Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.[NH:12]1[CH2:16][CH2:15][C@H:14]([OH:17])[CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>O.C(O)C>[Cl:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([N:12]3[CH2:16][CH2:15][C@H:14]([OH:17])[CH2:13]3)[S:3][C:4]=2[CH:10]=1
Reactant: O[C@H]1CCNC1
Reactant: Clc1ccc2nc(Cl)sc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O[C@H]1CCN(c2nc3ccc(Cl)cc3s2)C1
Temperature: 150 °C

Procedure:
A stirred mixture of 2,6-dichlorobenzo[d]thiazole (CAS #3622-23-9, 0.314 g, 3.00 mmol), (S)-pyrrolidin-3-ol (0.314 g, 3.60 mmol), and potassium carbonate (1.24 g, 9.00 mmol) in water/ethanol (10 mL/8 mL) was heated at 150° C. under microwave irradiation for 5 minutes. The reaction mixture was cooled to room temperature then partitioned between dichloromethane and saturated aqueous sodium carbonate. The organic layer was dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure to give a crude solid that was purified by crystallization from ethyl acetate/hexane. Crystals were collected by filtration, then dried under vacuum to provide (S)-1-(6-chlorobenzo[d]thiazol-2-yl)pyrrolidin-3-ol. 1H NMR (300 MHz, CD3OD) δ ppm 2.04-2.14 (m, 1H), 2.16-2.29 (m, 1H), 3.48-3.55 (m, 1H), 3.59-3.75 (m, 3H), 4.54-4.59 (m, 1H), 7.26 (dd, J=2, 8 Hz, 1H), 7.40 (d, J=8 Hz, 1H), 7.67 (d, J=2 Hz, 1H); MS (DCI/NH3) m/z 255 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:42]=[C:41]([O:43][CH3:44])[CH:40]=[CH:39][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([C@H:16]3[C@@H:20]4[O:21][C:22]([CH3:25])([CH3:24])[O:23][C@@H:19]4[C@@H:18]([CH2:26][N:27]([CH2:37][CH3:38])[CH:28]4[CH2:31][CH:30]([CH2:32][CH2:33][C:34]([OH:36])=O)[CH2:29]4)[CH2:17]3)[C:9]=2[N:10]=[CH:11][N:12]=1.C(N(CC)C(C)C)(C)C.[C:54]([C:58]1[CH:59]=[C:60]([NH2:65])[C:61]([NH2:64])=[CH:62][CH:63]=1)([CH3:57])([CH3:56])[CH3:55]>CN(C)C=O>[NH2:65][C:60]1[CH:59]=[C:58]([C:54]([CH3:56])([CH3:55])[CH3:57])[CH:63]=[CH:62][C:61]=1[NH:64][C:34](=[O:36])[CH2:33][CH2:32][CH:30]1[CH2:29][CH:28]([N:27]([CH2:26][C@@H:18]2[C@@H:19]3[C@@H:20]([O:21][C:22]([CH3:24])([CH3:25])[O:23]3)[C@H:16]([N:13]3[C:9]4[N:10]=[CH:11][N:12]=[C:7]([NH:6][CH2:5][C:4]5[CH:39]=[CH:40][C:41]([O:43][CH3:44])=[CH:42][C:3]=5[O:2][CH3:1])[C:8]=4[CH:15]=[CH:14]3)[CH2:17]2)[CH2:37][CH3:38])[CH2:31]1
Reactant: CC(C)(C)c1ccc(N)c(N)c1
Reactant: CCN(C[C@H]1C[C@@H](n2ccc3c(NCc4ccc(OC)cc4OC)ncnc32)[C@@H]2OC(C)(C)O[C@H]12)C1CC(CCC(=O)O)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN(C[C@H]1C[C@@H](n2ccc3c(NCc4ccc(OC)cc4OC)ncnc32)[C@@H]2OC(C)(C)O[C@H]12)C1CC(CCC(=O)Nc2ccc(C(C)(C)C)cc2N)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.8 %

Procedure:
N,N,N′,N′-Tetramethyl-0-(7-azabenzotriazol-1-yl)uronium Hexafluorophosphate (0.84 g, 2.2 mmol) added to a solution 3-(3-((((3aR,4R,6R,6aS)-6-(4-((2,4-dimethoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methyl)(ethyl)amino)cyclobutyl)propanoic acid (0.89 g, 1.5 mmol) and N,N-Diisopropylethylamine (0.84 ml, 4.8 mmol) and 4-tert-butylbenzene-1,2-diamine (0.29 g, 1.8 mmol) in N,N-Dimethylformamide (9 ml). The reaction was stirred overnight at RT, partially concentrated to ca. 2 ml and then NaHCO3 (saturated) was added. The mixture was extracted with EtOAc (3×) and the combined organics were dried with MgSO4, filtered and concentrated. The residue was purified by flash chromatography (DCM/7N NH3 in MeOH 94:6) to give the desired compound (0.88 g) as a colorless solid. Retention time C, 3.363 minutes.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:22]=[CH:21][C:9]([O:10][CH2:11][CH2:12][CH2:13][C:14]([CH3:20])([CH3:19])[C:15]([O:17][CH3:18])=[O:16])=[CH:8][CH:7]=1.[OH:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1.Br[CH2:31]CCOC1C=CC(OCCCCCC(C)(C)C(OC)=O)=CC=1.N1C=CN=C1>>[CH3:19][C:14]([CH3:20])([CH2:13][CH2:12][CH2:11][O:10][C:9]1[CH:21]=[CH:22][C:6]([O:5][CH2:4][CH2:3][CH2:2][O:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)=[CH:7][CH:8]=1)[C:15]([O:17][CH2:18][CH3:31])=[O:16]
Reactant: COC(=O)C(C)(C)CCCOc1ccc(OCCCBr)cc1
Reactant: Oc1cccnc1
Reactant: COC(=O)C(C)(C)CCCCCOc1ccc(OCCCBr)cc1
Agent: c1c[nH]cn1
Product: CCOC(=O)C(C)(C)CCCOc1ccc(OCCCOc2cccnc2)cc1

Procedure:
Methyl 5-[p-(3-bromopropoxy)phenoxy]-2,2-dimethylpentanoate and 3-hydroxypyridine were used as starting compounds in place of methyl 7-[p-(3-bromopropoxy)phenoxy]-2,2-dimethylheptanoate and imidazole, respectively, in EXAMPLE 33. The starting compounds were reacted and treated in a manner similar to EXAMPLE 33 to give the desired product, ethyl 2,2-dimethyl-5-[p-[3-(3-pyridyloxy)propoxy]phenoxy]pentanoate, as an oily substance. ##STR109##
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Cl[S:11]([C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=1)(=[O:13])=[O:12].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH2:1]([NH:9][S:11]([C:14]1[CH:15]=[CH:16][C:17]([C:18]([OH:20])=[O:19])=[CH:21][CH:22]=1)(=[O:13])=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:1]([NH:9][S:11]([C:14]1[CH:15]=[CH:16][C:17]([CH2:18][OH:19])=[CH:21][CH:22]=1)(=[O:13])=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCCCCCN
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCCCCNS(=O)(=O)c1ccc(C(=O)O)cc1
Product: CCCCCCCCNS(=O)(=O)c1ccc(CO)cc1

Procedure:
4-(Octylaminosulfonyl)benzoic acid is prepared in the usual way from octylamine and 4-(chlorosulfonyl)benzoic acid. This material is reduced with lithium aluminum hydride in THF in the usual fashion, and purified by chromatography with 1:3 ethyl acetate-dichloromethane to provide 4-(octylaminosulfonyl)benzyl alcohol as a colorless solid in 54% yield. Swern oxidation (DMSO-oxalyl chloride, dichloromethane) of this material provides 4-(octylaminosulfonyl)benzaldehyde as a colorless solid after chromatography. By the method of example 1(A), but using two equivalents of the phosphonium ylide, the aldehyde is chain-extended and converted to the dimethyl acetal, and by the method of example 2 this is condensed with glyoxylic acid to provide the title compound as a colorless solid, mp 223°-224° after recrystallization from ethyl acetate.
Reaction SMILES: CN=[C:3](Cl)[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1.ClS(O)(=O)=O.[CH3:17][N:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[CH2:23][C:24]([O:26][CH3:27])=[O:25].C([O-])(=[O:30])C.[Na+]>O>[CH3:17][N:18]1[C:22]([C:3](=[O:30])[C:4]2[CH:5]=[CH:6][C:7]([CH3:10])=[CH:8][CH:9]=2)=[CH:21][CH:20]=[C:19]1[CH2:23][C:24]([O:26][CH3:27])=[O:25]
Reactant: CN=C(Cl)c1ccc(C)cc1
Reactant: CC(=O)[O-]
Reactant: COC(=O)Cc1cccn1C
Agent: O=S(=O)(O)Cl
Agent: [Na+]
Solvent: O
Product: COC(=O)Cc1ccc(C(=O)c2ccc(C)cc2)n1C
Reaction time: 8 h
Yield: 36.9 %

Procedure:
N-Methyl 4-methylbenzimidoyl chloride (3.85 g, 23 mmole) was treated with alcohol free chloroform (4.5 ml) and chlorosulfonic acid (0.2 g, 1.7 mmole). Methyl 1-methyl-1H-pyrrole-2-acetate (3.5 g, 23 mmole) was added in one portion, the reaction was fitted with a calcium chloride drying tube and stirred overnight. The reaction was quenched with saturated aqueous sodium bicarbonate. The phases were separated and the organic phase was concentrated under reduced pressure. The residue (6.6 g of a red oil) was dissolved in methanol (50 ml) and treated with sodium acetate (3 g, 36 mmole) and water (10 ml). The reaction was heated at reflux overnight, then cooled in an ice bath. The title compound crystallized and was isolated by filtration, washed with cold methanol, and air dried to yield 2.3 g (37%) of a light tan solid, m.p. 117°-119° C.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11]Cl)=[CH:7][CH:6]=1)[CH:2]=[CH2:3].NC(N)=[S:15].O.N>C(O)C>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][SH:15])=[CH:7][CH:6]=1)[CH:2]=[CH2:3]
Reactant: NC(N)=S
Reactant: C=CCOc1ccc(CCl)cc1
Agent: N
Solvent: CCO
Solvent: O
Product: C=CCOc1ccc(CS)cc1
Yield: 80.9 %

Procedure:
A mixture of 2.00 g (10.9 mmol) 1-allyloxy-4-chloromethyl-benzene and 917 mg (12.1 mmol) thiourea in 3.0 ml ethanol was heated to reflux for 7 h. Solvents were distilled off and the crystalline residue was washed with cold ethanol and isolated by filtration. After addition of 2.5 ml ethanol, 1.0 ml water and 0.7 ml 25% aqueous ammonia, the mixture was heated to reflux for 1 h. Ethanol was distilled off, then acidified with 0.5 ml half conc. HCl and extracted with ethyl acetate. The solution was dried over MgSO4 and solvents were removed in vacuo to yield 1.59 g (81%) colorless oil, which was used immediately.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:11][CH2:12][OH:13])[CH2:8][CH2:9][OH:10])=[O:6].[N:14]([O-])=[O:15].[Na+].C(Cl)(Cl)Cl.CO>C(O)(=O)C>[Cl:1][CH2:2][CH2:3][N:4]([N:14]=[O:15])[C:5]([N:7]([CH2:11][CH2:12][OH:13])[CH2:8][CH2:9][OH:10])=[O:6]
Reactant: O=N[O-]
Reactant: O=C(NCCCl)N(CCO)CCO
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CC(=O)O
Product: O=NN(CCCl)C(=O)N(CCO)CCO
Yield: 65.9 %

Procedure:
4.0 g of 1-(2-chloroethyl)-3,3-bis(2-hydroxyethyl)urea are dissolved in 30 ml of acetic acid, and 2.5 g of sodium nitrite are added thereto under stirring. The mixture is stirred at room temperature for 4 hours. After the reaction, the mixture is treated in the same manner as described in Example 60-(2) (Solvent used for chromatography: chloroform-methanol (10:1)). 3.0 g of 1-(2-chloroethyl)-1-nitroso-3,3-bis(2-hydroxyethyl)urea are thereby obtained as a yellow oil.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([N:8]([CH3:31])[C@@H:9]2[CH2:13][CH2:12][N:11]([C:14]3[C:15]4[CH:22]=[CH:21][N:20]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:16]=4[N:17]=[CH:18][N:19]=3)[CH2:10]2)=[N:6][CH:7]=1.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.O>CN1C(=O)CCC1>[CH3:31][N:8]([C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3[CH:22]=[CH:21][N:20]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:10]1)[C:5]1[CH:4]=[N:3][C:2]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[CH:7][N:6]=1
Reactant: CN(c1cnc(Br)cn1)[C@@H]1CCN(c2ncnc3c2ccn3COCC[Si](C)(C)C)C1
Reactant: C1COCCN1
Solvent: CN1CCCC1=O
Solvent: O
Product: CN(c1cnc(N2CCOCC2)cn1)[C@@H]1CCN(c2ncnc3c2ccn3COCC[Si](C)(C)C)C1
Temperature: 25 °C

Procedure:
A solution of (R)-5-bromo-N-methyl-N-(1-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)pyrazin-2-amine (0.099 mmol) and morpholine (1.5 mL) in NMP (0.5 mL) was stirred at 195° C. for 2 hours in a microwave reactor. After cooling to the ambient temperature, it was poured into water, and extracted with EtOAc. The combined organic extracts were concentrated and the residue was purified by column chromatography on silica gel to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[S:16](=[O:18])(=[O:17])[CH2:15][CH2:14][CH2:13][S:12]2(=[O:20])=[O:19])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[H-].[Na+].[CH2:23]([CH:25]1[O:27][CH2:26]1)Cl.O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2([CH2:23][CH:25]3[O:27][CH2:26]3)[S:12](=[O:19])(=[O:20])[CH2:13][CH2:14][CH2:15][S:16]2(=[O:17])=[O:18])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2S(=O)(=O)CCCS2(=O)=O)cc1OC
Reactant: ClCC1CO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C2(CC3CO3)S(=O)(=O)CCCS2(=O)=O)cc1OC
Temperature: 100 °C

Procedure:
9.6 of 2-(3,4-dimethoxyphenyl)-m-dithiane-1,1,3,3-tetraoxide (prepared as described in Example 2) are dissolved in 35 ml of dimethylformamide and, with stirring under argon, treated with 1.2 g of sodium hydride at room temperature. The suspension is stirred at 40° C for a further 0.5 hour, then cooled and treated with 2.8 g of epichlorohydrin. The mixture is then heated at 100° C for 16 hours. After cooling to room temperature, the suspension is poured on to water and the oily material extracted with chloroform. After evaporation of the solvent, the residue is chromatographed on silica gel with chloroform/ethanol (98:2). The 2-(3,4-dimethoxyphenyl)-2-(2,3-epoxypropyl)-m-dithiane-1,1,3,3-tetraoxide obtained is recrystallized from methylene chloride/ethanol and has a melting point of 175°-176° C.
Reaction SMILES: [C:1]([C:5]1[CH:25]=[CH:24][C:8]([CH2:9][S:10][C:11]2[O:12][C:13]3[C:18]([C:19](=[O:22])[C:20]=2[CH3:21])=[C:17]([OH:23])[CH:16]=[CH:15][CH:14]=3)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1.O.C(OCC)(=O)C>N1C=CC=CC=1>[C:1]([C:5]1[CH:25]=[CH:24][C:8]([CH2:9][S:10][C:11]2[O:12][C:13]3[C:18]([C:19](=[O:22])[C:20]=2[CH3:21])=[C:17]([O:23][S:32]([C:29]2[CH:30]=[CH:31][C:26]([CH3:36])=[CH:27][CH:28]=2)(=[O:34])=[O:33])[CH:16]=[CH:15][CH:14]=3)=[CH:7][CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1c(SCc2ccc(C(C)(C)C)cc2)oc2cccc(O)c2c1=O
Solvent: O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)Oc2cccc3oc(SCc4ccc(C(C)(C)C)cc4)c(C)c(=O)c23)cc1
Reaction time: 8 h

Procedure:
2-(4-tert-butylbenzylmercapto)-3-methyl-5-hydroxy chromen-4-one (5 g, 14.1 mmol) is dissolved in pyridine in a 25 mL round bottom flask and p-toluenesulfonyl chloride (15 mmol) is added to it. The reaction mixture is stirred for 8 hours. Water is then added to the flask and the contents are poured into a separatory funnel. Ethyl acetate is added and the layers are separated. The organic layer is then washed with water and brine and dried over sodium sulfate and filtered. The filtrate is concentrated in vacuo and the residue obtained is purified by silica gel flash chromatography (hexanes:ethyl acetate) to afford the above product.
Reaction SMILES: CO[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][C:5]1=[O:9].[C:10]([NH2:14])(=[O:13])[CH:11]=[CH2:12].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C2NC3C(=CC=CC=3)SC=2C=CC=1>CO>[N:4]1([CH2:3][NH:14][C:10](=[O:13])[CH:11]=[CH2:12])[CH2:8][CH2:7][CH2:6][C:5]1=[O:9]
Reactant: COCN1CCCC1=O
Reactant: C=CC(N)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: c1ccc2c(c1)Nc1ccccc1S2
Solvent: CO
Product: C=CC(=O)NCN1CCCC1=O
Yield: 40 %

Procedure:
A mixture of 65.6 g of 1-methoxymethyl-2-pyrrolidone, 75.5 g of acrylarnide, 0.20 g of p-toluene sulfonic acid and 0.20 g of phenothiazine was stirred under N2 atmosphere at 150° C. for 1 hour, during which time the methanol was removed by distillation. The residue was cooled, and recrystallized from acetone to give the title compound in a yield of 40%. mp: 73-74° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][C:21]([O:23]CC)=[O:22])[CH:12]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[OH-].[Na+].Cl>C1COCC1.CCO>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][C:21]([OH:23])=[O:22])[CH:12]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)Cn1cc(Cc2cccc([N+](=O)[O-])c2)c2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)Cn1cc(Cc2cccc([N+](=O)[O-])c2)c2ccccc21
Temperature: 0 °C
Yield: 70.9 %

Procedure:
3-(3-Nitrophenyl)methyl-indole-N-acetic Acid, ethyl ester (0.175 g, 0.5 mmol) was dissolved in THF: EtOH (1:4, 5 mL) at room temperature with stirring. The mixture was cooled to 0° C. and treated with 1N NaOH (1.55 mL, 1.6 mmol). The mixture was allowed to stir at this temperature for 2 h. 1 N HCl was added and the mixture extracted with EtOAc (2×). The organics were combined and washed with a sat'd brine solution, dried over MgSO4, filtered and concentrated in vacuo. The residue was triturated with heptane and vacuum-filtered with several heptane washings to give 110 mg (69%) the desired compound as an off-white powder. mp 163-165° C.; 1H NMR (DMSO-d6, 300 MHz) δ 8.11 (s, 1H), 8.03 (d, J=8.1 Hz, 1H), 7.75 (d, J=8.1 Hz, 1H), 7.53 (t, J=8.1 Hz, 1H), 7.45 (d, J=8.1 Hz, 1H), 7.33 (d, J=8.4 Hz, 1H), 7.20 (s, 1H), 7.11 (t, J=7.2 Hz, 1H), 6.97 (t, J=7.2 Hz, 1H), 4.96 (s, 2H), 4.18 (s, 2H); LRMS calcd for C17H14N2O4S: 310.0; found 311 (M+1)+.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].[C:9]1([S:15](Cl)(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O>C(=O)([O-])[O-].[Na+].[Na+]>[C:9]1([S:15]([OH:17])(=[O:1])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:3]1(=[O:8])[NH:2][C:6](=[O:7])[CH2:5][CH2:4]1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=C1CCC(=O)N1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C1CCC(=O)N1
Product: O=S(=O)(O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In 45 g of 5% aqueous solution of sodium carbonate was dissolved 3.5 g of N-hydroxysuccinimide. To the resulting solution was dropwise added 6.0 g of benzenesulfonyl chloride at room temperature. After the dropping the reaction mixture was stirred at room temperature for 2 hours. Then, the reaction mixture was poured into 300 ml of water and the deposited crystalline product was collected by filtration. The crystalline product was washed with water until the washings had reached neutrality, and then recrystallized from acetone/water mixture to obtain succinimide benzenesulfonate.
Reaction SMILES: C(N(CC1C=CC=CC=1)C1([CH2:14][NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23](C)C=3)[N:19]=[C:18]([N:27]3[CH2:33][C:32]4[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=4[S:30](=[O:39])(=[O:38])[CH2:29][CH2:28]3)C=2)CCOC1)C1C=CC=CC=1.[NH2:47][CH2:48][CH2:49][OH:50]>>[O:38]=[S:30]1(=[O:39])[C:31]2[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=2[CH2:33][N:27]([C:18]2[CH:23]=[C:22]([NH:47][CH2:48][CH2:49][OH:50])[C:21]3[C:20](=[CH:25][CH:16]=[N:15][CH:14]=3)[N:19]=2)[CH2:28][CH2:29]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC3(N(Cc4ccccc4)Cc4ccccc4)CCOC3)c2c1
Reactant: NCCO
Product: O=S1(=O)CCN(c2cc(NCCO)c3cnccc3n2)Cc2ccccc21

Procedure:
The title compound was prepared in analogy to Example 12-1 in Scheme 5 by using 4-(4-chloro-1,6-naphthyridin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 2-1 by using 2,3,4,5-tetrahydro-1,4-benzothiazepine and 2,4-dichloro-1,6-naphthyridine) and 2-aminoethanol. MS obsd. (ESI+) [(M+H)+] 385, 1H NMR (400 MHz, CD3OD) δ ppm 9.66 (s, 1 H), 8.66-8.64 (d, J=6.8 Hz, 1 H), 8.26-8.24 (d, J=6.8 Hz, 1 H), 8.05-8.03 (d, J=7.6 Hz, 1 H), 7.97-7.95 (d, J=7.2 Hz, 1 H), 7.71-7.69 (d, J=7.2 Hz, 1 H), 7.56-7.54 (d, J=7.6 Hz, 1 H), 6.30 (s, 1 H), 5.38 (s, 1 H), 4.72-4.60 (m, 2 H), 3.87-3.86 (m, 2 H), 3.71-3.67 (m, 4 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=O.Cl.[CH3:13][O:14][NH2:15].O>N1C=CC=CC=1>[CH3:13][O:14][N:15]=[CH:7][C:6]1[CH:9]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[S:10][CH3:11]
Reactant: CON
Reactant: CSc1ccc(Br)cc1C=O
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CON=Cc1cc(Br)ccc1SC
Yield: 96.1 %

Procedure:
(Step 2) 5-Bromo-2-(methylsulfanyl)benzaldehyde obtained in Step 1 (11.0 g) and O-methylhydroxylamine hydrochloride (4.37 g) were stirred in pyridine (30 ml) at room temperature for 14 hr. The reaction solution was treated with water, and extracted with ethyl acetate. The extract was washed successively with 1N hydrochloric acid (twice) and saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give 5-bromo-2-(methylsulfanyl)benzaldehyde O-methyloxime (11.9 g).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[C:10]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27](C=C)[CH:26]=2)=[N:11][C:12]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]=[CH2:23])[CH:17]=2)=[N:13][CH:14]=1>ClCCCl.C(#N)C.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1C=CC(C=[Ru](Cl)Cl)=CC=1>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:14]=[N:13][C:12]2[NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH:17]=3)[CH:22]=[CH:23][C:27]3[CH:26]=[C:25]([NH:24][C:10]=1[N:11]=2)[CH:30]=[CH:29][CH:28]=3.[F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4]
Reactant: C=Cc1cccc(Nc2ncc(Cl)c(Nc3cccc(C=C)c3)n2)c1
Agent: Cl[Ru](Cl)=Cc1ccccc1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: Clc1cnc2nc1Nc1cccc(c1)/C=C\c1cccc(c1)N2
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: Clc1cnc2nc1Nc1cccc(c1)C=Cc1cccc(c1)N2
Product: O=C([O-])C(F)(F)F
Temperature: 130 °C
Yield: 66.9 %

Procedure:
A solution of 5-chloro-N,N′-bis(3-vinylphenyl)pyrimidine-2,4-diamine trifluoroacetate (21 mg, 0.045 mmol) in 1,2-dichloroethane (20 mL) was degassed by bubbling nitrogen for 5 minutes. Benzylidene-bis(tricyclohexylphosphine)dichlororuthenium (11 mg, 0.013 mmol) was added and the mixture was heated to 130° C. for 20 minutes in a microwave. The mixture was evaporated to give a dark mixture which was suspended in acetonitrile and filtered. The filtrate was purified by preparative LCMS (pH 2) to give the desired product as a trifluoroacetate salt (1.7 mg, 9%). LCMS for C18H14ClN4 (M+H)+: m/z=321.1. 1H NMR (400 MHz, CD3Cl): δ 8.85 (s, 1H), 8.75 (s, 1H), 7.90 (s, 1H), 7.55 (s, 1H), 7.25 (m, 3H), 7.02 (m, 4H), 6.60 (s, 2H).
Reaction SMILES: [C:1]1([C@H:7]([NH:9][C:10]2[C:11]3[CH:18]=[C:17]([C:19]4[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=4)[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>N.CO.C1COCC1.[Ni]>[NH2:24][CH2:23][C:22]1[CH:25]=[CH:26][C:19]([C:17]2[NH:16][C:12]3[N:13]=[CH:14][N:15]=[C:10]([NH:9][C@@H:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH3:8])[C:11]=3[CH:18]=2)=[CH:20][CH:21]=1
Reactant: C[C@@H](Nc1ncnc2[nH]c(-c3ccc(C#N)cc3)cc12)c1ccccc1
Agent: [Ni]
Agent: N
Solvent: CO
Solvent: C1CCOC1
Product: C[C@@H](Nc1ncnc2[nH]c(-c3ccc(CN)cc3)cc12)c1ccccc1

Procedure:
Raney-Nickel (0.1 g) catalyzed hydrogenation of 0.206 g (0.6 mmol) 4-[4-((R)-1-phenyl-ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzonitrile in a mixture of 5% ammonia in methanol (20 ml) and THF (4 ml) for 6 h at atmospheric pressure followed by filtration and evaporation of the solvent gives the title compound; m.p. 253-256° C.; MS-ES+: (M+H)+=344.
Reaction SMILES: [C:1]12([CH2:11][NH:12][C:13](=[O:23])[C:14]3[C:19]([Cl:20])=[CH:18][N:17]=[C:16]([CH:21]=O)[CH:15]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH2:24][CH2:25][CH2:26][CH2:27][N:28](C)[C:29](=O)OC(C)(C)C.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[ClH:20].[ClH:20].[C:1]12([CH2:11][NH:12][C:13](=[O:23])[C:14]3[C:19]([Cl:20])=[CH:18][N:17]=[C:16]([CH2:21][NH:24][CH2:25][CH2:26][CH2:27][NH:28][CH3:29])[CH:15]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: CN(CCCN)C(=O)OC(C)(C)C
Reactant: O=Cc1cc(C(=O)NCC23CC4CC(CC(C4)C2)C3)c(Cl)cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CNCCCNCc1cc(C(=O)NCC23CC4CC(CC(C4)C2)C3)c(Cl)cn1
Product: Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 114.9 %

Procedure:
N-(1-Adamantylmethyl)-5-chloro-2-formylisonicotinamide (Example 29(ii)) (0.2 g) was dissolved in methanol (10 mL) and tert-butyl 3-aminopropyl(methyl)carbamate, (0.39 g) added along with acetic acid (0.2 mL). The mixture was stirred for 15 minutes at ambient temperature and then sodium triacetoxyborohydride (0.25 g) was added and the reaction stirred for 20 hours, concentrated and the residue partitioned between 2M aqueous hydrochloric acid solution (10 mL) and ethyl acetate (10 mL). The layers were separated and the organic phase re-extracted with 2N hydrochloric acid (2×10 mL). The combined aqueous extracts were basified with 5M aqueous ammonium hydroxide solution, extracted into ethyl acetate (2×25 mL) and the combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was dissolved in dichloromethane and treated with dry hydrogen chloride in 1,4-dioxane (4N, 1 mL) and was concentrated after 2 hours to give the deprotected material. The residue was recrystallised from dichloromethane (10 mL) to afford the titled compound (0.110 g).