Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([S:12]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:14])=[O:13])=[CH:8][C:4]=1[C:5](O)=[O:6].C(Cl)(=O)C([Cl:25])=O.CN(C=O)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([S:12]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:14])=[O:13])=[CH:8][C:4]=1[C:5]([Cl:25])=[O:6]
Reactant: COc1ccc(S(=O)(=O)Oc2ccccc2)cc1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)Oc2ccccc2)cc1C(=O)Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.1 %

Procedure:
To a suspension of 2-methoxy-5-phenoxysulfonylbenzoic acid (4.0 g, 13 mmol) in dry toluene (100 mL) was added oxalyl chloride (2.3 mL, 26 mmol) at room temperature. A drop of DMF was added and the mixture stirred at room temperature for 2 h. The mixture was evaporated in vacuo and the residue triturated with 1:1 toluene/hexane to give the title compound as a solid (4.04 g).
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:18]3[CH:19]=[C:20]4[O:25][CH2:24][O:23][C:21]4=[CH:22][C:17]=3[CH2:16][C:15]([CH3:26])=[N:14][N:13]=2)=[CH:8][CH:7]=1>CN(C)C=O.O>[CH3:1][NH:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:18]3[CH:19]=[C:20]4[O:25][CH2:24][O:23][C:21]4=[CH:22][C:17]=3[CH2:16][C:15]([CH3:26])=[N:14][N:13]=2)=[CH:8][CH:7]=1)=[O:4]
Reactant: CN=C=O
Reactant: CC1=NN=C(c2ccc(N)cc2)c2cc3c(cc2C1)OCO3
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)Nc1ccc(C2=NN=C(C)Cc3cc4c(cc32)OCO4)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 71.1 %

Procedure:
0.8 ml (13.4 mmol) of methyl isocyanate was added to a solution containing 1.0 g (3.41 mmol) of 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine in 8 ml of dimethylformamide (DMF), then the reaction mixture was stirred at 25° C. for 24 hours. After diluting with 80 ml of water, filtering at 5° C. and drying at 60 to 100° C., 1.06 g of raw product, m.p.: 204°-207° C. (sintering from 160° C.) were obtained which, when recrystallized from 5 ml of ethanol, gave 0.85 g (71.4%) of-the aimed product, m.p.: 223°-224° C. (decomp.).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][PH:13](=[O:17])[O:14][CH2:15][CH3:16])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:18][Mg+].[Br-]>C1COCC1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][P:13]([CH3:18])(=[O:17])[O:14][CH2:15][CH3:16])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: C[Mg+]
Reactant: CCO[PH](=O)COS(=O)(=O)c1ccc(C)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CCOP(C)(=O)COS(=O)(=O)c1ccc(C)cc1
Yield: 77 %

Procedure:
To the crude ethyl (4-methylphenyl)sulfonyloxymethylphosphinate monochloridate (2.00 g, 6.39 mmol) in dry THF (30.0 mL) at −78° C. was added MeMgBr (2.20 mL, 6.97 mmol, 3.0 M in diethyl ether). The reaction was quenched immediately after the MeMgBr addition with 1 mL of acetic acid. The reaction mixture was diluted with ethyl acetate and H2O and the organic layer was washed twice with saturated aqueous NaHCO3 and once with H2O. The organic layer was concentrated and coevaporated with MeOH. The product was obtained by precipitation from hexanes to afford the title compound as a white solid (1.40 g, 77% over two steps): 1H NMR (200 MHz, DMSO-d6): δ 7.85 (m, 2H), 7.52 (m, 2H), 4.30 (d, J=12.0 Hz, 2H), 3.90 (m, 2H), 2.40 (s, 3H), 1.45 (d, J=21.0 Hz, 3H), 1.15 (m, 3H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=ethyl acetate-methanol (9:1); Rf=0.27.
Reaction SMILES: [N:1]1([C:6]2[N:11]=[C:10]([NH:12][C:13]3[CH:14]=[C:15]([NH:22][C@@H:23]4[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]4[NH:29]C(=O)OC(C)(C)C)[N:16]=[N:17][C:18]=3[C:19](=[O:21])[NH2:20])[CH:9]=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.FC(F)(F)C(O)=O>ClCCl>[N:1]1([C:6]2[N:11]=[C:10]([NH:12][C:13]3[CH:14]=[C:15]([NH:22][C@@H:23]4[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]4[NH2:29])[N:16]=[N:17][C:18]=3[C:19]([NH2:20])=[O:21])[CH:9]=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1cc(Nc2cccc(-n3cccn3)n2)c(C(N)=O)nn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)c1nnc(N[C@@H]2CCCC[C@@H]2N)cc1Nc1cccc(-n2cccn2)n1
Reaction time: 2 h
Yield: 25.4 %

Procedure:
To a solution of tert-butyl (1S,2R)-2-(5-(6-(1H-pyrazol-1-yl)pyridin-2-ylamino)-6-carbamoylpyridazin-3-ylamino)cyclohexylcarbamate (70 mg, 142 μmol) in dichloromethane (2.5 mL) was added trifluoroacetic acid (2.01 g, 1.35 mL, 17.6 mmol) and the mixture stirred at 25° for 2 h. The mixture was concentrated in vacuo and then diluted with dichloromethane and then washed successively with 1N NaOH (3×5 mL) and brine (5 mL). The organic phase was dried over sodium sulfate, concentrated in vacuo and then dried in vacuo to give 4-(6-(1H-pyrazol-1-yl)pyridin-2-ylamino)-6-((1R,2S)-2-aminocyclohexylamino)pyridazine-3-carboxamide (14.2 mg, 36.1 μmol, 25%) as a white solid. 1H NMR (DMSO-d6) δ: 11.93 (s, 1H), 8.63-8.71 (m, 1H), 8.45 (br. s., 1H), 7.78-7.94 (m, 3H), 7.71 (br. s., 1H), 7.51 (d, J=7.8 Hz, 1H), 7.05 (d, J=7.5 Hz, 1H), 6.92 (d, J=8.0 Hz, 1H), 6.63 (dd, J=2.5, 1.8 Hz, 1H), 4.02 (br. s., 1H), 3.18 (br. s., 1H), 1.46-1.79 (m, 7H), 1.20-1.41 (m, 3H); MS (EI/CI) m/z: 394.3 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=2)=[O:10])=[CH:4][C:3]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][N:28]=1>>[NH2:26][C:27]1[N:28]=[CH:29][C:30]([NH:33][C:15](=[O:17])[C:14]2[CH:13]=[CH:12][C:11]([C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[CH:4]=3)=[O:10])=[CH:19][CH:18]=2)=[CH:31][CH:32]=1
Reactant: Nc1ccc(N)nc1
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1
Product: Nc1ccc(NC(=O)c2ccc(C(=O)Nc3ccc(Cl)c(-c4ccccn4)c3)cc2)cn1

Procedure:
50 mg of 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 2,5-diaminopyridine via Procedure G. The product was purified on reverse phase HPLC to yield N1-(6-aminopyridin-3-yl)-N4-(4-chloro-3-(pyridin-2-yl)phenyl)terephthalamide. MS (Q1) 444 (M)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:15]=[C:14]([C:16]2[N:20]=[C:19]([C:21]3[CH:26]=[C:25]([CH3:27])[C:24]([CH2:28][CH:29]([CH3:31])[CH3:30])=[CH:23][N:22]=3)[O:18][N:17]=2)[CH:13]=[C:12]([CH3:32])[C:4]=1[O:5][CH2:6][C@@H:7]([OH:11])[CH2:8][NH:9]C)[CH3:2].[K+].[CH2:34]([S:36]([NH-])(=[O:38])=[O:37])[CH3:35]>CN(C=O)C>[CH2:1]([C:3]1[CH:15]=[C:14]([C:16]2[N:20]=[C:19]([C:21]3[CH:26]=[C:25]([CH3:27])[C:24]([CH2:28][CH:29]([CH3:30])[CH3:31])=[CH:23][N:22]=3)[O:18][N:17]=2)[CH:13]=[C:12]([CH3:32])[C:4]=1[O:5][CH2:6][C@@H:7]([OH:11])[CH2:8][NH:9][S:36]([CH2:34][CH3:35])(=[O:38])=[O:37])[CH3:2]
Reactant: CCS([NH-])(=O)=O
Reactant: CCc1cc(-c2noc(-c3cc(C)c(CC(C)C)cn3)n2)cc(C)c1OC[C@@H](O)CNC
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1cc(-c2noc(-c3cc(C)c(CC(C)C)cn3)n2)cc(C)c1OC[C@@H](O)CNS(=O)(=O)CC

Procedure:
A solution of the epoxide intermediate of Example 57 (step a, 25 mg, 61 μmol) and ethanesulfonamide potassium salt (27 mg, 184 μmol) in DMF (2 mL) is stirred at 60° C. for 18 h. The solvent is removed in vacuo and the crude product is purified by prep. HPLC to give the title compound (8 mg) as a colourless oil; LC-MS: tR=1.07 min, [M+H]+=517.12.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([C:8]2[CH:9]=C([CH:13]=[CH:14][CH:15]=2)C#N)=[O:7])=[CH:4][CH:3]=1.[C:18]([OH:21])(=[O:20])[CH3:19].S(=O)(=O)(O)O>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:9]=[C:19]([CH:13]=[CH:14][CH:15]=2)[C:18]([OH:21])=[O:20])=[O:7])=[CH:16][CH:17]=1
Reactant: CC(=O)O
Reactant: N#Cc1cccc(C(=O)c2ccc(Cl)cc2)c1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)c1cccc(C(=O)c2ccc(Cl)cc2)c1
Temperature: 10 °C

Procedure:
46.5 g of 3-p-chlorobenzoyl benzonitrile were added to a mixture of 350 cc of water, 350 cc of glacial acetic acid and 350 cc of concentrated sulfuric acid and the resulting mixture was refluxed for 3 hours and 40 minutes. After cooling to 10° C., the mixture was slowly added to water and the precipitate formed was recovered by vacuum filtration, was washed and dried to obtain 48 g of 3-p-chlorobenzoyl benzoic acid melting at 228° C. A sample of the product after crystallization from acetone melted at 234° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][NH:13][CH2:14][CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)=[CH:8][CH:7]=1.Br[CH2:27][CH2:28][O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31].CCN(C(C)C)C(C)C>CS(C)=O>[CH3:1][O:2][C:3](=[O:25])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]([CH2:27][CH2:28][O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH2:14][CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)=[CH:8][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: COC(=O)/C=C/c1ccc(CNCCc2c[nH]c3ccccc23)cc1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)/C=C/c1ccc(CN(CCO[Si](C)(C)C(C)(C)C)CCc2c[nH]c3ccccc23)cc1
Yield: 70.5 %

Procedure:
A solution of 3-(4-{[2-(1H-indol-3-yl)-ethylamino]-methyl}-phenyl)-(2E)-2-propenoic acid methyl ester (12.6 g, 37.7 mmol), (2-bromoethoxy)-tert-butyldimethylsilane (12.8 g, 53.6 mmol), (i-Pr)2NEt, (7.42 g, 57.4 mmol) in DMSO (100 mL) is heated to 50° C. After 8 hours the mixture is partitioned with CH2Cl2/H2O. The organic layer is dried (Na2SO4) and evaporated. The residue is chromatographed on silica gel to produce 3-[4-({[2-(tert-butyldimethylsilanyloxy)-ethyl]-[2-(1H-indol-3-yl)-ethyl]-amino}-methyl)-phenyl]-(2E)-2-propenoic acid methyl ester (13.1 g). Following the procedure described for the preparation of the hydroxamate compound in Example P1, 3-[4-({[2-(tert-butyldimethylsilanyloxy)-ethyl]-[2-(1H-indol-3-yl)-ethyl]-amino}-methyl)-phenyl]-(2E)-2-propenoic acid methyl ester (5.4 g, 11 mmol) is converted to N-hydroxy-3-[4-({[2-(tert-butyldimethylsilanyloxy)-ethyl]-[2-(1H-indol-3-yl)-ethyl]-amino}-methyl)-phenyl]-(2E)-2-propenamide (5.1 g,) and used without further purification. The hydroxamic acid (5.0 g, 13.3 mmol) is then dissolved in 95% TFA/H2O (59 mL) and heated to 40–50° C. for 4 hours. The mixture is evaporated and the residue purified by reverse phase HPLC to produce N-Hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide as the trifluoroacetate salt (m/z 380 [MH+]).
Reaction SMILES: [N:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][C@H:5]1[NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[N+]=[N-].[H][H]>C(O)C.C(OCC)(=O)C.[Pd]>[C:19]([O:18][C:16]([NH:15][C@@H:5]1[CH2:6][C@@H:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:8][CH2:9][C@@H:4]1[NH2:1])=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: CCOC(=O)[C@H]1CC[C@H](N=[N+]=[N-])[C@H](NC(=O)OC(C)(C)C)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H]1CC[C@H](N)[C@H](NC(=O)OC(C)(C)C)C1
Yield: 114.5 %

Procedure:
Ethyl (1S,3R,4S)-4-azido-3-(tert-butoxycarbonylamino)cyclohexane-1-carboxylate (4.0 g) was dissolved in a mixed solvent of ethanol (150 ml) and ethyl acetate (150 ml), and 5% palladium on carbon (0.5 g) was added to stir the mixture at room temperature for 17 hours in a hydrogen atmosphere. After insoluble matter was removed by filtration, the solvent was distilled off under reduced pressure to obtain the title compound (4.2 g) as a pale yellow oil.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([C:7]1[CH:12]=[CH:11][C:10](B(O)O)=[CH:9][CH:8]=1)=[O:6])#[N:2].[Br:16][C:17]1[C:18](I)=[N:19][C:20]([I:23])=[N:21][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[Br:16][C:17]1[C:18]([C:10]2[CH:11]=[CH:12][C:7]([C:5]([NH:4][CH2:3][C:1]#[N:2])=[O:6])=[CH:8][CH:9]=2)=[N:19][C:20]([I:23])=[N:21][CH:22]=1
Reactant: Brc1cnc(I)nc1I
Reactant: N#CCNC(=O)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: N#CCNC(=O)c1ccc(-c2nc(I)ncc2Br)cc1
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 50.2 %

Procedure:
To a mixture of 4-(cyanomethylcarbamoyl)phenylboronic acid (see example 3) (185 mg, 0.9 mmol) and 5-bromo-2,4-diiodopyrimidine (410 mg,1.0 mmol) in 1,4-dioxane (10 mL), was added 2M aqueous potassium carbonate (100 μL). The resulting mixture was stirred under nitrogen for 5 minutes then tetrakis(triphenylphophine)palladium(0) (52 mg, 0.045 mmol) was added under a nitrogen atmosphere. The mixture was heated at 80° C. overnight. The cooled reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic extracts were washed with water then brine, dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product as a brown solid. The crude material was purified by flash chromatography, eluting with 50% ethyl acetate/petroleum spirit to give 4-(5-bromo-2-iodopyrimidin-4-yl)-N-(cyanomethyl)benzamide (200 mg, 35% over 2 steps). LC-ESI-MS (method B): rt 6.2 min.; m/z 443.0/445.0 [M+H]+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([CH2:15][CH:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:12]([OH:14])=O)=[CH:7][C:6]=1[CH3:22])(=[O:4])=[O:3].C(Cl)(=O)C(Cl)=O.[NH2:29][C:30]1[CH:34]=[CH:33][N:32]([CH2:35][C:36]([CH3:39])([OH:38])[CH3:37])[N:31]=1.N1C(C)=CC=CC=1C>C(Cl)Cl>[OH:38][C:36]([CH3:39])([CH3:37])[CH2:35][N:32]1[CH:33]=[CH:34][C:30]([NH:29][C:12](=[O:14])[C@@H:11]([C:8]2[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[C:6]([CH3:22])[CH:7]=2)[CH2:15][CH:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[N:31]1
Reactant: Cc1cc([C@@H](CC2CCOCC2)C(=O)O)ccc1S(C)(=O)=O
Reactant: CC(C)(O)Cn1ccc(N)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: Cc1cc([C@@H](CC2CCOCC2)C(=O)Nc2ccn(CC(C)(C)O)n2)ccc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.7 %

Procedure:
2(R)-(4-methanesulfonyl-3-methyl-phenyl)-3-(tetrahydro-pyran-4-yl)-propionic acid (75 mg, 0.23 mmol) was dissolved in methylene chloride (2 mL) and N,N-dimethylfomamide (two drops) at 25° C. under argon. To this solution was added dropwise a solution of oxalyl chloride in methylene chloride (2 M solution, 120 μL, 0.24 mmol) which produced gas evolution and it was then stirred at 25° C. for 30 minutes. After this time, the reaction was concentrated in vacuo and the residue was then taken up in methylene chloride (2 mL). This solution was then added dropwise to a flask containing a solution of 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in Example 80, 36 mg, 0.23 mmol), 2,6-lutidine (54 μL, 0.46 mmol), and methylene chloride (2 mL) which was cooled to 0° C. The reaction was allowed to warm to 25° C. and stirred for a period of 2 h. After this time, the reaction quenched with a small amount of methanol and then concentrated in vacuo. It was then dissolved in ethyl acetate (25 mL) and washed with a 1N hydrochloric acid solution (1×10 mL) and a saturated aqueous sodium chloride solution (1×10 mL). The organic layer was then dried over sodium sulfate and concentrated with silica gel (2 g) in vacuo and purified on Biotage Flash chromatography system (40S column, silica gel, 10% methanol/ethyl acetate) to afford N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2(R)-(4-methanesulfonyl-3-methyl-phenyl)-3-(tetrahydro-pyran-4-yl)-propionamide (70 mg, 66%) as a white foam: [α]30589=−6.9° (c=0.16, methanol); ES-HRMS m/e calcd for C23H33N3O5S (M+H)+ 464.2214, observed 464.2208; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.03, 1.04 (2×s, 6 H, 2×CH3), 1.07-1.43 (m, 3H, 3×CH of 2×CH2), 1.49-1.70 (m, 3H, 3×CH of 2×CH2), 1.98-2.12 (m, 1H, CH), 2.62 (s, 3H, ArCH3), 3.14-3.25 (m, 2H, OCH2), 3.17 (s, 3H, SO2CH3), 3.73-3.83 (m, 2H, OCH2), 3.84 (s, 2H, NCH2), 3.90-3.99 (m, 1H, ArCH), 4.64 (s, 1H, OH), 6.43 (d, J=2.3 Hz, 1H, Ar), 7.41-7.46 (m, 2H, Ar), 7.48 (d, J=2.3 Hz, 1H, Ar),), 7.83 (d, J=8.5 Hz, 1H, Ar), 10.72 (s, 1H, NH)
Reaction SMILES: B.[Na].O.[OH:4][C:5]([C:14]([F:17])([F:16])[F:15])([C:10]([F:13])([F:12])[F:11])[C:6](OC)=[O:7].Cl>C(OCC)C>[F:11][C:10]([F:12])([F:13])[C:5]([C:14]([F:15])([F:17])[F:16])([OH:4])[CH2:6][OH:7]
Reactant: COC(=O)C(O)(C(F)(F)F)C(F)(F)F
Agent: B
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CCOCC
Product: OCC(O)(C(F)(F)F)C(F)(F)F
Yield: 95.8 %

Procedure:
To a mixture of 25.0 g of sodium boron hydride, 500 g of water, and 500 g of diethyl ether, with stirring, 100 g of methyl 2-hydroxy-3,3,3-trifluoro-2-trifluoromethylpropionate was added dropwise. The mixture was stirred for 10 hours, after which hydrochloric acid was added to quench the reaction. An organic layer was separated from the reaction mixture, concentrated, and distilled, obtaining 83.9 g of 3,3,3-trifluoro-2-trifluoromethyl-1,2-propane diol (yield 96%).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:11][NH:12][CH3:13].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4][N:12]([CH3:13])[CH3:11]
Reactant: O=Cc1ccc(F)cc1Br
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CN(C)Cc1ccc(F)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.8 %

Procedure:
Combine 2-bromo-4-fluorobenzaldehyde (5 g, 24.63 mmol), dimethylamine (2 M, 49.26 mL, 98.52 mmol) and acetic acid (8.47 mL, 147.78 mmol) in DCM (50 mL), and stir for 30 min. To this mixture, add sodium triacetoxyborohydride (49.26 mmol, 10.44 g) and stir overnight at RT. Wash with saturated NaHCO3 solution (100 mL), dry with aqueous saturated sodium chloride, and then dry over sodium sulfate. Filter the organics and remove the solvent under reduced pressure to give the title compound as a brownish oil (4.56 g). GCMS m/z 232 [M]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][OH:17])=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[O:18]1[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][S:26](Cl)(=[O:28])=[O:27])[CH2:20][CH2:19]1.O>ClCCl>[O:18]1[CH2:19][CH2:20][N:21]([CH2:24][CH2:25][S:26]([O:17][CH2:16][CH2:15][O:14][C:11]2[CH:12]=[CH:13][N:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[N:10]=2)(=[O:27])=[O:28])[CH2:22][CH2:23]1
Reactant: O=S(=O)(Cl)CCN1CCOCC1
Reactant: OCCOc1ccn(-c2ccc(Cl)c(Cl)c2)n1
Solvent: ClCCl
Solvent: O
Product: O=S(=O)(CCN1CCOCC1)OCCOc1ccn(-c2ccc(Cl)c(Cl)c2)n1
Yield: 39.4 %

Procedure:
To a solution of 2-(1-(3,4-dichlorophenyl)-1H-pyrazol-3-yloxy)ethanol (154 mg, 0.53 mmol) and tryethylamine (0.22 ml, 1.58 mmol) in dichlorometane (9 ml) was added a solution of 2-morpholinoethanesulfonyl chloride (prepared from 0.69 mmol of 2-morpholinoethanesulfonic acid and 1.14 ml of oxalyl dichloride in dichlorometane at 0° C.) and the final mixture was stirred at room temperature overnight. Water was added, the organic phase separated and the aqueous phase extracted with more dichlorometane. The combined organic phases were washed with saturated aqueous solution of NaHCO3 and water, and after drying over sodium sulphate, filtered and evaporated to dryness yielding 222 mg of crude compound. After column chromatography purification (silica gel, eluent: petroleum ether/ethyl acetate 8:2), 94 mg of 2-(1-(3,4-dichlorophenyl)-1H-pyrazol-3-yloxy)ethyl 2-morpholinoethanesulfonate as a solid was obtained, with a m.p.=120-122° C. after crystallization in acetone-petroleum ether.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][CH2:13]Cl)[CH:10]([CH2:15]Cl)[CH2:9][N:8]=[C:7]([C:17]3[CH:21]=[CH:20][S:19][CH:18]=3)[C:6]=2[CH:22]=1.[OH-:23].[Na+].C(Cl)(Cl)Cl>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH2:12][CH2:13][O:23][CH2:15][CH:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:21]=[CH:20][S:19][CH:18]=3)[C:6]=2[CH:22]=1
Reactant: [OH-]
Reactant: ClCCN1c2ccc(Cl)cc2C(c2ccsc2)=NCC1CCl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: Clc1ccc2c(c1)C(c1ccsc1)=NCC1COCCN21

Procedure:
A solution of 11 g of 7-chloro-1-(β-chloroethyl)-2-chloromethyl-5-(3-thienyl)-2,3-dihydro-1H-1,4-benzodiazepine in 60 ml of dioxane and 160 ml of 4.5% strength sodium hydroxide solution is heated under reflux for 5 hours. After the solvent has been stripped off in vacuo, the reaction product is isolated from chloroform and is then chromatographed on aluminium oxide of activity level II, using methylene chloride. After the methylene chloride has been stripped off, 6.5 g of 1,2,4,4a-tetrahydro-9-chloro-7-(3-thienyl)-5H-[1,4]oxazino[4,3-a][1,4]benzodiazepine are obtained as an oil. This product is converted into its hydrochloride by reaction with alcoholic hydrogen chloride solution, and the product is crystallised as the hydrochloride.0.3H2O from isopropanol. Melting point: 207° to 212° C.
Reaction SMILES: C([O:8][C:9]1[CH:29]=[CH:28][C:12]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[C:11]([CH2:30][CH2:31][CH3:32])[CH:10]=1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[CH2:30]([C:11]1[CH:10]=[C:9]([OH:8])[CH:29]=[CH:28][C:12]=1[O:13][CH2:14][CH2:15][C:16]1[N:17]=[C:18]([C:22]2[CH:27]=[CH:26][C:25]([C:9]3[CH:29]=[CH:28][CH:12]=[CH:11][CH:10]=3)=[CH:24][CH:23]=2)[O:19][C:20]=1[CH3:21])[CH2:31][CH3:32]
Reactant: [H][H]
Reactant: CCCc1cc(OCc2ccccc2)ccc1OCCc1nc(-c2ccccc2)oc1C
Agent: [Pd]
Solvent: CCO
Product: CCCc1cc(O)ccc1OCCc1nc(-c2ccc(-c3ccccc3)cc2)oc1C

Procedure:
A solution of 4-[2-(4-benzyloxy-2-propylphenoxy)ethyl]-5-methyl-2-phenyloxazole (3.16 mmol) in ethanol (100 mL) was treated with 5% Pd/C (160 mg) and hydrogen (60 psi) at ambient temperature for 18 h. The mixture was filtered and concentrated in vacuo to give a tan solid.
Reaction SMILES: C(OC[C@@H](OC(C)(C)C)C1C(C2C=CC(Cl)=CC=2)=C2C(=CC=1C)N=C(OS(C(F)(F)F)(=O)=O)C=C2)(=[O:6])C(C)(C)C.[Cl:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:57]=[CH:56][C:55]3[C:50](=[CH:51][C:52]([CH3:73])=[C:53]([C@H:65]([O:68][C:69]([CH3:72])([CH3:71])[CH3:70])[CH2:66][OH:67])[C:54]=3[C:58]3[CH:63]=[CH:62][C:61]([Cl:64])=[CH:60][CH:59]=3)[N:49]=2)=[CH:44][CH:43]=1.C(O[C@@H](C1C(C2C=CC(Cl)=CC=2)=C2C(=CC=1C)N=C(CC)C=C2)CO)(C)(C)C>>[Cl:41][C:42]1[CH:43]=[CH:44][C:45]([C:48]2[CH:57]=[CH:56][C:55]3[C:50](=[CH:51][C:52]([CH3:73])=[C:53]([C@H:65]([O:68][C:69]([CH3:70])([CH3:72])[CH3:71])[C:66]([OH:6])=[O:67])[C:54]=3[C:58]3[CH:63]=[CH:62][C:61]([Cl:64])=[CH:60][CH:59]=3)[N:49]=2)=[CH:46][CH:47]=1
Reactant: Cc1cc2nc(OS(=O)(=O)C(F)(F)F)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Reactant: Cc1cc2nc(-c3ccc(Cl)cc3)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C
Agent: CCc1ccc2c(-c3ccc(Cl)cc3)c([C@@H](CO)OC(C)(C)C)c(C)cc2n1
Product: Cc1cc2nc(-c3ccc(Cl)cc3)ccc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
(S)-2-(2,5-Bis(4-chlorophenyl)-7-methylquinolin-6-yl)-2-tert-butoxyacetic acid was prepared following the procedure used to prepare compound (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-ethyl-7-methylquinolin-6-yl)acetic acid (compound of Example 26), except that (S)-2-(2,5-bis(4-chlorophenyl)-7-methylquinolin-6-yl)-2-tert-butoxyethanol was used instead (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-ethyl-7-methylquinolin-6-yl)ethanol. 1H-NMR 300 MHz, (CD3OD) δ 8.15-8.02 (m, 4H), 7.98 (d, 1H), 7.70-7.60 (m, 5H), 7.38 (d, 1H), 5.24 (s, 1H), 2.74 (s, 3H), 0.98 (s, 9H); LCMS-ESI+ (m/z): [M+H]+ calcd for C28H25Cl2NO3: 495.4. Found: 494.2, 496.2, 498.2.