Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6](F)[N:5]=[CH:4][N:3]=1.[CH2:10]([OH:14])[C:11]#[C:12][CH3:13].C(N(CC)C(C)C)(C)C>CCCCCC>[CH2:10]([O:14][C:6]1[C:7]([F:8])=[C:2]([F:1])[N:3]=[CH:4][N:5]=1)[C:11]#[C:12][CH3:13]
Reactant: CC#CCO
Reactant: Fc1ncnc(F)c1F
Solvent: CCCCCC
Solvent: CCN(C(C)C)C(C)C
Product: CC#CCOc1ncnc(F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.1 %

Procedure:
0.5 g of 4,5,6-trifluoropyrimidine, 0.31 g of 2-butyn-1-ol and 0.62 ml of N,N-diisopropylethylamine were added to 1 ml of hexane, then the mixture was stirred at room temperature for 1 hour. Then the reaction mixture was subjected to silica gel column chromatography to obtain 0.55 g of 4-(2-butynyloxy)-5,6-difluoropyrimidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]2[S:7](=[O:17])[C:8]([C:14]([OH:16])=O)=[C:9]([O:10][CH:11]([CH3:13])[CH3:12])[C:5]=2[CH:4]=1.[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]2[S:7](=[O:17])[C:8]([C:14]([NH:27][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:16])=[C:9]([O:10][CH:11]([CH3:12])[CH3:13])[C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)C(OC(C)C)=C(C(=O)O)S2=O
Reactant: NCc1ccccc1
Product: COc1ccc2c(c1)C(OC(C)C)=C(C(=O)NCc1ccccc1)S2=O
Yield: 2.7 %

Procedure:
Following a procedure analogous to Example 28, Preparation B, 200 mg (0.71 mmol) of 5-methoxy-3-(1-methylethoxy)benzo[b]thiophene-2-carboxylic acid-1-oxide and 388 μL (3.55 mmol) of benzylamine gives 7 mg (52%) of 5-methoxy-3-(1-methylethoxy)-N-(phenylmethyl)benzo[b]thiophene-2-carboxamide-1-oxide as a yellow gum.
Reaction SMILES: C([Cl:4])(=O)C.S(Cl)(Cl)=O.[CH3:9][O:10][CH:11](OC)[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=1>>[Cl:19][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[Cl:18])[CH:11]([Cl:4])[O:10][CH3:9]
Reactant: COC(OC)c1ccc(Cl)c(Cl)c1
Reactant: CC(=O)Cl
Solvent: O=S(Cl)Cl
Product: COC(Cl)c1ccc(Cl)c(Cl)c1
Reaction time: 22 h
Yield: 99.8 %

Procedure:
A mixture of acetyl chloride (77 g) and thionyl chloride (0.8 ml) was added, with stirring, to 3,4-dichlorobenzaldehyde dimethyl acetal (110 g). The mixture was kept at laboratory temperature (about 27° C.) for 22 hours and then evaporated at 30° C. under reduced pressure (0.15 mm Hg) for about 4 hours until constant in weight. 3,4-Dichloro-α-methoxybenzyl chloride (112 g) was thus obtained as an oil, which was used without further purification as a starting material in the above preparations.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[C:10]([O:12][C@@H:13]2[CH2:17][CH2:16][O:15][CH2:14]2)[CH:9]=[C:8]([CH3:18])[C:7]=1[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][OH:26])[CH:20]=1)(=[O:3])[CH3:2].O[C:28]1[CH:41]=[CH:40][C:31]2[C@H:32]([CH2:35][C:36]([O:38][CH3:39])=[O:37])[CH2:33][O:34][C:30]=2[CH:29]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[C:1]([O:4][CH2:5][C:6]1[CH:11]=[C:10]([O:12][C@@H:13]2[CH2:17][CH2:16][O:15][CH2:14]2)[CH:9]=[C:8]([CH3:18])[C:7]=1[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][O:26][C:28]2[CH:41]=[CH:40][C:31]3[C@H:32]([CH2:35][C:36]([O:38][CH3:39])=[O:37])[CH2:33][O:34][C:30]=3[CH:29]=2)[CH:20]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)C[C@@H]1COc2cc(O)ccc21
Reactant: CC(=O)OCc1cc(O[C@@H]2CCOC2)cc(C)c1-c1cccc(CO)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(O[C@@H]5CCOC5)cc4COC(C)=O)c3)ccc21
Temperature: 0 °C
Reaction time: 12 h
Yield: 96 %

Procedure:
(R)-(3′-(Hydroxymethyl)-6-methyl-4-((tetrahydrofuran-3-yl)oxy)biphenyl-2-yl)methyl acetate 35d (127 mg, 0.36 mmol) was dissolved in 10 mL of dichloromethane, followed by addition of methyl (S)-2-(6-hydroxyl-2,3-dihydrobenzofuran-3-yl)acetate (89 mg, 0.43 mmol) and triphenylphosphine (112 mg, 0.43 mmol). The reaction solution was cooled down to 0° C., followed by addition of diisopropyl azodicarboxylate (87 mg, 0.43 mmol). The reaction solution was warmed up to room temperature and stirred for 12 hours. The resulting solution was concentrated under reduced pressure to obtain the crude title compound methyl 2-((S)-6-((2′-(acetoxymethyl)-6′-methyl-4′-(((R)— tetrahydrofuran-3-yl)oxy)biphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate 35e (189 mg) as a yellow oil, which was used directly in the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:33]=[CH:32][C:6]([CH2:7][N:8]2[C:30](=[O:31])[N:11]3[N:12]=[CH:13][C:14]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=4)=[C:15]([C:16]4[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=4)[C:10]3=[N:9]2)=[CH:5][CH:4]=1.[CH3:36][Mg]Br.CO>C1COCC1>[F:35][C:2]([F:1])([F:34])[C:3]1[CH:33]=[CH:32][C:6]([CH2:7][N:8]2[C:30](=[O:31])[N:11]3[NH:12][CH:13]([CH3:36])[C:14]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=4)=[C:15]([C:16]4[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=4)[C:10]3=[N:9]2)=[CH:5][CH:4]=1
Reactant: C[Mg]Br
Reactant: O=c1n(Cc2ccc(C(F)(F)F)cc2)nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Solvent: C1CCOC1
Solvent: CO
Product: CC1Nn2c(nn(Cc3ccc(C(F)(F)F)cc3)c2=O)C(c2ccc(Cl)cc2)=C1c1ccc(Cl)cc1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 98.6 %

Procedure:
To a solution of 2-(4-(trifluoromethyl)benzyl)-7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (250 mg, 0.485 mmol), prepared as described in Example 17, in THF (4 mL) at −20° C. was added methyl magnesium bromide (0.81 mL, 2.43 mmol, 3.0 M in Et2O). The reaction was stirred at −20° C. for 30 min. LC-MS showed that the reaction was complete. To the reaction mixture was added 20 mL of MeOH to quench the reaction. The reaction was allowed to warm to RT and the solvent was evaporated. The residue was diluted with EtOAc (100 mL), washed with H2O (10 mL) and saturated aqueous NaCl (5 mL×2). The organic layer was dried (MgSO4), filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using an automated system, eluting with a gradient of (0% to 80% EtOAc for 40 min. and holds at 80% for 10 min.) to give the title compound, 2-(4-(Trifluoromethyl)benzyl)-7,8-bis(4-chlorophenyl)-6-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (254 mg), as a beige solid in 98% yield. HPLC retention time: 4.23 min; MS [M+H]+: found 531. 1HNMR (CDCl3, 400 MHz) 67.52 (d, 2H), 7.38 (d, 2H), 7.17-7.11 (m, 4H), 7.05 (dd, 2H), 6.94 (dd, 2H), 4.94 (s, 2H), 4.16 (q, 1H), 1.24 (d, 3H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH:6]=1)=O.C(OC([N:22]1[CH2:27][CH2:26][CH:25]([C:28](=[S:30])[NH2:29])[CH2:24][CH2:23]1)=O)(C)(C)C>>[CH:6]1[C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=2[CH:13]=[CH:14][C:5]=1[C:3]1[N:29]=[C:28]([CH:25]2[CH2:26][CH2:27][NH:22][CH2:23][CH2:24]2)[S:30][CH:2]=1
Reactant: O=C(CBr)c1ccc2c(c1)CCCC2
Reactant: CC(C)(C)OC(=O)N1CCC(C(N)=S)CC1
Product: c1cc2c(cc1-c1csc(C3CCNCC3)n1)CCCC2

Procedure:
The preparation is carried out as described starting from 8 g (31.6 mmol) of 2-bromo-1-(5,6,7,8-tetrahydronaphthalen-2-yl)ethanone and 8 g (32.7 mmol) of 4-thiocarbamoylpiperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([S:29]([CH3:32])(=[O:31])=[O:30])[CH2:25][CH2:24]2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[F:33][C:34]([F:42])([F:41])[CH2:35]CS([O-])(=O)=O>>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17]([CH2:35][C:34]([F:42])([F:41])[F:33])[C:16]([C:21]([N:23]2[CH2:24][CH2:25][N:26]([S:29]([CH3:32])(=[O:30])=[O:31])[CH2:27][CH2:28]2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: O=S(=O)([O-])CCC(F)(F)F
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCN(S(C)(=O)=O)CC4)cc3c2)CC1
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCN(S(C)(=O)=O)CC2)n3CC(F)(F)F)CC1
Yield: 54 %

Procedure:
The title compound was synthesized in analogy to example 3, from [5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4-methanesulfonyl-piperazin-1-yl)-methanone (example 1) and 2,2,2-trifluoroethyl-methanesulfonate to afford the desired product as a colorless foam (54%). MS (ISP): 544.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[NH2:16])[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].Cl.[C:18](=N)(OCC)[CH2:19][CH2:20][CH3:21]>C(O)C>[C:7]1([C:5]([C:4]2[CH:13]=[CH:14][C:15]3[NH:16][C:18]([CH2:19][CH2:20][CH3:21])=[N:1][C:2]=3[CH:3]=2)=[O:6])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCCC(=N)OCC
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1N
Agent: Cl
Solvent: CCO
Product: CCCc1nc2cc(C(=O)c3ccccc3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 45.4 %

Procedure:
A mixture of 3,4 diaminobenzophenone (21.2 g; 0.1 mol) and ethyl butyrimidate hydrochloride (22.7 g; 0.15 mol) in ethanol (500 mL) was heated at reflux for a period of 6 hours. The mixture was stirred at ambient temperature for 18 hours. The solvent was evaporated and the residue was purified by flash chromatography on silica gel (EtOAc/Hexane; 1:1). Crystallization from ethyl acetate provided 12 g (45% yield) of the title compound as an off-white solid, m.p. 131-132° C. Anal. Calcd. for C17H16N2O: C, 77.25; H, 6.10; N, 10.60. Found: C, 77.20; H, 6.06; N, 10.72. Mass spectrum (EI; M+) m/z 264. 1H-NMR (DMSO-d6; 400 MHz) δ12.56 (br s, 1H), 7.84 (s, 1H), 7.73 (m, 2H), 7.65 (m, 1H), 7.60 (s, 2H), 7.56 (t, 2H), 2.82 (t, 2H), 1.80 (m, 2H), and 0.95 ppm (t, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:14][C:15](=[O:29])[C@@H:16]([NH:18][C:19]1[N:24]=[C:23](Cl)[N:22]=[C:21]([C:26]([NH2:28])=[O:27])[CH:20]=1)[CH3:17].C([O-])([O-])=O.[Cs+].[Cs+].CCOC(C)=O>CN(C=O)C>[NH2:14][C:15](=[O:29])[C@@H:16]([NH:18][C:19]1[N:24]=[C:23]([N:11]2[CH2:12][CH2:13][N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH2:9][CH2:10]2)[N:22]=[C:21]([C:26]([NH2:28])=[O:27])[CH:20]=1)[CH3:17]
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: C[C@H](Nc1cc(C(N)=O)nc(Cl)n1)C(N)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@H](Nc1cc(C(N)=O)nc(N2CCN(c3ccc(F)cc3)CC2)n1)C(N)=O
Temperature: 100 °C
Reaction time: 14 h
Yield: 80.4 %

Procedure:
A mixture of 1-(4-fluorophenyl)piperazine (112 mg, 0.62 mmol), (S)-6-((1-amino-1-oxopropan-2-yl)amino)-2-chloropyrimidine-4-carboxamide (150 mg, 0.62 mmol) and Cs2CO3 (235 mg, 0.62 mmol) in DMF (3.0 mL) was stirred at 100° C. for 14 hrs. The reaction was worked up with EtOAc and purified by silica gel flash chromatography (DCM/methanol) to give (S)-6-((1-amino-1-oxopropan-2-yl)amino)-2-(4-(4-fluorophenyl)piperazin-1-yl)pyrimidine-4-carboxamide as a white solid (193 mg, 80%). 1H NMR (CD3OD): 6.90-7.1 (4H, m), 6.55 (1H, s), 4.3 (1H, m), 3.98 (4H, m), 3.10 (4H, m), 1.40 (3H, d, J=7.0 Hz). LC/MS: m/z=388 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:15](=[O:16])[NH:14][C:7]2[N:8]=[C:9]([S:12][CH3:13])[N:10]=[CH:11][C:6]=2[CH:5]=1.I[CH2:18][CH3:19]>CN(C)C=O>[CH2:18]([N:14]1[C:7]2[N:8]=[C:9]([S:12][CH3:13])[N:10]=[CH:11][C:6]=2[CH:5]=[C:4]([CH3:3])[C:15]1=[O:16])[CH3:19]
Reactant: CSc1ncc2cc(C)c(=O)[nH]c2n1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1c(=O)c(C)cc2cnc(SC)nc21
Temperature: 50 °C
Yield: 78.2 %

Procedure:
To a suspension of NaH (261 mg of a 60% suspension of NaH in mineral oil) in 40 mL of dimethylformamide was added 6-methyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (926 mg, 4.48 mmol). The reaction mixture was heated to 50° C. resulting in a clear solution. The solution was cooled slightly, and iodoethane (491 μL, 6.14 mmol) was added. The reaction was heated at 50° C. for 10 minutes, then cooled to room temperature and partitioned between ice water and ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was partitioned between hexane and water. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Hexane was added and the resultant solid collected by filtration to provide 824 mg (78%) of 8-ethyl-6-methyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one, mp 84-86° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[CH2:11][NH:10][CH2:9][CH2:8][NH:7]1.Cl[C:13]1[CH:22]=[C:21]2[C:16]([C:17](=[O:28])[C:18]([C:25]([OH:27])=[O:26])=[CH:19][N:20]2[CH2:23][CH3:24])=[CH:15][C:14]=1[F:29]>N1C=CC=CC=1>[CH2:23]([N:20]1[C:21]2[C:16](=[CH:15][C:14]([F:29])=[C:13]([N:10]3[CH2:9][CH2:8][NH:7][CH:6]([C:2]4[O:1][CH:5]=[CH:4][CH:3]=4)[CH2:11]3)[CH:22]=2)[C:17](=[O:28])[C:18]([C:25]([OH:27])=[O:26])=[CH:19]1)[CH3:24]
Reactant: c1coc(C2CNCCN2)c1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)cc21
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(c4ccco4)C3)cc21
Yield: 44.6 %

Procedure:
A mixture of 2.508 g of 2-(2-furanyl)piperazine, 942 mg of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and 10 ml of pyridine was refluxed for 24 hours, then the solvent was removed. The residue was triturated with ether and chloroform, the solid collected, dissolved in 40% acetic acid and adjusted to pH 7 with 1N sodium hydroxide. The resulting solid was collected, washed with methanol and ether and dried, giving 600 mg of the desired product, mp 198° C.
Reaction SMILES: [S:1]1[C:5]([C:6]([O:8]CC)=O)=[N:4][CH:3]=[N:2]1.O.[NH2:12][NH2:13]>>[S:1]1[C:5]([C:6]([NH:12][NH2:13])=[O:8])=[N:4][CH:3]=[N:2]1
Reactant: CCOC(=O)c1ncns1
Reactant: NN
Solvent: O
Product: NNC(=O)c1ncns1

Procedure:
Ethyl 1,2,4-thiadiazole-5-carboxylate (I79) (246 mg, 1.555 mmol) and hydrazine hydrate (0.151 mL, 3.11 mmol) were heated at 80° C. for 5 hr. The solvents were removed in vacuo to afford a yellow solid in 173 mg.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][NH:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)(=[O:12])=[O:11])[CH3:2].[N:23]1([CH2:32][C:33](O)=[O:34])[CH:31]=[C:29]([CH3:30])[C:27](=[O:28])[NH:26][C:24]1=[O:25].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][N:6]([CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)(=[O:12])=[O:11])[C:33](=[O:34])[CH2:32][N:23]1[CH:31]=[C:29]([CH3:30])[C:27](=[O:28])[NH:26][C:24]1=[O:25])[CH3:2]
Reactant: CCOC(=O)CNCCNS(=O)(=O)c1nc2ccccc2s1
Reactant: Cc1cn(CC(=O)O)c(=O)[nH]c1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CN(CCNS(=O)(=O)c1nc2ccccc2s1)C(=O)Cn1cc(C)c(=O)[nH]c1=O
Reaction time: 5 h
Yield: 75 %

Procedure:
To the mixture of N-[2-(benzothiazole-2-sulfonylamino)-ethyl]-glycine ethyl ester (1.72 g, 5 mmol), (thymin-1-yl)-acetic acid (0.92 g, 5 mmol), HOBt (0.81 g, 6 mmol), and DCC (1.24 g, 6 mmol) in DMF (15 mL) was added N,N-diisopropylethylamine (1.31 mL, 7.5 mmol) at ambient temperature. The resulting reaction mixture was stirred for 5 h at the same temperature and the, solvent was removed in vacuo to 5 mL. The residue was dissolved in dichloromethane (50 mL) and the precipitate was filtered. The filtrate was washed with 1N HCl aqueous solution, saturated sodium bicarbonate solution, and brine. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated and the residue was triturated with ethyl alcohol. The resulting solid was filtered off and dried in vacuo to give the title compound (1.91 g, 75%) as a white solid. 1H NMR (500 MHz; DMSO-d6) δ 11.29 (s, 0.6H), 11.28(s, 0.4H), 8.99(brs, 0.6H), 8.82(brs, 0.4H), 8.28(m, 1H) 8.18(d, 1H) 7.66(m, 2H) 7.31(s, 0.6H) 7.42(s, 0.4H) 4.66(s, 1.2H) 4.47(s, 0.8H) 4.31(s, 0.8H), 4.05(s, 1.2H), 4.04(q, 1.2H), 3.55(t, 1.2H), 3.40˜3.34(m, 2.8H), 3.20(t, 0.8H), 1.73(s, 3H), 1.19(t, 1.2H), 1.14(t, 1.8H).
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][CH2:21][NH:22][CH:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]1>CN(C)C=O.C(OCC)(=O)C>[C:32]([O:31][C:29]([N:26]1[CH2:27][CH2:28][CH:23]([N:22]2[CH2:21][CH2:20][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[NH:13][C:1]2=[O:2])[CH2:24][CH2:25]1)=[O:30])([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)N1CCC(NCCc2ccccc2N)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Carbonyldiimidazole (8.73 g, 53.8 mmol) was added to a solution of tert-butyl 4-{[2-(2-aminophenyl)ethyl]amino}piperidine-1-carboxylate (17.2 g, 53.8 mmol) in dimethylformamide (200 mL), and stirred at room temperature for 2 h. The reaction was diluted with ethyl acetate and extracted with water, then saturated brine. The crude product was purified by chromatography (silica gel, 0–30% ethyl acetate in methylene chloride gradient elution). The title compound was obtained as a dark solid (4.8 g).
Reaction SMILES: [CH2:1]1[O:3][CH:2]1[CH2:4][OH:5].N1C=CC=CC=1.[CH3:12][O:13][C:14]([CH2:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1)=[O:15]>CCOCC>[CH3:12][O:13][C:14]([CH2:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([O:5][CH2:4][CH:2]2[O:3][CH2:1]2)=[O:22])=[CH:19][CH:18]=1)=[O:15]
Reactant: COC(=O)Cc1ccc(C(=O)Cl)cc1
Reactant: OCC1CO1
Solvent: CCOCC
Solvent: c1ccncc1
Product: COC(=O)Cc1ccc(C(=O)OCC2CO2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture containing 14.8 g (0.2 mole) of glycidol, 150 ml of anhydrous ether, 16 g (0.4 mole of pyridine and 43 g (0.2 mole) of 4-[(methoxycarbonyl)methyl]benzoyl chloride is stirred at room temperature for two hours. The mixture is filtered and the ether evaporated to leave an oil. This oil is distilled to give a colorless oil.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[N+:6]([CH:9]=[C:10]1[NH:15][CH2:14][CH2:13][CH2:12][S:11]1)([O-:8])=[O:7].C(N(CC)CC)C.Cl>CN(C)C=O>[C:1]([N:15]1[CH2:14][CH2:13][CH2:12][S:11][C:10]1=[CH:9][N+:6]([O-:8])=[O:7])(=[O:4])[CH2:2][CH3:3]
Reactant: O=[N+]([O-])C=C1NCCCS1
Reactant: CCC(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC(=O)N1CCCSC1=C[N+](=O)[O-]
Temperature: -25 °C
Reaction time: 0.58 h

Procedure:
Propionyl chloride (1.8 g) was added dropwise over a period of 15 minutes to a mixture of 2-(nitromethylene)-tetrahydro-2H-1,3-thiazine (2.0 g) and triethylamine (2.4 g) in dimethylformamide (8 ml) at -30° C. under nitrogen. The reaction mixture was stirred for a further period of 35 minutes at -25° C. and was then poured into 2% hydrochloric acid. The mixture was extracted with dichloromethane and the organic layer was washed with sodium chloride solution and dried (Na2SO4). The solvent was then removed under reduced pressure and the residue was purified by chromatography on silica gel using 1% methanol in dichloromethane as eluent to yield the required product as a yellow crystalline solid m.p. 84°-86° C.
Reaction SMILES: C([CH2:8][NH:9][CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)C1C=CC=CC=1.[ClH:16]>CO.CCOCC>[ClH:16].[CH3:8][NH:9][CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1
Reactant: c1ccc(CCNC2CCOCC2)cc1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: CNC1CCOCC1

Procedure:
The title compound was prepared according to Preparation 23 from benzylmethyl(tetrahydropyran-4-yl)amine (Preparation 87). Crude material was dissolved in methanol and a solution of 1M HCl in ether was added dropwise to form a precipitate. The product was filtered and washed with ether to give the title compound as the hydrochloride salt as a white crystalline solid. δH (CD3OD): 4.11-4.00 (2H, m), 3.53-3.43 (2H, m), 3.37-3.27 (1H, m), 2.74 (3H, s), 2.11-2.03 (2H, m), 1.74-1.60 (2H, m).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4](O)=[O:5].Cl.[CH3:13][NH:14][O:15][CH3:16].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([N:14]([O:15][CH3:16])[CH3:13])=[O:5]
Reactant: CNOC
Reactant: O=C(O)c1cc(F)ccc1Br
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1cc(F)ccc1Br
Reaction time: 1 h
Yield: 73 %

Procedure:
2-Bromo-5-fluorobenzoic acid (4.60 g, 0.02 mol), N,O-Dimethylhydroxylamine hydrochloride (2.05 g, 0.02 mol), carbon tertabromide (6.9 g, 0.02 mol) was added to mixture of methylene chloride (100 mL) and triethylamine (2.9 mL, 0.02 mol). Triphenylphospine (5.53 g, 0.02 mol) was added to the solution over 1 hour and stirred for another 1 hour. The solution was concentrated to an oil. Hexanes (100 mL) and Ethyl Acetate (100 mL) were added to the oil and stirred for 1 hour then filtered. The filtrate was concentrated and the residue was purified by chromatography (Hexanes/Ethyl Acetate) on silica gel to afford 2-bromo-5-fluoro-N-methoxy-N-methylbenzamide as a foamy white solid in 73% yield. 1H NMR (CDCl3, 500 MHz) δ3.00-3.98 (m, 6 H), 6.97-7.08 (m, 2H), 7.51-7.54 (m, 1H).
Reaction SMILES: Cl[S:2]([OH:5])(=[O:4])=[O:3].[C:6]([OH:16])(=O)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]C(C)C.C1(O)C=CC=CC=1>>[CH:7]1[C:6]([OH:16])=[CH:11][CH:10]=[C:9]([S:2]([OH:5])(=[O:4])=[O:3])[CH:8]=1
Reactant: CC(C)CCCCCC(=O)O
Reactant: O=S(=O)(O)Cl
Solvent: Oc1ccccc1
Product: O=S(=O)(O)c1ccc(O)cc1
Temperature: 95 °C
Reaction time: 0.12 h
Yield: 93.3 %

Procedure:
In the equipment according to FIG. 1, a mixture of 178.8 g (1.53 mole) of chlorosulfonic acid and 136.5 g (0.86 mole) of isononanoic acid was placed into one of the two graduated funnels and a mixture of 143 g (1.52 mole) of phenol and 104 g (0.66 mole) of isononanoic acid was placed into the other, and the two mixtures were added under control to the continuous-flow reactor in such a way that the residence time was about 7 minutes. The total time for adding the starting compounds to the reactor under control was about 2 hours. The reactor, heated to 95° C. under thermostatic control, had a length of 60 cm and was packed with glass rings. Throughout the reaction period, 10 liters of nitrogen per hour were passed through the receiver and through the reactor. This gave a 93.3% yield of crude phenolsulfonic acid diluted with isononanoic acid, of the following composition:
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([NH2:6])=[O:5].[B-](F)(F)(F)F.[CH3:17][CH2:18][O+](CC)CC.C(Cl)(Cl)Cl>C(Cl)Cl>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](=[NH:6])[O:5][CH2:17][CH3:18]
Reactant: CC[O+](CC)CC
Reactant: NC(=O)c1c(F)cccc1F
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCOC(=N)c1c(F)cccc1F
Reaction time: 24 h

Procedure:
2,6-Difluorobenzamide (1.56 g) in methylene chloride was added to triethyloxonium fluoborate (1.9 g) in methylene chloride and the mixture stirred for 24 hours. The solution was then washed three times with cold sodium carbonate solution and dried over sodium sulphate. The methylene chloride solution was evaporated to yield an oil. This was mixed with chloroform and the solution filtered from insoluble material. Evaporation of the chloroform gave the ethyl 2,6-difluorobenzimidate as a mobile oil.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[N:9]=[C:8]2[S:10][C:11]([SH:13])=[N:12][C:7]2=[CH:6][CH:5]=1)[CH3:2].[CH2:14]([O:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[O:27])=[CH:21][CH:20]=1)[CH2:15][CH2:16][CH3:17]>N1C=CC=CC=1>[CH2:14]([O:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:27])[N:3]([CH2:1][CH3:2])[C:4]2[N:9]=[C:8]3[S:10][C:11]([SH:13])=[N:12][C:7]3=[CH:6][CH:5]=2)=[CH:21][CH:20]=1)[CH2:15][CH2:16][CH3:17]
Reactant: CCNc1ccc2nc(S)sc2n1
Reactant: CCCCOc1ccc(N=C=O)cc1
Solvent: c1ccncc1
Product: CCCCOc1ccc(NC(=O)N(CC)c2ccc3nc(S)sc3n2)cc1
Reaction time: 3.5 h
Yield: 13.2 %

Procedure:
Into 13×100 mm pyrex reaction vial were added 5-ethylamino-thiazolo[5,4-b]pyridine-2-thiol (105 mg, 0.49 mmol), anhydrous pyridine (2 ml), and 4-butoxyphenyl isocyanate (135 μl, 0.74 mmol). The reaction mixture was stirred 3.5 h, then concentrated. Purification by preparative TLC (40% EtoAc in Hexanes) gave 26 mg (13%) of the title compound. 1H NMR (DMSO-d6) δ=0.91 (t, 3H), 1.10 (t, 3H), 1.39 (m, 2H), 1.61 (m, 2H), 3.91 (m, 1H), 6.80 (d, 2H), 7.30 (m, 3H), 7.99 (br d, 1H), 9.43 (s, 1H); ESIMS: m/z 401 (M−H); mp 134.3-135 C.