Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]([CH3:17])=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[C:18]1[C:27]2[C:22]3=[C:23]([CH2:28][CH2:29][O:30][C:21]3=[CH:20][CH:19]=1)[CH:24]=[CH:25][N:26]=2)(=O)=O.[CH2:33]([Sn](CCCC)(CCCC)C=C)[CH2:34]CC.[Li+].[Cl-]>O1CCOCC1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:17][C:16]1[C:7]([CH:33]=[CH2:34])=[C:8]([C:18]2[C:27]3[C:22]4=[C:23]([CH2:28][CH2:29][O:30][C:21]4=[CH:20][CH:19]=2)[CH:24]=[CH:25][N:26]=3)[C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2
Reactant: Cc1cc2ccccc2c(-c2ccc3c4c(ccnc24)CCO3)c1OS(=O)(=O)C(F)(F)F
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C=Cc1c(C)cc2ccccc2c1-c1ccc2c3c(ccnc13)CCO2
Yield: 113 %

Procedure:
A solution of 1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yltrifluoromethanesulfonate (5E) (89 mg, 0.194 mmol), tributyl(vinyl)tin (0.23 mL, 0/776 mmol), Pd(PPh3)4 (34 mg, 0.029 mmol) and LiCl (16 mg, 0.39 mmol) in dioxane (3 mL) was stirred at 110° C. under Ar for 5 hours. The reaction mixture was cooled, diluted with ethyl acetate and washed with saturated NaHCO3 solution (2×), brine and dried (MgSO4), filtered, concentrated and purified by flash column chromatography (silica gel, hexanes) to give 5F as a white solid (74 mg, 91%). LCMS-ESI+ (m/z): [M+H]+ calcd for C24H20NO: 338.42. Found: 338.2.
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.[CH2:10]([OH:24])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[H-].[Na+].CC1C=CC(C)=CC=1>O.C(O)(=O)C>[CH2:10]([O:24][C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: O=C(O)c1ccc(Br)o1
Reactant: CCCCCCCCCCCCCCO
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: Cc1ccc(C)cc1
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)O)o1

Procedure:
A mixture of 57.2 (0.300 mole) of 5-bromo-2-furoic acid, 102.0 g (0.45 mole) of tetradecanol, 18.0 g (0.750 mole) of sodium hydride and 2 liters of p-xylene are heated to reflux for 48 hours. The mixture is allowed to cool, then is acidified with acetic acid and diluted with 2 liters of water. The organic layer is separated, dried, evaporated to dryness, and the residue recrystallized from hexane to give 5-tetradecyloxy-2-furoic acid.
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([C:29]([OH:31])=O)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].[CH3:32][O:33][C:34]1[CH:35]=[C:36]2[C:41](=[CH:42][C:43]=1[O:44][CH3:45])[CH2:40][NH:39][CH2:38][CH2:37]2.C1(NC(N)=O)CCCCC1>CN(C1C=CN=CC=1)C.ClCCl>[C:16]([O:20][C:21]([N:23]1[CH2:24][CH2:25][CH:26]([C:29]([N:39]2[CH2:38][CH2:37][C:36]3[C:41](=[CH:42][C:43]([O:44][CH3:45])=[C:34]([O:33][CH3:32])[CH:35]=3)[CH2:40]2)=[O:31])[CH2:27][CH2:28]1)=[O:22])([CH3:17])([CH3:18])[CH3:19]
Reactant: COc1cc2c(cc1OC)CNCC2
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: NC(=O)NC1CCCCC1
Solvent: ClCCl
Product: COc1cc2c(cc1OC)CN(C(=O)C1CCN(C(=O)OC(C)(C)C)CC1)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 117.4 %

Procedure:
DCC (2.16 g, 0.011 mol), a catalytic amount of DMAP (0.098 g, 8 mmol) and 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (2.04 g, 0.009 mol) were added to a solution of 6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline (1.31 g, 0.008 mol) in dichloromethane (30 ml). The clear solution soon deposited a white solid corresponding to the cyclohexyl urea formation. The crude was stirred for 2 hours at room temperature. The solid was filtered and the crude was washed with water and dried over Na2SO4. The solvent was vacuum concentrated and the residue was purified by flash chromatography using a gradient consisting of different mixtures of dichloromethane/methanol to give pure tert-Butyl-4-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidine-1-carboxylate as yellow solid (3.8 g, 85% yield).
Reaction SMILES: [CH2:1]([C:5]1([CH2:17][CH2:18][CH2:19][CH3:20])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]#[CH:16])[CH:13]=2)[S:8][CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].C(N([CH2:26][CH3:27])CC)C.IC1[CH:39]=[CH:38][C:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:31]N=1>[Cu]I>[CH2:1]([C:5]1([CH2:17][CH2:18][CH2:19][CH3:20])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]#[C:16][C:27]3[CH:26]=[CH:31][C:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:38][CH:39]=3)[CH:13]=2)[S:8][CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCOC(=O)c1ccc(I)nc1
Reactant: CCN(CC)CC
Reactant: C#Cc1ccc2c(c1)C(CCCC)(CCCC)CCS2
Agent: [Cu]I
Product: CCCCC1(CCCC)CCSc2ccc(C#Cc3ccc(C(=O)OCC)cc3)cc21
Temperature: 55 °C
Reaction time: 20 h

Procedure:
A mixture of 0.234 g (0.82 mmol) of (4,4-dibutylthiochroman-6-yl)acetylene (Compound 35), 21 mg (0.11 mmol) of copper (I) iodide, and 1.45 g (14 mmol) of triethylamine were degassed with argon for 15 min. To the suspension was added 0.49 g (1.8 mmol) of ethyl 4-iodobenzoate (Compound 21) and then 0.065 g (0.09 mmol) of bis(triphenyliphosphine)palladium (II) chloride. The suspension was degassed with argon for an additional 5 minutes, the tube was sealed and the mixture stirred at 55° C. for 20 hours.
Reaction SMILES: [CH:1]1([CH:7]([NH:21][C:22]2[CH:31]=[CH:30][C:25]([C:26]([O:28]C)=[O:27])=[CH:24][CH:23]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:14]=[N:15][C:16](F)=[CH:17][CH:18]=3)[O:10][C:9]=2[CH3:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:32][C:33]([OH:38])([CH3:37])[CH2:34][CH2:35][OH:36].[OH-].[Li+].Cl>O1CCCC1.O>[CH:1]1([CH:7]([NH:21][C:22]2[CH:31]=[CH:30][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:14]=[N:15][C:16]([O:36][CH2:35][CH2:34][C:33]([OH:38])([CH3:37])[CH3:32])=[CH:17][CH:18]=3)[O:10][C:9]=2[CH3:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc(NC(c2cc(-c3ccc(F)nc3)oc2C)C2CCCCC2)cc1
Reactant: CC(C)(O)CCO
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1oc(-c2ccc(OCCC(C)(C)O)nc2)cc1C(Nc1ccc(C(=O)O)cc1)C1CCCCC1
Temperature: 80 °C
Reaction time: 10 h
Yield: 15.1 %

Procedure:
Methyl 4-({cyclohexyl[5-(6-fluoropyridin-3-yl)-2-methylfuran-3-yl]methyl}amino)benzoate (1.7 g) and 3-methyl-1,3-butanediol (2.1 g) were dissolved in tetrahydrofuran (10 mL), 2N lithium hydroxide (4 mL) was added, and the mixture was stirred at 80° C. for 10 hr. The reaction mixture was poured into water, and the mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (10% ethyl acetate/hexane to 50% ethyl acetate/hexane) to give the title compound (0.3 g, 16%) as an amorphous compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:7][C:8]2[C:13]([OH:14])=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:5][N:6]=1.ClCCl.CN(C)C=[O:21].ClC1C=CC=C(C(OO)=O)C=1>C(Cl)(Cl)Cl>[NH2:1][C:2]1[S:3][C:4]([S:7]([C:8]2[C:13]([OH:14])=[CH:12][CH:11]=[CH:10][N:9]=2)=[O:21])=[CH:5][N:6]=1
Reactant: CN(C)C=O
Reactant: Nc1ncc(Sc2ncccc2O)s1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Nc1ncc(S(=O)c2ncccc2O)s1
Yield: 12.2 %

Procedure:
To a mixture of 2-amino-5-(3-hydroxypyridin-2-ylthio)thiazole (4.6 g) in a mixture of chloroform (100 ml), dichloromethane (200 ml) and N,N-dimethylformamide (50 ml) was added dropwise the solution of 3-chloroperbenzoic acid (4.3 g) in chloroform (50 ml) at 5° C. with stirring. The mixture was stirred at room temperature for 5 hours. The reaction mixture was extracted with aqueous diluted hydrochloric acid and the aqueous layer was washed with ethyl acetate. The aqueous layer was adjusted to pH 5.7 using sodium bicarbonate and extracted with a mixture of tetrahydrofuran and ethyl acetate (1:1). The organic layer was washed with aqueous saturated sodium chloride and dried over magnesium sulfate. The solvent was concentrated under reduced pressure to give solid. The solid was subjected to column chromatography on silica gel (silica gel 60, 70-230 mesh; Merck: 250 g) and eluted with a mixture of chloroform and methanol (10:1). The fractions containing the objective compound were combined and concentrated under reduced pressure to give 2-amino-5-(3-hydroxypyridin-2-ylsulfinyl)thiazole (0.65 g, yield: 12.2%). mp: 155-158° C. (dec.) IR (Nujol): 3300, 3150, 1620, 1565, 1515, 1300 cm-1
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][C:22]=2[O:23][CH3:24])[N:19]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:18]=[C:17]3[S:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)(=[O:33])=[O:32])[CH2:10][CH2:9]1)C1C=CC=CC=1.[Cl:40]C(OC(Cl)=O)C>ClCCCl>[ClH:40].[CH3:24][O:23][C:22]1[CH:21]=[C:20]2[C:16]([C:17]([S:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)(=[O:32])=[O:33])=[N:18][N:19]2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:15][C:14]=1[N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(Cl)OC(=O)Cl
Reactant: COc1cc2c(cc1N1CCN(Cc3ccccc3)CC1)c(S(=O)(=O)c1ccccc1)nn2-c1ccccc1
Solvent: ClCCCl
Product: COc1cc2c(cc1N1CCNCC1)c(S(=O)(=O)c1ccccc1)nn2-c1ccccc1
Product: Cl
Temperature: 25 °C
Yield: 82 %

Procedure:
A mixture of 5-(4-benzylpiperazin-1-yl)-6-methoxy-1-phenyl-3-(phenyl-sulfonyl)-1H-indazole (190 mg, 0.353 mmol) and 1-chloroethylchloroformate (250 mg, 1.77 mmol) in 1,2-dichloroethane is heated at reflux temperature for 4 h, cooled to room temperature and concentrated to dryness. The resultant residue is dissolved in ethanol, heated at reflux temperature for 16 h and concentrated in vacuo to give the title compound as a white solid, 130 mg, (82% yield). This compound is purified by recrystalization from ethanol/ether to afford a white solid, mp 167–170° C., identified by NMR and mass spectral analyses.
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.[CH2:11]1[CH:15]2[CH2:16][NH:17][CH2:18][CH:14]2[CH2:13][O:12]1.C(N(CC)CC)C>C1C=CC=CC=1>[C:2]([N:17]1[CH2:18][CH:14]2[CH2:13][O:12][CH2:11][CH:15]2[CH2:16]1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: C1NCC2COCC12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: O=C(c1cccnc1)N1CC2COCC2C1
Temperature: 15 °C
Reaction time: 1.5 h

Procedure:
Nicotinoyl chloride hydrochloride, represented by formula (XII), (0.1 mole, 17.81 grams) was slowly added to a mixture of hexahydro-1H-furo(3,4-c)pyrrole, represented by formula (X), (0.1 mole, 11.3 grams), and triethylamine (0.2 mole, 20.24 grams) in 160 ml of benzene at 15°C. The reaction mixture was stirred for 1.5 hours at 15°C. and then left overnight at room temperature. The HCl salt of triethylamine was filtered and the salt was washed with benzene. The washings were combined with the filtrate and benzene was stripped under vacuum. The product, 5-nicotinoyl-hexahydro-1H-furo(3,4-c)pyrrole, represented by formula (XIII), light yellow viscous liquid, was purified by column chromatography (Alumina-eluted with methyl acetate).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:11]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[N:21]([CH3:46])[C:22]4[C:27]([N:28]=3)=[C:26]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[N:25]=[C:24]([N:35]3[C:39]5[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=5[N:37]=[C:36]3[CH2:44][CH3:45])[N:23]=4)[CH2:15][CH2:14]2)=[O:12])[CH2:10][CH2:9]1)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:7][C:8]1([C:11]([N:13]2[CH2:14][CH2:15][N:16]([CH2:19][C:20]3[N:21]([CH3:46])[C:22]4[C:27]([N:28]=3)=[C:26]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[N:25]=[C:24]([N:35]3[C:39]5[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=5[N:37]=[C:36]3[CH2:44][CH3:45])[N:23]=4)[CH2:17][CH2:18]2)=[O:12])[CH2:9][CH2:10]1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(C(=O)C4(NC(=O)OC(C)(C)C)CC4)CC3)n(C)c2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(C(=O)C4(N)CC4)CC3)n(C)c2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 63.8 %

Procedure:
A mixture of (1-{4-[2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethyl]piperazine-1-carbonyl}cyclopropyl)carbamic acid tert-butyl ester (0.123 g, 0.19 mmol) in DCM/TFA (5 mL/5 mL) was stirred for 4 h at room temperature. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the desired product was eluted using 2 M NH3 in MeOH. The eluent was concnentrated in vacuo and the residue was purified by flash chromatography (Si—PPC, MEOH:DCM, gradient 0:100 to 10:90) to give 432 as a white solid (0.066 g, 64%). LCMS (Method I): RT=2.47 min, [M+H]+ 462.3. 1H NMR (400 MHz, DMSO-d): δ 8.04-8.00 (m, 1 H); 7.66-7.61 (m, 1 H); 7.28-7.21 (m, 2 H); 4.18-4.22 (m, 4 H); 3.85 (s, 3 H); 3.82 (s, 2 H); 3.78 (t, J=4.6 Hz, 4 H); 3.58-3.53 (m, 4 H); 3.27 (q, J=7.4 Hz, 2 H); 2.55-2.45 (m, 4 H); 1.34 (t, J=7.4 Hz, 3 H); 0.92-0.87 (m, 2 H); 0.82-0.75 (m, 2 H)
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].IC.[Cl:9][C:10]1[CH:38]=[CH:37][C:13]([C:14]([CH:16]2[CH2:21][CH2:20][N:19]([S:22]([NH:25][C@H:26]([CH:34]([CH3:36])[CH3:35])[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])(=[O:24])=[O:23])[CH2:18][CH2:17]2)=[O:15])=[CH:12][CH:11]=1>CN(C=O)C.C(OCC)(=O)C>[CH3:1][N:25]([S:22]([N:19]1[CH2:20][CH2:21][CH:16]([C:14](=[O:15])[C:13]2[CH:12]=[CH:11][C:10]([Cl:9])=[CH:38][CH:37]=2)[CH2:17][CH2:18]1)(=[O:23])=[O:24])[C@H:26]([CH:34]([CH3:35])[CH3:36])[C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28]
Reactant: O=C([O-])[O-]
Reactant: CC(C)[C@@H](NS(=O)(=O)N1CCC(C(=O)c2ccc(Cl)cc2)CC1)C(=O)OC(C)(C)C
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CI
Product: CC(C)[C@H](C(=O)OC(C)(C)C)N(C)S(=O)(=O)N1CCC(C(=O)c2ccc(Cl)cc2)CC1
Reaction time: 3 h
Yield: 63 %

Procedure:
Anhydrous potassium carbonate (152 mg, 1.1 mmol) and iodomethane (0.034 ml, 0.5 mmol) were added to a solution of tert-butyl 2-(R)-{[4-(4-chlorobenzoyl)piperidine-1-sulfonyl]amino}-3-methylbutyrate (100 mg, 0.22 mmol) in DMF (1.5 ml) at RT. After 3 h, the reaction mixture was diluted with ethyl acetate (30 ml) and then washed with 0.1M HCl and brine, and dried over MgSO4. The solvent was removed in vacuo and the residue was chromatographed (PTLC, SiO2, 25% ethyl acetate/hexane) to give tert-butyl 2-(R)-{methyl-[4-(4-chlorobenzoyl)piperidine-1-sulfonyl]amino}-3-methylbutyrate as a colorless oil (63%).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:7](=[O:20])[NH:6][C:5]=2[S:4][CH:3]=1.Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]2[N:39]=[C:38](C(Cl)(Cl)Cl)[O:37][N:36]=2)=[CH:25][CH:24]=1.C(=O)([O-])[O-:45].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[CH3:1][C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:7](=[O:20])[N:6]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[C:35]4[NH:39][C:38](=[O:45])[O:37][N:36]=4)=[CH:25][CH:24]=3)[C:5]=2[S:4][CH:3]=1
Reactant: ClC(Cl)(Cl)c1nc(-c2ccccc2-c2ccc(CBr)cc2)no1
Reactant: Cc1csc2[nH]c(=O)n(CCc3ccccc3)c(=O)c12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1csc2c1c(=O)n(CCc1ccccc1)c(=O)n2Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.2 %

Procedure:
A mixture of 5-methyl-3-(2-phenylethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (1.5 g), 3-[4′-(bromomethyl)biphenyl-2-yl]-5-(trichloromethyl)-1,2,4-oxadiazole (2.49 g), potassium carbonate (0.8 g) and N,N-dimethylformamide (30 mL) was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed successively with 5% aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography and dissolved in tetrahydrofuran (15 mL) and methanol (15 mL). 1N Aqueous sodium hydroxide solution (15 mL) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was adjusted to pH 4 with water and 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as colorless crystals (1.27 g, 46%).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:23]=[C:22]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:21]=[CH:20][C:16]=2[C:17]([OH:19])=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:28][O:29][C:30]1[CH:45]=[CH:44][C:33]([C:34]([NH:36][C:37]2[CH:38]=[N:39][CH:40]=[CH:41][C:42]=2[NH2:43])=[O:35])=[CH:32][CH:31]=1>>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:23]=[C:22]([C:24]([CH3:26])([CH3:25])[CH3:27])[CH:21]=[CH:20][C:16]=2[C:17]([NH:43][C:42]2[CH:41]=[CH:40][N:39]=[CH:38][C:37]=2[NH:36][C:34](=[O:35])[C:33]2[CH:32]=[CH:31][C:30]([O:29][CH3:28])=[CH:45][CH:44]=2)=[O:19])[CH2:10][CH2:9]1)=[O:2])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(C(C)(C)C)ccc2C(=O)O)CC1
Reactant: COc1ccc(C(=O)Nc2cnccc2N)cc1
Product: COc1ccc(C(=O)Nc2cnccc2NC(=O)c2ccc(C(C)(C)C)cc2OC2CCN(C(=O)OC(C)(C)C)CC2)cc1

Procedure:
Using methods substantially equivalent to those described in Example 101-D, 2-(N-Boc-piperidine-4-yloxy)-4-(tert-butyl)benzoic acid (1.0 g, 2.65 mmol) is converted into the acid chloride and used to acylate N3-(4-methoxybenzoyl)-3,4-pyridinediamine (600 mg, 2.47 mmol). After purification by chromatography (SiO2: 30% to 50% EtOAc in chloroform) 589 mg (40%) of the title compound is obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][O:8][C:9]([NH:11][CH2:12][C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)=[O:10])[CH:2]=1.[Cl-].[NH4+].F[P-](F)(F)(F)(F)F.[N:31]1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][O:8][C:9](=[O:10])[NH:11][CH2:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([NH2:31])=[O:18])=[CH:15][CH:14]=2)[CH:2]=1
Reactant: O=C(NCc1ccc(C(=O)O)cc1)OCc1cccnc1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1ccc(CNC(=O)OCc2cccnc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 4-({[(pyridin-3-ylmethoxy)carbonyl]amino}methyl)benzoic acid (1.0 g, 3.49 mmol), ammonium chloride (0.47 g, 8.73 mmol) and BOP (2.32 g, 5.24 mmol) in DMF (10 mL) was treated with DIEA (1.13 g. 8.73 mmol) and the resulting solution was stirred at ambient temperature for 16 hours. The reaction mixture was diluted with water (150 mL) and the resulting solids were filtered, washed with additional water and dried in vacuo to give pyridin-3-ylmethyl{[4-(aminocarbonyl)phenyl]methyl}carbamate as a white solid. MS: cal'd 286 (MH+), exp 286 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4]C=1C.OS(O)(=O)=O.[OH-].[Na+].[C:19]([O:22][CH2:23][CH3:24])(=[O:21])[CH3:20]>>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:20]=1[C:19]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(C)=O
Reactant: Cc1ccc([N+](=O)[O-])cc1F
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)c1ccc([N+](=O)[O-])cc1F
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a mixture of 2-fluoro-4-nitrotoluene (1.0 g, 6.4 mmol, Aldrich) and Na2Cr2O7 (2.74 g, 8.4 mmol) in 13.7 ml of HOAC was added slowly 6.83 ml of H2SO4. This mixture was slowly heated to 90° C. for 1 h to give a greenish heterogeneous solution. The mixture was cooled to room temperature and diluted with ethyl acetate. The PH of the solution was adjusted to 4 with NaOH (aq.). The mixture was extracted with more ethyl acetate. The organic layer was washed with NaHCO3 (sat.), then brine and dried over Na2SO4. After filtration, the solution was concentrated to dryness which then was dissolved in 6 ml of SOCl2, and heated at 80° C. for 1 h. The excess of SOCl2 was removed under reduced pressure and the residue was dissolved in 5 ml of CH2Cl2, 2 ml of EtOH and 2 ml of pyridine. The mixture was stirred at room temperature for 2 h and concentrated to dryness. Ethyl 2-fluoro-4-nitrobenzoate was obtained as a white solid after column chromatography of the residue with ethyl acetate/hexane (1/9). This solid was then dissolved in 10 ml of ethyl acetate, and Pd/C (50 mg) was added. Hydrogenation with a hydrogen balloon converted ethyl 2-fluoro-4-nitrobenzoate into the title compound.
Reaction SMILES: [NH2:1][C@@H:2]([CH:5]([CH3:7])[CH3:6])[CH2:3][OH:4].[C:8](=O)(OCC)[O:9]CC.C([O-])([O-])=O.[K+].[K+]>>[CH3:6][CH:5]([C@H:2]1[CH2:3][O:4][C:8](=[O:9])[NH:1]1)[CH3:7]
Reactant: CC(C)[C@H](N)CO
Reactant: CCOC(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)[C@H]1COC(=O)N1

Procedure:
The title compound was prepared according to Evans, Mathre and Scott (J. Org. Chem., 50, 1830 (1985)) from (S)-(+)-2-amino-3-methyl-1-butanol and diethyl carbonate in the presence of K2CO3.
Reaction SMILES: C([NH:9][C:10]1[S:11][CH2:12][C@@H:13]2[CH2:18][N:17]([C:19]3[N:24]=[CH:23][C:22]([F:25])=[CH:21][N:20]=3)[CH2:16][C@:14]2([C:26]2[CH:27]=[C:28]([NH:32][C:33]([C:35]3[C:40]([F:41])=[CH:39][C:38]([F:42])=[CH:37][N:36]=3)=[O:34])[CH:29]=[CH:30][CH:31]=2)[N:15]=1)(=O)C1C=CC=CC=1.[ClH:43].CON.N1C=CC=CC=1>C1COCC1.C(O)C>[ClH:43].[NH2:9][C:10]1[S:11][CH2:12][C@@H:13]2[CH2:18][N:17]([C:19]3[N:20]=[CH:21][C:22]([F:25])=[CH:23][N:24]=3)[CH2:16][C@:14]2([C:26]2[CH:27]=[C:28]([NH:32][C:33]([C:35]3[C:40]([F:41])=[CH:39][C:38]([F:42])=[CH:37][N:36]=3)=[O:34])[CH:29]=[CH:30][CH:31]=2)[N:15]=1
Reactant: O=C(NC1=N[C@@]2(c3cccc(NC(=O)c4ncc(F)cc4F)c3)CN(c3ncc(F)cn3)C[C@H]2CS1)c1ccccc1
Agent: CON
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: CCO
Product: NC1=N[C@@]2(c3cccc(NC(=O)c4ncc(F)cc4F)c3)CN(c3ncc(F)cn3)C[C@H]2CS1
Temperature: 25 °C
Reaction time: 70 h

Procedure:
N-[3-[(4aR,7aS)-2-Benzamido-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-7a-yl]phenyl]-3,5-difluoro-pyridine-2-carboxamide (330 mg, 0.53 mmol) is dissolved in THF (10 mL) and diluted with ethanol (10 mL). O-Methylhydroxylamine hydrochloride (453 mg, 5.32 mmol) and pyridine (430 μL, 5.91 mmol) are added and the reaction is stirred at room temperature over the weekend (70 hrs). The reaction is warmed to 60° C. and stirred for 24 hrs. The mixture is concentrated onto silica gel (˜10 g) and purified via silica gel chromatography using a 0-10% gradient of 7 N ammonia methanol in dichloromethane to give the free base of the title compound. This material is dissolved in dichloromethane (5 mL) and 1 M hydrogen chloride in diethyl ether (0.49 mL, 490 μmol) is added. The solvent is removed in vacuo to give the title compound (159 mg, 54%). ES/MS (m/e): 486(M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[Cl:19][C:20]1[C:21]([C:26](O)=[O:27])=[N:22][CH:23]=[CH:24][CH:25]=1>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:26]([C:21]3[C:20]([Cl:19])=[CH:25][CH:24]=[CH:23][N:22]=3)=[O:27])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: O=C(O)c1ncccc1Cl
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Product: C[C@]1(c2cc(NC(=O)c3ncccc3Cl)ccc2F)N=C(N)OCC1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and 3-chloro-pyridine-2-carboxylic acid following procedure I yielded the title compound as a colorless solid. MS (ISP): m/z=399.1 [M+H]+.