Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[O:13][CH2:12][C:11](=O)[N:10]([CH:15]([CH3:17])[CH3:16])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.B.CSC>CO.C(OCC)(=O)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[O:13][CH2:12][CH2:11][N:10]([CH:15]([CH3:17])[CH3:16])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)N1CC(c2cccc(Cl)c2)OCC1=O
Agent: B
Solvent: CSC
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)N1CCOC(c2cccc(Cl)c2)C1
Product: Cl

Procedure:
The title compound, m.p. 224°-5° C. (methanol-ethyl acetate), was prepared from 2-[3-chlorophenyl]-4-[1-methylethyl]-5-oxomorpholine and borane-methyl sulphide by an analogous procedure to that described in Example 1.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:11]([CH2:35][CH:36]([CH3:38])[CH3:37])=[N:12][C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)=[CH:17][C:16]([C:27]1[S:28][CH:29]=[C:30]([C:32]([OH:34])=O)[N:31]=1)=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:40][NH:41][O:42][CH3:43].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>O.CN(C)C=O>[CH2:35]([C:11]1[C:10]([CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[C:19]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:27]3[S:28][CH:29]=[C:30]([C:32]([N:41]([O:42][CH3:43])[CH3:40])=[O:34])[N:31]=3)[CH:17]=2)[N:12]=1)[CH:36]([CH3:37])[CH3:38]
Reactant: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(-c4nc(C(=O)O)cs4)cc23)cc1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1csc(-c2ccc3nc(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c4ccc(C)cc4)c3c2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.5 %

Procedure:
A mixture of 2-[3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-4-(4-methylphenyl)-6-quinolinyl]-1,3-thiazole-4-carboxylic acid (0.27 g, 0.5 mmol), N,O-dimethylhydroxylamine hydrochloride (0.06 g, 0.6 mmol), ethyl-3(3-dimethylaminopropyl)carbodiimide hydrochloride (0.12 g, 0.6 mmol), 1-hydroxy-1H-benzotriazole (0.09 g, 0.6 mmol), triethylamine (0.08 ml, 0.6 mmol) and N,N-dimethylformamide (10 ml) was stirred at room temperature for 2 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was crystallized from diisopropyl ether to give tert-butyl {[2-isobutyl-6-(4-{[methoxy(methyl)amino]carbonyl}-1,3-thiazol-2-yl)-4-(4-methylphenyl)quinolin-3-yl]methyl}carbamate (0.24 g, yield 85%) as white crystals.
Reaction SMILES: O.O.O.[C:4]([O-:7])(=[O:6])[CH3:5].[C:8]([O-:11])(=[O:10])[CH3:9].[Pb+2].[CH3:13][C@@H:14]([C@@H:17]1[C@:34]2([CH3:35])[C@H:20]([C@H:21]3[C@H:31]([CH2:32][CH2:33]2)[C@:29]2([CH3:30])[C:24]([CH2:25][C@@H:26](O)[CH2:27][C@@H:28]2[OH:36])=[CH:23][CH2:22]3)[CH2:19][CH2:18]1)[CH2:15]O.O>CN(C)C=O.C(OC(=O)C)(=O)C>[C:4]([O:7][C@H:26]1[CH2:27][C@H:28]([OH:36])[C@@:29]2([CH3:30])[C:24](=[CH:23][CH2:22][C@@H:21]3[C@@H:31]2[CH2:32][CH2:33][C@@:34]2([CH3:35])[C@H:20]3[CH2:19][CH2:18][C@@H:17]2[C@H:14]([CH3:15])[CH2:13][O:10][C:8](=[O:11])[CH3:9])[CH2:25]1)(=[O:6])[CH3:5]
Reactant: C[C@H](CO)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(=O)[O-]
Agent: [Pb+2]
Solvent: O
Solvent: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)OC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(C)=O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 24 h
Yield: 41.7 %

Procedure:
To a solution of 2.4 g of lead diacetate-trihydrate in 180 ml of dimethylformamide and 24 ml of acetic anhydride was added 4.6 g of (20S)-20-methylpregn-5-ene-1α,3β,21-triol. After standing at room temperature for 24 hr., the mixture was poured onto 1 kg of a 3:1 water--ice mixture and then extracted with ether. The ether extract was washed with water, dried (Na2SO4) and evaporated by means of a water aspirator. The residue was chromatographed on 100 g of silica gel. Elution with 1:1 hexane--ether afforded 1.14 g (20%) of (20S)-3β,21-diacetyloxy-20-methylpregn-5-en-1α-ol, mp 148°-149°. Elution with ether gave first 0.24 g (4.6%) of (20S)-3β-acetyloxy-20-methylpregn-5-ene-1α,21-diol, mp 202°-203° and then 2.94 g (57%) of (20S)-21-acetyloxy-20-methylpregn-5-ene-1α,3β -diol, mp 121°-121°. Finally, elution with ethyl acetate afforded 0.79 g (17%) of starting triol.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][S:3][C:2]1=[C:6]([C:12](=[O:21])[NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:7]([O:9]CC)=O.[H-].[Na+].[C:24]([O:33][CH2:34][CH3:35])(=[O:32])/[CH:25]=[CH:26]\[C:27]([O:29][CH2:30][CH3:31])=[O:28].O>CN(C)C=O>[CH2:34]([O:33][C:24]([CH:25]1[CH:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:7](=[O:9])[C:6](=[C:2]2[S:1][CH:5]=[CH:4][S:3]2)[C:12](=[O:21])[N:13]1[CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:32])[CH3:35]
Reactant: CCOC(=O)/C=C\C(=O)OCC
Reactant: CCOC(=O)C(C(=O)NCc1ccccc1)=C1SC=CS1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1C(=O)C(=C2SC=CS2)C(=O)N(Cc2ccccc2)C1C(=O)OCC
Reaction time: 0.5 h

Procedure:
A mixture of ethyl 2-(1,3-dithiol-2-ylidene)-2-(N-benzylcarbamoyl)acetate (1.0 g) and dimethylformamide (25 ml) is added dropwise to a suspension of sodium hydride (63% dispersion in oil, 144 mg) in dimethylformamide (10 ml). Said addition is carried out under ice-cooling. The mixture is stirred at the same temperature for 30 minutes. A solution of diethyl maleate (0.6 ml) in dimethylformamide (10 ml) is added dropwise thereto. The mixture is stirred at room temperature overnight. The mixture is poured into water, and extracted with ethyl acetate. The extract is washed with a saturated sodium chloride solution, dried and then distilled to remove the solvent. The mixture is purified by silica gel column chromatography (solvent, n-hexane:ethyl acetate=1:2) to give 1-benzyl-5-(1,3-dithiol-2-ylidene)-4,6-dioxopiperidine-2,3-dicarboxylic acid diethyl ester (196 mg) as yellow oil.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][OH:15])=[CH:12][CH:11]=1.F[C:19]1[CH:24]=[C:23]([I:25])[CH:22]=[CH:21][N:20]=1>O>[I:25][C:23]1[CH:22]=[CH:21][N:20]=[C:19]([O:15][CH2:14][C:13]2[CH:16]=[CH:17][C:10]([O:9][CH3:8])=[CH:11][CH:12]=2)[CH:24]=1
Reactant: COc1ccc(CO)cc1
Reactant: Fc1cc(I)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(COc2cc(I)ccn2)cc1
Reaction time: 0.5 h
Yield: 68.4 %

Procedure:
With cooling with ice, sodium hydride (60% oily, 4.93 g, 0.188 mmol) was added to a DMF (250 mL) solution of 4-methoxybenzyl alcohol (17.04 g), and stirred for 30 minutes. 2-Fluoro-4-iodopyridine (25.0 g) was added, and stirred at room temperature for 2 hours. Water was added to the reaction liquid, and extracted with diethyl ether. The organic layer was washed with saturated saline, and dried with anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure, then diisopropyl ether was added to the obtained residue, and the obtained solid was collected by filtration to obtain the entitled compound (26.15 g, 68%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12](Br)=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:16]1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[CH3:62][N:63]1[CH:67]=[CH:66][C:65]([NH2:68])=[N:64]1.C1(C)C=CC=CC=1>C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([NH:68][C:65]2[CH:66]=[CH:67][N:63]([CH2:62][CH3:16])[N:64]=2)=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1ccc(N)n1
Reactant: Brc1ccc(OCc2ccccc2)cn1
Reactant: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCn1ccc(Nc2ccc(OCc3ccccc3)cn2)n1
Temperature: 120 °C

Procedure:
11.2 5-Benzyloxy-2-bromo-pyridine (0.53 mmol), sodium-tert.-butyl at (1.4 eq.), tris-(dibenzylidene-acetone)-dipalladium (0.01 eq.), BINAP (0.01 eq.) and 1-methyl-1H-pyrazole-3-amine (1.2 eq.) are filled under nitrogen in a microwave reaction vessel. Degassed Toluene (50 eq.) is added. The reaction suspension is heated to 120° C. for 10 min. Ethyl acetate is added to the reaction suspension and filtrated over celite. The solvent of the filtrate is removed in vacuo. “A11” is obtained after column chromatography (heptan/ethyl acetate) as a colourless powder in a yield of 29%; HPLC (method C): 1.60 min); LC-MS (m Method A): 1.008 min, 281.15 (M+H+); 1H-NMR (DMSO-d6, 500 MHz): δ [ppm] 8.859 (s, 1H), 7.886 (d, 1H, J=2.5 Hz), 7.449-7.429 (m, 3H), 7.400-7.370 (m, 2H), 7.342-7.308 (m, 2H), 7.246 (d, 1H, J=9.0 Hz), 6.169 (d, 1H, J=2.5 Hz), 5.062 (s, 2H), 3.709 (s, 3H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:21]1[CH:22]=[CH:23][C:24]([F:29])=[C:25]([CH:28]=1)[CH:26]=[O:27].[O:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>C([Sn](CCCC)(CCCC)C1OC=CC=1)CCC>[F:29][C:24]1[CH:23]=[CH:22][C:21]([C:31]2[O:30][CH:34]=[CH:33][CH:32]=2)=[CH:28][C:25]=1[CH:26]=[O:27]
Reactant: O=Cc1cc(Br)ccc1F
Reactant: C1CCOC1
Agent: CCCC[Sn](CCCC)(CCCC)c1ccco1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=Cc1cc(-c2ccco2)ccc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
Tri(dibenzylideneacetone)-dipalladium (0.18 g, 0.2 mmol), and triphenylphosphine (0.21 g, 0.8 mmol) were dissolved in tetrahydrofuran (60 mL), followed by stirring at room temperature for 30 minutes. Then, 5-bromo-2-fluorobenzaldehyde (0.4 g, 2.0 mmol) and 2-(tributylstannyl)-furan (1.25 mL, 4. 0 mmol) were added thereto, followed by heating under reflux for 10 hours. The mixture was cooled to room temperature, and after the conventional treatment, the residue was purified by silica gel column chromatography (hexane: ethyl acetate=8:1), to give 2-fluoro-5-(2-furyl)benzaldehyde (0.38 g, 100%).
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([S:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[N:3]=1.[CH2:17]([OH:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[H-].[Na+].[Cl-].[Na+]>CN(C)C=O>[CH2:17]([O:24][C:2]1[S:6][N:5]=[C:4]([S:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[N:3]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OCc1ccccc1
Reactant: COc1ccc(CSc2nsc(Cl)n2)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CSc2nsc(OCc3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.3 %

Procedure:
Into 2 ml of N,N-dimethylformamide were dissolved 200 mg of 5-chloro-3-(4-methoxybenzyl)thio-1,2,4-thiadiazole and 87 mg of benzyl alcohol, 35 mg of sodium hydride (60% in oil) was added thereto under ice-cooling, and the reaction mixture was stirred for 1 hour under ice-cooling and for 4 hours at room temperature. The reaction mixture was added to saturated sodium chloride aqueous solution, and extracted with t-butyl methyl ether. The organic layer was concentrated, and the residue obtained was subjected to silica gel column chromatography to give 165 mg of 5-benzyloxy-3-(4-methoxybenzyl)thio-1,2,4-thiadiazole (hereinafter, referred to as the present compound (33)).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=1[CH:5]=[C:6]1[CH2:10][CH2:9][NH:8][C:7]1=[O:11].[H-].[Na+].[CH3:18]I.O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=1[CH:5]=[C:6]1[CH2:10][CH2:9][N:8]([CH3:18])[C:7]1=[O:11]
Reactant: CI
Reactant: COc1ccccc1C=C1CCNC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccccc1C=C1CCN(C)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The intermediate 3-(2′-methoxybenzylidene)-2-pyrrolidone (5.0 g) obtained in Example 317 was dissolved in dimethylformamide (50 ml) and sodium hydride (0.99 g) was added thereto under ice-cooling. The mixture was stirred at room temperature for 30 min. Methyl iodide (1.72 ml) was added under ice-cooling and the mixture was stirred for 8 hr at room temperature. After completing of the reaction, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (3.6 g).
Reaction SMILES: [CH2:1]=O.[CH2:3]([O:7][C:8]1[C:13]([CH2:14]N)=[CH:12][C:11]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[C:10]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[N:9]=1)[CH2:4][CH2:5][CH3:6].[C:33]([BH3-])#[N:34].[Na+]>C(#N)C.C(O)(=O)C>[CH2:3]([O:7][C:8]1[C:13]([CH2:14][N:34]([CH3:33])[CH3:1])=[CH:12][C:11]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[C:10]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[N:9]=1)[CH2:4][CH2:5][CH3:6]
Reactant: [BH3-]C#N
Reactant: CCCCOc1nc(-c2ccc(F)cc2)c(-c2ccc(S(C)(=O)=O)cc2)cc1CN
Reactant: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CCCCOc1nc(-c2ccc(F)cc2)c(-c2ccc(S(C)(=O)=O)cc2)cc1CN(C)C
Reaction time: 0.25 h

Procedure:
Aqueous 37% formaldehyde (1 ml) was added to a stirring solution of 2-butoxy-6-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]pyridine-3-methylamine [Example 32] (250 mg, 0.58 mmol) in 5 ml acetonitrile. Sodium cyanoborohydride (54 mg, 0.875 mmol) was added and the reaction mixture was stirred for 15 minutes. Two drops of acetic acid was added and the reaction mixture was stirred for 2 hours. The reaction mixture was concentrated to a paste and the titled material was purified by silica gel chromatography. Anal Calc'd. C25H29N2O3SF+0.25 H2O: C, 65.12; H, 6.45; N, 6.08. Found: C, 65.12; H, 6.46; N, 6.19.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[CH3:8][O:9][C:10]([CH3:22])([CH3:21])[CH2:11][CH2:12][CH:13]1[CH2:18][CH:17]([CH3:19])[CH2:16]C(O)C1.C([O-])(=O)C.[Na+]>C1(C)C=CC=CC=1>[C:5]([O:4][CH:1]1[CH2:16][CH:17]([CH3:19])[CH2:18][CH:13]([CH2:12][CH2:11][C:10]([O:9][CH3:8])([CH3:22])[CH3:21])[CH2:2]1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: COC(C)(C)CCC1CC(C)CC(O)C1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(C)(C)CCC1CC(C)CC(OC(C)=O)C1

Procedure:
Acetic anhydride (1.4 mL, 0.014 mol), 3-(3-methoxy-3-methylbut-1-yl)-5-methylcyclohexan-1-ol (2.0 g, 0.0033 mol), toluene (3.0 mL) and sodium acetate (0.05 g) were combined and heated at reflux for 16 hours. Workup provided 1-acetoxy-3-(3-methoxy-3-methylbut-1-yl)-5-methylcyclohexane, bp0.5 175-177~-C. (1.61 g) as a mixture of diastereoisomers (ratio 92.3:3.2:4.5); NMR(CDCl3)δ 0.6(q,1H), 0.9(d,3H), 1.0-1.3(m,3H), 1.2(s,6H), 1.4-1.6(m,4H), 1.6-2.0(m,4H), 2.1(s,3H), 3.2(s,3H), 5.1(m,1H); IR(neat) 2960, 2925, 1740, 1460, 1380, 1250, 1085, 1015 cm-1 ; MS(m/e) 43, 73, 93, 108, 149, 164, 181, 241, 242.
Reaction SMILES: [CH2:1]([C:8]1[NH:9][C:10]([CH2:13][OH:14])=[CH:11][N:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[Cl:15]N1C(=O)CCC1=O>>[Cl:15][C:11]1[N:12]=[C:8]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[NH:9][C:10]=1[CH2:13][OH:14]
Reactant: CCCCCCCc1ncc(CO)[nH]1
Reactant: O=C1CCC(=O)N1Cl
Product: CCCCCCCc1nc(Cl)c(CO)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.4 %

Procedure:
To a solution of 2-heptyl-5-(hydroxymethyl)-imidazole (10.0 g, 51 mmol) in EtOH1,4-dioxane (1:1; 600 mL) was added N-chlorosuccinimide (7.9 g, 59 mmol). After being stirred for 1 hour at room temperature the solvents were removed on a rotary evaporator an the solid residue was partitioned between ethyl acetate and water (300 mL each). The organic phase was washed with water (150 mL), dried (MgSO4), filtered and concentrated to afford 12.4 g crude product. Recrystallization (1:1 EtOAc/hexane, 60 mL) gave 5.7 g (45%) of white crystals; m.p. 134°-140°. NMR (200 MHz, CDCl3 /CD3OD) δ 4.50 (s, 2H); 4.00-3.80 (br s, 2H); 2.65 (t 2H, 5Hz); 1.80-1.60 (m, 2H); 1.40-1.20 (m, 8); 0.90-0.80 (m, 3H). Mass Spec. 230.
Reaction SMILES: [CH:1]1([C:4]2[CH:20]=[C:7]3[N:8]=[CH:9][CH:10]=[C:11]([S:12][C:13]4[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=4)[N:6]3[N:5]=2)[CH2:3][CH2:2]1.Cl[C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)=[N:24][N:23]=1>CC(O)(C)C.C(Cl)Cl>[Cl:38][C:35]1[CH:34]=[CH:33][C:32]([C:25]2[C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:22]([NH:19][C:16]3[CH:15]=[CH:14][C:13]([S:12][C:11]4[N:6]5[N:5]=[C:4]([CH:1]6[CH2:3][CH2:2]6)[CH:20]=[C:7]5[N:8]=[CH:9][CH:10]=4)=[CH:18][CH:17]=3)=[N:23][N:24]=2)=[CH:37][CH:36]=1
Reactant: Clc1ccc(-c2nnc(Cl)c3ccccc23)cc1
Reactant: Nc1ccc(Sc2ccnc3cc(C4CC4)nn23)cc1
Solvent: CC(C)(C)O
Solvent: ClCCl
Product: Clc1ccc(-c2nnc(Nc3ccc(Sc4ccnc5cc(C6CC6)nn45)cc3)c3ccccc23)cc1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A resealable tube charged with a mixture of 4-(2-cyclopropylpyrazolo[1,5-a]pyrimidin-7-ylthio)benzenamine (100 mg, 0.354 mmol) and 1-chloro-4-(4-chlorophenyl)phthalazine (97 mg, 0.354 mmol) in tBuOH (2 mL) was heated to 100° C. After 3 hrs, the mixture was cooled to RT, diluted with CH2Cl2, and washed with water and brine. After drying the organic fraction with sodium sulfate, the solvent was removed in vacuo. The residue was purified by silica gel chromatography using 20-90% Hexanes:EtOAc to afford 4-(4-chlorophenyl)-N-(4-(2-cyclopropylpyrazolo[1,5-a]pyrimidin-7-ylthio)phenyl)phthalazin-1-amine. MS: Found M+H+=521.2.
Reaction SMILES: Cl[C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:7]1([C:5]2[N:6]=[C:2]([N:23]3[CH2:22][CH2:21][N:20]([C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:19])[CH2:25][CH2:24]3)[S:3][CH:4]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1nc(-c2ccccc2)cs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2nc(-c3ccccc3)cs2)CC1
Yield: 25.4 %

Procedure:
A solution of 2-chloro-4-phenyl-1,3-thiazole (1.54 mg, 7.87 mmol), 1-(tert-butoxycarbonyl)-piperazine (4.40 g, 23.6 mmol) and potassium carbonate (1.09 g, 7.87 mmol) in dimethylformamide (26 ml) was stirred at 120° C. for 2 hours. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give 691 mg (25.4%) of tert-butyl 4-(4-phenyl-1,3-thiazol-2-yl)piperazine-1-carboxylate as a solid.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9]C)=[O:8].[OH-].[Li+]>O1CCCC1.CO.O>[OH:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1sccc1O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1sccc1O
Temperature: 22 °C
Reaction time: 18 h

Procedure:
10.0 g of methyl 3-hydroxy-thiophene-2-carboxylate were dissolved in a mixture of 90 ml of tetrahydrofuran (THF) and 90 ml of methanol, and a solution of 25.2 g of lithium hydroxide in 25 ml of water was added. The reaction mixture was stirred at 22° C. for 18 h and then heated at 55° C. for 6 h. The reaction mixture was concentrated to 50 ml in a rotary evaporator, acidified to pH=1 with 2 molar hydrochloric acid and extracted 3 times with 50 ml of t-butyl methyl ether each time. The combined organic phases were dried over magnesium sulfate and concentrated.
Reaction SMILES: [NH2:1][N:2]1[C:6]([CH2:7][CH3:8])=[CH:5][CH:4]=[C:3]1[C:9]([C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[C:14]#[N:15])=O.[CH3:19][C:20](=O)[CH2:21][C:22](=[O:24])[CH3:23].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:22]([C:21]1[C:20]([CH3:19])=[N:1][N:2]2[C:6]([CH2:7][CH3:8])=[CH:5][CH:4]=[C:3]2[C:9]=1[C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[C:14]#[N:15])(=[O:24])[CH3:23]
Reactant: CC(=O)CC(C)=O
Reactant: CCc1ccc(C(=O)c2cccc(C#N)c2)n1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCc1ccc2c(-c3cccc(C#N)c3)c(C(C)=O)c(C)nn12
Yield: 24.8 %

Procedure:
To a solution of 3-[(1-amino-5-ethyl-1H-pyrrol-2-yl)carbonyl]benzonitrile (200 mg) in toluene (6 mL) was added 2,4-pentanedione (837 mg) and p-toluenesulfonic acid monohydrate (32 mg) at ambient temperature. The reaction mixture was refluxed for 1 hour. The residue was purified by flash silica gel chromatography (silica gel, 80 mL) eluted with hexane-ethyl acetate=10-1 to give 3-(3-acetyl-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-4-yl)benzonitrile (63 mg, 24.8%) as an yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[CH2:11][C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][C:13]=2[O:22][CH3:23])=[CH:4][CH:3]=1.[CH:24]1([CH2:29][C:30](O)=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:24]1([CH2:29][C:30]([NH:1][C:2]2[CH:10]=[C:9]3[C:5]([CH2:6][CH2:7][N:8]3[CH2:11][C:12]3[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][C:13]=3[O:22][CH3:23])=[CH:4][CH:3]=2)=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C(O)CC1CCCC1
Reactant: COC(=O)c1ccc(CN2CCc3ccc(N)cc32)c(OC)c1
Product: COC(=O)c1ccc(CN2CCc3ccc(NC(=O)CC4CCCC4)cc32)c(OC)c1
Yield: 26 %

Procedure:
Using a similar procedure to that described in Example 185, but starting from methyl 4-(6-aminoindolin-1-ylmethyl)-3-methoxybenzoate and 2-cyclopentylacetic acid, there was obtained methyl 4-[6-(2-cyclopentylacetamido) indolin-1-ylmethyl]-3-methoxybenzoate in 26% yield as an off-white solid, partial NMR: 2.3 (br s,3H,CHCH2), 3.0 (t,2H,H3 -indoline), 3.4 (t,2H,H2 -indoline).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:19])=[C:6]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([F:17])=[CH:16][C:11]=3[NH:10][C:9]2=[O:18])[CH:7]=1.[C:20](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:19])=[C:6]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([F:17])=[CH:16][C:11]=3[N:10]([CH3:20])[C:9]2=[O:18])[CH:7]=1
Reactant: O=c1[nH]c2cc(F)ccc2n1-c1cc(Cl)ccc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: Cn1c(=O)n(-c2cc(Cl)ccc2O)c2ccc(F)cc21

Procedure:
A mixture of 1,3-dihydro-1-(5-chloro-2-hydroxyphenyl)-5-fluoro-2H-benzimidazol-2-one (300 mg, 1.1 mmol), anhydrous potassium carbonate (415 mg) and Iodomethane (68 μl) in 10 ml absolute acetone was refluxed for 5 hours. The mixture was filtered, concentrated in vacuo and the crude product was subjected to column chromatography using methylene chloride:acetone (20:1) as eluent. The fraction containing the product was concentrated in vacuo and the title compound was obtained as white crystals, M.p. 247°-250° C.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:16]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][C:26]([O:28][CH2:29]Cl)=[O:27])=[O:17])[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[Na+].[I-:32]>>[C:1]([NH:11][C@H:12]([C:16]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][C:26]([O:28][CH2:29][I:32])=[O:27])=[O:17])[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccccc1CC(=O)OCCl
Reactant: [I-]
Agent: [Na+]
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccccc1CC(=O)OCI

Procedure:
Chloromethyl 2-(N-CBZ-L-valyloxy)phenylacetate is treated with NaI and purified as described in the Examples above to yield the title compound.