Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([CH2:7][O:8][C:9]2[CH:17]=[CH:16][CH:15]=[C:11]([C:12]([OH:14])=O)[C:10]=2[C:18]([OH:20])=O)=[CH:4][CH:3]=1.Cl.[NH2:22][CH:23]1[CH2:29][CH2:28][C:27](=[O:30])[NH:26][C:24]1=[O:25]>N1C=CC=CC=1>[Cl:1][C:2]1[S:6][C:5]([CH2:7][O:8][C:9]2[CH:17]=[CH:16][CH:15]=[C:11]3[C:10]=2[C:18](=[O:20])[N:22]([CH:23]2[CH2:29][CH2:28][C:27](=[O:30])[NH:26][C:24]2=[O:25])[C:12]3=[O:14])=[CH:4][CH:3]=1
Reactant: NC1CCC(=O)NC1=O
Reactant: O=C(O)c1cccc(OCc2ccc(Cl)s2)c1C(=O)O
Agent: Cl
Solvent: c1ccncc1
Product: O=C1CCC(N2C(=O)c3cccc(OCc4ccc(Cl)s4)c3C2=O)C(=O)N1
Yield: 36.8 %

Procedure:
A mixture of 3-(5-chloro-thiophen-2-ylmethoxy)-phthalic acid (1.6 g, 5.1 mmol), alpha-amino-glutarimide hydrochloride (0.88 g, 5.4 mmol) in pyridine was refluxed overnight. The mixture was evaporated and the residue was purified by flash column chromatography (methanol/methylene chloride) to give 4-(5-chloro-thiophen-2-ylmethoxy)-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione as a white solid (0.76 g, 36% yield); HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min. 240 nm, 60/40 CH3CN/0.1% H3PO4, 2.63 min (99.3%); mp, 217-219° C.; 1H NMR (DMSO-d6) δ 2.01-2.07 (m, 1H, CHH), 2.54-2.57 (m, 2H, CH2), 2.62-2.95 (m, 1H, CHH), 5.10 (dd, J=6.12 Hz, 1H, CH), 5.50 (s, 2H, CH2), 7.07-7.87 (m, 5H, Ar), 11.11 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.93, 30.90, 48.75, 65.38, 115.94, 116.80, 120.44, 126.55, 127.83, 129.09, 133.31, 136.93, 137.54, 154.76, 165.14, 166.68, 169.77, 169.86, 172.73. Anal Calcd For C18H13N2O5SCl: C, 53.41; H, 3.24; N, 6.92; S, 7.92%; Cl, 8.76. Found: C, 53.39; H, 2.95; N, 6.80; S, 7.62%; Cl, 9.01.
Reaction SMILES: COC1C(OC)=NS(=O)(=O)N=1.CN.CO[C:16]1[C:20]([NH:21][CH3:22])=[N:19][S:18](=[O:24])(=[O:23])[N:17]=1.[CH3:25][N:26]([CH2:28][C:29]1[S:30][CH:31]=[C:32]([CH2:34][S:35][CH2:36][CH2:37][NH2:38])[N:33]=1)[CH3:27]>>[CH3:27][N:26]([CH2:28][C:29]1[S:30][CH:31]=[C:32]([CH2:34][S:35][CH2:36][CH2:37][NH:38][C:16]2[C:20]([NH:21][CH3:22])=[N:19][S:18](=[O:24])(=[O:23])[N:17]=2)[N:33]=1)[CH3:25]
Reactant: CN(C)Cc1nc(CSCCN)cs1
Reactant: CNC1=NS(=O)(=O)N=C1OC
Agent: CN
Agent: COC1=NS(=O)(=O)N=C1OC
Product: CNC1=NS(=O)(=O)N=C1NCCSCc1csc(CN(C)C)n1

Procedure:
Reaction of a methanolic suspension of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide with one equivalent of methylamine and treatment of the resultant 3-methoxy-4-methylamino-1,2,5-thiadiazole 1,1-dioxide with one equivalent of 2-[(2-dimethylaminomethyl-4-thiazolyl)methylthio]ethylamine [prepared in Example 33, Step E], produces the title compound which is identical to the product prepared in Example 33.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.C([Li])CCC.CCCCCC.[CH2:21]([O:23][C:24](=[O:31])[CH2:25]/[N:26]=[CH:27]/[N:28]([CH3:30])[CH3:29])[CH3:22].ClC1[CH2:34][N:35]([CH2:47][C:48]2[CH:53]=[CH:52][C:51]([O:54][CH3:55])=[CH:50][C:49]=2[O:56][CH3:57])[C:36](=[O:46])[C:37]2[CH:43]=[C:42]([O:44][CH3:45])[CH:41]=[CH:40]C=2N=1.C(O)(=O)C>C1COCC1.O>[CH2:21]([O:23][C:24]([C:25]1[N:26]=[CH:27][N:28]2[C:30]=1[CH2:34][N:35]([CH2:47][C:48]1[CH:53]=[CH:52][C:51]([O:54][CH3:55])=[CH:50][C:49]=1[O:56][CH3:57])[C:36](=[O:46])[C:37]1[CH:43]=[C:42]([O:44][CH3:45])[CH:41]=[CH:40][C:29]2=1)=[O:31])[CH3:22]
Reactant: CCOC(=O)C/N=C/N(C)C
Reactant: COc1ccc(CN2CC(Cl)=Nc3ccc(OC)cc3C2=O)c(OC)c1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: CCCCCC
Solvent: O
Product: CCOC(=O)c1ncn2c1CN(Cc1ccc(OC)cc1OC)C(=O)c1cc(OC)ccc1-2
Temperature: -70 °C
Reaction time: 1 h

Procedure:
Hexamethyldisilazane (48.5 mL, 66 mmol) was dissolved in TBF (150 mL), cooled under argon to −70° C., and treated slowly with a 1.6 M solution of n-butyllithium in hexane (145 ml, 233 mmol). After stirring for 1 h at −70° C., a solution of (E)-(dimethylamino-methyleneamino)-acetic acid ethyl ester (21 g, 133 mmol) in THF (50 mL) was added, and stirring continued for 1 h at −70° C. Then a solution of 2-chloro-4-(2,4-dimethoxy-benzyl)-7-methoxy-3,4-dihydro-benzo[e][1,4]diazepin-5-one (24.9 g, 66 mmol) in TBF (150 mL) was added at −70° C., and subsequently allowed to warm to 10° C. over ca. 1 h, then cooled again to −30° C. Neat acetic acid (38 mL, 664 mmol) was added slowly at −30° C. with cooling, the muddy suspension was allowed to warm to 0° C., water (40 mL) added, and the resulting solution was refluxed for 1 h, leading to the formation of a thick precipitate. The hot suspension was diluted with water (450 mL), cooled to 30° C., filtered, and the white crystals washed with THF/water 1:1 (400 mL), and dried at 25 mbar/60° C. Yield: 16.7 g (56%). mp 204° C. m/z 451 (M).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:24]([CH3:26])[CH3:25])[C:7]([N:9]1[C@H:13]([C:14]([O:16]CC)=[O:15])[CH2:12][C:11]2([CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[CH2:10]1)=[O:8])=[O:4].C1COCC1.[Li+].[OH-]>C(O)(C)(C)C>[CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:24]([CH3:26])[CH3:25])[C:7]([N:9]1[CH:13]([C:14]([OH:16])=[O:15])[CH2:12][C:11]2([CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[CH2:10]1)=[O:8])=[O:4]
Reactant: CCOC(=O)[C@@H]1CC2(CCOCC2)CN1C(=O)[C@@H](NC(=O)OC)C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: COC(=O)N[C@H](C(=O)N1CC2(CCOCC2)CC1C(=O)O)C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.4 %

Procedure:
In a 10 mL round-bottomed flask, (S)-ethyl 2-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-8-oxa-2-azaspiro[4.5]decane-3-carboxylate (300 mg, 810 μmol) was combined with THF 6(ml) and tert-butanol (1 ml) to give a colorless solution. LiOH (1.0M, 1.62 ml, 1.62 mmol, Eq: 2) was added and stirred at room temperature for 2 hr. Then more LiOH (1.0M, 1 ml, 1 mmol) was added and stirred for an another 2 hr. THF was removed and the aqueous was acidified with 1N HCl to pH=3 and diluted with EtOAc (100 ml). It was washed with brine (10 ml), dried with MgSO4, filtered and concentrated to afford 2-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-8-oxa-2-azaspiro[4.5]decane-3-carboxylic acid as a white solid (270 mg, 97.4%). ESI-LRMS m/e calcd for C16H26N2O6 [M+] 342. found 341 [M+H+].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:15]2[CH:20]=[N:19][CH:18]=[C:17]([C:21]3[CH:22]=[N:23][N:24]4[CH:29]=[C:28](Cl)[CH:27]=[CH:26][C:25]=34)[N:16]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.[CH3:60][N:61](C=O)C.O>[OH-].[Na+].C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N.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:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:15]2[CH:20]=[N:19][CH:18]=[C:17]([C:21]3[CH:22]=[N:23][N:24]4[CH:29]=[C:28]([C:60]#[N:61])[CH:27]=[CH:26][C:25]=34)[N:16]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2cncc(-c3cnn4cc(Cl)ccc34)n2)C1
Reactant: CN(C)C=O
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2cncc(-c3cnn4cc(C#N)ccc34)n2)C1
Temperature: 150 °C

Procedure:
A mixture of (R)-3-[6-(6-Chloro-pyrazolo[1,5-a]pyridin-3-yl)-pyrazin-2-ylamino]-piperidine-1-carboxylic acid tert-butyl ester (129 mg, 0.3 mmol), zinc cyanide (40 mg, 0.342 mmol), S-Phos (11.1 mg, 0.027 mmol) and Pd2(dba)3 (11 mg, 0.012 mmol) in DMF-water (1.36 ml, 99:1 DMF:water) was degassed for 5 min then back filled with nitrogen. The reaction mixture was then heated to 150° C. in a microwave reactor for 30 min. The crude reaction mixture was diluted with 2N NaOH (1 ml) and ethyl acetate (10 ml). The aqueous layer was back extracted with ethyl acetate (10 ml), then the pooled ethyl acetate phases were washed with brine and dried with sodium sulfate and concentrated in vacuo to an oil. The crude oil was purified by column chromatography (0-100% ethyl acetate in heptane) which gave (R)-3-[6-(6-cyano-pyrazolo[1,5-a]pyridin-3-yl)-pyrazin-2-ylamino]-piperidine-1-carboxylic acid tert-butyl ester as a greenish oil (70 mg). (R)-3-[6-(6-cyano-pyrazolo[1,5-a]pyridin-3-yl)-pyrazin-2-ylamino]-piperidine-1-carboxylic acid tert-butyl ester (70 mg, 0.167 mmol) was dissolved in anhydrous DCM (2 ml) then 4 N HCl in dioxane (0.417 mL, 10 eq.) was added. The resulting mixture was capped and stirred at 23° C. After 4 h the reaction mixture was concentrated which gave the title compound 21 as a light yellow solid (64 mg). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.54-1.68 (m, 1H) 1.79-2.01 (m, 2H) 2.01-2.16 (m, 1H) 2.78-3.05 (m, 2H) 3.19-3.30 (m, 1H) 3.44 (none, 1H) 4.27 (br. s., 1H) 7.68 (d, J=8.59 Hz, 1H) 7.84 (s, 1H) 8.38 (s, 1H) 8.54 (d, J=9.35 Hz, 1H) 8.98 (s, 1H) 9.67 (s, 1H); LCMS M+1 320.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:12][CH2:11][CH2:10][NH:9][C:8](=O)[C:7]=2[CH:14]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:12][CH2:11][CH2:10][NH:9][CH2:8][C:7]=2[CH:14]=1
Reactant: COc1ccc2c(c1)C(=O)NCCS2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CNCCS2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
7-Methoxy-5-oxo-2,3,4,5-tetrahydro-1,4-benzothiazepine (0.300 g) was treated with LiAlH4 (0.160 g) in THF (10 ml) at reflux overnight. The mixture was cooled to room temperature and Na2SO4.10H2O was added slowly to quench the reaction. The resulting mixture was stirred at room temperature for 1 hour and filtered through a short celite column. Removal of the solvents led to the desired product as a colorless oil.
Reaction SMILES: O[CH2:2][C:3]1(CO)[CH2:8][C:7]2[CH:9]=[CH:10][S:11][C:6]=2[S:5](=[O:13])(=[O:12])[N:4]1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1.C(N(CC)CC)C.CS(OS(C)(=O)=O)(=O)=O.[CH3:41][O:42][CH2:43][CH2:44][NH:45][CH2:46][CH2:47][O:48][CH3:49]>C1COCC1>[CH3:41][O:42][CH2:43][CH2:44][N:45]([CH2:2][C:3]1[N:4]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[S:5](=[O:13])(=[O:12])[C:6]2[S:11][CH:10]=[CH:9][C:7]=2[CH:8]=1)[CH2:46][CH2:47][O:48][CH3:49]
Reactant: COCCNCCOC
Reactant: COc1ccc(CN2C(CO)(CO)Cc3ccsc3S2(=O)=O)cc1
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCCN(CCOC)CC1=Cc2ccsc2S(=O)(=O)N1Cc1ccc(OC)cc1
Reaction time: 1 h

Procedure:
To a solution of the product from Step C (1.60 g, 4.75 mmol) and triethylamine (1.44 g, 14.2 mmol) in anhydrous THF (100 mL) at ambient temperature was added methanesulfonic anhydride (1.24 g, 7.13 mmol). After 1 h, the reaction mixture was divided into two equal portions; to one of these portions was added bis(2-methoxyethyl)amine (6 mL). The mixture was stirred for 72 h, evaporated to dryness and the residue extracted with ethyl acetate (2×100 mL). The combined extracts were dried (MgSO4), filtered and evaporated to a residue which was purified by column chromatography (silica, 20-30% ethyl acetate/hexane) to give an oil (0.71 g) which solidified upon standing: mp 75°-77° C.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:5]=1[C:6](O)=[O:7])#[N:2].[NH2:15][C:16]1[CH:20]=[C:19]([CH3:21])[NH:18][N:17]=1>C(O)(=O)C>[CH3:14][O:13][C:11]1[CH:12]=[C:4]2[C:5](=[CH:9][CH:10]=1)[C:6](=[O:7])[NH:2][C:1]([NH:15][C:16]1[CH:20]=[C:19]([CH3:21])[NH:18][N:17]=1)=[CH:3]2
Reactant: Cc1cc(N)n[nH]1
Reactant: COc1ccc(C(=O)O)c(CC#N)c1
Solvent: CC(=O)O
Product: COc1ccc2c(=O)[nH]c(Nc3cc(C)[nH]n3)cc2c1
Temperature: 130 °C
Reaction time: 1 h
Yield: 82.9 %

Procedure:
2-Cyanomethyl-4-methoxy-benzoic acid (1.91 g, 0.01 mol), 3-amino-5-methylpyrazol (1 g, 0.01 mol) and acetic acid (15 ml) were sealed in bottle (20 ml). The mixture was heated at 130° C. for 20 minutes under microwave irradiation. The mixture was concentrated and the residue was dissolved in 5 ml MeOH. The solution was added dropwise to 200 ml water. After stirred for 1 hour, solid was collected and dried to give product (2.24 g, 82% yield). LC-MS: 271 (MH+)
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.C(N(CC)CC)C.[N:17]1[O:18][N:19]=[C:20]2[CH:25]=[C:24]([C:26](Cl)=[O:27])[CH:23]=[CH:22][C:21]=12>ClCCl>[CH3:1][N:2]([CH2:3][CH:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)[C:26]([C:24]1[CH:23]=[CH:22][C:21]2=[N:17][O:18][N:19]=[C:20]2[CH:25]=1)=[O:27]
Reactant: CNCC1CCOCC1
Reactant: O=C(Cl)c1ccc2nonc2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(CC1CCOCC1)C(=O)c1ccc2nonc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl tetrahydro-2H-pyran-4-carboxylate (5 ml, 40.0 mmol) was added to a solution of methylamine (generated by heating a mixture of methylamine hydrochloride and sodium hydroxide pellets) in THF (30 ml) and the mixture heated at 110° C. in a bomb reactor overnight. The solvents were evaporated, the residue dissolved in THF (100 ml), and LiAlH4 (4.6 g, 121 mmol) added, and the mixture heated at 70° C. for 1 h. The mixture was cooled to 0° C., concentrated NaOH solution added and the THF evaporated. Chloroform (100 ml) was added to the residue and the resulting solid was filtered off and the filtrate concentrated under vacuum to give N-methyl-N-tetrahydro-2H-pyran-4-ylmethylamine as a pale brown oil. The preceding amine (1 g, 7.8 mmol) was dissolved in dichloromethane (50 ml), and triethylamine (4 ml) and [2,1,3]-benzoxadiazole-5-carbonylchloride (1.7 g, 9.3 mmol), as a solution in dichloromethane (20 ml), were added, slowly. The mixture was stirred at room temperature for 1 h, the mixture washed with 1N HCl (20 ml), and saturated sodium bicarbonate solution (20 ml), dried (MgSO4) and evaporated. The residue was purified by silica gel chromatography eluting with ethyl acetate/chloroform (3:1) to give the title compound as a pale brown oil. 1H NMR (300 MHz, CDCl3, 2-rotamers) δ 7.93 (d, J=9.3 Hz, 1H), 7.83 (br s, 1H), 7.38-7.45 (m, 1H), 4.10-3.90 (m, 2H), 3.52-3.20 (m, 4H), 3.13 and 3.05 (both s, total 3H), 2.18-1.80 (m, 1H), 1.73-1.40 ppm (m, 4H).
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]2[OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:14][CH2:15][C:16](Cl)=[O:17].C([O-])(O)=O.[Na+]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:14][CH2:15][C:16]([O:13][C@@H:8]1[CH2:9][CH2:10][CH2:11][CH2:12][C@H:7]1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:17]
Reactant: O[C@@H]1CCCC[C@H]1c1ccccc1
Reactant: O=C(Cl)CCl
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(CCl)O[C@@H]1CCCC[C@H]1c1ccccc1
Yield: 100.3 %

Procedure:
A mixture of 790 g (4.48 mole) of pure (-)-(1R,2S)-2-phenylcyclohexanol, 1.5 L of methylene chloride, 450 mL (5.625 mole) of chloroacetyl chloride, and 2.2 g (0.96 mole) of 4-dimethylaminopyridine was heated at reflux for 8 hours. On cooling, the reaction mixture was stirred with 2 ×1.5 L=3.0 L of saturated NaHCO3 for 30 minutes. The organic layer was dried (Na2SO4) and evaporated to dryness, finally at 0.5 mm for 4 hours to afford 1.136 kg of the title compound (100%) as an oil.
Reaction SMILES: [Si]([O:8][C@@H:9]1[CH2:13][C@@H:12]([NH:14][C:15]2[CH:20]=[C:19]([NH:21][C@H:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:24][C@H:23]3[O:31][CH3:32])[N:18]=[CH:17][N:16]=2)[CH2:11][C@@H:10]1[CH2:33][OH:34])(C(C)(C)C)(C)C.N1C=CC=CC=1.Cl[S:42]([NH2:45])(=[O:44])=[O:43]>C(#N)C>[S:42](=[O:44])(=[O:43])([O:34][CH2:33][C@H:10]1[CH2:11][C@H:12]([NH:14][C:15]2[CH:20]=[C:19]([NH:21][C@H:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:24][C@H:23]3[O:31][CH3:32])[N:18]=[CH:17][N:16]=2)[CH2:13][C@H:9]1[OH:8])[NH2:45]
Reactant: NS(=O)(=O)Cl
Reactant: CO[C@@H]1Cc2ccccc2[C@@H]1Nc1cc(N[C@H]2C[C@H](CO)[C@H](O[Si](C)(C)C(C)(C)C)C2)ncn1
Solvent: c1ccncc1
Solvent: CC#N
Product: CO[C@@H]1Cc2ccccc2[C@@H]1Nc1cc(N[C@H]2C[C@H](COS(N)(=O)=O)[C@H](O)C2)ncn1
Reaction time: 3 h
Yield: 57 %

Procedure:
A solution of {(1R,2R,4S)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-[(6-{[(1S,2R)-2-methoxy-2,3-dihydro-1H-inden-1-yl]amino}pyrimidin-4-yl)amino]cyclopentyl}methanol (0.112 g, 0.231 mmol) (azetroped with toluene) and pyridine (0.0374 mL, 0.462 mmol) in anhydrous acetonitrile (2.3 mL) was cooled to 0° C. A 2 N solution of chlorosulfonamide in acetonitrile (0.116 mL) was added dropwise and the reaction was stirred for 3 h. Additional 2 N solution of chlorosulfonamide in acetonitrile (0.026 mL) and pyridine (0.0041 g, 0.052 mol) were added and the reaction was stirred for 1 h then quenched with methanol. The solution was concentrated in vacuo and purified by flash chromatography (0 to 10% MeOH/DCM) to afford the title compound as a white solid (0.059 g, 57%). 1H NMR (CD3OD, 400 MHz, δ): 8.26 (s, 1H); 8.01 (s, 1H); 7.26-7.16 (m, 3H); 5.70 (s, 1H); 5.47-5.33 (bs, 1H); 4.35 (t, J=4.5 Hz, 1H); 4.31 (d, J=7.5 Hz, 1H); 4.28 (d, J=7.5 Hz, 1H); 4.25-4.21 (m, 1H); 4.15-4.11 (dd, J=7.3 Hz; J=2.5 Hz, 1H); 3.36 (s, 3H); 3.16-3.00 (m, 2H); 2.54-2.45 (m, 1H); 2.26-2.19 (m, 1H); 2.10-1.98 (m, 1H); 1.87-1.78 (m, 1H); 1.77-1.69 (m, 1H). LC/MS: Rt=1.11 min, ES+ 450 (FA standard).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[Cl-].[Li+].CN(C)C=O.[CH:17]12[O:23][CH:18]1[CH2:19][CH2:20][CH2:21][CH2:22]2>CC(C)=O>[OH:23][CH:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH:17]1[N:4]1[C:3](=[O:8])[C:2]([CH3:9])([CH3:1])[NH:6][C:5]1=[O:7]
Reactant: C1CCC2OC2C1
Reactant: CC1(C)NC(=O)NC1=O
Agent: [Cl-]
Agent: [Li+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)NC(=O)N(C2CCCCC2O)C1=O
Temperature: 60 °C

Procedure:
A mixture of 128.1 g of 5,5-dimethylhydantoin (1 mol), 1 g of lithium chloride and 200 ml of dimethylformamide is stirred at 100° C in a 500 ml glass apparatus having a stirrer, thermometer, dropping funnel and reflux condenser. 100 g of cyclohexene oxide (1.02 mols) are added dropwise to this solution over the course of 120 minutes, whilst stirring. Thereafter the mixture is stirred for a further 5 hours at 125°-130° C. After cooling to about 60° C, the reaction mixture is filtered and is concentrated to dryness on a rotary evaporator at 70° C under a waterpump vacuum. Thereafter the residue is dried to constant weight at 90° C/0.1 Hg. 217.8 g of a yellowish, crystalline material (96.4% of theory) are obtained, and this can be recrystallised, for example from acetone. The purified product melts at 159°-161° C. Elementary analysis shows the following values:
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[NH:6][CH2:5][CH:4]([CH2:7][S:8][CH2:9][CH3:10])[O:3]1.[OH-].[Na+].[Cl:14][CH:15]([Cl:19])[C:16](Cl)=[O:17].CC1(C)N(C(=O)CCl)CC(CSCC)O1>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:11])[N:6]([C:16](=[O:17])[CH:15]([Cl:19])[Cl:14])[CH2:5][CH:4]([CH2:7][S:8][CH2:9][CH3:10])[O:3]1
Reactant: O=C(Cl)C(Cl)Cl
Reactant: CCSCC1CNC(C)(C)O1
Agent: CCSCC1CN(C(=O)CCl)C(C)(C)O1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: CCSCC1CN(C(=O)C(Cl)Cl)C(C)(C)O1

Procedure:
To 52.5 milliliters of 25 percent w/v, 2,2-dimethyl-5-ethylthiomethyl oxazolidine solution in 100 milliliters of benzene was added 6.5 grams of 50% solution of sodium hydroxide (10% excess) was added 12.1 grams of dichloroacetyl chloride dropwise. The reaction mixture was cooled in an ice bath with vigorous stirring during the dropwise addition. The temperature was maintained at below 10° C. during the addition and allowed to stir about 30 minutes at room temperature. The work-up procedure was similar to (a) supra. There was obtained a yield of 15.3 grams of the title compound, nD30 1.4980.
Reaction SMILES: C[O:2][C:3]1[N:4]=[N:5][C:6]([C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)=[CH:7][C:8]=1[C:9]1[NH:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[CH:15][CH:14]=[C:13]([CH2:24][N:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)[CH:12]=2.[OH-].[Na+]>C(O)C>[C:18]1([C:17]2[C:16]3[C:11](=[CH:12][C:13]([CH2:24][N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:8]2[C:3](=[O:2])[NH:4][N:5]=[C:6]([C:31]3[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=3)[CH:7]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COc1nnc(-c2ccncc2)cc1-c1[nH]c2cc(CN3CCCCC3)ccc2c1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=c1[nH]nc(-c2ccncc2)cc1-c1[nH]c2cc(CN3CCCCC3)ccc2c1-c1ccccc1
Temperature: 150 °C
Yield: 59.8 %

Procedure:
62 mg 2-(3-Methoxy-6-pyridin-4-yl-pyridazin-4-yl)-3-phenyl-6-piperidin-1-ylmethyl-1H-indole are dissolved in 0.5 mL ethanol. 0.75 mL 1 N aqueous sodium hydroxide are added. The reaction mixture is heated to 150° C. in a microwave oven for 15 minutes. Purification by HPLC affords 36 mg (58%) 4-(3-phenyl-6-piperidin-1-ylmethyl-1H-indol-2-yl)-6-pyridin-4-yl-2H-pyridazin-3-one as its trifluoro-acetate salt.
Reaction SMILES: [C:1]1([C:7]2[C:8]([O:10][C:11](=[O:13])[CH:12]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:16])=O.N1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:16][C:12]1[C:11](=[O:13])[O:10][C:8](=[O:9])[C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(Cl)Cl
Reactant: O=C1C=C(c2ccccc2)C(=O)O1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: O=C1OC(=O)C(c2ccccc2)=C1Cl
Temperature: 11 °C
Reaction time: 0.17 h

Procedure:
With ice-cooling, 10.0 g (57 mmol) of phenylmaleic anhydride were added to 57 ml of thionyl chloride, and the mixture was, over a period of 10 min, admixed dropwise with 9.08 g (115 mmol) of pyridine, the temperature being maintained at 10-12° C. The mixture was stirred at 10-12° C. for 30 min, heated at 75° C. for 10 min. using a preheated heating bath and allowed to cool, and excess thionylchloride was stripped off at 60° C. at reduced pressure. The residue was then boiled with 120 ml of toluene and filtered, and the residue was washed with 50 ml of hot toluene. The filtrate was concentrated under reduced pressure, titrated with petroleum ether and dried. Yield: 8.5 g, m.p. 82-83° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]([CH2:11][NH2:12])[CH2:7][C:8](Cl)=[O:9].[CH2:13]([NH2:16])[CH2:14][CH3:15]>C(Cl)(Cl)Cl>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]([CH2:11][NH2:12])[CH2:7][C:8]([NH:16][CH2:13][CH2:14][CH3:15])=[O:9]
Reactant: NCC(CC(=O)Cl)c1ncc[nH]1
Reactant: CCCN
Solvent: ClC(Cl)Cl
Product: CCCNC(=O)CC(CN)c1ncc[nH]1

Procedure:
0.01 mol of the compound obtained in stage A of Example 16 is dissolved in 50 cm3 of chloroform. 0.025 mol of propylamine is added and the whole is heated under reflux for 5 hours while stirring and then cooled. The reaction mixture is then evaporated to dryness and extracted twice with chloroform. The chloroform phases are combined and dried over calcium chloride and the solvent is evaporated in vacuo on a water bath. The residue is purified by chromatography.