Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:14]([CH3:22])[C:13]([C:23](OC)=[O:24])=[CH:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.C1(C)C=CC=CC=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([S:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:14]([CH3:22])[C:13]([CH:23]=[O:24])=[CH:12]2)(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cn(S(=O)(=O)c2cccc(Cl)c2)c(-c2ccccc2)c1C
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1c(C=O)cn(S(=O)(=O)c2cccc(Cl)c2)c1-c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 87.4 %

Procedure:
A solution (15 mL) of methyl 1-[(3-chlorophenyl)sulfonyl]-4-methyl-5-phenyl-1H-pyrrole-3-carboxylate (700 mg) in tetrahydrofuran was cooled to −78° C., a 1.5 mol/L toluene solution (4.3 mL) of diisobutylaluminum hydride was added dropwise, and the mixture was further stirred at −78° C. for 30 min. 1 mol/L Hydrochloric acid (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. A solution (20 mL) of the residue in acetonitrile was cooled to 0° C., tetra-n-propylammonium perruthenate (76 mg), N-methylmorpholine N-oxide (377 mg) and molecular sieves 4A powder (1.5 g) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, the residue was suspended in ethyl acetate, and the suspension was filtered through celite. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→2:1) to give 1-[(3-chlorophenyl)sulfonyl]-4-methyl-5-phenyl-1H-pyrrole-3-carbaldehyde as a brown solid (yield 565 mg, 88%). 1-[(3-Chlorophenyl)sulfonyl]-4-methyl-5-phenyl-1H-pyrrole-3-carbaldehyde (560 mg) was dissolved in methanol (25 mL), and methylammonium chloride (1.05 g) and sodium cyanoborohydride (294 mg) were added. The mixture was stirred at room temperature for 1 hr, and concentrated under reduced pressure. The residue was dissolved in water, and the solution was alkalized with a saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→ethyl acetate). The obtained oil was dissolved in ethyl acetate (5 mL), and a 4 mol/L hydrogen chloride-ethyl acetate solution (0.5 mL) was added. The precipitated crystals were collected by filtration and vacuum-dried to give the title compound as a colorless solid (yield 154 mg, 24%).
Reaction SMILES: [CH2:1]([CH:6]1[C:10](=[O:11])[CH2:9][CH2:8][CH:7]1[CH:12](C(OC)=O)[C:13]([O:15][CH3:16])=[O:14])[CH2:2][CH2:3][CH2:4][CH3:5].C(C1C(=O)CCC1CC(O)=O)CCCC>O>[CH2:1]([CH:6]1[C:10](=[O:11])[CH2:9][CH2:8][CH:7]1[CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCC1C(=O)CCC1C(C(=O)OC)C(=O)OC
Agent: CCCCCC1C(=O)CCC1CC(=O)O
Solvent: O
Product: CCCCCC1C(=O)CCC1CC(=O)OC
Reaction time: 4 h
Yield: 95.9 %

Procedure:
The same 1 L four-neck flask that was used in Example 1 was charged with 600 g of raw material containing 550 g (1.94 mol) of dimethyl 2-pentyl-3-oxo-cyclopentylmalonate produced in the same manner as in Production Example 1 and the raw material was heated to 215° C. with stirring under normal pressure. Then, the supply of water to the bottom of the reactor was started. During the supply of water, the supply rate of water was adjusted to 18 g/h from the start of the supply to the 1st hour, to 12 g/h from the 1st hour to the 2nd hour, to 6 g/h from the 2nd hour to the 3rd hour and to 3 g/h after the 3rd hour with measuring the content of water in the reaction solution by a Karl Fischer's coulometric titration (instrument: Trace-water measuring device AQ-7, manufactured by HIRANUMA SANGYO Co., Ltd.) such that the content of water was limited to 0.4% by weight or less. Then, the reaction was completed for 4 hours from the start of the supply of water. The maximum water concentration in the reaction solution was 0.14% by weight. During the reaction, the difference (X−Y) between the integrating molar number X (excluding distilled water content) of the water to be supplied and the molar number Y of the water reacted with dimethyl 2-pentyl-3-oxo-cyclopentylmalonate was 10.3% at a maximum based on the molar number of the supplied dimethyl 2-pentyl-3-oxo-cyclopentylmalonate. It was found that the reaction product contained 420 g (1.86 mol, yield: 96.0%) of methyl 2-pentyl-3-oxo-cyclopentylacetate and 5.8 g (0.027 mol) of 2-pentyl-3-oxo-cyclopentylacetic acid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1.N1C=CC=CC=1.[Cl:16][CH2:17][C:18](Cl)=[O:19]>CCOCC>[CH3:1][C:2]1[C:7]([NH:8][C:18](=[O:19])[CH2:17][Cl:16])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: Cc1ccc(N)c(C)n1
Reactant: O=C(Cl)CCl
Solvent: CCOCC
Solvent: c1ccncc1
Product: Cc1ccc(NC(=O)CCl)c(C)n1
Reaction time: 1 h

Procedure:
A solution of 2,6-dimethyl-3-aminopyridine (24.9 grams) in ether (200 ml), and pyridine (21 grams) are charged into a glass reaction vessel equipped with mechanical stirrer, thermometer and addition funnel. The reaction mixture is cooled to a temperature below about 10° C and chloroacetyl chloride (11.3 grams) is slowly added over a period of about 15 minutes. Stirring and cooling is continued for an additional period of about 1 hour to ensure the completion of the reaction. The resulting precipitate is then recovered by filtration, is washed with aqueous potassium carbonate and with water, and is dried to yield the desired product N-(2,6-dimethyl-3-pyridyl)-α-chloroacetamide.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)[N:3]=1.[F:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[C:25]([F:27])[CH:26]=1>>[F:20][C:21]1[CH:22]=[C:23]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:14][C:15]3[CH:19]=[CH:18][NH:17][N:16]=3)[N:3]=2)[CH:24]=[C:25]([F:27])[CH:26]=1
Reactant: COc1ccc2c(Cl)nc(Nc3cc[nH]n3)cc2c1
Reactant: OB(O)c1cc(F)cc(F)c1
Product: COc1ccc2c(-c3cc(F)cc(F)c3)nc(Nc3cc[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 3,5-difluoro-phenylboronic acid to give [1-(3,5-difluoro-phenyl)-6-methoxy-isoquinolin-3-yl]-(1H-pyrazol-3-yl)-amine. LC-MS m/e 353(MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([I:8])[C:3]=1[CH2:9][C:10]([OH:12])=[O:11].OS(O)(=O)=O.[CH3:18][CH2:19]O>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([I:8])[C:3]=1[CH2:9][C:10]([O:12][CH2:18][CH3:19])=[O:11]
Reactant: CCO
Reactant: O=C(O)Cc1c(Cl)cccc1I
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1c(Cl)cccc1I
Temperature: 25 °C

Procedure:
A mixture of 2-(2-chloro-6-iodophenyl)acetic acid (10 g, 34 mmol) in 100 mL EtOH was treated with 2 mL concentrated H2SO4, and refluxed for 15 hours. The resulting mixture was cooled to room temperature and concentrated. The residue was diluted with 200 mL EtOAc, washed with water (3×50 mL), saturated NaCl (20 mL), dried over sodium sulfate and concentrated. The crude mixture was purified by column chromatography (10-20% EtOAc/hexane) to give 9.5 g of pale yellow oil. MS m/e: (M+H)+ 324.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([N:27]([CH3:35])[CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])=[O:26])=[CH:21][CH:20]=3)[CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)=[C:8]([CH3:36])[C:7]=2[CH:37]=1)#[N:2].O1CCCC1.[OH-].[Li+]>C(O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([C:25]([N:27]([CH3:35])[CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:26])=[CH:23][CH:24]=3)[CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)=[C:8]([CH3:36])[C:7]=2[CH:37]=1)#[N:2]
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(C#N)cc3c2C)C2CCCCC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(C(Nc2ccc(C(=O)N(C)CCC(=O)O)cc2)C2CCCCC2)oc2ccc(C#N)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.5 %

Procedure:
To a mixture of ethyl 3-{[(4-{[(5-cyano-3-methyl-1-benzofuran-2-yl)(cyclohexyl)methyl]amino}phenyl)carbonyl](methyl)amino}-propanoate (193 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N lithium hydroxide aqueous solution (770 μL), and the mixture was stirred at room temperature for 3 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (770 μL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (163 mg, 90%) as a white solid.
Reaction SMILES: [CH2:1]1[CH:9]2[CH:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:3][C:2]1=[O:10].C([O-])(O)=[O:12].[Na+].ClC1C=CC=CC=1C(OO)=O.[O-]S([O-])(=S)=O.[Na+].[Na+]>ClCCl>[CH2:1]1[CH:9]2[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]2[CH2:3][C:2](=[O:10])[O:12]1
Reactant: O=C([O-])O
Reactant: O=C1CC2CCCCC2C1
Agent: O=C(OO)c1ccccc1Cl
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: O=C1CC2CCCCC2CO1
Temperature: 20 °C
Reaction time: 17 h

Procedure:
To a stirred mixture of 3.16 g (23 mmol) of (3a alpha, 7a alpha)-octahydro-2H-inden-2-one, 17.3 g (207 mmol) of NaHCO3 and 300 mL of dichloromethane was added 9.29 g of 85% m. chloroperoxybenzoic acid in small portions over 15 min. The reaction mixture was stirred for 17 h at 20° C., then 200 mL of 10% aqueous Na2S2O3 was added and, after 15 min, the organic phase was separated. Extraction of the aqueous portion with 2×100 mL of dichloromethane, washing of the combined organic solutions with 10% Na2CO3 and concentration of the dried (MgSO4) solutions under vacuum gave 3.51 g (95%) of racemic (4a alpha, 8a alpha)-octahydro-3H-2-benzopyran-3-one. TLC Rf 0.40 (SiO2, ethyl ether, iodine-brown).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[C:12]([OH:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[N:9]2)[CH:5]=[CH:4][C:3]=1[S:18]([NH2:21])(=[O:20])=[O:19].C(=O)([O-])[O-].[K+].[K+].[CH:28](I)([CH3:30])[CH3:29].[OH-].[Na+]>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([N:8]2[C:12]([O:13][CH:28]([CH3:30])[CH3:29])=[CH:11][C:10]([C:14]([F:16])([F:17])[F:15])=[N:9]2)[CH:5]=[CH:4][C:3]=1[S:18]([NH2:21])(=[O:19])=[O:20]
Reactant: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2O)cc1F
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Oc1cc(C(F)(F)F)nn1-c1ccc(S(N)(=O)=O)c(F)c1
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
2-Fluoro-4-(5-hydroxy-3-trifluoromethyl-pyrazol-1-yl)-benzenesulfonamide (163 mg) and potassium carbonate (276 mg) were mixed in dimethyl formamide, followed by the addition of isopropyl iodide. The reaction mixture was stirred at 50° C. for 1.5 hours. After cooling to room temperature, 0.5 N sodium hydroxide solution (10 ml) was added, and the product was extracted with ethyl acetate (50 ml) and benzene (25 ml). The organic layer was dried with sodium sulfate, and the solvent was evaporated in vacuo to give the crude product, which was purified by preparative silica gel plate using 5:2 of hexane:ethyl acetate to afford the title compound (32 mg). The title compound was characterized by tandem high pressure liquid chromatography/mass spectrometry and yielded a retention time of 7.523 minutes and had a parent ion at 368 AMU.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:6](=[N:7][O:8][N:9]=2)[C:5]([S:11](Cl)(=[O:13])=[O:12])=[CH:4][CH:3]=1.[NH2:15][C:16]1[CH:17]=[C:18]([C:22]2[NH:26][N:25]=[N:24][N:23]=2)[CH:19]=[CH:20][CH:21]=1>>[Cl:1][C:2]1[C:10]2=[N:9][O:8][N:7]=[C:6]2[C:5]([S:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[NH:26][N:25]=[N:24][N:23]=3)[CH:17]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)c2nonc12
Product: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1ccc(Cl)c2nonc12
Yield: 52 %

Procedure:
The product was prepared according to General Procedure 6, described in Example 65, with 4-chloro-7-chlorosulfonyl-2,1,3-benzoxadiazole (13.9 mg, 0.055 mmol) and 5-(3-aminophenyl)tetrazole (8.0 mg, 0.050 mmol). The title compound was obtained in 52% yield (9.8 mg). MS (ESI+) calcd mass for C13H8ClN7O3S 377.009786, found 377.010126.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:7]1[CH2:8][NH:9][CH2:10][CH2:11][CH:12]=1)[C:5]#[N:6].Cl[C:14]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:15]>>[CH3:1][O:2][N:3]=[C:4]([C:7]1[CH2:8][N:9]([C:14]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:15])[CH2:10][CH2:11][CH:12]=1)[C:5]#[N:6]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CON=C(C#N)C1=CCCNC1
Product: CON=C(C#N)C1=CCCN(C(=O)Oc2ccccc2)C1
Yield: 81.8 %

Procedure:
α-(Methoxyimino)-α-(1,2,5,6-tetrahydropyridin-3-yl)acetonitrile (D8) (0.5 g, 0.003 moles) was treated with phenyl chloroformate (0.42 ml, 0.0033 moles) according to the method of Example 1. The crude product was crystallised from diethyl ether/pentane to give the title compound (E3) as a white crystalline solid (0.7 g, 81%) m.p. 111°-112° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10](I)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7].[C:16]([C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17].C1C=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.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([NH:24][C:23]2[CH:25]=[CH:26][C:20]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:21][CH:22]=2)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: COC(=O)c1cccc(I)c1C(=O)OC
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(Nc2ccc(C(C)(C)C)cc2)c1C(=O)OC
Yield: 74 %

Procedure:
A mixture of 3-iodophthalic acid dimethyl ester (1.0 g, 3.1 mmol), 4-tert-butylaniline (0.46 g, 3.1 mmol), Pd2(dba)3 (0.13 g, 0.14 mmol), rac-BINAP (0.058 g, 0.093 mmol), and cesium carbonate (1.4 g, 4.3 mmol), in 6 mL toluene was heated to reflux under nitrogen for 24 hours. The reaction mixture was cooled, diluted with CH2Cl2 (10 mL), and filtered through Celite, and the filter was washed with additional CH2Cl2 (30 mL). The filtrate was evaporated, and the residue was chromatographed using a hexanes-ethyl acetate gradient, eluting 0.78 g of the product at 85:15 hexanes-ethyl acetate, in 74% yield: 1H NMR (CDCl3) δ 1.32 (s, 9H), 3.86 (s, 3H), 3.88 (s, 3H), 7.01-7.11 (m, 3H), 7.27-7.36 (m, 4H), 8.07 (br, 1H).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH2:5][C:6]3[C:12]([C:13]4[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=4)=[N:11][N:10]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:7]=3[C:8]=2[CH:9]=1.CC1(C)C(C)(C)OB([C:37]2[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:20][O:19][C:16]1[CH:15]=[CH:14][C:13]([C:12]2[C:6]3[CH2:5][C:4]4[S:3][C:2]([C:37]5[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=5)=[CH:9][C:8]=4[C:7]=3[N:10]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:26])([CH3:28])[CH3:27])[N:11]=2)=[CH:18][CH:17]=1
Reactant: COc1ccc(-c2nn(COCC[Si](C)(C)C)c3c2Cc2sc(Br)cc2-3)cc1
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(-c2nn(COCC[Si](C)(C)C)c3c2Cc2sc(-c4ccncc4)cc2-3)cc1
Temperature: 100 °C
Yield: 65 %

Procedure:
A mixture of the corresponding 2-Bromo-6-(4-methoxy-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.76 g, 1.5 mmol), 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (0.3 g, 2.3 mmol), Na2CO3 (2 M, 3.7 mL), and Pd(PPh3)2Cl2 (14.6 mg, 0.012 mmol) in toluene/ethanol (1:1, 10 mL) was heated at 100° C. for 8 hr. The solution was cooled to room temperature and extracted with ethyl acetate. The target product was purified by gravity column chromatography (20% EtOAc in hexane) to give 6-(4-Methoxy-phenyl)-2-pyridin-4-yl-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene as brown solid in 65% yield.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:15]C(=O)C)[S:5][C:6]=1[C:7]#[C:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1.O>O.NN>[CH3:1][C:2]1[N:3]=[C:4]([NH2:15])[S:5][C:6]=1[C:7]#[C:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(=O)Nc1nc(C)c(C#Cc2cccnc2)s1
Agent: NN
Solvent: O
Product: Cc1nc(N)sc1C#Cc1cccnc1

Procedure:
As shown in step 2-ii of Scheme 2, compound 1003 (400 mg, 1.56 mmol) was stirred in hydrazine hydrate at 70° C. for 20 minutes. Water was added and the resulting precipitate was collected by filtration, washed with water, and dried under high vacuum to produce 4-methyl-5-(pyridin-3-ylethynyl)thiazol-2-amine (compound 1004), which was used in subsequent reactions as is.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][C:13]3([C:27]4[CH:26]=[N:25][N:24]([CH3:28])[C:23]=4[C:22]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[O:16]3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([O:29][CH3:30])[CH:3]=1.[CH3:31][SH:32]>CN(C=O)C>[CH3:30][O:29][C:4]1[CH:3]=[C:2]([S:32][CH3:31])[CH:7]=[CH:6][C:5]=1[C:8]([N:10]1[CH2:11][CH2:12][C:13]2([C:27]3[CH:26]=[N:25][N:24]([CH3:28])[C:23]=3[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:16]2)[CH2:14][CH2:15]1)=[O:9]
Reactant: COc1cc(F)ccc1C(=O)N1CCC2(CC1)Oc1ccccc1-c1c2cnn1C
Reactant: CS
Solvent: CN(C)C=O
Product: COc1cc(SC)ccc1C(=O)N1CCC2(CC1)Oc1ccccc1-c1c2cnn1C
Temperature: 80 °C

Procedure:
A mixture of (4-fluoro-2-methoxyphenyl)(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone (500 mg, 1.23 mmol) and methanethiol (172 mg, 2.45 mmol) in DMF (5 mL) was heated at 80° C. for 36 h. The reaction led to the desired product as well as O-demethylated version of the product. To the crude reaction mixture was added 3 eq of iodomethane to remethylate to the desired product. The reaction mixture was washed with 1N HCl, sat. aq. NaHCO3, and brine. The organics were dried over sodium sulfate and evaporated. The crude product was purified by column chromatography eluting with 50-100% ethyl acetate in hexanes to give (2-methoxy-4-(methylthio)phenyl)(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone (60%). ESI-MS m/z calc. 435.2. found 436.1 (M+1)+. Retention time: 1.53 minutes (3 min run).
Reaction SMILES: S1C=CC(CC[O:8][C:9](=[O:25])[CH2:10][CH2:11][C:12]([C:23]#[N:24])([S:14][C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[S:16])[CH3:13])=C1.N(C(C#N)(C)CCC(O)=O)=NC(C#N)(C)CCC(O)=O.C(SSC(=S)C1C=CC=CC=1)(=S)C1C=CC=CC=1>C(OCC)(=O)C>[C:23]([C:12]([S:14][C:15](=[S:16])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([CH3:13])[CH2:11][CH2:10][C:9]([OH:25])=[O:8])#[N:24]
Reactant: CC(C#N)(CCC(=O)OCCc1ccsc1)SC(=S)c1ccccc1
Agent: CC(C#N)(CCC(=O)O)N=NC(C)(C#N)CCC(=O)O
Agent: S=C(SSC(=S)c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Product: CC(C#N)(CCC(=O)O)SC(=S)c1ccccc1
Temperature: 25 °C

Procedure:
The synthesis scheme for (thiophen-3-yl)ethyl-4-cyano-4-(phenylcarbonothioylthio)pentanoate is shown in FIG. 15 and is performed as follows. First, the intermediary molecule, 4-Cyano-4-((thiobenzoyl)sulfanyl)pentanoic acid is synthesized by dissolving 4,4′-Azobis(4-cyanovaleric acid) (4.19 g, 0.0149 mol) and bis(thiobenzoyl)disulfide (3.07 g, 0.01 mol) in ethyl acetate (200 mL) in a 500 mL round-bottom flask equipped with a condenser. The mixture is degassed by bubbling with nitrogen and heated to reflux for 20 hours under nitrogen. The reaction is allowed to cool to room temperature, and the solvent is removed in vacuum. The crude product is purified by column chromatography (silica gel) using ethyl acetate:hexanes 2:3 as the eluent. After removal of solvent, the red fraction gives 4-cyano-4-((thiobenzoyl)sulfanyl)-pentanoic acid as a red oil. The product is solidified upon sitting at −20° C. 1H NMR (CDCl3) δ (ppm): 1.93 (s, 3H, CH3); 2.38-2.80 (m, 4H, CH2CH2); 7.42 (m, 2H, m-ArH); 7.56 (t, 1H, J=8 Hz p-ArH); 7.91 (d, 2H, J=7.3 Hz, o-ArH). 13C NMR (CDCl3) δ (ppm): 24.1, 29.5, 32.9, 45.6, 118.4, 126.7, 128.6, 133.1, 144.4, 177.3, 222.1.
Reaction SMILES: C(OC(=O)C)(=O)C.[C:8]([N:11]1[CH2:15][CH2:14][CH:13]([C:16]2[N:24]3[C:19]([C:20]([NH2:25])=[N:21][CH:22]=[N:23]3)=[C:18]([C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([NH:35][C:36]4[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:39]=[CH:38][C:37]=4[F:46])=[O:34])=[C:28](F)[CH:27]=3)[CH:17]=2)[CH2:12]1)(=[O:10])[CH3:9]>>[C:8]([N:11]1[CH2:15][CH2:14][CH:13]([C:16]2[N:24]3[C:19]([C:20]([NH2:25])=[N:21][CH:22]=[N:23]3)=[C:18]([C:26]3[CH:27]=[CH:28][C:29]([NH:32][C:33]([NH:35][C:36]4[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:39]=[CH:38][C:37]=4[F:46])=[O:34])=[CH:30][CH:31]=3)[CH:17]=2)[CH2:12]1)(=[O:10])[CH3:9]
Reactant: CC(=O)N1CCC(c2cc(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)c(F)c3)c3c(N)ncnn23)C1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N1CCC(c2cc(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)cc3)c3c(N)ncnn23)C1
Yield: 25 %

Procedure:
Example 206 (91 mg, 0.182 mmol) is allowed to react with acetic anhydride (20 mg, 0.200 mmol) following the procedure to make N-{4-[7-(1-acetylpyrrolidin-3-yl)-4-aminopyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′ [2-fluoro-5-(trifluoromethyl)-phenyl]urea. The product was purified by ether trituration to yield 25 mg (25%) pure desired product. 1H NMR (300 MHz, DMSO-d6) δ 10.12 (s, 1H), 10.05 (bs, 1H), 8.54 (d, J=5.1 Hz, 1H), 8.26 (t, J=8.4 Hz, 1H), 8.00 (s, 1H), 7.92 (s, 1H), 7.39 to 7.23 (m, 3H), 6.65 (d, J=4.5 Hz, 1H), 3.94 to 3.29 (m, 5H), 2.94 to 2.15 (m, 2H), 1.95 (s, 3H); MS [M+H]+=543.2; HPLC RT=2.66.
Reaction SMILES: Cl.Cl.Cl.[CH2:4]([N:6]([CH2:32][CH3:33])[CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[C:22]([CH:23]=1)=[N:21][C:20]1[C:15](=[CH:16][CH:17]=[C:18]([O:24][CH2:25][CH2:26][N:27]([CH2:30][CH3:31])[CH2:28][CH3:29])[CH:19]=1)[CH:14]=2)[CH3:5].[Cl:34][Pt-2:35](Cl)(Cl)(Cl)(Cl)[Cl:36].[K+].[K+]>C(O)C>[CH2:30]([N:27]([CH2:28][CH3:29])[CH2:26][CH2:25][O:24][C:18]1[CH:17]=[CH:16][C:15]2[C:20]([CH:19]=1)=[N:21][C:22]1[C:13](=[CH:12][CH:11]=[C:10]([O:9][CH2:8][CH2:7][N:6]([CH2:32][CH3:33])[CH2:4][CH3:5])[CH:23]=1)[CH:14]=2)[CH3:31].[Pt:35]([Cl:36])[Cl:34]
Reactant: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: CCN(CC)CCOc1ccc2cc3ccc(OCCN(CC)CC)cc3nc2c1
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: Cl[Pt]Cl

Procedure:
A suspension of 3,6-bis(2-diethylaminoethoxy)acridine trihydrochloride and one equivalent of potassium hexachloroplatinate is refluxed in ethanol. The precipitate is collected giving the desired 1:1 complex.