Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1]N(C)CCN(C)C.[Si:9]([O:16][CH2:17][C@@H:18]1[C@@H:22]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=2)[CH2:21][N:20]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:19]1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].C([Li])(CC)C.CCCCCC>C(OCC)C.C(OCC)(=O)C>[CH3:1][CH:19]1[C@H:18]([CH2:17][O:16][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[C@@H:22]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=2)[CH2:21][N:20]1[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]
Reactant: CN(C)CCN(C)C
Reactant: CC(C)(C)OC(=O)N1C[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](c2cccc(F)c2)C1
Agent: [Li]C(C)CC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CCOCC
Product: CC1[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](c2cccc(F)c2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 20.7 %

Procedure:
N,N,N′,N′-Tetramethylethylenediamine (0.268 mL, 2.4 mmol) was added to a solution of 3-(R)-((tert-butyldimethylsilyloxy)methyl)-4-(S)-(3-fluorophenyl)-1-tert-butoxycarbonylpyrrolidine (1.0 g, 2.4 mmol, from Step A) in 5 mL of diethyl ether at −78° C. under nitrogen. sec-Butyllithium (2.2 mL, 1.3M in cyclohexane, 2.8 mmol) was then added dropwise. After 45 min., (MeO)2SO2 (0.298 mL, 4.8 mmol) was added, and the reaction mixture was slowly warmed to room temperature overnight. The reaction was quenched with 5 mL of sat. aq. ammonium chloride, and the mixture was partitioned between diethyl ether and water. The aqueous layer was extracted three times with diethyl ether and the combined organic extracts were dried over Na2SO4. Flash chromatography (95:5 hexane:ethyl acetate) provided 210 mg (21% yield) of the title compound, contaminated with small amounts of the other regioisomer. ESI-MS (M+H): 424.3; HPLC A: 5.33 min.
Reaction SMILES: [OH:1]OS([O-])=O.[K+].[CH3:7][S:8][C:9]1[N:14]=[C:13]([C:15]2[NH:19][N:18]=[CH:17][C:16]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:12]=[CH:11][N:10]=1.[OH2:26]>CO>[CH3:7][S:8]([C:9]1[N:14]=[C:13]([C:15]2[NH:19][N:18]=[CH:17][C:16]=2[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:12]=[CH:11][N:10]=1)=[O:1].[CH3:7][S:8]([C:9]1[N:14]=[C:13]([C:15]2[NH:19][N:18]=[CH:17][C:16]=2[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:12]=[CH:11][N:10]=1)(=[O:1])=[O:26]
Reactant: O=S([O-])OO
Reactant: CSc1nccc(-c2[nH]ncc2-c2ccccc2)n1
Reactant: O
Agent: [K+]
Solvent: CO
Product: CS(=O)(=O)c1nccc(-c2[nH]ncc2-c2ccccc2)n1
Product: CS(=O)c1nccc(-c2[nH]ncc2-c2ccccc2)n1
Reaction time: 18 h

Procedure:
A solution of Oxone (538 mg, 0.88 mmol, 1.2 equiv) in water (3 mL) was added to a solution of 2-(methylthio)-4-(4-phenyl-1H-pyrazol-5-yl)pyrimidine (3-3, 196 mg, 0.73 mmol, 1 equiv) in methanol (50 mL), and the resulting mixture was stirred under ambient conditions for 18 hours. The reaction was concentrated and the residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic layer was washed with brine, dried over magnesium sulfate and concentrated to give a mixture (3:2) of 2-(methylsulfinyl)-4-(4-phenyl-1H-pyrazol-5-yl)pyrimidine (3-4) and 2-(methylsulfonyl)-4-(4-phenyl-1H-pyrazol-5-yl)pyrimidine (3-5), respectively.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([SH:13])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CN(C=O)C.Cl[CH2:20][C:21](=[O:27])[CH2:22][C:23]([O:25][CH3:26])=[O:24].C([O-])([O-])=O.[K+].[K+]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:13][CH2:20][C:21](=[O:27])[CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: COC(=O)CC(=O)CCl
Reactant: COc1cc(S)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CC(=O)CSc1cc(OC)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 3-methoxy-5-(trifluoromethyl)benzenethiol (1.36 g) and DMF (dry) (10 mL) were added methyl 4-chloroacetoacetate (1.146 mL) and K2CO3 (1.806 g) at room temperature. The mixture was stirred at room temperature for 1 h. The mixture was poured into water at room temperature and extracted with EtOAc. The organic layer was separated, washed successively with 1N HCl and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (1.120 g).
Reaction SMILES: CN(CCN(C)C)C.[Li+].CC([N-]C(C)C)C.[Br:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1.CN([CH:27]=[O:28])C>CCOCC>[Br:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][C:23]=1[CH:27]=[O:28]
Reactant: CN(C)C=O
Reactant: Brc1cccnc1
Agent: CC(C)[N-]C(C)C
Agent: CN(C)CCN(C)C
Agent: [Li+]
Solvent: CCOCC
Product: O=Cc1ccncc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.8 %

Procedure:
To a solution of TMEDA (1.91 mL, 12.7 mmol) and LDA (12.7 mmol) in ether (50 mL) at −78° C. was added 3-bromo-pyridine (1.22 mL, 12.7 mmol). After 60 minutes at −78° C., DMF (1.08 mL, 13.9 mmol) was added, and the mixture allowed to warm to room temperature. After 1 hour at room temperature the reaction was quenched with saturated aqueous NaHCO3 (100 mL), extracted with CH2Cl2 (4×15 mL), dried (MgSO4), filtered and concentrated in vacuo to give the crude oil. Purification by column chromatography on silica gel (Hexanes:EtOAc 4:1) afforded the title compound as a crystalline solid (1.2 g, 51%). 1H NMR (CDCl3) 7.70 (d, 1H, J=4.8 Hz), 8.71 (d, 1H, J=4.8 Hz), 8.91 (s, 1H), 10.36 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:11]2=[O:20])=[CH:6][CH:5]=1.O=C(Cl)[O:25][C:26](Cl)(Cl)Cl.[NH:31]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[N:31]1([C:26]([N:17]2[CH2:16][CH2:15][C:12]3([C:11](=[O:20])[N:10]([C:7]4[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:21])[F:22])=[CH:5][CH:6]=4)[CH2:14][CH2:13]3)[CH2:19][CH2:18]2)=[O:25])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: C1CCCNCC1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Product: O=C(N1CCCCCC1)N1CCC2(CC1)CCN(c1ccc(OC(F)(F)F)cc1)C2=O

Procedure:
This material was prepared in analogy to example 251 step B) from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one, diphosgene and azepane. MS (ESI): 440.4 (MH+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:17][C@H:16]([CH2:18][NH:19][C:20](=[O:22])[CH3:21])[O:15][C:14]3=[O:23])=[CH:9][CH:8]=2)=[CH:3][CH2:2]1.[C:24]([CH:28]1[CH2:33][CH2:32][CH:31]([C:34](O)=[O:35])[CH2:30][CH2:29]1)([CH3:27])([CH3:26])[CH3:25]>>[C:24]([CH:28]1[CH2:29][CH2:30][CH:31]([C:34]([N:1]2[CH2:6][CH2:5][C:4]([C:7]3[CH:12]=[CH:11][C:10]([N:13]4[CH2:17][C@H:16]([CH2:18][NH:19][C:20](=[O:22])[CH3:21])[O:15][C:14]4=[O:23])=[CH:9][CH:8]=3)=[CH:3][CH2:2]2)=[O:35])[CH2:32][CH2:33]1)([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3=CCNCC3)cc2)C(=O)O1
Reactant: CC(C)(C)C1CCC(C(=O)O)CC1
Product: CC(=O)NC[C@H]1CN(c2ccc(C3=CCN(C(=O)C4CCC(C(C)(C)C)CC4)CC3)cc2)C(=O)O1

Procedure:
Using an analogous procedure to that described in Example 20, the TFA salt of Example 2 was reacted with 4-tert-butylcyclohexanecarboxylic acid in place of N-acetylglycine, to give the title compound. Yield=208 mg, 58%. MS: ESP+ (M+H)=482.
Reaction SMILES: [F:1][C:2]1[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:3]=1[O:4][C:5]1[C:6]([N+:36]([O-])=O)=[C:7]([NH:30][CH2:31][C:32](OC)=[O:33])[CH:8]=[CH:9][C:10]=1[C:11]1[C:12]2[CH:21]=[N:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:13]=2[C:14](=[O:18])[N:15]([CH3:17])[CH:16]=1.[Cl-].[NH4+]>C(OCC)(=O)C.CO.ClCCl.[Zn]>[F:1][C:2]1[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:3]=1[O:4][C:5]1[C:10]([C:11]2[C:12]3[CH:21]=[N:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:13]=3[C:14](=[O:18])[N:15]([CH3:17])[CH:16]=2)=[CH:9][CH:8]=[C:7]2[C:6]=1[NH:36][C:32](=[O:33])[CH2:31][NH:30]2
Reactant: COC(=O)CNc1ccc(-c2cn(C)c(=O)c3c2cnn3COCC[Si](C)(C)C)c(Oc2ccc(F)cc2F)c1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: ClCCl
Solvent: CO
Solvent: CCOC(C)=O
Product: Cn1cc(-c2ccc3c(c2Oc2ccc(F)cc2F)NC(=O)CN3)c2cnn(COCC[Si](C)(C)C)c2c1=O
Temperature: 0 °C
Reaction time: 16 h
Yield: 24.3 %

Procedure:
A suspension of methyl {[3-(2,4-difluorophenoxy)-4-(6-methyl-7-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}-6,7-dihydro-1H-pyrazolo[3,4-c]pyridin-4-yl)-2-nitrophenyl]amino}acetate (0.048 g, 0.078 mmol) in ethyl acetate (0.452 mL) and methanol (0.452 mL) was cooled to 0° C. and then treated with saturated ammonium chloride solution (0.0679 mL, 1.01 mmol) at that temperature. Zinc (0.0408 g, 0.624 mmol) was added to the reaction mixture in two portions over 5 min and the reaction mixture was stirred at RT for 16 h. The reaction mixture was diluted with dichloromethane and filtered through a pad of Celite. The solids were washed with additional dichloromethane and the filtrate was concentrated in vacuo to yield a crude residue. The residue was dissolved in dichloromethane and the organic phase was washed with saturated sodium bicarbonate solution, dried with sodium sulfate, filtered, and concentrated in vacuo to give the crude product. Purification via preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water 0.1% ammonium hydroxide, at flow rate of 60 mL/min) gave the desired product (10.5 mg, 24%) along with a small amount of the oxidized product, 8-(2,4-difluorophenoxy)-7-(6-methyl-7-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}-6,7-dihydro-1H-pyrazolo[3,4-c]pyridin-4-yl)quinoxalin-2(1H)-one. This mixture was used in the next step without separation. LCMS calculated for C27H30F2N5O4Si (M+H)+: m/z=554.2. found: 554.1.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][CH:25]=1)[C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:9]1)=[O:7].C(N(C(C)C)CC)(C)C.[CH2:35]([C:39]1[CH:44]=[CH:43][C:42]([CH:45](Br)[C:46]2[CH:51]=[CH:50][C:49]([CH2:52][CH:53]([CH3:55])[CH3:54])=[CH:48][CH:47]=2)=[CH:41][CH:40]=1)[CH:36]([CH3:38])[CH3:37].Cl>ClCCl>[CH2:52]([C:49]1[CH:50]=[CH:51][C:46]([CH:45]([NH:2][C:3]2[CH:4]=[C:5]([CH:23]=[CH:24][CH:25]=2)[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:9]2)=[O:7])[C:42]2[CH:43]=[CH:44][C:39]([CH2:35][CH:36]([CH3:38])[CH3:37])=[CH:40][CH:41]=2)=[CH:47][CH:48]=1)[CH:53]([CH3:55])[CH3:54]
Reactant: Nc1cccc(C(=O)n2cc(CCCC(=O)O)c3ccccc32)c1
Reactant: CC(C)Cc1ccc(C(Br)c2ccc(CC(C)C)cc2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Cc1ccc(C(Nc2cccc(C(=O)n3cc(CCCC(=O)O)c4ccccc43)c2)c2ccc(CC(C)C)cc2)cc1
Reaction time: 15 h
Yield: 95.5 %

Procedure:
To a solution of 4-[1-(3-aminobenzoyl)indol-3-yl]butyric acid hydrochloride (14.5 g) and diisopropylethylamine (22 ml) in dichloromethane (300 ml) was added bis(4-isobutylphenyl)methyl bromide (14.5 g) at room temperature. After stirring for 15 hours, diisopropylethylamine (7 ml) and bis(4-isobutylphenyl)methyl bromide 2.0 g) were added to the mixture. The mixture was stirred for 6 hours at room temperature and acidified by 7% hydrochloric acid (50 ml). The separated organic layer was washed with water and dried over magnesium sulfate. After the solvent was removed in vacuo, the residue was chromatographed on a column of silica gel (200 g) and eluted with chloroform to give a solid of 4-[1-[3-[bis(4-isobutylphenyl)methylamino]benzoyl]indol-3-yl]butyric acid (23.15 g).
Reaction SMILES: [N:1]1([CH2:10][C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.C(N(CC)CC)C.[SH2:26]>N1C=CC=CC=1.O>[N:1]1([CH2:10][C:11]2[CH:18]=[CH:17][C:14]([C:15](=[S:26])[NH2:16])=[CH:13][CH:12]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: N#Cc1ccc(Cn2cnc3ccccc32)cc1
Reactant: S
Solvent: CCN(CC)CC
Solvent: O
Solvent: c1ccncc1
Product: NC(=S)c1ccc(Cn2cnc3ccccc32)cc1
Yield: 87 %

Procedure:
A stirred solution of 4-(1H-benzimidazol-1-ylmethyl)benzonitrile (0.50 g, 2.14 mmol) and triethylamine (Et3N) (0.24 g, 2.37 mmol) in pyridine (2 mL), was bubbled through with H2S (g) at room temperature for 2 h. The reaction mixture was diluted with water and filtered. The filtercake was washed with cold water and dried under vacuum to afford the title compound in 87% yield, identified by NMR and mass spectral analyses. 1H NMR (400 MHz, DMSO-d6): 5.54 (s, 2H), 7.16-7.22 (m, 2H), 7.30 (d, J=8.8 Hz, 2H), 7.45-7.52 (m, 1H), 7.62-7.68 (m, 1H), 7.79 (d, J=8.8 Hz, 2H), 9.30 (bs, 1H), 9.80 (bs, 1H). LCMS (ESI+) 268 (MH+).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[C:12]([I:13])=[C:11]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[O:10][N:9]=1)(=[O:3])[CH3:2].N1[CH:33]=[CH:32][CH:31]=CC=1>ClCCl>[C:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[C:12]([I:13])=[C:11]([N:14]([S:15]([C:18]2[CH:19]=[CH:20][C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:22][CH:23]=2)(=[O:17])=[O:16])[C:1]([O:4][CH2:5][CH:32]([CH3:31])[CH3:33])=[O:3])[O:10][N:9]=1)(=[O:3])[CH3:2]
Reactant: c1ccncc1
Reactant: CC(=O)OCCOc1noc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1I
Solvent: ClCCl
Product: CC(=O)OCCOc1noc(N(C(=O)OCC(C)C)S(=O)(=O)c2ccc(C(C)(C)C)cc2)c1I
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a string solution of 2-{[5-({[4-(tert-butyl)phenyl]sulfonyl}amino)-4-iodo-3-isoxazolyl]oxy}ethyl acetate (Preparation 23) (9.44 g) in dichloromethane was added pyridine (1.65 ml) followed by the slow addition of isobutylchloroforomate (2.41 ml) over 10 minutes. The reaction mixture was stirred at room temperature for one hour. The solvent was removed in vacuo to yield the crude material. This was purified using column chromatography (300 g silica, compound loaded with dichloromethane (15 ml)) using a gradient elution of hexane (100% to 75%) and ethyl acetate (0% to 25%) to yield the desired compound as a yellow oil (7.70 g).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].Br[CH:13]([Cl:16])[CH2:14][CH3:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(Cl)(Cl)Cl>[Cl:16][CH2:13][CH2:14][CH2:15][O:11][C:8]1[CH:9]=[CH:10][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=1
Reactant: CC(=O)Nc1ccc(O)cc1
Reactant: CCC(Cl)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1ccc(OCCCCl)cc1
Yield: 23 %

Procedure:
A mixture of 4-acetamidophenol (182.2 g, 1.2 moles), bromochloropropane (157.4 g, 1.0 mole), and potassium carbonate (145.0 g, 1.05 moles) was refluxed overnight in 700 ml of acetone. The acetone solution formed white crystals after being placed in a refrigerator overnight. The solution was filtered and the crystals washed with acetone. The filtrate was stripped to dryness, and the residue dissolved in chloroform and extracted with a 5% sodium hydroxide solution. Removal of the chloroform gave an oil. The white crystals obtained earlier were also dissolved in chloroform and extracted with a 5% sodium hydroxide solution. Removal of the chloroform gave a white solid. The white solid and oil were combined with acetone and placed in a refrigerator; white crystals were obtained. A 5-g sample of the white solid was recrystallized from acetone a second time to furnish 1.76 g (after drying in vacuo overnight at 80° C.) (23% yield) of white crystalline product, m.p. 125°-127° C.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C([O-])([O-])=O.[Na+].[Na+].[CH2:17]([O:24][CH:25]([CH3:28])[CH2:26][OH:27])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CS(C)=O.O>[CH2:17]([O:24][CH:25]([CH3:28])[CH2:26][O:27][C:9]1[C:2]([Br:1])=[C:3]([CH:6]=[CH:7][CH:8]=1)[CH:4]=[O:5])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(CO)OCc1ccccc1
Reactant: O=Cc1ccc(F)cc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(COc1cccc(C=O)c1Br)OCc1ccccc1
Temperature: 130 °C
Reaction time: 72 h

Procedure:
A mixture of 2-bromo-4-fluoro-benzaldehyde (30.0 g, 148 mmol), Na2CO3 (78.31 g, 738.8 mmol) and 2-benzyloxy propanol (24.56 g, 147.8 mmol) in anhydrous DMSO (300 mL) was heated with stirring at 130° C. (bath temp) for 72 h under N2. The reaction mixture was cooled to rt and diluted with H2O and extracted with EtOAc. The organic layer was washed with H2O then brine, dried (MgSO4), and concentrated in vacuo. The residue was purified by flash chromatography (hexane to 30% EtOAc in hexane) to give the title compound: yield 3.84 g (7%).
Reaction SMILES: SCC(C(CS)O)O.[CH3:9][O:10][C:11](=[O:25])[NH:12][C:13]1[S:14][C:15]2[CH:21]=[C:20]([S:22]C#N)[CH:19]=[CH:18][C:16]=2[N:17]=1>O.C(O)C.P([O-])(O)(O)=O.[K+]>[CH3:9][O:10][C:11](=[O:25])[NH:12][C:13]1[S:14][C:15]2[CH:21]=[C:20]([SH:22])[CH:19]=[CH:18][C:16]=2[N:17]=1
Reactant: COC(=O)Nc1nc2ccc(SC#N)cc2s1
Agent: O=P([O-])(O)O
Agent: OC(CS)C(O)CS
Agent: [K+]
Solvent: CCO
Solvent: O
Product: COC(=O)Nc1nc2ccc(S)cc2s1
Temperature: 20 °C
Reaction time: 18 h
Yield: 91.1 %

Procedure:
a solution of 5 mg of potassium dihydrogen phosphate in 1.1 cm3 of water at 20° C., followed by 480 mg of DL-dithiothreitol, are added to a white suspension of 280 mg of methyl(6-thiocyanato-1,3-benzothiazol-2-yl)carbamate in 11 cm3 of ethanol at 20° C. The white suspension is stirred for 18 h at reflux. The reaction mixture is cooled to 20° C., then 10 cm3 of water are added and the mixture is stirred for 15 minutes. The precipitate is spin-filter-dried and then washed with large volumes of water. 231 mg of methyl(6-sulphanyl-1,3-benzothiazol-2-yl)carbamate are obtained in the form of a cream powder, the characteristics of which are as follows:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([CH3:8])[CH:7]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[CH2:36]([O:38][C:39]([C:41]1([CH3:45])[CH2:44][CH2:43][NH:42]1)=[O:40])[CH3:37]>C1COCC1.C(Cl)Cl>[CH2:36]([O:38][C:39]([C:41]1([CH3:45])[CH2:44][CH2:43][N:42]1[C:10](=[O:12])[CH2:9][C:4]1[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[CH:3]=1)=[O:40])[CH3:37]
Reactant: CCOC(=O)C1(C)CCN1
Reactant: Cc1cc(C)cc(CC(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOC(=O)C1(C)CCN1C(=O)Cc1cc(C)cc(C)c1
Temperature: 20 °C
Reaction time: 15 h

Procedure:
To a solution of (3,5-dimethyl-phenyl)-acetic acid (1 eq.) in either DCM or THF was added HOBt (1.1 eq.), EDC.HCl (1.5 eq.). Then, 2-methyl-azetidine-2-carboxylic acid ethyl ester hydrochloride, Intermediate 13 (1 eq.) and TEA (4 eq.) were added. The reaction was stirred at 20° C. for 15 h. The crude was concentrated under reduced pressure and partitioned between a saturated aqueous solution of NaHCO3 and EtOAc. The aqueous layer was extracted three times with EtOAc. The organic layers were combined, washed with water then with brine, dried over MgSO4, filtered and concentrated under reduced pressure to afford 1-[2-(3,5-dimethyl-phenyl)-acetyl]-2-methyl-azetidine-2-carboxylic acid ethyl ester.
Reaction SMILES: C([NH:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)(=[O:3])C.[ClH:17]>>[OH2:3].[ClH:17].[ClH:17].[ClH:17].[NH2:4][CH:5]1[CH2:6][CH2:7][N:8]([C:11]2[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=2)[CH2:9][CH2:10]1
Reactant: CC(=O)NC1CCN(c2ccncc2)CC1
Agent: Cl
Product: NC1CCN(c2ccncc2)CC1
Product: O

Procedure:
The product from step (iii) (0.52 g) in 1 molar hydrochloric acid (11.9 ml) was heated at 95° C. for 5 hours. The solvent was evaporated and the residue, on drying over potassium hydroxide in vacuo gave 4-amino-1-(4-pyridyl)piperidine trihydrochloride hydrate, 0.70 g as a light brown solid: m.p >300° C.; NMR (d6DMSO) δ8.28(4H,m) , 7.22(2H,d), 4.27(2H,bd), 3.5 to 3.15(3H+H2O), 2.09(2H,m), 1.59(2H dq); m/e 178(M+H)+ ; calculated for C10H15N3. 3HCl. 0.75 H2O: C, 40.0; H, 6.5; N, 14.0. found: C, 40.4; H, 6.3; N, 13.5%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)=[N:8][C:7](=[O:17])[C:6]=2[CH:18]=1.[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH2:19]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)=[N:8][C:7](=[O:17])[C:6]=2[CH:18]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: O=c1nc(-c2ccccn2)sc2ccc(O)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1nc(-c2ccccn2)sc2ccc(OCc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.4 %

Procedure:
A mixture of 6-hydroxy-2-(2-pyridyl)-4H-1,3-benzothiazine-4-one (0.30 g, 1.1 mmol), benzyl bromide (0.61 g, 3.5 mmol) and potassium carbonate (0.32 g, 2.3 mmol) and DMF (10 ml) was stirred at room temperature for 2 hrs. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water and dried. The solvent was evaporated under reduced pressure. The obtained crystals were recrystallized from tetrahydrofuran-hexane to give the titled compound (0.39 g, 95%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)#[N:2].[H-].[Na+].[CH2:14](Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>CN(C)C=O>[CH2:14]([N:8]1[C:9]2[C:5](=[CH:4][C:3]([C:1]#[N:2])=[CH:11][CH:10]=2)[CH:6]=[CH:7]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: ClCc1ccccc1
Reactant: N#Cc1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc2c(ccn2Cc2ccccc2)c1
Reaction time: 0.5 h
Yield: 98.4 %

Procedure:
5-Cyanoindole (1.0 g, 7.0 mmol) was dissolved in N,N-dimethylformamide (14 mL) and cooled in an ice-water bath. Sodium hydride (0.31 g, 60%, 7.8 mmol) was added, and the resulting suspension was stirred for 30 min. Benzyl chloride (0.85 mL, 0.94 g, 7.4 mmol) was added, and the cooling was discontinued. The stirring was continued for 65 hours at room temperature. Water (150 mL) was added, and the mixture was extracted with ethyl acetate (3×25 mL). The combined organic phases were washed with brine (30 mL) and dried with sodium sulfate (1 hour). Filtration and concentration yielded the crude material. Purification by flash chromatography on silica gel eluting with ethyl acetate/heptanes=1:3 afforded 1.60 g 1-benzyl-1H-indole-5-carbonitrile.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>O>[CH3:12][NH:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: C1CNCCN1
Reactant: CNS(=O)(=O)c1ccc(F)cc1
Solvent: O
Product: CNS(=O)(=O)c1ccc(N2CCNCC2)cc1
Temperature: 120 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
4-fluoro-N-methylbenzenesulfonamide (189 mg, 0.999 mmol) and piperazine (430 mg, 4.99 mmol) were combined and the reaction mixture was stirred at 120° C. for 2 h. It was diluted with water (5 mL) and stirred until a fine suspension resulted. The precipitate was filtered, washed with water (5×3 mL) and dried in vacuum to afford N-methyl-4-(piperazin-1-yl)benzenesulfonamide (222 mg, 0.869 mmol, 87% yield) as a white solid. ESI-MS:m/z 256 (M+H)+.
Reaction SMILES: N1C=CC=C(NC(=S)OC/C=C(\C)/CC/C=C(\C)/CC/C=C(\C)/CCC=C(C)C)C=1.[CH2:31]([CH2:41]/[C:42](/[CH3:51])=[CH:43]/[CH2:44][CH2:45]/[C:46](/[CH3:50])=[CH:47]/[CH2:48][OH:49])/[CH:32]=[C:33](/[CH2:35][CH2:36][CH:37]=[C:38]([CH3:40])[CH3:39])\[CH3:34].[N:52]1[CH:57]=[CH:56][C:55]([N:58]=[C:59]=[O:60])=[CH:54][CH:53]=1>>[N:52]1[CH:57]=[CH:56][C:55]([NH:58][C:59](=[O:60])[O:49][CH2:48]/[CH:47]=[C:46](\[CH3:50])/[CH2:45][CH2:44]/[CH:43]=[C:42](\[CH3:51])/[CH2:41][CH2:31]/[CH:32]=[C:33](\[CH3:34])/[CH2:35][CH2:36][CH:37]=[C:38]([CH3:40])[CH3:39])=[CH:54][CH:53]=1
Reactant: O=C=Nc1ccncc1
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CO
Agent: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C(C)=C/COC(=S)Nc1cccnc1
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C(C)=C/COC(=O)Nc1ccncc1
Yield: 3 %

Procedure:
Similar to the preparation of 38a, the reaction of alcohol 1 with 4-pyridyl isocyanate afforded the desired compound 39 in 3% yield (10 mg) as a viscous oil. Column (DCM/MeOH); TLC Rf: 0.34 (10% MeOH/DCM); LCMS: MS (m/z): 411 (M+H).