Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][CH2:9][C:10]([N:12]1[CH2:17][CH2:16][CH:15]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:28][C@H:27]([CH2:29][NH:30][C:31](=[O:33])[CH3:32])[O:26][C:25]3=[O:34])=[CH:20][CH:19]=2)[CH2:14][CH2:13]1)=[O:11])C1C=CC=CC=1>CO.[Pd]>[OH:8][CH2:9][C:10]([N:12]1[CH2:13][CH2:14][CH:15]([C:18]2[CH:19]=[CH:20][C:21]([N:24]3[CH2:28][C@H:27]([CH2:29][NH:30][C:31](=[O:33])[CH3:32])[O:26][C:25]3=[O:34])=[CH:22][CH:23]=2)[CH2:16][CH2:17]1)=[O:11]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3CCN(C(=O)COCc4ccccc4)CC3)cc2)C(=O)O1
Agent: [Pd]
Solvent: CO
Product: CC(=O)NC[C@H]1CN(c2ccc(C3CCN(C(=O)CO)CC3)cc2)C(=O)O1
Reaction time: 20 h

Procedure:
A mixture of (S)-(-)-N-[[3-[4-[1-[(benzyloxy)acetyl]-4-piperidinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (EXAMPLE 18, 207 mg) and 10% palladium-on-carbon (100 mg) in methanol (9mL) is shaken on a Parr apparatus under a hydrogen atmosphere at 40 psi for 20 hours, the catalyst is removed by filtration through Celite and the filtrate is concentrated under reduced pressure to give the crude product which is chromatographed on silica gel (230-400 mesh, 20 g), eluting with a gradient of methanol/methylene chloride (5/95-10/90). Pooling and concentration of those fractions with an Rf=0.26 by TLC (methanol/chloroform, 10/90) and recrystallization from methylene chloride/diethyl ether gives the title compound, mp 155-157° C.
Reaction SMILES: [C:1]([C:5]1[C:6]([OH:21])=[CH:7][C:8]([CH:12]([CH:14]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)O)=[C:9]([OH:11])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C(Cl)(Cl)Cl>[C:1]([C:5]1[C:6]([OH:21])=[CH:7][C:8]2[CH2:12][C:14]3([O:11][C:9]=2[CH:10]=1)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(O)c(C(O)C2CCCCCC2)cc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1cc2c(cc1O)CC1(CCCCCC1)O2
Temperature: 25 °C
Yield: 43.6 %

Procedure:
To 0.66 g of 5-t-butyl-2-(cycloheptylhydroxymethyl)benzene-1,4-diol dissolved in 20 ml of chloroform was added 0.44 g of p-toluenesulfonic acid monohydrate and the mixture was stirred at room temperature for a whole day and night. After the reaction mixture was poured into water and extracted with chloroform, the organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated. The concentrate was purified by silica gel column chromatography (in n-hexane containing 10% ethyl acetate) to give 0.27 g of 6-t-butyl-5-hydroxy-2,3-dihydrobenzofuran-2-spiro-1′-cycloheptane as a white solid (yield 43%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[Mg]Br.C([O:14][CH:15]1[CH2:23][C:22]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]2[CH:17]([CH2:18][N:19]([CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH2:20]2)[C:16]1=[O:43])(=O)C.[Cl-].[NH4+].C(OCC)C>O1CCCC1>[CH2:36]([N:19]1[CH2:18][CH:17]2[CH:21]([C:22]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:23][CH:15]([OH:14])[C:16]2([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[OH:43])[CH2:20]1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: CC(=O)OC1CC(c2ccccc2)(c2ccccc2)C2CN(Cc3ccccc3)CC2C1=O
Reactant: COc1ccccc1[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccccc1C1(O)C(O)CC(c2ccccc2)(c2ccccc2)C2CN(Cc3ccccc3)CC21
Temperature: 0 °C
Yield: 64.8 %

Procedure:
To a suspension of 84.4 g of 2-methoxyphenylmagnesium bromide in 1000 cm3 of tetrahydrofuran is added dropwise, at room temperature and with stirring, a solution of 22 g of (3aRS,5RS,7aRS)-5-acetoxy-2-benzyl-7,7-diphenylperhydro-4-isoindolone in 220 cm3 of tetrahydrofuran. The reaction mixture is stirred at room temperature for 18 hours, treated with 200 cm3 of saturated aqueous ammonium chloride solution, and taken up with 200 cm3 of diethyl ether and 200 g of ice. The organic phase is separated off after settling, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized in 250 cm3 of petroleum ether and then recrystallized in 200 cm3 of methanol; the crystals are washed with 200 cm3 of isopropyl ether. 16.4 g of (3aRS,4RS,5RS,7aRS)-2-benzyl-7,7-diphenyl-4-(2-methoxyphenyl)perhydro-4,5-isoindolediol are obtained, melting at 236° C.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[S:3]([NH:6][C:7]1[CH:8]=[C:9]([CH:20]=[CH:21][CH:22]=1)[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)=O)(=[O:5])=[O:4].Cl.[NH2:25][OH:26]>C(O)C>[CH3:1][N:2]([CH3:23])[S:3]([NH:6][C:7]1[CH:8]=[C:9]([CH:20]=[CH:21][CH:22]=1)/[C:10](=[N:25]/[OH:26])/[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)(=[O:5])=[O:4]
Reactant: NO
Reactant: COc1ccc(C(=O)c2cccc(NS(=O)(=O)N(C)C)c2)cc1
Agent: Cl
Solvent: CCO
Product: COc1ccc(/C(=N\O)c2cccc(NS(=O)(=O)N(C)C)c2)cc1
Yield: 17.3 %

Procedure:
To a solution of 3-[N-(dimethylaminosulfonyl)-amino]-4'-methoxybenzophenone (9 g) in ethanol (180 ml) is added hydroxylamine hydrochloride (11.23 g), and the resultant mixture is refluxed for 7 hours. The reaction mixture is concentrated in vacuum, and the residue is basified with aqueous sodium hydrogencarbonate and shaken with methylene chloride. The methylene chloride layer is washed with water, dried over anhydrous sodium sulfate and concentrated in vacuum. The residue is chromatographed on a column of silica gel, which is eluted with 20% methanolmethylene chloride. The eluate is concentrated in vacuum to give a crystalline product, which is washed with hot isopropyl ether to give a mixture of (Z)- and (E)-isomers (8.5 g). The mixture is crystallized from ethyl acetateisopropyl ether to give (E)-3-[N-(dimethylaminosulfonyl)-amino]-4'-methoxybenzophenone oxime (1.63 g) as crystals melting at 162° to 164° C.
Reaction SMILES: [CH:1]([C:4]1[NH:5][CH:6]=[CH:7][N:8]=1)([CH3:3])[CH3:2].F[C:10]1[CH:20]=[CH:19][C:13]([C:14](OCC)=[O:15])=[CH:12][CH:11]=1>>[CH:1]([C:4]1[N:5]([C:10]2[CH:20]=[CH:19][C:13]([CH2:14][OH:15])=[CH:12][CH:11]=2)[CH:6]=[CH:7][N:8]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ncc[nH]1
Reactant: CCOC(=O)c1ccc(F)cc1
Product: CC(C)c1nccn1-c1ccc(CO)cc1

Procedure:
Prepared from 2-isopropylimidazol and ethyl 4-fluorobenzoate.
Reaction SMILES: F[C:2]1[C:7]([CH:8]2[CH2:13][CH2:12][CH2:11][O:10][CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[S:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[C:15]1[NH:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1.O>[O:10]1[CH2:11][CH2:12][CH2:13][CH:8]([C:7]2[C:2]([O:30][C:27]3[CH:26]=[CH:25][C:24]([NH:23][C:15]4[S:14][C:18]5[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=5[N:16]=4)=[CH:29][CH:28]=3)=[N:3][CH:4]=[CH:5][CH:6]=2)[CH2:9]1
Reactant: Oc1ccc(Nc2nc3ccccc3s2)cc1
Reactant: Fc1ncccc1C1CCCOC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: O
Product: c1cnc(Oc2ccc(Nc3nc4ccccc4s3)cc2)c(C2CCCOC2)c1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
2-Fluoro-3-(tetrahydro-2H-pyran-3-yl)pyridine (0.10 g, 0.55 mmol), 4-(benzo[d]thiazol-2-ylamino)phenol (0.33 g, 1.38 mmol), and cesium carbonate (0.54 g, 1.66 mmol) were mixed in NMP (2 mL). The reaction mixture was placed under a nitrogen atmosphere and stirred at 120° C. for 16 h. The reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc (2×). The combined organic layers were washed with 1 M aqueous sodium hydroxide, sat. sodium chloride, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting crude product was purified by silica gel chromatography to give N-(4-(3-(tetrahydro-2H-pyran-3-yl)pyridin-2-yloxy)phenyl)benzo[d]thiazol-2-amine. MS (ESI, pos. ion) m/z: 404.1 (M+1). IC50 (uM) +++++.
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4].[NH2:20][C:21]1[CH:22]=[CH:23][C:24]2[O:28][C:27]([C:29]([O:31]C(C)(C)C)=[O:30])=[CH:26][C:25]=2[CH:36]=1>CC#N>[CH2:1]([N:5]1[C:9](=[O:10])[C:8]([NH:20][C:21]2[CH:22]=[CH:23][C:24]3[O:28][C:27]([C:29]([OH:31])=[O:30])=[CH:26][C:25]=3[CH:36]=2)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)(C)OC(=O)c1cc2cc(N)ccc2o1
Reactant: CCCCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Solvent: CC#N
Product: CCCCN1C(=O)C(Nc2ccc3oc(C(=O)O)cc3c2)=C(c2ccccc2)S1(=O)=O
Temperature: 160 °C
Yield: 28.9 %

Procedure:
A mixture of 2-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (1.000 g, 3.336 mmol), tert-butyl 5-amino-1-benzofuran-2-carboxylate (0.778 g, 3.336 mmol) and TEA (0.340 ml, 2.471 mmol) in MeCN (5 ml) was heated in a microwave reactor at 160° C. for 1.5 h. The reaction mixture was evaporated and the residue was purified by flash chromatography using 5:1 DCM/EtOAc (+1% AcOH) as eluent to give the title compound (0.425 g, 29%). 1H NMR (500 MHz CD3OD); δ 13.54 (bs, 1H), 9.63 (s, 1H), 7.34 (s, 1H), 7.29 (d, 1H), 7.14-6.97 (m, 6H), 3.71 (t, 2H), 1.75 (qnt, 2H), 1.42 (sex, 2H), 0.95 (t, 2H); Mass Spectrum: M−H+ 439
Reaction SMILES: [CH2:1]([N:3]1[C:15]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:14]2[C:5]([C:6](N)=[N:7]C3C=CC=CC=32)=[N:4]1)[CH3:2].[CH3:25][C:26]([CH3:42])([CH3:41])[C:27]([NH:29][C:30]1[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:31]=1B(O)O)=[O:28]>>[C:6]([C:5]1[C:14]([C:31]2[CH:32]=[CH:33][C:34]([O:36][CH3:37])=[CH:35][C:30]=2[NH:29][C:27](=[O:28])[C:26]([CH3:42])([CH3:41])[CH3:25])=[C:15]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:3]([CH2:1][CH3:2])[N:4]=1)#[N:7]
Reactant: COc1ccc(B(O)O)c(NC(=O)C(C)(C)C)c1
Reactant: CCn1nc2c(N)nc3ccccc3c2c1CCc1ccccc1
Product: CCn1nc(C#N)c(-c2ccc(OC)cc2NC(=O)C(C)(C)C)c1CCc1ccccc1

Procedure:
Using a modification on the method described in Part B of Example 573, 4-bromo-1-ethyl-5-(2-phenylethyl)-1H-pyrazole-3-carbonitrile (prepared as described in Part E of Example 41, 10.3 g, 33.9 mmol) was coupled with 2-[(2,2-dimethylpropanoyl)amino]-4-methoxyphenylboronic acid (prepared as described in Part A of Example 573, 15.3 g, 60.9 mmol). The reaction was worked up and purified as described in Part B of Example 573 to yield 1.7 g of N-{2-[3-cyano-1-ethyl-5-(2-phenylethyl)-1H-pyrazol-4-yl]-5-methoxyphenyl}-2,2-dimethylpropanamide as a colorless liquid, MS (ESI) m/z 431.17 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([NH:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]2[N:28]=[C:29]([NH:32][C:33](=[O:35])[CH3:34])[S:30][CH:31]=2)=[CH:21][CH:20]=1)[NH:9]C(=O)OC(C)(C)C)(C)(C)C.[ClH:37]>ClCCl.O1CCOCC1>[ClH:37].[NH2:9][C:8]([NH:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]2[N:28]=[C:29]([NH:32][C:33](=[O:35])[CH3:34])[S:30][CH:31]=2)=[CH:21][CH:20]=1)=[NH:7]
Reactant: CC(=O)Nc1nc(CCc2ccc(CNC(NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cc2)cs1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(=O)Nc1nc(CCc2ccc(CNC(=N)N)cc2)cs1
Reaction time: 15 h

Procedure:
A mixture of di-tert-butyl{[(4-{2-[2-(acetylamino)-1,3-thiazol-4-yl]ethyl}benzyl)amino]methylidene}biscarbamate (20 mg), dichloromethane (2 drops) and 4N hydrogen chloride in 1,4-dioxane (0.5 ml) was stirred for 15 hours. The precipitated crystals were filtered and washed with 1,4-dioxane to give N-(4-{2-[4-({[amino(imino)methyl]amino}-methyl)phenyl]ethyl}-1,3-thiazol-2-yl)acetamide hydrochloride (13 mg).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[CH3:16][N:17]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:19]([CH2:20][C@@H:21]([C:23]([OH:25])=[O:24])[NH2:22])=[CH:18]1>>[C:23]([C@@H:21]([NH:22][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:20][C:19]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:17]([CH3:16])[CH:18]=1)([OH:25])=[O:24]
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Reactant: Cn1cc(C[C@H](N)C(=O)O)c2ccccc21
Product: Cn1cc(C[C@H](Nc2nc3ccc(Cl)cc3cc2C(=O)O)C(=O)O)c2ccccc21
Yield: 21 %

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with 1-methyl-L-tryptophan to provide the title compound in 21% yield as yellow needles (recrystallization from DMF/water).
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](O)=[O:11])=[CH:8][CH:7]=1>CN(C)C=O.ClC1C=CC=CC=1>[F:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([Cl:3])=[O:11])=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(F)cc1
Solvent: Clc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Thionyl chloride (3.8 g, 32.1 mmol) was slowly added to a solution of 4-fluorobenzoic acid 1a (3.0 g, 21.4 mmol) and N,N-dimethylformamide (5 drops) in 15 mL of chlorobenzene under a stream of nitrogen gas. The mixture was stirred at 60° C. for 2 hr. The solvent was removed under reduced pressure to afford 4-fluorobenzoyl chloride 1b. Yield: 3.0 g (88%).
Reaction SMILES: Br[C:2]1([C:7]([NH:9][C:10]([NH2:12])=[O:11])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3]1.[Na+].[C:14]([O:17][CH2:18][C:19]1[CH2:20][S:21][C@@H:22]2[C@H:29]([NH:30][C:31](=[O:40])/[C:32](/[C:35]3[O:36][CH:37]=[CH:38][CH:39]=3)=[N:33]\[OH:34])[C:28](=[O:41])[N:23]2[C:24]=1[C:25]([O-:27])=[O:26])(=[O:16])[CH3:15].C([O-])(=O)C>CS(C)=O.CCO>[C:14]([O:17][CH2:18][C:19]1[CH2:20][S:21][C@@H:22]2[C@H:29]([NH:30][C:31](=[O:40])/[C:32](/[C:35]3[O:36][CH:37]=[CH:38][CH:39]=3)=[N:33]\[O:34][C:2]3([C:7]([NH:9][C:10]([NH2:12])=[O:11])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3]3)[C:28](=[O:41])[N:23]2[C:24]=1[C:25]([OH:27])=[O:26])(=[O:16])[CH3:15]
Reactant: CC(=O)OCC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)/C(=N\O)c3ccco3)[C@H]2SC1
Reactant: NC(=O)NC(=O)C1(Br)CCCC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCO
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)/C(=N\OC3(C(=O)NC(N)=O)CCCC3)c3ccco3)[C@H]2SC1
Yield: 85 %

Procedure:
This was prepared from 1-bromo-1-ureidocarbonylcyclopentane and (6R,7R)-3-acetoxymethyl-7-[Z-2-(fur-2-yl)-2-hydroxyiminoacetamido]-ceph-3-em-4-carboxylic acid sodium salt, in a similar manner to Example 2. [α]D22 +95° (c 0.55, DMSO), λmax (EtOH) 275 nm (ε16,500), νmax (Nujol) 3420, 3300 (NH, NH2), 3700-2100 (bonded OH), 1788 (β-lactam), 1735 (acetate), 1710, 1690, 1565, 1550 cm-1 (CONH, CONHCONH2), τ (DMSO d6) 7.92 (OAc), 4.95, 5.28 (dd J 13) (3 --CH2), 6.23, 6.49 (dd, J 18) (2 --CH2), 4.71 (d, J=5) (6 H), 4.09 (dd J=5, 8) (7 H), 0.02 (d, J=8) (CONH), 2.11, 3.19, 3.32 (furyl), 7.9-8.3 (cyclopentyl), 0.65 (CONHCO), 2.17, 2.64 (CONH2). Yield: 85%.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH2:7]2.[NH:16]1[C:20]2[CH:21]=[CH:22][C:23]([CH:25]=O)=[CH:24][C:19]=2[N:18]=[N:17]1.N1CCCCC1>CO>[NH:16]1[C:20]2[CH:21]=[CH:22][C:23](/[CH:25]=[C:7]3/[C:8](=[O:13])[NH:9][C:10]4[C:6]/3=[CH:5][C:4]([O:3][C:2]([F:1])([F:14])[F:15])=[CH:12][CH:11]=4)=[CH:24][C:19]=2[N:18]=[N:17]1
Reactant: O=Cc1ccc2[nH]nnc2c1
Reactant: O=C1Cc2cc(OC(F)(F)F)ccc2N1
Solvent: CO
Solvent: C1CCNCC1
Product: O=C1Nc2ccc(OC(F)(F)F)cc2/C1=C\c1ccc2[nH]nnc2c1
Temperature: 60 °C
Yield: 23.3 %

Procedure:
A scintillation vial was charged with 5-(trifluoromethoxy)indolin-2-one (27 mg, 0.124 mmol), 1H-benzo[d][1,2,3]triazole-5-carbaldehyde (20 mg, 0.136 mmol), piperidine (2 uL, 0.012 mmol) and MeOH (2 mL). The reaction was then heated to 60° C. for 2 hrs. The MeOH was removed in vacuo and the residue purified by column chromatography (silica gel, 95:4:1, CH2Cl2/MeOH/AcOH) to give the title compound as a yellow solid (10 mg, 23%). 1H NMR (400 MHz, CD3OD) δ 8.23 (s, 1H), 8.04 (d, J=4.5 Hz, 1H), 8.02 (s, 1H), 7.77 (d, J=9.3 Hz, 1H), 7.42 (s, 1H), 7.21-7.18 (m, 1H), 6.99 (s, 1H); MS ESI 347.0 [M+H]+, calcd for [C16H9F3N4O2+H]+ 347.08.
Reaction SMILES: CCOCC.[CH:6]1([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[N+:19]([O-])([OH:21])=[O:20]>O>[CH:6]1([C:12]2[CH:13]=[CH:14][C:15]([OH:18])=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=2)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: O=[N+]([O-])O
Reactant: Oc1ccc(C2CCCCC2)cc1
Solvent: O
Solvent: CCOCC
Product: O=[N+]([O-])c1cc(C2CCCCC2)ccc1O
Temperature: 25 °C

Procedure:
To a stirred mixture of 50 ml of water, 50 ml of ether and 10.0 g of 4-cyclohexylphenol, was added dropwise 12.6 ml of 60% nitric acid while cooling with ice. The temperature of the mixture was raised to room temperature and the reaction was carried out for a day. After 500 ml of water was added, the reaction mixture was extracted with 500 ml of ethyl acetate, washed with water and a brine successively and dried with anhydrous sodium sulfate. The drying agent was filtered off and the solvent was distilled away. The residue was purified by subjecting to silica-gel column-chromatography [eluent:chloroform] to give 6.92 g of 4-cyclohexyl-2-nitrophenol.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:19])[CH:17]=[CH2:18])=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[O:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=2)[CH2:22][CH2:21]1>>[O:20]1[CH2:21][CH2:22][N:23]([C:26]2[CH:27]=[CH:28][C:29]([NH:30][C:2]3[N:7]=[C:6]([S:8][C:9]4[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:19])[CH:17]=[CH2:18])=[CH:11][CH:10]=4)[CH:5]=[CH:4][N:3]=3)=[CH:31][CH:32]=2)[CH2:24][CH2:25]1
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: C=CC(=O)Nc1ccc(Sc2ccnc(Cl)n2)cc1
Product: C=CC(=O)Nc1ccc(Sc2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)cc1
Yield: 53.6 %

Procedure:
In a procedure analogous to Example 8, reaction of N-(4-(2-chloropyrimidin-4-ylthio)phenyl)acrylamide (540 mg, 1.85 mmol) and 4-morpholinoaniline (400 mg, 2.24 mmol) furnished the product (430 mg, 54%).
Reaction SMILES: C1C=C(O[C:8](OC2N=CC=CC=2)=[S:9])N=CC=1.[NH2:17][C:18]1[CH:33]=[CH:32][C:21]2[N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:23]=[N:24][C:20]=2[C:19]=1[CH3:34]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:28]([O:27][C:25]([N:22]1[C:21]2[CH:32]=[CH:33][C:18]([N:17]=[C:8]=[S:9])=[C:19]([CH3:34])[C:20]=2[N:24]=[CH:23]1)=[O:26])([CH3:29])([CH3:30])[CH3:31]
Reactant: Cc1c(N)ccc2c1ncn2C(=O)OC(C)(C)C
Reactant: S=C(Oc1ccccn1)Oc1ccccn1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1c(N=C=S)ccc2c1ncn2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of di-2-pyridyl thionocarbonate (DPT) (14.3 g) and 4-dimethylaminopyridine (0.1 g) in CH2Cl2 (500 mL) is added dropwise over 30 minutes a solution of 5-amino-1-tert-butoxycarbonyl-4-methylbenzimidazole (7.82 g) in CH2Cl2 (250 mL). The mixture is stirred for 15 minutes at room temperature then rotary evaporated. The residue is purified by flash chromatography on silica gel, eluting with 10% ethyl acetate/hexane to afford 1-tert-butoxycarbonyl-4-methyl-5-benzimidazolylisothiocyanate as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[C:4]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)[N:3]=1.[CH3:16][C:17]1[C:18]([CH2:23][NH2:24])=[N:19][CH:20]=[CH:21][CH:22]=1>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:24][CH2:23][C:18]2[C:17]([CH3:16])=[CH:22][CH:21]=[CH:20][N:19]=2)=[O:10])[CH:5]=[C:4]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)[N:3]=1
Reactant: Nc1nc(C(=O)O)cc(-c2ccco2)n1
Reactant: Cc1cccnc1CN
Solvent: CN(C)C=O
Product: Cc1cccnc1CNC(=O)c1cc(-c2ccco2)nc(N)n1
Reaction time: 2 h
Yield: 35.2 %

Procedure:
A suspension of 2-amino-6-(2-furyl)pyrimidine-4-carboxylic acid (206 mg, 1.0 mmol) in DMF (5 mL) was treated with N,N′-carbonyldiimidazole (162 mg, 1.0 mmol), stirred for 2 h, treated with 3-methylpyridine-2-methanamine (244 mg, 2.0 mmol), stirred for 2 h, poured onto water (50 mL) and extracted with EtOAc (2×25 mL). The extracts were washed with water, concentrated in vacuo, and the crude product was triturated with ether to give the title compound (109 mg, 35%) as a yellow solid.
Reaction SMILES: [I:1]I.[NH2:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6]([S:12][CH3:13])[N:5]=1>C(O)C.S([O-])([O-])(=O)=O.[Ag+2]>[NH2:3][C:4]1[C:11]([I:1])=[CH:10][C:7]([C:8]#[N:9])=[C:6]([S:12][CH3:13])[N:5]=1
Reactant: II
Reactant: CSc1nc(N)ccc1C#N
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: CSc1nc(N)c(I)cc1C#N
Temperature: 25 °C
Reaction time: 3 h
Yield: 81 %

Procedure:
3.75 g (1.5 eq) of silver sulfate and 2.85 g (1.4 eq) of iodine are added successively to a solution of 1.32 g (8.02 mmol) of 6-amino-2-(methylthio)nicotinonitrile in 65 ml of ethanol. The reaction medium is stirred at room temperature for 3 hours. The solid is filtered and the residue rinsed thoroughly with methanol. The filtrate is evaporated and redissolved in ethyl acetate. The organic phase is washed with water three times, dried on magnesium sulfate and evaporated to yield 1.89 g (81%) of 6-amino-5-iodo-2-(methylthio)nicotinonitrile in the form of a brown powder.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH2:16]([S:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=O)=[CH:23][CH:22]=1)[CH2:17][CH2:18][CH3:19].[C:30]([C:32]1[CH:37]=[CH:36][C:35]([SH:38])=[CH:34][CH:33]=1)#[N:31]>CN(C)C1C=CN=CC=1.ClCCl>[CH2:16]([S:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([S:38][C:35]2[CH:36]=[CH:37][C:32]([C:30]#[N:31])=[CH:33][CH:34]=2)=[O:27])=[CH:28][CH:29]=1)[CH2:17][CH2:18][CH3:19]
Reactant: N#Cc1ccc(S)cc1
Reactant: CCCCSc1ccc(C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCSc1ccc(C(=O)Sc2ccc(C#N)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N,N'-dicyclohexylcarbodiimide (0.99 g, 0.005 mol), was added in one portion to a stirred solution of compound 2 (1.04 g, 0.005 mol), compound 10 (0.56 g, 0.004 mol) and 4-(dimethylamino)pyridine (0.20 g, 0.002 mol), in dry dichloromethane (50 ml) at room temperature. The reaction mixture was stirred at room temperature overnight. The product was extracted into ether (200 ml) and was washed with aqueous potassium hydroxide solution (5%, 2×250 ml). The ether layer was evaporated in vacuo and the product was purified by column chromatography [silica gel/petroleum fraction (bp 40°-60° C.), dichloromethane, 1:1] and was recrystallised from ethanol to afford a white solid which was dried in vacuo (P2O5).
Reaction SMILES: C([Li])CCC.CCCCCC.Br[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(CO[CH2:24][C:25]2([OH:39])[CH2:31][O:30][CH2:29][CH2:28][N:27]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:26]2)CC1.S([O-])(O)(=O)=O.[Na+]>C1COCC1>[CH2:24]([C:25]1([OH:39])[CH2:31][O:30][CH2:29][CH2:28][N:27]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:26]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CCOCC(O)(COCC2CC2)C1
Reactant: Brc1ccccc1
Agent: O=S(=O)([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCOCC(O)(Cc2ccccc2)C1
Temperature: -80 °C
Yield: 54.5 %

Procedure:
1.6M solution of butyl lithium in hexane (150 mL, 0.24 mol, 1.1 eq) was added to a solution of bromobenzene (25.3 mL, 0.24 mol, 1.1 eq) in THF (200 mL) at −60° C. in a stream of argon. The reaction mixture was cooled to −80° C., and a solution of tert-butyl 6-[(cyclopropylmethoxy)methyl]-6-hydroxy-1,4-oxazepane-4-carboxylate (Preparation 80, 50 g, 0.22 mol, 1 eq) in THF was added. Then the mixture was cooled to −100° C., and a solution of etherate (30.4 g, 0.24 mol, 1.1 eq) was added at this temperature for 30 min. The reaction mixture was heated to 0° C. for 5 h, and 5M sodium hydrogen sulfate solution (50 mL) was added. The organic layer was separated, evaporated, and the residue was distributed between water and ether. The organic layer was separated, washed with water and brine, dried, evaporated, and the residue was dissolved in MeOH (200 mL). Ethylenediamine (30 mL) was added to the mixture, which was heated until boiled, cooled, evaporated, and coevaporated with dioxane. The residue was purified by chromatography on silica (1 L; carbon tetrachloride→chloroform, then MeOH 5%), evaporated and dried to give title compound (37.15 g, 0.12 mol, 55%).