Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[S:16]([CH3:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:19]([N-]C(C)C)(C)C.[Li+].CI.CO>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[S:16]([CH2:18][CH3:19])=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)c1cc(O)ccc1OCc1ccccc1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Solvent: CO
Product: CCS(=O)c1cc(O)ccc1OCc1ccccc1
Reaction time: 0.25 h

Procedure:
A solution of 0.4 g of 4-benzyloxy-3-methylsulfinylphenol pmb (1.05 mmol) in 40 ml of tetrahydrofuran is cooled to −50° C. and 0.784 ml of a dimolar solution of lithium diisopropylamide (1.57 mmol) in tetrahydrofuran is then added. The reaction mixture is stirred for 15 minutes and 0.13 ml of methyl iodide (1.1 mmol) is added. After stirring for 15 minutes, methanol is added and the solvents are evaporated off under reduced pressure. The 4-benzyloxy-3-ethylsulfinylphenol pmb is obtained in the form of a white solid (0.3 g, 72%) after purification on silica gel (40 g SiO2, eluent: 4/1 heptane/ethyl acetate)
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]1([C:12]2[C:18]3[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:17]=3[N:16]3[C:24]([C:27]([NH2:29])=O)=[N:25][N:26]=[C:15]3[CH2:14][N:13]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(Cl)CCl>CN(C)C=O>[C:6]1([C:12]2[C:18]3[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:17]=3[N:16]3[C:24]([C:27]#[N:29])=[N:25][N:26]=[C:15]3[CH2:14][N:13]=2)[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: NC(=O)c1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2

Procedure:
4 ml of phosphorous oxychloride is added to a solution of 1.69 g (0.005 mole) of 6-phenyl-8-chloro-4H-s-triazolo[4,3-a] [1,4]benzodiazepine-1-carboxamide in 5 ml of dimethylformamide, and stirring maintained for 10 minutes at 80°. The reaction mixture is then poured on ice and extraced with ethylene chloride. The extract is washed with water and saturated sodium chloride solution, dried over magnesium sulphate and concentrated by evaporation. The residue is chromatographed on silica gel with the use of benzene and benzene/ethyl acetate mixtures as eluant. The fractions containing the desired nitrile [Rf = 0.5 in the eluant system benzene/chloroform/ethyl acetate (4:4:2)] are combined and concentrated by evaporation. The residue is crystallised from ethyl acetate/petroleum ether to obtain 6-phenyl-8-chloro-4H-s-triazolo [4,3-a][1,4]benzodiazepine-1-carbonitrile, M.P. 191°-192°.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9]([C:11]1([C:16](OC)=[O:17])[CH2:15][CH:14]=[CH:13][CH2:12]1)=O.O.[OH-].[Na+]>O1CCCC1.C1(C)C=CC=CC=1>[OH:8][CH2:9][C:11]1([CH2:16][OH:17])[CH2:15][CH:14]=[CH:13][CH2:12]1
Reactant: COC(=O)C1(C(=O)OC)CC=CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: OCC1(CO)CC=CC1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
The desired diol 2 was prepared via LAH reduction of the corresponding diester 1. To a flame dried round-bottomed flask was placed lithium aluminum hydride (LAH, Aldrich 95%, 6.99 g, 175 mmol) and anhydrous tetrahydrofuran (THF, 235 mL). The resulting suspension was cooled to 0° C. and then a solution of the dimethyl diester 1 in 58 mL of anhydrous THF was added dropwise via an additional funnel. The resulting mixture was allowed to stir at ° C. for 4 hours while monitored by TLC. The reaction mixture was then carefully quenced by sequential addition of 6 mL of water, 6 mL of 3 N aqueous solution of NaOH and 17.5 mL of water. The resulting mixture was allowed to slowly come to room temperature and then filtered through a bed of Celite. The resultant solid cake was washed repeatedly with refluxing THF (total of 250 mL). The filtrate was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford a light yellow oil which was dissolved in 150 mL of refluxing toluene and the water was azeotropically removed. Removal of the remaining toluene gave an off-white solid, which was recrystallized from refluxing toluene. The desired diol 2 was obtained as white needles in 86.2% yield. Mp (DSC) 81.21° C., 1H-NMR (CDCl3, 300 MHz) δ 5.59 (s, 2H), 3.73 (s, 2H), 3.63 (s, 4H), 2.16 (S, 4H); 13C-NMR (CDCl3, 300 MHz) δ 128.69, 69.19, 47.53, 38.61; FT-IR (CH2Cl2) (cm−1) 3323, 3055, 2918, 2846, 1619, 1442, 1419, 1357, 1266 1114, 1093, 1025, 955, 909, 896.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([C:13](=[O:16])[CH2:14][CH3:15])[C:9](=[O:12])[CH2:10][CH3:11].[OH:17][C:18]1[CH:28]=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[C:22]([C:21]1[CH:20]=[CH:19][C:18]([O:17][CH2:2][CH2:3][CH2:4][CH2:5][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([C:13](=[O:16])[CH2:14][CH3:15])[C:9](=[O:12])[CH2:10][CH3:11])=[CH:28][CH:27]=1)([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: CCC(=O)C(CCCCCCBr)C(=O)CC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1ccc(OCCCCCCCCCCC(C(=O)CC)C(=O)CC)cc1

Procedure:
A mixture of 26.3 g. (0.0758 mole) of 4-(6-bromohexyl)-3,5-heptanedione, 13.1 g. (0.0787 mole) of ethyl p-hydroxybenzoate, 31.5 g. (0.228 mole) of powdered potassium carbonate, 4 g. of potassium iodide and 500 ml. of acetone was heated at reflux for 36 hours. The reaction mixture was concentrated in vacuo and partitioned between water and methylene dichloride. The organic layer was washed successively with sodium hydroxide solution, water, hydrochloric acid, water and sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solution was concentrated and the residue crystallized and recrystallized from n-pentane to give 4-[10-(4-carbethoxyphenoxy)decyl]-3,5-heptanedione, m.p. 45°-46° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12](F)[N:11]=1.[H-].[Na+].O>CN(C=O)C>[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:8][CH2:7][CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[N:11]=1
Reactant: OCC1CCOCC1
Reactant: Fc1cccc(F)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1cccc(OCC2CCOCC2)n1
Temperature: 80 °C
Reaction time: 8 h
Yield: 74.8 %

Procedure:
To a solution of tetrahydro-2H-pyran-4-yl methanol (1.00 g) and 2,6-difluoropyridine (1.19 g) in DMF (10 mL) was added 60% sodium hydride (410 mg), and the mixture was stirred at 80° C. for 8 hours. Water (50 mL) was added dropwise to the reaction mixture, followed by extraction with ethyl acetate (100 mL). The organic layer was washed sequentially with water and saturated brine and dried, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=80/20) to obtain 2-fluoro-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridine (1.36 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)[CH:7]=[CH:8][C:9]=1[S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:12])=[O:11])([O-])=O.O.NN>CCO.C1COCC1.[Ni]>[NH2:1][C:4]1[CH:5]=[C:6]([N:19]2[CH2:20][CH2:21][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:23][CH2:24]2)[CH:7]=[CH:8][C:9]=1[S:10]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:11])=[O:12]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(S(=O)(=O)c3ccccc3)c([N+](=O)[O-])c2)CC1
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(S(=O)(=O)c3ccccc3)c(N)c2)CC1
Reaction time: 2 h
Yield: 101.1 %

Procedure:
To a solution of tert-butyl 4-[3-nitro-4-(phenylsulfonyl)phenyl]-1-piperazinecarboxylate (0.85 g, 1.8 mmol) in 20 mL of a 4:1 EtOH:THF solvent system is added Raney nickel (130 mg suspension in EtOH) followed by hydrazine monohydrate (0.44 mL, 9.1 mmol). The mixture is stired vigorously for 2 h and then filtered through celite that is pretreated with water. The filtrate is concentrated, and the residue crystallized from MeOH/EtOAc/hexane to give 0.76 g (99%) of the aniline as a white solid, mp 135-137° C.
Reaction SMILES: [N:1]1([C:7]2[C:12]([C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=3)=[N:11][CH:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:21][N:22]1[C:26]([CH3:27])=[C:25]([CH:28]=O)[C:24]([CH3:30])=[N:23]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+].[OH-].[Na+]>O1CCCC1>[CH3:21][N:22]1[C:26]([CH3:27])=[C:25]([CH2:28][N:4]2[CH2:5][CH2:6][N:1]([C:7]3[C:12]([C:13]4[CH:14]=[CH:15][C:16]([C:17]#[N:18])=[CH:19][CH:20]=4)=[N:11][CH:10]=[CH:9][N:8]=3)[CH2:2][CH2:3]2)[C:24]([CH3:30])=[N:23]1
Reactant: Cc1nn(C)c(C)c1C=O
Reactant: N#Cc1ccc(-c2nccnc2N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nn(C)c(C)c1CN1CCN(c2nccnc2-c2ccc(C#N)cc2)CC1
Yield: 58.7 %

Procedure:
Suspend 4-(3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3′-yl)-benzonitrile (0.179 g, 0.675 mmol) in tetrahydrofuran (4 mL). Add 1,3,5-trimethyl-1H-pyrazole-4-carbaldehyde (0.098 g, 0.71 mmol) in tetrahydrofuran (490 μL), then sodium triacetoxyborohydride (0.15 g, 0.071 mmol) and stir under nitrogen at room temperature for 3 hr. Add saturated aqueous sodium hydrogen carbonate (10 mL) followed by 2 N sodium hydroxide (1 mL) to the mixture and extract with DCM (3×20 mL). Pass the combined DCM extracts through an IST Phase Separator Frit®, concentrate, and purify (silica gel chromatography, eluting with 0:100 to 12:88 methanol:DCM), to give the title compound (153.5 mg, 59%). MS (ES): m/z=388 [M+H]+.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=O)([CH3:3])[CH3:2].[C:17]([C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24](=[O:29])[CH2:23]2)(=[O:19])[CH3:18]>>[C:17]([C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24](=[O:29])[C:23]2=[CH:7][C:6]1[CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:11]([O:12][CH3:13])=[C:10]([CH:14]([CH3:16])[CH3:15])[CH:9]=1)(=[O:19])[CH3:18]
Reactant: COc1c(C(C)C)cc(C=O)cc1C(C)C
Reactant: CC(=O)c1ccc2c(c1)CC(=O)N2
Product: COc1c(C(C)C)cc(C=C2C(=O)Nc3ccc(C(C)=O)cc32)cc1C(C)C

Procedure:
3,5-Diisopropyl-4-methoxybenzaldehyde was condensed with 5-acetyl-2-oxindole to give 0.3 g of 5-Acetyl-3-(3,5-diisopropyl-4-methoxybenzylidene)-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: Cl.[NH2:2][C:3]1([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.C(N(CC)CC)C.Br[CH2:22][CH2:23][O:24][CH2:25][CH2:26]Br>CN(C)C=O.C(OCC)(=O)C>[O:24]1[CH2:25][CH2:26][N:2]([C:3]2([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2)[CH2:22][CH2:23]1
Reactant: CCOC(=O)C1(N)CCCCC1
Reactant: BrCCOCCBr
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(N2CCOCC2)CCCCC1

Procedure:
Ethyl 1-aminocyclohexancarboxylate hydrogen chloride (5.800 g), triethylamine (13.62 mL) and 1-bromo-2-(2-bromoethoxy)ethane (4.21 mL) were stirred together in N,N-dimethylformamide (50 mL) at 95° C. overnight. The reaction mixture was diluted with ethyl acetate (150 mL), washed with water (100 mL) and brine (100 mL), dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography eluting with a gradient of 5% to 25% ethyl acetate/hexanes provided the title compound.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([C:18]4[CH:19]=[CH:20][C:21]([CH2:25][OH:26])=[N:22][C:23]=4[F:24])=[C:13]([C:14]([F:17])([F:16])[F:15])[C:8]=3[N:7]=[N:6]2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>ClCCl.C(OCC)(=O)C>[CH3:34][S:35]([O:26][CH2:25][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[CH:11]=[CH:10][C:9]3[N:5]([CH2:4][CH:1]4[CH2:3][CH2:2]4)[N:6]=[N:7][C:8]=3[C:13]=2[C:14]([F:15])([F:17])[F:16])=[C:23]([F:24])[N:22]=1)(=[O:37])=[O:36]
Reactant: OCc1ccc(-c2ccc3c(nnn3CC3CC3)c2C(F)(F)F)c(F)n1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CS(=O)(=O)OCc1ccc(-c2ccc3c(nnn3CC3CC3)c2C(F)(F)F)c(F)n1
Temperature: 0 °C

Procedure:
{5-[1-(Cyclopropylmethyl)-4-(trifluoromethyl)-1H-benzotriazol-5-yl]-6-fluoropyridin-2-yl}methanol (20 mg, 0.055 mmol) was dissolved in dichloromethane (0.36 mL), cooled to 0° C. and treated with triethylamine (0.023 mL, 0.16 mmol) followed by methanesulfonyl chloride (4.7 uL, 0.060 mmol). The mixture was warmed to room temperature and stirred until complete, at which time the mixture was diluted with ethyl acetate and washed with sodium bicarbonate (2×5 mL, aqueous saturated). The organic layer was dried with sodium sulfate, filtered and concentrated in vacuo, providing the titled compound.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[I-].[CH3:16][O:17][C:18]([CH2:20][CH2:21][CH2:22][Zn+])=[O:19]>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:8]([O:7][C:5]([C:4]1[CH:3]=[C:2]([CH2:22][CH2:21][CH2:20][C:18]([O:17][CH3:16])=[O:19])[CH:14]=[CH:13][CH:12]=1)=[O:6])([CH3:11])([CH3:10])[CH3:9]
Reactant: COC(=O)CCC[Zn+]
Reactant: CC(C)(C)OC(=O)c1cccc(I)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [I-]
Solvent: C1CCOC1
Product: COC(=O)CCCc1cccc(C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 39.9 %

Procedure:
A mixture of tert-butyl 3-iodobenzoate (2 g, 6.58 mmol) and tetrakis(triphenylphosphine)palladium(0) (250 mg, 0.329 mmol) in THF (10 ml) was treated with a freshly prepared 3-methoxycarbonylpropylzinc iodide (0.25 M in THF, 27 ml, 6.58 mmol). The mixture was stirred at room temperature for 3 hours, quenched with saturated aqueous ammonium chloride (5 ml) and extracted with diethyl ether. The organic phase was washed with saturated aqueous ammonium chloride, brine, dried over sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel (hexane:ethyl acetate=9:1) to give the title material (0.73 g, 40%) as a colorless oil.
Reaction SMILES: [Cl:1]Cl.[C:3]1(=[O:13])[NH:7][C:6](=[O:8])[C:5]2=[CH:9][CH:10]=[CH:11][CH:12]=[C:4]12.[K]>C(Cl)(Cl)(Cl)Cl>[Cl:1][N:7]1[C:3](=[O:13])[C:4]2=[CH:12][CH:11]=[CH:10][CH:9]=[C:5]2[C:6]1=[O:8]
Reactant: ClCl
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1c2ccccc2C(=O)N1Cl
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 94 %

Procedure:
To 100 ml. of carbon tetrachloride saturated with chlorine at 0° C. to 5° C. were added 5 grams (27 mmoles) of potassium phthalimide. The resulting yellow-green suspension was allowed to warm to room temperature and then was stirred for 60-90 minutes. The solvent then was removed in vacuo, and about 100 ml. of water were added to the resulting white solid. The mixture was filtered, and the collected solid was washed with water and vacuum dried to obtain 4.6 grams (94% yield) of N-chlorophthalimide.
Reaction SMILES: ClC1C(=O)C(C#N)=C(C#N)C(=[O:9])C=1Cl.[F:15][C:16]1[C:24]2[N:23]([CH3:25])[C:22]3[CH2:26][CH2:27][N:28]([CH2:30][C:31]4[N:32]=[CH:33][NH:34][C:35]=4[CH3:36])[CH2:29][C:21]=3[C:20]=2[CH:19]=[CH:18][CH:17]=1.O>C1COCC1>[F:15][C:16]1[C:24]2[N:23]([CH3:25])[C:22]3[CH2:26][CH2:27][N:28]([CH2:30][C:31]4[N:32]=[CH:33][NH:34][C:35]=4[CH3:36])[C:29](=[O:9])[C:21]=3[C:20]=2[CH:19]=[CH:18][CH:17]=1
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Reactant: Cc1[nH]cnc1CN1CCc2c(c3cccc(F)c3n2C)C1
Solvent: C1CCOC1
Solvent: O
Product: Cc1[nH]cnc1CN1CCc2c(c3cccc(F)c3n2C)C1=O
Reaction time: 4 h
Yield: 20.5 %

Procedure:
A solution of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (133 mg) in THF (4 ml) was added dropwise to a stirred solution of 6-fluoro-2,3,4,5-tetrahydro-5-methyl-2-[(5-methyl-1H-imidazol-4-yl)methyl]-1Hpyrido[4,3-b]indole (70 mg) in THF (12 ml) at -10° under nitrogen, and stirring was continued for 4 h. Water (20 ml) was then added, and the resulting solution was left to stand overnight. Excess THF was removed in vacuo, and the resultant aqueous solution was extracted with ethyl acetate (3×50 ml). The combined, dried organic extracts were adsorbed onto silica and purified by FCC eluting with System A (100:10:1) to give the title compound (15 mg), m.p. 231.5°-233°.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([O:30][CH2:31][CH2:32][NH2:33])[N:18]=[C:17]([S:34][CH3:35])[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:36]1([CH3:46])[CH:41]=[CH:40][C:39]([S:42](Cl)(=[O:44])=[O:43])=[CH:38][CH:37]=1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([O:30][CH2:31][CH2:32][NH:33][S:42]([C:39]3[CH:40]=[CH:41][C:36]([CH3:46])=[CH:37][CH:38]=3)(=[O:44])=[O:43])[N:18]=[C:17]([S:34][CH3:35])[N:16]=2)(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(SC)nc1OCCN
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(SC)nc1OCCNS(=O)(=O)c1ccc(C)cc1
Yield: 34.7 %

Procedure:
According to Example 36f) 2 g of 4-tert.-butyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-methylsulfanyl-pyrimidin-4-yl]-benzenesulfonamide was reacted with 1.19 g p-toluenesulfonylchloride to give 0.9 g 4-tert.-butyl-N-[6-(2-p-toluenesulfonylamino-ethoxy)-5-(o-methoxyphenoxy)-2-methylsulfanyl-pyrimidin-4-yl]-benzenesulfonamide. LC-MS: tR=6.24 min, [M+1]+=673.34.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([CH:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=3)[CH2:14][CH2:13][NH:12]2)[CH2:10][CH2:9]1.C=O.[C:25]([BH3-])#N.[Na+].[OH-].[Na+]>C(O)(=O)C.C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([CH:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=3)[CH2:14][CH2:13][N:12]2[CH3:25])[CH2:9][CH2:10]1
Reactant: [BH3-]C#N
Reactant: COc1ccc2c(c1)C(C1(c3ccccc3Cl)CC1)NCC2
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CC#N
Product: COc1ccc2c(c1)C(C1(c3ccccc3Cl)CC1)N(C)CC2
Reaction time: 0.25 h

Procedure:
A mixture of 1-[1-(2-chlorophenyl)cyclopropyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline (2.5 g, prepared as described in Example RC10), 37-40% aqueous formaldehyde solution (2.9 ml), sodium cyanoborohydride (0.75 g) and acetonitrile (100 ml) was stirred for 15 minutes. Glacial acetic acid was added to neutralise the solution and stirring was continued for a further 45 minutes. The mixture was basified with aqueous sodium hydroxide solution, then extracted with ethyl acetate. The extracts yielded 1-[1-(2-chlorophenyl)cyclopropyl]-7-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:5]([NH2:7])=[O:6])[CH3:4].C(N(CC)CC)C.[F:15][C:16]1[CH:31]=[CH:30][CH:29]=[CH:28][C:17]=1[CH2:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1.FC1C=CC=CC=1CC1C=C(C=CC=1OCC1C=CC=CC=1F)C=O.[BH4-].[Na+]>O.CO>[F:15][C:16]1[CH:31]=[CH:30][CH:29]=[CH:28][C:17]=1[CH2:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH:2][C@H:3]([CH3:4])[C:5]([NH2:7])=[O:6])=[CH:22][CH:21]=1
Reactant: O=Cc1ccc(OCc2ccccc2F)cc1
Reactant: C[C@@H](N)C(N)=O
Agent: Cl
Agent: O=Cc1ccc(OCc2ccccc2F)c(Cc2ccccc2F)c1
Agent: [BH4-]
Solvent: CO
Solvent: O
Solvent: CCN(CC)CC
Product: C[C@@H](NCc1ccc(OCc2ccccc2F)cc1)C(N)=O
Temperature: 25 °C
Yield: 30.3 %

Procedure:
In a 50 L glass reactor, dry methanol 21.43 L, containing 0.01% water, D-alaninamide hydrochloride (589.9 g; 4.72 mol), triethylamine (477.8 g; 4.72 mol) 4-(2-fluorobenzyloxy)benzaldehyde (1000 g, 4.33 mol) prepared as described in Example 23.1a) with GC purity 93.20 (area %, see Example 24A) and a content of 3-(2-fluorobenzyl)-4-(2-fluorobenzyloxy)benzaldehyde of 0.43% by weight determined by GC (see Example 24B), and 3A° molecular sieves (430.62 g) are loaded under stirring and under nitrogen at room temperature. The mixture is heated up to 40° C. and stirred at this temperature for 4 hours. The reaction temperature is then lowered to 10° C. and sodium borohydride (82.58 g, 2.16 mol) is added portion wise in 30 min. The reaction mixture is warmed up to room temperature while stirring for additional 6 hours at 20±2° C. The reaction mixture is filtered and evaporated to dryness under vacuum. The residue is taken up with water (16 L) and toluene (14 L) at 60° C., the organic phase is separated and added with water (16 L). The two phases mixture is warmed up to 60° C.±2 under stirring. The organic phase is separated and added with water (16 L). The two phases mixture is warmed up to 60° C.±2 under stirring. The organic phase is dried by azeotropic distillation at about 60° C. under vacuum. The aqueous phases are combined together (solution A, about 50 L). The toluenic solution is gradually cooled to 10° C. The mixture is kept under stirring and under nitrogen at 10° C.±2 for 4 hours. The mixture is filtered and the cake is washed with cold (10° C.) toluene (2 L), dried under vacuum at room temperature to provide 393.3 g (1.31 mol; 30.3% yield) of (R)-2-[4-(2-fluorobenzyloxy)benzylamino]propanamide (I′b) as white solid.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:8][C@:7]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:9]([CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C@H:3]1[CH2:4][CH2:5][C@H:6]2[O:23][CH2:24][C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:26]=1.[N-]=[N+]=[N-].[Na+].[C:43](O)(=[O:45])[CH3:44]>C(OC(OCC)OCC)C>[C:43]([NH:1][C@@H:2]1[CH2:8][C@:7]2([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:9]([CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C@H:3]1[CH2:4][CH2:5][C@H:6]2[O:23][CH2:24][C:25]1[CH:26]=[C:27]([C:35]([F:38])([F:36])[F:37])[CH:28]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:30]=1)(=[O:45])[CH3:44]
Reactant: N[C@@H]1C[C@@]2(c3ccccc3)[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1
Reactant: CC(=O)O
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(OCC)OCC
Product: CC(=O)N[C@@H]1C[C@@]2(c3ccccc3)[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1
Temperature: 90 °C
Yield: 24 %

Procedure:
To (1R*,2R*,5S*,6R*)-6-amino-8-benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-1-phenyl-8-azabicyclo[3.2.1]octane (Example 108; 256 mg, 0.48 mmol) and sodium azide (75 mg, 1.15 mmol) in triethylorthoformate (0.25 ml) was added glacial acetic acid (2.5 ml) and the reaction mixture heated at 90° C. for 3 hours. The reaction mixture was cooled then concentrated in vacuo and partitioned between saturated sodium hydrogen carbonate solution and dichloromethane. The organics were dried (MgSO4) and concentrated in vacuo to give a brown oil. This was purified by flash column chromatography [5% methanol in dichloromethane] to give the title compound (66 mg, 24%).
Reaction SMILES: [N:1]1([CH2:6][CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][NH:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:13]1([C:22](Cl)=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14]1>C(N(CC)CC)C>[CH:13]1([C:22]([N:8]2[CH2:9][CH2:10][CH2:11][CH2:12][CH:7]2[CH2:6][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14]1
Reactant: O=C(Cl)C1C=Cc2ccccc21
Reactant: C1CCC(CN2CCCC2)NC1
Solvent: CCN(CC)CC
Product: O=C(C1C=Cc2ccccc21)N1CCCCC1CN1CCCC1
Yield: 32.2 %

Procedure:
From 2.36 g of 2-(pyrrolidin-1-ylmethyl)piperidine. 2.5 g of indene-1-carbonyl chloride and 4.88 ml of triethylamine. 1.4 g of 1-(indene-1-carbonyl)-2-(pyrrolidin-1-ylmethyl)piperidine was obtained using a procedure similar to that in Example 2. In a mixed solvent to methanol, water and ethanol (2:1:1), this compound was catalytically reduced with 10% palladium on carbon. After completion of the reduction, the catalyst was filtered off. After evaporation of the solvent, the residue was treated with a 4N 1,4-dioxane solution of hydrogen chloride to obtain 1.05 g of the title compound, melting at 218°-221° C.