Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([C@@H:13]1[CH2:26][CH2:25][C:16]2([O:20][C@H:19]([CH2:21][OH:22])[C@@H:18]([CH2:23][OH:24])[O:17]2)[CH:15]=[C:14]1[C:27]([O:29][CH2:30][CH3:31])=[O:28])(=[O:12])=[O:11].O.C(C(CCCC)C([O-])=O)C.[K+:43]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N-:9][S:10]([C@@H:13]1[CH2:26][CH2:25][C:16]2([O:17][C@H:18]([CH2:23][OH:24])[C@@H:19]([CH2:21][OH:22])[O:20]2)[CH:15]=[C:14]1[C:27]([O:29][CH2:30][CH3:31])=[O:28])(=[O:12])=[O:11].[K+:43]
Reactant: CCOC(=O)C1=CC2(CC[C@H]1S(=O)(=O)Nc1ccc(F)cc1Cl)O[C@H](CO)[C@@H](CO)O2
Agent: CCCCC(CC)C(=O)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C1=CC2(CC[C@H]1S(=O)(=O)[N-]c1ccc(F)cc1Cl)O[C@H](CO)[C@@H](CO)O2
Temperature: 25 °C
Yield: 85.4 %

Procedure:
100 mg (0.208 mmol) of ethyl (2R,3R,8R)-8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]deca-6-ene-7-carboxylate [a compound described as a low polarity compound (first peak) of Example 162 in WO 2007/032362] was dissolved in 1 mL of ethyl acetate, and 2 mL of a solution containing 38 mg (0.208 mmol) of potassium 2-ethylhexanoate hydrate in ethyl acetate was added thereto under stirring at room temperature. The resulting reaction solution was concentrated under reduced pressure, and to the residue, diethyl ether was added. A precipitated solid was obtained by filtration and washed with diethyl ether, whereby 92 mg of a crude product was obtained as an amorphous solid. Then, the crude product was dissolved in ethyl acetate, and the resulting solution was heated under reflux at 130° C. for 2 hours. After the resulting mixture was cooled, a precipitated solid was obtained by filtration and washed with ethyl acetate, whereby the title compound was obtained as a white crystal.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([N:8]2[C@@H:15]3[C@@H:10]([CH2:11][CH2:12][NH:13][CH2:14]3)[CH2:9]2)[CH:5]=[N:4][CH:3]=1.CC1C=C(C)N=C(N2[C@@H]3[C@@H](CCNC3)C2)N=1.[F:32][C:33]1[CH:34]=[CH:35][C:36]([N:42]2[N:46]=[CH:45][CH:44]=[N:43]2)=[C:37]([CH:41]=1)[C:38](O)=[O:39].S1C=CC=C1C1C=CC=CC=1C(O)=O>C(Cl)Cl>[F:32][C:33]1[CH:34]=[CH:35][C:36]([N:42]2[N:46]=[CH:45][CH:44]=[N:43]2)=[C:37]([C:38]([N:13]2[CH2:12][CH2:11][C@@H:10]3[C@@H:15]([N:8]([C:6]4[CH:5]=[N:4][CH:3]=[C:2]([CH3:1])[N:7]=4)[CH2:9]3)[CH2:14]2)=[O:39])[CH:41]=1
Reactant: Cc1cncc(N2C[C@@H]3CCNC[C@@H]32)n1
Reactant: O=C(O)c1cc(F)ccc1-n1nccn1
Agent: Cc1cc(C)nc(N2C[C@@H]3CCNC[C@@H]32)n1
Agent: O=C(O)c1ccccc1-c1cccs1
Solvent: ClCCl
Product: Cc1cncc(N2C[C@@H]3CCN(C(=O)c4cc(F)ccc4-n4nccn4)C[C@@H]32)n1

Procedure:
The title compound was prepared in a manner analogous to Example 1, substituting (1R,6S)-8-(6-methylpyrazin-2-yl)-3,8-diazabicyclo[4.2.0]octane (Intermediate 30) for (1R,6S)8-(4,6-dimethyl-pyrimidin-2-yl)-3,8-diaza-bicyclo[4.2.0]octane and 5-fluoro-2-[1,2,3]triazol-2-yl-benzoic acid (Intermediate 13) for 2-thiophen-2-yl-benzoic acid. DCM was used in place of DMF. MS (ESI) mass calcd. For C20H20FN7O, 393.43; m/z found 394.1 [M+H]+. 1H NMR (CD3OD): 8.11-7.84 (m, 2H), 7.81-7.58 (m, 1H), 7.52-6.40 (m, 4H), 4.70-4.26 (m, 1H), 4.23-3.67 (m, 4H), 3.67-3.40 (m, 1H), 3.12-1.53 (m, 7H).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:12][CH2:13][C:14]([O:16]C)=[O:15])[CH:9]=2)[CH2:4]1.O.C(=O)([O-])[O-].[K+].[K+].[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>C(OCC)(=O)C>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH:2][CH:3]2[CH2:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([O:12][CH2:13][C:14]([OH:16])=[O:15])[CH:9]=3)[CH2:4]2)(=[O:34])=[O:33])=[CH:28][CH:27]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: COC(=O)COc1ccc2c(c1)CC(N)C2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)COc1ccc2c(c1)CC(NS(=O)(=O)c1ccc(Cl)cc1)C2
Reaction time: 2 h
Yield: 93.5 %

Procedure:
2.71 g of methyl (2-aminoindan-5-yl)oxyacetate hydrochloride are added to a mixture of 80 ml of ethyl acetate, 40 ml of water and 415 mg of potassium carbonate and a solution of 2.11 g of 4-chlorophenylsulfonyl chloride in 40 ml of ethyl acetate is added dropwise thereto. The mixture is stirred for 2 hours and the ethyl acetate layer is separated. The ethyl acetate layer is washed successively with an aqueous 10% hydrochloric acid solution, an aqueous saturated sodium bicarbonate solution and an aqueous sodium chloride solution, dried and evaporated to remove solvent. 30 ml of methanol and 20 ml of 1N sodium hydroxide solution are added to the residue and the mixture is stirred at room temperature for 20 minutes. The reaction mixture is adjusted to pH 1 with an aqueous 10% hydrochloric acid solution and extracted with a mixture of chloroform and tetrahydrofuran. The extract is dried and evaporated to remove solvent. The residue is recrystallized from tetrahydrofuran-n-hexane-isopropyl ether to give 3.57 g of {2-[(4-chlorophenyl)sulfonylamino]indan-5-yl}oxyacetic acid as yellow prisms. Yield: 94% m.p. 170°-172° C.
Reaction SMILES: O[CH:2]1[O:6][C:5](=O)[CH:4]=[C:3]1[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.O.[NH2:17][NH2:18]>C(O)C>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:3]2[CH:2]=[N:18][NH:17][C:5](=[O:6])[CH:4]=2)=[CH:9][CH:10]=1
Reactant: COc1ccc(C2=CC(=O)OC2O)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2cn[nH]c(=O)c2)cc1
Temperature: 85 °C
Reaction time: 8 h
Yield: 86.7 %

Procedure:
A suspension of 5-hydroxy-4-(4-methoxyphenyl)-5H-furan-2-one (2.00 g, 9.7 mmol) in 15 mL of ethanol was stirred as hydrazine hydrate (0.97 g, 2.0 eq) was added in dropwise. The reaction was stirred at 85° C. overnight, and then the solvent was reduced. The solid was collected and washed with cold EtOH to give 1.7 g (87%) of 5-(4-methoxyphenyl)-2H-pyridazin-3-one: MS m/z 203 (M+H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][CH2:21][O:22][CH3:23].[C:24]1([C:34](O)=[O:35])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][N:25]=1>>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH2:20][CH2:21][O:22][CH3:23])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:34]([C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=[CH:26][N:25]=3)=[O:35])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: O=C(O)c1nccc2ccccc12
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCCN
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCCCNC(=O)c1nccc2ccccc12

Procedure:
According to the general method of Example 50, 1-(4-aminobutyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine and isoquinoline-1-carboxylic acid were combined to provide N1-{4-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butyl}-1-isoquinolinecarboxamide as a yellow crystalline solid, m.p. 61.0-63.0° C. 1H NMR (300 MHz, DMSO-d6) δ8.94 (t, J=5.9 Hz, 1H), 8.87 (d, J=8.5 Hz, 1H), 8.51 (d, J=5.6 Hz, 1H), 8.05-7.96 (m, 3H), 7.84-7.96 (m, 1H), 7.70-7.65 (m, 1H), 7.61 (dd, J=8.3, 1.1 Hz, 1H), 7.37 (dt, J=7.7, 1.0 Hz, 1H), 7.19 (dt, J=7.6, 1.2 Hz, 1H), 6.53 (broad s, 2H), 4.60 (t, J=7.2 Hz, 2H), 3.81 (t, J=6.7 Hz, 2H), 3.41 (m, 2H), 3.28-3.12 (m, 5H), 1.92-1.76 (m, 4H); MS (EI) m/e 468.2261 (468.2274 calcd for C27H28N6O2).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[C:10]2[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]1=2.[CH3:23][NH:24][C:25](=[O:41])[C:26]1[CH:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][N:27]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:22][N:19]1[CH2:20][CH2:21][C:9]2[N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[C:29]3[CH:30]=[CH:31][C:26]([C:25]([NH:24][CH3:23])=[O:41])=[N:27][CH:28]=3)[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]=2[CH2:18]1
Reactant: CNC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1ccc2c(c1)c1c(n2-c2ccccc2Br)CCN(C)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CNC(=O)c1ccc(-c2ccccc2-n2c3c(c4cc(C)ccc42)CN(C)CC3)cn1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a de-aerated solution of 5-(2-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.28 mmol), N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamide (148 mg, 0.56 mmol) and K2CO3 (115 mg, 0.84 mmol) in DME-water (2:1) was added Pd(PPh3)4 (16 mg, 0.014 mmol). The reaction mixture was stirred at 90° C. for 2 h, additional Pd (PPh3)4 (16 mg, 0.014 mmol) was added into the reaction mixture and stirring continued at 90° C. for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (30 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 5-(2-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)phenyl)-N-methylpicolinamide as an off-white solid. 1H NMR (TFA salt, CD3OD) δ (ppm): 8.21 (d, 1H), 7.82 (d, 1H), 7.76 (m, 3H), 7.6 (d, 2H), 7.23 (s, 1H), 6.9 (d, 2H), 4.7 (m, 1H), 4.3 (m, 1H), 3.63 (m, 1H), 3.42 (m, 1H), 2.8-3.1 (m, 7H), 2.6 (m, 1H), 2.4 (s, 3H).
Reaction SMILES: [CH2:1]([OH:7])[CH:2]([OH:6])[CH2:3][CH2:4][OH:5].[CH3:8][C:9]([CH3:11])=O.[O-]S([O-])(=O)=O.[Mg+2].C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[OH:5][CH2:4][CH2:3][CH:2]1[CH2:1][O:7][C:9]([CH3:11])([CH3:8])[O:6]1
Reactant: CC(C)=O
Reactant: OCCC(O)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CO
Product: CC1(C)OCC(CCO)O1
Temperature: 25 °C
Reaction time: 120 h
Yield: 75 %

Procedure:
Butane-1,2,4-triol (5.0 g, 47 mmol) was dissolved in MeOH (5 ml). Acetone (20 ml), MgSO4 (ca. 500 mg), and para-toluene sulfonic acid (p-TsOH) (catalytic amount) were added, and the mixture was allowed to stir for 5 days at room temperature. The mixture was filtered and the filtrate concentrated under reduced pressure. Methylene chloride (CH2Cl2) (20 ml) and water (20 ml) were added, the layers were separated, and the organic layer was washed with water (2×20 ml). The organic layer was dried (MgSO4), filtered, and the filtrate concentrated under reduced pressure to afford the product as a clear oil (5.15 g, 75%): 1H NMR (CDCl3) 4.23(dt, 1H, J=6.86 Hz), 4.04(t, 1H, J=6.06 Hz), 3.72(m, 2H), 3.54(t, 1H, J=7.72 Hz), 2.55(broad s, 1H), 1.77(dt, 2H, J=6.67 Hz), 1.34(d, 6H, J=15.68 Hz)ppm; IR (neat) 3420, 2980, 2930, 2870, 1710, 1455, 1370, 1250, 1215, 1155, 1055, 855, 732 cm-1.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([OH:9])=O.[NH2:10][CH:11]([CH2:19][CH3:20])[C:12]([O:14][CH2:15][CH:16]([CH3:18])[CH3:17])=[O:13]>>[CH2:15]([O:14][C:12](=[O:13])[CH:11]([NH:10][C:7](=[O:9])[CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH2:19][CH3:20])[CH:16]([CH3:17])[CH3:18]
Reactant: O=C(O)Cc1cccs1
Reactant: CCC(N)C(=O)OCC(C)C
Product: CCC(NC(=O)Cc1cccs1)C(=O)OCC(C)C

Procedure:
Following General Procedure BI above and using 2-thiopheneacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][CH:16]3[CH2:18][CH2:17]3)[N:12]3[N:19]=[CH:20][CH:21]=[C:11]3[N:10]=2)[CH:5]=[CH:4][C:3]=1[OH:22].P(Cl)(Cl)(Cl)=O.[OH-].[Na+].CN([CH:33]=[O:34])C>>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][CH:16]3[CH2:18][CH2:17]3)[N:12]3[N:19]=[CH:20][C:21]([CH:33]=[O:34])=[C:11]3[N:10]=2)[CH:5]=[CH:4][C:3]=1[OH:22]
Reactant: CN(C)C=O
Reactant: Oc1ccc(Nc2cc(NC3CC3)n3nccc3n2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1cnn2c(NC3CC3)cc(Nc3ccc(O)c(Cl)c3)nc12
Temperature: 45 °C
Yield: 65 %

Procedure:
To 2-chloro-4-(7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidin-5-ylamino)phenol (582 mg, 1.84 mmol) in DMF (4.5 mL) cooled to 0° C. was added phosphorous oxychloride (0.514 mL, 5.52 mmol) dropwise. The reaction mixture was stirred while warming to 45° C. over 3 h. This was cooled down to 0° C. and added slowly to an ice-cold solution of 2M NaOH while stirring. Upon completion, the mixture was stirred at room temperature for 1 h. The resulting solid was filtered off and washed with water to provide 412 mg (65%) of 5-(3-chloro-4-hydroxyphenylamino)-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde. LCMS (ES): >95% pure, m/z 344 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[CH:8]([OH:12])[CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1.[H-].[Na+].[CH3:15]I>O1CCCC1>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[CH:8]([O:12][CH3:15])[CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: OC1CCCc2nc(Cl)ccc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1CCCc2nc(Cl)ccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 61 %

Procedure:
To a solution of 2-chloro-5,6,7,8-tetrahydroquinolin-5-ol (319 mg, 1.737 mmol) in tetrahydrofuran (8 mL) was added in small portions sodium hydride (83 mg, 2.085 mmol; 60 on mineral oil). After stirring the resulting suspension for 20 min at RT methyl iodide (0.119 ml, 1.911 mmol) was added dropwise. The reaction mixture was stirred at RT for 20 h. The reaction was quenched by addition of a saturated ammonium chloride solution. The layers were separated and the aqueous layer was extracted with ethyl acetate (3×). The combined organic layers were washed with brine and dried over sodium sulfate, filtered, and evaporated to dryness. The crude was purified by flash chromatography (silica gel, cyclohexane/ethylacetate) yielding a slightly yellow oil. Amount 210 mg. Yield 61%.
Reaction SMILES: C([NH:4][C@:5]1([C:22](NC(C)(C)C)=[O:23])[C@@H:9]([CH2:10][CH2:11][CH2:12][B:13]2[O:17]C(C)(C)C(C)(C)[O:14]2)[CH2:8][NH:7][CH2:6]1)(=O)C.Cl.C(O)(=[O:32])C>O>[NH2:4][C@:5]1([C:22]([OH:23])=[O:32])[C@@H:9]([CH2:10][CH2:11][CH2:12][B:13]([OH:14])[OH:17])[CH2:8][NH:7][CH2:6]1
Reactant: CC(=O)O
Reactant: CC(=O)N[C@@]1(C(=O)NC(C)(C)C)CNC[C@@H]1CCCB1OC(C)(C)C(C)(C)O1
Agent: Cl
Solvent: O
Product: N[C@@]1(C(=O)O)CNC[C@@H]1CCCB(O)O
Temperature: 130 °C
Reaction time: 18 h
Yield: 79 %

Procedure:
A solution of (3R,4S)-3-acetamido-N-tert-butyl-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl)pyrrolidine-3-carboxamide (198 mg, 0.5 mmol) in 2:1:1 concentrated HCl:glacial acetic acid:water (8 mL) in a pressure bottle was stirred for 2 h at 60° C., then capped and stirred for 18 h at 130° C., cooled to room temperature, and uncapped. The solution was diluted with water (20 mL), then extracted with methylene chloride (20 mL) and concentrated. The residue was treated with water (20 mL) and concentrated three times to remove excess HCl, then dissolved in water (40 mL) and treated with DOWEX® 550A-OH resin (3 g) which had been rinsed with methanol. The mixture was stirred for 40 min, then filtered and the resin washed successively with water, methanol, methylene chloride, water, methanol, and methylene chloride. The resin was then stirred four times with 1N HCl (15 mL) and filtered, and the combined filtrates were concentrated. The residue was treated with water (20 mL) and concentrated three times to remove excess HCl, then dissolved in 1.5-2.0 mL water and subjected to HPLC gradient purification as follows: 0-25% B with A=0.1% trifluoroacetic acid/water and B=0.1% trifluoroacetic acid/acetonitrile. The appropriate fractions were concentrated, treated three times with 1 N HCl (10 mL) and concentrated, treated three times with water (10 mL) and concentrated, then dissolved in water (10 mL), frozen, and lyophilized overnight to afford (3R,4S)-3-amino-4-(3-boronopropyl)pyrrolidine-3-carboxylic acid (114 mg, 79%) as a pale amber glass. NMR (D2O) δ 3.90 (d, J=13 Hz, 1 H), 3.71 (dd, J1=11.5 Hz, J2=8.5Hz, 1 H), 3.46 (d, J=13Hz, 1H), 3.21 (t, J=12 Hz, 1 H), 2.50-2.65 (m, 1 H), 1.5-1.65 (m, 1 H), 1.10-1.40 (m, 3 H), 0.60-0.75 (m, 2 H). MS (m+1): 217.3; MS (m−H2O+1): 199.1.
Reaction SMILES: [C:1]1([S:7][C:8](Cl)(Cl)Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:13]1[CH:18]=[CH:17][CH:16]=C[N:14]=1>C(N)=O>[C:1]1([S:7][C:8]2[CH:16]=[CH:17][CH:18]=[CH:13][N:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClC(Cl)(Cl)Sc1ccccc1
Reactant: Clc1ccccn1
Solvent: NC=O
Product: c1ccc(Sc2ccccn2)cc1
Temperature: 75 °C
Yield: 62 %

Procedure:
A solution of phenyl(trichloromethyl)sulfane (0.25 g, 1.099 mmol) in formamide (16.40 ml) was degassed with nitrogen and treated with 2-chloropyridine (0.114 ml, 1.209 mmol). The reaction solution was heated at 75° C. overnight. GCMS indicates a yield of 62% of 2-(phenylthio)pyridine, and a 22% byproduct of disulfide.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[N:3]=1.[O:24]([CH:31]1[CH2:36][CH2:35][CH2:34][NH:33][CH2:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C>O1CCCC1>[CH3:8][C:6]1[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[N:3]=[C:2]([N:33]2[CH2:34][CH2:35][CH2:36][CH:31]([O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:32]2)[N:7]=1
Reactant: c1ccc(OC2CCCNC2)cc1
Reactant: CCCC(C(=O)OC)c1c(C)nc(Cl)nc1-c1ccc(C)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCC(C(=O)OC)c1c(C)nc(N2CCCC(Oc3ccccc3)C2)nc1-c1ccc(C)cc1
Yield: 19.3 %

Procedure:
This compound was prepared according to the method C from methyl 2-(2-chloro-4-methyl-6-p-tolylpyrimidin-5-yl)pentanoate (0.095 g; 0.285 mmol), 3-phenoxypiperidine (0.152 g; 0.856 mmol) and triethyl amine (0.200 mL; 1.43 mmol) in tetrahydrofuran (2 mL). Purification by flash chromatography on silica gel using a gradient of ethyl acetate (2-30%) in heptane furnished 0.026 g (38%) of the titled compound as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[C:8]([CH2:25][CH2:26][CH2:27][CH3:28])=[N:9][N:10]([C:15]3[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=3[Cl:24])[C:11]=2[C:12](Cl)=[O:13])=[C:4]([F:31])[CH:3]=1.[NH3:32]>C1COCC1>[Br:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[C:8]([CH2:25][CH2:26][CH2:27][CH3:28])=[N:9][N:10]([C:15]3[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=3[Cl:24])[C:11]=2[C:12]([NH2:32])=[O:13])=[C:4]([F:31])[CH:3]=1
Reactant: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2Cl)c(C(=O)Cl)c1Cc1ccc(Br)cc1F
Reactant: N
Solvent: C1CCOC1
Product: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2Cl)c(C(N)=O)c1Cc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
A solution of 4-(4-bromo-2-fluorobenzyl)-3-n-butyl-1-(2-chloro-5-nitrophenyl)-1H-pyrazole-5-carbonyl chloride (from Step D, theoretically 1.32 mmol) in 10 mL of dry THF was cooled to -50° C. and maintained at that temperature under protection from moisture as ammonia gas was gently bubbled in until saturated. The mixture was allowed to warm slowly to room temperature and stirred overnight. Concentration of the reaction mixture yielded a thick yellow oil, which was purified by flash chromatography on silica gel (elution with 1% and then 3% MeOH in CH2Cl2). Evaporation of the pooled product fractions yielded 625 mg (93%) of the title compound as a slightly yellow solid, mp 145°-147° C.; nearly homogeneous by TLC in 95:5 CH2Cl2 ; mass spectrum (FAB) m/e 509, 511 (M+1)+. 200 MHz 1H NMR (CDCl3) δ0.89 (t, J=7.1 Hz, 3H), 1.35 (m, 2H), 1.59 (m, 2H, partially obscured by H2O peak), 2.58 (t, J=7.7 Hz, 2H), 4.04 (s, 2H), 5.51 (br s, 2H), 6.91 (dd, J≈8, 8 Hz, 1H), 7.25-7.32 (m, 2H), 7.66 (d, J=8.8 Hz, 1H), 8.25 (dd, J=8.8, 2.6 Hz, 1H), 8.41 (d, J=2.6 Hz, 1H).
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].C(N)(=O)C1C=CC=CC=1.Br[CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:38]=[CH:37][CH:36]=[CH:35][C:22]=1[C:23]([NH:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:27]=1[CH:28]=[CH:29][NH:30]2)=[O:24]>CCOCC>[CH3:2][C:1]([NH:5][CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:38]=[CH:37][CH:36]=[CH:35][C:22]=1[C:23]([NH:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:27]=1[CH:28]=[CH:29][NH:30]2)=[O:24])([CH3:4])[CH3:3]
Reactant: O=C(Nc1cccc2[nH]ccc12)c1ccccc1OCCCCBr
Reactant: CC(C)(C)N
Agent: NC(=O)c1ccccc1
Solvent: CCOCC
Product: CC(C)(C)NCCCCOc1ccccc1C(=O)Nc1cccc2[nH]ccc12

Procedure:
Using the procedure of Example 30 but at 50° C. and replacing tert-pentylamine by tert-butylamine and 2-(3-chloropropoxy)-N-1H-indol-4-yl)benzamide by 2-(4-bromobutoxy)-N-(1H-indol4-yl)benzamide, and with chromatography on silica (eluant:CHCl3 /acetone/TEA of 6:3:1), the residue was taken up in ether to obtain 2-[4-[1,1-dimethylethylamino)-butoxy]-N-(1H-indol-4-yl)benzamide melting at 147° C. The acid fumarate which melted at 224°-225° C. with sublimation after crystallization from ethanol, was prepared.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:14])=[CH:4][C:5]2[S:9](=[O:11])(=[O:10])[NH:8][C:7](=O)[C:6]=2[CH:13]=1.O.[NH2:16][NH2:17]>C(O)COCCO>[Cl:1][C:2]1[C:3]([Cl:14])=[CH:4][C:5]2[S:9](=[O:11])(=[O:10])[N:8]=[C:7]([NH:16][NH2:17])[C:6]=2[CH:13]=1
Reactant: O=C1NS(=O)(=O)c2cc(Cl)c(Cl)cc21
Reactant: NN
Solvent: O
Solvent: OCCOCCO
Product: NNC1=NS(=O)(=O)c2cc(Cl)c(Cl)cc21
Yield: 59.6 %

Procedure:
50.2 g (0.2 mol) of 5,6-dichloro-3-keto-2H,3H-1,2-benzisothiazole 1,1-dioxide in 200 ml of diethylene glycol are stirred with 35 g of hydrazine hydrate for 30 hours at 160° C. to 165° C. Working up analogously to Example 1 gives 31.7 g (63% of theory) of 5,6-dichloro-3-hydrazino-1,2-benzisothiazole 1,1-dioxide which decomposes at 276° C.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C@@H:2]([CH2:4][C:5]([OH:7])=[O:6])[OH:3].CO[C:12](OC)([CH3:14])[CH3:13]>C1(C)C=CC=CC=1>[CH3:13][C:12]1([CH3:14])[O:3][C@H:2]([CH2:4][C:5]([OH:7])=[O:6])[C:1](=[O:9])[O:8]1
Reactant: O=C(O)C[C@@H](O)C(=O)O
Reactant: COC(C)(C)OC
Solvent: Cc1ccccc1
Product: CC1(C)OC(=O)[C@@H](CC(=O)O)O1

Procedure:
A solution of 25.05 g D-malic acid and 68.1 g 2,2-dimethoxypropane in 200 mL toluene was refluxed for 2 hours under nitrogen. The solvent was removed under reduced pressure to give the title compound as a white solid. 1H NMR (CDCl3, 500 MHz) δ 4.76 (dd, J=3.9 & 6.6 Hz, 1H), 3.02 (dd, J=3.9 & 17.2 Hz, 1H), 2.88 (dd, J=6.6 & 17.2 Hz, 1H), 1.64 (s, 3H), 1.59 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH2:9][NH2:10].C(N(C(C)C)CC)(C)C.[C:20]1([CH:26]([CH2:30][CH3:31])[C:27](Cl)=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH2:9][NH:10][C:27](=[O:28])[CH:26]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:30][CH3:31]
Reactant: Cc1ccc(F)c(CN)c1
Reactant: CCC(C(=O)Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC(C(=O)NCc1cc(C)ccc1F)c1ccccc1
Reaction time: 0.5 h

Procedure:
A solution of (2-fluoro-5-methylphenyl)methanamine (1-f, 50 mg, 0.26 mmol, Oakwood Products, Inc., West Columbia, S.C.) and diisopropylethylamine (88 uL, 0.52 mmol) in dichloromethane (1 mL) was treated at room temperature with 2-phenylbutanoyl chloride (1-a, 47 mg, 0.26 mmol). The reaction mixture was stirred for 30 min, partitioned between dichloromethane and 0.1N—NaOH. The aqueous layer was removed and the organic layer washed with 0.1N-HCl. The aqueous layer was removed by filtering through a plastic frit. The organic layer was evaporated in vacuo to give the desired product (1-2); HRMS (M+1)=286.1586.