Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[S:12][CH:13]=[CH:14][N:15]=3)=[CH:9][S:8][C:4]=2[N:5]=[CH:6][N:7]=1.FC(F)(F)C(O)=O.[NH2:23][CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:29]=[CH:30][C:31]([C:34]([NH:36][CH3:37])=[O:35])=[N:32][CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C>[CH3:37][NH:36][C:34]([C:31]1[CH:30]=[CH:29][C:28]([O:27][CH2:26][CH2:25][CH2:24][NH:23][C:2]2[C:3]3[C:10]([C:11]4[S:12][CH:13]=[CH:14][N:15]=4)=[CH:9][S:8][C:4]=3[N:5]=[CH:6][N:7]=2)=[CH:33][N:32]=1)=[O:35]
Reactant: Clc1ncnc2scc(-c3nccs3)c12
Reactant: CNC(=O)c1ccc(OCCCN)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)N(C)C
Product: CNC(=O)c1ccc(OCCCNc2ncnc3scc(-c4nccs4)c23)cn1
Temperature: 120 °C
Yield: 82.1 %

Procedure:
A mixture of 4-chloro-5-(1,3-thiazol-2-yl)thieno[2,3-d]pyrimidine (0.050 g, 0.20 mmol), 5-(3-aminopropoxy)-N-methylpyridine-2-carboxamide trifluoroacetate (0.070 g, 0.22 mmol), potassium carbonate (0.272 g, 1.97 mmol) and N,N-dimethylacetamide (2.4 mL) was heated at 120° C. for 13 h. The solvent was evaporated in vacuo, and the residue was treated with 5% sodium bicarbonate (20 mL) and ethyl acetate (20 mL). The precipitate was filtered and washed with water and ethyl ether. The resulting white solid was purified by column chromatography over silica gel to give 70 mg (81%) N-methyl-5-(3-[5-(1,3-thiazol-2-yl)thieno[2,3-d]pyrimidin-4-yl]aminopropoxy)pyridine-2-carboxamide. MS [M+H]=427, LC/MS (EI) tR 3.54 min (Method D), 1H NMR (10% MeOD/CDCl3) δ (ppm) 10.85 (s, 1H), 8.30 (s, 1H), 8.12 (d, J=2.4 Hz, 1H), 8.00 (d, J=8.7 Hz, 1H), 7.94 (b, 1H), 7.71 (s, 1H), 7.50 (d, J=3.6 Hz, 1H), 7.28 (s, 1H), 7.21 (dd, J=8.7, 3.0 Hz, 1H), 4.15 (t, J=0.6 Hz, 2H), 3.80-3.74 (m, 2H), 2.94 (d, J=0.6 Hz, 3H), 2.24-2.18 (m, 2H).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[NH:12])[CH:7]=[CH:8][CH:9]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:24][C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27](Cl)=[O:28]>O.O1CCCC1>[ClH:24].[Cl:24][C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27]([NH:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[NH:12])[CH:7]=[CH:8][CH:9]=1)=[O:28]
Reactant: N=C(Nc1cccc(N)c1)N1CCCC1
Reactant: O=C(Cl)c1ccccc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: N=C(Nc1cccc(NC(=O)c2ccccc2Cl)c1)N1CCCC1
Temperature: 0 °C

Procedure:
A solution of the product of Example 1, step (b), 1.38 g, 0.0050 moles, was dissolved in 20 ml of water. The solution was gradually treated with sodium carbonate, 0.84 g, 0.0100 moles, and cooled to 0° C. A solution of 2-chlorobenzoyl chloride, 0.96 g, 0.0053 moles, in 10 ml of tetrahydrofuran was added. This mixture was allowed to stir over the weekend. The mixture was then diluted with water to 100 ml and washed with 20 ml of chloroform. The mixture was made basic with 50% sodium hydroxide and extracted with 20 ml of chloroform (twice). The chloroform was dried with potassium carbonate, filtered and evaporated by vacuum evaporation. The residue was taken up in 20 ml of isopropanol, treated with 1 ml of concentrated hydrochloric acid, and then diluted to 250 ml with ether. The solid that precipitated was collected by filtration and washed with 10 ml of ether (twice). The solid was then recrystallized with methanol and ether and dried in the vacuum oven to provide N-(3-(((2-chlorophenyl)carbonyl)amino)phenyl)-1-pyrrolidinecarboximidamide monohydrochloride. Yield: 1.1 g, m.p. 145° C. (dec).
Reaction SMILES: [N+:1]([C:4]1[C:5]([C:11]([C:13]2[C:14]([CH3:20])=[N:15][CH:16]=[CH:17][C:18]=2[CH3:19])=[O:12])=[N:6][CH:7]=[C:8]([Cl:10])[CH:9]=1)([O-])=O>C(O)(=O)C.C(OCC)(=O)C.[Fe]>[NH2:1][C:4]1[C:5]([C:11]([C:13]2[C:14]([CH3:20])=[N:15][CH:16]=[CH:17][C:18]=2[CH3:19])=[O:12])=[N:6][CH:7]=[C:8]([Cl:10])[CH:9]=1
Reactant: Cc1ccnc(C)c1C(=O)c1ncc(Cl)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1ccnc(C)c1C(=O)c1ncc(Cl)cc1N
Temperature: 80 °C
Yield: 60.1 %

Procedure:
To a mixture of iron powder (220 mg, 4.0 mmol) in 4 ml of acetic acid at 80° C. was slowly added a solution of (3-Nitro-5-chloro-pyridin-2-yl)-(2,4-dimethyl-pyridin-3-yl)-methanone (260 mg, 0.89 mmol) in 2 ml of acetic acid. After the completion of addition the mixture was stirred at 80° C. for half an hour and then cooled. The mixture was diluted with ethyl acetate, filtered through celite and the filtrate was concentrated. The residue was purified by flash column (50% ethyl acetate in hexane) to afford 140 mg of title compound as off-white solid. MS: (M+H)/z=262.0.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([C:16](=[O:20])[C:17](Cl)=[O:18])=[CH:8]2)=[CH:4][CH:3]=1.[NH2:23][C:24]1[S:25][CH:26]=[N:27][N:28]=1>COCCOC>[S:25]1[CH:26]=[N:27][N:28]=[C:24]1[NH:23][C:17](=[O:18])[C:16]([C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]([CH2:6][C:5]2[CH:21]=[CH:22][C:2]([F:1])=[CH:3][CH:4]=2)[CH:8]=1)=[O:20]
Reactant: Nc1nncs1
Reactant: O=C(Cl)C(=O)c1cn(Cc2ccc(F)cc2)c2ccccc12
Solvent: COCCOC
Product: O=C(Nc1nncs1)C(=O)c1cn(Cc2ccc(F)cc2)c2ccccc12
Reaction time: 12 h
Yield: 49.1 %

Procedure:
A solution of 2-(1-(4-fluorobenzyl)-1H-indol-3-yl)-2-oxo-acetyl chloride (318 mg) in dry 1,2-dimethoxyethane (5 ml) is added dropwise to a suspension of 2-amino-1,3,4-thiadiazole (91 mg) and dry, ground K2CO3 (138 mg) in 5 ml of 1,2-dimethoxyethane, operating at room temperature. The reaction mixture is left under stirring for 12 hours then poured into water (60 ml). The resulting suspension is stirred for 30 minutes. The precipitate is filtered off and suspended in methanol (10 ml) under stirring for 30 minutes. The solid is recovered by filtration and dried to give N-(1,3,4-thiadiazol-2-yl)-2-(1-(4-fluorobenzyl)-1H-indol-3-yl)-2-oxo-acetamide (168 mg).
Reaction SMILES: [CH:1]12[C:9](=[O:10])[O:8][C:6](=O)[CH:3]([CH2:4][CH2:5]1)[CH2:2]2.[NH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][N:19]([C:22]2[N:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[CH2:18][CH2:17]1>ClCCl>[N:23]1[CH:24]=[CH:25][CH:26]=[N:27][C:22]=1[N:19]1[CH2:20][CH2:21][N:16]([CH2:15][CH2:14][CH2:13][CH2:12][N:11]2[C:6](=[O:8])[CH:3]3[CH2:2][CH:1]([CH2:5][CH2:4]3)[C:9]2=[O:10])[CH2:17][CH2:18]1
Reactant: O=C1OC(=O)C2CCC1C2
Reactant: NCCCCN1CCN(c2ncccn2)CC1
Solvent: ClCCl
Product: O=C1C2CCC(C2)C(=O)N1CCCCN1CCN(c2ncccn2)CC1

Procedure:
1,3-Cyclopentanedicarboxylic acid (4.0 g., 25 mmole) was converted to the anhydride by refluxing for 3 hours in 20 ml. of acetic anhydride. After removal of excess acetic anhydride, extraction with hexane and evaporation of the hexane, 3.95 g. of cyclopentane-1,3-dicarboxylic anhydride was obtained. The anhydride was combined with 6.51 g. (27 mmole) of 1-(4-aminobutyl)-4-(2-pyrimidinyl)piperazine in 50 ml. of dichloromethane and stirred at room temperature overnight. The dichloromethane was removed in vacuo and replaced with 75 ml. of toluene. The mixture was refluxed for 24 hours with water separation via a Dean-Stark trap. The product was concentrated under vacuum and chromatographed on 200 g. of silica gel with 5% ethanol/chloroform. The product-containing fractions were combined and concentrated and the residue crystallized (2 crops) from isopropanol with addition of 4N HCl/isopropanol. A second recrystallization from isopropanol gave 1.1 g. of the title compound as the dihydrochloride, hemihydrate; m.p. 201°-203° C.(d).
Reaction SMILES: [O:1]=[O+][O-].[CH3:4][O:5][C:6](=[O:20])[C:7]([N:11]1[C@H:14]([S:15][C:16](=[O:18])[CH3:17])[CH2:13][C:12]1=[O:19])=C(C)C>CO>[CH3:4][O:5][C:6](=[O:20])[C:7]([N:11]1[C@H:14]([S:15][C:16](=[O:18])[CH3:17])[CH2:13][C:12]1=[O:19])=[O:1]
Reactant: O=[O+][O-]
Reactant: COC(=O)C(=C(C)C)N1C(=O)C[C@H]1SC(C)=O
Solvent: CO
Product: COC(=O)C(=O)N1C(=O)C[C@H]1SC(C)=O

Procedure:
4 equivalents of ozone are introduced over a period of 60 minutes into a solution, cooled to -15°, of 150 mg of 2-[(4R)-4-acetylthio-2-oxoazetidin-1-yl]-3-methylcrotonic acid methyl ester in 3 ml of methanol. The reaction mixture is rinsed with nitrogen, diluted with methylene chloride and washed for 2 minutes with a 5% aqueous sodium bisulphite solution. The organic phase is dried over sodium sulphate and concentrated in vacuo. IR spectrum of the resulting oily title compound (in methylene chloride): characteristic bands at 3.30-3.40, 5.52, 5.70, 5.83 (sh), 5.86, 6.98, 7.08 (sh), 7.40, 7.82-8.00 (broad, sh), 8.07, 8.19, 8.30 (sh), 8.46, 8.90, 9.22, 9.52, 9.91, 10.30 and 10.73μ. The product obtained can be used in the next stage without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:13]2[CH2:18][C@@H:17]([C:19](=[O:26])[CH2:20][C:21](OCC)=[O:22])[CH2:16][CH2:15][N:14]2[C:27]([O:29][CH3:30])=[O:28])[CH:5]=[C:6]([F:12])[C:7]=1[C:8]([F:11])([F:10])[F:9].[OH-].[Na+].[NH2:33]O.Cl>CO.O>[F:1][C:2]1[CH:3]=[C:4]([C@H:13]2[CH2:18][C@@H:17]([C:19]3[O:26][NH:33][C:21](=[O:22])[CH:20]=3)[CH2:16][CH2:15][N:14]2[C:27]([O:29][CH3:30])=[O:28])[CH:5]=[C:6]([F:12])[C:7]=1[C:8]([F:10])([F:9])[F:11]
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](c2cc(F)c(C(F)(F)F)c(F)c2)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1c1cc(F)c(C(F)(F)F)c(F)c1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 43 %

Procedure:
Cis-methyl 2-(3,5-difluoro-4-(trifluoromethyl)phenyl)-4-(3-ethoxy-3-oxopropanoyl)-piperidine-1-carboxylate (1.489 g, 3.40 mmol) was dissolved in MeOH (15 mL) and cooled to −40° C. Sodium hydroxide (0.896 mL, 3.40 mmol) dissolved in water (1.500 mL) was added and the reaction stirred at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.209 mL, 3.40 mmol) was added and stirring continued for 3.5 h at −40° C. The reaction mixture was then added to a prewarmed 80° C. solution of hydrogen chloride (17.59 mL, 105.54 mmol) and stirred for 20 min. The solvent was evaporated in vacuo. DCM (100 mL) and water (100 mL) were added, shaken and the phases separated. The organic phase was dried with a phase separator and evaporated in vacuo. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 20-65% Acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer over 30 minutes with a flow of 100 mL/min. Cis-methyl 2-(3,5-difluoro-4-(trifluoromethyl)phenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (0.594 g, 42.9%) was isolated as a white solid. 1H NMR (600 MHz, cdcl3) δ 1.82-1.89 (m, 1H), 2.08-2.16 (m, 1H), 2.19-2.27 (m, 1H), 2.32-2.38 (m, 1H), 3.04-3.11 (m, 1H), 3.34-3.41 (m, 1H), 3.68 (s, 3H), 4.09-4.15 (m, 1H), 5.04-5.08 (m, 1H), 5.57 (s, 1H), 6.80 (d, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]#[N:9].[Cl:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17](=O)[CH2:16][CH2:15][CH2:14]2.B(F)(F)F.CCOCC>>[NH2:9][C:8]1[C:16]2[CH2:15][CH2:14][C:13]3[CH:12]=[C:11]([Cl:10])[CH:20]=[CH:19][C:18]=3[C:17]=2[N:1]=[C:2]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2
Reactant: O=C1CCCc2cc(Cl)ccc21
Reactant: N#Cc1ccccc1N
Agent: FB(F)F
Solvent: CCOCC
Product: Nc1c2c(nc3ccccc13)-c1ccc(Cl)cc1CC2

Procedure:
2-amino-1-cyano-benzene (5.0 g, 42.3 mmol), 6-chloro-3, 4-dihydro-[2H]-napthalen-1-one (Organon Laboratories) (8.8 g, 48.7 mmol) and boron trifluoride diethyl etherate (1M, 6.4 ml, 52.4 mmol) were treated according to the general procedure described herein to give the title compound.
Reaction SMILES: [CH3:1][N:2]([CH2:19][C:20]([OH:22])=[O:21])[S:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]2)=[CH:8][CH:7]=1)(=[O:5])=[O:4].C(N1C=CN=C1)(N1[CH:29]=[CH:28]N=C1)=O.C(O)C>O1CCCC1>[CH2:28]([O:21][C:20](=[O:22])[CH2:19][N:2]([CH3:1])[S:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:13][CH2:14][C:15](=[O:18])[CH2:16][CH2:17]2)=[CH:8][CH:7]=1)(=[O:5])=[O:4])[CH3:29]
Reactant: CN(CC(=O)O)S(=O)(=O)c1ccc(N2CCC(=O)CC2)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)CN(C)S(=O)(=O)c1ccc(N2CCC(=O)CC2)cc1
Reaction time: 0.75 h
Yield: 134 %

Procedure:
A solution of 0.53 g (1.6 mmol) {methyl-[4-(4-oxo-piperidin-1-yl)-benzenesulfonyl]-amino}-acetic acid in 8 mL anhydrous tetrahydrofuran was treated with 0.32 g (2.0 mmol) 1,1′-carbonyl-diimidazole. After stirring for 45 minutes, 1 mL of ethanol was added. The resulting mixture was then permitted to stir overnight. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate. The organics were washed twice with saturated sodium bicarbonate, twice with water, dried over sodium sulfate and concentrated in vacuo. After drying via high vacuum overnight, 0.76 g of the title compound was isolated as a red solid; 1H NMR (CDCl3) δ 1.23-1.29 (m, 3H), 2.59 (t, J=6.15 Hz, 4H), 2.87 (s, 1H), 3.76 (t, J=6.09 Hz, 4H), 3.96 (s, 2H), 4.11-4.18 (m, 2H), 6.89-6.96 (m, 2H), 7.67-7.75 (m, 2H); MS (ES) m/z 355.3 (MH+); HRMS for C16H22N2O5S: 355.1332.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1[C:12]([C:13]([O:15]C)=[O:14])=[CH:11][CH:10]=[C:9]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:8]=1)=[S:6].Cl>O.CCOCC>[CH2:17]([C:9]1[N:8]=[C:7]([C:5]([OH:4])=[S:6])[C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)c1ccc(Cc2ccccc2)nc1C(=S)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: O=C(O)c1ccc(Cc2ccccc2)nc1C(O)=S
Temperature: 40 °C
Reaction time: 4 h

Procedure:
15.0 g (0.375 mol) sodium hydroxide are dissolved in 40 ml water and added to a stirred mixture of 7.3 g (0.023 mol) 6-benzylthiopyridine-2,3-dicarboxylic acid dimethyl ester in 40 ml ether. It is stirred for 4 hours at 40° C., the aqueous phase is acidified with concentrated hydrochloric acid, and the product is extracted with ethyl acetate, the solvent then being dried across magnesium sulfate and compressed. The product crystallizes from the residue.
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:26]1[CH:27]=[CH:28][C:29]2[N:30]([CH:32]=[C:33]([C:35]([CH3:42])([CH3:41])[C:36]([O:38][CH2:39][CH3:40])=[O:37])[N:34]=2)[N:31]=1.C(=O)(O)[O-].[Na+].[C:48]([OH:55])(=[O:54])/[CH:49]=[CH:50]/[C:51]([OH:53])=[O:52]>CO>[C:48]([OH:55])(=[O:54])/[CH:49]=[CH:50]/[C:51]([OH:53])=[O:52].[C:48]([OH:55])(=[O:54])/[CH:49]=[CH:50]/[C:51]([OH:53])=[O:52].[C:19]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:26]3[CH:27]=[CH:28][C:29]4[N:30]([CH:32]=[C:33]([C:35]([CH3:41])([CH3:42])[C:36]([O:38][CH2:39][CH3:40])=[O:37])[N:34]=4)[N:31]=3)[CH2:11][CH2:10]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)C(C)(C)c1cn2nc(Cl)ccc2n1
Reactant: NCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)C(C)(C)c1cn2nc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)ccc2n1
Yield: 78.2 %

Procedure:
4.2 g of 4-(diphenylmethoxy)-1-piperidinepropaneamine and 1.76 g of ethyl 2-(6-chloroimidazo[1,2-b]pyridazin-2-yl)-2-methylpropionate were stirred at 192-200° C. for 3.5 hours. After cooling, an aqueous sodium bicarbonate solution was added thereto and extracted with ethyl acetate. The extract was washed with a brine solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography to be eluted with ethyl acetate:methanol:triethyl amine (100:5:1). The desired fraction was collected and dissolved in 16 mL of ethyl acetate, and a solution prepared by dissolving 867 mg of fumaric acid in 16 mL of methanol was added thereto, followed by concentration. To the residue was added acetone and the crystals formed were collected by filtration, washed with acetone and dried to provide 2.30 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1.[CH2:13]([NH:16][CH2:17][CH:18]=[CH2:19])[CH:14]=[CH2:15]>CN(C=O)C>[CH2:13]([N:16]([CH2:17][CH:18]=[CH2:19])[C:4]1[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=[C:2]([Cl:1])[N:3]=1)[CH:14]=[CH2:15]
Reactant: Cc1csc2c(Cl)nc(Cl)nc12
Reactant: C=CCNCC=C
Solvent: CN(C)C=O
Product: C=CCN(CC=C)c1nc(Cl)nc2c(C)csc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 61.1 %

Procedure:
In DMF was dissolved 1.50 g (6.8 mmol) of 2,4-dichloro-7-methylthieno[3,2-d]pyrimidine, and then 1.56 9 (16.1 mmol) of diallylamine was added dropwise to the resulting solution under ice cooling over 5 minutes. The reaction mixture was stirred at 0° C. for one hour and then allowed to resume room temperature, followed by stirring for one hour. After completion of the reaction, ice water was added to the reaction mixture, followed by extraction with ethyl acetate (50 ml×3). After the organic layer was washed successively with 1N hydrochloric acid, water and brine and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1:15) to give 1.17 g (yield: 61.1%) of the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[Cl:23][C:24]1[CH:39]=[CH:38][C:27]([O:28][C:29]2[N:37]=[CH:36][CH:35]=[CH:34][C:30]=2[C:31](Cl)=[O:32])=[CH:26][CH:25]=1>C1COCC1>[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([O:28][C:29]2[N:37]=[CH:36][CH:35]=[CH:34][C:30]=2[C:31]([NH:1][CH2:2][CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:20])[CH3:21])[CH:12]=3)[CH2:7][CH2:6]2)=[O:32])=[CH:38][CH:39]=1
Reactant: O=C(Cl)c1cccnc1Oc1ccc(Cl)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)c3cccnc3Oc3ccc(Cl)cc3)CC2)c1

Procedure:
Prepared by Procedure Q1 (THF) and Scheme AT using N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 2-(4-chlorophenoxy)nicotinoyl chloride: ESMS m/e: 535.2 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[N:7]([C:9]1[CH:14]=[C:13](Cl)[N:12]=[CH:11][N:10]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].O.[NH2:18][NH2:19]>CC(O)C>[C:1]([O:5][C:6](=[O:16])[N:7]([C:9]1[CH:14]=[C:13]([NH:18][NH2:19])[N:12]=[CH:11][N:10]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Cl)ncn1
Reactant: NN
Solvent: CC(C)O
Solvent: O
Product: CN(C(=O)OC(C)(C)C)c1cc(NN)ncn1
Temperature: 90 °C

Procedure:
A mixture of (6-Chloro-pyrimidin-4-yl)-methyl-carbamic acid tert-butyl ester (10 g, 41.1 mmol), hydrazine monohydrate (6.5 g, 130.0 mmol), and 2-propanol (50 mL) is heated to 90° C. for 4 hours. The reaction mixture is then cooled to room temperature, and concentrated. The resultant crude product is treated with a mixture of water (80 mL) and ethanol (15 mL), heated for 30 minutes, and slowly cooled to room temperature. White precipitate forms. After filtration, the undissolved solid is washed with water, dried under vacuum overnight to give (6-Hydrazino-pyrimidin-4-yl)-methyl-carbamic acid tert-butyl ester as white powder in needle form: 1H NMR 400 MHz (d6-DMSO) δ 8.23 (s, 1H), 8.19 (s, 1H), 7.14 (s, 1H), 4.29 (s, 2H), 3.23 (s, 3H), 1.49 (s, 9H); MS m/z 240.10 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH3:9])[C:3]=1[NH:10][CH:11]1[CH2:15][CH2:14][O:13][C:12]1=O.C([O-])(=[S:19])C.[NH4+]>CS(C)=O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH3:9])[C:3]=1[NH:10][CH:11]1[CH2:15][CH2:14][S:19][C:12]1=[O:13]
Reactant: CCc1cccc(C)c1NC1CCOC1=O
Reactant: CC([O-])=S
Agent: [NH4+]
Solvent: CS(C)=O
Product: CCc1cccc(C)c1NC1CCSC1=O
Temperature: 0 °C
Yield: 48.4 %

Procedure:
11 g (0.05 mol) of N-(2-methyl-6-ethylphenyl)amino-tetrahydrofuran-2-one and 4.7 g (0.05 mol) of ammonium thioacetate are stirred in 80 ml of dimethylsulfoxide at 90° to 100° C. After cooling, the solution is poured into ice-water and extracted with methylene chloride. The combined extracts are repeatedly washed with water, dried over sodium sulfate and filtered and the filtrate is concentrated. Distillation of the residue under a high vacuum yields 5.7 g (48.5% of theory) of colourless N-(2-methyl-6-ethylphenyl)-amino-tetrahydrothiophen-2-one. Boiling point 167°-173° C. under 0.5 mm Hg.
Reaction SMILES: O.[C:2]1([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=[C:4]([OH:5])[CH:3]=1.[Cl:11][C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1[S:19](Cl)(=[O:21])=[O:20]>C([O-])(O)=O.[Na+].C(OCC)C>[OH:5][C:4]1[CH:3]=[C:2]([O:10][S:19]([C:13]2[CH:14]=[CH:15][CH:16]=[C:17]([Cl:18])[C:12]=2[Cl:11])(=[O:21])=[O:20])[CH:9]=[C:7]([CH3:8])[CH:6]=1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Reactant: Cc1cc(O)cc(O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: Cc1cc(O)cc(OS(=O)(=O)c2cccc(Cl)c2Cl)c1
Yield: 53.4 %

Procedure:
A solution of orcinol monohydrate (0.7.1 g, 5.0 mmol) and 2,3-dichlorobenzenesulfonyl chloride (1.23 g, 5.0 mmol) in saturated NaHCO3 (20 mL) and diethyl ether (20 mL was stirred at room temperature for 2 days. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (3×50 mL). The organic phase was washed with brine (2×50 mL) and dried over Na2SO4. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (methylene chloride to 2% ethyl acetate in methylene chloride) to give the title compound as a pale yellow oil (0.89 g, 55%). 1H-NMR (300 MHz, CDCl3) δ 2.24 (s, 3 H), 5.23 (s, 1 H), 6.43 (t, 1 H, J×2.2 Hz), 6.54 (d, 2 H, J=1.1 Hz), 7.34 (t, 1 H, J=8.1 Hz), 7.75 (dd, 1 H, J=0.8, 4.0 Hz), and 7.91 (dd, 1 H, J=0.8, 4.0 Hz).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[CH:7][C:6]=1[CH:15]([CH3:17])[CH3:16])=[O:4].Cl.[N:19]1([C:25]2[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[S:27][N:26]=2)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[S:27]1[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:25]([N:19]2[CH2:20][CH2:21][N:22]([CH2:2][C:3]([C:5]3[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[CH:7][C:6]=3[CH:15]([CH3:17])[CH3:16])=[O:4])[CH2:23][CH2:24]2)=[N:26]1
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Reactant: CC(=O)Nc1ccc(C(=O)CCl)c(C(C)C)c1
Agent: Cl
Product: CC(=O)Nc1ccc(C(=O)CN2CCN(c3nsc4ccccc34)CC2)c(C(C)C)c1
Yield: 66.7 %

Procedure:
Starting with N-[4-(2-chloro-acetyl)-3-isopropyl-phenyl]-acetamide (0.876 g, 3.453 mmol), and 3-piperazin-1-yl-benzo[d]isothiazole hydrochloride (0.883 g, 3.453 mmol) and following the procedure as outlined in Example 517, N-{4-[2-(4-benzo[d]isothiazol-3-yl-piperazin-1-yl)-acetyl]-3-isopropyl-phenyl}-acetamide (0.1.0 g, 2.302 mmol) was obtained as its hydrochloride salt from treatment with dioxane/HCl(gas). Yield=67%. 100% purity at 254 nM. 1H NMR (400 MHz, DMSO-d6) δ 10.44–10.29 (bm, 2H), 8.13 (d, J=8.49 Hz, 1H), 8.09 (d, J=8.49 Hz, 1H), 7.81 (d, J=9.12 Hz, 1H), 7.73–7.68 (m, 2H), 7.57 (t, J=7.49 Hz, 1H), 7.45 (t, J=7.49 Hz, 1H), 5.04 (s, 2H), 4.13–4.02 (m, 2H), 3.76–3.45 (m, 18H, H2O), 2.06 (s, 3H), 1.18 (d, J=6.85 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][OH:9])=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>C(Cl)Cl>[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([O:9][CH2:8][CH2:7][O:6][C:5]2[CH:10]=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCOc1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCOc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(4-chlorophenoxy)ethanol (2.0 g, 11.6 mmol) in DCM (10 mL) was added Et3N (5 mL) and 4-methylbenzene-1-sulfonyl chloride (TsCl; 2.43 g, 12.8 mmol) sequentially. The reaction mixture was stirred at room temperature overnight and partitioned between water and ethyl acetate. The organic layer was washed with water, 5% sodium bicarbonate (NaHCO3), and brine and concentrated. The resulting residue was washed with hexane to afford the title compound quantitatively.