Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].[F:10][C:11]([C:14]1[CH:15]=[C:16]([CH:32]=[CH:33][CH:34]=1)[O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:25]([NH2:31])=[N:26][CH:27]=[C:28]([CH3:30])[CH:29]=2)=[CH:20][CH:19]=1)([F:13])[CH3:12]>C1COCC1>[F:10][C:11]([C:14]1[CH:15]=[C:16]([CH:32]=[CH:33][CH:34]=1)[O:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[C:25]3=[N:31][S:6](=[O:8])(=[O:7])[CH2:5][CH2:4][N:26]3[CH:27]=[C:28]([CH3:30])[CH:29]=2)=[CH:22][CH:23]=1)([F:13])[CH3:12]
Reactant: O=S(=O)(Cl)CCCl
Reactant: Cc1cnc(N)c(-c2ccc(Oc3cccc(C(C)(F)F)c3)cc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1=CN2CCS(=O)(=O)N=C2C(c2ccc(Oc3cccc(C(C)(F)F)c3)cc2)=C1
Reaction time: 0.17 h

Procedure:
To a suspension of NaH (60%, 96 mg) in THF (dry) (10 mL) was added 2-chloroethanesulfonyl chloride (0.101 mL) at 0° C. and the mixture was stirred for 10 min at the same temperature. A solution of 3-(4-(3-(1,1-difluoroethyl)phenoxy)phenyl)-5-methylpyridin-2-amine (164 mg) in THF (dry) (10 mL) was added at 0° C. and the mixture was stirred at room temperature under nitrogen overnight. The mixture was quenched with water at 0° C. Water, EtOAc and THF were added and the mixture was extracted. Silica-gel was added to the organic phase and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (silica gel, eluted with MeOH in EtOAc) and concentrated in vacuo to give 9-{4-[3-(1,1-difluoroethyl)phenoxy]phenyl}-7-methyl-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide as a white solid. Platinum(IV) oxide (30 mg) was added to a solution of the prepared 9-{4-[3-(1,1-difluoroethyl)phenoxy]phenyl}-7-methyl-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide in THF (dry) (15 mL) and MeOH (15 ml). The mixture was stirred at room temperature under hydrogen for 3 hr. Activated carbon was added and the insoluble solid was removed by filtration through silica gel/Celite pad (eluted with EtOAc, to remove catalytic poison). Platinum(IV) oxide (30 mg) was added and the mixture was stirred at room temperature under hydrogen overnight. Activated carbon was added and the insoluble solid was removed by filtration through silica gel/Celite pad (eluted with EtOAc) and the filtrate was concentrated in vacuo. The residue was crystallized from THF/IPE to give the title compound (47.6 mg) as colorless crystals.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][C@@:20]2([CH3:21])[C@@H:16]([CH2:17][CH2:18][C@@H:19]2[OH:23])[C@H:15]2[C@@:6]1([F:26])[C@:7]1([CH3:25])[C:12]([CH2:13][CH2:14]2)=[CH:11][C:10](=[O:24])[CH:9]=[CH:8]1)(=[O:3])[CH3:2].O.[CH3:28][S:29]([CH3:31])=O>C(O)(=O)C.C(OC(=O)C)(=O)C>[C:1]([O:4][C@H:5]1[CH2:22][C@@:20]2([CH3:21])[C@@H:16]([CH2:17][CH2:18][C@@H:19]2[O:23][CH2:28][S:29][CH3:31])[C@H:15]2[C@@:6]1([F:26])[C@:7]1([CH3:25])[C:12]([CH2:13][CH2:14]2)=[CH:11][C:10](=[O:24])[CH:9]=[CH:8]1)(=[O:3])[CH3:2]
Reactant: CS(C)=O
Reactant: CC(=O)O[C@H]1C[C@]2(C)[C@@H](O)CC[C@H]2[C@@H]2CCC3=CC(=O)C=C[C@]3(C)[C@@]12F
Solvent: CC(=O)OC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CSCO[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](OC(C)=O)C[C@]12C

Procedure:
To a solution of (11β,17β)-11-(acetyloxy)-9-fluoro-17-hydroxyandrosta-1,4-dien-3-one (1.6 g, 4.42 mmole) in dry dimethylsulfoxide (30 ml), acetic acid (10 ml) and acetic anhydride (20 ml) were added. The starting steroid disappeared in 20 hours. The mixture was added into water and was extracted with chloroform (3×100 ml). The chloroform extracts were combined, washed with dilute brine and water, dried (anhydrous magnesium sulfate) and was evaporated in vacuo. The residue was dissolved in chloroform-hexane (1:1) and was absorbed on a column of silica gel (45 g). Elutions of the column successively with the same solvent mixture, chloroform and chloroform-ethyl acetate mixtures (2,3,5 and 10% ethyl acetate) gave (i) the homogeneous (tlc) title compound (1.1 g), (ii) a mixture of the 17α-isomer of the title compound and (11β)-11-(acetyloxy)-9-fluoroandrosta-1,4-dien-3,17-dione (300 mg), and (iii) (11β)-11-(acetyloxy)-9-fluoroandrosta-1,4-dien-3,17-dione (280 mg).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:37][CH:38]([S:40]([C:43]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=1)(=[O:42])=[O:41])[CH3:39].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19]([C:46]2[CH:47]=[CH:48][C:43]([S:40]([CH:38]([CH3:39])[CH3:37])(=[O:42])=[O:41])=[CH:44][CH:45]=2)=[CH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)OC(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Reactant: CC(C)S(=O)(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)S(=O)(=O)c1ccc(C(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Yield: 86.8 %

Procedure:
To a mixture of toluene-4-sulfonic acid-1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl ester (prepared as in Example 43, 0.15 g, 0.28 mmol), 4-(propane-2-sulfonyl)phenyl boronic acid (0.12 g, 0.72 mmol) and dichlorobis(triphenylphosphine)palladium (II) (21 mg, 0.03 mmol) in dioxane (3 mL) was added an aqueous sodium carbonate solution (2 M, 0.36 mL). The resulting mixture was subjected to microwave irradiation for 2 h at 100° C. The mixture was diluted with ethyl acetate (100 mL), washed with a saturated aqueous sodium bicarbonate solution (2×30 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 25% ethyl acetate/hexanes) afforded 1-benzenesulfonyl-2-{2-cyclopentyl-1-[4-(propane-2-sulfonyl)-phenyl]-vinyl}-1H-pyrrolo[2,3-b]pyridine (130 mg, 84%) as a white solid: LC/MS m/e calcd for C29H30N2O4S2 [M+H]+ 535.70, observed 535.4.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:13]([F:16])([F:15])[F:14])=[N:4][NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:24][C:25]([N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([O:40][CH3:41])[CH:34]=2)[CH2:29][CH2:28]1)=[O:26].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([N:30]2[CH2:31][CH2:32][N:27]([C:25](=[O:26])[CH2:24][N:5]3[C:6]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)=[C:2]([Cl:1])[C:3]([C:13]([F:14])([F:16])[F:15])=[N:4]3)[CH2:28][CH2:29]2)=[CH:34][C:35]=1[O:40][CH3:41]
Reactant: COc1cc(N2CCN(C(=O)CCl)CC2)ccc1Cl
Reactant: FC(F)(F)c1n[nH]c(-c2ccccc2)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(N2CCN(C(=O)Cn3nc(C(F)(F)F)c(Cl)c3-c3ccccc3)CC2)ccc1Cl

Procedure:
Protocol T was followed using 4-Chloro-5-phenyl-3-trifluoromethyl-1H-pyrazole, K2CO3, 2-Chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=2/3, Rf=0.92) afforded the title compound as a white solid. 1H NMR (400 MHz, CDCl3): 7.78-7.84 (m, 2H), 7.36-7.52 (m, 4H), 6.38-6.48 (m, 2H), 5.2 (s, 2H), 3.88 (s, 3H), 3.62-3.78 (m, 4H), 3.18-3.26 (s, 4H). 13C NMR (400 MHz, CDCl3) 164.4, 156, 150.4, 130.4, 130, 128.6, 110.2, 102.4, 56.4, 52, 50.4, 44.6, 42.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]=[C:11]2[CH:16]3[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]3)[CH2:12]2)=[CH:5][CH:4]=1.[O:19]1[CH2:29][CH:20]1[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>CO>[Cl-:2].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]=[C:11]2[CH:16]3[CH2:15][CH2:14][N+:13]([CH2:29][CH:20]([OH:19])[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])([CH2:18][CH2:17]3)[CH2:12]2)=[CH:5][CH:4]=1
Reactant: Clc1ccc(CC=C2CN3CCC2CC3)cc1
Reactant: CC(C)(C)OC(=O)CC1CO1
Agent: Cl
Solvent: CO
Product: CC(C)(C)OC(=O)CC(O)C[N+]12CCC(CC1)C(=CCc1ccc(Cl)cc1)C2
Product: [Cl-]

Procedure:
Partially dissolve 3-[2-(4-chlorophenyl)ethylidene]-quinuclidine hydrochloride (0.12 g, 0.5 mmole) in 5 ml of anhydrous methanol and stir under nitrogen atmosphere. Add t-butyl 3,4-epoxybutyrate (0.16 g, 1.0 mmole) and stir at room temperature for three days. Remove methanol in vacuo and purify the residue by preparative thin-layer chromatography on silica gel (acetonitrile: NH4OH, 90:10) to provide the title compound.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:14](C=O)=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1[Cl:17])(=[O:3])[CH3:2].Cl.[O:19]([NH2:21])[CH3:20].[CH2:22](N(CC)CC)C>C(Cl)Cl>[C:1]([NH:4][CH:5]1[C:14](=[N:21][O:19][CH3:20])[CH:13]=[C:8]([C:9]([O:11][CH3:12])=[O:10])[C:7]([CH3:22])=[C:6]1[Cl:17])(=[O:3])[CH3:2]
Reactant: CCN(CC)CC
Reactant: CON
Reactant: COC(=O)c1cc(Cl)c(NC(C)=O)c(C=O)c1
Agent: Cl
Solvent: ClCCl
Product: CON=C1C=C(C(=O)OC)C(C)=C(Cl)C1NC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.7 %

Procedure:
To a cooled solution (ice bath) of 2.6 g (10.15 mmole) of methyl 4-acetamido-3-chloro-5-formylbenzoate in 75 ml of methylene chloride was added 1.16 g (13.87 mmole) of methoxylamine hydrochloride followed by 1.93 mL (13.87 mmole) of triethylamine. The ice bath was removed and the resulting mixture stirred overnight at room temperature. The reaction mixture was then washed with water and dried over anhydrous magnesium sulfate. The solvent was removed using a rotary evaporator, yielding 2.29 g methyl 4-acetamido-3-chloro-5-methoxyimino-methylbenzoate used without further purification in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]#[C:12][CH2:13][CH2:14][O:15][CH3:16])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH2:31][CH2:32][CH2:33]Cl)=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1.[CH3:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>COCCO>[Cl:1][C:2]1[CH:10]=[C:9]([C:11]#[C:12][CH2:13][CH2:14][O:15][CH3:16])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH2:31][CH2:32][CH2:33][N:39]3[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][CH2:38]3)=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1
Reactant: COCCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCCl)c(OC)cc23)c2c1OCO2
Reactant: CN1CCNCC1
Solvent: COCCO
Product: COCCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCN4CCN(C)CC4)c(OC)cc23)c2c1OCO2
Yield: 67.8 %

Procedure:
This was prepared by the method described in example 13 using N-[5-Chloro-7-(4-methoxybut-1-yn-1-yl)-1,3-benzodioxol-4-yl]-7-(3-chloropropoxy)-6-methoxyquinazolin-4-amine (200 mg, 0.40 mmol) and 1-methylpiperazine (198 mg, 1.98 mmol) in 2-methoxyethanol (4 ml). The crude product was purified by column chromatography on silica using increasing concentrations of methanolic ammonia in dichloromethane as eluent. There was thus obtained the title compound (154 mg, 68%) as a pale brown solid; NMR Spectrum:(DMSOd6) 1.95 (quintet, 2H), 2.14 (s, 3), 2.2-2.6 (m, 8H), 2.47 (t, 2H), 2.72 (t, 2H), 3.31 (s, 3H), 3.53 (t, 2H), 3.92 (s, 3H), 4.18 (s, 2H), 6.14 (s, 2H), 7.08 (s, 1H), 7.16 (s, 1H), 7.82 (s, 1H), 8.32 (s, 1H), 9.50 (s, 1H); Mass Spectrum: M+H+ 568/570.
Reaction SMILES: C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N.[N+]([O-])(O)=O.[N+:22]([O:25][CH2:26][CH2:27][NH2:28])([O-:24])=[O:23].[C:29]1([CH:39]2[S:43][C:42](=[O:44])[NH:41][CH:40]2[C:45](O)=[O:46])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1>O1CCCC1>[N+:22]([O:25][CH2:26][CH2:27][NH:28][C:45]([CH:40]1[CH:39]([C:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH:32]=[CH:31][CH:30]=2)[S:43][C:42](=[O:44])[NH:41]1)=[O:46])([O-:24])=[O:23]
Reactant: NCCO[N+](=O)[O-]
Reactant: O=C1NC(C(=O)O)C(c2cccc3ccccc23)S1
Agent: CCOP(=O)(C#N)OCC
Solvent: C1CCOC1
Solvent: O=[N+]([O-])O
Solvent: CCN(CC)CC
Product: O=C1NC(C(=O)NCCO[N+](=O)[O-])C(c2cccc3ccccc23)S1
Temperature: 25 °C
Reaction time: 4 h
Yield: 55.5 %

Procedure:
1.23 ml of triethylamine and 0.36 ml of diethyl cyanophosphonate were added, whilst ice-cooling and stirring, to a suspension of 370 mg of N-(2-nitrooxyethyl)amine nitrate and 500 mg of 5-(1-naphthyl)-2-oxothiazolidine-4-carboxylic acid in 50 ml of dry tetrahydrofuran, and the resulting mixture was stirred at room temperature for 4 hours. At the end of this time, the solvent was removed by distillation under reduced pressure, and the residue was mixed with ethyl acetate. The resulting mixture was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, and the crystalline residue was recrystallized from ethanol, to give 367 mg of the title compound as colorless crystals, melting at 151°-153° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]=[C:21]3[C:17]([N:18]=[CH:19][N:20]3[C@@H:23]3[CH2:27][C@H:26]([N:28]4[CH:32]=[C:31]([CH2:33][OH:34])[CH:30]=[N:29]4)[C@@H:25]([OH:35])[C@H:24]3[OH:36])=[C:16]([NH:37][CH2:38][CH:39]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[N:15]=2)[CH2:10]1.FC(F)(F)C(O)=O.O[C@@H]1[C@H](O)[C@@H](N2C=C(C)C=N2)C[C@H]1N1C=NC2C1=NC(NC1CCC(N[C:104]([NH:106][CH:107]3[CH2:112][CH2:111][N:110]([C:113]4[CH:118]=[CH:117][CH:116]=[CH:115][N:114]=4)[CH2:109][CH2:108]3)=[O:105])CC1)=NC=2NCC(C1C=CC=CC=1)C1C=CC=CC=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[OH:36][C@@H:24]1[C@H:25]([OH:35])[C@@H:26]([N:28]2[CH:32]=[C:31]([CH2:33][OH:34])[CH:30]=[N:29]2)[CH2:27][C@H:23]1[N:20]1[CH:19]=[N:18][C:17]2[C:21]1=[N:22][C:14]([N:11]1[CH2:12][CH2:13][C@@H:9]([NH:8][C:104]([NH:106][CH:107]3[CH2:108][CH2:109][N:110]([C:113]4[CH:118]=[CH:117][CH:116]=[CH:115][N:114]=4)[CH2:111][CH2:112]3)=[O:105])[CH2:10]1)=[N:15][C:16]=2[NH:37][CH2:38][CH:39]([C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: Cc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(NC5CCC(NC(=O)NC6CCN(c7ccccn7)CC6)CC5)nc43)[C@H](O)[C@@H]2O)c1
Reactant: N[C@@H]1CCN(c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4C[C@H](n5cc(CO)cn5)[C@@H](O)[C@H]4O)c3n2)C1
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC1CCN(c2ccccn2)CC1)N[C@@H]1CCN(c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4C[C@H](n5cc(CO)cn5)[C@@H](O)[C@H]4O)c3n2)C1

Procedure:
This compound is prepared from (1R,2S,3R,5S)-3-[2-((R)-3-amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-5-(4-hydroxymethyl-pyrazol-1-yl)-cyclopentane-1,2-diol trifluoroacetate (Example 76) using a procedure analogous to that of 1-{4-[9-[(1R,2S,3R,4S)-2,3-dihydroxy-4-(4-methyl-pyrazol-1-yl)-cyclopentyl]-6-(2,2-diphenyl-ethylamino)-9H-purin-2-ylamino]-cyclohexyl}-3-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-urea trifluoroacetate (Example 42). MS (ES+) m/e 400 (MH+/2)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]([NH:7][C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:15])=[S:6].Cl.I[CH3:18].[OH-].[Na+]>O.C(O)C>[NH2:1][CH2:2][CH2:3][NH:4][C:5](=[N:7][C:8]1[C:9]([Cl:15])=[CH:10][CH:11]=[CH:12][C:13]=1[Cl:14])[S:6][CH3:18]
Reactant: CI
Reactant: NCCNC(=S)Nc1c(Cl)cccc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CSC(=Nc1c(Cl)cccc1Cl)NCCN

Procedure:
A solution of 12.68 g. of 1-(2-aminoethyl)-3-(2,6-dichlorophenyl)thiourea in 80 ml. of ethanol, 4.0 ml. of concentrated hydrochloric acid and 12 ml. of iodomethane was refluxed for 2 hours. On cooling, the mixture was poured onto 200 ml. of water and sufficient 4N sodium hydroxide was added to bring the pH to 11. The aqueous solution was extracted 3 × 150 ml. of methylene chloride, and the combined organic layers were washed 1 × 100 ml. of water, dried over potassium carbonate and concentrated. The resulting gum gave a solid on standing, i.e., 1-(2-aminoethyl)-3-(2,6-dichlorophenyl)-2-methylthiopseudourea, m.p. 74°-79°, whose spectral data were consistent with the assigned structure. The material was too labile for purification and was acidified with hydrochloric acid and crystallized from ethanol-ether to give 14.10 g. (84%) of 1-(2-aminoethyl)-3-(2,6-dichlorophenyl)-2-methylthiopseudourea dihydrochloride, m.p. 179°-184°. Two crystallizations from ethanol-ether gave an analytical sample, m.p. 179°-182°.
Reaction SMILES: Cl.[N:2]1([CH2:8][C:9]23[CH2:17][CH:13]4[CH2:14][CH:15]([CH2:16]2)[C:11]([NH2:18])([CH2:12]4)[CH2:10]3)[CH2:7][CH2:6][S:5][CH2:4][CH2:3]1.Cl[CH2:20][C:21]([N:23]1[CH2:27][CH2:26][CH2:25][C@H:24]1[C:28]#[N:29])=[O:22].C([O-])([O-])=O.[K+].[K+]>CS(C)=O.CCOC(C)=O>[N:2]1([CH2:8][C:9]23[CH2:17][CH:13]4[CH2:12][C:11]([NH:18][CH2:20][C:21]([N:23]5[CH2:27][CH2:26][CH2:25][C@H:24]5[C:28]#[N:29])=[O:22])([CH2:10]2)[CH:15]([CH2:14]4)[CH2:16]3)[CH2:7][CH2:6][S:5][CH2:4][CH2:3]1
Reactant: NC12CC3CC1CC(CN1CCSCC1)(C3)C2
Reactant: N#C[C@@H]1CCCN1C(=O)CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#C[C@@H]1CCCN1C(=O)CNC12CC3CC1CC(CN1CCSCC1)(C3)C2
Reaction time: 3 h
Yield: 35.3 %

Procedure:
To a stirred solution of the hydrochloride salt (0.17 g, 0.51 mmol) obtained in step II above in DMSO (2.0 mL) at room temperature under nitrogen atmosphere was added (2S)-1-(chloroacetyl)pyrrolidine-2-carbonitrile (0.09 g, 0.52 mmol) and K2CO3 (0.35 g, 2.55 mmol. After stirring the reaction mixture for 3 h, it was diluted with EtOAc and washed with water and brine, dried over Na2SO4 and the solvent was removed under reduced pressure. The crude product was purified by column chromatography to obtain (2S)-1-{N-[2-(thiomorpholin-4-ylmethyl)hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrile as an off-white solid (0.07 g) in 35% yield. m/z (M+1) 389; 1H NMR (CDCl3) 300 MHz δ 4.83-4.75 (m, 1H), 3.90-3.45 (m, 4H), 2.85-2.70 (m, 4H), 2.70-2.60 (m, 4H), 2.48-2.35 (m, 2H), 2.35-2.15 (m, 4H), 2.0-1.75 (m, 4H), 1.68-1.40 (m, 5H), 1.38-1.25 (m, 1H).
Reaction SMILES: Cl[S:2]([OH:5])(=O)=[O:3].[CH2:6]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH:7]([CH3:9])[CH3:8].[C:16]([NH2:20])([CH3:19])([CH3:18])[CH3:17]>C1(C)C=CC=CC=1>[C:16]([NH:20][S:2]([C:13]1[CH:14]=[CH:15][C:10]([CH2:6][CH:7]([CH3:9])[CH3:8])=[CH:11][CH:12]=1)(=[O:5])=[O:3])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)Cc1ccccc1
Reactant: CC(C)(C)N
Reactant: O=S(=O)(O)Cl
Solvent: Cc1ccccc1
Product: CC(C)Cc1ccc(S(=O)(=O)NC(C)(C)C)cc1
Temperature: 40 °C
Yield: 54.2 %

Procedure:
Chlorosulfonic acid (28.6 mL, 0.43 mol) was added dropwise to stirred iso-butylbenzene (11.14 g, 0.083 mol) at 0° C. The reaction mixture was then heated to 40° C. for 0.5 h, poured into ice-water (150 mL) and extracted with ethyl acetate (400 mL). The organic phase was washed with water and brine and dried over MgSO4. The solvent was removed in vacuo and the residue was dissolved in CHCl3 (50 mL). To this stirred solution, tert-butylamine (43.7 mL, 0.416 mol) was added dropwise. The reaction was heated to reflux for 10 min and then cooled to room temperature. The reaction mixture was then diluted with toluene (200 mL) and washed with water and brine. The organic phase was dried over MgSO4 and the solvent was removed in vacuo. Purification using column chromatography with hexane:acetone (4:1) as eluent yielded the sub-title compound as a white solid (12.0 mg, 0.045 mol) in 54% yield.
Reaction SMILES: O.N.[C:3]([N:7]1[C@H:11]([C:12](=[O:40])[NH:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[N:20]=[CH:19][N:18]=[C:17]3[NH:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=3)=[C:27]([Cl:39])[CH:26]=2)[CH2:10][C@@H:9]([O:41]C(=O)C)[CH2:8]1)(=[O:6])[CH:4]=[CH2:5].C(Cl)(Cl)Cl>CO>[Cl:39][C:27]1[CH:26]=[C:25]([NH:24][C:17]2[C:16]3[C:21](=[CH:22][CH:23]=[C:14]([NH:13][C:12]([C@@H:11]4[CH2:10][C@@H:9]([OH:41])[CH2:8][N:7]4[C:3](=[O:6])[CH:4]=[CH2:5])=[O:40])[CH:15]=3)[N:20]=[CH:19][N:18]=2)[CH:30]=[CH:29][C:28]=1[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1
Reactant: C=CC(=O)N1C[C@H](OC(C)=O)C[C@H]1C(=O)Nc1ccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c2c1
Agent: N
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: O
Product: C=CC(=O)N1C[C@H](O)C[C@H]1C(=O)Nc1ccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c2c1
Temperature: 80 °C
Reaction time: 26 h
Yield: 66.3 %

Procedure:
0.32 ml of ammonia water was added to 130 mg of the compound obtained in Example 148 diluted with 10 ml of methanol, and the solution was refluxed with stirring at 80° C. for 26 hours. The reacted solution was cooled to room temperature, and filtered under a reduced pressure to obtain solid. The solid was subjected to column chromatography (eluent-chloroform:methanol=15:1) to obtain the title compound (80 mg, 66%).
Reaction SMILES: [C:1]([C:4]1[C:5]([C:19](=[O:21])[CH3:20])=[C:6]([CH3:18])[N:7]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=2[CH3:17])[C:8]=1[CH3:9])(=[O:3])[CH3:2].Br[CH2:23][CH3:24].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:1]([C:4]1[C:5]([C:19](=[O:21])[CH3:20])=[C:6]([CH3:18])[N:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:23][CH3:24])=[CH:12][C:11]=2[CH3:17])[C:8]=1[CH3:9])(=[O:3])[CH3:2]
Reactant: CCBr
Reactant: CC(=O)c1c(C(C)=O)c(C)n(-c2ccc(O)cc2C)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc(-n2c(C)c(C(C)=O)c(C(C)=O)c2C)c(C)c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of 1-[4-acetyl-1-(4-hydroxy-2-methyl-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone (prepared as outline in Example 63; 56 mg, 0.20 mmol) in 2 mL of dry DMF was added bromoethane (100 μL) and K2CO3 powder (50 mg). The resulting reaction mixture was warmed to 50° C. and stirred for 1 h. It was quenched by addition of 20 mL of H2O, extracted with diethyl ether (20 mL×2). The combined organic extracts were washed with brine (50 mL), dried (MgSO4), filtered, and concentrated in vacuo to afford 1-[4-acetyl-1-(4-ethoxy-2-methyl-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone: MS (ESI) 314 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9](=O)[CH2:10][F:11].[CH3:13][C:14]([S@:17]([NH2:19])=[O:18])([CH3:16])[CH3:15]>C1COCC1.[Cl-].[Na+].O.C(O[Ti](OC(C)C)(OC(C)C)OC(C)C)(C)C>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1/[C:9](=[N:19]\[S@@:17]([C:14]([CH3:16])([CH3:15])[CH3:13])=[O:18])/[CH2:10][F:11]
Reactant: CC(C)(C)[S@](N)=O
Reactant: O=C(CF)c1cccc(F)c1F
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[S@@](=O)/N=C(/CF)c1cccc(F)c1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 40.7 %

Procedure:
To a solution of 1-(2,3-difluorophenyl)-2-fluoroethanone (18.9 g, 109 mmol) in THF (400 mL) was added (R)-(+)-2-methyl-2-propanesulfinamide (26.3 g, 217 mmol) followed by tetraisopropoxytitanium (93 g, 326 mmol). The reaction was heated to reflux for 2 h. The mixture was allowed to cool to room temperature and then treated with brine (400 ml). The resulted suspension was stirred for 15 min and filtered through a pad of celite. The filter cake was washed with EtOAc. The filtrate was extracted with EtOAc (2×). The organic extracts were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated and purified by silica gel column (0-20% EtOAc/hexane) to afford (R,E)-N-(1-(2,3-difluorophenyl)-2-fluoroethylidene)-2-methylpropane-2-sulfinamide (12.3 g, 44.4 mmol, 40.9% yield) as yellow oil, MS m/z=278.0 [M+H]+. calculated for C12H14F3NOS: 277.3