Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C([NH:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=O.C(N(CC)CC)C.[C:21](#[N:24])[CH:22]=[CH2:23]>C1COCC1>[C:21]([CH2:22][CH2:23][N:9]1[CH2:8][CH2:7][CH:6]([NH2:5])[CH2:11][CH2:10]1)#[N:24]
Reactant: O=C(NC1CCNCC1)C(F)(F)F
Reactant: C=CC#N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N#CCCN1CCC(N)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 29.9 %

Procedure:
A mixture of 3 g (15.3 mmol) of 4-trifluoroacetamidopiperidine, 3 g (4.25 mL, 30.6 mmol) of triethylamine, 3 mL (45.9 mmol) of acrylonitrile in 10 mL of THF was stirred at room temperature for 17 hr. The solvent and volatile were evaporated under reduced pressure. The residue was dissolved in 20 mL of methanol and 4 mL of 30% NH4OH and the solution was refluxed for 5 hr. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel eluting first with 500 mL of dichloromethane, then 500 mL of 0.5% methanol/dichloromethane, followed by 1000 mL of 9:1:0.1 dichloromethane/methanol/ammonium hydroxide to give 0.7 g (30% yield) of the N-(2-cyanoethyl)-4-aminopiperidine.
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][C:7]([CH:8]=[CH:9][S:10]([NH:13][C:14](=O)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].P(Cl)(Cl)(Cl)(Cl)[Cl:25]>C1C=CC=CC=1>[N+:1]([C:4]1[CH:23]=[CH:22][C:7]([CH:8]=[CH:9][S:10]([N:13]=[C:14]([Cl:25])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=C(NS(=O)(=O)C=Cc1ccc([N+](=O)[O-])cc1)c1ccccc1
Solvent: c1ccccc1
Product: O=[N+]([O-])c1ccc(C=CS(=O)(=O)N=C(Cl)c2ccccc2)cc1
Reaction time: 8 h

Procedure:
A suspension of N-(4-nitrostyrylsulfonyl)benzamide (14.9 g., 0.045 mole) in 500 ml. of dry benzene is refluxed and stirred with phosphorus pentachloride (10.4 g., 0.05 mole) for 8 hr. The reaction mixture after standing overnight at 25° C. provides 8.2 g. of solid, m.p. 158°-166° C. Concentration of the mother liquor to about 100 ml. provides an additional 2.5 g. of solid, m.p. 158°-161° C. The combined crude solid crystallized from ethyl acetate affords analytically pure N-(4-nitrostyrylsulfonyl)benzimidoyl chloride, m.p. 168°-175° C.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH2:14].[O-:16][C:17]#[N:18].[K+].CO>Cl.O>[CH3:15][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:17]([NH2:18])=[O:16]
Reactant: CN(C)CCCCCCCCCCCN
Reactant: N#C[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: O
Product: CN(C)CCCCCCCCCCCNC(N)=O
Yield: 21.7 %

Procedure:
A solution of this amine (4.6 g) in dilute hydrochloric acid (40 ml) and concentrated hydrochloric acid (12 ml) was treated with potassium cyanate (7.0 g) in water (10 ml). The mixture was refluxed for 18 hours and the solvent removed leaving a white solid. To this methanol (10 ml) was added and the mixture filtered. The solvent was evaporated from the filtrate which was then chromatographed on a basic alumina column eluting with 10% methanol in chloroform, to give a yellow solid which was washed with ether to give N,N-dimethyl-N-(11-ureidoundecyl)amine as a white solid (1.2g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1Cl)([O-:3])=[O:2].[CH2:14]([CH2:16][NH2:17])[OH:15]>O>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[NH:17][CH2:16][CH2:14][OH:15])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1Cl
Reactant: NCCO
Solvent: O
Product: O=[N+]([O-])c1cccc([N+](=O)[O-])c1NCCO

Procedure:
0.05 mol (10.125 g) of 2,6-dinitrochlorobenzene is added gradually, whilst stirring, to 25 ml of ethanolamine, the reaction medium being cooled so that the temperature does not exceed 50° C. The reaction medium is poured into 100 ml of iced water. The expected product precipitates. It is filtered off, washed with water and recrystallised from ethanol. After drying in vacuo, it melts at 100° C.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:21][C@H:20]([CH2:22][NH:23][C:24](=O)[CH3:25])[O:19][C:18]4=[O:27])=[CH:13][C:12]=3[F:28])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:38])=CC=1>O1CCOCC1>[O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:21][C@H:20]([CH2:22][NH:23][C:24](=[S:38])[CH3:25])[O:19][C:18]4=[O:27])=[CH:13][C:12]=3[F:28])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CC3)OCCO4)c(F)c2)C(=O)O1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Product: CC(=S)NC[C@H]1CN(c2ccc(N3CCC4(CC3)OCCO4)c(F)c2)C(=O)O1
Yield: 55 %

Procedure:
The title compound was prepared by reacting (S)-N-{3-[4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (1.0 mmol, prepared as per procedure described in U.S. Pat. No. 5,668,286) with Lawesson's reagent (1.1 mmol), in dioxane (10 ml) at a temperature 65° C. for 12 hours followed by silica gel column chromatographic purification in 55% yield. Mp; 141-143° C., Mass m/z 410.1 (ES+, 100%) for C19H24FN3O4S.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:15]3[C:16]([CH3:41])=[CH:17][C:18]([F:40])=[C:19]([NH:21][C:22]([NH:24][C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([CH2:32][N:33]5[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]5)[CH:26]=4)=[O:23])[CH:20]=3)[C:8](=[O:14])[N:9]2[CH2:12][CH3:13])=[CH:4][N:3]=1.[CH:42]([NH2:44])=[O:43].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+]>[CH2:12]([N:9]1[C:10]2[C:5](=[CH:4][N:3]=[C:2]([NH:44][CH:42]=[O:43])[CH:11]=2)[CH:6]=[C:7]([C:15]2[CH:20]=[C:19]([NH:21][C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[C:27]([CH2:32][N:33]4[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]4)[CH:26]=3)=[O:23])[C:18]([F:40])=[CH:17][C:16]=2[CH3:41])[C:8]1=[O:14])[CH3:13]
Reactant: CCn1c(=O)c(-c2cc(NC(=O)Nc3ccc(F)c(CN4CCN(C)CC4)c3)c(F)cc2C)cc2cnc(Cl)cc21
Reactant: NC=O
Agent: Cl[Pd+]
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: NCCc1[c-]cccc1
Solvent: C1COCCO1
Product: CCn1c(=O)c(-c2cc(NC(=O)Nc3ccc(F)c(CN4CCN(C)CC4)c3)c(F)cc2C)cc2cnc(NC=O)cc21
Temperature: 100 °C
Reaction time: 8 h
Yield: 43.4 %

Procedure:
A mixture of 1-(5-(7-chloro-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)-3-(4-fluoro-3-((4-methylpiperazin-1-yl)methyl)phenyl)urea (0.120 g, 0.207 mmol), formamide (0.041 ml, 1.033 mmol) and K2CO3 (0.057 g, 0.413 mmol) in dioxane (3 mL) was sparged with Ar, treated with BrettPhos Palladacycle (8.05 mg, 10.33 μmol), sparged again with Ar, and heated to 100° C. for 1 h. The mixture was cooled to RT, treated with EtOAc and satd. NaHCO3, filtered to remove insoluble material and the layers separated. The organic layer was washed with brine, dried over MgSO4 and concentrated to dryness. The material was treated with a small amount of DCM, allowed to stand at RT, and the resulting solid collected via filtration and dried. The filtrate was concentrated to dryness, layered with a small amount of DCM and allowed to stand at RT overnight. The resulting solid was collected via filtration and combined with the above-isolated solid to afford N-(1-ethyl-3-(4-fluoro-5-(3-(4-fluoro-3-((4-methylpiperazin-1-yl)methyl)phenyl)ureido)-2-methylphenyl)-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)formamide (53 mg, 44% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.38 (m, 1H), 9.05 (s, 1H), 8.69 (d, J=18.4 Hz, 1H), 8.44 (s, 1H), 8.21 (s, 1H), 7.96 (d, J=8.4 Hz, 1H), 7.90 (s, 1H), 7.43 (dd, J=6.5, 2.8 Hz, 1H), 7.30 (ddd, J=8.9, 4.4, 2.8 Hz, 1H), 7.16 (d, J=12.2 Hz, 1H), 7.05 (t, J=9.3 Hz, 1H), 6.96 (s, 1H), 4.19 (m, 2H), 3.42 (s, 2H), 2.41-2.19 (m, 8H), 2.10 (s, 3H), 2.07 (s, 3H), 1.24 (m, 3H); MS (ESI) m/z: 590.2 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:17]=2[F:26])=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:28][OH:29]>N1C=CC=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:17]=2[F:26])=[N:28][OH:29])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(C(F)(F)F)cc1F)C1CCN(Cc2ccccc2)CC1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: ON=C(c1ccc(C(F)(F)F)cc1F)C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.4 %

Procedure:
A mixture of (1-benzyl-piperidin-4-yl)-(2-fluoro-4-trifluoromethyl-phenyl)-methanone (5.0 g, 13.66 mmol), hydroxylamine hydrochloride (1.1 g, 16.39 mmol) and pyridine (50 mL) was stirred at room temperature overnight when the mixture was distilled to remove pyridine (35 mL). The solid residue was washed with heptane then ether. The resulting solid was partitioned between a saturated solution of NaHCO3 and EtOAc. The organic layer was dried (MgSO4), filtered and evaporated. The solid residue was washed with 3:1 heptane/EtOAc and dried under vacuum to obtain 2.1 g (40%) of the desired product as a white solid
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.N1CCC[C@H]1C(O)=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[CH:33]=[C:34]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1)[CH3:35]>CN(C=O)C.[Cu]I>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6](/[CH:33]=[C:34](/[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=3)\[CH3:35])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: CC(=CBr)c1ccccn1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: C/C(=C\n1c2c(c3cc(C)ccc31)CN(C)CC2)c1ccccn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (700 mg, 3.5 mmol) was dissolved in DMF. Copper (I) iodide, L-proline (0.116 g, 0.7 mmol) and potassium phosphate (1.484 g, 7 mmol) were added and the reaction mixture was stirred for 10 min. at RT. 2-(1-Bromoprop-1-en-2-yl)pyridine (1.03 g, 5.25 mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated overnight at 85° C. (prolonged heating in some cases was required). DMF was evaporated under reduced pressure, the residue was diluted with water and the solid was filtered. The solid material was purified by silica gel chromatography (100-200 mesh). 1H NMR (CDCl3, HCl salt) δ (ppm): 8.62 (d, 1H), 7.78 (t, 1H), 7.60 (s, 1H), 7.50 (d, 1H), 7.28 (m, 1H), 7.18 (s, 1H), 7.10 (d, 1H), 7.05 (d, 1H), 4.40 (s, 2H), 3.50 (m, 2H), 3.20 (m, 2H), 2.95 (s, 3H), 2.42 (s, 3H), 2.05 (s, 3H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]3[CH:18]=[CH:17][S:16][CH:15]=3)[CH:12]=2)[CH:7]=[N:6]1.[NH:19]1[CH2:23]C=C[CH2:20]1>>[CH3:20][N:19]([CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]3[CH:18]=[CH:17][S:16][CH:15]=3)[CH:12]=2)[CH:7]=[N:6]1)[CH3:23]
Reactant: C1=CCNC1
Reactant: ClCCCn1ncc2ccc(-c3ccsc3)cc21
Product: CN(C)CCCn1ncc2ccc(-c3ccsc3)cc21

Procedure:
1-(3-(N-pyrrolin-3-yl)propyl)-6-(3-thienyl)-1H-indazole: (20.2 mg, 82%); from 1-(3-chloropropyl)-6-(3-thienyl)-1H-indazole (22.0 mg, 0.08 mmol) and neat 3-pyrroline (250 mg, 3.6 mmol).
Reaction SMILES: N[C@H](C(O)=O)CC1C=CC=CC=1.[C:13]([CH:17]1[N:21]([CH3:22])[C:20](=[O:23])[CH2:19][N:18]1[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])([CH3:16])([CH3:15])[CH3:14].C(NC(C)C)(C)C.[Li]CCCC.C(OC(N1CC(=O)N(C)[C@@H]1C(C)(C)C)=O)(C)(C)C.Br[CH2:62][C:63]1[CH:68]=[CH:67][C:66]([O:69][CH3:70])=[CH:65][C:64]=1[I:71].[NH4+].[Cl-]>C1COCC1>[C:27]([O:26][C:24]([N:18]1[C@@H:19]([CH2:62][C:63]2[CH:68]=[CH:67][C:66]([O:69][CH3:70])=[CH:65][C:64]=2[I:71])[C:20](=[O:23])[N:21]([CH3:22])[C@@H:17]1[C:13]([CH3:16])([CH3:14])[CH3:15])=[O:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: CN1C(=O)CN(C(=O)OC(C)(C)C)C1C(C)(C)C
Reactant: COc1ccc(CBr)c(I)c1
Agent: CN1C(=O)CN(C(=O)OC(C)(C)C)[C@H]1C(C)(C)C
Agent: N[C@@H](Cc1ccccc1)C(=O)O
Agent: [Cl-]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1ccc(C[C@H]2C(=O)N(C)[C@H](C(C)(C)C)N2C(=O)OC(C)(C)C)c(I)c1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 23 %

Procedure:
This product was obtained using the general procedure reported in the literature [(D. Seebach, E. Dziadulewicz, L. Behrendt, S. Cantoreggi, R. Fitzi, “Synthesis of Nonproteinogenic (R)- or (S)-Amino Acids Analogues of Phenylalanine, Isotopically Labelled and Cyclic Amino Acids from tert-Butyl 2-(tert-Butyl)-3-methyl-4-oxo-1-imidazolidinecarboxylate (Boc-BMI).” Liebigs Ann. Chem., pp 1215-1232 (1989)]. Diisopropylamine (0.9 mL, 6.4 mmol) dissolved in dry THF (5 mL) was cooled to −78° C. under argon and a solution of BuLi (2.5 M in hexane, 2.5 mL) was added drop wise. After 20 min of stirring at −78° C., a solution of (S)-tert-butyl-2-tert-butyl-3-methyl-4-oxoimidazolidine-1-carboxylate (3.0 g, 11.9 mmol) was added drop wise and the reaction mixture was stirred for 30 min at −40° C. A solution of 2-iodo-4-methoxybenzyl bromide (20) (2.08 g, 6.4 mmol) in dry THF (2 mL) was then added drop wise to the reaction mixture. The new reaction mixture was stirred for 2 hours at the same temperature and then poured into a saturated solution of NH4Cl. The product was extracted with EtOAc and the organic layer was washed with NaHCO3 solution followed by brine. The organic phase was dried over anhydrous Na2SO4, filtered and evaporated to produce a yellow oil. Flash chromatographic purification of the oily product provided pure (2S,5S)-tert-Butyl-5-(2′-iodo-4′-methoxybenzyl)-2-tert-butyl-3-methyl-4-oxoimida-zolidine-1-carboxylate (27) as a white solid (743.7 mg, 23%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[N:3]=1.[I:22][C:23]1[N:24]=[CH:25][NH:26][CH:27]=1>>[I:22][C:23]1[N:24]=[CH:25][N:26]([C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[N:3]=2)[CH:27]=1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)cc(Br)n2)cc1
Reactant: Ic1c[nH]cn1
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)cc(-n3cnc(I)c3)n2)cc1

Procedure:
The title compound was prepared 2-bromo-4-trifluoromethyl-6-(4-trifluoromethylphenyl)-pyridine (example A.19) (2.22 g, 6 mmol) and commercially available 4-iodo-imidazole (1.28 g, 6.6 mmol) according to the general procedure IVa. Obtained as a white solid (2.70 g, 86%, 92% purity). MS (ISP) 484.2 [(M+H)+].
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9]([C@H:12]1[CH2:17][CH2:16][C@H:15]([NH2:18])[CH2:14][CH2:13]1)(=[O:11])=[O:10].[C:19]1([S:25]([N:28]2[C:32]3=[N:33][CH:34]=[C:35]([N+:38]([O-:40])=[O:39])[C:36](Cl)=[C:31]3[CH:30]=[CH:29]2)(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(C(C)C)CC)(C)C>CC(O)C>[C:19]1([S:25]([N:28]2[C:32]3=[N:33][CH:34]=[C:35]([N+:38]([O-:40])=[O:39])[C:36]([NH:18][C@H:15]4[CH2:16][CH2:17][C@H:12]([S:9]([CH3:8])(=[O:10])=[O:11])[CH2:13][CH2:14]4)=[C:31]3[CH:30]=[CH:29]2)(=[O:26])=[O:27])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CS(=O)(=O)[C@H]1CC[C@H](N)CC1
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1Cl
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)[C@H]1CC[C@H](Nc2c([N+](=O)[O-])cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Temperature: 120 °C

Procedure:
A mixture of trans 4-methanesulfonyl-cyclohexylamine trifluoroacetic acid salt (383 mg, 1.32 mmol), 1-benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (536 mg, 1.60 mmol), diisopropylethylamine (0.69 mL, 4.0 mmol) in propan-2-ol (5.5 mL), were heated at 120° C. for 10 minutes using microwave irradiation. The mixture was cooled to 0° C. and filtered, the resulting solid washed with propan-2-ol and ether, then dried under vacuum to give 588 mg (93%) of trans (1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-yl)-(4-methanesulfonyl-cyclohexyl)-amine as a bright yellow solid. 1H NMR (400 MHz, CDCl3) δ: 9.11 (s, 1H), 8.99 (d, 1H), 8.20 (m, 2H), 7.64 (m, 2H), 7.53 (t, 2H), 6.66 (d, 1H), 3.95 (ddd, 1H), 2.95 (m, 1H), 2.91 (s, 3H), 2.40 (m, 4H), 1.85 (m, 2H), 1.52 (m, 2H).
Reaction SMILES: [O:1]=[C:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[N:12][C:6]=2[S:5][C:4]2[CH:13]=[C:14]([CH:17]([CH3:21])[C:18]([OH:20])=[O:19])[CH:15]=[CH:16][C:3]1=2.[N+](=[CH2:24])=[N-].C(O)(=O)C.C(Cl)(Cl)Cl>C(O)C.O>[O:1]=[C:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[N:12][C:6]=2[S:5][C:4]2[CH:13]=[C:14]([CH:17]([CH3:21])[C:18]([O:20][CH3:24])=[O:19])[CH:15]=[CH:16][C:3]1=2
Reactant: C=[N+]=[N-]
Reactant: CC(C(=O)O)c1ccc2c(c1)Sc1ncccc1CC2=O
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)C(C)c1ccc2c(c1)Sc1ncccc1CC2=O
Reaction time: 0.03 h

Procedure:
To 30 mg of 2-(5,6-dihydro-6oxo benzo[b]pyrido[3,2-f]-thiepin-9yl)-propionic acid in 5 ml of ethanol was added dropwise etherial solution of diazomethane at 0° C. After 2 minutes, to this was added acetic acid to decompose an excess of the reagent, then were added chloroform and water. The organic layer was collected, washed with 5% sodium hydrogencarbonate solution, then saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain the residue, which was chromatographed over silica gel, eluted with benzene/chloroform(4/1) and there was obtained 30 mg of methyl 2-(5,6-dihydro-6-oxo benzo[b]pyrido[3,2-f]thiepin-9yl)-propionate as colorless glutinous substance.
Reaction SMILES: [Cl:1]/[C:2](/[C:12]([F:15])([F:14])[F:13])=[CH:3]\[C@@H:4]1[C@H:6]([C:7](O)=[O:8])[C:5]1([CH3:11])[CH3:10].C(N(CC)CC)C.S(Cl)([Cl:25])=O.S(=O)=O.Cl>C1(C)C=CC=CC=1.C(Cl)Cl>[Cl:1]/[C:2](/[C:12]([F:15])([F:14])[F:13])=[CH:3]\[C@@H:4]1[C@H:6]([C:7]([Cl:25])=[O:8])[C:5]1([CH3:11])[CH3:10]
Reactant: O=S(Cl)Cl
Reactant: CC1(C)[C@H](/C=C(\Cl)C(F)(F)F)[C@@H]1C(=O)O
Agent: Cl
Agent: O=S=O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)[C@H](/C=C(\Cl)C(F)(F)F)[C@@H]1C(=O)Cl
Temperature: 45 °C
Reaction time: 5 h

Procedure:
A 1 liter dry, clean jacketed split reaction vessel equipped with agitator, thermometer, condenser, nitrogen blanket and vent to a scrubber system was charged with toluene (450 ml) and agitated whilst 1R cis-Z 3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethyl-cyclopropane carboxylic acid (89.4 gm=0.369 mol) was added followed by triethylamine (0.21 gm=2.1 mmol). The reaction mixture was then heated to 45° C., using oil circulation on the jacket, and thionyl chloride (62.0 gm=0.52 mol) was then charged over 105 minutes maintaining on temperature. The reaction mass was then agitated for 5 hours at 45° C. then tested by GLC for completion of reaction showing 2% residual acid. A further addition of thionyl chloride (4.4 gm=37 mmol) was then made and the reaction mass allowed to cool with stirring overnight. The following day, residual thionyl chloride, dissolved sulphur dioxide and hydrogen chloride gases were removed by distillation of about 320 ml toluene under vacuum. GC, GCMS and NMR analysis of the product were consistent with the structure of the acid chloride (IIIa). Yield, 175 gm of a 54% solution of the acid chloride in toluene, 97% theory. αD=+46° (c=0.012, DCM).
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH3:19])=[C:7]([CH3:18])[C:8]2[O:13][C:12]([OH:15])([CH3:14])[CH2:11][CH2:10][C:9]=2[C:16]=1[CH3:17])(=[O:3])[CH3:2].[H-].[Na+].[CH:22]([O:25][C:26](=[O:34])[C:27]([CH3:33])([CH3:32])[CH2:28][CH2:29][CH2:30]Br)([CH3:24])[CH3:23].Cl>C1C=CC=CC=1.CS(C)=O.C(OCC)C.O>[C:1]([O:4][C:5]1[C:6]([CH3:19])=[C:7]([CH3:18])[C:8]([O:13][CH2:30][CH2:29][CH2:28][C:27]([CH3:32])([CH3:33])[C:26]([O:25][CH:22]([CH3:23])[CH3:24])=[O:34])=[C:9]([CH2:10][CH2:11][C:12](=[O:15])[CH3:14])[C:16]=1[CH3:17])(=[O:3])[CH3:2]
Reactant: CC(C)OC(=O)C(C)(C)CCCBr
Reactant: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(O)O2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: c1ccccc1
Solvent: O
Product: CC(=O)CCc1c(C)c(OC(C)=O)c(C)c(C)c1OCCCC(C)(C)C(=O)OC(C)C
Reaction time: 0.67 h
Yield: 58 %

Procedure:
A solution containing 14.0 g (0.053 moles) of 6-acetoxy-3,4-dihydro-2-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran in 240 ml of benzene is added, by slow dripping and under nitrogen atmosphere, to a suspension containing 1.82 g (0.074 moles) of 97% sodium hydride in 100 ml of dimethylsulfoxide. After 40 minutes the solution is dripped into a solution containing 13.3 g (0.052 moles) of 2,2-dimethyl-5-bromopentanoic acid isopropyl ester in 60 ml of benzene and the mixture is reacted at 65° C. for 19 hours. The reaction mixture is then diluted with ethyl ether and water, acidified to pH 5 by means of a 10% aqueous solution of hydrochloric acid and the product is recovered pure by chromatography on silica gel column with eluent ethylene chloride-ethyl ether in 90:10 ratio. After evaporating the solvent an oil is obtained, 13.03 g with a yield of 58%, having the following chemical-physical characteristics:
Reaction SMILES: [Cl:1][C:2]1[CH:43]=[CH:42][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:13][CH:14]=3)[C:9]([C:28](=O)[C:29]([CH3:32])([CH3:31])[CH3:30])=[C:8]2[CH2:34][C:35]([CH3:41])([CH3:40])[C:36]([O:38][CH3:39])=[O:37])=[CH:4][CH:3]=1.[BH3-]C#N.[Na+]>ClC(Cl)C.[Zn+2].[I-].[I-]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:13][CH:14]=3)[C:9]([CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[C:8]2[CH2:34][C:35]([CH3:41])([CH3:40])[C:36]([O:38][CH3:39])=[O:37])=[CH:42][CH:43]=1
Reactant: COC(=O)C(C)(C)Cc1c(C(=O)C(C)(C)C)c2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(Cl)cc1
Agent: [BH3-]C#N
Agent: [I-]
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: COC(=O)C(C)(C)Cc1c(CC(C)(C)C)c2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(Cl)cc1
Reaction time: 3 h

Procedure:
A mixture of methyl 3-[1-(4-chlorobenzyl)-3-trimethylacetyl-5-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethylpropanoate (EP 419,049; Example 8, Step A) (15.64 g), ZnI2 (25.2 g), and NaBH3CN (16.4 g) in 210 mL dichloroethane was stirred using a mechanical stirrer at r.t. for 30 minutes and then at 73° C. for 3 hours. The reaction mixture was allowed to cool, poured onto NH4OAc (aq), and extracted (3x EtOAc). The organic phase was dried (MgSO4), evaporated, and the residue chromatographed (silica gel; ether/hexane 1:3) to give the title compound as a solid.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:35][CH2:34][C@@:33]2([CH3:36])[C@@H:11]([CH2:12][CH2:13][C@@H:14]3[C@@H:32]2[C@@H:31]([O:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[C@@H:30]([O:42]C(=O)C)[C@@:29]2([CH3:46])[C@H:15]3[CH2:16][C@@H:17]3[O:22][C@@:21]4([O:28][CH2:27][C@H:25]([CH3:26])[CH2:24][CH2:23]4)[C@@H:19]([CH3:20])[C@@H:18]32)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[NH4+]>C1COCC1>[Si:1]([O:8][C@H:9]1[CH2:35][CH2:34][C@@:33]2([CH3:36])[C@@H:11]([CH2:12][CH2:13][C@@H:14]3[C@@H:32]2[C@@H:31]([O:37][Si:38]([CH3:39])([CH3:40])[CH3:41])[C@@H:30]([OH:42])[C@@:29]2([CH3:46])[C@H:15]3[CH2:16][C@@H:17]3[O:22][C@@:21]4([O:28][CH2:27][C@H:25]([CH3:26])[CH2:24][CH2:23]4)[C@@H:19]([CH3:20])[C@@H:18]32)[CH2:10]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@H](O[Si](C)(C)C)[C@H]2[C@@H](CC[C@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@@]32C)[C@@H]2C[C@@H]3O[C@]4(CC[C@@H](C)CO4)[C@@H](C)[C@@H]3[C@@]12C
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5C[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@]5(C)[C@H]4[C@@H](O[Si](C)(C)C)[C@@H](O)[C@]3(C)[C@H]1[C@@H]2C

Procedure:
(3β,5α,11β,12β,25R)-3-(t-butyldimethylsilyloxy)-11-(trimethylsilyloxy)-12-acetoxyspirostane was deacetylated by treatment with lithium aluminum hydride in THF followed by catious addition aqueous ammonium chloride. The resulting title compound suffered 11 to 12 silyl group migration on silica gel, and thus had to used unpurified.