Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]([C:18]3[C:26]4[N:25]=[C:24]([CH:27]([CH3:29])[CH3:28])[NH:23][C:22]=4[CH:21]=[CH:20][CH:19]=3)=[O:17])[CH2:10][CH2:9]2)[CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>CN(C)C=O>[CH3:39][S:40]([N:1]1[CH2:2][CH2:3][CH:4]([CH2:7][N:8]2[CH2:9][CH2:10][CH:11]([CH2:14][NH:15][C:16]([C:18]3[C:26]4[N:25]=[C:24]([CH:27]([CH3:29])[CH3:28])[NH:23][C:22]=4[CH:21]=[CH:20][CH:19]=3)=[O:17])[CH2:12][CH2:13]2)[CH2:5][CH2:6]1)(=[O:42])=[O:41]
Reactant: CC(C)c1nc2c(C(=O)NCC3CCN(CC4CCNCC4)CC3)cccc2[nH]1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)c1nc2c(C(=O)NCC3CCN(CC4CCN(S(C)(=O)=O)CC4)CC3)cccc2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 40 %

Procedure:
2-Isopropyl-1H-benzoimidazole-4-carboxylic acid (1-piperidin-4-ylmethylpiperidin-4-ylmethyl)amide (40 mg, 0.1 mmol) was dissolved in N,N-dimethylformamide (1.0 mL) at room temperature. To this solution was added N,N-diisopropylethylamine (0.175 mL, 1 mmol) followed by methanesulfonyl chloride (11.5 mg, 0.1 mmol). The mixture was stirred at room temperature for 16 h, then concentrated in vacuo and the residue purified by preparative reverse-phase HPLC to afford the bis trifluoroacetate salt of the title compound as a white solid (27.2 mg, 0.04 mmol, 40%). (m/z): [M+H]+ calcd for C24H37N5O3S 476.27; found 476.2. Retention time (anal. HPLC: 2-65% MeCN/H2O over 4 min)=1.66 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:20])[C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:16][CH:17]=[C:18]([Cl:19])[C:11]=12)[NH2:5].[Cl:21][C:22]1[CH:27]=[C:26](Cl)[N:25]=[C:24]([NH2:29])[N:23]=1.Cl.[OH-].[Na+]>O.C(O)C>[Cl:21][C:22]1[N:23]=[C:24]([NH2:29])[N:25]=[C:26]([NH:5][C:4]2[CH:6]=[C:7]([F:20])[C:8]([O:9][C:10]3[CH:15]=[CH:14][N:13]=[C:12]4[NH:16][CH:17]=[C:18]([Cl:19])[C:11]=34)=[C:2]([F:1])[CH:3]=2)[CH:27]=1
Reactant: Nc1cc(F)c(Oc2ccnc3[nH]cc(Cl)c23)c(F)c1
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1nc(Cl)cc(Nc2cc(F)c(Oc3ccnc4[nH]cc(Cl)c34)c(F)c2)n1

Procedure:
162 mg (0.55 mmol) of 3,5-difluoro-4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]aniline and 90 mg (0.55 mmol) of 4,6-dichloropyrimidine-2-amine are suspended in 6 ml of water/ethanol 1:1. 56 μl (0.65 mmol) of 37% strength hydrochloric acid are added, and the mixture is heated at reflux for 3 h. Using 1N aqueous sodium hydroxide solution, the pH is adjusted to 7, and the mixture is extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated. The residue is purified by preparative HPLC.
Reaction SMILES: C(OC([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[F:18])[NH:11][C:10](=[O:19])[CH2:9]1)=O)(C)(C)C>CO>[F:18][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:17]=1[NH:8][CH2:9][C:10](=[O:19])[NH:11]2
Reactant: CC(C)(C)OC(=O)N1CC(=O)Nc2cccc(F)c21
Solvent: CO
Product: O=C1CNc2c(F)cccc2N1

Procedure:
A solution of 4-(ten-butyloxy)carbonyl-5-fluoro- 1,2,3,4-tetrahydroquinoxalin-2-one (XXII, EXAMPLE 23, 6.13 g) in 75 ml of methanol saturated with HCI(g) is stirred at 20°-25° for 7.5 hr. The solvent is then removed under reduced pressure and aqueous sodium bicarbonate is added to the residue. The solid is collected and washed with a small amount of water and then dichloromethane and dried to give the title compound, mp 246°-248° NMR (CDCl3) 4.04, 4.10, 6.54, 6.63-6.74 and 8.54 δ.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]1([C:14]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)O)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[C:8]1([C:14]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:4]2[CH:5]=[CH:6][C:1]([OH:7])=[CH:2][CH:3]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Oc1ccccc1
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: Oc1ccc(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 100 °C
Yield: 75.8 %

Procedure:
75.2 g (0.8 mol) of phenol and 52 g (0.2 mol) of triphenylcarbinol were boiled by heating on an oil bath and the resulting water was gradually removed together with excess phenol. When generation of water stopped, the reaction mixture was cooled to about 100° C. by allowing it to stand. Thereafter 2 g of zinc chloride was added and the mixture was heated to 130° to 140° C. whereupon white crystals rapidly precipitated. After heating for 30 minutes, the mixture was allowed to cool and 100 ml of methanol was added thereto, and the crystals were separated by filtration to obtain 51 g of p-triphenylmethylphenol having a melting point of 293° to 295° C.
Reaction SMILES: [CH3:1][C:2]1([CH2:21][CH2:22][CH:23]=[C:24]2[S:28][C:27](=[O:29])[NH:26][C:25]2=[O:30])[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([CH3:20])[C:6]([CH3:19])=[C:7]([O:12]C3CCCCO3)[CH:8]=2)[O:3]1.O>CO.Cl>[OH:12][C:7]1[CH:8]=[C:9]2[C:4](=[C:5]([CH3:20])[C:6]=1[CH3:19])[O:3][C:2]([CH2:21][CH2:22][CH:23]=[C:24]1[S:28][C:27](=[O:29])[NH:26][C:25]1=[O:30])([CH3:1])[CH2:11][CH2:10]2
Reactant: Cc1c(OC2CCCCO2)cc2c(c1C)OC(C)(CCC=C1SC(=O)NC1=O)CC2
Agent: Cl
Solvent: CO
Solvent: O
Product: Cc1c(O)cc2c(c1C)OC(C)(CCC=C1SC(=O)NC1=O)CC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 5-{3-[2,7,8-trimethyl-6-(tetrahydro-pyran-2-yloxy)-chroman-2-yl]-propylidene}-thiazolidine-2,4-dione from Step 3 (155 mg) in MeOH (10 mL) were added 10 drops of conc. HCl, and the mixture was stirred at RT for 3 h, then poured into water and extracted with EtOAc. The crude product was purified by silica gel column chromatography eluting with 30-40% EtOAc in hexane to give 5-[3-(6-hydroxy-2,7,8-trimethyl-chroman-2-yl)-propylidene]-thiazolidine-2,4-dione. 1H-NMR (300 MHz, CDCl3) δ (ppm): 7.08 (t, J=7.6 MHz, 1H), 6.38 (s, 1H), 2.70 (m, 2H), 2.37 (m, 2H), 2.14, 2.11 (2s, 6H), 2.00-0.180 (m, 4H), 1.25 (s, 3H) ppm. 13C-NMR (75 MHz, CDCl3) δ (ppm): 171.45, 167.17, 165.43, 146.63, 145.06, 139.75, 126.04, 125.86, 122.03, 117.81, 112.20, 74.41, 60.53, 37.52, 31.51, 26.30, 23.74, 22.06, 21.09, 14.18, 12.00, 11.90 ppm. MS (m/z): 348 (M+H+), 370 (M+Na+).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([NH:6][C:7]2[C:8]3[CH:9]=[CH:10][N:11]=[CH:12][C:13]=3[CH:14]=[CH:15][CH:16]=2)[CH2:2]1.[OH:17][CH2:18][CH2:19][O:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH:24]=O>>[CH:12]1[C:13]2[C:8](=[C:7]([NH:6][CH:3]3[CH2:4][CH2:5][N:1]([CH2:24][C:23]4[CH:22]=[C:21]([CH:28]=[CH:27][CH:26]=4)[O:20][CH2:19][CH2:18][OH:17])[CH2:2]3)[CH:16]=[CH:15][CH:14]=2)[CH:9]=[CH:10][N:11]=1
Reactant: O=Cc1cccc(OCCO)c1
Reactant: c1cc(NC2CCNC2)c2ccncc2c1
Product: OCCOc1cccc(CN2CCC(Nc3cccc4cnccc34)C2)c1

Procedure:
Reaction of N-(pyrrolidin-3-yl)isoquinolin-5-amine with 3-(2-hydroxyethoxy)benzaldehyde using the method of Example 8 afforded the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:10][CH2:9][C:8]([OH:18])([C:11]2[CH:12]=[C:13]([S:16][CH3:17])[S:14][CH:15]=2)[CH2:7]1)=[O:5])[CH3:2].[CH3:19]I>>[CH2:1]([O:3][C:4]([N:6]1[CH2:10][CH2:9][C:8]([O:18][CH3:19])([C:11]2[CH:12]=[C:13]([S:16][CH3:17])[S:14][CH:15]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC(O)(c2csc(SC)c2)C1
Reactant: CI
Product: CCOC(=O)N1CCC(OC)(c2csc(SC)c2)C1
Yield: 75 %

Procedure:
Using an analogous procedure to that described in the second paragraph of the portion of Example 1 which is concerned with the preparation of starting materials, 1-ethoxycarbonyl-3-hydroxy-3-(2-methylthiothien-4-yl)pyrrolidine was reacted with methyl iodide to give 1-ethoxycarbonyl-3-methoxy-3-(2-methylthiothien-4-yl)pyrrolidine as an oil in 75% yield.
Reaction SMILES: [C:1]([O:4][CH2:5][O:6][C:7]1[C:8]([C:15]([NH:17][C@H:18]2[CH2:26][O:25][C:24](=[O:27])[C@H:23]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C@@H:22]([OH:35])[C@H:21]([CH3:36])[O:20][C:19]2=[O:37])=[O:16])=[N:9][CH:10]=[CH:11][C:12]=1[O:13][CH3:14])(=[O:3])[CH3:2]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].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:1]([O:4][CH2:5][O:6][C:7]1[C:8]([C:15]([NH:17][C@H:18]2[CH2:26][O:25][C:24](=[O:27])[C@H:23]([CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C@@H:22]([O:35][CH2:24][C:23]([CH3:28])=[CH2:22])[C@H:21]([CH3:36])[O:20][C:19]2=[O:37])=[O:16])=[N:9][CH:10]=[CH:11][C:12]=1[O:13][CH3:14])(=[O:3])[CH3:2]
Reactant: COc1ccnc(C(=O)N[C@H]2COC(=O)[C@H](Cc3ccccc3)[C@@H](O)[C@H](C)OC2=O)c1OCOC(C)=O
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: C=C(C)CO[C@H]1[C@H](C)OC(=O)[C@@H](NC(=O)c2nccc(OC)c2OCOC(C)=O)COC(=O)[C@@H]1Cc1ccccc1
Yield: 40 %

Procedure:
Compound 6 was prepared in 40% yield using Compound 3 (13.4 g, 25.97 mmol) with dppf (1.44 g, 2.60 mmol), Pd2dba3 (0.59 g, 0.65 mmol) and ethyl methallylcarbonate (4.87 g, 33.8 mmol). Filtration through a bed of silica gel (hexane-acetone) afforded a white solid, which upon recrystallization from toluene gave white tetragonal crystals: m.p.=102-104° C. Spectral data were consistent with the assigned structure.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([NH:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[O:13])=[CH:9][CH:10]=2)[C:5]([NH:20][C:21]([NH2:23])=[NH:22])=[N:4][CH:3]=1.Cl.NC(N)=N.O>CS(C)=O>[C:6]([O:18][C:17](=[O:19])[CH2:16][CH2:15][NH:14][C:12]([C:8]1[CH:7]=[C:6]2[C:11]([C:2]([Cl:1])=[CH:3][N:4]=[C:5]2[NH:20][C:21]([NH2:23])=[NH:22])=[CH:10][CH:9]=1)=[O:13])([CH3:11])([CH3:7])[CH3:5]
Reactant: N=C(N)Nc1ncc(Cl)c2ccc(C(=O)NCCC(=O)O)cc12
Agent: Cl
Agent: N=C(N)N
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)CCNC(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Temperature: 80 °C
Yield: 33.7 %

Procedure:
N-[(4-Chloro-1-guanidino-7-isoquinolinyl)carbonyl]-β-alanine ##STR61## NaH (114 mg, 60% dispersion in mineral oil, 2.85 mmol) was added portionwise to a stirred solution of guanidine hydrochloride (272 mg, 2.85 mmol) in DMSO (8 mL) and the solution was heated at 80° C. for 20 min. N-[(1,4-Dichloro-7-isoquinolinyl)carbonyl]-P-alanine t-butyl ester (420 mg, 1.14 mmol) was added and the mixture heated at 90° C. overnight. The cooled mixture was poured into water, extracted with EtOAc, and the combined organic extracts were washed with water, saturated brine, dried (Na2SO4) and evaporated in vacuo. The residue was crystallised from i-Pr2O-CH2Cl2 to give N-[(4-chloro-1-guanidino-7-isoquinolinyl)carbonyl]-β-alanine t-butyl ester (190 mg, 0.48 mmol).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:10]=1[O:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:5](O)=[O:6].[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[S:36][C:35]3[CH:37]=[C:38]([O:41][CH3:42])[CH:39]=[CH:40][C:34]=3[CH:33]=2)=[CH:28][CH:27]=1.[Al+3].[Cl-].[Cl-].[Cl-]>>[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[S:36][C:35]3[CH:37]=[C:38]([O:41][CH3:42])[CH:39]=[CH:40][C:34]=3[C:33]=2[C:5]([C:4]2[CH:3]=[C:2]([CH3:1])[C:10]([O:11][CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)=[C:9]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:8]=2)=[O:6])=[CH:28][CH:27]=1
Reactant: Cc1cc(C(=O)O)cc(C(C)(C)C)c1OCCN1CCCCC1
Reactant: COc1ccc(-c2cc3ccc(OC)cc3s2)cc1
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2cc(C)c(OCCN3CCCCC3)c(C(C)(C)C)c2)cc1
Yield: 40.6 %

Procedure:
1.3 g of the title compound (as a tan amorphous powder) was prepared from 2 g (5.62 mmol) of 3-methyl-4-[2-(1-piperidinyl)ethoxy]-5-t-butylbenzoic acid, 1.5 g (5.6 mmol) of 2-(4-methoxyphenyl)-6-methoxybenzo[b]thiophene, and 5.25 g (39.3 mmol) of AlCl3 in a manner similar to that used Preparation 15.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[N+:8]([C:11]1[CH:12]=[C:13]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:15][CH:16]=1)([O-:10])=[O:9]>N1C=CC=CC=1>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][S:17]([C:13]2[CH:12]=[C:11]([N+:8]([O-:10])=[O:9])[CH:16]=[CH:15][CH:14]=2)(=[O:18])=[O:19])[CH:3]=1
Reactant: Nc1cccnc1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Solvent: c1ccncc1
Product: O=[N+]([O-])c1cccc(S(=O)(=O)Nc2cccnc2)c1
Temperature: 50 °C
Yield: 76.6 %

Procedure:
To a stirred solution of 3-aminopyridine (2 g, 21.3 mmol) in pyridine (100 ml) was added 3-nitrobenzene sulphonyl chloride (4.43 g, 20 mmol) and the mixture was heated to 50° C. for 3 hours. After cooling it was partitioned between ethyl acetate and water and the organic washed with water (×2) and half saturated aqueous sodium chloride solution, separated, dried and evaporated to give a crude yield of 4.96 g. It was then triturated with dichloromethane and sonicated for 0.25 hours before being filtered and dried to give the product as a pink solid (4.279 g, 72%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([OH:26])[C:9]1[C:16](=[O:17])[N:12]2[CH2:13][CH2:14][CH2:15][N:11]2[C:10]=1[C:18]1[CH:23]=[CH:22][N:21]=[C:20]([S:24][CH3:25])[N:19]=1>C(Cl)Cl.[O-2].[Mn+4].[O-2]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:9]1[C:16](=[O:17])[N:12]2[CH2:13][CH2:14][CH2:15][N:11]2[C:10]=1[C:18]1[CH:23]=[CH:22][N:21]=[C:20]([S:24][CH3:25])[N:19]=1)=[O:26]
Reactant: CSc1nccc(-c2c(C(O)c3ccccc3Cl)c(=O)n3n2CCC3)n1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CSc1nccc(-c2c(C(=O)c3ccccc3Cl)c(=O)n3n2CCC3)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 69 %

Procedure:
To a solution of 2-[(2-chloro-phenyl)-hydroxy-methyl]-3-(2-methylsulfanyl-pyrimidin-4-yl)-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazol-1-one, 22, (0.22 g, 0.56 mmol) in CH2Cl2 (3 mL) is added manganese (IV) oxide (0.30 g, 3.40 mmol). After stirring for 18 hours at room temperature, the mixture is filtered through celite and washed with CH2Cl2. The filtrate is concentrated in vacuo. The crude residue is purified over silica (5% MeOH/chloroform) to afford 165 mg (69% yield) of the desired product. 1H NMR (300 MHz, CDCl3) δ 8.69 (d, J=5.1 Hz, 1H), 7.78 (dd, J=7.2, 1.8 Hz, 1H), 7.81 (d, J=5.1 Hz, 1H), 7.46-7.33 (m, 4H), 4.44 (t, J=7.2 Hz, 2H), 4.03 (t, J=7.2 Hz, 2H), 2.76 (dddd, J=7.2, 7.2, 7.2, 7.2 Hz, 2H), 2.63 (s, 3H); ESI+ MS: m/z (rel intensity) 387.1 (100, M++H).
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.C(N(CC)C(C)C)(C)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37].C([O-])(O)=O.[Na+]>ClCCl>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][S:36]([CH3:35])(=[O:38])=[O:37])[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: CS(=O)(=O)Cl
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Temperature: 25 °C

Procedure:
To a stirred mixture of Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (30 mg, 0.0818 mmol, Eq: 1.00) in dichloromethane (500 μl) was added at room temperature N,N-diisopropylethylamine (31.6 mg, 42.7 μl, 245 μmol, Eq: 3) and methanesulfonyl chloride (14.1 mg, 123 μmol). The mixture was allowed to stir at room temperature over night. The crude reaction diluted with 5 mL sat NaHCO3 and extracted with DCM (2×10 mL). The organic layers were dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 10 g, 0% to 10% MeOH in DCM) to yield the title compound as an white solid (16.2 mg, 48.5%), MS (ISP) m/z=409.3 [(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][CH:17]=[CH:16]3)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH:22]1[CH:23]=[CH:24][C:25]([NH:28][C:29](NC2C=CC=CC=2)=[O:30])=[CH:26][CH:27]=1>>[C:25]1([NH:28][C:29]([N:18]2[C:19]3[C:15](=[CH:14][C:13]([NH:12][S:9]([C:4]4[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=4)(=[O:11])=[O:10])=[CH:21][CH:20]=3)[CH:16]=[CH:17]2)=[O:30])[CH:26]=[CH:27][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(Nc1ccccc1)Nc1ccccc1
Reactant: O=S(=O)(Nc1ccc2[nH]ccc2c1)c1cc(Cl)cc(Cl)c1
Product: O=C(Nc1ccccc1)n1ccc2cc(NS(=O)(=O)c3cc(Cl)cc(Cl)c3)ccc21

Procedure:
Yield: 124 mg (the product also contains 3,5-dichloro-N-(1H-indol-5-yl)-phenylsulphonamide and diphenylurea)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].O1CCOCC1.C(=O)(O)[O-].[Na+:22].S([O-])([O-])=O.[Na+].[Na+]>O>[Na+:22].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([O-:10])=[O:9]
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=S([O-])c1ccccc1Cl
Temperature: 75 °C
Yield: 97.8 %

Procedure:
A mixture of 2-chlorobenzenesulfonyl chloride (2.5 g) and dioxane (35 mL) was treated with a mixture of sodium bicarbonate (2.0 g), sodium sulfite (3.0 g) and water (17 mL), and the resulting mixture was heated at 75° C. for 30 minutes. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was triturated with ethanol, filtered and the filtrate concentrated under reduced pressure. The residue was triturated with acetonitrile to afford the title compound as a white solid (2.3 g).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[S:20]1[CH:24]=[CH:23][C:22]([CH:25]=O)=[CH:21]1>>[S:20]1[CH:24]=[CH:23][C:22]([CH2:25][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)=[CH:21]1
Reactant: O=Cc1ccsc1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4ccsc4)CC3)nn12

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with thiophene-3-carbaldehyde was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-(thiophen-3-ylmethyl)piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[N+:14]([O-:16])=[O:15])[CH2:5][CH:4]=[CH:3][CH2:2]1.ClC1C=C(C=CC=1)C(OO)=[O:22]>C(Cl)Cl>[F:13][C:11]1[CH:10]=[CH:9][C:8]([N+:14]([O-:16])=[O:15])=[C:7]([CH:12]=1)[O:6][CH:1]1[CH2:5][CH:4]2[CH:3]([O:22]2)[CH2:2]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=[N+]([O-])c1ccc(F)cc1OC1CC=CC1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(F)cc1OC1CC2OC2C1
Temperature: 25 °C

Procedure:
To 2-(cyclopent-3-enyloxy)-4-fluoro-1-nitrobenzene (2.05 g) in methylene chloride (45.0 ml) at 0° C. was added 3-chloroperoxybenzoic acid (2.95 g) and the mixture was allowed to warm to room temperature overnight. The reaction mixture was diluted with methylene chloride and washed with 10% aq. K2CO3. The organic layer was passed through a hydrophobic frit and solvent evaporated to give the desired product.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([O:9]C=CC)=[CH:5][CH:4]=1.OCC(CO)(CO)CO.C(Cl)(Cl)(Cl)[Cl:25]>C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:25][C:7]1[CH:8]=[C:3]([C:2]([F:14])([F:13])[F:1])[CH:4]=[CH:5][C:6]=1[OH:9]
Reactant: CC=COc1ccc(C(F)(F)F)cc1
Reactant: ClC(Cl)(Cl)Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: OCC(CO)(CO)CO
Product: Oc1ccc(C(F)(F)F)cc1Cl
Reaction time: 2 h

Procedure:
A mixture of 0.5 mol of propenyl 4-trifluoromethylphenyl ether, 0.25 mol of pentaerythritol and 5 g of p-toluenesulphonic acid in 500 ml of carbon tetrachloride was stirred and refluxed under nitrogen for 40 minutes. The resulting solution was washed with 250 ml of water, and then dried by azeotroping 150 ml solvent in vacuo. After addition of 150 ml of fresh carbon tetrachloride, chlorine was passed into the solution for 2 hours, after which the solution was washed with 250 ml of water and the solvent was evaporated. The remaining product was purified by fractional distillation to give 74.8 g of 2chloro-4-trifluoromethylphenol, b.p: 52°-53.5° C. at 6 Torr., which was identified and shown by gas chromatography to have a purity of greater than 97%.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[CH:13]1([C:19](Cl)=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH:13]1([C:19]([NH:1][CH2:2][CH2:3][C:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][CH:5]=2)=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: NCCc1c[nH]c2ccccc12
Product: O=C(NCCc1c[nH]c2ccccc12)C1CCCCC1
Yield: 81.2 %

Procedure:
10 g of tryptamine and 10 g of cyclohexylcarbonyl chloride were treated in the same manner as described in Example 4-(1). 13.7 g of N-cyclohexylcarbonyl-tryptamine (i.e., 3-(2-cyclohexylcarbonylaminoethyl)-indole) were thereby obtained. Yield: 81.2%
Reaction SMILES: [N:1]1[C:9]2[CH:8]=[N:7][CH:6]=[N:5][C:4]=2[N:3]([CH2:10][C@@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2C(OC(C)(C)C)=O)[N:2]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH:12]1[CH2:13][CH2:14][CH2:15][C@H:11]1[CH2:10][N:3]1[C:4]2[N:5]=[CH:6][N:7]=[CH:8][C:9]=2[N:1]=[N:2]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1Cn1nnc2cncnc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ncc2nnn(C[C@@H]3CCCN3)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.8 %

Procedure:
1,1-Dimethylethyl (2S)-2-(3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-ylmethyl)-1-pyrrolidinecarboxylate (1.98 g, 6.54 mmol) was dissolved in a mixture of CH2Cl2 (10 mL) and TFA (2.5 mL) and allowed to stir at room temperature overnight. When the reaction was complete as determined by LCMS, the solution was concentrated in vacuo, and the residue was dissolved in CH2Cl2 (5 mL) and washed with 1 N aq. NaOH (30 mL). The aqueous layer was extracted with CH2Cl2 (3×20 mL). The combined organic layers were dried over anhydrous MgSO4 and concentrated in vacuo to provide 3-[(2S)-2-pyrrolidinylmethyl]-3H-[1,2,3]triazolo[4,5-d]pyrimidine (758 mg, 57%). LCMS: (M+H)+: 205.1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:40])[CH:9]1[CH:14]2[CH2:15][CH2:16][CH:10]1[CH2:11][N:12]([CH2:17][C@H:18]([NH:29]C(=O)OCC1C=CC=CC=1)[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=1)[CH2:13]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[NH2:29][C@H:18]([CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=1)[CH2:17][N:12]1[CH2:11][CH:10]2[CH:9]([N:8]([CH3:40])[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])[CH:14]([CH2:15][CH2:16]2)[CH2:13]1
Reactant: CN(C(=O)OC(C)(C)C)C1C2CCC1CN(C[C@@H](COc1ccc(C#N)cc1)NC(=O)OCc1ccccc1)C2
Agent: [Pd]
Solvent: CCO
Product: CN(C(=O)OC(C)(C)C)C1C2CCC1CN(C[C@H](N)COc1ccc(C#N)cc1)C2
Yield: 95 %

Procedure:
Benzyl (1S)-2-{8-[(tert-butoxycarbonyl)(methyl)amino]-3-azabicyclo[3.2.1]oct-3-yl}-1-[(4-cyanophenoxy)methyl]ethylcarbamate (see step (vi) above; 1.8 g, 3.3 mmol) was dissolved in ethanol (50 mL of 95%). The solution was hydrogenated over 5% Pd/C for 1 h, after which the mixture was filtered through Celite®. The filtrate was concentrated in vacuo to give 1.3 g (95%) of the sub-title compound.