Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([C:11]3[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=3[OH:18])=[N:8][C:7](=O)[C:6]=2[CH:20]=1.C(N(CC)CC)C.Cl.[NH:29]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[NH2:30]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([C:7]2[N:8]=[C:9]([C:11]3[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=3[OH:18])[N:29]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[N:30]=2)[CH:20]=1
Reactant: O=c1nc(-c2cc(Cl)ccc2O)oc2ccc(Cl)cc12
Reactant: CCOC(=O)CNN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)Cn1nc(-c2cc(Cl)ccc2O)nc1-c1cc(Cl)ccc1O

Procedure:
6.0 g of chloro-2-(5-chloro-2-hydroxyphenyl)benz[e][1,3]oxazin-4-one (Example 16), 3.0 ml of triethylamine and 3.3 g of ethyl hydrazinoacetate hydrochloride are boiled under reflux for 2 h in 60 ml of ethanol. On cooling, the product precipitates in crystalline form. It is filtered off and washed with ethanol. After drying, ethyl [3,5-bis(5-chloro-2-hydroxyphenyl)-[1,2,4]triazol-1-yl]acetate is obtained as colorless crystals of m.p. 195-200° C.
Reaction SMILES: Cl[C:2]([CH:4]1[CH2:9][CH2:8][CH2:7][N:6]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:5]1)=[O:3].[NH2:20][C:21]1[C:22]([OH:31])=[C:23]([CH:28]=[CH:29][CH:30]=1)[C:24]([O:26][CH3:27])=[O:25]>ClCCl>[CH2:13]([O:12][C:10]([N:6]1[CH2:7][CH2:8][CH2:9][CH:4]([C:2](=[O:3])[NH:20][C:21]2[CH:30]=[CH:29][CH:28]=[C:23]([C:24]([O:26][CH3:27])=[O:25])[C:22]=2[OH:31])[CH2:5]1)=[O:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)C1CCCN(C(=O)OCc2ccccc2)C1
Reactant: COC(=O)c1cccc(N)c1O
Solvent: ClCCl
Product: COC(=O)c1cccc(NC(=O)C2CCCN(C(=O)OCc3ccccc3)C2)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
Benzyl 3-(chlorocarbonyl)piperidine-1-carboxylate (500 mg, 3 mmol) and methyl 3-amino-2-hydroxybenzoate (1.014 g, 3.6 mmol) were added in anhydrous dichloromethane (20 mL) and the mixture was stirred at room temperature overnight. The mixture was extracted with dichloromethane (100 mL×4) and the organic phase was dried with anhydrous sodium sulfate and evaporated under reduced pressure. 1.2 g benzyl-3-(2-hydroxy-3-(methoxycarbonyl)phenylcarbamoyl)piperidine-1-carboxylate was obtained. Yield: 97%. LC-MS (ESI) m/z: 413 (M+1)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]1[CH2:12][C:11](=[O:13])[CH:10]([CH2:14]OS(C)(=O)=O)[CH:9]1/[CH:20]=[CH:21]/[CH:22]([O:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][O:30]1)[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].OCC1CCCC1=O.C(N(C(C)C)CC)(C)C>CCOCC>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]1[CH2:12][C:11](=[O:13])[C:10](=[CH2:14])[CH:9]1/[CH:20]=[CH:21]/[CH:22]([O:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][O:30]1)[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCC(/C=C/C1C(OC2CCCCO2)CC(=O)C1COS(C)(=O)=O)OC1CCCCO1
Agent: O=C1CCCC1CO
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: C=C1C(=O)CC(OC2CCCCO2)C1/C=C/C(CCCCC)OC1CCCCO1
Yield: 100.9 %

Procedure:
In a similar way to Example 24, (1), 293 mg of crude 4(RS)-(tetrahydropyran-2-yloxy)-3(RS)-[3-(tetrahydropyran-2-yloxy)-trans-1-octenyl]-2(SR)-(methanesulfonyloxymethyl)cyclopentanone was prepared from 243 mg of 4(RS)-(tetrahydropyran-2-yloxy)-3(RS)-]3-(tetrahydropyran-2-yloxy)trans-1-octenyl]-2(SR)-(hydroxymethyl)cyclopentanone. The crude product was reacted with diisopropylethylamine in ether in a similar way to Example 24, (2) to give 239 mg of crude 4(RS)-(tetrahydropyran-2-yloxy)-3(RS)-[3-(tetrahydropyran-2-yloxy)trans-1-octenyl]-2-methylidenecyclopentanone.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][CH3:8])(=[O:6])[CH2:4][OH:5].[CH3:9][S:10][C:11]1[N:12]=[C:13](Cl)[C:14]2[CH:19]=[C:18]([CH2:20][CH3:21])[N:17]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=3)[C:15]=2[N:16]=1>C1C=CC=CC=1>[CH3:8][O:7][C:3](=[O:6])[CH2:4][O:5][C:13]1[C:14]2[CH:19]=[C:18]([CH2:20][CH3:21])[N:17]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:31])([F:32])[F:30])[CH:24]=3)[C:15]=2[N:16]=[C:11]([S:10][CH3:9])[N:12]=1
Reactant: CCc1cc2c(Cl)nc(SC)nc2n1Cc1cccc(C(F)(F)F)c1
Reactant: COC(=O)CO
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CCc1cc2c(OCC(=O)OC)nc(SC)nc2n1Cc1cccc(C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 72 h
Yield: 54.6 %

Procedure:
To a suspension of 72 mg (3.00 mmol) of sodium hydride in 2 mL of benzene was added 225 mg (2.49 mmol) of methyl glycolate and a solution of 300 mg (0.78 mmol) of 2-(methylthio)-4-chloro-6-ethyl-7-[[3-(trifluoromethyl)-phenyl]methyl]-7H-pyrrolo[2,3-d]pyrimidine in 2 ml of benzene. The mixture was then heated at 60° C. After 24 hours the reaction was cooled to ambient temperature and an additional 36 mg of sodium hydride and 110 mg of methyl glycolate were added. After 3 days, the reaction was partitioned by the addition of 2 mL of 2 M sodium hydrogen sulfate and 20 mL of ethyl acetate. The organic phase was washed with 10 mL of water, dried with sodium sulfate and concentrated. The product was purified by flash chromatography (30 g silica, methylene chloride-heptane gradient 2:1 to 100:0) to provide 187 mg (54%) of [[2-(methylthio)-6-ethyl-7-[[3-(trifluoromethyl)phenyl]methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid methyl ester as a white solid. nmr (500 MHz, CDCl3) δ1.26 (t, J=7.4 Hz, 3H), 2.52 (s, 3H), 2.56 (q, J=7.4 Hz, 2H), 3.79 (s, 3H),5.05 (s, 2H), 5.42 (s, 2H), 6.32 (s, 1H), 7.18 (d, J=7.8 Hz, 1H), 7.39 (t, J=7.8 Hz, 1H), 7.44 (s, 1H), 7.51 (d, J=7.8 Hz, 1H)
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([NH:16][C:17]2[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=2)[N:3]=1.[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH3:15][O:14][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][C:9]=1[O:12][CH3:13])[C:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[N:3][C:4]([NH:16][C:17]1[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=1)=[CH:5]2
Reactant: OB(O)c1ccccc1
Reactant: COc1cc2cc(Nc3cc(C)[nH]n3)nc(Cl)c2cc1OC
Product: COc1cc2cc(Nc3cc(C)[nH]n3)nc(-c3ccccc3)c2cc1OC

Procedure:
Similar procedure as described in example 131 was used, starting from (1-Chloro-6,7-dimethoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and Phenylboronic acid to give (6,7-dimethoxy-1-phenyl-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 361(MH+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:22]=CC=1)[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH2:16][C:17]2[NH:18][CH:19]=[CH:20][N:21]=2)=[CH:8]1)#N.[OH-:25].[K+].[CH2:27]([OH:29])[CH3:28]>O>[C:27]([C:28]1[CH:22]=[C:5]([CH:4]=[CH:3][CH:1]=1)[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH2:16][C:17]2[NH:18][CH:19]=[CH:20][N:21]=2)=[CH:8]1)([OH:25])=[O:29]
Reactant: CCO
Reactant: [OH-]
Reactant: N#Cc1cccc(Cn2cc(Cc3ncc[nH]3)c3ccccc32)c1
Agent: [K+]
Solvent: O
Product: O=C(O)c1cccc(Cn2cc(Cc3ncc[nH]3)c3ccccc32)c1

Procedure:
1-(3-Cyanobenzyl)-3-(1-imidazolylmethyl)indole (1.0 g) was dissolved in ethanol (5 ml) and a solution of potassium hydroxide (0.5 g) in water (5 ml) was added. The mixture was heated under reflux for 6 hours and then worked up, as described in Example 11, to give 1-(3-carboxybenzyl)-3-(1-imidazolylmethyl)indole (0.70 g), m.p. 201.5°-203.5° C. (from ethanol). Found: C, 72.16; H, 5.19; N, 12.66. C20H17N3O2 requires: C, 72.49; H, 5.17; N, 12.68.
Reaction SMILES: [CH3:1][C@@H:2]1[N:7]([C:8]2[C:9]3[CH2:24][CH2:23][N:22]([C:25]4[N:30]=[CH:29][CH:28]=[CH:27][N:26]=4)[CH2:21][C:10]=3[N:11]=[C:12]([C:14]3[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=3)[N:13]=2)[CH2:6][CH2:5][O:4][CH2:3]1.[O:31]1[CH2:36]COCC1.C(N(CC)CC)C.C(Cl)(Cl)=O.[NH2:48][CH:49]1[CH2:52][CH2:51][CH2:50]1>C1(C)C=CC=CC=1>[CH:49]1([NH:48][C:36]([NH:18][C:17]2[CH:19]=[CH:20][C:14]([C:12]3[N:13]=[C:8]([N:7]4[CH2:6][CH2:5][O:4][CH2:3][C@@H:2]4[CH3:1])[C:9]4[CH2:24][CH2:23][N:22]([C:25]5[N:26]=[CH:27][CH:28]=[CH:29][N:30]=5)[CH2:21][C:10]=4[N:11]=3)=[CH:15][CH:16]=2)=[O:31])[CH2:52][CH2:51][CH2:50]1
Reactant: C1COCCO1
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(N)cc2)nc2c1CCN(c1ncccn1)C2
Reactant: NC1CCC1
Agent: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CCC3)cc2)nc2c1CCN(c1ncccn1)C2
Temperature: 50 °C
Reaction time: 72 h

Procedure:
(S)-4-(4-(3-methylmorpholino)-7-(pyrimidin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)aniline (0.0501 g, 0.000124 mol) in dry 1,4-Dioxane (2.00 mL, 0.0256 mol) was added Triethylamine (0.0190 mL, 0.000136 mol) followed by 20% Phosgene in toluene (1:4, Phosgene:Toluene, 0.080 mL). The reaction mixture was heated at 50° C. for 1 hour. The reaction mixture was cooled to room temperature and then added aminocyclobutane (0.0638 mL, 0.000745 mol). The reaction mixture was stirred for 3 days. The reaction mixture was concentrated and purified by HPLC. 1H NMR (400 MHz, DMSO) δ 8.59 (s, 1H), 8.43 (d, J=4.7, 2H), 8.20 (d, J=8.8, 2H), 7.48 (d, J=8.8, 2H), 6.69 (t, J=4.7, 1H), 6.51 (d, J=8.1, 1H), 4.89 (d, J=18.7, 1H), 4.72 (d, J=18.7, 1H), 4.21-4.03 (m, 3H), 3.91-3.78 (m, 2H), 3.70 (dd, J=11.2, 2.7, 1H), 3.60 (t, J=9.2, 3H), 3.41 (t, J=12.7, 1H), 2.74 (s, 2H), 2.20 (dt, J=14.3, 5.1, 2H), 1.92-1.77 (m, 2H), 1.60 (ddd, J=21.1, 13.6, 8.3, 2H), 1.25 (d, J=6.6, 3H). LC/MS-m/z+501.3 (M+H)+
Reaction SMILES: CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.[C:20]([O:24][C:25]([NH:27][CH2:28][C:29]([NH:31][C@H:32]1[CH2:36][N:35]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C@H:34]([C:44](O)=[O:45])[CH2:33]1)=[O:30])=[O:26])([CH3:23])([CH3:22])[CH3:21].[Cl:47][C:48]1[CH:49]=[C:50]([CH:58]=[C:59]([Cl:61])[CH:60]=1)[O:51][CH:52]1[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1.ON1C2C=CC=CC=2N=N1>O1CCCC1.CN(C)C=O>[C:20]([O:24][C:25]([NH:27][CH2:28][C:29]([NH:31][C@H:32]1[CH2:36][N:35]([C:37]([O:39][C:40]([CH3:42])([CH3:41])[CH3:43])=[O:38])[C@H:34]([C:44]([N:55]2[CH2:56][CH2:57][CH:52]([O:51][C:50]3[CH:58]=[C:59]([Cl:61])[CH:60]=[C:48]([Cl:47])[CH:49]=3)[CH2:53][CH2:54]2)=[O:45])[CH2:33]1)=[O:30])=[O:26])([CH3:21])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)NCC(=O)N[C@@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: Clc1cc(Cl)cc(OC2CCNCC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC(=O)N[C@@H]1C[C@@H](C(=O)N2CCC(Oc3cc(Cl)cc(Cl)c3)CC2)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 105.6 %

Procedure:
N-Methylmorpholine (120 μL) and ]-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (188 mg) were added to a solution of trans-4-(N-tert-butoxycarbonylglycylamino)-N-tert-butoxycarbonyl-L-proline (Compound D103 (B), 400 mg), 4-(3,5-dichlorophenoxy)piperidine (518 mg), and 1-hydroxybenzotriazole (140 mg) in tetrahydrofuran (12 mL) and N,N-dimethylformamide (4 mL) at room temperature. After stirring at room temperature for 12 hr, the reaction mixture was partitioned between ethyl acetate and 1 N hydrochloric acid. The organic layer was washed with saturated sodium hydrogen carbonate and brine. After drying over anhydrous sodium sulfate, the organic layer was evaporated in vacuo. The residue was washed with hexane to give the titled compound (671 mg) as a white solid: 1H NMR (400 MHz, CDCl3) δ 1.43 (s, 9H), 1.46 (s, 9H), 1.70-2.00 (m, 4H), 2.14-2.29 (m, 2H), 3.35-3.82 (m, 8H), 4.51-4.60 (m, 2H), 4.64 (br t, 0.5H), 4.78 (m, 0.5H), 5.11 (br s, 1H), 6.40 (m, 1H), 6.77-6.80 (m, 2H), and 6.96-6.98 (m, 1H); IR (KBr) 3311, 2978, 1701, 1655, 1570, 1441, 1255, 1163, 1049 cm−1; mass spectrum (FAB+) m/e 615 (M).
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[C:4]([S:6][CH2:7][C:8]1([CH:16]=[CH:15][CH:14]=[CH:13][CH2:12]1)[C:9](O)=[O:10])=[S:5])[CH3:2].S(Cl)([Cl:21])=O>ClCCl>[CH2:1]([N:3]([CH2:17][CH3:18])[C:4]([S:6][CH2:7][C:8]1([CH:16]=[CH:15][CH:14]=[CH:13][CH2:12]1)[C:9]([Cl:21])=[O:10])=[S:5])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCN(CC)C(=S)SCC1(C(=O)O)C=CC=CC1
Solvent: ClCCl
Product: CCN(CC)C(=S)SCC1(C(=O)Cl)C=CC=CC1
Yield: 100 %

Procedure:
1-((Diethylcarbamothioylthio)methyl)benzoic acid (0.1 g) was refluxed in a solution of thionyl chloride (1 mL, in excess) and dichloromethane (10 mL) for 2 h. The reaction was then evaporated to dryness and the product obtained as a pale yellow liquid (yield 100%). The product was diluted with dichloromethane to a volume of 1.00 mL (standard solution of 0.353 M) for subsequent reaction with OH terminated Star-PEG MW 116,000 (see below). Conversion of the carboxylic acid to the acid chloride was further verified by the observation that the starting material was a white solid, which was partially insoluble in dichloromethane, whilst the product was a pale, yellow liquid which was completely soluble in dichloromethane. 1H NMR (CD2Cl2, 400 MHz) δ 1.27-1.29 (br.m, 6H, 2×CH3), 3.76 (br.q, J=7.0 Hz, 2H, CH2N), 4.04 (br.q, J=7.0 Hz, 2H, CH2N), 4.66 (s, 2H, CH2S), 7.53 (d, J=8.4 Hz, 2H, aromatic, 8.04 (d, J=8.4 Hz, 2H, aromatic) ppm. 13C(CD2Cl2, 400 MHz) δ 11.8, 12.9, 41.3, 47.5, 50.5, 53.5, 53.7, 54.0, 54.3, 54.5, 130.4, 132.0, 132.5, 146.6, 168.4, 194.3 ppm.
Reaction SMILES: [P:1]([O:13][CH2:14][N:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:41])[C:23]2[CH:28]=[C:27]([Cl:29])[C:26]([Cl:30])=[CH:25][C:24]=2[O:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=2[O:39][CH3:40])=[CH:17][C:16]1=[O:42])([O:8]C(C)(C)C)([O:3]C(C)(C)C)=[O:2].CC(O)=O>CC#N.O>[P:1]([OH:3])([OH:8])([O:13][CH2:14][N:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:41])[C:23]2[CH:28]=[C:27]([Cl:29])[C:26]([Cl:30])=[CH:25][C:24]=2[O:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=2[O:39][CH3:40])=[CH:17][C:16]1=[O:42])=[O:2]
Reactant: COc1cc(F)ccc1Oc1cc(Cl)c(Cl)cc1C(=O)Nc1ccn(COP(=O)(OC(C)(C)C)OC(C)(C)C)c(=O)c1
Solvent: CC(=O)O
Solvent: O
Solvent: CC#N
Product: COc1cc(F)ccc1Oc1cc(Cl)c(Cl)cc1C(=O)Nc1ccn(COP(=O)(O)O)c(=O)c1
Yield: 54.6 %

Procedure:
A solution of di-tert-butyl [4-[[4,5-dichloro-2-(4-fluoro-2-methoxy-phenoxy)benzoyl]amino]-2-oxo-1-pyridyl]methyl phosphate (40 mg, 0.06197 mmol) in CH3CN (800.0 μL), water (800.0 μL) and AcOH (800 μL, 14.07 mmol) was heated at 90° C. for 15 min then evaporated and co-evaporated with CH3CN (3×). The material was triturated with CH3CN, filtered, washed with CH3CN and desiccated to give [4-[[4,5-dichloro-2-(4-fluoro-2-methoxy-phenoxy)benzoyl]amino]-2-oxo-1-pyridyl]methyl dihydrogen phosphate (1) (19 mg, 0.03385 mmol, 54.6%) as a white solid. ESI-MS m/z calc. 532.00055, found 533.3 (M+1)+; Retention time: 1.5 minutes. 1H NMR (400 MHz, DMSO-d6) δ 10.58 (s, 1H), 7.91 (s, 1H), 7.62 (d, J=7.6 Hz, 1H), 7.27 (dd, J=8.9, 5.8 Hz, 1H), 7.13 (dd, J=10.7, 3.0 Hz, 1H), 6.90 (d, J=2.3 Hz, 1H), 6.86 (s, 1H), 6.86-6.81 (m, 1H), 6.44 (dd, J=7.6, 2.4 Hz, 1H), 5.52 (d, J=9.7 Hz, 2H), 3.76 (s, 3H) ppm. 31P NMR (162 MHz, DMSO-d6-85% H3PO4 aq. as internal standard—0 ppm) δ −2.12 (t, J=9.4 Hz) ppm.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH2:5][CH2:6][S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([C@H:23]2[CH2:28][CH2:27][C@H:26]([CH3:29])[CH2:25][CH2:24]2)[CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[O:15])=[N:10][CH:9]=1)[CH3:2].[CH3:31][N:32]([CH3:37])[S:33](Cl)(=[O:35])=[O:34]>>[CH2:1]([O:3][C:4](=[O:30])[CH2:5][CH2:6][S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([CH:17]2[CH2:22][CH2:21][N:20]([S:33](=[O:35])(=[O:34])[N:32]([CH3:37])[CH3:31])[CH2:19][CH2:18]2)[C@H:23]2[CH2:28][CH2:27][C@H:26]([CH3:29])[CH2:25][CH2:24]2)=[O:15])=[N:10][CH:9]=1)[CH3:2].[CH3:31][N:32]([CH3:37])[S:33]([N:20]1[CH2:19][CH2:18][CH:17]([N:16]([C@H:23]2[CH2:28][CH2:27][C@H:26]([CH3:29])[CH2:25][CH2:24]2)[C:14](=[O:15])[NH:13][C:11]2[S:12][C:8]([S:7][CH2:6][CH2:5][C:4]([OH:3])=[O:30])=[CH:9][N:10]=2)[CH2:22][CH2:21]1)(=[O:35])=[O:34]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: CCOC(=O)CCSc1cnc(NC(=O)N(C2CCNCC2)[C@H]2CC[C@H](C)CC2)s1
Product: CCOC(=O)CCSc1cnc(NC(=O)N(C2CCN(S(=O)(=O)N(C)C)CC2)[C@H]2CC[C@H](C)CC2)s1
Product: CN(C)S(=O)(=O)N1CCC(N(C(=O)Nc2ncc(SCCC(=O)O)s2)[C@H]2CC[C@H](C)CC2)CC1

Procedure:
3-{2-[3-(1-Dimethylsulfamoyl-piperidin-4-yl)-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-propionic acid ethyl ester was prepared in a similar manner to Example 554 using 3-{2-[3-(trans-4-methyl-cyclohexyl)-3-piperidin-4-yl-ureido]-thiazol-5-ylsulfanyl}-propionic acid ethyl ester and dimethylsulfamoyl chloride. Hydrolisis using general procedure (F) gave the title compound
Reaction SMILES: C([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=O)=[CH:13][CH:12]=2)[N:6]=1)CCC.[CH2:20](Cl)[CH2:21]Cl.P(Cl)(Cl)(Cl)=O.[CH3:29][CH2:30]OCC>>[CH2:29]([C:10]1[CH:9]=[N:8][C:7]([C:11]2[CH:12]=[CH:13][C:14]([C:15]#[N:17])=[CH:18][CH:19]=2)=[N:6][CH:5]=1)[CH2:30][CH2:20][CH3:21]
Reactant: CCCCc1ccnc(-c2ccc(C(N)=O)cc2)n1
Reactant: ClCCCl
Reactant: CCOCC
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCc1cnc(-c2ccc(C#N)cc2)nc1

Procedure:
11.23 G. of 4-(4-n-butylpyrimid-2-yl)-benzoic acid amide are maintained at reflux for 90 minutes in a mixture of 250 ml. of ethylene chloride and 4.5 ml. of phosphorus oxychloride with stirring. The mixture, diluted with ether, is washed with 2-N sodium hydroxide and then with water until neutral. The organic phase is dried over sodium sulfate and evaporated to give 11.77 g. of 5-n-butyl-2-(4-cyanophenyl)-pyrimidine which are distilled in a high vacuum; melting point 60.9°-61.8° C.
Reaction SMILES: S([C:5]1[O:13][C:12]2[CH:11]=[C:10](C)[NH:9][C:8](=[O:15])[C:7]=2[CH:6]=1)(=O)(=O)N.O1C=CC=[C:17]1C(C)=CC(O)=O.O1C=CC=C1C=C(C)C(O)=O>>[CH3:17][C:11]1[C:12]2[O:13][CH:5]=[CH:6][C:7]=2[C:8](=[O:15])[NH:9][CH:10]=1
Reactant: CC(=CC(=O)O)c1ccco1
Reactant: Cc1cc2oc(S(N)(=O)=O)cc2c(=O)[nH]1
Agent: CC(=Cc1ccco1)C(=O)O
Product: Cc1c[nH]c(=O)c2ccoc12

Procedure:
The title compound was prepared according to the procedure described for 2-sulfamoyl-6-methylfuro[3.2-c]pyridin-4-(5H)-one (Example 12 Step A) except 3-(2-furanyl)-3-methylacrylic acid was substituted for 3-(2-furanyl)methacrylic acid. Title compound was obtained in 41% yield, m.p. 239°-241° C., after crystallization from methanol.
Reaction SMILES: [C:1]([O:12][CH3:13])(=[O:11])[C:2]1[CH:10]=[CH:9][C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.Br[CH2:15][CH3:16].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:15]([O:8][C:7]1[CH:9]=[CH:10][C:2]([C:1]([O:12][CH3:13])=[O:11])=[CH:3][C:4]=1[O:5][CH3:6])[CH3:16]
Reactant: CCBr
Reactant: COC(=O)c1ccc(O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc(C(=O)OC)cc1OC
Temperature: 70 °C
Yield: 96.8 %

Procedure:
A mixture of methyl vanillate (6.376 g, 35 mmol), bromoethane (4.359 g, 40 mmol), and K2CO3 (5.528 g, 40 mmol) in DMF (40 mL) was heated at 70° C. for 2 hours. The reaction mixture was quenched with water, filtered, washed with water, and dried under vacuum with P2O5 to give methyl 4-ethoxy-3-methoxybenzoate as white solid (7.123 g, 97%). 1H NMR (300 MHz, CDCl3) δ 7.66 (dd, 1H), 7.55 (d, 1H), 6.88 (d, 1H), 4.17 (q, 2H), 3.93 (s, 3H), 3.89 (s, 3H), 1.50 (t, 3H); LC-MS (ESI) m/z 211 (M+H)+.
Reaction SMILES: [C:1]([Cl:6])(=[O:5])C(Cl)=O.[Cl:7][C:8]1[CH:16]=[C:15]([C:17]2[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=2)[CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11].CN(C)C=O>O1CCCC1>[C:1]([Cl:6])([Cl:7])=[O:5].[Cl:7][C:8]1[CH:16]=[C:15]([C:17]2[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=2)[CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11]
Reactant: O=C(Cl)C(=O)Cl
Agent: Cn1cc(-c2ccc(C(=O)O)c(Cl)c2)cn1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(Cl)Cl
Temperature: 35 °C

Procedure:
Oxalyl chloride (0.49 ml) was added to a solution of 2-chloro-4-(1-methyl-1H-pyrazol-4-yl)-benzoic acid (0.41 g) from Example 114 and dimethylformamide (0.012 ml) in anhydrous tetrahydrofuran (20 ml). The reaction was heated at 35° C. for ten minutes. The resulting solution was evaporated in vacuo to dryness to yield the crude 2-chloro-4-(1-methyl-1H-pyrazol-4-yl)-benzoic acid carbonyl chloride. Following co-evaporation with anhydrous methylene chloride, the acid chloride was dissolved in dichloromethane (20 ml) followed by the addition of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]-benzodiazepine (0.888 g) and diisopropylethylamine (1.06 ml). The resulting solution was stirred at room temperature for 2 hours. The reaction was diluted with dichloromethane and washed with water followed by 1N hydrochloric acid. The organic phase was washed with brine and dried over anhydrous magnesium sulfate. The dichloromethane was filtered and concentrated in vacuo to dryness. . The residue was purified by flash column chromatography on silica pressure eluting with hexane/ethyl acetate (2/1) to afford 1,4 g of the title compound as a colorless solid m.p. 105-109° C.
Reaction SMILES: O[CH:2]([C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][N:14]=1)[C:3]1[S:7][C:6]([NH:8][C:9]([NH2:11])=[NH:10])=[N:5][C:4]=1[CH3:12].S(=O)(=O)(O)O.[OH-:25].[Na+].[C:27](#[N:29])[CH3:28]>>[C:27]([NH:29][CH:2]([C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][N:14]=1)[C:3]1[S:7][C:6]([NH:8][C:9]([NH2:11])=[NH:10])=[N:5][C:4]=1[CH3:12])(=[O:25])[CH3:28]
Reactant: [OH-]
Reactant: Cc1ccnc(C(O)c2sc(NC(=N)N)nc2C)c1
Reactant: CC#N
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CC(=O)NC(c1cc(C)ccn1)c1sc(NC(=N)N)nc1C

Procedure:
A solution of N-(5-(hydroxy-(4-methylpyridin-2-yl)methyl)-4-methylthiazol-2-yl)guanidine (0.54 g) and 96% sulfuric acid (6.5 ml) in acetonitrile (26 ml) was stirred at 5° C. for 18 hours. The pH of the mixture was adjusted to 12 with 4N aqueous sodium hydroxide, and the mixture was extracted with ethyl acetate three times. The combined organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was triturated with ethyl acetate, collected by filtration and dried. The crude compound was recrystallized from ethanol/n-hexane to give N-(5-(acetylamino-(4-methylpyridin-2-yl)methyl)-4-methylthiazol-2-yl)-guanidine (211 mg).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)[C:11](=[O:25])[CH:10]=1)C1C=CC=CC=1>[Pd].C1COCC1.CO>[OH:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:19][CH:20]=2)[C:11](=[O:25])[CH:10]=1
Reactant: CS(=O)(=O)c1ccc(-n2ccc(OCc3ccccc3)cc2=O)cc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(-n2ccc(O)cc2=O)cc1
Reaction time: 1 h
Yield: 101.8 %

Procedure:
A stirring suspension of 4-(benzyloxy)-1-(4-(methylsulfonyl)phenyl)-pyridine-2(1H)-one (3.0 g, 8.44 mmol) and palladium on activated carbon (1.63 g, 10 wt. %, wet, Aldrich) in THF (150 mL) and methanol (250 mL) was under hydrogen (balloon) for 1 hr. The resulting mixture was purged with nitrogen and then diluted with THF (150 mL) and methanol (50 mL). After stirring under nitrogen for 30 min, the mixture was filtered through a pad of CELITE® 545 filter aid and the filtrate was evaporated under reduced pressure to give 2.28 g crude product as a dark greenish solid. MS (ESI) 266 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH:4]([NH:6][CH:7]1[CH2:12][C:11]([CH3:14])([CH3:13])[NH:10][C:9]([CH3:16])([CH3:15])[CH2:8]1)[CH3:5].[CH3:18][C:19]1([CH3:28])[CH2:24]C(O)[CH2:22][C:21]([CH3:27])([CH3:26])[NH:20]1.[NH2-].[Li+].CO>CCCCCCC>[CH3:18][C:19]1([CH3:28])[CH2:24][CH:1]([O:2][C:3](=[O:17])[CH:4]([NH:6][CH:7]2[CH2:8][C:9]([CH3:16])([CH3:15])[NH:10][C:11]([CH3:14])([CH3:13])[CH2:12]2)[CH3:5])[CH2:22][C:21]([CH3:27])([CH3:26])[NH:20]1
Reactant: CC1(C)CC(O)CC(C)(C)N1
Reactant: COC(=O)C(C)NC1CC(C)(C)NC(C)(C)C1
Agent: [Li+]
Agent: [NH2-]
Solvent: CCCCCCC
Solvent: CO
Product: CC(NC1CC(C)(C)NC(C)(C)C1)C(=O)OC1CC(C)(C)NC(C)(C)C1
Yield: 76.2 %

Procedure:
To the same flask as used in Example 1 were added 24.4 g (0.1 mole) of N-(2,2,6,6-tetramethyl-4-piperidinyl)aminopropionic acid methyl ester, 17.3 g (0.11 mole) of 2,2,6,6-tetramethyl-4-piperidinol, 0.23 g of lithium amide and 100 g of heptane. The temperature was raised with stirring, and reaction was carried out at 98° to 105° C. for 6 hours, during which methanol was removed from the reaction system by means of the Deanstark trap. After completion of the reaction, water was added to the reaction solution to dissolve the product in the heptane layer. The heptane layer was separated, and heptane in the layer was removed by distillation to obtain 28 g of N-(2,2,6,6-tetramethyl-4-piperidinyl)aminopropionic acid (2,2,6,6-tetramethyl-4-piperidinyl)ester as a pale yellow liquid. Yield, 73.5% based on N-(2,2,6,6-tetramethyl-4-piperidinyl)aminopropionic acid methyl ester. A pale yellow oily product was obtained by the subsequent column chromatographic separation.