Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][OH:12])=[CH:7][CH:6]=1.[Br:13][C:14]1[C:15](Cl)=[N:16][CH:17]=[CH:18][C:19]=1[CH3:20].O>C1COCC1.CCOC(C)=O>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][O:12][C:15]2[C:14]([Br:13])=[C:19]([CH3:20])[CH:18]=[CH:17][N:16]=2)=[CH:7][CH:6]=1
Reactant: COc1ccc(CO)cc1
Reactant: Cc1ccnc(Cl)c1Br
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(COc2nccc(C)c2Br)cc1
Temperature: 75 °C
Reaction time: 0.08 h

Procedure:
To a mixture of 60% NaH in mineral oil (0.290 g, 7.27 mmol) in THF (15 mL) at RT in a resealable pressure vessel was added (4-methoxyphenyl)methanol (0.906 ml, 7.27 mmol). After 5 minutes, 3-bromo-2-chloro-4-picoline (1.00 g, 4.84 mmol) was added and the mixture was heated to 75° C. After 1 hr, water was added and the mixture was diluted with EtOAc. After washing with water and brine, the organic fraction was dried with sodium sulfate and purified by silica gel chromatography using 0-30% EtOAc:hexanes to afford 2-(4-methoxybenzyloxy)-3-bromo-4-methylpyridine as a colorless oil. M+H+=308.0.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH:3]([CH2:8][CH2:9][CH2:10][CH3:11])[CH2:4][CH2:5][CH2:6][OH:7].[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.Cl>N1C=CC=CC=1>[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20]([O:7][CH2:6][CH2:5][CH2:4][CH:3]([C:2]([F:12])([F:13])[F:1])[CH2:8][CH2:9][CH2:10][CH3:11])(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: CCCCC(CCCO)C(F)(F)F
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CCCCC(CCCOS(=O)(=O)c1ccc(C)cc1)C(F)(F)F

Procedure:
0.27 g (1.4 mmol) of 4-trifluoromethyloctanol was dissolved in 5 ml of pyridine and cooled with ice, and 0.27 g (1.4 mmol) of p-toluenesulfonyl chloride was added thereto under stirring, followed by reaction at 15°-20° C. for 3 hours. After the reaction, the mixture was acidified with 2N-hydrochloric acid and extracted with diethyl ether. The resultant ether layer was dired on anhydrous sodium sulfate, followed by distilling-off of the solvent to obtain 4-trifluoromethyloctyl p-toluenesulfonate. Then, 0.4 g (1.1 mmol) of the 4-trifluoromethyloctyl p-toluenesulfonate was dissolved in 1 ml of ethanol and then added to a preliminarily prepared solution of 48 mg (1.1 mmol) of sodium hydroxide and 0.23 g (1.1 mmol) of p-hydroxyphenyl benzyl ether in 1 ml of ethanol. The mixture was heated to 85°-90° C. for 5 hours of reaction and then cooled by standing. The reaction mixture was poured into 20 ml of 2N-hydrochloric acid and extracted with diethyl ether. The resultant ether layer was dried on anhydrous sodium sulfate and purified by silica gel column chromatography (eluent: benzene) to obtain 0.30 g (yield: 69%) of p-benzyloxy(4-trifluoromethyloctyloxy)phenyl.
Reaction SMILES: [H-].[Na+].CCCC(C)C.[Br:9][C:10]1[CH:11]=[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[NH:13][CH:14]=1.Br[CH2:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[N+:29]([O-:31])=[O:30]>CN(C)C(=O)C>[Br:9][C:10]1[CH:11]=[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:13]([CH2:21][C:22]2[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=2[N+:29]([O-:31])=[O:30])[CH:14]=1
Reactant: CCOC(=O)c1cc(Br)c[nH]1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CCCC(C)C
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1cc(Br)cn1Cc1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Wash 60% mineral oil suspended sodium hydride (1.2 equiv; 1.1 g, 27.52 mmoles) with a small amount of iso-hexane (×2). Suspend in N,N-dimethylacetamide (15 mL) and chill in an ice-bath. Add ethyl 4-bromo-1H-pyrrole-2-carboxylate (5.0 g, 22.93 mmoles) portionwise over 15 minutes allowing gas evolution to subside between additions. Stir at room temperature for 15 minutes to give a brown solution. Add 2-(bromomethyl)-4-chloro-1-nitro-benzene (1.15 equiv; 6.61 g, 26.37 mmoles) in portions over 15 minutes and stir the resulting purple solution at room temperature for 2.5 h. Cool in an ice-bath and quench with water (10 mL). Partition between 1M hydrochloric acid (100 mL) and EtOAc (300 mL). Wash the organic layer with water (2×100 mL) then brine. Dry over Na2SO4 and decolorize with activated charcoal. Filter through celite and evaporate to give ethyl 4-bromo-1-(5-chloro-2-nitrobenzyl)-1H-pyrrole-2-carboxylate as a an orange oil (9.1 g, quantitative). 1H-NMR (CDCl3) δ: 8.12 (1H, d), 7.40 (1H, dd), 7.07 (1H, d), 6.92 (1H, d), 6.53 (1H, d), 5.87 (2H, s), 4.17 (2H, q), 1.25 (3H, t).
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][C:11]1=[O:19].[Cl:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=1[Cl:30])[C:24](Cl)=[O:25].O>C(Cl)Cl>[Cl:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=1[Cl:30])[C:24]([NH:9][CH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][C:11]1=[O:19])=[O:25]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: NC1C(=O)Nc2ccccc21
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(NC1C(=O)Nc2ccccc21)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.5 %

Procedure:
Under argon atmosphere and ice cooling, a solution of 16.5 g of triethylamine in 50 ml of methylene chloride was added dropwise to a stirred mixture of 15.05 g of 3-amino-2,3-dihydro-1H-indol-2-one hydrochloride and 17.20 g of 3,4-dichlorobenzoyl chloride suspended in 300 ml of methylene chloride. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was treated with 100 ml of water, and the whole was stirred for additional 2 hours. The resulting precipitates were collected by filtration, washed and then recrystallized from dimethylformamide-water to afford 22.9 g of 3,4-dichloro-N-(2,3-dihydro-2-oxo-1H-indol-3-yl)benzamide as colorless needle crystals. Melting point: 283° to 285° C. (decomposed), IR (Nujol) (cm-1) : 3280, 3160, 3100, 1710, 1690, 1635, MS (m/z): 322 & 320 (M+), 147 (base).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([CH3:15])=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[I-].[CH3:17][N+:18](C)(C)[CH2:19]C1C(C2C=CC=CC=2)=CC=CC=1>>[CH3:17][N:18]([CH2:2][C:3]1[C:4]([CH3:15])=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1)[CH3:19]
Reactant: Cc1c(CCl)cccc1-c1ccccc1
Reactant: C[N+](C)(C)Cc1ccccc1-c1ccccc1
Agent: [I-]
Product: Cc1c(CN(C)C)cccc1-c1ccccc1

Procedure:
An additional method for preparing the intermediate 3-chloromethyl-2-methyl[1,1'-biphenyl] involves a Sommelet-Hauser rearrangement of N,N,N-trimethyl[1,1'-biphenyl]-2-methanaminium iodide to give 3-dimethylaminomethyl-2-methyl-[1,1'-biphenyl], which is then converted into the 3-chloromethyl derivative by treatment with ethyl chloroformate. The N,N,N-trimethyl-[1,1'-biphenyl]-2-methanaminium iodide starting material may be prepared in four steps from 2-biphenylcarboxylic acid via the acid chloride, dimethyl carboxamide, and dimethylaminomethyl derivatives.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]=[C:6]([CH:8]([CH3:22])[C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:11]([F:21])[CH:10]=2)[O:5][N:4]=1.[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>CN(C=O)C>[F:21][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][C:12]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:8]([C:6]1[O:5][N:4]=[C:3]([CH2:2][N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:7]=1)[CH3:22]
Reactant: C1COCCN1
Reactant: CC(c1ccc(-c2ccccc2)c(F)c1)c1nc(CCl)no1
Solvent: CN(C)C=O
Product: CC(c1ccc(-c2ccccc2)c(F)c1)c1nc(CN2CCOCC2)no1
Temperature: 0 °C
Reaction time: 8 h
Yield: 103.8 %

Procedure:
To a solution of 1.52 g of 3-chloromethyl-5-(3-fluoro-4-phenyl-α-methylbenzyl)-1,2,4-oxadiazole in 30 ml of DMF was added 1.68 g of morpholine. The mixture was allowed to stand at room temperature overnight, then poured into ice-water and extracted with benzene. The organic phase was washed with water, dried over sodium sulfate and evaporated. The residue was chromatographed over silica gel using benzene-ethyl acetate (5:2, v/v) as an eluent to yield 1.83 g of 5-(3-fluoro-4-phenyl-α-methylbenzyl)-3-morpholinomethyl-1,2,4-oxadiazole as an oil. It was crystallized from diisopropyl ether to give colorless needles, m.p. 91.5°-92.5° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][OH:14])[C@H:10]([CH2:15][O:16][C:17]2[N:18]=[N:19][C:20]([CH2:37][CH2:38][CH2:39][CH3:40])=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:25][CH:24]=3)[CH:22]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:43]I.O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][O:14][CH3:43])[C@H:10]([CH2:15][O:16][C:17]2[N:18]=[N:19][C:20]([CH2:37][CH2:38][CH2:39][CH3:40])=[C:21]([C:23]3[CH:24]=[CH:25][C:26]([O:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:27][CH:28]=3)[CH:22]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCc1nnc(OC[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CO)cc1-c1ccc(OCc2ccccc2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCc1nnc(OC[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2COC)cc1-c1ccc(OCc2ccccc2)cc1
Reaction time: 0.17 h

Procedure:
To a stirred solution of (±)-trans-3-[5-(4-benzyloxy-phenyl)-6-butyl-pyridazin-3-yloxymethyl]-4-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (Example 6, 1.0 mmol, 547 mg) in THF (4.0 mL) at 0° C., NaH (60% dispersion in mineral oil, 1.5 mmol, 60 mg) was added and stirring continued for 10 min at room temperature, then methyl iodide (1.5 mmol, 94 μL) was added. The resulting mixture was stirred at room temperature for 2 hour, poured into water, and extracted with ethyl acetate. The organic layers were combined and concentrated under reduced pressure. The product was purified by column chromatography using 50% ethyl acetate in hexanes to give (±)-trans-3-[5-(4-benzyloxy-phenyl)-6-butyl-pyridazin-3-yloxymethyl]-4-methoxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester, which was dissolved in dichloromethane (1.0 mL), added 4.0 M HCl in dioxane (1.0 mL) and stirred at room temperature for 1 hour. Solvents were evaporated to give (±)-trans-4-(4-benzyloxy-phenyl)-3-butyl-6-(4-methoxymethyl-pyrrolidin-3-ylmethoxy)-pyridazine dihydrochloride.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]4[N:27]([CH3:31])[CH:28]=[CH:29][N:30]=4)[CH2:23][CH2:22][C:21]([C:32]([O:34]C)=[O:33])=[CH:20][C:19]=3[CH:36]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].O.Cl>O1CCCC1.CO>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]4[N:27]([CH3:31])[CH:28]=[CH:29][N:30]=4)[CH2:23][CH2:22][C:21]([C:32]([OH:34])=[O:33])=[CH:20][C:19]=3[CH:36]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3Cc2nccn2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2nccn2C)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 79.9 %

Procedure:
To a solution of methyl 7-(4-butoxyethoxyphenyl)-1-[(1-methylimidazol-2-yl)methyl]-2,3-dihydro-1-benzazepine-4-carboxylate (367 mg) in a mixture of tetrahydrofuran (24 ml) and methanol (24 ml) was added 1N sodium hydroxide solution (8 ml), and the mixture was stirred at room temperature for 3 days. Then, to the mixture was added water at 0° C., and 1N hydrochloric acid was further added to neutralize, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, which was recrystallized from hexane-ethyl acetate to give 7-(4-butoxyethoxyphenyl)-1-[(1-methylimidazol-2-yl)methyl]-2,3-dihydro-1-benzazepine-4-carboxylic acid (285 mg) as yellow crystals.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C@H:7]([NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@H:6]([O:21][CH3:22])[CH2:5]1)(=[O:3])[NH2:2].Br[CH:24]([CH2:34][CH2:35][CH3:36])[C:25](=O)[C:26]([O:28][CH2:29][CH2:30]CC)=[O:27].C(=O)(O)[O-].[Na+]>C1COCC1>[CH2:13]([O:12][C:11]([NH:10][C@H:7]1[CH2:8][CH2:9][N:4]([C:1]2[O:3][C:24]([CH2:34][CH2:35][CH3:36])=[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[N:2]=2)[CH2:5][C@H:6]1[O:21][CH3:22])=[O:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCCCOC(=O)C(=O)C(Br)CCC
Reactant: CO[C@@H]1CN(C(N)=O)CC[C@@H]1NC(=O)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCc1oc(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OC)C2)nc1C(=O)OCC
Yield: 74.1 %

Procedure:
The same operation as in Example (103c) was performed using cis(±)-benzyl (1-carbamoyl-3-methoxypiperidin-4-yl)carbamate obtained in Example (103b) (0.95 g, 3.09 mmol), butyl 3-bromo-2-oxohexanoate obtained in Example (116a) (5.1 g, 19.2 mmol), sodium bicarbonate (0.64 g, 7.6 mmol) and THF (20 mL). The resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/4, 2/3, 1/1, 3/2, 2/1) to obtain 1.02 g of the title compound as a light yellow solid (70%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:11]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:19]=2)(=[O:17])=[O:16])[CH2:12][O:13][CH3:14])[C:5]([C:8](O)=[O:9])=[N:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[NH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>C(Cl)Cl>[C:43]1([NH:42][C:8]([C:5]2[C:4]([N:11]([S:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([C:25]([F:27])([F:28])[F:26])[CH:19]=3)(=[O:17])=[O:16])[CH2:12][O:13][CH3:14])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)=[O:9])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: Nc1ccccc1
Reactant: COCN(c1cc(Cl)cnc1C(=O)O)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCN(c1cc(Cl)cnc1C(=O)Nc1ccccc1)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reaction time: 1 h

Procedure:
To a magnetically stirred solution of 5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carboxylic acid (229 mg, 0.50 mmol) in anhydrous methylene chloride (5 mL) was added oxalyl chloride (0.5 mL) at room temperature. The reaction was heated at reflux for 1 h, then concentrated to dryness. The residue was dissolved in methylene chloride (4 mL) and this solution was added dropwise to a magnetically stirred solution of triethylamine (1.0 mL) and aniline (93 mg, 1.00 mmol) in methylene chloride (2 mL). The reaction mixture was stirred 1 h (the reaction was monitored by LCMS), quenched with saturated aqueous NH4Cl (50 mL), and the aqueous layer was extracted with EtOAc (3×75 mL). The combined extracts were washed with 0.5 M HCl (50 mL) and water (50 mL), dried (MgSO4), filtered, and concentrated. The residue was purified by chromatography on silica gel using a gradient of ethyl acetate-hexane (0:100 to 100:0) to afford pure 5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carboxylic acid phenylamide. MS m/z 556.1 (M+Na); 502.1 (M+H-MeOH).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][CH2:15][C:16](O)=[O:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[H][H]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][CH2:15][CH2:16][OH:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCCC(CCC(=O)O)C1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC(CCCO)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.6 %

Procedure:
To a solution of commercially available 3-[1-(tert-butoxycarbonyl)-3-piperidinyl]propionic acid (2.57 g, 10.0 mmol) in 100 mL of anhydrous THF was added slowly a solution of BH3.THF complex in THF (1.0 M, 20 mL, 2.0 equiv) at room temperature under N2. The solution was stirred for 16 h at room temperature. Water was added carefully (hydrogen evolution!), and the resulting solution was concentrated under reduced pressure. The residue was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure to give the alcohol (2.35 g, 97%) as a colorless oil. LC-MS (ESI) m/z 244 (M+H+).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH:3]1[CH2:12][CH:11]2[CH2:13][CH:4]1[C:5]1[CH:10]2[CH2:9][CH2:8][CH2:7][CH:6]=1.[H][H]>[Pd].CO>[F:1][C:2]([F:14])([F:15])[CH:3]1[CH2:12][CH:11]2[CH2:13][CH:4]1[CH:5]1[CH:10]2[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: FC(F)(F)C1CC2CC1C1=CCCCC12
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: FC(F)(F)C1CC2CC1C1CCCCC21
Reaction time: 0.75 h

Procedure:
A 400 ml autoclave is charged with 177 g of the thus purified octahydro-2-trifluormethyl-1,4-methanonaphthalene, methanol (100 ml, Burdick & Jackson, HPLC grade), and palladium on activated carbon (1.5 g containing 10% Pd, Alfa products, powder). The autoclave is closed and sealed, then it is shaken under 50 psig hydrogen pressure for 20 minutes at room temperature. The hydrogen pressure is increased to 200 psig for 10 minutes at room temperature followed by 600 psig at 70° C. for 45 minutes. The decahydro-2-trifluormethyl-1,4-methanonaphthalene product is purified by distillation at reduced pressure. The crude product is treated with sulfuric acid as described in Example 2.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][N:17]3[CH:21]=[CH:20][N:19]=[N:18]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH2:34][C:33](=[O:35])[NH:32][N:31]=2)=[CH:26][CH:25]=1>>[CH3:22][O:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[NH:31][N:32]=[C:33]([O:35][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][N:17]5[CH:21]=[CH:20][N:19]=[N:18]5)=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][N:3]=3)[CH:34]=2)=[CH:28][CH:29]=1
Reactant: COc1ccc(C2=NNC(=O)C2)cc1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCn1ccnn1
Product: COc1ccc(-c2cc(Oc3ncnc4cc(OCCn5ccnn5)c(OC)cc34)n[nH]2)cc1
Yield: 0 %

Procedure:
Using a procedure analogous to that described in Example 23, 4-chloro-6-methoxy-7-(2-(1,2,3-triazol-1-yl)ethoxy)quinazoline (160 mg, 0.52 mol) was reacted with 3-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazol-5-one (120 mg, 0.63 mol), (prepared as described for the starting material in Example 10), to give 4-(5-(4-methoxyphenyl)pyrazol-3-yloxy)-6-methoxy-7-(2-(1,2,3-triazol-1-yl)ethoxy)quinazoline (105 mg, 44%).
Reaction SMILES: [C:1]12[C:12]([NH:13][CH:14]3[CH2:19][CH2:18][CH:17]([NH:20][C:21](=O)OC(C)(C)C)[CH2:16][CH2:15]3)=[N:11][CH:10]=[N:9][C:8]=1[S:7][C:6]1[CH2:5][CH2:4][CH2:3][C:2]2=1.[H-].[H-].[H-].[H-].[Al+3].[Li+]>O1CCCC1>[CH3:21][NH:20][CH:17]1[CH2:18][CH2:19][CH:14]([NH:13][C:12]2[C:1]3[C:2]4[CH2:3][CH2:4][CH2:5][C:6]=4[S:7][C:8]=3[N:9]=[CH:10][N:11]=2)[CH2:15][CH2:16]1
Reactant: CC(C)(C)OC(=O)NC1CCC(Nc2ncnc3sc4c(c23)CCC4)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNC1CCC(Nc2ncnc3sc4c(c23)CCC4)CC1
Temperature: 25 °C
Yield: 100.5 %

Procedure:
A solution of tert-butyl N-[4-([7-thia-9,11-diazatricyclo[6.4.0.0^[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]amino)cyclohexyl]carbamate (1.1 g, 2.83 mmol, 1.00 equiv) in tetrahydrofuran (20 mL) was added into a solution of lithium aluminium tetrahydride (530 mg, 13.95 mmol, 5.00 equiv) in tetrahydrofuran (30 mL) dropwise with stirring at room temperature. The resulting solution was heated to reflux for 30 min in an oil bath. The reaction was then quenched by the addition of 20 mL of tetrahydrofuran/water. The solids were filtered out. The filtrate was extracted with 3×100 mL of dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum to give 0.86 g (crude) of 1-N-methyl-4-N-[7-thia-9,11-diazatricyclo[6.4.0.0^[2,6]]dodeca-1(8), 2(6),9,11-tetraen-12-yl]cyclohexane-1,4-diamine as yellow oil. LC-MS: (ES, m/z): 303 [M+H]+
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([C:17]3[C:25]4[C:20](=[C:21]([CH2:26][S:27][CH3:28])[CH:22]=[CH:23][CH:24]=4)[NH:19][CH:18]=3)[CH2:11][C:12](OCC)=[O:13])=[CH:9][C:4]=2[CH:3]=[CH:2]1.ClC1C=CC(C(C2C3C(=C(CSC)C(F)=CC=3)NC=2)CCO)=CC=1>>[S:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([C:17]3[C:25]4[C:20](=[C:21]([CH2:26][S:27][CH3:28])[CH:22]=[CH:23][CH:24]=4)[NH:19][CH:18]=3)[CH2:11][CH2:12][OH:13])=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: CCOC(=O)CC(c1ccc2sccc2c1)c1c[nH]c2c(CSC)cccc12
Agent: CSCc1c(F)ccc2c(C(CCO)c3ccc(Cl)cc3)c[nH]c12
Product: CSCc1cccc2c(C(CCO)c3ccc4sccc4c3)c[nH]c12

Procedure:
The title compound was prepared starting from 1.17 g (2.87 mmol) of the compound from Example 49A in analogy to the synthesis of the compound from Example 16. 0.93 g (88% of theory) of the title compound were obtained.
Reaction SMILES: CO.[N+](C1C=C(C=CC=1)CO)([O-])=O.C(OC([N:21]([C:37]1[C:42]([O:43][CH3:44])=[N:41][C:40]([CH3:45])=[CH:39][N:38]=1)[S:22]([C:25]1[C:26]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[N:27][CH:28]=[CH:29][CH:30]=1)(=[O:24])=[O:23])=O)C(C)C.C1(B(O)O)C=CC=CC=1>>[CH3:44][O:43][C:42]1[C:37]([NH:21][S:22]([C:25]2[C:26]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[N:27][CH:28]=[CH:29][CH:30]=2)(=[O:24])=[O:23])=[N:38][CH:39]=[C:40]([CH3:45])[N:41]=1
Reactant: COc1nc(C)cnc1N(C(=O)OCC(C)C)S(=O)(=O)c1cccnc1-c1ccccc1
Agent: O=[N+]([O-])c1cccc(CO)c1
Agent: OB(O)c1ccccc1
Solvent: CO
Product: COc1nc(C)cnc1NS(=O)(=O)c1cccnc1-c1ccccc1

Procedure:
1H NMR (d6-DMSO): 2.2 (s, 3H), 3.6 (s, 3H), 7.3-7.55 (m, 6H), 7.6 (dd, 1H), 8.4 (dd, 1H), 8.8 (dd, 1H), 10.5 (br s, 1H); mass spectrum (positive fast atom bombardment (+ve FAB), methanol/m-nitrobenzyl alcohol (NBA)): 357 (M+H)+; starting from N-(isobutoxycarbonyl)-N-(3-methoxy-5-methylpyrazin-2-yl)-2-phenylpyridine-3-sulphonamide; 1H NMR (d6-DMSO): 0.6 (d, 6H), 1.7 (m, 1H), 2.55 (s, 3H), 3.7 (d, 2H), 3.9 (s, 3H), 7.4-7.55 (m, 5H), 7.8 (dd, 1H), 8.9 (dd, 1H), 8.95 (dd, 1H); mass spectrum (+ve CI): 457 (M+H)+; itself obtained using an analogous procedure to that described in Example 1, part (iii) but using phenylboronic acid.
Reaction SMILES: [CH2:1]1[CH2:31][O:30][C:3]2([CH2:20][CH2:19][C:18]3[C@@:5]([OH:29])([CH2:6][CH2:7][C@@H:8]4[C:17]=3[C@@H:16]([C:21]3[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=3)[CH2:15][C@@:13]3([CH3:14])[C@H:9]4[CH2:10][CH2:11][C:12]3=[O:28])[CH2:4]2)[O:2]1.[NH:32]1[CH:36]=[CH:35][N:34]=[CH:33]1.CN(C)CC(O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH2:1]1[CH2:31][O:30][C:3]2([CH2:20][CH2:19][C:18]3[C@@:5]([OH:29])([CH2:6][CH2:7][C@@H:8]4[C:17]=3[C@@H:16]([C:21]3[CH:26]=[CH:25][C:24]([N:32]5[CH:36]=[CH:35][N:34]=[CH:33]5)=[CH:23][CH:22]=3)[CH2:15][C@@:13]3([CH3:14])[C@H:9]4[CH2:10][CH2:11][C:12]3=[O:28])[CH2:4]2)[O:2]1
Reactant: C[C@]12C[C@H](c3ccc(I)cc3)C3=C4CCC5(C[C@]4(O)CC[C@H]3[C@@H]1CCC2=O)OCCO5
Reactant: c1c[nH]cn1
Agent: CN(C)CC(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C[C@]12C[C@H](c3ccc(-n4ccnc4)cc3)C3=C4CCC5(C[C@]4(O)CC[C@H]3[C@@H]1CCC2=O)OCCO5
Temperature: 25 °C
Yield: 89 %

Procedure:
A mixture of compound 3 (9.7 g, 18 mmol), imidazole (1.4 g, 20 mmol), cuprous iodide (346 mg, 1.8 mmol), N, N-dimethyl glycine (374 mg, 3.6 mmol) and potassium carbonate (5 g, 36 mmol) in anhydrous DMSO (10 mL) was degassed three times applying vacuum and nitrogen and was immersed in to a preheated oil bath at 110° C. The reaction mixture was heated for 60 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (150 mL) and filtered through a Celite pad. The filtrate was transferred to a reparatory funnel and was washed with water, brine and dried over anhydrous sodium sulfate. The solvent was removed under vacuum to afford the crude product, which on purification by chromatography on SiO2 column eluting with 30% acetone in dichloromethane gave 7.6 g (91%) of required product 4 as a pale yellow solid.