Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][C:21](=O)N(C)C)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.Cl[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30](C)[N:29]=1>CCCCCC.CCOC(C)=O>[ClH:19].[Cl:19][C:16]1[CH:17]=[CH:18][C:11]2[CH2:10][CH2:9][NH:8][CH2:14][CH2:13][C:12]=2[C:15]=1[S:20][CH2:21][C:30]1[CH:31]=[CH:32][CH:33]=[C:28]([CH3:27])[N:29]=1
Reactant: Cc1cccc(CCl)n1
Reactant: CN(C)C(=O)Sc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1cccc(CSc2c(Cl)ccc3c2CCNCC3)n1
Product: Cl

Procedure:
Use a method similar to the Example 387, using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine and 2-chloromethyl-6-methylpyridine to give, after chromatography on silica gel eluting with hexane/EtOAc (4:1) and deprotection by the General Procedure 1-4, the title compound as a white solid. MS (ES+) m/z: 319 (M+H)+.
Reaction SMILES: [C:1]([OH:10])(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[NH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18].C(Cl)CCl>C(Cl)Cl>[OH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([NH:11][CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:10]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: O=C(O)c1ccccc1O
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NCCNC(=O)c1ccccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.2 %

Procedure:
Salicylic acid (4.3 g, 0.0312 mol) was taken up in 60 mL of CH2Cl2 along with tert-butyl 2-aminoethylcarbamate (5.0 g, 0.0312 mol) and EDC (6.6 g, 0.0343 mol). The resulting reaction mixture was stirred at room temperature for 8 h and then quenched with saturated aqueous NaHCO3. The organic layer was separated and washed with brine, dried (Na2SO4) and concentrated under reduced pressure. Purification by chromatography (1:1 pentane/EtOAc) afforded 5.7 g of tert-butyl 2-(2-hydroxybenzamido)ethylcarbamate (65%). tert-Butyl 2-(2-hydroxybenzamido)ethylcarbamate (650 mg, 2.31 mmol) was taken up in 4 mL of 4 N HCl in dioxane and allowed to stir at room temperature for 2 h. The reaction mixture was diluted with EtOAc and concentrated under reduced pressure to afford the HCl salt of N-(2-aminoethyl)-2-hydroxybenzamide. This material was taken up in DMF (15 mL) along with (R)-α-lipoic acid (TCI, 478 mg, 2.31 mmol) along with EDC (443 mg, 2.54 mmol) and DIEA (1.2 mL, 6.93 mmol). The resulting reaction mixture was stirred at room temperature for 4 h and then diluted with EtOAc (60 mL). The organic layer was washed with water (4×5 mL), brine, dried (Na2SO4) and concentrated under reduced pressure to afford (S)—N-(2-(5-(1,2-dithiolan-3-yl)pentanamido)ethyl)-2-hydroxybenzamide (420 mg, 49%). Mass calculated for C17H24N2O3S2: 368.12. found: [M+H]+=369.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[N:4]=[C:5]([S:32][CH3:33])[C:6]([C:20]1[CH:21]=[C:22]([O:30][CH3:31])[C:23]2OCOC[C:24]=2[CH:29]=1)=[N:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=[C:17]([CH3:19])[O:16][N:15]=2)=[CH:10][CH:9]=1.[CH3:35][O:36]C1C=C(C=C(OC)C=1)C=O>>[CH3:1][O:2][C:3](=[O:34])[N:4]=[C:5]([S:32][CH3:33])[C:6]([C:20]1[CH:29]=[C:24]([O:36][CH3:35])[CH:23]=[C:22]([O:30][CH3:31])[CH:21]=1)=[N:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=[C:17]([CH3:19])[O:16][N:15]=2)=[CH:10][CH:9]=1
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc2c(c(OC)c1)OCOC2
Reactant: COc1cc(C=O)cc(OC)c1
Product: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)cc(OC)c1

Procedure:
The same procedure was carried out as in Examples (21d) to (21h), except that 3,5-dimethoxybenzaldehyde was used instead of 8-methoxy-4H-benzo[1,3]dioxine-6-carboaldehyde in Example (21d), to give the first eluting enantiomer of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:17])=[CH:9][C:10]2[CH:15]=[CH:14][C:13](O)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.Cl[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N+:25]([O-:27])=[O:26].[C:28](=[O:31])([O-])[O-].[K+].[K+]>CN(C)C=O>[N+:25]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:17])=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([O:31][C:28]3[CH:22]=[CH:23][CH:24]=[CH:19][C:20]=3[N+:25]([O-:27])=[O:26])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1)([O-:27])=[O:26]
Reactant: O=[N+]([O-])c1ccccc1Cl
Reactant: O=C([O-])[O-]
Reactant: CC(=Cc1ccc(O)cc1)c1ccc(O)cc1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=Cc1ccc(Oc2ccccc2[N+](=O)[O-])cc1)c1ccc(Oc2ccccc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 9 h

Procedure:
4,4'-Dihydroxy-alpha-methylstilbene (22.6 grams, 0.20 hydroxyl equivalent) from Example 1-B, o-chloronitrobenzene (39.4 grams, 0.25 mole), -325 mesh anhydrous potassium carbonate (34.5 grams, 0.25 mole) and N,N-dimethylformamide (200 mililiters) are added to a reactor and stirred under a nitrogen atmosphere with heating to 130 deg. C. After 9 hours at the 130 deg. C. temperature, high pressure liquid chromatographic analysis demonstrates that complete conversion of the 4,4'-dihydroxy-alpha-methylstilbene to a single major product has occurred. At this time, the reaction slurry is cooled to room temperature (24 deg. C.), filtered, then rotary evaporated to a constant weight of 53.6 grams of reddish brown colored liquid product.
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:14][CH2:13][CH:12]([CH:15]2[CH2:19][C:18]3[CH:20]=[C:21]([C:24]4[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=4)[CH:22]=[CH:23][C:17]=3[O:16]2)[CH2:11][CH2:10]1)=O)(C)(C)C>O1CCOCC1.ClCCl>[CH3:33][S:30]([C:27]1[CH:26]=[CH:25][C:24]([C:21]2[CH:22]=[CH:23][C:17]3[O:16][CH:15]([CH:12]4[CH2:13][CH2:14][NH:9][CH2:10][CH2:11]4)[CH2:19][C:18]=3[CH:20]=2)=[CH:29][CH:28]=1)(=[O:31])=[O:32].[ClH:1]
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(-c4ccc(S(C)(=O)=O)cc4)ccc3O2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc(-c2ccc3c(c2)CC(C2CCNCC2)O3)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of HCl in dioxane (4 N, 5.0 mL) is added to 4-[5-(4-methanesulfonyl-phenyl)-2,3-dihydro-benzofuran-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (750 mg) in dichloromethane (1 mL) and the resulting mixture is stirred for 5 min at room temperature. The solvents are evaporated in vacuo to give the title compound as its hydrochloric acid salt. Mass spectrum (ESI+): m/z=358 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][NH2:21])=[CH:15][CH:14]=3)=[CH:11][C:10]([C:22]([F:25])([F:24])[F:23])=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][NH:21][S:34]([CH3:33])(=[O:36])=[O:35])=[CH:15][CH:14]=3)=[CH:11][C:10]([C:22]([F:23])([F:25])[F:24])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: NCCc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(Cl)cc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NCCc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(Cl)cc2)cc1

Procedure:
To a solution of 2-{4-[1-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}ethanamine obtained by Example 53 (400 mg) and triethylamine (0.46 ml) in dichloromethane (20 ml) was added dropwise methanesulfonyl chloride (0.25 ml) at room temperature.
Reaction SMILES: [CH2:1]([C:4]([CH2:10][CH2:11][CH3:12])([CH2:7][O:8][CH3:9])[CH2:5][OH:6])[CH2:2][CH3:3].[CH3:13][Si:14](Cl)([CH3:16])[CH3:15]>>[CH2:10]([C:4]([CH2:1][CH2:2][CH3:3])([CH2:5][O:6][Si:14]([CH3:16])([CH3:15])[CH3:13])[CH2:7][O:8][CH3:9])[CH2:11][CH3:12]
Reactant: CCCC(CO)(CCC)COC
Reactant: C[Si](C)(C)Cl
Product: CCCC(CCC)(COC)CO[Si](C)(C)C

Procedure:
According to the procedure as described in Example 1,2,2-di-n-propyl-1-methoxy-3-[(trimethylsilyl)oxy]propane was prepared from intermediate 2,2-di-n-propyl-3-methoxy-1-propanol and reagent trimethylsilyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([OH:13])=O)=[CH:7][N:6]=1)=[O:4].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C.[Cl:38][C:39]1[CH:47]=[C:46]2[C:42]([C:43]([CH2:55][C:56]3[CH:61]=[CH:60][CH:59]=[C:58]([Cl:62])[CH:57]=3)([CH:49]3[CH2:54][CH2:53][CH2:52][NH:51][CH2:50]3)[C:44](=[O:48])[NH:45]2)=[CH:41][CH:40]=1>C1(C)C=CC=CC=1.ClCCl>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([N:51]2[CH2:52][CH2:53][CH2:54][CH:49]([C:43]3([CH2:55][C:56]4[CH:61]=[CH:60][CH:59]=[C:58]([Cl:62])[CH:57]=4)[C:42]4[C:46](=[CH:47][C:39]([Cl:38])=[CH:40][CH:41]=4)[NH:45][C:44]3=[O:48])[CH2:50]2)=[O:13])=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(C(=O)O)cn1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCCNC1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C(=O)N2CCCC(C3(Cc4cccc(Cl)c4)C(=O)Nc4cc(Cl)ccc43)C2)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of pyridine-2,5-dicarboxylic acid-2-methyl ester (0.54 g, 3.0 mmol) (from Example 83 a supra) in toluene (15 mL) was added diphenylphosphoryl azide (0.958 g, 3.5 mmol) (Aldrich), followed by the addition of triethylamine (0.35 g, 3.6 mmol) (Aldrich). The mixture was stirred at room temperature for 0.5 hour and the mixture became clear. Then the mixture was heated at 80° C. for 2 hours. After cooling to room temperature, the crude (0.21 mL, 0.38 mmol) was added to a solution of rac-6-chloro-3-(3-chloro-benzyl)-3-piperidin-3-yl-1,3-dihydro-indol-2-one (120 mg, 0.32 mmol) (from Example 25a supra) in dichloromethane (3 mL), followed by the addition of triethylamine (0.11 mL, 0.80 mmol) The mixture was stirred at room temperature for 0.5 hour. The mixture was partitioned between dichlormethane and water. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed with water, brine, dried over MgSO4 and concentrated. The residue was purified by chromatography to give rac-5-{3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carbonyl}-pyridine-2-carboxylic acid methyl ester as a white solid. (Yield 65 mg, 36.5%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][C:5]2=O.[CH3:13][C:14]([S:17]([NH2:19])=[O:18])([CH3:16])[CH3:15].CCCCCCC>C1COCC1.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][C:5]2=[N:19][S:17]([C:14]([CH3:16])([CH3:15])[CH3:13])=[O:18]
Reactant: CC(C)(C)S(N)=O
Reactant: O=C1CCOc2ccc(Br)cc21
Agent: [Ti+4]
Agent: CC[O-]
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: CC(C)(C)S(=O)N=C1CCOc2ccc(Br)cc21
Temperature: 60 °C
Yield: 82.6 %

Procedure:
6-Bromochroman-4-one (5.0 g, 22 mmol) and 2-methylpropane-2-sulfinamide (2.6 g, 22 mmol) were dissolved in dry THF (80 mL). Titanium ethoxide (10 g, 44 mmol) was added. The resulting mixture was heated at 60° C. for 2 days. An additional portion of titanium ethoxide (1.0 g, 8.4 mmol) was added after 12 h. The mixture was mixed with heptane and evaporated onto silica gel. Flash chromatography on silica (0-50% EtOAc in heptane) gave the title compound (6.0 g, 83% yield). 1H NMR (500 MHz, CDCl3) δ ppm 1.34 (s, 9 H) 3.26-3.32 (m, 1 H) 3.47-3.54 (m, 1 H) 4.28-4.40 (m, 2 H) 6.83 (d, 1 H) 7.46 (dd, 1 H) 8.06 (d, 1 H); MS (ES+) m/z 330 [M+H]+.
Reaction SMILES: C[C:2]1(C)[O:9][CH2:8][CH2:7][C@H:6]2[N:3]1[C:4](=[O:13])[C@H:5]2[N:10]=[N+:11]=[N-:12].CC(C)=[O:17].OS(O)(=O)=O.O=[Cr](=O)=O.C(O)(C)C>CC(C)=O>[N:10]([C@H:5]1[C@H:6]([CH2:7][C:8]([O:9][CH3:2])=[O:17])[NH:3][C:4]1=[O:13])=[N+:11]=[N-:12]
Reactant: CC(C)=O
Reactant: CC1(C)OCC[C@@H]2[C@H](N=[N+]=[N-])C(=O)N21
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Product: COC(=O)C[C@@H]1NC(=O)[C@H]1N=[N+]=[N-]

Procedure:
In 30 ml of acetone is dissolved 330 mg of trans-2,2-dimethyl-7-azido-1-aza-3-oxabicyclo[4.2.0]octan-8-one and under ice-cooling and stirring, 3.3 ml (8N solution) of Jones reagent is added. The mixture is stirred for 2.5 hours, after which 5 ml of isopropyl alcohol is added and the mixture is further stirred for 10 minutes. The insolubles are filtered off with the aid of Celite and the filtrate is concentrated under reduced pressure. The residue is shaken with tetrahydrofuran and a small amount of saturated aqueous sodium chloride. The tetrahydrofuran layer is taken and extracted three times with tetrahydrofuran. The tetrahydrofuran layers are combined, dried over anhydrous sodium sulfate and, after additiion of a solution of diazomethane in ether, the mixture is allowed to stand. The solvent is then distilled off and the residue is shaken with water and ethyl acetate. The ethyl acetate layer is taken, washed with aqueous sodium hydrogen carbonate and water in this order and dried over anhydrous sodium sulfate. It is concentrated under reduced pressure and the residue is purified by silica gel column chromatography to give trans-3-azido-4-methoxycarbonylmethyl-2-oxoazetidine.
Reaction SMILES: CON(C)[C:4](=[O:12])[C:5]1[C:6](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH2:7].[C:14]1(Br)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1.[CH3:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].C([Li])CCC.Cl>C1COCC1>[C:14]1([C:27]2([C:4](=[O:12])[C:5]3[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=3[NH2:7])[CH:26]=[CH:25][CH:30]=[CH:29][CH2:28]2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: CCCCCC
Reactant: CON(C)C(=O)c1ccccc1N
Reactant: Brc1cccc2ccccc12
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Nc1ccccc1C(=O)C1(c2cccc3ccccc23)C=CC=CC1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 18 %

Procedure:
The reaction of the above-mentioned scheme 2 was performed specifically as follows. That is, first, anthranilic acid N-methoxy-N-methylamide (5-1) (2.00 g, 11.1 mmol) and 1-naphthyl bromide (5-2) (2.29 g, 11.1 mmol) were dissolved in 60 mL of dehydrated THF. Next, this solution was cooled to −78° C., and while this temperature was maintained, an n-butyllithium hexane solution (13.8 mL, 1.6 M, and 22.2 mmol) was dropped thereinto over 20 minutes with stirring. After dropping, 20 mL of 1N hydrochloric acid was added thereto and extraction was performed with 150 mL of ethyl acetate. This was washed with 100 mL of water twice and subsequently was washed with 50 mL of saturated saline. The organic solvent was removed therefrom and this was then purified by column chromatography using chloroform as a developing solvent. Thus 1′-naphthyl-2-aminobenzophenone (5-3) was obtained. The yield amount was 500 mg, and the yield was 18%. The instrumental analysis data of this 1′-naphthyl-2-aminobenzophenone (5-3) is indicated below.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=1)[C@@H:3]([CH:5]1[CH2:10][O:9][C@@H:8]([O:11][CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C@H:7]([CH3:17])[NH:6]1)[OH:4].[CH3:27][O:28][CH2:29][C:30]([Cl:32])=[O:31]>>[ClH:32].[F:26][C:21]1[CH:20]=[C:19]([CH:24]=[C:23]([F:25])[CH:22]=1)[CH2:18][C@H:2]([NH:1][C:30](=[O:31])[CH2:29][O:28][CH3:27])[C@@H:3]([C@H:5]1[CH2:10][O:9][C@@H:8]([O:11][CH2:12][C:13]([CH3:15])([CH3:16])[CH3:14])[C@H:7]([CH3:17])[NH:6]1)[OH:4]
Reactant: COCC(=O)Cl
Reactant: C[C@@H]1NC([C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)CO[C@H]1OCC(C)(C)C
Product: COCC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)[C@H]1CO[C@@H](OCC(C)(C)C)[C@H](C)N1
Product: Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 65.1 %

Procedure:
Dissolve (1S,2S)-2-amino-3-(3,5-difluorophenyl)-1-[(5S,6R)-6-(2,2-dimethylpropoxy)-5-methylmorpholin-3-yl]-propan-1-ol (31 mg, 0.083 mmol) in dry 1:1 dichloromethane:diethyl ether (1 mL) under nitrogen. Cool to 0° C. and add dropwise methoxyacetyl chloride (7.6 μL, 0.083 mmol). Stir for 1 hour, quench with methanol, concentrate and purify (reverse-phase HPLC, eluting with 10:90 to 50:50 acetonitrile:water with 8 mM hydrochloric acid), to give the title compound (26 mg, 65%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH3:24])[CH2:9][C:10]([N:12]2[C@@H:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:15][O:14][C:13]2=[O:23])=[O:11])=[CH:4][CH:3]=1.C[Si](C)(C)[N-][Si](C)(C)C.[K+].CC(C1C=C(C(C)C)C(S([N:50]=[N+:51]=[N-:52])(=O)=O)=C(C(C)C)C=1)C.C(O)(=O)C.C([O-])(=O)C.[K+]>C1COCC1>[N:50]([C@@H:9]([C@H:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[CH3:24])[C:10]([N:12]1[C@@H:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:15][O:14][C:13]1=[O:23])=[O:11])=[N+:51]=[N-:52]
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)N=[N+]=[N-])c(C(C)C)c1
Reactant: C[C@H](CC(=O)N1C(=O)OC[C@@H]1c1ccccc1)c1ccc(F)cc1
Agent: CC(=O)[O-]
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C[C@@H](c1ccc(F)cc1)[C@H](N=[N+]=[N-])C(=O)N1C(=O)OC[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred solution of the product from Step B (1.18 g, 3.61 mmol) in anhydrous THF (40 mL) was added potassium hexamethyldisilazide (8.7 mL, 0.5M in toluene, 4.35 mmol) at −78° C. The resultant mixture was stirred at −78° C. for 30 min. A precooled solution of trisyl azide (1.56 g, 5.04 mmol) in THF (30 mL) was added via cannula. After 1.5 min the reaction was quenched with glacial acetic acid (0.95 mL, 16.6 mmol) and potassium acetate (1.77 g, 18.1 mmol). The cooling bath was removed, and the reaction was stirred at room temperature for 12 h. The solution was partitioned between ethyl acetate and brine. The aqueous phase was extracted with three portions of ethyl acetate. The organic phases were combined, washed with saturated aqueous sodium bicarbonate solution, dried over sodium sulfate, and evaporated in vacuo. Purification by flash chromatography (silica gel, 80:20 hexanes/ethyl acetate) afforded the desired product.
Reaction SMILES: Br[CH:2]1[CH2:17][CH2:16][C:5]2=[C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[S:7][C:8]([S:9][CH3:10])=[C:4]2[C:3]1=O.[C:19]([NH2:27])(=[S:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(O)C>O>[CH3:10][S:9][C:8]1[S:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]2[C:4]=1[C:3]1[N:27]=[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[S:26][C:2]=1[CH2:17][CH2:16]2
Reactant: NC(=S)c1ccccc1
Reactant: CCOC(=O)c1sc(SC)c2c1CCC(Br)C2=O
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1sc(SC)c2c1CCc1sc(-c3ccccc3)nc1-2
Yield: 33.9 %

Procedure:
A mixture of ethyl 5-bromo-4,5,6,7-tetrahydro-3-methylthio-4-oxobenzo[c]thiophene-1-carboxylate (6.99 g), thiobenzamide (5.49 g) and ethanol (150 ml) was refluxed under heating for 3 hours, after which it was poured over water (500 ml) and extracted with ethyl acetate-tetrahydrofuran (3:1, v/v). The organic layer was washed with water and dried (MgSO4), after which the solvent was distilled off. The residue was subjected to silica gel column chromatography and eluted with chloroform-hexane (1:1, v/v) to yield ethyl 4,5-dihydro-8-methylthio-2-phenylthieno[3,4-e]benzothiazole-6-carboxylate (2.63 g, 33.9%), which was then recrystallized from ethyl acetate-hexane. Colorless needles. Melting point 153-154° C.
Reaction SMILES: Cl[C:2](Cl)(Cl)[C@H:3]1[O:8][C:7](=[O:9])[C@H:6]([CH3:10])[C@@H:5]([CH3:11])[O:4]1.S(=O)(=O)(O)O.[CH3:19]C(O)C>O>[CH3:10][C@H:6]([C@H:5]([OH:4])[CH3:11])[C:7]([O:8][CH:3]([CH3:19])[CH3:2])=[O:9]
Reactant: C[C@H]1O[C@@H](C(Cl)(Cl)Cl)OC(=O)[C@@H]1C
Reactant: CC(C)O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(C)OC(=O)[C@H](C)[C@@H](C)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 1.0 g of (2R, 5R, 6R)-2-trichloromethyl-5,6-dimethyl-1,3-dioxan-4-one obtained by procedures similar to (1)-(4) of Example 1 were added 0.1 ml of concentrated sulfuric acid and 10 ml of 2-propanol and stirred at room temperature for one hour, and 20 ml of water was added to effect ether extraction. After drying the ether phase over anhydrous sodium sulfate, the ether was distilled off and the residue was subjected to distillation to give 0.4 g of isopropyl (2R, 3R)-2-methyl-3-hydroxybutanoate. The NMR chart is shown in FIG. 6. ##STR44##
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[CH2:5][N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]#[CH:19])=[CH:13][CH:14]=2)[C:9]([C:20]2[CH:25]=[CH:24][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=2)=[N:8][C:7]1=[O:29].[Cl:33][CH2:34][C:35](Cl)=[O:36].C(N(CC)CC)C.O.C(Cl)Cl>C(Cl)Cl>[Cl:33][CH2:34][C:35]([NH:1][C:2]1[CH:32]=[CH:31][CH:30]=[C:4]([CH2:5][N:6]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]#[CH:19])=[CH:13][CH:14]=3)[C:9]([C:20]3[CH:25]=[CH:24][C:23]([CH:26]([CH3:27])[CH3:28])=[CH:22][CH:21]=3)=[N:8][C:7]2=[O:29])[CH:3]=1)=[O:36]
Reactant: O=C(Cl)CCl
Reactant: C#CCOc1ccc2c(c1)c(-c1ccc(C(C)C)cc1)nc(=O)n2Cc1cccc(N)c1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: C#CCOc1ccc2c(c1)c(-c1ccc(C(C)C)cc1)nc(=O)n2Cc1cccc(NC(=O)CCl)c1
Yield: 95.7 %

Procedure:
A solution of 200 mg (0.47 mmol) 1-(3-amino-benzyl)-4-(4-isopropyl-phenyl)-6-propargyloxy-1H-quinazolin-2-one in 3 ml CH2Cl2 is treated at 0° C. with 41 μl (0.52 mmol; 1.1 eq.) chloroacetyl chloride and 79 μl (0.57 mmol; 1.2 eq.) triethylamine. The mixture is allowed to come to rt. Extractive work-up with water/CH2Cl2 yields 225 mg (95%) of a yellow solid. m.p. 170-172° C.
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:16]3[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=3)=[N:9][C:10]3[N:11]([N:13]=[CH:14][CH:15]=3)[CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH:25]1[CH2:30][CH2:29][CH:28]([C:31]2[NH:35][C:34]3[CH:36]=[C:37]([C:40]([F:43])([F:42])[F:41])[CH:38]=[CH:39][C:33]=3[N:32]=2)[CH2:27][CH2:26]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]1([C:7]2[C:8]([C:16]3[CH:23]=[CH:22][C:19]([CH2:20][N:25]4[CH2:30][CH2:29][CH:28]([C:31]5[NH:35][C:34]6[CH:36]=[C:37]([C:40]([F:43])([F:42])[F:41])[CH:38]=[CH:39][C:33]=6[N:32]=5)[CH2:27][CH2:26]4)=[CH:18][CH:17]=3)=[N:9][C:10]3[N:11]([N:13]=[CH:14][CH:15]=3)[CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: FC(F)(F)c1ccc2nc(C3CCNCC3)[nH]c2c1
Reactant: O=Cc1ccc(-c2nc3ccnn3cc2-c2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Product: FC(F)(F)c1ccc2nc(C3CCN(Cc4ccc(-c5nc6ccnn6cc5-c5ccccc5)cc4)CC3)[nH]c2c1
Reaction time: 8 h
Yield: 44.8 %

Procedure:
250 mg (0.84 mmol) 4-(6-phenylpyrazolo[1,5-a]pyrimidin-5-yl)benzaldehyde and 308 mg (1 mmol) 2-piperidine-4-yl-6-trifluoromethyl-1H-benzimidazole hydrochloride salt were treated as previously described. Additional NaBH(OAc)3 has been added after one, two and three hours (two equivalents each). After a further hour stirring at room temperature additional 31 mg 2-piperidine-4-yl-6-trifluoromethyl-1H-benzimidazole hydrochloride salt and two equivalents NaBH(OAc)3 were added. After stirring overnight and two further additions of NaBH(OAc)3 the solvents were evaporated. Workup and purification yields 208 mg of the desired compound.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([CH2:10][CH2:11][O:12][CH2:13][CH2:14][N:15]([CH:18]([CH3:21])[CH2:19][OH:20])[CH:16]=O)[CH:8]=[CH:9][C:2]1=2.Cl.O.[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([CH2:10][CH2:11][O:12][CH2:13][CH2:14][N:15]([CH3:16])[CH:18]([CH3:21])[CH2:19][OH:20])[CH:8]=[CH:9][C:2]1=2
Reactant: CC(CO)N(C=O)CCOCCc1ccc2sccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(CO)N(C)CCOCCc1ccc2sccc2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 48.7 %

Procedure:
In 4.3 mL of tetrahydrofuran is dissolved 0.43 g of N-[2-(2-benzo[b]thiophen-5-ylethoxy)ethyl]-N-(2-hydroxy-1-methylethyl)-formamide. To the solution thus obtained is dropwise added at an ice-cooled temperature 5.60 mL of 1 mol/L solution of borane-tetrahydrofuran complex in tetrahydrofuran. The resulting mixture is stirred at ambient temperature for 1.5 hours. The reaction mixture is acidified with 1.9 mL of 6 mol/L hydrochloric acid and heated under reflux for one hour. After cooling the reaction mixture to ambient temperature, water and ethyl acetate are added, pH is adjusted to 9.5 with 2 mol/L aqueous solution of sodium hydroxide, and the organic layer is separated. The organic layer is washed with saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure, and the oily product thus obtained is purified by column chromatography (eluent: chloroform:methanol=30:1) to obtain 0.20 g of 2-[[2-(2-benzo[b]thiophen-5-ylethoxy)ethyl](methyl)amino]-1-propanol as a light yellow-colored oily product.