosta-1,4-dien-3-one (1.0 g; 2.9 mmole) in dry pyridine (12 ml) was stirred in an ice bath and methanesulfonyl chloride (0.435 ml; 644 mg; 5.6 mmole) was added. The solution was left standing at 0°-5° C. for 20 hours and then poured into ice-cold 20% hydrochloric acid. The mixture was extracted with chloroform, the chloroform solution was washed with water, a dilute sodium bicarbonate solution and water, dried (anhydrous magnesium sulfate) and evaporated to afford a solid (1.20 g). One crystallization from ethyl acetatehexane gave a specimen (1.0 g), melting point 210°-211° C. (dec.), with consistent spectral data.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH:18]3[CH2:24][CH2:23][CH2:22][CH2:21][N:20]([O:25]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C:19]3=[O:45])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:25][N:20]1[CH2:21][CH2:22][CH2:23][CH2:24][CH:18]([S:15]([C:12]2[CH:11]=[CH:10][C:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[CH:14][CH:13]=2)(=[O:17])=[O:16])[C:19]1=[O:45]
Reactant: COc1ccc(-c2ccc(S(=O)(=O)C3CCCCN(OC(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(-c2ccc(S(=O)(=O)C3CCCCN(O)C3=O)cc2)cc1
Reaction time: 0.5 h

Procedure:
3-(4′-Methoxy-biphenyl-4-sulfonyl)-1-trityloxy-azepan-2-one prepared from step G (5.1 mg, 0.00826 mmol) in 0.75 ml of anhydrous CH2Cl2 was added 0.75 ml of TFA and the resulting solution was stirred for 30 min. After TLC indicated the completion of the reaction (<30 min), the reaction mixture was concentrated under reduced pressure to gave a crude material, which was then purified by a column chromatography (0˜5% MeOH in CH2Cl2). MS: 376.0 (M+H)+, 398.1 (M+Na)+.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:28]=[CH:27][C:12]([O:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([OH:26])=[C:21]([O:24][CH3:25])[CH:22]=3)[N:17]=[CH:16][N:15]=2)=[C:11]([F:29])[CH:10]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:36][N:37]1[CH2:42][CH2:41][N:40]([CH2:43][CH2:44][CH2:45]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:39][CH2:38]1>CN(C=O)C.O>[Cl:8][C:9]1[CH:28]=[CH:27][C:12]([O:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:26][CH2:45][CH2:44][CH2:43][N:40]4[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]4)=[C:21]([O:24][CH3:25])[CH:22]=3)[N:17]=[CH:16][N:15]=2)=[C:11]([F:29])[CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCN2CCN(C)CC2)cc1
Reactant: COc1cc2c(Oc3ccc(Cl)cc3F)ncnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1cc2c(Oc3ccc(Cl)cc3F)ncnc2cc1OCCCN1CCN(C)CC1
Temperature: 90 °C
Reaction time: 5 h
Yield: 48.1 %

Procedure:
A mixture of the trifluoroacetic acid salt of 4-(4-chloro-2-fluorophenoxy)-7-hydroxy-6-methoxyquinazoline (3.2 g, 7.4 mmol), potassium carbonate (6.1 g, 44.2 mmol) and 3-(4-methyl-1-piperazinyl)propyl-4-toluene sulphonate (3.0 g, 9.6 mmol) in DMF (60 ml) was stirred at 90° C. for 5 hours and allowed to cool to ambient temperature. The reaction mixture was poured into water (700 ml) and extracted 5 times with ethyl acetate. The combined extracts were washed with water, saturated aqueous sodium hydrogen carbonate, water and saturated brine. The ethyl acetate solution was dried over magnesium sulphate, filtered and the solvent removed under vacuum to give a residue which was purified by silica column chromatography, eluting with dichloromethane/methanol/0.880 aqueous ammonia (100/8/1). The relevant fractions were combined and evaporated under vacuum to give a residue which was triturated with ether, filtered and dried to give 4-(4-chloro-2-fluorophenoxy)-6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinazoline (1.64 g, 48%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9](I)=[CH:10]3)[C:6]=2[CH:16]=1.[N:17]1[CH:22]=[CH:21][CH:20]=[C:19](B(O)O)[CH:18]=1.[F-].[K+]>CC#N>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9]([C:19]4[CH:18]=[N:17][CH:22]=[CH:21][CH:20]=4)=[CH:10]3)[C:6]=2[CH:16]=1
Reactant: OB(O)c1cccnc1
Reactant: Brc1ccc2c(c1)-c1nc(I)cn1CCO2
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Product: Brc1ccc2c(c1)-c1nc(-c3cccnc3)cn1CCO2
Temperature: 85 °C
Yield: 12.7 %

Procedure:
A mixture of 9-bromo-2-iodo-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene (150 mg, 0.39 mmol), 3-pyridylboronic acid (51 mg, 0.42 mmol), bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium(II) (8 mg, 0.01 mmol) and KF (1 mL, 2M aqueous solution) in MeCN (1 mL) was heated at 85° C. for 30 h. Further 3-pyridylboronic acid (26 mg, 0.21 mmol), bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium(II) (4 mg, 0.01 mmol). The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si-PCC, gradient 0-100% EtOAc in cyclohexane) then (C18, gradient 15-60% MeOH in H2O). The resulting residue was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH affording 9-Bromo-2-pyridin-3-yl-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene as a white solid (17 mg, 18%). LCMS: RT 3.40 min [M+H]+ 342.0 and 344.0. 1H NMR (CDCl3, 400 MHz): δ 8.81 (1H, d, J=2.55 Hz), 8.55 (1H, ddd, J=4.87, 1.80, 0.93 Hz), 8.13 (1H, dt, J=7.96, 1.06 Hz), 7.76 (1H, td, J=7.73, 1.82 Hz), 7.68 (1H, s), 7.34 (1H, dd, J=8.68, 2.56 Hz), 7.17 (1H, ddd, J=7.49, 4.86, 1.22 Hz), 6.91 (1H, d, J=8.68 Hz), 4.50-4.44 (4H, m)
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].[O-]CC.[Na+].[CH2:20](Br)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].Cl>C(O)C>[C:1]([NH:4][C:5]([CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH3:20])([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: CCCCCCCCCCCCCCCCBr
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCCCCCCCCCCCCCCCC(NC(C)=O)(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Yield: 71.6 %

Procedure:
Diethyl 2-acetamidomalonate (3.0 g) was dissolved in 50 ml of dry ethanol and 1.13 g of sodium ethoxide was added thereto. A solution of 5.5 g of hexadecyl bromide in 20 ml of ethanol was added thereto at room temperature with stirring. The inside of the reaction vessel was displaced with nitrogen and the mixture was refluxed for about 15 hours. The mixture was neutralized with a 1N aqueous hydrochloric acid solution and concentrated. The concentrate was purified by silica gel column chromatography to give 4.37 g of diethyl 2-acetamido-2-hexadecylmalonate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:20])O)[CH:5]=[CH:6][CH:7]=1.C[Si](Cl)(C)C.[I-].[Na+]>C(#N)C>[Cl:20][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:13]=1[N:12]=[CH:11][C:10]([CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)=[CH:19]2
Reactant: OC(c1cccc(Cl)c1)c1cnc2c(Cl)cccc2c1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: Clc1cccc(Cc2cnc3c(Cl)cccc3c2)c1
Temperature: 150 °C
Yield: 78.3 %

Procedure:
A stirred suspension of (3-chlorophenyl)(8-chloro-3-quinolinyl)methanol (D2)(1.4 g, 4.6 mmol), trimethylsilyl chloride (3.5 ml, 28 mmol) and sodium iodide (4.2 g, 28 mmol) in acetonitrile (28 ml) was heated in a sealed tube in a microwave oven at 150° C. for 35 mins. The mixture was filtered and the solid washed with dichloromethane (5 ml) and diethyl ether (5 ml). The filtrate and washings were concentrated in vacuo to a dark brown solid, which was redissolved in dichloromethane (75 ml) and the solution washed with 10% aqueous sodium sulfite solution (75 ml), dried (MgSO4) and concentrated in vacuo to an oil. The oil was purified by chromatography over silica gel eluting with a gradient of acetone/toluene to give the title compound (D3) as a pale yellow solid (1.04 g, 3.6 mmol, 78%).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]2)=[CH:4][C:3]=1[CH2:22][NH:23][C:24]([NH:26][C:27]1[CH:28]=[N:29][C:30]([CH3:33])=[CH:31][CH:32]=1)=[O:25].[ClH:34].O1CCOCC1>CO>[ClH:1].[ClH:34].[ClH:1].[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[CH2:8][CH2:9][NH:10][CH2:11][CH2:12]2)=[CH:4][C:3]=1[CH2:22][NH:23][C:24]([NH:26][C:27]1[CH:28]=[N:29][C:30]([CH3:33])=[CH:31][CH:32]=1)=[O:25]
Reactant: Cc1ccc(NC(=O)NCc2cc(CN3CCN(C(=O)OC(C)(C)C)CC3)ccc2Cl)cn1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1ccc(NC(=O)NCc2cc(CN3CCNCC3)ccc2Cl)cn1
Reaction time: 16 h

Procedure:
The tert tert-butyl 4-(4-chloro-3-((3-(6-methylpyridin-3-yl)ureido)methyl)benzyl)piperazine-1-carboxylate from above (954 mg, 2.01 mmol) was dissolved in 40 mL of methanol and treated with 10 mL of 4N HCl in dioxane (40.2 mmol) with stirring for 16 h. The solvents were removed to afford 1.13 g of 1-(2-chloro-5-(piperazin-1-ylmethyl)benzyl)-3-(6-methylpyridin-3-yl)urea trihydrochloride salt as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][S:9]([C:11]2[N-:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=2)=[O:10])=[N:6][CH:5]=[CH:4][C:3]=1[O:20][CH2:21][CH2:22][CH2:23][O:24][CH3:25].[Na+].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[CH3:1][C:2]1[C:7]([CH2:8][S+:9]([O-:10])[C:11]2[NH:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[N:19]=2)=[N:6][CH:5]=[CH:4][C:3]=1[O:20][CH2:21][CH2:22][CH2:23][O:24][CH3:25]
Reactant: COCCCOc1ccnc(CS(=O)c2nc3ccccc3[n-]2)c1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COCCCOc1ccnc(C[S+]([O-])c2nc3ccccc3[nH]2)c1C
Temperature: 25 °C
Reaction time: 25 h

Procedure:
100 g of rabeprazole sodium salt (amorphous) is dissolved at approximately 25° C. in 450 ml of ethyl acetate. The solution is kept at approximately 25° C. and 8 ml of sodium bicarbonate saturated solution is added. The mixture is seeded with a small amount of Form γ, then kept under stirring at approximately 25° C. for 25 hours. The resulting white solid is filtered by suction, washed with 100 ml of ethyl acetate and dried under vacuum at 45° C. The resulting product has an XRPD spectrum substantially as reported in FIG. 1 and a DSC thermogram substantially as shown in FIG. 2, which prove that the compound is crystalline. The compound water content determined according to Karl Fischer is approximately 4.5-4.7%.
Reaction SMILES: [H-].[Na+].[CH3:3]I.[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C@H:13]2[CH2:18][CH2:17][C@H:16]([CH2:19][CH2:20][CH2:21][OH:22])[CH2:15][CH2:14]2)=[CH:9][CH:8]=1>C1COCC1>[CH2:19]([C@H:16]1[CH2:17][CH2:18][C@H:13]([C:10]2[CH:11]=[CH:12][C:7]([O:6][CH3:5])=[CH:8][CH:9]=2)[CH2:14][CH2:15]1)[CH2:20][CH2:21][O:22][CH3:3]
Reactant: COc1ccc([C@H]2CC[C@H](CCCO)CC2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCC[C@H]1CC[C@H](c2ccc(OC)cc2)CC1

Procedure:
60 ml of THF are added under an N2 atmosphere to 100 mmol of NaH in the form of an oil dispersion. The mixture is stirred vigorously and heated to 45° C.-50° C. 120 mmol of methyl iodide are then added, and 80 mmol of trans-4-(p-methoxyphenyl)cyclohexylpropyl alcohol [prepared as described above by malonic ester synthesis and reduction using LiAlH4 ] in 20 ml of THF are subsequently added dropwise over the course of 30 minutes. The mixture is subsequently stirred for a further 30 minutes at the same temperature, and the reaction mixture is then cooled and carefully hydrolyzed using aqueous THF. When the vigorous evolution of H2 is complete, the mixture is subjected to customary work-up, giving trans-4-(4-oxapentyl)-(p-methoxyphenyl)cyclohexane, C 19 N (15.1) I.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH2:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1)[CH:12]1[C:21]2[N:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:15][CH2:14][CH2:13]1.[NH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH2:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][N:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)=[CH:25][CH:24]=1)[CH:12]1[C:21]2[N:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:15][CH2:14][CH2:13]1
Reactant: O=Cc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: c1cnc2c(c1)CCCC2N(Cc1ccc(CN2CCCC2)cc1)Cc1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.4 %

Procedure:
Using General Procedure B: To a stirred solution of 4-{[(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzaldehyde (150 mg, 0.37 mmol), pyrrolidine (30 μL, 0.36 mmol) and AcOH (20 μL, 0.37 mmol) in THF (4 mL) was added NaBH(OAc)3 (235 mg, 1.11 mmol) and the mixture was stirred at room temperature for 1.5 hours. Purification of the crude white foam (205 mg) by column chromatography on silica gel (100:1:1—CH2Cl2:MeOH:NH4OH) afforded the desired product (160 mg, 96%) as a white foam.
Reaction SMILES: C([S-])C.[Na+].CN(C)C=O.C[O:11][C:12]1[CH:34]=[CH:33][C:15]([C:16]([C:18]2[CH:23]=[C:22]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:21]([OH:28])=[C:20]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH:19]=2)=[O:17])=[CH:14][CH:13]=1.Cl>C1C=CC=CC=1>[OH:11][C:12]1[CH:13]=[CH:14][C:15]([C:16]([C:18]2[CH:23]=[C:22]([C:24]([CH3:26])([CH3:27])[CH3:25])[C:21]([OH:28])=[C:20]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH:19]=2)=[O:17])=[CH:33][CH:34]=1
Reactant: COc1ccc(C(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc1
Agent: CC[S-]
Agent: Cl
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(C(=O)c2ccc(O)cc2)cc(C(C)(C)C)c1O
Temperature: 23 °C
Reaction time: 16 h

Procedure:
To a freshly prepared, stirred solution of 0.25 mole of sodium ethanethiolate in 250 ml. of N,N-dimethylformamide at 0° C. is added 34 g. (0.10 mole) of 4-(4-methoxybenzoyl)-2,6-di(t-butyl)phenol, and the resulting solution is refluxed for 3 hours. The solution is stirred at 23° C. for about 16 hours, then acidified with 10 percent hydrochloric acid and extracted with dichloromethane. The organic extracts are washed twice with 10 percent hydrochloric acid, then with water, then dried and evaporated to provide an oil residue. The residue is dissolved in benzene and cooled. A solid crystallizes after many hours. It is recrystallized from a benzene-hexane mixture, then sublimed to provide white crystals of 4-(4-hydroxybenzoyl)-2,6-di(t-butyl)-phenol, m.p. 188°-189.5° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[CH3:55][C:56]1[O:60][N:59]=[CH:58][C:57]=1[C:61](Cl)=[O:62]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([C:61]([C:57]2[CH:58]=[N:59][O:60][C:56]=2[CH3:55])=[O:62])[CH2:49][CH2:48]1
Reactant: Cc1oncc1C(=O)Cl
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: Cc1oncc1C(=O)N1CCC(CC(=O)Nc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 44 %

Procedure:
The desired compound was prepared according to the procedure of Example A20, using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 5-methylisoxazole-4-carbonyl chloride as starting materials in 44% yield. 1H NMR (300 MHz, DMSO-d6): δ 10.05 (s, 1H), 9.41 (s, 2H), 9.02 (s, 1H), 8.65 (s, 1H), 8.33 (s, 2H), 8.20 (s, 1H), 7.65 (s, 1H), 7.30 (d, 1H), 7.05 (d, 1H), 4.42 (m, 1H), 3.70 (m, 1H), 3.12 (m, 2H), 2.98 (m, 4H), 2.49 (s, 3H), 2.30 (m, 2H), 2.12 (m, 1H), 1.80 (m, 2H), 1.20 (m, 2H). LCMS for C29H30ClN8O3 (M+H)+: m/z=573.2.
Reaction SMILES: C([O:3][C:4](=[O:10])[CH:5]([CH:8]=O)[CH:6]=O)C.Cl.[C:12]([NH:16][NH2:17])([CH3:15])([CH3:14])[CH3:13].C(NN)(C)(C)C.[OH-].[Na+].Cl>C(O)C>[C:12]([N:16]1[CH:6]=[C:5]([C:4]([OH:3])=[O:10])[CH:8]=[N:17]1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CCOC(=O)C(C=O)C=O
Reactant: CC(C)(C)NN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)n1cc(C(=O)O)cn1
Temperature: 32 °C
Reaction time: 3 h

Procedure:
Formyl-3-oxo-propionic acid ethyl ester (75.85 g, 525.6 mmol) was dissolved in ethanol (1 L) at room temp. Tert-butylhydrazine hydrochloride (65.5 g, 525.6 mmol) was added at room temp and the reaction temperature gradually increased to 32° C. The flask was then placed in an ice-bath to cool it back to 20° C. It took ca. 1 h for t-butylhydrazine to fully dissolve. The solution was stirred at room temp. for 3 h. The reaction mixture was cooled in an ice-bath. Sodium hydroxide (4N, 152.4 g) was added to neutralize the hydrochloric acid. Most of the ethanol was then removed in vacuo and methanol (300 ml) was added followed by additional sodium hydroxide (4N, 304.8 g, 1.05 mol). The internal temperature gradually rose to 32° C. The reaction flask was then placed in a water bath to cool it back to room temp. and the reaction was allowed to stir at room temp. for 18 h. Methanol (300 ml) was then removed in vacuo with the water bath temperature kept below 30° C. The reaction mixture was then cooled to 0° C. and hydrochloric acid (6N, 190 ml) was added slowly to keep internal temperature below 15° C. The solution was adjusted to pH=2. The resulting suspension was allowed to stir in the ice-bath for 2 h, and the solid was filtered. After drying at 60° C. in vacuo for 2.5 days, 1-tert-butyl-1H-pyrazole-4-carboxylic acid (56.06 g) of off-white solid was collected. The mother liquor was extracted 3 times with dichloromethane (200 ml×3). The combined organic layer was washed once with brine (100 ml) and dried over magnesium sulfate. After concentrating in vacuo and drying, 16.5 g of yellowish solid was collected. The crude material was crystallized in hot iso-propyl acetate (25 ml) and heptane (25 ml). After cooling to room temp, the solid was filtered off and the cake was washed with mixed solvent of isopropyl acetate and heptane (1/1 (v/v, 14 ml) and dried in oven at 60° C. in vacuo for 5 h. A second crop of 1-tert-butyl-1H-pyrazole-4-carboxylic acid (7 g) was collected as a white solid.