Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][CH:11]2[NH2:14])=[CH:7][CH:6]=1)([O-:4])=[O:3].C(N(CC)CC)C.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>CN(C=O)C>[ClH:1].[N+:2]([C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][CH:11]2[NH:14][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:7][CH:6]=1)([O-:4])=[O:3]
Reactant: BrCc1ccccc1
Reactant: NC1CCc2ccc([N+](=O)[O-])cc21
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc2c(c1)C(NCc1ccccc1)CC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 6-nitro-1-aminoindane hydrochloride (1.90 g, 8.85 mmol) in DMF (30 ml) was added triethylamine (250 ml, 18.06 mmol) followed by benzyl bromide (1.07 ml, 9.03 mmol). The mixture was warmed to room temperature, stirred for 3 hr, dumped into water (100 ml), and extracted with ethyl acetate (3×70 ml). The combined extracts were washed with water, dried over magnesium sulfate, filtered through a small plug of silica gel and reduced to a syrup. The titled compound was isolated as the hydrochloride salt: (1.34 g, 50%); m.p. 234°-235° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]2[C:8]([C:18](=O)[C:19]([O:21][CH3:22])=[O:20])=[C:9]([C:13](OCC)=[O:14])[C:10]([O:11][CH3:12])=[C:4]2[C:3]1=[O:24].C(OC(NCC(N(CC(OC)OC)C)=O)=O)C1C=CC=CC=1.C(O)(=O)C.[NH2:51][NH2:52]>C(O)(=O)C>[CH3:12][O:11][C:10]1[C:9]2[C:13](=[O:14])[NH:52][N:51]=[C:18]([C:19]([O:21][CH3:22])=[O:20])[C:8]=2[N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[C:3](=[O:24])[C:4]=12
Reactant: CCOC(=O)c1c(OC)c2n(c1C(=O)C(=O)OC)CCN(C)C2=O
Reactant: NN
Agent: COC(CN(C)C(=O)CNC(=O)OCc1ccccc1)OC
Solvent: CC(=O)O
Product: COC(=O)c1n[nH]c(=O)c2c(OC)c3n(c12)CCN(C)C3=O
Temperature: 160 °C

Procedure:
A solution of ethyl 2-methyl-8-(methoxy)-6-[methoxy(oxo)acetyl]-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylate (1.28 g, 3.78 mmol; prepared in a manner similar to that described in Example 62, step 5 to 8, starting with 1-methylpiperazin-2-one (Example 7, step 1 to 3) and hydrazine acetate (1.05 g, 11.36 mmol) in glacial acetic acid (8 mL) was heated at 160° C. in an microwave oven for 20 minutes. The mixture was concentrated under vacuum. The residue was partitioned between chloroform and brine. The organic extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was triturated in a 4:1 mixture of ethanol and diethyl ether. The precipitate was filtered to afford the title compound. ES MS M+1=321
Reaction SMILES: Cl.[N:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12](Cl)=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[C:15]12([NH2:25])[CH2:24][CH:19]3[CH2:20][CH:21]([CH2:23][CH:17]([CH2:18]3)[CH2:16]1)[CH2:22]2.N1C=CC=CC=1>O>[C:15]12([NH:25][C:12]([C:8]3[CH:7]=[C:6]4[C:11](=[CH:10][CH:9]=3)[N:2]=[CH:3][CH:4]=[CH:5]4)=[O:13])[CH2:22][CH:21]3[CH2:20][CH:19]([CH2:18][CH:17]([CH2:23]3)[CH2:16]1)[CH2:24]2
Reactant: NC12CC3CC(CC(C3)C1)C2
Reactant: O=C(Cl)c1ccc2ncccc2c1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: O=C(NC12CC3CC(CC(C3)C1)C2)c1ccc2ncccc2c1
Yield: 10.8 %

Procedure:
Prepared from 6-quinolinecarbonyl chloride hydrochloride (1.51 g, 10 mmol), 1-adamantanamine (1.73 g, 10 mmol), pyridine (5 mL), and water (200 mL) yielding 330 mg (11%) of (42):
Reaction SMILES: [C:1](=[S:6])([S:4][CH3:5])[S:2][CH3:3].[S:7]([O:12]C)([O:10][CH3:11])(=[O:9])=[O:8]>>[CH3:11][O:10][S:7]([O-:12])(=[O:9])=[O:8].[CH3:3][S:2][C:1](=[S+:6][CH3:11])[S:4][CH3:5]
Reactant: CSC(=S)SC
Reactant: COS(=O)(=O)OC
Product: COS(=O)(=O)[O-]
Product: CSC(SC)=[S+]C
Temperature: 90 °C
Reaction time: 1 h
Yield: 192.9 %

Procedure:
Dimethyl trithiocarbonate (2.76 g, 20 mmol) was treated with dimethyl sulfate (2.5 g, 20 mmol) and stirred at 90° C. for 1 h, and cooled to 25° C. The solid was broken up under ether, collected by filtration, and washed with ether to give the title compound (5.1 g, 91%).
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6]([SH:8])[N:5]=[C:4]2[NH:9][N:10]=[C:11]([CH3:12])[C:3]=12.[OH-].[Na+].CI.[CH3:17]C(O)=O>O>[OH:1][C:2]1[N:7]=[C:6]([S:8][CH3:17])[N:5]=[C:4]2[NH:9][N:10]=[C:11]([CH3:12])[C:3]=12
Reactant: CC(=O)O
Reactant: Cc1n[nH]c2nc(S)nc(O)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CI
Solvent: O
Product: CSc1nc(O)c2c(C)n[nH]c2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 4-hydroxy-6-mercapto-3-methylpyrazolo[3,4-d]pyrimidine (A-1) (2.86 g, 11.8 mmol) and NaOH (0.8 g, 20 mmol) in water (20 mL) at 5° C., was added CH3I (2.0 g, 14.2 mmol). After stirred at ambient temperature for 30 min, the solution was acidified with HOAc to give the crude product of the title compound (A-2), which used in next step without further purification. MS-ESI (m/z): 197.0 (M+H)+.
Reaction SMILES: Cl[C:2]([O:4][C:5]1C=C[CH:8]=[CH:7][CH:6]=1)=[O:3].[N:11]1C=CC=C(N)[N:12]=1.[N:18]1C=CC=CN=1.N1C=CC=CC=1>C(N(CC)CC)C>[C:2](=[O:3])([O:4][C:5]1[N:11]=[N:12][CH:8]=[CH:7][CH:6]=1)[NH2:18]
Reactant: c1ccnnc1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1cccnn1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: NC(=O)Oc1cccnn1

Procedure:
The reaction of a haloformate, such as phenyl chloroformate, and a pyridazineamine generally is carried out by combining a slight excess of haloformate with the pyridazine in an organic solvent, such as pyridine or triethylamine, and stirring the mixture for about 1 to about 24 hours at a temperature of about 0° to about 30° C. The product of the reaction, a pyridazinyl carbamate, is generally isolated by acidifying the reaction mixture, for instance by the addition of a mineral acid, such as hydrochloric acid or sulfuric acid, and collecting by filtration the precipitate which forms. The carbamate normally needs no further purification, but if desired it can be crystallized from common solvents, such as benzene, acetone, ethyl acetate, and the like.
Reaction SMILES: S1CCCC1.[Cl:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=1.[C:15]1([CH:21]=[N+]=[N-])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>ClCCl.C([O-])(=O)C.[Rh+2].C([O-])(=O)C>[Cl:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]2[CH:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:12]2)=[CH:9][CH:8]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: [N-]=[N+]=Cc1ccccc1
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: C1CCSC1
Solvent: ClCCl
Product: Clc1ccc(C2OC2c2ccccc2)cc1
Yield: 26 %

Procedure:
To a stirred solution of tetrahydrothiophene (0.1 mmol), rhodium (II) acetate (0.01 mmol) and p-chlorobenzaldehyde (1 mmol) in dichloromethane (4 ml) was added a solution of phenyldiazomethane (1 mmol in 6 ml of tert-butylmethyl ether) at room temperature over a period of 24 hours. After addition was completed the solvent was removed in vacuo and the residue was chromatographed over silica to provide the title oxirane in 26% yield.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1[OH:21])[O:6][CH2:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[CH:10][CH:9]=1)=[O:2]>CCO.[OH-].[Na+].O>[CH:1]([C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1[OH:21])[O:6][CH2:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1)=[O:2]
Reactant: COC(=O)c1ccc(COc2ccc(O)c(C=O)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=Cc1cc(OCc2ccc(C(=O)O)cc2)ccc1O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 99.7 %

Procedure:
A suspension of compound 40 (0.50 g, 1.75 mmol) in a mixture of EtOH (5 mL) and 1N aq NaOH was stirred at room temperature for 2.5 h to give a light yellow solution. The reaction mixture was diluted with water (50 mL), washed with EtOAc (25 mL) and acidified with conc HCl (˜1 mL). The off-white precipitate that formed was collected, washed with water, and dried under high vacuum to give 0.475 g (100%) of 4-[(3-formyl-4-hydroxyphenoxy)methyl]benzoic acid (isotucaresol; III) as a cream-colored powder: mp 222-224° C. (dec); Rf 0.46 (10% MeOH-EtOAc); 1H NMR (300 MHz, acetone-d6) δ10.62 (br s, 1 H, OH), 10.00 (s, 1H, CHO), 8.06 (d, 2H, J=8 Hz, H-2,6), 7.62 (d, 2H, J=8 Hz, H-3,5), 7.43 (d, 1H, J=3 Hz, H-2′), 7.33 (dd, J=3, 8.9 Hz, H-6′), 6.95 (d, 2H, J=8.9 Hz, H-5′), 2.44 (br s, 1H, OH); 13C NMR (75 MHz, acetone-d6) δ197.2, 167.2, 156.7, 152.6, 143.3, 130.9, 130.6, 128.1, 126.5, 121.6, 119.1, 117.6, 70.7; HRMS calcd. for M+NH4+ 290.1028, found 290.1037; Anal. calcd. for C15H12O5.0.25 H2O: C, 65.09; H, 4.55. Found: C, 65.46; H, 4.56.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[NH2:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[CH:25][N:24]=[CH:23]2.C([O-])(O)=O.[Na+]>ClCCl>[Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([S:8]([NH:19][C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[N:26]=[CH:25][N:24]=[CH:23]3)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Reactant: Nc1ccc2ncncc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1c(Cl)cccc1S(=O)(=O)Nc1ccc2ncncc2c1
Reaction time: 0.08 h
Yield: 23.9 %

Procedure:
To a solution of 3-chloro-2-methylbenzenesulphonyl chloride (163 mg, 0.723 mmol) in dichloromethane (4 mL) was added pyridine (140 μL, 1.72 mmol) and the mixture was stirred under N2 for 5 min, after which time 6-aminoquinazoline [21] (100 mg, 0.689 mmol) was added. The resulting mixture was stirred for 4 h at room temperature, then saturated NaHCO3 solution (10 mL) was added and the mixture was extracted into ethyl acetate (20 mL). The organic phase was washed with brine, dried (Na2SO4), filtered and evaporated to give a residue that was purified using flash chromatography to afford a pale yellow solid (55 mg, 24%), single spot at Rf 0.56 (ethyl acetate). mp>270° C. (appeared to decompose at about 150° C.), HPLC purity 98% (tR 2.06 min in 10% water-acetonitrile). 1H NMR (CDCl3): δ 9.28 (1H, s), 9.25 (1H, s), 7.98 (1H, d, J=4.4 Hz), 7.95 (1H, d, J=5.2 Hz), 7.59-7.53 (3H, m), 7.25-7.20 (1H, m), 2.76 (3H, s). LCMS: 332.11 (M−). FAB-MS (MH+, C15H12ClN3O2S): calcd 334.0417, found 334.0420.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([NH:15][C:16]2[N:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][N:17]=2)[CH:7]=[C:8]([C:10]2[CH:11]=[N:12][NH:13][CH:14]=2)[CH:9]=1.[CH3:26][C:27]1([C:30]([O:32]C)=[O:31])[O:29][CH2:28]1>CN(C=O)C.CCOC(C)=O>[OH:29][C:27]([CH3:28])([CH2:26][N:12]1[CH:11]=[C:10]([C:8]2[CH:7]=[C:6]([NH:15][C:16]3[N:21]=[C:20]([C:22]([F:23])([F:25])[F:24])[CH:19]=[CH:18][N:17]=3)[CH:5]=[C:4]([CH3:3])[CH:9]=2)[CH:14]=[N:13]1)[C:30]([OH:32])=[O:31]
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cn[nH]c2)c1
Reactant: COC(=O)C1(C)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnn(CC(C)(O)C(=O)O)c2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride (23.5 mg, 0.59 mmol) at 0° C. was added to an oven-dried vial containing N-[3-methyl-5-(1H-pyrazol-4-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (75 mg, 0.24 mmol) in DMF (0.8 mL). The mixture was stirred for 10 minutes, and then methyl 2-methylglycidate (0.03 mL, 0.24 mmol) was added. The reaction was warmed to room temperature and stirred overnight, followed by subsequent heating to 70° C. overnight. The mixture was cooled to room temperature, diluted with EtOAc, washed with water (3×), then brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (45 to 85% ACN/water with 0.1% TFA modifier) to afford racemic 2-hydroxy-2-methyl-3-[4-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1H-pyrazol-1-yl]propanoic acid. MS ESI calcd. for C19H18F3N5O3 [M+H]+ 422. found 422.
Reaction SMILES: C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:31]1[C:39]2[C:34](=[N:35][CH:36]=[C:37]([C:40]3[CH:41]=[C:42]([CH:46]=[CH:47][C:48]=3[CH3:49])[C:43]([OH:45])=[O:44])[CH:38]=2)[O:33][C:32]=1[C:50]1[CH:55]=[CH:54][C:53]([F:56])=[CH:52][CH:51]=1.C[CH2:58][O:59][C:60](C)=[O:61]>CO.CS(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:56][C:53]1[CH:54]=[CH:55][C:50]([C:32]2[O:33][C:34]3=[N:35][CH:36]=[C:37]([C:40]4[CH:41]=[C:42]([CH:46]=[CH:47][C:48]=4[CH3:49])[C:43]([OH:45])=[O:44])[CH:38]=[C:39]3[C:31]=2[C:60]([O:59][CH3:58])=[O:61])=[CH:51][CH:52]=1
Reactant: Cc1ccc(C(=O)O)cc1-c1cnc2oc(-c3ccc(F)cc3)c(Br)c2c1
Reactant: CCOC(C)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: CS(C)=O
Product: COC(=O)c1c(-c2ccc(F)cc2)oc2ncc(-c3cc(C(=O)O)ccc3C)cc12
Reaction time: 8 h
Yield: 67 %

Procedure:
1,3-bis(diphenylphosphino)propane (160 mg, 0.387 mmol) was added to a stirring solution of palladium(II) acetate (44 mg, 0.19 mmol) and 3-(3-bromo-2-(4-fluorophenyl)furo[2,3-b]pyridin-5-yl)-4-methylbenzoic acid (275 mg, 0.645 mmol) in MeOH (2.1 mL) and DMSO (4.3 mL) at 80° C. in a Parr bomb which was charged with 150 psi CO (g) and allowed to stir overnight. The mixture was diluted with EtOAc and washed with sat NaHCO3, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated and triturated with DCM to give the expected product 3-(2-(4-fluorophenyl)-3-(methoxycarbonyl)furo[2,3-b]pyridin-5-yl)-4-methylbenzoic acid (176 mg, 0.434 mmol, 67% yield) consistent by LCMS and NMR. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.95 (1H, br. s.), 8.42 (1H, d, J=2.01 Hz), 8.34 (1H, d, J=2.01 Hz), 8.14-8.21 (2H, m), 7.93 (1H, dd, J=8.03, 1.76 Hz), 7.84 (1H, d, J=1.76 Hz), 7.45-7.53 (3H, m), 3.89 (3H, s), 2.32 (3H, s). LC-MS retention time: 2.16 min; m/z (MH+): 406. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters SunFire 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% acetonitrile/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% acetonitrile/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[N:12]=[C:13]([C:16](Cl)=[O:17])[S:14][CH:15]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[C@H:19]12[O:28][C@H:23]([O:24][C@@H:25]1[CH2:26][OH:27])[CH2:22][NH:21][CH2:20]2.C(N(CC)CC)C>C1COCC1.C(Cl)Cl>[OH:27][CH2:26][C@@H:25]1[C@@H:19]2[O:28][C@@H:23]([CH2:22][N:21]([C:16]([C:13]3[S:14][CH:15]=[C:11]([C:7]4[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=4[CH3:10])[N:12]=3)=[O:17])[CH2:20]2)[O:24]1
Reactant: OC[C@H]1O[C@@H]2CNC[C@H]1O2
Reactant: CC(=O)Nc1nc(C)c(-c2csc(C(=O)Cl)n2)s1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nc(C)c(-c2csc(C(=O)N3C[C@H]4O[C@H](CO)[C@@H](C3)O4)n2)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2′-Acetylamino-4′-methyl-[4,5′]bithiazolyl-2-carbonyl chloride, prepared as in Step I of Example 13, described above (200 mg, 0.66 mmol, 1 eq.), is dissolved in THF (8 ml) and DCM (4 ml). (1R,5R,7R)-6,8-Dioxa-3-azabicyclo[3.2.1]oct-7-ylmethanol, synthesized according the literature (Guarna et al., 1999, J. Org. Chem., 64, 7347) (96.2 mg; 0.66 mmol; 1 eq.), and triethylamine (0.37 ml; 2.65 mmol; 4 eq.) are added and the mixture is stirred 1 hour at rt. Solvents are evaporated and the crude product is purified by preparative HPLC, affording Compound (51) as a white-off powder (110 mg; 40%). M− (ESI): 408.99; M+ (ESI): 410.89. HPLC (method A), Rt: 2.15 min (purity: 99.8%).
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([O:19][C:20]([C:22]1[C:26]([CH2:27][CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]2)=[C:25]([CH:37]=O)[NH:24][C:23]=1[CH3:39])=[O:21])[CH3:18].N1CCCCC1>C(O)C>[CH2:17]([O:19][C:20]([C:22]1[C:26]([CH2:27][CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]2)=[C:25]([CH:37]=[C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[CH:15][C:7]=3[C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[NH:11][C:10]2=[O:16])[NH:24][C:23]=1[CH3:39])=[O:21])[CH3:18]
Reactant: CCOC(=O)c1c(C)[nH]c(C=O)c1CCCN1CCN(C)CC1
Reactant: O=C1Cc2c(cccc2-c2ccccc2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3cccc(-c4ccccc4)c32)c1CCCN1CCN(C)CC1
Temperature: 70 °C
Yield: 29.3 %

Procedure:
To a solution of 4-phenyl-1,3-dihydro-indol-2-one (41.9 mg, 0.20 mmol) and 5-formyl-2-methyl-4-[3-(4-methyl-piperazin-1-yl)-propyl]-1H-pyrrole-3-carboxylic acid ethyl ester (64.2 mg, 0.20 mmol) in ethanol (1 mL) was added piperidine (0.1 mL). The reaction mixture was stirred at 70° C. for over-night. The solvent was evaporated and the residue was purified on a silica gel column eluting with MeOH—CH2CL2 1:9 to provide 2-methyl-4-[3-(4-methyl-piperazin-1-yl)-propyl]-5-(2-oxo-4-phenyl-1,2-dihydro-indol-3-ylidenemethyl)-1H-pyrrole-3-carboxylic acid ethyl ester as a yellow solid (30 mg, 29%).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH2:11][CH3:12])=[N:9][N:10]=2)[CH:5]=[CH:6][N:7]=1>CO.[Pt]=O>[ClH:1].[CH2:11]([C:8]1[N:4]2[CH2:5][CH2:6][NH:7][CH2:2][C:3]2=[N:10][N:9]=1)[CH3:12]
Reactant: CCc1nnc2c(Cl)nccn12
Agent: O=[Pt]
Solvent: CO
Product: CCc1nnc2n1CCNC2
Product: Cl

Procedure:
The title compound was prepared from 8-chloro-3-ethyl-1,2,4-triazolo[4,3-a]pyrazine (2.70 g, 14.8 mmol, from Step A) and platinum oxide (0.4 g) in 200 mL of methanol in a paar shaker under hydrogen (50 psi) for 14 hours. Filtration through Celite followed by concentration gave the title compound as a solid. 1H NMR (500 MHz, CD3OD) δ 1.36 (t, 3H, J=6.0 Hz), 2.84 (q, 2H, J=6.0 Hz), 3.70 (t, 2H, J=8.0 Hz), 4.28 (t, 2H, J=8.0 Hz). 4.06(s, 2H). ESI-MS 153 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9](=[O:15])[CH2:8][CH2:7][CH2:6]2.[Cl:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:22]=1[CH:23]=O.[OH-].[Na+]>C(O)C>[Cl:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:22]=1/[CH:23]=[C:8]1/[C:9](=[O:15])[C:10]2[C:5]([CH2:6][CH2:7]/1)=[CH:4][C:3]([O:2][CH3:1])=[C:12]([O:13][CH3:14])[CH:11]=2
Reactant: O=Cc1ccncc1Cl
Reactant: COc1cc2c(cc1OC)C(=O)CCC2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc2c(cc1OC)C(=O)/C(=C/c1ccncc1Cl)CC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 40.4 %

Procedure:
At room temperature, a mixture of 6,7-dimethoxy-1-tetralone (1.44 g, 7 mmol) and 3-chloro-4-pyridinecarboxaldehyde (1.0 g, 7 mmol) was added in one portion to a solution of sodium hydroxide (280 mg, 1 equiv) in ethanol (7 mL). After being stirred at room temperature for 4 h, the solid obtained was filtered and rinsed with ethanol then diethyl ether to give the title compound 85 (Yield 932 mg, 44%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:16]([S:18](Cl)(=[O:20])=[O:19])[CH3:17].O>N1C=CC=CC=1.C(OCC)(=O)C>[C:14]([C:11]1[N:12]([CH3:13])[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:18]([CH2:16][CH3:17])(=[O:20])=[O:19])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1)#[N:15]
Reactant: Cn1c(C#N)ccc1-c1ccc(N)cc1
Reactant: CCS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CCS(=O)(=O)Nc1ccc(-c2ccc(C#N)n2C)cc1
Reaction time: 4 h
Yield: 80.6 %

Procedure:
5-(4-Aminophenyl)-1-methyl-1H-pyrrole-2-carbonitrile (1.3 g, 6 mmol) was dissolved in pyridine (10 mL), ethane sulfonyl chloride (0.54 mL, 5.7 mmol) was added, the mixture was stirred for 4 hours, and then water was added. The mixture was diluted with ethyl acetate and washed with water, saturated CuSO4, 2N HCl, brine, dried over MgSO4, and concentrated. Flash chromatography (5%-50% ethyl acetate in hexane) afforded N-[4-(5-cyano-1-methyl-1H-pyrrol-2-yl)phenyl]ethanesulfonamide (1.33 g).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH:12]=[C:11]([Cl:23])[C:10]=1[O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1C(=O)N([Br:39])C(=O)C1>CN(C=O)C.O>[Br:39][C:12]1[C:13]([O:15][Si:16]([C:19]([CH3:20])([CH3:21])[CH3:22])([CH3:18])[CH3:17])=[CH:14][C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2])=[C:10]([O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:26])[CH3:27])[C:11]=1[Cl:23]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(Cl)c(O[Si](C)(C)C(C)(C)C)c(O[Si](C)(C)C(C)(C)C)c1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1cc(O[Si](C)(C)C(C)(C)C)c(O[Si](C)(C)C(C)(C)C)c(Cl)c1Br
Yield: 27 %

Procedure:
A solution of 0.100 g (0.20 mmol) of 14 and 0.0354 g (0.20 mmol) of NBS in 2 mL of DMF under argon was stirred at 50° C. for 2 day. The solution was diluted with 30 mL of water, extracted three times with diethyl ether (30 mL each), and the combined extracts were washed with brine, dried (MgSO4), concentrated, and column chromatographed on silica gel using a mixture of hexane and diethyl ether (100:1) as eluent to give 31.4 mg (27% yield) of 4 and 62.9 mg (54% yield) of 15. Compound 15: 1H NMR (CDCl3) δ 6.54 (s, 1H, Ar, C6-H), 1.03 (s, 18H, t-Bu), 0.97 (s, 9H, t-Bu), 0.23 (s, 12H, Me), 0.17 (s, 6H, Me).
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=O)([CH3:5])[C:3]#[CH:4].CN(C)C=O.[NH2:20][C:21]1[CH:22]=[C:23]([CH:40]=[CH:41][C:42]=1[F:43])[O:24][C:25]1[N:30]=[C:29]2[S:31][C:32]([NH:34][C:35]([CH:37]3[CH2:39][CH2:38]3)=[O:36])=[N:33][C:28]2=[CH:27][CH:26]=1.O>C(Cl)(=O)C(Cl)=O.CN(C)C(=O)C>[CH:37]1([C:35]([NH:34][C:32]2[S:31][C:29]3[C:28]([N:33]=2)=[CH:27][CH:26]=[C:25]([O:24][C:23]2[CH:40]=[CH:41][C:42]([F:43])=[C:21]([NH:20][C:9](=[O:11])[C:8]4[CH:12]=[CH:13][CH:14]=[C:6]([C:2]([CH3:1])([CH3:5])[C:3]#[CH:4])[CH:7]=4)[CH:22]=2)[N:30]=3)=[O:36])[CH2:38][CH2:39]1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1F
Reactant: C#CC(C)(C)c1cccc(C(=O)O)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Product: C#CC(C)(C)c1cccc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)sc4n3)ccc2F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.5 %

Procedure:
To a solution of 3-(1,1-dimethylprop-2-yn-1-yl)benzoic acid (0.10 g, 0.5 mmol) in oxalyl chloride (1 mL) was added N,N-dimethylformamide (40 μL), and the mixture was stirred at room temperature for 30 min, and concentrated to dryness under reduced pressure. This was dissolved in a mixed solution of N,N-dimethylacetamide (1 mL) and tetrahydrofuran (1 mL), and the solution was added dropwise to a solution of N-[5-(3-amino-4-fluorophenoxy)[1,3]thiazolo[5,4-b]pyridin-2-yl]cyclopropanecarboxamide (0.12 g, 0.33 mmol) produced in Example C63(vi) in N,N-dimethylacetamide (1 mL) under ice-cooling. The reaction mixture was stirred at room temperature for 3 hr, and poured into water (100 mL), and the mixture was extracted with ethyl acetate (100 mL×2). The ethyl acetate layers were combined, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=0/100→100/0), and recrystallized from methanol to give the title compound (62 mg, 37%) as colorless crystals.
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].Cl.[C:9]1([CH2:15][CH2:16][C:17]2[N:18]=[C:19]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[S:20][CH:21]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C.O>ClCCl>[C:9]1([CH2:15][CH2:16][C:17]2[N:18]=[C:19]([CH:22]3[CH2:27][CH2:26][N:25]([C:1](=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5])[CH2:24][CH2:23]3)[S:20][CH:21]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: c1ccc(CCc2csc(C3CCNCC3)n2)cc1
Reactant: CCCCC(=O)Cl
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCC(=O)N1CCC(c2nc(CCc3ccccc3)cs2)CC1
Reaction time: 8 h

Procedure:
Pentanoyl chloride (133 mg) is added to a solution of 4-[4-(2-phenylethyl)-1,3-thiazol-2-yl]piperidine hydrochloride (II-1, 309 mg) and triethylamine (0.7 ml) in dichloromethane (3 ml). The mixture is stirred overnight, and water is then added. The aqueous phase is separated off and extracted with ethyl acetate, and the combined organic phases are then dried with sodium sulphate and concentrated. The residue is purified. This gives 1-{4-[4-(2-phenylethyl)-1,3-thiazol-2-yl]piperidin-1-yl}pentan-1-one (179 mg).