Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[CH3:14].[C:15](OCC)(=[O:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17]>C1COCC1>[F:13][C:10]1[CH:11]=[CH:12][C:7]([C:15](=[O:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:8]([CH3:14])[CH:9]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: Cc1cc(F)ccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)c1ccc(F)cc1C
Temperature: -78 °C
Reaction time: 1 h
Yield: 65.4 %

Procedure:
n-Butyllithium (1.6 M in hexane, 109 mL, 0.175 mol) was added dropwise to a −78° C. solution of 1-bromo-4-fluoro-2-methylbenzene (30 g, 0.16 mol) in THF (500 mL) under N2. After complete addition, the reaction mixture was stirred for 1 h at −78° C. The bright yellow solution was quickly cannulated to another flask containing a pre-cooled (−78° C.) solution of diethyl oxalate (27.8 g, 0.19 mol) in THF (400 mL). After stirring for another 30 min at −78° C., the reaction mixture was quenched by the addition of saturated NH4Cl solution (800 mL). The aqueous layer was extracted with EtOAc (3×400 mL) and the combined organics were dried (Na2SO4), concentrated in vacuo and purified via silica gel chromatography to provide ethyl 2-(4-fluoro-2-methylphenyl)-2-oxoacetate (22.0 g, yield, 66% yield). 1H NMR (400 MHz, CDCl3): δ 7.73 (dd, J=9.2, 5.6 Hz, 1 H), 7.02-6.96 (m, 2 H), 4.40 (m, 2 H), 2.60 (s, 3 H), 1.29 (t, J=6.8 Hz, 3 H). MS (ESI) m/z: 233.0 [M+Na]+
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH2:7])=[N:4][N:3]=1.OP([O-])([O-])=O.[K+].[K+].[C:15]([NH:22][CH2:23][CH2:24][NH2:25])([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]>CN(C=O)C>[NH2:7][C:5]1[S:6][C:2]([NH:25][CH2:24][CH2:23][NH:22][C:15](=[O:16])[O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[N:3][N:4]=1
Reactant: Nc1nnc(Br)s1
Reactant: CC(C)(C)OC(=O)NCCN
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCNc1nnc(N)s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.4 %

Procedure:
A mixture of 5-bromo-1,3,4-thiadiazol-2-ylamine (5.40 g), K2HPO4 (7.84 g), and Boc-ethylenediamine (9.6 g) in 20 ml of DMF is stirred at ambient temperature for 18 hours. The solid paste obtained is recrystallized from 100 ml of acetonitrile and 100 ml of water to provide 6.18 g (79%) of the title compound.
Reaction SMILES: N[C@H:2]([C:8](O)=[O:9])CCCCN.[NH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]([NH:20][C:21]([C@H:23]([N:31]([CH3:56])[C:32]([C@H:34]([NH:46][C:47](=[O:55])/[CH:48]=[CH:49]/[CH2:50][C:51]([NH2:54])([CH3:53])[CH3:52])[CH2:35][C:36]1[CH:45]=[CH:44][C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=1)=[O:33])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[C:17](=[O:19])[NH2:18]>>[C:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]([NH:20][C:21]([C@H:23]([N:31]([CH3:56])[C:32]([C@H:34]([NH:46][C:47](=[O:55])/[CH:48]=[CH:49]/[CH2:50][C:51]([NH2:54])([CH3:53])[CH3:52])[CH2:35][C:36]1[CH:45]=[CH:44][C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=1)=[O:33])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[C:17](=[O:19])[NH2:18])(=[O:9])[CH3:2]
Reactant: NCCCC[C@H](N)C(=O)O
Reactant: CN(C(=O)[C@@H](Cc1ccc2ccccc2c1)NC(=O)/C=C/CC(C)(C)N)[C@H](Cc1ccccc1)C(=O)N[C@@H](CCCCN)C(N)=O
Product: CC(=O)NCCCC[C@H](NC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)NC(=O)/C=C/CC(C)(C)N)C(N)=O

Procedure:
This compound was prepared by acetylation of the epsilon amino group in the lysine fragment using the general method described above and using the compound prepared in example 19 as starting material.
Reaction SMILES: [S:1]([C:4]1[C:12]2[CH2:11][CH2:10][CH2:9][C:8]=2[C:7]([OH:13])=[CH:6][CH:5]=1)[C:2]#[N:3].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:21][C:22]([O:24][CH3:25])=[O:23]>C(#N)C>[CH3:25][O:24][C:22](=[O:23])[CH2:21][O:13][C:7]1[CH:6]=[CH:5][C:4]([S:1][C:2]#[N:3])=[C:12]2[C:8]=1[CH2:9][CH2:10][CH2:11]2
Reactant: N#CSc1ccc(O)c2c1CCC2
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)COc1ccc(SC#N)c2c1CCC2

Procedure:
7-Thiocyanato-indan-4-ol (Example 1B) (3.23 g, 16.89 mmol), cesium carbonate (11 g, 33.8 mmol) and methyl bromoacetate (2.58 g, 16.89 mmol) were stirred in 20 ml acetonitrile at ambient temperature for 4 h. The reaction was filtered and concentrated. The crude product was recrystallized from ethyl acetate/heaxanes to afford the title product. MS m/z 239 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-])=O)=[CH:8][CH:9]=2)[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:3]1[C:20](O)=[O:21].Cl.[CH2:24]([O:26][C:27](=[O:37])[C@H:28]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[NH2:29])[CH3:25]>>[NH2:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:2]([CH3:1])[C:3]([C:20]([NH:29][C@H:28]([C:27]([O:26][CH2:24][CH3:25])=[O:37])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:21])=[C:4]2[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)[C@@H](N)Cc1ccccc1
Reactant: Cn1c(C(=O)O)c(-c2ccccc2)c2cc([N+](=O)[O-])ccc21
Agent: Cl
Product: CCOC(=O)[C@H](Cc1ccccc1)NC(=O)c1c(-c2ccccc2)c2cc(N)ccc2n1C

Procedure:
Ethyl N-[(5-amino-1-methyl-3-phenyl-1H-indol-2-yl)carbonyl]-L-phenylalaninate was prepared from 1-methyl-5-nitro-3-phenyl-1H-indole-2-carboxylic acid and L-phenylalanine ethyl ester hydrochloride followed the procedure of Example 8 Step 2 as a pale yellow solid: MS (ESI) m/z 442 (MH+); HRMS calcd for C27H28N3O3: 442.2128; found (ESI+): 442.2122.
Reaction SMILES: [CH3:1][N:2]1[C:19]2[C@:14]([CH3:21])([CH2:15][CH2:16][C:17](=[O:20])[CH:18]=2)[C@@H:13]2[C@H:4]([C@H:5]3[C@@:9]([CH2:11][CH2:12]2)([CH3:10])[CH2:8][C:7](=[O:22])[CH2:6]3)[CH2:3]1.N#N.[H-].C(O[Al](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[Li+].Cl>C1COCC1>[OH:22][C@H:7]1[CH2:6][C@H:5]2[C@H:4]3[C@H:13]([CH2:12][CH2:11][C@:9]2([CH3:10])[CH2:8]1)[C@:14]1([CH3:21])[C:19](=[CH:18][C:17](=[O:20])[CH2:16][CH2:15]1)[N:2]([CH3:1])[CH2:3]3
Reactant: CN1C[C@H]2[C@@H]3CC(=O)C[C@@]3(C)CC[C@@H]2[C@@]2(C)CCC(=O)C=C12
Agent: CC(C)(C)O[Al](OC(C)(C)C)OC(C)(C)C
Agent: Cl
Agent: N#N
Solvent: C1CCOC1
Product: CN1C[C@H]2[C@@H]3C[C@H](O)C[C@@]3(C)CC[C@@H]2[C@@]2(C)CCC(=O)C=C12
Temperature: 0 °C
Reaction time: 24 h

Procedure:
To a solution of 6-methyl-6-azaandrost-4-ene-3,16-dione (13, R2 =H) (273 mg, 0.906 mmoles) in THF (15 mL) at 0° C. in a N2 atmosphere was added lithium tri-tertbutoxyaluminum hydride (1.0M/THF) (2.36 mL, 2.6 mmoles) and the mixture stirred at 0° C. for 24 hours. The pH was brought to 4 with 0.5M HCl, and the mixture evaporated in vacuo. The residue was dissolved in methylene chloride and washed with H2O and brine and dried over MgSO4. Evaporation in vacuo and flash chromatography on silica gel with 4% methanol in methylene chloride gave (14, R2 =H) as a white solid. NMR (CDCl3): δ 1.03 (s, 3H, 18-Me); 1.29 (s, 3H, 19-Me); 2.87 (s, 3H, N-CH3); 4.46 (m, 1H, 16-H); 5.32 (s, 1H, 4-H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15])(=[O:3])[CH3:2].C(Cl)(=O)C([Cl:20])=O.C(Cl)(Cl)Cl>CN(C=O)C>[C:1]([NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([Cl:20])=[O:10])=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(C(=O)Cl)cc1[N+](=O)[O-]

Procedure:
4-Acetamido-3-nitrobenzoic acid 1 (Alfa Aesar, 5.6 g, 25 mmol), oxalyl chloride (4.76 g, 38 mmol), chloroform (50 ml), DMF (few drops) were stirred at 40° C. for 3 hours. The solvent was removed in vacuo to give a yellow solid that was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1)=[O:12]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][S:21]([C:18]2[CH:17]=[CH:16][C:15]([CH2:14][CH2:13][C:11]([O:10][CH3:9])=[O:12])=[CH:20][CH:19]=2)(=[O:23])=[O:22])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: COC(=O)CCc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: COC(=O)CCc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 82.4 %

Procedure:
4-Chloroaniline (957 mg, 7.5 mmol) was dissolved in pyridine (25 mL). The resulting mixture was cooled down to 0° C. Methyl 3-(4-chlorosulphonyl)phenylpropionate (1.314 g, 5.0 mmol) was added in portions. The mixture was stirred between 0° C. and room temperature overnight. Solvents were evaporated to dryness. The crude oil was dissolved in ethyl acetate (30 mL) and washed with 10% HCl (2×15 mL) and brine (1×15 mL). Organic phase was dried over magnesium sulfate before filtering and removal of solvent. The desired product, e.g. methyl 3-{4-[(4-chloroanilino)sulfonyl]phenyl}propanoate (1.458 g, 82.4%), was obtained as a colorless solid, in 98.5% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(/[CH:14]=[CH:15]/[CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1>CO.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: COC(=O)C/C=C/C1(c2ccc(F)cc2)CCCCC1
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCCC1(c2ccc(F)cc2)CCCCC1
Reaction time: 8 h

Procedure:
To a solution of (E)-methyl 4-(1-(4-fluorophenyl)cyclohexyl)but-3-enoate (Intermediate I-11C, 421 mg, 1.523 mmol) in methanol (20 mL) was added about 100 mg of 10% Pd on carbon (wet, 50%), and the mixture was stirred under hydrogen (50 psi) overnight. The catalyst was filtered off and the solvent was evaporated off to give the desired methyl 4-(1-(4-fluorophenyl)cyclohexyl)butanoate (quantitative yield) as an oil. 1H NMR (400 MHz, CDCl3) δ ppm 7.26 (2H, dd, J=8.91, 5.39 Hz), 7.00 (2H, t, J=8.80 Hz), 4.07 (2H, q, J=7.12 Hz), 2.12 (2H, t, J=7.37 Hz), 2.04 (2H, dd, J=13.42, 5.72 Hz), 1.24-1.63 (12H, m), 1.21 (3H, t, J=7.15 Hz).
Reaction SMILES: N1CCC[C@H]1C(O)=O.[S:9]1[C:13]([CH:14]=O)=[CH:12][C:11]2[CH:16]=[CH:17][CH:18]=[CH:19][C:10]1=2.[CH3:20][C:21]1([CH3:29])[O:28][C:26](=[O:27])[CH2:25][C:23](=[O:24])[O:22]1.CC1NC(C)=C(C(OCC)=O)CC=1C(OCC)=O>CCO>[S:9]1[C:13]([CH2:14][CH:25]2[C:26](=[O:27])[O:28][C:21]([CH3:29])([CH3:20])[O:22][C:23]2=[O:24])=[CH:12][C:11]2[CH:16]=[CH:17][CH:18]=[CH:19][C:10]1=2
Reactant: O=Cc1cc2ccccc2s1
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCO
Product: CC1(C)OC(=O)C(Cc2cc3ccccc3s2)C(=O)O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Proline (0.695 g, 5.98 mmol) was added to a solution of benzo[b]thiophene-2-carbaldehyde (5.00 g, 29.9 mmol) and Meldrum's acid (4.31 g, 29.9 mmol) in EtOH (50 mL). The mixture was stirred at room temperature for 1 hour and diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (7.57 g, 29.9 mmol) was added. Stirring was continued for 5 hours at room temperature and the precipitated product isolated by filtration rinsing further with iPrOH and dried under reduced pressure to provide the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[O:8][CH:9]([C:18]([OH:20])=[O:19])[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[CH2:13][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:21]O>>[CH3:1][C:2]1[C:7]2[O:8][CH:9]([C:18]([O:20][CH3:21])=[O:19])[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[CH2:13][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CO
Reactant: Cc1cccc2c1OC(C(=O)O)Oc1ccccc1C2
Product: COC(=O)C1Oc2ccccc2Cc2cccc(C)c2O1

Procedure:
4-Methyl-12H-dibenzo-[d,g][1,3]dioxocin-6-carboxylic acid from Example 1 (1.8 g, 6.6 mmol) was mixed with 75 ml of methanol and 5 g of Dowex™ sulfonic acid resin and the mixture heated at reflux for 16 hours. The mixture was allowed to cool, the resin removed by filtration, and the volatile components removed by evaporation under reduced pressure The residue was taken up in 150 ml of ether and the solution extracted with saturated aqueous sodium bicarbonate and dried over magnesium sulfate. The volatiles were removed by evaporation under reduced pressure and the light yellow residual solid, which amounted to 1.29 g, was recrystallized from ethanol to obtain 0.77 g (41 percent of theory) of the title compound as a solid melting at 104°-105° C. The proton nmr spectrum was consistent with the assigned structure.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]2[N:11]([C:20]([CH3:24])=[C:21]([CH3:23])[N:22]=2)[CH:12]=[C:13]([C:15](OCC)=[O:16])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[CH2:1]([O:8][C:9]1[C:10]2[N:11]([C:20]([CH3:24])=[C:21]([CH3:23])[N:22]=2)[CH:12]=[C:13]([CH2:15][OH:16])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(OCc2ccccc2)c2nc(C)c(C)n2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc2c(OCc3ccccc3)cc(CO)cn2c1C
Reaction time: 1 h
Yield: 38.3 %

Procedure:
A solution of 1.2 g of 8-benzyloxy-6-ethoxycarbonyl-2,3-dimethylimidazo[1,2-a]pyridine in 20 ml of tetrahydrofuran is treated in small portions with 0.2 g of lithium aluminium hydride at room temperature, stirred for one hour and treated successively with 0.2 ml of water, 0.2 ml of 6 molar sodium hydroxide solution and 0.6 ml of water. It is then extracted twice with methylene chloride (50 ml each time), the combined organic phases are concentrated to dryness in vacuo and the residue is purified on silica gel (eluent: methylene chloride/methanol 13/1). 0.4 g of the title compound of melting point 213-5° C. (acetone) is obtained.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH:14]=2)O1.C([O-])([O-])=O.[K+].[K+].Br[C:30]1[C:31]([F:48])=[CH:32][C:33]([F:47])=[C:34]([NH:36][C:37](=[O:46])[O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:35]=1>CN(C=O)C>[CH2:39]([O:38][C:37]([NH:36][C:34]1[C:33]([F:47])=[CH:32][C:31]([F:48])=[C:30]([C:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:13][CH:14]=2)[CH:35]=1)=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: O=C(Nc1cc(Br)c(F)cc1F)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC=C(c2cc(NC(=O)OCc3ccccc3)c(F)cc2F)CC1
Temperature: 80 °C
Yield: 24.3 %

Procedure:
To a 250-mL RB-flask containing tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-1(2H)-pyridinecarboxylate (4.58 g, 14.8 mmol), K2CO3 (6.14 g, 44.4 mmol) and PdCl2dppf (1.48 mmol, 1.21 g) was added a solution of benzyl 5-bromo-2,4-difluorophenylcarbamate (5.05, 14.8 mmol) in DMF (150 mL) at room temperature under argon. The mixture was heated to 80° C. under argon overnight. After cooling to room temperature, the mixture was filtered through Celite and the Celite was washed with EtOAc (3×100 mL). The filtrates were washed with H2O (3×200 mL), brine (100 mL), dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified flash chromatography (EtOAc/hexanes 1:9) to afford tert-butyl 4-(5-{[(benzyloxy)carbonyl]amino}-2,4-difluorophenyl)-3,6-dihydro-1(2H)-pyridinecarboxylate (1.60 g, 24.5%): 1H NMR (400 MHz, CDCl3) δ 8.08 (s, 1H), 7.45-7.35 (m, 5H), 6.85-6.70 (m, 1H), 5.95-5.85 (m, 1H), 5.20 (s, 2H), 4.05 (m, 2H), 3.6-3.5 (m, 2H), 2.5-2.4 (m, 2H), 1.50 (s, 9H); ESMS m/e: 443.3 (M−H+).
Reaction SMILES: [F:1][C:2]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:3]=1[O:4][C:5]1[CH:13]=[C:12]2[C:8]([CH:9](C3C=CC=CC=3)[CH2:10][C:11]2=[O:14])=[CH:7][C:6]=1[NH:21][S:22]([CH3:25])(=[O:24])=[O:23].[BH4-].[Na+]>CO.[OH-].[Na+]>[F:1][C:2]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:3]=1[O:4][C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][CH:11]2[OH:14])=[CH:7][C:6]=1[NH:21][S:22]([CH3:25])(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Nc1cc2c(cc1Oc1ccc(F)cc1F)C(=O)CC2c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CS(=O)(=O)Nc1cc2c(cc1Oc1ccc(F)cc1F)C(O)CC2
Reaction time: 16 h
Yield: 96.5 %

Procedure:
2.13 g of 6-(2,4-difluorophenoxy)-5-methylsulfonylamino-3-phenyl-1-indanone is dissolved in 20 ml of methanol and 5.5 ml of 1N sodium hydroxide solution. At 0° C., 400 mg of sodium borohydride is added to the mixture. After 16 hours at 20° C., the mixture is concentrated, combined with water, neutralized with 1N sulfuric acid, and vacuum-filtered, thus obtaining 1.7 g of N-[6-(2,4-difluorophenoxy)1-hydroxy-5-indanyl]methanesulfonamide, mp 119° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([CH2:10][CH2:11][S:12][C:13]1[S:17][CH:16]=[CH:15][CH:14]=1)(O)=[O:8].[O-]S([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[OH:8][CH2:7][CH2:10][CH2:11][S:12][C:13]1[S:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)CCSc1cccs1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: OCCCSc1cccs1
Temperature: 0 °C
Yield: 95.8 %

Procedure:
To a suspension of lithium aluminum hydride (20.1 g, 0.53 mol) in THF (125 ml), cooled to 0° C. was added a solution of 5-(2-carboxyethylthio)thiophene (25.0 g, 0.13 mol) in THF (125 ml) dropwise. The mixture was refluxed for 2 hours, cooled to 0° C. and saturated Na2SO4 was added dropwise. The solid was filtered, washed with CHCl3 and the filtrate was concentrated. Water was added to the residue and extracted with CHCl3. Drying and solvent evaporation gave an oily, product (21.7 g, 96%).
Reaction SMILES: [C:1]([C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([S:16][Si:17]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19])[CH:11]=2)[CH2:8][CH2:7][O:6][CH:5](C)[CH2:4]1)#[N:2].C(C1(C2C=CC=C(I)C=2)CCOCC1)#N>>[C:1]([C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([S:16][Si:17]([CH:21]([CH3:23])[CH3:22])([CH:24]([CH3:26])[CH3:25])[CH:18]([CH3:19])[CH3:20])[CH:11]=2)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1)#[N:2]
Reactant: CC1CC(C#N)(c2cccc(S[Si](C(C)C)(C(C)C)C(C)C)c2)CCO1
Agent: N#CC1(c2cccc(I)c2)CCOCC1
Product: CC(C)[Si](Sc1cccc(C2(C#N)CCOCC2)c1)(C(C)C)C(C)C

Procedure:
The titled compound was prepared according to the procedure described in example 29C for the preparation of (2SR,4RS)-4-cyano-2-methyl-4-(3-triisopropylsilylthiophenyl)-3,4,5,6-tetrahydro-2H-pyran using 4-cyano-4-(3-iodophenyl)-3,4,5,6-tetrahydro-2H-pyran in place of (2SR,4RS)-4-cyano-4-(3-iodophenyl)-2-methyl-3,4,5,6-tetrahydro-2H-pyran.
Reaction SMILES: [CH:1](=O)[CH3:2].[C:4]([O:8][C:9]([NH:11][CH2:12][C@H:13]([NH:18][CH2:19][CH3:20])[C:14]([O:16][CH3:17])=[O:15])=[O:10])([CH3:7])([CH3:6])[CH3:5].C([BH3-])#N.[Na+].O>O1CCCC1>[C:4]([O:8][C:9]([NH:11][CH2:12][C@H:13]([N:18]([CH2:1][CH3:2])[CH2:19][CH3:20])[C:14]([O:16][CH3:17])=[O:15])=[O:10])([CH3:7])([CH3:6])[CH3:5]
Reactant: CCN[C@@H](CNC(=O)OC(C)(C)C)C(=O)OC
Reactant: CC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCN(CC)[C@@H](CNC(=O)OC(C)(C)C)C(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.4 %

Procedure:
150 μl (2.4 mmol) of acetaldehyde are added to 369 mg (1.5 mmol) of methyl (S)-3-tert-butoxycarbonylamino-2-ethylaminopropanoate in 5 ml of tetrahydrofuran then stirred for 30 minutes at ambient temperature. After cooling to 0° C., 189 mg (3 mmol) of sodium cyanoborohydride are added and the reaction medium is stirred at ambient temperature for 36 h. Water is added and the medium is extracted with ethyl acetate. The organic phase is washed with water, dried over magnesium sulphate, filtered then concentrated. The crude residue obtained is purified by chromatography over silica gel eluted with a 70/30 heptane/ethyl acetate mixture. 150 mg (38%) of methyl (S)-3-tert-butoxycarbonylamino-2-diethylaminopropanoate are obtained in the form of a colourless oil.
Reaction SMILES: Cl[C:2](=[N:4][OH:5])[CH3:3].C(N(CC)CC)C.[CH3:13][C:14]1([CH3:27])[O:19][C:18]2[CH:20]=[CH:21][CH:22]=[C:23]([C:24]#[CH:25])[C:17]=2[C:16](=[O:26])[O:15]1.P(=O)(O)(O)O>C(OC)(C)(C)C.O>[CH3:13][C:14]1([CH3:27])[O:19][C:18]2[CH:20]=[CH:21][CH:22]=[C:23]([C:24]3[O:5][N:4]=[C:2]([CH3:3])[CH:25]=3)[C:17]=2[C:16](=[O:26])[O:15]1
Reactant: CC(Cl)=NO
Reactant: C#Cc1cccc2c1C(=O)OC(C)(C)O2
Agent: O=P(O)(O)O
Solvent: COC(C)(C)C
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1cc(-c2cccc3c2C(=O)OC(C)(C)O3)on1
Reaction time: 8 h

Procedure:
53 ml of the solution of 1-chloro-1-(N-hydroxyimino)ethane 45 described above and 6.3 ml of triethylamine are added with stirring at 0° C. to a solution of 8.0 g of 2,2-dimethyl-5-(ethynyl)-4H-(1,3)benzodioxin-4-one in 400 ml of methyl tert-butyl ether, and the mixture is allowed to come to room temperature and is subsequently stirred overnight. A further 53 ml of the solution of 1-chloro-1-(N-hydroxyimino)ethane described above and 6.3 ml of triethylamine are added and the reaction solution is stirred at room-temperature for 24 h. It is then poured into water containing phosphoric acid (pH 4) at 0° C. and extracted with methyl tert-butyl ether, and the combined organic phases are carefully washed with water, dried over sodium sulfate and concentrated. 8.8 g of crude product remain, which is chromatographed on silica gel using n-hexane/ethyl acetate. 4.1 g of colorless crystals are obtained, m.p. 74° C. (cf. Table 1, No. 1.020).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[N:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.CO.[F:13][CH:14]([F:28])[O:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([O:24][CH:25]([F:27])[F:26])[CH:23]=1)[CH:19]=[O:20].[OH-].[K+]>O>[F:13][CH:14]([F:28])[O:15][C:16]1[CH:17]=[C:18]([CH:19]([C:5]2[C:4]3[C:8](=[N:9][CH:10]=[C:2]([Br:1])[CH:3]=3)[NH:7][CH:6]=2)[OH:20])[CH:21]=[C:22]([O:24][CH:25]([F:26])[F:27])[CH:23]=1
Reactant: O=Cc1cc(OC(F)F)cc(OC(F)F)c1
Reactant: Brc1cnc2[nH]ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: OC(c1cc(OC(F)F)cc(OC(F)F)c1)c1c[nH]c2ncc(Br)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.7 %

Procedure:
To 5-bromo-7-azaindole (67, 86.4 mg, 0.000438 mol) methanol (10.0 mL) were added 3,5-bis-difluoromethoxy-benzaldehyde (529, 110.0 mg, 0.46 mmol) and potassium hydroxide (200.0 mg, 3.6 mmol) under art atmosphere of nitrogen. The reaction was stirred at room temperature overnight. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane to give the compound as a white solid (530, 70 mg, 35%). MS (ESI) [M+H+]+=435.1, 437.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.[CH3:9][O:10][CH:11]([O:14][CH3:15])[CH2:12]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8][CH2:12][CH:11]([O:14][CH3:15])[O:10][CH3:9])[CH:3]=1
Reactant: COC(CBr)OC
Reactant: Sc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(CSc1cccc(Br)c1)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.4 %

Procedure:
Part A: A suspension of 3-bromothiophenol (15.2 g, 81 mmol), bromoacetaldehyde dimethylacetal (9.5 mL, 81 mmol) and potassium carbonate (12.2 g, 88 mmol) in acetone (90 mL) was stirred at ambient temperature overnight. The solid was filtered and rinsed with ether. Evaporation of the filtrate afforded 23 g of 1-bromo-3-((2,2-dimethoxyethyl)thio)benzene which was carried forward without further purification.