Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl.[CH3:7][CH:8]1[CH2:12]OC(=O)[O:9]1>>[OH:9][CH:8]([CH3:12])[CH2:7][N:1]1[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: CC1COC(=O)O1
Reactant: c1nc[nH]n1
Agent: Cl
Product: CC(O)Cn1cncn1
Temperature: 0 °C

Procedure:
The starting material may be prepared as follows. A mixture of 1,2,4-triazole (5 g.) and 4-methyl-1,3-dioxolan-2-one was heated at 150° for 18 hours. Concentrated aqueous hydrochloric acid (8 ml.) was added dropwise to the ice-cooled mixture and the mixture was washed with chloroform. The aqueous phase was neutralised with aqueous potassium carbonate solution and extracted with chloroform, and the chloroform extract was dried and evaporated to dryness to give 1-(2-hydroxypropyl)-1,2,4-triazole (7.8 g.) which was characterised as the hydrogen oxalate, m.p. 110°-112° (after crystallisation from EtOH).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C:3]1=[O:7].C([N-]C(C)C)(C)C.[Li+].[Br:16][C:17]([CH2:19]Br)=[CH2:18]>C1COCC1>[Br:16][C:17](=[CH2:18])[CH2:19][CH:4]1[CH2:5][CH2:6][N:2]([CH3:1])[C:3]1=[O:7]
Reactant: CN1CCCC1=O
Reactant: C=C(Br)CBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C(Br)CC1CCN(C)C1=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 57 %

Procedure:
1-Methyl-2-pyrrolidinone (3.87 mL, 40.3 mmol) was combined with 25 mL of THF and cooled to −78° C. Lithium diisopropylamide (26.9 mL, 40.3 mmol) (1.5M in THF) was added slowly and the mixture was agitated for 30 minutes. 2,3-Dibromopropene (4.93 mL, 40.3 mmol) was added and the mixture was agitated overnight and allowed to warm up to ambient temperature. The reaction was quenched with sodium bicarbonate solution and extracted twice with ether. The extracts were washed with brine and evaporated. The crude product was purified by chromatography on silica gel, eluting with 30-50% ethyl acetate/hexane, to provide the title compound (5.01 g, 56.9% yield) as clear oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]#[N:12])=[CH:5]2.[H-].[Na+].Cl[CH2:16][C@@H:17]([CH2:26][O:27][Si:28]([CH3:34])([CH3:33])[C:29]([CH3:32])([CH3:31])[CH3:30])[O:18][Si:19]([CH3:25])([CH3:24])[C:20]([CH3:23])([CH3:22])[CH3:21]>CN(C=O)C.O>[Si:19]([O:18][C@H:17]([CH2:26][O:27][Si:28]([C:29]([CH3:30])([CH3:32])[CH3:31])([CH3:33])[CH3:34])[CH2:16][N:7]1[C:8]2[C:4](=[CH:3][C:2]([CH3:1])=[CH:10][CH:9]=2)[CH:5]=[C:6]1[C:11]#[N:12])([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:25])[CH3:24]
Reactant: Cc1ccc2[nH]c(C#N)cc2c1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](CCl)O[Si](C)(C)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)cc(C#N)n2C[C@@H](CO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Reaction time: 0.5 h
Yield: 48.8 %

Procedure:
To a solution of 39 mg of 5-methyl-1H-indole-2-carbonitrile (0.25 mmol) in 0.5 mL of DMF 15 mg of NaH (60% in oil, 0.375 mmol) was added and mixture was stirred for 30 min. Then 170 mg of (R)-5-(chloromethyl)-2,2,3,3,8,8,9,9-octamethyl-4,7-dioxa-3,8-disiladecane (0.5 mmol) was added and stirring continued for 24 hs. The reaction mixture was diluted with 10 mL of water and extracted with DCM. Combined organic extracts dried over sodium sulfate, concentrated and purified using silica gel column eluting with hexane-ethyl acetate 50:1 to afford 56 mg of (S)-1-(2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-5-methyl-1H-indole-2-carbonitrile. 1H NMR (600 MHz, CDCl3): δ 8.09 (d, 1H, J=8.8 Hz), 7.35 (s, 1H), 7.24 (d, 1H, J=8.8 Hz), 7.18 (s, 1H), 4.04 (m, 1H), 3.82 (m, 1H), 3.77 (m, 2H), 3.68 (m, 1H), 2.43 (s, 3H), 1.08 (m, 18H), 0.26 (m, 12H).
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:3]#[N:4].[CH3:11][C:12](=O)[CH2:13][C:14](=[O:17])[CH2:15][CH3:16]>CO>[NH2:4][C:3]1[C:13]([C:14](=[O:17])[CH2:15][CH3:16])=[C:12]([CH3:11])[NH:1][C:2]=1[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CCC(=O)CC(C)=O
Reactant: N#CC(N)c1ccccc1
Solvent: CO
Product: CCC(=O)c1c(C)[nH]c(-c2ccccc2)c1N
Yield: 53 %

Procedure:
Starting from 2-amino-2-phenylacetonitrile and hexane-2,4-dione, the open-chain intermediate compound is obtained, b.p. 160° C./0.3 mm Hg. The title compound is obtained in an overall yield of 53%, m.p. 166°-168° C. (from methanol).
Reaction SMILES: [CH3:1][NH:2][CH3:3].Br[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[C:12]2[C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[N:27](C(OC(C)(C)C)=O)[CH:26]=[CH:25]3)=[CH:7][CH:6]=1>CC([O-])=O.CC([O-])=O.[Pd+2].C1(C)C=CC=CC=1>[CH3:1][N:2]([CH3:3])[C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[C:12]2[C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[NH:27][CH:26]=[CH:25]3)=[CH:9][CH:10]=1
Reactant: CNC
Reactant: CC(C)(C)OC(=O)n1ccc2cc(-c3nc4ccccc4c(=O)n3-c3ccc(Br)cc3)ccc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CN(C)c1ccc(-n2c(-c3ccc4[nH]ccc4c3)nc3ccccc3c2=O)cc1
Yield: 33.2 %

Procedure:
Dimethylamine (0.3 mL, 0.58 mmol) was added to a solution of tert-butyl 5-(3-(4-bromophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-indole-1-carboxylate (0.200 g, 0.38 mmol), NatOBu (0.112 g, 1.20 mmol), Pd(OAc)2 (0.013 g, 0.06 mmol) and (t-Bu)3PHBF4 (0.034 g, 0.12 mmol) were added to toluene (5 mL). The mixture was microwaved at 300 W (max. power) and 90° C. for 30 min, before the mixture was concentrated in vacuo. Purification by flash chromatography on silica gel, eluting with 20% to 60% EtOAc in hexanes, afforded the title compound as a brown-yellow solid (0.048 g, 33%). 1H-NMR (300 MHz, DMSO-d6): δ11.14 (s, 1H), 8.16 (d, J=7.7 Hz, 1H), 7.83-7.88 (m, 1H), 7.67-7.73 (m, 2H), 7.52-7.57 (m, 1H), 7.33 (s, 1H), 7.18 (d, J=8.7 Hz, 1H), 7.03-7.08 (m, 3H), 6.54 (d, J=8.8 Hz, 2H), 6.39 (s, 1H), 2.83 (s, 6H). MS (APCI) m/z: 381 (M+H)+.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]([C:22]2[CH:29]=[CH:28][C:25]([CH:26]=O)=[C:24]([N+:30]([O-:32])=[O:31])[CH:23]=2)[CH:17]=1.O>O1CCCC1>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]([C:22]2[CH:29]=[CH:28][C:25]([CH:26]=[CH:5][C:3]#[N:4])=[C:24]([N+:30]([O-:32])=[O:31])[CH:23]=2)[CH:17]=1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: COc1ccnc(-c2ccc(C=O)c([N+](=O)[O-])c2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccnc(-c2ccc(C=CC#N)c([N+](=O)[O-])c2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (60% dispersion in mineral oil, 192 mg) in tetrahydrofuran (10 ml) was added a solution of diethyl cyanomethylphosphonate (0.777 ml) dropwise at 0° C., and the mixture was stirred at ambient temperature for 30 minutes. Then to the resultant mixture was added a solution of 4-(4-methoxypyridin-2-yl)-2-nitrobenzaldehyde (1.03 g) in tetrahydrofuran (20 ml) dropwise at 0° C., and the mixture was stirred at ambient temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was triturated with diisopropyl ether, filtered and dried to give 4-(4-methoxypyridin-2-yl)-2-nitrocinnamonitrile (1.11 g) as a mixture of regioisomers.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:13]([C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:20]([CH:23]([CH3:25])[CH3:24])=[N:21][N:22]=3)[N:19]=2)=[CH:12][N:11]([CH:26]2[CH2:30][CH2:29][NH:28][CH2:27]2)[N:10]=1.CCN(C(C)C)C(C)C.[C:40](Cl)(=[O:42])[CH3:41]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:13]([C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:20]([CH:23]([CH3:24])[CH3:25])=[N:21][N:22]=3)[N:19]=2)=[CH:12][N:11]([CH:26]2[CH2:30][CH2:29][N:28]([C:40](=[O:42])[CH3:41])[CH2:27]2)[N:10]=1
Reactant: CC(=O)Cl
Reactant: CC(C)c1nnc2ccc(-c3cn(C4CCNC4)nc3-c3ccc(F)cc3F)nn12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCC(n2cc(-c3ccc4nnc(C(C)C)n4n3)c(-c3ccc(F)cc3F)n2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 84.7 %

Procedure:
To a round bottom flask was added 6-(3-(2,4-difluorophenyl)-1-(pyrrolidin-3-yl)-1H-pyrazol-4-yl)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine (0.150 g, 0.366 mmol, Example #Q.1.1.1), DCM (10 mL), DIPEA (0.077 mL, 0.440 mmol) and acetyl chloride (0.029 mL, 0.403 mmol). The reaction mixture was stirred at ambient temperature for about 10 min. The reaction mixture was diluted with DCM (50 mL) and washed with saturated aqueous NaHCO3 (50 mL), dried with MgSO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (40 g RediSep® silica gel; DCM/MeOH gradient from 1:0 to 9:1) to give the title compound (0.140 g, 84%): LC/MS (Table 1, Method g) Rt=2.07 min; MS m/z: 452.4 (M+H)+.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH:13]=[O:14].Br[CH2:16][CH2:17][CH2:18][Cl:19]>CS(C)=O>[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:16][CH2:17][CH2:18][Cl:19])[CH:8]=[C:7]2[CH:13]=[O:14]
Reactant: ClCCCBr
Reactant: O=Cc1c[nH]c2ccc(Cl)cc12
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: O=Cc1cn(CCCCl)c2ccc(Cl)cc12
Reaction time: 0.5 h
Yield: 84.3 %

Procedure:
To a stirred mixture of powdered potassium hydroxide (85%, 2.6 g, 39 mmol) in methyl sulfoxide (20 mL) was added dropwise a solution of 5-chloroindole-3-carboxaldehyde (3.5 g, 19 mmol) in methyl sulfoxide (5 mL). The mixture was stirred for 30 min and 1-bromo-3-chloropropane (2.9 mL, 29 mmol) was added dropwise. The mixture was stirred for 1 h and partitioned between ethyl acetate (3×40 mL) and water (100 mL). The combined organic extracts were washed (water, brine), dried (sodiurn sulfate) and concentrated in vacuo. The solid residue was recrystallised (2-propanol) to give the product as a white solid (4.1 g, 82%): mp 107-108° C.; Found: C, 56.51; H, 4.26; N, 5.44%. C12H11Cl2NO requires: C, 56.27; H, 4.33; N, 5.47%.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16].CON(C)[C:20](=[O:36])[CH:21]([O:34][CH3:35])[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1>>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[O:11][C:12]([C:20](=[O:36])[CH:21]([O:34][CH3:35])[C:22]3[CH:23]=[CH:24][C:25]([N:28]4[CH2:29][CH2:30][O:31][CH2:32][CH2:33]4)=[CH:26][CH:27]=3)=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16]
Reactant: COC(C(=O)N(C)OC)c1ccc(N2CCOCC2)cc1
Reactant: COc1cc(-c2ccco2)cc(OC)c1Cl
Product: COc1cc(-c2ccc(C(=O)C(OC)c3ccc(N4CCOCC4)cc3)o2)cc(OC)c1Cl

Procedure:
1-(5-(4-chloro-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(4-morpholinophenyl)ethanone was prepared from 2-(4-chloro-3,5-dimethoxyphenyl)furan and N,2-dimethoxy-N-methyl-2-(4-morpholinophenyl)acetamide according to the procedure used in Example 30. Purification by chromatography (70% EtOAc/hexanes) gave the product as a pale yellow solid (0.201 g, 43% yield). MS: m/z 472.2 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([N:14]([C:19]([C:21]2[C:22]([NH:31][CH2:32][C:33]3[O:34][CH:35]=[CH:36][CH:37]=3)=[N:23][C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])=[N:25][CH:26]=2)=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:11][C@@H:10]([C:38](O)=[O:39])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[CH3:64][C:65]1([OH:71])[CH2:70][CH2:69][NH:68][CH2:67][CH2:66]1>C(#N)C.C(N(CC)CC)C>[C:27]([C:24]1[N:23]=[C:22]([NH:31][CH2:32][C:33]2[O:34][CH:35]=[CH:36][CH:37]=2)[C:21]([C:19]([N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C@@H:12]2[CH2:11][C@H:10]([C:38]([N:68]3[CH2:69][CH2:70][C:65]([OH:71])([CH3:64])[CH2:66][CH2:67]3)=[O:39])[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:13]2)=[O:20])=[CH:26][N:25]=1)([CH3:28])([CH3:29])[CH3:30]
Reactant: CC(C)CN(C(=O)c1cnc(C(C)(C)C)nc1NCc1ccco1)[C@H]1C[C@@H](C(=O)O)CN(C(=O)OC(C)(C)C)C1
Reactant: CC1(O)CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)CN(C(=O)c1cnc(C(C)(C)C)nc1NCc1ccco1)[C@@H]1C[C@H](C(=O)N2CCC(C)(O)CC2)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 94.3 %

Procedure:
(3R*,5S*)-1-(tert-Butoxycarbonyl)-5-[({2-tert-butyl-4-[(2-furylmethyl)amino]pyrimidin-5-yl}carbonyl)(isobutyl)amino]piperidine-3-carboxylic acid (100 mg), HOBt (41 mg) and WSC.HCl (52 mg) were dissolved in acetonitrile (3 ml), 4-methylpiperidin-4-ol monohydrochloride (27 mg) and triethylamine (75 μl) were added and the mixture was stirred at room temperature for 15 hr. The reaction mixture was concentrated, the residue was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography. The fraction eluted with ethyl acetate-hexane (1:5-3:1) was concentrated under reduced pressure to give the object compound (110 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:14])=[C:4](I)[C:5]([O:11][CH3:12])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.I[CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1>>[C:8]([C:6]1[C:5]([O:11][CH3:12])=[C:4]([CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[C:3]([CH3:14])=[C:2]([Cl:1])[CH:7]=1)(=[O:10])[CH3:9]
Reactant: CC(C)(C)OC(=O)N1CCC(I)CC1
Reactant: COc1c(C(C)=O)cc(Cl)c(C)c1I
Product: COc1c(C(C)=O)cc(Cl)c(C)c1C1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
This compound was prepared using procedures analogous to those for Example 139 step 2 with 1-(5-chloro-3-iodo-2-methoxy-4-methylphenyl)ethanone and tert-butyl 4-iodopiperidine-1-carboxylate as starting materials. LCMS calculated for C20H28ClNO4Na (M+Na)+: m/z=404.1; Found: 404.1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[S:15][CH:16]=[C:17]([CH2:19]Cl)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1)(=[O:24])=[O:23].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[S:15][CH:16]=[C:17]([CH2:19][O:31][C:28]3[CH:27]=[CH:26][C:25]([S:22]([CH3:21])(=[O:24])=[O:23])=[CH:30][CH:29]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(CCl)cs2)CC1
Reactant: CS(=O)(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2nc(COc3ccc(S(C)(=O)=O)cc3)cs2)CC1

Procedure:
A mixture of 4-(4-Chloromethyl-thiazol-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 1, 463 mg, 1.46 mmol), 4-methanesulfonyl-phenol (252 mg, 1.46 mmol) and K2CO3 (404 mg, 2.92 mmol) in acetone (25 mL) was heated under reflux overnight. After cooling, the solid was filtered through a pad of celite. The filtrate was concentrated in vacuo. The residue was purified on silica gel (EtOAc-hexanes, 1:1) to afford the desired product. 1H NMR (CDCl3): δ 7.88 (2H, d, J=8.8 Hz), 7.23 (1H, s), 7.12 (2H, d, J=8.8 Hz), 5.24 (2H, s), 4.21 (2H, br), 3.17 (1H, m), 3.04 (3H, s), 2.88 (2H, m), 2.11 (2H, m), 1.73 (2H, m), 1.47 (9H, s).
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[CH2:7]([S:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:38]=[CH:37][C:17]([C:18]([N:20]2[CH2:25][CH2:24][CH:23]([N:26]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH2:30][CH2:29][C:27]3=[O:28])[CH2:22][CH2:21]2)=[O:19])=[CH:16][CH:15]=1)[CH3:8]>O.CO>[CH2:7]([S:9]([CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:38]=[CH:37][C:17]([C:18]([N:20]2[CH2:21][CH2:22][CH:23]([N:26]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH2:30][CH2:29][C:27]3=[O:28])[CH2:24][CH2:25]2)=[O:19])=[CH:16][CH:15]=1)=[O:2])[CH3:8]
Reactant: CCSCCCOc1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCS(=O)CCCOc1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29 %

Procedure:
Sodium metaperiodate (0.28 g) is dissolved in water (4 ml) and thereto is added a solution of 1-{1-[4-(3-ethylthiopropoxy)benzoyl]-4-piperidinyl}-3,4-dihydrocarbostyril (0.4 g) in methanol (15 ml) and the mixture is stirred at room temperature overnight. The reaction mixture is concentrated and the residue is extracted with chloroform. The extract is dried with magnesium sulfate and the solvent is distilled off. The resulting residue is purified by silica gel column chromatography (solvent n-hexane ethyl acetate=1:2→ethyl acetate:methanol=20:1) to give 1-{1-[4-(3-ethylsulfinylpropoxy)benzoyl]-4-piperidinyl}-3,4-dihydrocarbostyril (0.12 g).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:10][C:11]([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[O:12])[CH:6]=[CH:7][C:8]=1[Cl:9].C(N(C(C)C)CC)(C)C.[CH:28]([C@@H:30]1[CH2:35][CH2:34][CH2:33][N:32]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:31]1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:2][C:3]1[CH:4]=[C:5]([NH:10][C:11]([CH:13]2[CH2:14][CH2:15][N:16]([CH2:28][C@@H:30]3[CH2:35][CH2:34][CH2:33][N:32]([C:36]([O:38][C:39]([CH3:40])([CH3:42])[CH3:41])=[O:37])[CH2:31]3)[CH2:17][CH2:18]2)=[O:12])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: O=C(Nc1ccc(Cl)c(Cl)c1)C1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@@H](CN2CCC(C(=O)Nc3ccc(Cl)c(Cl)c3)CC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.4 %

Procedure:
To a mixture of N-(3,4-dichlorophenyl)piperidine-4-carboxamide hydrochloride (1.55 g) in dichloromethane (100 mL) was added di-iso-propylethylamine (1.3 mL). The solution was stirred for 15 minutes after which tert-butyl (3R)-3-formylpiperidine-1-carboxylate (1.17 g) and sodium triacetoxyborohydride (1.59 g) was added. The reaction was stirred at room temperature overnight. The reaction mixture was partitioned between dichloromethane and water and the aqueous layer extracted with dichloromethane. The combined organic layers were washed with brine, dried over magnesium sulfate and evaporated to give the title compound as a white foam (2.34 g, 100%).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[C:21]([C:25]([NH:27][C@H:28]4[C@H:32]([OH:33])[CH2:31][NH:30][CH2:29]4)=[O:26])=[C:22]([CH3:24])[NH:23][C:16]=23)[CH2:4][CH2:3]1.C([O:37][CH2:38][C:39](Cl)=[O:40])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[C:21]([C:25]([NH:27][C@H:28]4[C@H:32]([OH:33])[CH2:31][N:30]([C:38](=[O:37])[CH2:39][OH:40])[CH2:29]4)=[O:26])=[C:22]([CH3:24])[NH:23][C:16]=23)[CH2:4][CH2:3]1
Reactant: CC(=O)OCC(=O)Cl
Reactant: COc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@@H]4CNC[C@H]4O)c(C)[nH]c23)c1
Agent: Cl
Product: COc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@@H]4CN(C(=O)CO)C[C@H]4O)c(C)[nH]c23)c1

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-N-[(3R*,4R*)-4-hydroxypyrrolidin-3-yl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f17) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: Cl[C:2](=[C:13]1[C@:30]2([CH3:31])[C@H:16]([C@H:17]3[C:27](=[CH:28][CH2:29]2)[C@:25]2([CH3:26])[C:20](=[CH:21][C:22](=[O:32])[CH2:23][CH2:24]2)[CH2:19][CH2:18]3)[CH2:15][CH2:14]1)[CH:3]([Cl:12])[S:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].CN([CH:36]=[O:37])C.C[O-].[Na+]>CO.O>[Cl:12][CH:3]([S:4]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:5])[C:2]([O:37][CH3:36])=[C:13]1[C@:30]2([CH3:31])[C@H:16]([C@H:17]3[C:27](=[CH:28][CH2:29]2)[C@:25]2([CH3:26])[C:20](=[CH:21][C:22](=[O:32])[CH2:23][CH2:24]2)[CH2:19][CH2:18]3)[CH2:15][CH2:14]1
Reactant: CN(C)C=O
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1C2=CC[C@]2(C)C(=C(Cl)C(Cl)S(=O)c3ccccc3)CC[C@@H]12
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=C1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)C3=CC[C@]12C)C(Cl)S(=O)c1ccccc1
Reaction time: 0.5 h

Procedure:
20,21-Dichloro-21-(phenylsulfinyl)pregna-4,9(11),17(20)-trien-3-one (VII, Example 2, 1.0 g), dry DMF (20 ml) and methanol (4 ml) are stirred under nitrogen and cooled to -25°. Sodium methoxide in methanol (25%, 1 ml) is added dropwise. After 30 minutes, the mixture is quenched with water (0.33 ml) and allowed to warm to 20°-25°. The product is isolated by diluting the mixture with water and extracting with ethyl acetate. The organic layer is separated and dried over sodium sulfate and then concentrated under reduced pressure to give the title compound: NMR (CDCl3) 0.85, 0.87, 0.98, 1.36, 1.34, 3.89, 3.84, 5.03, 5.10, 5.23, 5.43, 5.53, 5.72, 5.75 and 7.4-8.0δ.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:7][CH:8]=[CH:9][N:10]=1.[H-].[Na+].[CH:13]([Si:16](Cl)([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])([CH3:15])[CH3:14].O>CN(C)C=O.C(OCC)C>[CH:13]([Si:16]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[N:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:7][CH:8]=[CH:9][N:10]=1)([CH3:15])[CH3:14]
Reactant: c1c[nH]c(-c2nccs2)c1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: CC(C)[Si](C(C)C)(C(C)C)n1cccc1-c1nccs1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80.4 %

Procedure:
2-(1H-Pyrrol-2-yl)-1,3-thiazole (1.42 g, 9.45 mmol) known in the literature {Eur. J. Org. Chem. (European Journal of Organic Chemistry) vol. 2000, no. 13, 2449-2458 (2000)} was dissolved in N,N-dimethylformamide (100 mL), and cooled to 0° C. Sodium hydride (60% oil, 570 mg, 14.3 mmol) and triisopropylsilyl chloride (4.0 mL, 18.7 mmol) were added, and stirring was carried out at room temperature for 30 minutes under nitrogen atmosphere. Water (100 mL) and diethyl ether (100 mL) were added, and the solution was separated. The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: hexane) to afford the desired compound (2.33 g, yield 80%) as a pale yellow oil.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:7][C:8]([OH:14])=[C:9]([C:12]=1[CH3:13])[CH:10]=[O:11])(=[O:3])[CH3:2].[CH:19]([Mg]Br)([CH3:21])[CH3:20]>O1CCCC1>[C:1]([O:4][C:5]1[C:6]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:7][C:8]([OH:14])=[C:9]([CH:10]([OH:11])[CH:19]([CH3:21])[CH3:20])[C:12]=1[CH3:13])(=[O:3])[CH3:2]
Reactant: CC(C)[Mg]Br
Reactant: CC(=O)Oc1c(C(C)(C)C)cc(O)c(C=O)c1C
Solvent: C1CCOC1
Product: CC(=O)Oc1c(C(C)(C)C)cc(O)c(C(O)C(C)C)c1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under argon atmosphere, 5-acetoxy-4-t-butyl-2-hydroxy-6-methylbenzaldehyde was dissolved in 10 ml of anhydrous tetrahydrofuran, 10 ml of isopropylmagnesium bromide (0.76M in tetrahydrofuran) was added dropwise and the mixture was stirred at room temperature for 30 minutes. After the reaction was quenched with distilled water, the reaction mixture was combined with IN hydrochloric acid and extracted with ethyl acetate. The organic layers were washed with saturated brine, then dried over anhydrous magnesium sulfate, and then concentrated to give 0.44 g of 4-acetoxy-5-t-butyl-2-(1-hydroxy-2-methylpropyl)-3-methylphenol as a yellow amorphous material (yield 100%).