Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:7]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@@H:6]([C:15]([O-:17])=[O:16])[CH2:5][CH2:4][CH2:3]1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([Mg]Br)=[CH:21][CH:20]=1.[CH2:27]1COCC1>>[C:11]([O:10][C:8]([NH:7][C@H:6]([CH2:5][CH2:4][CH2:3][C:2]([C:22]1[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=1)=[O:1])[C:15]([O:17][CH3:27])=[O:16])=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)N1C(=O)CCC[C@@H]1C(=O)[O-]
Reactant: Clc1ccc([Mg]Br)cc1
Product: COC(=O)[C@@H](CCCC(=O)c1ccc(Cl)cc1)NC(=O)OC(C)(C)C
Reaction time: 1.5 h

Procedure:
To a solution of 1-tert-butyl(R)-6-oxopiperidine-1,2-dicarboxylate (CAS No. 183890-36-0, 9.00 g) in THF (120 ml), 4-chlorophenylmagnesium bromide (1.0 M solution in diethyl ether, 42 ml) was added in a nitrogen atmosphere at −78° C. over 20 minutes. The reaction solution was stirred at −78° C. to −40° C. for 1.5 hours, and then quenched with a saturated ammonium chloride solution at −40° C. Water was added to the reaction solution, followed by extraction with ethyl acetate. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain methyl(R)-2-tert-butoxycarbonylamino-6-(4-chlorophenyl)-6-oxohexanoate (9.53 g). A solution of 4 N hydrogen chloride in ethyl acetate (90 ml) was added to a solution of methyl(R)-2-tert-butoxycarbonylamino-6-(4-chlorophenyl)-6-oxohexanoate (9.53 g) in ethyl acetate (90 ml) at room temperature, and the reaction solution was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was made basic with a saturated sodium bicarbonate solution. Then, chloroform was added to the residue, and the mixture was stirred at room temperature for two hours. The organic layer was separated, dried over magnesium sulfate, and then concentrated under reduced pressure. Sodium cyanoborohydride (3.29 g) and then acetic acid (4.27 ml) were added to a solution of the residue in methanol (150 ml) at 0° C., and the reaction solution was stirred at 0° C. for one hour and at room temperature for one hour. A saturated sodium bicarbonate solution was added to the reaction solution, followed by extraction with chloroform. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) and solidified with a heptane-diisopropyl ether system to obtain 2.47 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[CH2:30][CH2:29][CH2:28][N:12]2[C:13]=1[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([C:23]([O:25]CC)=O)=[N:21][N:22]=2)[N:19]=1.[CH2:31]1COCC1.C[Mg]Cl>O.C(Cl)Cl.[Cl-].[NH4+]>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[CH2:30][CH2:29][CH2:28][N:12]2[C:13]=1[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([C:23](=[O:25])[CH3:31])=[N:21][N:22]=2)[N:19]=1
Reactant: CCOC(=O)c1nnc2ccc(-c3c(-c4ccc(F)cc4F)nc4n3CCC4)nn12
Reactant: C1CCOC1
Agent: C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: ClCCl
Product: CC(=O)c1nnc2ccc(-c3c(-c4ccc(F)cc4F)nc4n3CCC4)nn12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 97 %

Procedure:
A 100 mL round bottom flask was charged with ethyl 6-(2-(2,4-difluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine-3-carboxylate (3.04 g, 7.41 mmol). THF (37.0 mL) was added and the mixture was stirred at ambient temperature for about 15 min. The slurry was cooled to about −40° C. and a solution of methylmagnesium chloride (3 M in THF, 9.88 mL, 29.6 mmol) was added slowly while keeping the internal temperature between about −30° C. and −40° C. After about 15 min the mixture was cooled to about −55° C. followed by the slow addition of saturated ammonium chloride solution (about 10 mL). The mixture was then warmed to ambient temperature and diluted with water (50 mL), DCM (75 mL), and saturated aqueous ammonium chloride solution (50 mL). The layers were separated and the aqueous solution was extracted with DCM (2×100 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound (2.74 g, 97%): LC/MS (Table 1, Method h) Rt=1.22 min; MS m/z: 381.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][C:21]([C:25]3[CH:26]=[N:27][NH:28][CH:29]=3)=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][CH:22]=[C:21]([C:25]5[CH:29]=[N:28][NH:27][CH:26]=5)[CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2cc(-c3cn[nH]c3)ccc21
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CC1c2ccc(-c3cn[nH]c3)cc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-6-(1H-pyrazol-4-yl)-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [Cl:1]Cl.[O:3]([C:10]1[CH:15]=CC=[CH:12][C:11]=1[O:16][CH3:17])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl:18][CH2:19][CH2:20][Cl:21]>>[Cl:18][C:19]1[C:20]([Cl:21])=[CH:12][C:11]([O:16][CH3:17])=[C:10]([O:3][C:4]2[CH:9]=[CH:8][C:7]([Cl:1])=[CH:6][CH:5]=2)[CH:15]=1
Reactant: COc1ccccc1Oc1ccccc1
Reactant: ClCl
Reactant: ClCCCl
Product: COc1cc(Cl)c(Cl)cc1Oc1ccc(Cl)cc1

Procedure:
With stirring, 11.5 g of chlorine are introduced at room temperature into a solution of 8 g of 2-phenoxyanisole in 85 ml of 1,2-dichloroethane in the course of 20 minutes. The reaction mixture is then stirred for 30 minutes at room temperature. The solvent is removed by evaporation and the crystalline residue is recrystallised from methanol, affording 4,5-dichloro-2-(4-chlorophenoxy)anisole in the form of white crystals with a melting point of 105°-106° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[N:11]=[C:10]3[C:20](=[O:26])[N:21]([CH:23]([CH3:25])[CH3:24])[CH2:22][C:9]=23)=[CH:4][CH:3]=1.I[CH3:28]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[N:11]=[C:10]3[C:20](=[O:26])[N:21]([CH:23]([CH3:24])[CH3:25])[CH:22]([CH3:28])[C:9]=23)=[CH:4][CH:3]=1
Reactant: CC(C)N1Cc2c(nn(-c3ccccc3Cl)c2-c2ccc(Cl)cc2)C1=O
Reactant: CI
Solvent: C1CCOC1
Product: CC(C)N1C(=O)c2nn(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)c2C1C
Reaction time: 0.17 h
Yield: 16 %

Procedure:
To a solution of 3-(4-chloro-phenyl)-2-(2-chloro-phenyl)-5-isopropyl-4,5-dihydro-2H-pyrrolo[3,4-c]pyrazol-6-one 3A-1 (19 mg, 0.05 mmol) in THF (0.5 ml) at −78° C. was added LiHMDSi (55 μl, 0.055 mmol). A deep blue-black solution was formed. The reaction mixture was stirred for 0.17 hour and then iodomethane (4.4 μl, 0.07 mmol) was added dropwise. The reaction mixture was stirred at −78° C. for 0.25 h (until a yellow color formed) and at room temperature for 2 hours, quenched with sat'd aq NH4Cl, and extracted with EtOAc. The organic solution was washed with sat'd aq NaCl, dried, and concentrated in vacuo. The residue was purified on 1 mm chromatotron plates using a 1:1 EtOAc/hexane solution to give 6A-1 as a white solid (3.2 mg, 14%); +ES MS (M+1) 400.3; 1H NMR (CDCl3): δ 7.4-7.3 (m, 4H), 7.28-7.24 (m, 2H), 7.1-7.06 (m, 2H), 4.84-4.77 (m, 1H), 4.37-4.27 (m, 1H), 1.48-1.4 (m, 9H).
Reaction SMILES: Cl.[CH:2]([NH2:4])=[NH:3].C[O-].[Na+].CN([CH:11]=[C:12]1[C:18](=O)[C:17]2[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=2[N:15]([C:24](=[O:34])[C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=2)[CH2:14][CH2:13]1)C>CO>[N+:31]([C:28]1[CH:29]=[CH:30][C:25]([C:24]([N:15]2[C:16]3[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=3[C:18]3[N:3]=[CH:2][N:4]=[CH:11][C:12]=3[CH2:13][CH2:14]2)=[O:34])=[CH:26][CH:27]=1)([O-:33])=[O:32]
Reactant: CN(C)C=C1CCN(C(=O)c2ccc([N+](=O)[O-])cc2)c2ccccc2C1=O
Reactant: N=CN
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=C(c1ccc([N+](=O)[O-])cc1)N1CCc2cncnc2-c2ccccc21
Reaction time: 0.08 h
Yield: 107.7 %

Procedure:
To a solution of 0.152 g (1.89 mmol) of formamidine hydrochloride in 10 ml of methanol under argon is added 0.102 g (1.89 mmol) of sodium methoxide. After stirring 5 min., a solution of 0.46 g (1.26 mmol) of 4-[(dimethylamino)methylene]-1,2,3,4-tetrahydro-1-(4-nitrobenzoyl)-5H-1-benzazepine-5-one in 5 ml of methanol is added and the mixture stirred 18 hours. The solvent is removed, dichloromethane added, and the mixture filtered. The solid is washed with dichloromethane. The combined filtrate is concentrated to dryness to give 0.47 g of tan foam. The preceding solid is purified by chromatography on silica gel. The compound is dissolved in ethyl acetate-dichloromethane and applied to the column. The column is then eluted with ethyl acetate to give 0.25 g of product as pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:40])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:27]([O:29][CH3:30])=[O:28])([CH3:26])[CH3:25])[CH2:14][C:13](=O)[NH:12][CH:11]3[C:32]3[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=3[CH3:39])[C:5]2=[CH:4][CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:42]>C1COCC1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:40])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:27]([O:29][CH3:30])=[O:28])([CH3:26])[CH3:25])[CH2:14][C:13](=[S:42])[NH:12][CH:11]3[C:32]3[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=3[CH3:39])[C:5]2=[CH:4][CH:3]=1
Reactant: COC(=O)C(C)(C)Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)Oc1ccc(Cl)cc1C1CC(=S)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 40 °C
Yield: 83.1 %

Procedure:
A mixture of chiral (2′S, 3S, 4′R)-6-chloro-4′-[5-chloro-2-(1-methoxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (300 mg, 0.52 mmol) prepared in Example 6 and P2S5 (227 mg, 1.02 mmol) in THF (3 mL) was heated at 40° C. for 2 h, and then diluted with toluene (20 mL). The mixture was concentrated in vacuo and the residue was washed with DCM twice. The DCM solution was collected and purified by flash column chromatography to give the title compound as white solid (260 mg).
Reaction SMILES: C(OC([N:8]1[CH:21]([C:22](O)=[O:23])[CH2:20][C:19]2[CH:18]=[C:17]3[C:12]([O:13][C@@H:14]([C:26]4[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]5[CH:39]=[CH:38][C:37]([Cl:40])=[C:36]([Cl:41])[CH:35]=5)=[CH:28][CH:27]=4)[C:15](=[O:25])[NH:16]3)=[CH:11][C:10]=2[CH2:9]1)=O)(C)(C)C.Cl.[CH3:43][O:44][C:45](=[O:62])[C@@H:46]([NH2:61])[CH2:47][C:48]1[CH:53]=[CH:52][C:51]([C:54]2[CH:59]=[CH:58][C:57]([CH3:60])=[CH:56][CH:55]=2)=[CH:50][CH:49]=1>>[ClH:40].[CH3:43][O:44][C:45](=[O:62])[C@@H:46]([NH:61][C:22]([CH:21]1[CH2:20][C:19]2[CH:18]=[C:17]3[C:12]([O:13][C@@H:14]([C:26]4[CH:27]=[CH:28][C:29]([O:32][CH2:33][C:34]5[CH:39]=[CH:38][C:37]([Cl:40])=[C:36]([Cl:41])[CH:35]=5)=[CH:30][CH:31]=4)[C:15](=[O:25])[NH:16]3)=[CH:11][C:10]=2[CH2:9][NH:8]1)=[O:23])[CH2:47][C:48]1[CH:53]=[CH:52][C:51]([C:54]2[CH:59]=[CH:58][C:57]([CH3:60])=[CH:56][CH:55]=2)=[CH:50][CH:49]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccc(C)cc2)cc1
Reactant: CC(C)(C)OC(=O)N1Cc2cc3c(cc2CC1C(=O)O)NC(=O)[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Agent: Cl
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)C(=O)N3

Procedure:
(S)-2-({(S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-methyl-biphenyl-4-yl)-propionic acid methyl ester hydrochloride (74 mg, LC/MS: m/z 751) was prepared from (S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylic acid 6-tert-butyl ester (150 mg) and (S)-2-Amino-3-(4′-methyl-biphenyl-4-yl)-propionic acid methyl ester hydrochloride according to general procedures A and C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[N:5][C:4]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:3]1.[BH4-].[Na+].[CH4:15]>CO.[Cl-].[Na+].CCOCC>[CH3:1][N:2]1[CH:6]=[N:5][C:4]([C:7]2[CH2:8][N:9]([CH3:15])[CH2:10][CH2:11][CH:12]=2)=[N:3]1
Reactant: Cn1cnc(-c2cccnc2)n1
Reactant: C
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: CN1CCC=C(c2ncn(C)n2)C1
Temperature: -10 °C
Reaction time: 3 h

Procedure:
A suspension of 6.3 g (0.020 mol) of the methiodide of 57 (prepared from 57 by the procedure described in Example 1) in 75 ml of methanol was cooled to -10° C., and 1.0 g (0.026 mol) of sodium borohydride was added. When the gas evolution had ceased, the mixture was stirred for 3 h at room temperature. Evaporation in vacuo give a red oil which was dissolved in 100 ml of a saturated sodium chloride solution. Extraction with 4×100 ml of dichloromethane, drying of the organic phase over magnesium sulfate, and evaporation in vacuo gave a red oil. The oil was dissolved in 50 ml of ether and stirred with charcoal. Filtration and evaporation gave the base of 59 as a colorless oil, 58. Yield: 1.6 g (0.009 mol, 45%). A 0.5 g portion of 58 was converted to the title compound. M.P. 181°-183° C. Anal. (C11H16N4O2) C, H, N.
Reaction SMILES: [N+:1]([C:4]1[C:9]([CH:10]=O)=[CH:8][C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[CH:5]=1)([O-:3])=[O:2].C(O)(=O)C.[CH2:20]([N:22]([CH2:30][CH3:31])[C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1)[CH3:21]>C(O)C>[N+:1]([C:4]1[C:9]([CH:10]=[N:29][C:26]2[CH:25]=[CH:24][C:23]([N:22]([CH2:30][CH3:31])[CH2:20][CH3:21])=[CH:28][CH:27]=2)=[CH:8][C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[CH:5]=1)([O-:3])=[O:2]
Reactant: CCN(CC)c1ccc(N)cc1
Reactant: COc1cc(C=O)c([N+](=O)[O-])cc1OC
Solvent: CCO
Solvent: CC(=O)O
Product: CCN(CC)c1ccc(N=Cc2cc(OC)c(OC)cc2[N+](=O)[O-])cc1
Yield: 83 %

Procedure:
To a refluxing, stirred suspension of 63.3 g (0.3 mole) of 6-nitroveratraldehyde and 1.0 ml glacial acetic acid in 800 ml ethanol was added over 15 min a solution containing 54 g (0.33 mole of N,N-diethyl-p-phenylenediamine in 50 ml ethanol. The resulting solution was stirred and refluxed for 1 hr, then stored at 0°. The solid was collected, washed with 200 ml cold ethanol, and air dried to give 89 g (83%) of the product m.p. 117° -122°.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[CH:11][N:10]=[C:9]([CH2:13][S:14][C:15]3[NH:19][C:18]4=[CH:20][S:21][CH:22]=[C:17]4[N:16]=3)[CH:8]=2)[CH2:3][CH2:2]1.ClC1C=CC=C(C(OO)=[O:31])C=1>>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[CH:11][N:10]=[C:9]([CH2:13][S:14]([C:15]3[NH:16][C:17]4=[CH:22][S:21][CH:20]=[C:18]4[N:19]=3)=[O:31])[CH:8]=2)[CH2:3][CH2:2]1
Reactant: c1nc(CSc2nc3cscc3[nH]2)cc(N2CCOCC2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Product: O=S(Cc1cc(N2CCOCC2)ncn1)c1nc2cscc2[nH]1

Procedure:
180 mg of 2-(6-morpholino-4-pyrimidinylmethylthio)-1H-thieno[3,4-d]imidazole were oxidized with m-chloroperbenzoic acid in analogy to Example 1g. 140 mg of 2-(6-morpholino-4-pyrimidinylmethylsulfinyl)-1H-thieno[3,4-d]imidazole were obtained (melting point 107° C. [decomposition]).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:13][N:14]=[C:7]1[CH:6]=[CH:5]2.CCN(C(C)C)C(C)C.C(C(CCCC)COC(=O)CC[SH:38])C.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:15]1([C:12]2[N:8]3[C:9]4[C:4]([CH:5]=[CH:6][C:7]3=[N:14][N:13]=2)=[CH:3][C:2]([SH:38])=[CH:11][CH:10]=4)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Ic1ccc2c(ccc3nnc(-c4ccccc4)n32)c1
Reactant: CCCCC(CC)COC(=O)CCS
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Sc1ccc2c(ccc3nnc(-c4ccccc4)n32)c1
Temperature: 80 °C

Procedure:
To 7-Iodo-1-phenyl-[1,2,4]triazolo[4,3-a]quinoline (1.5 g, 4.0 mmol) in 1,4-dioxane (15 mL) was added iPr2NEt (1.4 mL, 8.1 mmol), and the reaction was degassed with N2 for 10 minutes. 3-Mercapto-propionic acid 2-ethylhexyl ester (975 mg, 4.5 mmol) was added, followed by Pd2dba3 (93 mg, 0.1 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (117 mg, 0.2 mmol). The reaction was sealed and heated overnight at 80° C., and then cooled to room temperature and concentrated. The residue was purified by silica gel chromatography (60-100% EtOAc in hexanes) to give the thiol intermediate as an oil. The oil was dissolved in THF (9 mL) and cooled to −78° C. Sodium tert-butoxide (780 mg, 8.1 mmol) was added, and the reaction was stirred at room temperature overnight. The mixture was diluted with 1N NaOH, and the aqueous layer was washed with Et2O. The aqueous layer was acidified with 1N HCl and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated, and the crude material was purified by silica gel chromatography (60-100% EtOAc in hexanes) to give the desired product, 10e.
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:10][CH:9]([CH2:11][CH2:12][O:13][CH3:14])[S:8](=[O:16])(=[O:15])[C:7]2[S:17][C:18]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:19][C:6]1=2)(=O)[CH3:2]>O1CCCC1.CCOCC>[CH2:1]([NH:4][CH:5]1[CH2:10][CH:9]([CH2:11][CH2:12][O:13][CH3:14])[S:8](=[O:16])(=[O:15])[C:7]2[S:17][C:18]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:19][C:6]1=2)[CH3:2]
Reactant: COCCC1CC(NC(C)=O)c2cc(S(N)(=O)=O)sc2S1(=O)=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCNC1CC(CCOC)S(=O)(=O)c2sc(S(N)(=O)=O)cc21

Procedure:
To a stirred solution of 4-acetamido-5,6-dihydro-6-(2-methoxyethyl)-4H-thieno[2,3-b]thiopyran-2-sulfonamide-7,7-dioxide (4.4 g, 0.0115 mol) in tetrahydrofuran (45 ml) under nitrogen and heated to reflux was added borane dimethylsulfide complex (5 ml, 0.05 mol of a 10 M complex) over about 20 minutes. Stirring was continued at reflux for 3 hours, then at room temperature overnight and another 5 hours and then concentrated in vacuo at room temperature. Methanol (50 ml) was carefully added to the white residue. The resulting solution was saturated with anhydrous HCl gas and then was stirred at reflux for 1 hour. The solution was concentrated in vacuo and the residue was taken up in ethyl acetate (50 ml) and saturated sodium bicarbonate (20 ml). The ethyl acetate solution was separated and washed with saturated NaCl, dried, filtered and concentrated in vacuo. The procedure gave a mixture of cis and trans isomers (3.2 g) as a white gummy foam which was chromatographed on silica gel (300 g) using 7.5% methanol-chloroform. Mixed fractions (0.87 g) were chromatographed again using 5% methanol-ether. There was obtained 1.62 g of the a-isomer, mp 132°-134° C. and 0.35 g of the β-isomer, mp 167°-169° C. The hydrochloride salts of the α (trans) and β-isomer (cis) racemates were prepared using ethanolic-HCl and diluting with ether. MP's were 173°-175° C. and 264.5°-266° C., respectively.
Reaction SMILES: [CH:1]([N:4]([CH3:27])[C:5]1[C:6](OS(C(F)(F)F)(=O)=O)=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][C:11]([C:15]([O:17][CH3:18])=[O:16])=[CH:10][CH:9]=2)([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:36]2[CH:37]=[CH:38][C:39]3[S:43][CH:42]=[N:41][C:40]=3[CH:44]=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[S:43]1[C:39]2[CH:38]=[CH:37][C:36]([C:6]3[C:5]([N:4]([CH:1]([CH3:2])[CH3:3])[CH3:27])=[N:14][C:13]4[C:8](=[CH:9][CH:10]=[C:11]([C:15]([O:17][CH3:18])=[O:16])[CH:12]=4)[N:7]=3)=[CH:44][C:40]=2[N:41]=[CH:42]1
Reactant: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N(C)C(C)C)nc2c1
Reactant: CC1(C)OB(c2ccc3scnc3c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(-c3ccc4scnc4c3)c(N(C)C(C)C)nc2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 82.6 %

Procedure:
To a solution of methyl 3-(isopropyl(methyl)amino)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate (150 mg, 0.37 mmol) in dioxane (5 mL) was added 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazole (288 mg, 1.1 mmol), K3PO4 (234 mg, 1.1 mmol), Pd(PPh3)4 (21 mg, 0.018 mmol) and water (3 drops). The resulting solution was stirred for 1 h at 90° C. and then concentrated in vacuo to give a residue, which was purified by silica gel column chromatography eluting with 2%-5% ethyl acetate in petroleum ether to afford methyl 2-(benzo[d]thiazol-5-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate as a yellow solid (120 mg, 83%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH2:9][CH2:8]/[C:7](=[CH:10]/O)/[C:6](=[N:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH:5]=1)[CH3:2].C(N(CC)CC)C.CS(Cl)(=O)=O.[F:32][C:33]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=1[SH:40]>O1CCCC1.O>[F:32][C:33]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=1[S:40][CH:10]=[C:7]1[C:6](=[N:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH:5]=[C:4]([O:3][CH2:1][CH3:2])[CH2:9][CH2:8]1
Reactant: CCOC1=CC(=Nc2ccc(C)cc2)/C(=C\O)CC1
Reactant: Fc1ccc(S)c(F)c1
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC1=CC(=Nc2ccc(C)cc2)C(=CSc2ccc(F)cc2F)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.4 %

Procedure:
100 mg (0.39 mmol) of (Z)-4-ethoxy-2-[(4-methylphenyl)imino]cyclohex-3-en-1-ylidene methanol are dissolved in 10 ml of anhydrous tetrahydrofuran, and 325 μl (2.3 mmol) of triethylamine and 60 μl (0.78 mmol) of methanesulphonyl chloride are added at 0° C. After 30 min of stirring at 25° C., the mixture is once more cooled to 0° C., 40 μl (0.35 mmol) of 2,4-difluorobenzenethiol are added and the mixture is stirred at 25° C. for a further 30 min. The reaction mixture is diluted with water and extracted with ethyl acetate, and the organic phase is washed with saturated aqueous sodium chloride solution and dried over sodium sulphate. Purification of the residue by column chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate) gives 41 mg of N-(6-{[(2,4-difluorophenyl)sulphanyl]methylene}-3-ethoxycyclohex-2-en-1-ylidene)-4-methylaniline as an isomer mixture (ratio about 1:1).
Reaction SMILES: [NH2:1][C:2](=[C:10]([C:15](=O)[CH:16]([CH3:18])[CH3:17])[C:11]([O:13][CH3:14])=[O:12])[C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1.C1(C)C=CC=CC=1.[C:27]([N:29]([CH3:34])[S:30]([CH3:33])(=[O:32])=[O:31])#[N:28]>[Ti](Cl)(Cl)(Cl)Cl.O>[F:9][C:6]1[CH:7]=[CH:8][C:3]([C:2]2[C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:15]([CH:16]([CH3:18])[CH3:17])[N:28]=[C:27]([N:29]([S:30]([CH3:33])(=[O:32])=[O:31])[CH3:34])[N:1]=2)=[CH:4][CH:5]=1
Reactant: COC(=O)C(C(=O)C(C)C)=C(N)c1ccc(F)cc1
Reactant: CN(C#N)S(C)(=O)=O
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1c(-c2ccc(F)cc2)nc(N(C)S(C)(=O)=O)nc1C(C)C
Temperature: 110 °C
Reaction time: 4.5 h
Yield: 80.3 %

Procedure:
10.0 g (37.7 mmol) of methyl 2-[1-amino-1-(4-fluorophenyl)methylene]-4-methyl-3-oxopentanoate were introduced into 50 ml of toluene together with 10.17 g (75.4 mmol) of N-cyano-N-methylmethanesulphonamide and the mixture was treated at room temperature with 3.61 g (18.9 mmol) of titanium tetrachloride. The reaction progressed exothermically. The red-orange-coloured suspension was heated to 110° C. and stirred for 4.5 h. It was then cooled to room temperature and treated with 30 ml of water. The organic phase was separated off and the aqueous phase was extracted with ethyl acetate (30 ml). The combined organic phases were washed with 30 ml of water and dried over magnesium sulphate. After filtering and concentrating the solution in a water-jet vacuum and drying in vacuo, 11.54 g of crude product were obtained in the form of a tacky oil.