Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[CH:18]([N:19]([CH3:27])[C:20](=[O:26])[C:21]([N:23]([CH3:25])[CH3:24])=[O:22])[CH2:17][NH:16][CH2:15][CH2:14][N:13]3[C:28](=[O:31])[C:29]=2[OH:30])=[O:9])=[CH:4][C:3]=1[CH3:34].C(N(CC)CC)C.C(O[C:45]1(O[Si](C)(C)C)[CH2:47][CH2:46]1)C.[BH3-]C#N.[Na+]>CO.C(O)(=O)C>[CH:45]1([N:16]2[CH2:17][CH:18]([N:19]([CH3:27])[C:20](=[O:26])[C:21]([N:23]([CH3:24])[CH3:25])=[O:22])[C:12]3=[N:11][C:10]([C:8]([NH:7][CH2:6][C:5]4[CH:32]=[CH:33][C:2]([F:1])=[C:3]([CH3:34])[CH:4]=4)=[O:9])=[C:29]([OH:30])[C:28](=[O:31])[N:13]3[CH2:14][CH2:15]2)[CH2:47][CH2:46]1
Reactant: Cc1cc(CNC(=O)c2nc3n(c(=O)c2O)CCNCC3N(C)C(=O)C(=O)N(C)C)ccc1F
Reactant: CCOC1(O[Si](C)(C)C)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: CO
Product: Cc1cc(CNC(=O)c2nc3n(c(=O)c2O)CCN(C2CC2)CC3N(C)C(=O)C(=O)N(C)C)ccc1F
Temperature: 25 °C

Procedure:
N-(2-{[(4-fluoro-3-methylbenzyl)amino]carbonyl}-3-hydroxy-4-oxo-4,6,7,8,9,10-hexahydropyrimido[1,2-d][1,4]diazepin-10-yl)-N,N′,N′-trimethylethanediamide (prepared as described in Example 11, Step 1-7) was dissolved in methanol and treated with triethylamine (2 eq.), [(1-ethoxycyclopropyl)oxy](trimethyl)silane and acetic acid pH=5.5. To the mixture was then added NaCNBH3 (4 eq.) and reaction was refluxed overnight. After cooling to room temperature, mixture was concentrated under reduced pressure and purified by prep RP HPLC (C18, 5 μM, H2O/MeCN with 1% of TFA as eluant) affording desired compound as a white solid. 1H NMR (300 MHz, CD3CN) δ 12.67 (bs, 1H), 10.01 (bs, 1H), 7.49 (d, J=7.52 Hz, 1H), 7.45-7.40 (m, 1H), 7.21 (t, J=8.62 Hz, 1H), 5.51-5.41 (m, 2H), 4.76 (dd, J=14.6 Hz, J=6.86 Hz, 1H), 4.66 (dd, J=14.6 Hz, J=6.41 Hz, 1H), 4.27-4.00 (m, 4H), 3.51-3.36 (m, 2H), 3.27 (s, 3H), 3.19 (s, 3H), 3.17 (s, 3H), 2.46 (s, 3H), 1.37-1.31 (m, 2H), 1.19-1.10 (m, 2H); MS (ES) C25H31FN6O5 requires 514. Found: 515 (M+H+).
Reaction SMILES: C([Li])CCC.[CH2:6]([C:12]1[C:17]([CH2:18][CH2:19][CH3:20])=[C:16]([CH2:21][CH2:22][CH3:23])[C:15]([CH2:24][CH2:25][CH3:26])=[C:14]([CH2:27][CH2:28][CH3:29])[C:13]=1[CH2:30][C:31]#[C:32][CH2:33][CH2:34][CH3:35])[C:7]#[C:8][CH2:9][CH2:10][CH3:11].I[C:37]1[CH:42]=[CH:41][C:40](I)=[C:39]([I:44])[C:38]=1[I:45].CN1C(=O)N(C)CCC1.Cl>Cl[Cu].C1COCC1>[I:44][C:39]1[C:38]([I:45])=[CH:37][C:42]2[C:41](=[C:8]([CH2:9][CH2:10][CH3:11])[C:7]3[CH2:6][C:12]4[C:13]([CH2:30][C:31]=3[C:32]=2[CH2:33][CH2:34][CH3:35])=[C:14]([CH2:27][CH2:28][CH3:29])[C:15]([CH2:24][CH2:25][CH3:26])=[C:16]([CH2:21][CH2:22][CH3:23])[C:17]=4[CH2:18][CH2:19][CH3:20])[CH:40]=1
Reactant: Ic1ccc(I)c(I)c1I
Reactant: CCCC#CCc1c(CC#CCCC)c(CCC)c(CCC)c(CCC)c1CCC
Agent: Cl[Cu]
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: CCCc1c(CCC)c(CCC)c2c(c1CCC)Cc1c(c(CCC)c3cc(I)c(I)cc3c1CCC)C2
Yield: 32.5 %

Procedure:
n-Butyl lithium (3.0 ml, 4.8 mmols, 1.6mol/l) was added to a THF solution (20 ml) of Cp2ZrCl2 (0.702 g, 2.4 mmols) at −78° C. After the mixture was stirred for an hour, 1,2-bis(2-hexynyl)-3,4,5,6-tetrapropylbenzene (0.813 g, 2.0 mmols) was added to the mixture. A cooling bath was withdrawn, and the mixture was stirred for an hour. Tetraiodobenzene (1.16 g, 2.0 mmols), DMPU (0.73 ml, 6.0 mmols) and CuCl (0.416 g, 4.2 mmols) were added to the mixture. After stirring for an hour at 50° C., 3N HCl was added to terminate the reaction. The reaction mixture was extracted with chloroform. The extract was then washed with sodium hydrogencarbonate aqueous solution and brine. After the pressure was reduced, column chromatography was performed using silica gel as the packing material to give the title compound (0.477 g) as a pink solid. The isolation yield was 33%
Reaction SMILES: Cl[C:2]1[C:7]([I:8])=[CH:6][N:5]=[CH:4][N:3]=1.N1C=CC(=O)NC=1.CCN(CC)CC.[C:23]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]>CN1C(=O)CCC1>[C:26]([O:25][C:23]([N:30]1[CH2:35][CH2:34][N:33]([C:2]2[C:7]([I:8])=[CH:6][N:5]=[CH:4][N:3]=2)[CH2:32][CH2:31]1)=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: Clc1ncncc1I
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=c1ccnc[nH]1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CCN(c2ncncc2I)CC1
Yield: 98.6 %

Procedure:
A mixture of 4-chloro-5-iodopyrimidine (3.00 g, 12.5 mmol) (prepared from 4(3H)-pyrimidinone according to the literature: Takao Sakamoto, et al. (1986) Chem. Pharm. Bull., 2719-2724), Et3N (5.22 mL, 37.4 mmol), 1-Boc piperazine (2.79 g, 15.0 mmol) and NMP (30 mL) was heated at 75° C. for 6 hours. After cooling, the reaction mixture was partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by column chromatography (2:1 hexanes/EtOAc) to give 4-(5-Iodo-pyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (4.81 g, 99%) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 8.70 (s, 1H), 8.62 (s, 1H), 3.57 (s, 8H), 1.49 (s, 9H). LCMS (APCI+) m/z 391 [M+H]+; Rt=2.96 minutes.
Reaction SMILES: C(OC(=O)C)(=O)C.[N+:8]([O-:11])(O)=[O:9].[Cl:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=1[CH3:21]>O>[Cl:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[C:16]([N+:8]([O-:11])=[O:9])=[CH:15][C:14]=1[CH3:21]
Reactant: COc1ccc(C)c(Cl)c1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: COc1cc(Cl)c(C)cc1[N+](=O)[O-]
Temperature: -5 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
Acetic anhydride (10 mL) at −10° C. was treated with concentrated nitric acid (>69% pure, 1 mL) and then treated portionwise with 2-chloro-4-methoxy-1-methylbenzene (0.78 g, 5 mmol) at a rate that maintained the internal temperature lower than −5° C. The solution was stirred for additional one hour while warming to room temperature, poured into an ice and water mixture, and extracted with ethyl acetate several times. The organic layers were combined, washed with 10% Na2CO3 and brine, dried (MgSO4), and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel eluting with 9:1 hexanes/ethyl acetate to provide 0.75 g (71%) of the desired product. MS (DCI) m/e 219 (M+NH4)+; 1H NMR (CDCl3, 300 MHz) δ 7.78 (s, 1H), 7.09 (s, 1H), 3.94 (s, 3H), 2.35 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][CH:8]([OH:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([OH:18])=[O:17].[C:19]([N:27]=[C:28]=[S:29])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O1CC[CH2:32][CH2:31]1>>[C:19]([NH:27][C:28]([NH:1][C:2]1[N:6]([CH2:7][CH:8]([OH:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([O:18][CH2:31][CH3:32])=[O:17])=[S:29])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C1CCOC1
Reactant: Nc1c(C(=O)O)cnn1CC(O)c1ccccc1
Reactant: O=C(N=C=S)c1ccccc1
Product: CCOC(=O)c1cnn(CC(O)c2ccccc2)c1NC(=S)NC(=O)c1ccccc1
Yield: 93 %

Procedure:
A suspension of 5 (2.7 g, 10 mmol) and benzoyl isothiocyanate (1.7 g, 11 mmol) in anhydrous tetrahydrofuran (THF) (20 mL) was refluxed for 12 h. The solvent was evaporated under reduced pressure; the oil residue crystallized adding diethyl ether (30 mL) to afford the pure product 6 (4.07 g, 93%) as a white solid; mp 171-172° C. 1H NMR: δ 1.29 (t, J=7.0, 3H, CH3), 3.97-4.20 (m, 5H, 2CH2+OH, 1H disappears with D2O), 4.58-4.68 (m, 1H, CHO), 7.05-7.98 (m, 10H Ar), 8.02 (s, 1H, H-3), 8.70 (s, 1H, NH, disappears with D2O), 12.05 (s, 1H, NH, disappears with D2O). IR cm−1: 3221 (NH), 3190-2940 (OH), 1708 and 1671 (2 CO). Anal. (C22H22N4O4S) C, H, N, S.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1.[Cl-].[CH3:37][Zn+]>C1COCC1>[CH3:14][C:13]([C:11]1[S:12][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:37])[N:7]=2)=[C:9]([C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[N:10]=1)([CH3:16])[CH3:15]
Reactant: C[Zn+]
Reactant: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)c(-c2ccnc(Cl)n2)s1
Agent: [Cl-]
Solvent: C1CCOC1
Product: Cc1nccc(-c2sc(C(C)(C)C)nc2-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)n1
Temperature: 60 °C
Reaction time: 16 h
Yield: 46.8 %

Procedure:
To a suspension of N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide (200 mg, 0.371 mmol) and tetrakis(triphenylphoshine)palladium (8.6 mg, 7.4 μmol) in THF (5 mL) was added a 2 M solution of methylzinc chloride in THF (0.371 mL, 0.742 mmol). The suspension was stirred for 16 h at 60° C. The reaction mixture was partitioned between water and EtOAc, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated, and purified via column chromatography, eluting with 0-100% EtOAc/DCM. The desired fractions were combined and concentrated to generate 90 mg (0.174 mmol, 46.8% yield) of the title compound as a white powder. 1H NMR (400 MHz, DMSO-d6): δ 10.75 (s, 1H), 8.47 (d, J=5.3 Hz, 1H), 7.52-7.58 (m, 1H), 7.40-7.50 (m, 4H), 7.29 (t, J=7.8 Hz, 1H), 6.64 (d, J=5.3 Hz, 1H), 2.58 (s, 3H), 1.42 (s, 9H). MS (ESI): 520.0 [M+H]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH:11]([C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([CH:24]([CH3:26])[CH3:25])[C:21]=1[O:22][CH3:23])[CH:17]=O)([CH3:13])[CH3:12]>>[CH:24]([C:20]1[CH:19]=[C:16]([CH:15]=[C:14]([CH:11]([CH3:13])[CH3:12])[C:21]=1[O:22][CH3:23])[CH:17]=[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][C:2]1=[O:10])([CH3:25])[CH3:26]
Reactant: O=C1Cc2ccccc2N1
Reactant: COc1c(C(C)C)cc(C=O)cc1C(C)C
Product: COc1c(C(C)C)cc(C=C2C(=O)Nc3ccccc32)cc1C(C)C

Procedure:
2-Oxindole was condensed with 3,5-diisopropyl-4-methoxybenzaldehyde using method B to give 3-(3,5-diisopropyl-4-methoxy-benzylidene)-1,3-dihydro-indol-2-one as a yellow-orange solid which was reduced using method E to give 2 g (100%) of 3-(3,5-diisopropyl-4-methoxybenzyl)-1,3-dihydroindol-2-one as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:11][CH2:10][O:9][C:8]2=[O:12])=[N:3]1.[N+:13]([O-])([OH:15])=[O:14].[OH-].[Na+]>S(=O)(=O)(O)O>[CH3:1][N:2]1[CH:6]=[C:5]([N+:13]([O-:15])=[O:14])[C:4]([N:7]2[CH2:11][CH2:10][O:9][C:8]2=[O:12])=[N:3]1
Reactant: Cn1ccc(N2CCOC2=O)n1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cn1cc([N+](=O)[O-])c(N2CCOC2=O)n1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 3-(1-methyl-1H-pyrazol-3-yl)-1,3-oxazolidin-2-one (85 mg) in conc. sulfuric acid (2.5 mL) was added fuming nitric acid (32 μL) under ice-cooling, and the mixture was stirred at 0° C. for 2 hr. The reaction mixture was neutralized with 8M aqueous sodium hydroxide solution under ice-cooling, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (58 mg).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6]N=O.CCCCCCC.[CH2:16]=[C:17]=[O:18].[C]=O>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.CN1CCCC1=O>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:17]([CH3:16])=[O:18]
Reactant: CCCCCON=O
Reactant: C=C=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [C]=O
Agent: [Cl-]
Solvent: CCCCCCC
Solvent: CN1CCCC1=O
Product: CCCCCOC(C)=O
Reaction time: 5 h
Yield: 18.8 %

Procedure:
To the same reaction vessel as in Example 9 were charged bistriphenylphosphinedibromopalladium (0.198 g, 0.25 mmole), stannous chloride (0.095 g, 0.5 mmole), tetra-n-butylammonium chloride (0.139 g, 0.5 mmole) and n-amyl nitrite (70 ml, 474.4 mmoles), together with n-heptane (150 ml) and N-methylpyrrolidone (50 ml). Then, ketene, carbon monooxide and nitrogen were introduced to the mixture at the rate of 10.1 ml/min (0.45 mmole/min), 300 ml/min and 100 ml/min, respectively, and the reaction was effected at 90° C. for 5 hours. The reaction product was analyzed by gas chromatography, revealing that di-n-amyl malonate (82.3 mmoles, 60.7%) and n-amyl acetate (25.5 mmoles, 18.8%) were obtained.
Reaction SMILES: [CH2:1]([PH2:4])[CH2:2][CH3:3].[CH:5]([CH:7]=[O:8])=[O:6]>O1CCCC1>[CH2:1]([P:4]1[CH:5]([OH:6])[CH:7]([OH:8])[P:4]([CH2:1][CH2:2][CH3:3])[CH:5]([OH:6])[CH:7]1[OH:8])[CH2:2][CH3:3]
Reactant: O=CC=O
Reactant: CCCP
Solvent: C1CCOC1
Product: CCCP1C(O)C(O)P(CCC)C(O)C1O

Procedure:
Following the procedure of Example 1, mono-n-propylphosphine, in tetrahydrofuran, as solvent, is reacted with a 40% aqueous glyoxal solution, to give 1,4-di-n-propyl-2,3,5,6-tetrahydroxy-1,4-diphosphorinane, a solid melting at 131-133° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([OH:12])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.C[O:14][C:15]([C@@H:17]1O[CH2:18]1)=[O:16].[H-].[Na+].Cl.[Si](C=[N+]=[N-])(C)(C)[CH3:24]>CS(C)=O.O>[CH:3]1[C:4]2[C:9]3[N:1]([CH:17]([C:15]([OH:14])=[O:16])[CH:18]=[CH:24][C:8]=3[C:7]([C:10]([OH:12])=[O:11])=[CH:6][CH:5]=2)[CH:2]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Reactant: COC(=O)[C@H]1CO1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)c1ccc2ccn3c2c1C=CC3C(=O)O
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To 1H-indole-6-carboxylic acid, 7-chloro-3-cyclohexyl-2-phenyl-, methyl ester (62 mg, 0.169 mmol) under N2 at r.t. in a microwave reaction tube was added a solution of methyl (2R)-glycidate (69 mg, 0.676 mmol) in DMSO (1 ml) and NaH (27 mg, 0.675 mmol, 60% in oil), and the reaction mixture stirred at r.t. for 1 hr 25 min. The reaction mixture was then placed under microwave irradiation in an Emrys Optimizer (Personal Chemistry) at 200° C. and with the absorption level set to high for 30 min. The mixture was acidified with hydrochloric acid (1N), diluted with water. The brown precipitates were filtered, washed with water twice and then dried. The material was then dissolved in a mixture of benzene/MeOH (1 ml/1 ml), and added with TMSCHN2 (0.34 ml, 0.68 mmol, 2M in hexane). The reaction was then stirred at r.t. for 2 hr 20 min., quenched with AcOH and the volatiles were evaporated. The residue was purified by Biotage flash chromatography (gradient elution, 0 to 50% EtOAc/Hexane) to gave the dimethyl ester (1,4-oxazino[2,3,4-hi]indole-2,9-dicarboxylic acid, 6-cyclohexyl-2,3-dihydro-5-phenyl-, dimethyl ester). The stereochemical integrity at the α-hydroxyl carbon (C2) was not determined. 1H NMR (500 MHz): (CD3OD) δ 7.59-7.56 (overlapping m, 3H), 7.53-7.51 (m, 1H), 7.43 (d, J=8.5, 2H), 7.37 (d, J=8.5, 1H), 5.41 (t, J=3.8, 1H), 4.47 (dd, J=3.8, 12.8, 1H), 4.18 (dd, J=3.8, 12.8, 1H), 3.92 (s, 3H), 3.74 (s, 3H), 2.74 (m, 1H), 1.98-1.75 (b overlapping m, 7H), 1.40-1.31 (b m, 3H); Analytical HPLC method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90% MeOH-10% H2O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Flow Rate=5 ml/min, Column: Xterra MS C18 S7 3.0×50 mm; LC/MS: (ES+) m/z (M+H)+=434.15, HPLC Rt=2.000 min.
Reaction SMILES: [CH2:1]([SH:4])[CH2:2][CH3:3].[C:5]12([NH:15][C:16](=[O:25])[C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[N:19][C:18]=3Cl)[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]3)[CH2:6]1)[CH2:12]2.C(=O)([O-])[O-].[K+].[K+]>C(#N)CCC.CCOC(C)=O>[C:5]12([NH:15][C:16](=[O:25])[C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[N:19][C:18]=3[S:4][CH2:1][CH2:2][CH3:3])[CH2:6][CH:7]3[CH2:8][CH:9]([CH2:10][CH:11]([CH2:13]3)[CH2:12]1)[CH2:14]2
Reactant: CCCS
Reactant: O=C(NC12CC3CC(CC(C3)C1)C2)c1ccc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCC#N
Solvent: CCOC(C)=O
Product: CCCSc1nc(Cl)ccc1C(=O)NC12CC3CC(CC(C3)C1)C2
Temperature: 150 °C
Yield: 121.1 %

Procedure:
1-Propanethiol (0.499 mL, 5.50 mmol) was added dropwise to N-adamantan-1-yl-2,6-dichloronicotinamide (1.63 g, 5 mmol) and potassium carbonate (2.07 g, 15.00 mmol) in butyronitrile (15 mL) at 20° C. over a period of 2 minutes under nitrogen. The resulting suspension was heated at 150° C. for 2 hours. The reaction mixture was diluted with EtOAc (60 mL), and washed sequentially with water (20 mL) and saturated brine (20 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford N-adamantan-1-yl-6-chloro-2-(propylthio)nicotinamide (2.21 g, 100%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:30][CH3:31])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[O:27][CH2:28][CH3:29])=[N:13][C:14]=1[CH2:15][CH3:16].[CH2:32](Br)C#C>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:30][CH3:31])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[O:27][CH2:28][C:29]#[CH:32])=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: C#CCBr
Reactant: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Product: C#CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but substituting propargylbromide and making non-critical variations provided the title compound as a white solid. IR (diffuse reflectance) 3451, 3293, 2964, 2932, 1563, 1493, 1469, 1390, 1204, 1184, 1087, 1076, 820, 742, 646 cm−1; OAMS supporting ions at: ESI+ 465.8; MS (EI) m/z 465 (M+); HRMS (FAB) calcd for C26H25CL2N3O+H1 466.1453, found 466.1455. [α]25D=−56 (c 0.83, methylene chloride). Anal. Calcd for C26H25Cl2N3O: C, 66.96; H, 5.40; N, 9.01. Found: C, 66.96; H, 5.49; N, 8.93.
Reaction SMILES: [O-]CC.[Na+].[Na].Cl[C:7]1[C:15]2[O:14][N:13]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[C:11]=2[CH:10]=[CH:9][C:8]=1[O:23][CH2:24][C:25]#[N:26].[ClH:27].[NH2:28][OH:29]>C(O)C.O>[OH:29][NH:28][C:25](=[NH:26])[CH2:24][O:23][C:8]1[CH:9]=[CH:10][C:11]2[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])=[N:13][O:14][C:15]=2[C:7]=1[Cl:27]
Reactant: N#CCOc1ccc2c(-c3ccccc3F)noc2c1Cl
Reactant: NO
Reactant: Cl
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CCO
Product: N=C(COc1ccc2c(-c3ccccc3F)noc2c1Cl)NO

Procedure:
A solution of sodium ethoxide, prepared from 0.50 g of sodium and 15 ml of absolute ethanol is added to a stirred suspension of 6.0 g of {[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetonitrile and 1.4 g of hydroxylamine hydrochloride in 60 ml of absolute ethanol. The reaction mixture is refluxed for 30 min, poured into water and the precipitate is collected and dried. The precipitate is dissolved in warm methanol and treated with ethereal hydrogen chloride to give N-hydroxy-{[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetimidamide, mp 218° C. (dec.).
Reaction SMILES: O.[OH-].[Li+].[Cl:4][C:5]1[CH:10]=[CH:9][C:8](/[C:11](=[N:22]\[O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]3[N:34]=[C:35]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[O:36][C:37]=3[CH3:38])=[CH:27][CH:26]=2)/[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]C)=[O:19])=[CH:7][CH:6]=1.O.Cl>O1CCCC1.CO>[Cl:4][C:5]1[CH:6]=[CH:7][C:8](/[C:11](=[N:22]\[O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]3[N:34]=[C:35]([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)[O:36][C:37]=3[CH3:38])=[CH:27][CH:26]=2)/[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:9][CH:10]=1
Reactant: COC(=O)CCCCCC/C(=N/OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)c1ccc(Cl)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C(/CCCCCCC(=O)O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.6 %

Procedure:
Lithium hydroxide monohydrate (43.7 mg) was added to a solution of methyl Z-8-(4-chlorophenyl)-8-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]octanoate (200 mg) in tetrahydrofuran (10 ml)-water (4 ml)-methanol (4 ml) and stirred at room temperature for 3 hours. 1N hydrochloric acid (1.1 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain Z-8-(4-chlorophenyl)-8-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]octanoic acid (169 mg, yield 87%) as colorless crystals. m.p. 54-57° C.
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20](F)[C:21]=3[Cl:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([F:30])=[CH:9][C:8]=1[F:31].Cl.[OH:33][CH:34]1[CH2:37][NH:36][CH2:35]1.CN1CCCC1>C(O)C>[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20]([N:36]4[CH2:37][CH:34]([OH:33])[CH2:35]4)[C:21]=3[Cl:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([F:30])=[CH:9][C:8]=1[F:31]
Reactant: OC1CNC1
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Agent: CN1CCCC1
Agent: Cl
Solvent: CCO
Solvent: CN(C)C=O
Product: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(N4CC(O)C4)c(Cl)c32)c(F)cc1F
Temperature: 85 °C
Reaction time: 0.17 h
Yield: 92.4 %

Procedure:
To 3.5 g of N,N-dimethylformamide were added 2.00 g of 1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 1.00 g of 3-hydroxyazetidine hydrochloride, and 2.00 g of N-methylpyrrolidine together with 0.2 ml of ethanol, and the mixture was stirred at 85° C. for 10 minutes. The solvent and the like were distilled off under reduced pressure. After adding 10 ml of ethanol to the residue, the mixture was heated under reflux for 10 minutes and allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 2.10 g of the title compound as a pale yellow powder.