Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[S:9][CH:10]=[C:11]([NH:13][C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[N:18]=3)=[O:15])[N:12]=2)[CH:5]=[CH:4][N:3]=1.[CH3:30][CH2:31][OH:32].CC[O-].[Na+].CCO>CN(C=O)C>[CH2:31]([O:32][C:2]1[CH:7]=[C:6]([C:8]2[S:9][CH:10]=[C:11]([NH:13][C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[N:18]=3)=[O:15])[N:12]=2)[CH:5]=[CH:4][N:3]=1)[CH3:30]
Reactant: O=C(Nc1cccc(CN2CCOCC2)n1)Nc1csc(-c2ccnc(Cl)c2)n1
Reactant: CCO
Agent: CC[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1cc(-c2nc(NC(=O)Nc3cccc(CN4CCOCC4)n3)cs2)ccn1
Reaction time: 2.5 h

Procedure:
To a mixture of 1-[2-(2-chloropyridin-4-yl)thiazol-4-yl]-3-(6-morpholin-4-ylmethyl-pyridin-2-yl)urea (100 mg, 0.23 mmol, Example 90) and EtOH (50 mL) was added a 21 wt % NaOEt/EtOH solution (0.4 mL, 1.2 mmol) and DMF (2 mL). The mixture was heated to reflux for 15 h then additional 21 wt % NaOEt/EtOH solution (10 mL) were added. After 2.5 h, the reaction was complete as judged by LC/MS. The reaction mixture was concentrated in vacuo then diluted with EtOAc and the solid was filtered off. The filtrate was concentrated in vacuo to afford an orange slushy oil which was purified by silica flash chromatography (5-10% MeOH/CH2Cl2) to afford the title compound as a yellow solid. MS m/z: 441.1 (M+H). Calc'd for C21H24N6O3S: 440.16.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][CH:11]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([N:22]([CH:31]([CH3:33])[CH3:32])[C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[O:21])[C:15]2[CH:34]=[CH:35][CH:36]=[CH:37][C:14]=2[N:13]([C:38]2[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=2)[C:12]1=[O:44]>C(Cl)Cl>[O:18]=[C:17]1[N:16]([CH2:19][C:20]([N:22]([CH:31]([CH3:33])[CH3:32])[C:23]2[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)=[O:21])[C:15]2[CH:34]=[CH:35][CH:36]=[CH:37][C:14]=2[N:13]([C:38]2[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=2)[C:12](=[O:44])[CH:11]1[NH:10][C:8]([NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:9]
Reactant: O=C=Nc1ccccc1
Reactant: COc1ccc(N(C(=O)CN2C(=O)C(N)C(=O)N(c3cccnc3)c3ccccc32)C(C)C)cc1
Solvent: ClCCl
Product: COc1ccc(N(C(=O)CN2C(=O)C(NC(=O)Nc3ccccc3)C(=O)N(c3cccnc3)c3ccccc32)C(C)C)cc1

Procedure:
A solution of phenyl isocyanate (36.6 mg, 0.295 mmol) in methylene chloride (1 ml) was added to a solution of 2-(3-Amino-2,4-dioxo-5-pyridin-3-yl-2,3,4,5-tetrahydrobenzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl) acetamide (140 mg, 0.295 mmol) in methylene chloride (1 ml) and the resultant solution stirred at rt for 16 h. The solvent was removed in vacuo and the residue recrystalised from 5% methanol in ethyl acetate to afford the title compound product (49 mg) as a white powder. 1H NMR (300 MHz, CDCl-3). s 8.72 (s, 1H), 8.56 (d, 1H, J=8.0), 7.92 (d, 1H, J=8.0), 6.91-7.43 (m, 16H), 6.43 (d, 1H, J=8.3), 5.43 (d, 1H, J=8.3), 4.95 (sept, 1H, J=6.8), 4.60 (d, 1H, J=11.8), 4.18 (d, 1H, J=11.8), 3.88 (s, 3H), 1.06 (m, 6H). Low resolution MS (FAB) m/e 593 (m+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH3:19])=[C:6]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)=[O:10])[CH:7]=1.[C:20]1(=[O:26])[O:25][C:23](=[O:24])[CH2:22][CH2:21]1>N1C=CC=CC=1>[CH3:19][O:18][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:20](=[O:26])[CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:7][C:6]=1[NH:8][C:9]([NH:11][C:12]1[CH:17]=[N:16][CH:15]=[CH:14][N:13]=1)=[O:10]
Reactant: COc1ccc(N)cc1NC(=O)Nc1cnccn1
Reactant: O=C1CCC(=O)O1
Solvent: c1ccncc1
Product: COc1ccc(NC(=O)CCC(=O)O)cc1NC(=O)Nc1cnccn1
Yield: 48.7 %

Procedure:
A solution of 1-(5-amino-2-methoxyphenyl)-3-pyrazin-2-yl-urea (Compound 14, Example 4) (260 mg, 1 mmol) and succinic anhydride (131 mg, 1.3 mmol) in dry pyridine (10 mL) was stirred 16 h at room temperature. The resulting solid was collected by filtration and triturated with chloroform, and dried in vacuo to afford the off-white product (175 mg, 50%). 1H NMR (300 Mhz, d6-DMSO) δ: 10.15 (s, 1H), 10.05 (s, 1H), 9.87 (s, 1H), 8.90 (s, 1H), 8.33 (s, 2H), 8.24 (s, 1H), 7.42 (dd, J=8.8, 2.2 Hz, 1H), 6.96 (d, J=8.8 Hz, 1H), 3.87 (s, 3H), 2.54 (br s, 4H).
Reaction SMILES: [OH:1][C:2]1[C:9]([C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:8][C:5]([CH2:6]O)=[CH:4][C:3]=1[C:14]([CH3:17])([CH3:16])[CH3:15].[ClH:18]>CCCCCC>[OH:1][C:2]1[C:9]([C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:8][C:5]([CH2:6][Cl:18])=[CH:4][C:3]=1[C:14]([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)c1cc(CO)cc(C(C)(C)C)c1O
Reactant: Cl
Solvent: CCCCCC
Product: CC(C)(C)c1cc(CCl)cc(C(C)(C)C)c1O
Reaction time: 8 h

Procedure:
176 grams of 4-hydroxy-3,5-di-tert-butyl-benzyl alcohol was slurried in 350 ml of hexane. 240 cc of concentrated HCl was added to the slurry and stirred overnight. The two phases were allowed to separate and the hexane phase washed twice with water. The dried hexane was then extracted with magnesium sulfate and filtered. Rotofilm evaporation yielded 168 grams of product--a pungent yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[CH:22]=[CH:21][C:20]([C:23](O)=[O:24])=[C:19]2[C:14]=1[CH:15]=[CH:16][CH:17]=[N:18]2.[N+:26]([C:29]1[N:30]=[CH:31][NH:32][CH:33]=1)([O-])=O>C(Cl)Cl.CO>[N:32]1[CH:33]=[C:29]([NH:26][C:23]([C:20]2[CH:21]=[CH:22][C:13]([C:3]3[C:4]([Cl:12])=[C:5]([O:10][CH3:11])[CH:6]=[C:7]([O:8][CH3:9])[C:2]=3[Cl:1])=[C:14]3[C:19]=2[N:18]=[CH:17][CH:16]=[CH:15]3)=[O:24])[NH:30][CH:31]=1
Reactant: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)O)c3ncccc23)c1Cl
Reactant: O=[N+]([O-])c1c[nH]cn1
Solvent: CO
Solvent: ClCCl
Product: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3cnc[nH]3)c3ncccc23)c1Cl
Temperature: 70 °C
Reaction time: 3 h

Procedure:
The title compound was prepared in analogy to the procedures described in Example 14 but using 5-(2,6-dichloro-3,5-dimethoxy-phenyl)-quinoline-8-carboxylic acid (Step 159.1), stirring the reaction mixture for 3 h at 70° C., and using 4-nitro-imidazole instead of 2-nitroimidazole in Step 14.3. The title compound: ESI-MS: 442.9 [M+H]+; tR=3.93 min (System 1); TLC: Rf=0.17 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](Cl)=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:23][CH2:24][C:25]([NH2:28])([CH3:27])[CH3:26].C(N)C(C)C>>[NH2:28][C:25]([CH3:27])([CH3:26])[CH2:24][NH:23][C:13]1[C:12]2[C:17](=[CH:18][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:10][CH:11]=2)[N:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20]
Reactant: CC(C)(N)CN
Reactant: O=[N+]([O-])c1cnc2cc(OCc3ccccc3)ccc2c1Cl
Solvent: CC(C)CN
Product: CC(C)(N)CNc1c([N+](=O)[O-])cnc2cc(OCc3ccccc3)ccc12
Yield: 73.6 %

Procedure:
7-Benzyloxy-4-chloro-3-nitroquinoline (14.5 g, 46.0 mmol), prepared as described in Parts A-D of Example 1, was treated according to the general method described in Part E of Example 1. 1,2-Diamino-2-methylpropane (5.29 mL, 50.6 mmol) was used in lieu of isobutylamine. After the work-up, the crude product was passed through a layer of silica gel (eluting sequentially with chloroform and 96:4 chloroform:methanol) to provide 12.4 g of (2-amino-2-methylpropyl)(7-benzyloxy-3-nitroquinolin-4-yl)amine as a yellow solid.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]#[N:12])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.Br[CH2:14][CH:15]1[CH2:17][CH2:16]1.C[Si]([N-][Si](C)(C)C)(C)C.[K+]>C1COCC1>[CH:15]1([CH2:14][C:8]2([C:11]#[N:12])[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)[CH2:17][CH2:16]1
Reactant: N#CC1CCC2(CC1)OCCO2
Reactant: BrCC1CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: N#CC1(CC2CC2)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 1,4-dioxaspiro[4.5]decane-8-carbonitrile (20 g; 119.6136 mmol) and (bromomethyl)cyclopropane (17.76 g 12.6 ml; 131.57 mmol) in THF (100 ml) at −10° C. was added KHMDS (0.5M solution in toluene; 263.15 ml ; 131.57 mmol) dropwise and the solution allowed to warm to ambient temperature with stirring for 18 hours. The reaction was cooled in an ice bath and quenched with sat. ammonium chloride solution and the solvent evaporated. The residue was partitioned between EtOAc (300 ml) and water (100 ml adjusted to pH 4 with 1 N HCl). The organic phase was separated, dried over MgSO4, filtered and evaporated to give an orange oil. (21.0 g) 1H NMR δ (ppm)(CDCl3): 3.99-3.89 (4H, m), 2.08 (2H, d, J=13.5 Hz), 1.96-1.72 (9H, m), 0.96-0.82 (1H, m), 0.59-0.53 (2H, m), 0.17 (2H, q, J=5.1 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.S([O-])([O-])(=O)=O.[Na+].[Na+].[F:17][C:18]([F:26])(S(F)(=O)=O)C(O)=O.O>C(#N)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:7][CH:18]([F:26])[F:17])=[CH:4][CH:3]=1
Reactant: OCc1ccc(Br)cc1
Reactant: O=C(O)C(F)(F)S(=O)(=O)F
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: FC(F)OCc1ccc(Br)cc1
Temperature: 45 °C
Yield: 37.1 %

Procedure:
To a solution of 4-bromobenzyl alcohol (5.6 g) in acetonitrile (15 ml), sodium sulfate (0.28 g) was added. While warmed to 45° C., 2,2-difluoro-2-(fluorosulfonyl)acetic acid (1.78 g) was slowly dropwise added, and the mixture was heated and refluxed at 45° C. for 4 hours. The reaction solution was poured into water, the mixture was extracted with diethyl ether and the organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off in vacuo and the residue obtained was purified with silica gel column chromatography (hexane:ethyl acetate=19:1 to 17:3) to afford the above-identified compound (0.88 g).
Reaction SMILES: C(C1[CH:17]=[CH:16][C:6]2[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:8][O:9][C:5]=2[CH:4]=1)#N.[C:18]([OH:21])(=[O:20])[CH3:19].Cl>O>[C:10]1([C:7]2[C:6]3[CH:16]=[CH:17][C:19]([C:18]([OH:21])=[O:20])=[CH:4][C:5]=3[O:9][CH:8]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC(=O)O
Reactant: N#Cc1ccc2c(-c3ccccc3)coc2c1
Agent: Cl
Solvent: O
Product: O=C(O)c1ccc2c(-c3ccccc3)coc2c1

Procedure:
A mixture of 54.7 g of 6-cyano-3-phenylbenzofuran, 200 ml of acetic acid and 100 ml of hydrochloric acid is heated to its reflux temperature and maintained at reflux for about 20 hours. An additional 100 ml of hydrochloric acid is added and the mixture is refluxed further for about 27 hours. The reaction mixture is then added to water and the aqueous solution is extracted with diethyl ether. The ether layer is extracted with dilute sodium hydroxide solution. The basic aqueous solution is acidified with 6N hydrochloric acid and the solid precipitate is collected by filtration. The solid is recrystallized from aqueous ethanol to provide 3-phenyl-6-benzofurancarboxylic acid, m.p. 160°-170° C.
Reaction SMILES: [Br:1][C:2]1[C:7](Br)=[CH:6][CH:5]=[CH:4][N:3]=1.NC1C([N+:16]([O-:18])=[O:17])=CC=CN=1>Br>[Br:1][C:2]1[C:7]([N+:16]([O-:18])=[O:17])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Brc1cccnc1Br
Reactant: Nc1ncccc1[N+](=O)[O-]
Agent: Br
Product: O=[N+]([O-])c1cccnc1Br

Procedure:
Bouillon et al in Tetrahedron, 2002, 58, 17, 3323-3328 reported a three-step process for the preparation of 2,3-dibromopyridine from 2-amino-3-nitropyridine. The process involves diazotization of 2-amino-3-nitropyridine followed by addition of CuBr in 47% HBr to obtain 2-bromo-3-nitropyridine. The 2-bromo-3-nitropyridine so obtained is reduced with Fe and acetic acid to 3-amino-2-bromopyridine and subsequent diazotization to give 2,3-dibromopyridine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C@@H:5]([NH:10][C:11](=[O:25])[C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]2)=[CH:14][CH:13]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].[NH2:27][CH2:28][C@@H:29]([C:31]1[CH:32]=[CH:33][C:34]([OH:42])=[C:35]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH:36]=1)[OH:30]>>[CH2:1]([O:3][C:4](=[O:26])[C@@H:5]([NH:10][C:11](=[O:25])[C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:19][CH2:20][CH:21]([NH:27][CH2:28][C@H:29]([OH:30])[C:31]3[CH:32]=[CH:33][C:34]([OH:42])=[C:35]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH:36]=3)[CH2:22][CH2:23]2)=[CH:14][CH:13]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2]
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Reactant: CCOC(=O)[C@H](CC(C)C)NC(=O)c1ccc(N2CCC(=O)CC2)cc1
Product: CCOC(=O)[C@H](CC(C)C)NC(=O)c1ccc(N2CCC(NC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1

Procedure:
The title compound was prepared from ethyl 4-methyl-2-[(2S)-4-(4-oxo-piperidin-1-yl)-benzoylamino]-pentanoic acid ethyl ester (which was obtained in Example 165) and N-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 10) according to the procedure of Example 180 as an off-white solid; mp>85° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 0.86 (d, J=6.3 Hz, 3 H), 0.92 (d, J=6.3 Hz, 3 H), 1.18 (t, J=7.1 Hz, 3 H), 1.20–1.40 (m, 2 H), 1.45–1.95 (m, 5 H), 2.55–2.92 (m, 5 H), 2.92 (s, 3 H), 3.70–3.85 (m, 2 H), 4.10 (q, J=7.1 Hz, 2 H), 4.40–4.55 (m, 2 H), 6.82 (d, J=8.3 Hz, 1 H), 6.94 (d, J=8.9 Hz, 2 H), 7.00 (dd, J=8.3, 2.0 Hz, 1 H), 7.18 (d, J=2.0 Hz, 1 H), 7.75 (d, J=8.9 Hz, 2 H), 8.33 (d, J=7.7 Hz, 1 H); MS (ES) m/z: 591.3 (MH+); HRMS Calcd. for C29H43N4O7S (MH+): 591.2847. Found: 591.2840.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH2:36][CH2:37][NH:38][CH3:39])[C:27]=1[C:28](O)=[O:29].CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:25][C:26]1[C:27]2[C:28](=[O:29])[N:38]([CH3:39])[CH2:37][CH2:36][O:35][C:31]=2[CH:32]=[CH:33][CH:34]=1
Reactant: CNCCOc1cccc(N)c1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCOc2cccc(N)c2C1=O
Reaction time: 1 h
Yield: 10.2 %

Procedure:
Sodium hydride (8.81 g, 220.38 mmol) was added portionwise to 2-(methylamino)ethanol (16.55 g, 220.38 mmol) in THF (500 mL) at 0° C. over a period of 10 minutes under an atmosphere of argon. The resulting solution was stirred at 0° C. for 1 hour and then 2-amino-6-fluorobenzonitrile (20 g, 146.92 mmol) was added in one portion and the mixture heated at 85° C. for 2 hours. The mixture was quenched with water and then evaporated. The residue was dissolved in EtOAc (300 mL), and the mixture washed sequentially with water (2×300 mL), and then with a saturated solution of NaCl (300 mL). The organic layer was dried over MgSO4, and then evaporated. The residue was purified by chromatography on silica, eluting with a gradient of 0-10%, of a 7M solution of NH3 in MeOH, in CH2Cl2. Fractions containing product were evaporated to afford 2-amino-6-(2-methylaminoethoxy)benzonitrile (12.08 g, 43% yield); Mass spectrum: m/z (ESI+) (M+H)+=192.43. b) Potassium hydroxide (32 g, 570.35 mmol) was added in one portion to 2-amino-6-(2-methylaminoethoxy)benzonitrile (16 g, 83.67 mmol) in ethanol (160 mL). The resulting mixture was heated at 90° C. for 2 days. The mixture was then diluted with water (1000 mL) and acidified to ˜pH1 with 2M HCl. The mixture was loaded onto an SCX column and the product was eluted first using MeOH and then with a 7M solution of NH3 in MeOH. Fractions containing product were combined and evaporated to afford 2-amino-6-(2-methylaminoethoxy)benzoic acid which was used without further purification. c) HATU (35.0 g, 92.04 mmol) was added in one portion to 2-amino-6-(2-methylaminoethoxy)benzoic acid (17.59 g, 83.67 mmol) and DIPEA (15.92 mL, 92.04 mmol) in DMF (200 mL) and the resulting solution was stirred for 1 hour. The mixture was evaporated and the residue dissolved in EtOAc (500 mL). The mixture was washed sequentially with a saturated solution of Na2CO3 (500 mL), water (500 mL), and finally with a saturated solution of NaCl (500 mL). The organic layer was dried over MgSO4, and then evaporated. The residue was purified by chromatography on silica, eluting with a gradient of 0-100% EtOAc in isohexane. Fractions containing product were combined and evaporated to afford 6-amino-4-methyl-2,3-dihydro-1,4-benzoxazepin-5-one (1.635 g, 10% yield); 1H NMR spectrum: (300 MHz, DMSO) δ 3.09 (s, 3H), 3.44 (t, 2H), 4.20 (t, 2H), 5.74 (br s, 2H), 6.22 (dd, 1H), 6.52 (dd, 1H), 7.08 (appt t, 1H); Mass spectrum: m/z (ESI+) (M+H)+=193.41.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]3[O:26][CH2:27][O:28][C:22]=3[CH:21]=2)[C:10]2[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]4[O:26][CH2:27][O:28][C:22]=4[CH:21]=3)[C:10]3[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: CCc1cc2c(NCc3ccc4c(c3)OCO4)nc(Cl)nc2s1
Product: CCc1cc2c(NCc3ccc4c(c3)OCO4)nc(-n3cncn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-6-ethyl-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-6-ethyl-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: C[Si](Cl)(C)C.Br[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH3:13][O:14][C:15]1[CH:22]=[C:21]([O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)[CH:20]=[C:19]([B:30]2[O:34][C:33](C)(C)C(C)(C)[O:31]2)[C:16]=1C=O>C1COCC1.[Zn]>[CH2:11]([O:10][C:8](=[O:9])[CH2:7][CH:33]1[O:34][B:30]([OH:31])[C:19]2[CH:20]=[C:21]([O:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)[CH:22]=[C:15]([O:14][CH3:13])[C:16]1=2)[CH3:12]
Reactant: COc1cc(OC2CCCCO2)cc(B2OC(C)(C)C(C)(C)O2)c1C=O
Reactant: CCOC(=O)CBr
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: CCOC(=O)CC1OB(O)c2cc(OC3CCCCO3)cc(OC)c21
Temperature: 55 °C
Reaction time: 0.25 h

Procedure:
To a mixture of zinc powder (0.98 g, 15.0 mmol) in anhydrous THF (30 mL) was added TMSCl (0.39 mL, 3.0 mmol) at 40° C. The resulting mixture was stirred at 55° C. for 15 min and cooled to 37° C. After addition of ethyl 2-bromoacetate (1.35 mL, 12.0 mmol), the reaction mixture was stirred at this temperature for an additional 30 min. To a solution of 2-methoxy-4-(tetrahydro-2H-pyran-2-yloxy)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (1.09 g, 3.0 mmol) in anhydrous THF (40 mL) was added dropwise the above prepared solution at −78° C. The reaction mixture was allowed to warm to room temperature and stirred for 1.5 h before quenched by aqueous ammonium chloride (20 mL). The resulting mixture was extracted with ethyl acetate (50 mL×2) and the combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (EtOAc/PE=1/4) on silica gel to give the title compound as a yellow solid. (0.86 g, Y: 82.3%). MS (ESI) m/z=267 [M+H]+.
Reaction SMILES: [N:1](=[C:3]1[N:7]=[C:6]([CH3:8])[C:5]([CH3:10])([CH3:9])[S:4]1)[OH:2].[CH:11]([N:14]=[C:15]=[O:16])([CH3:13])[CH3:12]>>[CH:11]([NH:14][C:15]([O:2][N:1]=[C:3]1[N:7]=[C:6]([CH3:8])[C:5]([CH3:10])([CH3:9])[S:4]1)=[O:16])([CH3:13])[CH3:12]
Reactant: CC1=NC(=NO)SC1(C)C
Reactant: CC(C)N=C=O
Product: CC1=NC(=NOC(=O)NC(C)C)SC1(C)C

Procedure:
2-oxo-4,5,5-trimethyl-3-thiazoline-oxime was reacted with isopropyl isocyanate as described in Example 4 to yield 2-oxo-4,5,5-trimethyl-3-thiazoline-O-(isopropylcarbamoyl)-oxime, m.p. 114°-116° C.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.[Br:29]Br>C(#N)C.C(OCC)(=O)C>[C:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH2:16]2)=[CH:9][C:10]=1[Br:29])(=[O:3])[CH3:2]
Reactant: BrBr
Reactant: CC(=O)Oc1ccc(N2CCN(C)CC2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(=O)Oc1ccc(N2CCN(C)CC2)cc1Br
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A solution of 4-(4-methylpiperazin-1-yl)phenyl acetate 247 mg (1.05 mmol) and p-toluenesulfonic acid 209 mg (1.1 mmol) in acetonitrile was cooled in an ice bath and bromine 0.056 ml (1.1 mmol) was added dropwise. The reaction was stirred at room temperature until complete (3-4 hours), was diluted with ethyl acetate and extracted with water and saturated NaHCO3. The organic phase, dried over Na2SO4 and evaporated, was purified by flash chromatography (DCM/MeOH 85/15) to give the product as a dark brown oil. HPLC (254 nm) method 2 Rt 4.05 min. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.25 (s, 3H) 2.36 (s, 3H) 2.39 (m, 4H) 3.44 (m, 4H) 6.50 (dd. J=2.1, 8.3 Hz, 1H) 7.03 (d, J=8.3 Hz, 1H) 7.21 (d, J=2.1 Hz, 1H). Mass. Calc. 313.0546 Mass. Found: 313.0538
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:30][C@H:31]2[CH2:51][CH2:50][C:33]3([O:37][C@H:36]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[C@@H:35]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[O:34]3)[CH2:32]2)[C:13](=O)[CH2:14][CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH:24]3[O:28]CCO3)=[CH:20][N:19]=2)=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C([O-])(=O)C.[NH4+:56].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([C:13]2[NH:56][C:16]([C:18]3[N:19]=[CH:20][C:21]([CH:24]=[O:28])=[CH:22][CH:23]=3)=[CH:15][CH:14]=2)[CH2:30][C@H:31]2[CH2:51][CH2:50][C:33]3([O:37][C@H:36]([C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)[C@@H:35]([C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=4)[O:34]3)[CH2:32]2)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: [NH4+]
Reactant: CS(=O)(=O)c1ccc(C(C[C@H]2CCC3(C2)O[C@H](c2ccccc2)[C@@H](c2ccccc2)O3)C(=O)CCC(=O)c2ccc(C3OCCO3)cn2)cc1Cl
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(C(C[C@H]2CCC3(C2)O[C@H](c2ccccc2)[C@@H](c2ccccc2)O3)c2ccc(-c3ccc(C=O)cn3)[nH]2)cc1Cl
Temperature: 110 °C
Reaction time: 1 h
Yield: 31.7 %

Procedure:
To a solution of 5-[3-chloro-4-(methylsulfonyl)phenyl]-1-[5-(1,3-dioxolan-2-yl)pyridin-2-yl]-6-[(2R,3R,7R)-2,3-diphenyl-1,4-dioxaspiro[4.4]non-7-yl]hexane-1,4-dione (276 mg) in acetic acid (2 mL) was added ammonium acetate (466 mg), and the mixture was stirred at 110° C. for 1 hr. After cooling to room temperature, the mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution. The reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (80.0 mg, yield 32%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [NH3:1].[CH:2]1([C:8](Cl)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1>C(Cl)(Cl)Cl>[CH:2]1([C:8]([NH2:1])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: N
Reactant: O=C(Cl)C1CCCCC1
Solvent: ClC(Cl)Cl
Product: NC(=O)C1CCCCC1
Yield: 46.1 %

Procedure:
Aqueous ammonia was added to solution of cyclohexanecarbonyl chloride (500 mg, 3.41 mmol) in CHCl3 (10 ml). After completion of reaction, the reaction mixture was diluted with CHCl3 (2×30 ml). The organic layer was washed with saturated sodium bicarbonate solution, brine and dried over anhydrous sodium sulfate. The organic layer was concentrated under vacuum, crude compound was washed with hexane (2×8 ml) and dried to afford 200 mg (46.1%) of cyclohexanecarboxamide.