Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(OCCC(C)C)=O.[Cl-:9].[Li+].N[C:12]1[C:13]([O:24][CH3:25])=[CH:14][C:15]([Cl:23])=[C:16]2[C:21]=1[C:20](=[O:22])[NH:19][CH2:18][CH2:17]2>C(#N)C.[Cu](Cl)Cl>[Cl:23][C:15]1[CH:14]=[C:13]([O:24][CH3:25])[C:12]([Cl:9])=[C:21]2[C:16]=1[CH2:17][CH2:18][NH:19][C:20]2=[O:22]
Reactant: COc1cc(Cl)c2c(c1N)C(=O)NCC2
Reactant: [Cl-]
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Agent: [Li+]
Solvent: CC#N
Product: COc1cc(Cl)c2c(c1Cl)C(=O)NCC2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 91.3 %

Procedure:
Isopentyl nitrite (20 mL, 0.149 mol) was added dropwise to a heated (55° C.) suspension of copper (II) chloride (40 g, 0.298 mol) and lithium chloride (38 g, 0.905 mol) in acetonitrile (500 mL). The mixture was stirred at that temperature for 5 minutes, then 8-amino-5-chloro-7-methoxy-3,4-dihydroisoquinolin-1(2H)-one (296d, 20 g, 0.089 mol) was added in portions. After the addition was complete, stirring was continued at 55° C. for 45 minutes. The reaction mixture was cooled to room temperature, quenched with saturated aqueous ammonium chloride (300 mL), and extracted with ethyl acetate (4×200 mL). The combined organic layers were washed with aqueous ammonium chloride (200 mL) and brine (100 mL), dried over sodium sulfate, and concentrated under vacuum to give crude 5,8-dichloro-7-methoxy-3,4-dihydroisoquinolin-1(2H)-one (296e, 20 g, 90% purity, 92% yield) as a brown solid. MS: 245 [M+1].
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[NH2:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][OH:18]>C(N(CC)CC)C>[N+:11]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[NH:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][OH:18])([O-:13])=[O:12]
Reactant: Nc1ccccc1CO
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1Cl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cccc([N+](=O)[O-])c1Nc1ccccc1CO
Yield: 54.3 %

Procedure:
2.85 g (14 mmol) of 1-chloro-2,6-dinitrobenzene and 1.73 g (14 mmol) of 2-aminobenzyl alcohol were dissolved in 30 ml of triethylamine and heated under reflux for 24 hours. After concentrating, the residue was purified by silica gel column chromatography. Thus 2.2 g of 2-((2,6-dinitrophenyl)amino) benzyl alcohol was obtained. 0.29 g (1 mmol) of this powder was dissolved in 20 ml of dry dimethylformamide. After adding 40 mg (1 mmol) of sodium hydride (in oil, content: 60%), the reaction mixture was stirred at room temperature for 15 minutes and then at 150° C. for 2 hours. After cooling, 200 ml of ethyl acetate was added thereto and the mixture was washed with water, dried over magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography. Thus 0.14 g of the title compound was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[S:4][C:3]=1[C:14]#[N:15].C[Sn]([N:20]=[N+:21]=[N-:22])(C)C>C1(C)C(C)=CC=CC=1>[F:13][C:10]1[CH:9]=[CH:8][C:7]([C:5]2[S:4][C:3]([C:14]3[NH:22][N:21]=[N:20][N:15]=3)=[C:2]([NH2:1])[CH:6]=2)=[CH:12][CH:11]=1
Reactant: N#Cc1sc(-c2ccc(F)cc2)cc1N
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Solvent: Cc1ccccc1C
Product: Nc1cc(-c2ccc(F)cc2)sc1-c1nnn[nH]1
Reaction time: 3 h

Procedure:
The mixture consisting of 0.65 g of 3-amino-2-cyano-5-(4-fluorophenyl)thiophene, 7.5 ml of xylene and 0.93 g of trimethyltin azide is stirred at 130–140° C. for 3 hours. Afterwards, the mixture is concentrated at 40° C. under reduced pressure and the residue is stirred with water with the addition of 1% trifluoroacetic acid. The precipitate is filtered off with suction and dried at 40° C. under reduced pressure.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([CH3:10])[N:3]=1.[Cl:11][C:12]([Cl:22])([Cl:21])[CH2:13][O:14][S:15]([N:18]=[C:19]=[O:20])(=[O:17])=[O:16].CCCCCC>ClCCl>[CH3:9][O:8][C:6]1[N:5]=[C:4]([CH3:10])[N:3]=[C:2]([NH:1][C:19]([NH:18][S:15]([O:14][CH2:13][C:12]([Cl:22])([Cl:21])[Cl:11])(=[O:16])=[O:17])=[O:20])[N:7]=1
Reactant: O=C=NS(=O)(=O)OCC(Cl)(Cl)Cl
Reactant: COc1nc(C)nc(N)n1
Solvent: ClCCl
Solvent: CCCCCC
Product: COc1nc(C)nc(NC(=O)NS(=O)(=O)OCC(Cl)(Cl)Cl)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.5 %

Procedure:
14.0 g (0.1 mole) of 2-amino-4-methoxy-6-methyl-1,3,5-triazine were suspended in 250 ml of dichloromethane, and a solution of 25.5 g (0.1 mole) of 2,2,2-trichloro-eth-1-oxysulfonyl isocyanate in 100 ml of dichloromethane was added dropwise at 0° to 5° C. The reaction mixture was further stirred for 18 hours at room temperature and cooled to 0° C., and n-hexane was added. The precipitated reaction product was filtered off under suction and recrystallized from absolute ethanol. 35.3 g (89.4% of theory) of N-(4-methoxy-6-methyl-1,3,5-triazin-2-yl)-N'-(2,2,2-trichloro-eth-1-oxy-sulfonyl)-urea of melting point 128° C. were obtained.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH:3]=1.S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[F:19][C:16]1[CH:17]=[CH:18][C:13]2[O:12][CH2:11][C:4]3[CH:3]=[C:2]([F:1])[CH:10]=[CH:9][C:5]=3[C:6](=[O:8])[C:14]=2[CH:15]=1
Reactant: O=C(O)c1ccc(F)cc1COc1ccc(F)cc1
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C1c2ccc(F)cc2COc2ccc(F)cc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65.1 %

Procedure:
To 15 g of 4-fluoro-2-[(4-fluorophenyoxy)methyl]benzoic acid is added 60 g of thionyl chloride and the mixture is refluxed with heating for 1 hour. After cooling the reaction mixture to room temperature, dry toluene is added and the solvent is distilled off under reduced pressure. The residue is added with dichloromethane and the mixture is cooled to 0° C. and added with 15 g of powdery anhydrous aluminum chloride, which is stirred for 15 minutes. The reaction mixture is added with ice-water and extracted with toluene. After the extract is successively washed with water and a saturated saline solution and dried over magnesium sulfate, the solvent is distilled off under reduced pressure. The residue is subjected to silica-gel chromatography and eluted with toluene to give 9.1 g of 2,8-difluoro-6,11-dihydrodibenz[b,e]oxepin-11-one (oil). Mass spectrum m/z: 246(M+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]([O:11]CC)OCC)[O:5][CH:6]=1.C([Li])(CC)C.[B:19](OC(C)C)([O:24]C(C)C)[O:20]C(C)C.Cl>CCOCC>[CH:7]([C:4]1[O:5][C:6]([B:19]([OH:24])[OH:20])=[CH:2][CH:3]=1)=[O:11]
Reactant: CCOC(OCC)c1cc(Br)co1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]C(C)CC
Solvent: CCOCC
Product: O=Cc1ccc(B(O)O)o1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 98.2 %

Procedure:
An amount of 1.0 g (4.1 mmol) of 4-bromo-2-(diethoxymethyl)furan, is dissolved in ether (15 mL) and cooled to −78° C. To this is added 4.3 mL (6.02 mmol) of sec-butyllithium. After stirring at −78° C. for 30 minutes, triisopropyl borate (1.10 mL, 5.01 mmol) is added dropwise. The mixture is stirred at −78° C. for 1.5 hours and brought to room temperature for 2 hours. The mixture is hydrolyzed with 2N HCl and stirred at room temperature for 1 hour. The ether layer is separated and the water layer is washed once more with ether. The combined ether layers is washed once with brine and dried with sodium sulfate. Evaporated to give 563 mg of the boronic acid as dark oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH3:22])[CH:6]=1)[CH3:2].Br[C:25]1[CH:26]=[N:27][N:28]([CH2:30][CH2:31][CH3:32])[CH:29]=1>>[CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[N:14]([C:25]3[CH:26]=[N:27][N:28]([CH2:30][CH2:31][CH3:32])[CH:29]=3)[C:13]=2[CH3:22])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Reactant: CCCn1cc(Br)cn1
Product: CCCn1cc(-n2c(C)c(Sc3cccc(C(=O)OCC)c3)c3ccc(Cl)cc32)cn1

Procedure:
Prepared according to the procedure described in Example 55, Step 2 using the following starting materials: 3-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid ethyl ester and 4-bromo-1-propylpyrazole.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=O)[CH:5]=[CH:4][N:3]=1.[C:16]([O:20][C:21]([N:23]1[CH2:27][CH2:26][CH:25]([CH2:28][NH2:29])[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([N:23]1[CH2:27][CH2:26][CH:25]([CH2:28][NH:29][CH2:11][C:10]2[CH:13]=[CH:14][CH:15]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)[CH:9]=2)[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: O=Cc1cccc(-c2ccnc(Cl)n2)c1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)C1
Product: CC(C)(C)OC(=O)N1CCC(CNCc2cccc(-c3ccnc(Cl)n3)c2)C1

Procedure:
Intermediate 1 was coupled with 3-Aminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester following procedure B. LC-MS showed the product had the expected M+H+ of 403.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:12]=2[C:13]#[N:14])=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].BrBr.S(Cl)([Cl:29])(=O)=O>C(O)(=O)C>[Cl:29][C:11]1[C:12]([C:13]#[N:14])=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[NH:9][C:10]=1[C:15]([F:18])([F:16])[F:17]
Reactant: O=S(=O)(Cl)Cl
Reactant: N#Cc1cc(C(F)(F)F)[nH]c1-c1ccc(Cl)cc1
Agent: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: N#Cc1c(-c2ccc(Cl)cc2)[nH]c(C(F)(F)F)c1Cl
Reaction time: 1 h
Yield: 84 %

Procedure:
A mixture of 2-(p-chloropheny1)-5-(trifluoromethyl)pyrrole-3-carbonitile (8.12 g, 0.03 mol) and sodium acetate (0.25 g, 0.003 mol) in acetic acid at 70° C. is treated dropwise with bromine (0.48 g, 0.003 mol). When the color has disappeared, the reaction mixture is treated dropwise with sulfuryl chloride (6.1 g, 0.045 mol) over a 1 hour period, held at 70° C. for 1 hour, concentrated in vacuo and diluted with water. The reaction mixture is filtered, the filter cake is washed with water and dried to yield the title product as a white solid, 7.7 g (84% yield), mp 242°-243° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C@:15]3([CH2:19][S:18][C:17]([NH2:20])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12](I)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[F:28][C:29]1[CH:34]=[CH:33][N:32]=[CH:31][C:30]=1B(O)O.O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Br:1][C:2]1[CH:3]=[C:4]2[C@:15]3([CH2:19][S:18][C:17]([NH2:20])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:30]4[CH:31]=[N:32][CH:33]=[CH:34][C:29]=4[F:28])[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1
Reactant: OB(O)c1cnccc1F
Reactant: NC1=N[C@@]2(CS1)c1cc(I)ccc1Oc1ncc(Br)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: NC1=N[C@@]2(CS1)c1cc(-c3cnccc3F)ccc1Oc1ncc(Br)cc12
Temperature: 100 °C
Yield: 45.5 %

Procedure:
A pressure reaction vessel was charged with (S)-3-bromo-7-iodo-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-thiazol]-2′-amine (1.2 g, 2.53 mmol, prepared as described in Method BB26), potassium carbonate (1.75 g, 12.66 mmol), 4-fluoropyridin-3-ylboronic acid (0.71 g, 5.06 mmol), tetrakis(triphenylphosphine)palladium(0) (0.29 g, 0.25 mmol), dioxane (16.87 mL) and water (8.44 mL). The reaction was stirred and heated at 100° C. for 45 min. After cooling for rt, LCMS showed about 50% conversion. More Pd(PPh3)4 (30 mg) and 4-fluoropyridin-3-ylboronic acid (300 mg) were added and reaction was heated at 100° C. for another 30 min. After cooling for rt, the organic layer was separated with a separatory funnel, dried over sodium sulfate, filtered, and concentrated to afford yellow oil which was purified with reverse phase HPLC. Fractions containing product were concentrated and saturated aq. NaHCO3 (25 mL) was added. A white solid precipitated out of solution which was filtered off and dried to afford a white solid, (S)-3-bromo-7-(4-fluoropyridin-3-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-thiazol]-2′-amine (0.51 g, 1.15 mmol, 46% yield). MS m/z=443.0 [M+H]+. Calc'd for C19H12BrFN4OS: 441.99.
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Br:8])[N:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[Br:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1
Reactant: OB(O)c1ccccc1
Reactant: Brc1cncc(Br)n1
Product: Brc1cncc(-c2ccccc2)n1

Procedure:
Prepared according to the procedure described in Example 42, Step 2, using 2,6-dibromo-pyrazine and phenylboronic acid.
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][CH:28]=1>O1CCCC1>[C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][N:15]([C:34]([NH:33][C:30]4[CH:29]=[CH:28][C:27]([C:26]([F:25])([F:36])[F:37])=[CH:32][CH:31]=4)=[O:35])[CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(C(F)(F)F)cc1)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.5 %

Procedure:
To a solution of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and triethylamine (0.113 ml, 0.812 mmol) in tetrahydrofuran (2 ml) was added 4-trifluoromethylphenyl isocyanate (0.184 ml, 1.22 mmol), and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was recrystallized from a mixed solvent of hexane and ethyl acetate to give 248 mg (70.5%) of the desired product as a solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.C([O:14][C:15](=O)[C@@H:16]([C@@H:30]1[C@:47]2([CH3:48])[C@H:33]([C@H:34]3[C@H:44]([CH2:45][CH2:46]2)[C@:42]2([CH3:43])[C:37]([CH2:38][C@@H:39]([O:56][CH:57]4[CH2:62][CH2:61][CH2:60][CH2:59][O:58]4)[CH2:40][C@@H:41]2[O:49][CH:50]2[CH2:55][CH2:54][CH2:53][CH2:52][O:51]2)=[CH:36][CH2:35]3)[CH2:32][CH2:31]1)[CH2:17][CH2:18][C@@H:19]([F:29])[C:20]([O:23][CH:24]([O:26][CH2:27][CH3:28])[CH3:25])([CH3:22])[CH3:21])C>CCOCC>[O:51]1[CH2:52][CH2:53][CH2:54][CH2:55][CH:50]1[O:49][C@@H:41]1[C@@:42]2([CH3:43])[C:37](=[CH:36][CH2:35][C@@H:34]3[C@@H:44]2[CH2:45][CH2:46][C@@:47]2([CH3:48])[C@H:33]3[CH2:32][CH2:31][C@@H:30]2[C@H:16]([CH2:15][OH:14])[CH2:17][CH2:18][C@@H:19]([F:29])[C:20]([O:23][CH:24]([O:26][CH2:27][CH3:28])[CH3:25])([CH3:22])[CH3:21])[CH2:38][C@@H:39]([O:56][CH:57]2[CH2:62][CH2:61][CH2:60][CH2:59][O:58]2)[CH2:40]1
Reactant: CCOC(=O)[C@H](CC[C@@H](F)C(C)(C)OC(C)OCC)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)C[C@H](OC5CCCCO5)[C@]4(C)[C@H]3CC[C@]12C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(C)OC(C)(C)[C@H](F)CC[C@@H](CO)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)C[C@H](OC5CCCCO5)[C@]4(C)[C@H]3CC[C@]12C
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 0.34 g. (0.0090 mole) of lithium aluminum hydride and 17 ml. of tetrahydrofuran at 0° C. was added 4.26 g. of [1α,3β,24R]-1,3-bis[(tetrahydro-2H-pyran-2-yl)oxy]-25-(1-ethoxyethoxy)-24-fluorocholest-5-en-21-oic acid ethyl ester in 60 ml. of tetrahydrofuran. The mixture was heated at 50° C. for 1.5 hr, recooled to 0° C., and diluted with 200 ml. of ether. The mixture was then quenched with the dropwise addition of 0.68 ml. of water and 0.55 ml. of 10% aqueous sodium hydroxide. The mixture was stirred at 25° C. for 0.5 hr and was filtered. The solids were triturated with ether and filtered. Evaporation of solvent afforded [1α,3β,24R]-1,3-bis[(tetrahydro-2H-pyran-2-yl)oxy]-25-(1-ethoxyethoxy)-24-fluorocholest-5-en-21-ol, [α]D25 +7° (c 1.1, CHCl3).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[N:11]=[CH:10]3)[N:5]=[C:4]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:3]=1.[Cl:27][C:28]1[C:33]([Cl:34])=[CH:32][CH:31]=[CH:30][C:29]=1[N:35]=[C:36]=[O:37]>>[C:23]([C:4]1[CH:3]=[C:2]([NH:1][C:36]([NH:35][C:29]2[CH:30]=[CH:31][CH:32]=[C:33]([Cl:34])[C:28]=2[Cl:27])=[O:37])[N:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[N:12]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[N:11]=[CH:10]3)[N:5]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)n1ncc2cc(-n3nc(C(C)(C)C)cc3N)ccc21
Reactant: O=C=Nc1cccc(Cl)c1Cl
Product: CC(C)(C)OC(=O)n1ncc2cc(-n3nc(C(C)(C)C)cc3NC(=O)Nc3cccc(Cl)c3Cl)ccc21
Yield: 50.4 %

Procedure:
Using general method A, t-butyl 5-(5-amino-3-t-butyl-1H-pyrazol-1-yl)-1H-indazole-1-carboxylate (0.150 g, 0.422 mmol, 1.00 eq) and 2,3-dichlorophenyl isocyanate (0.0557 ml, 0.422 mmol, 1.00 eq). were combined to yield t-butyl 5-(3-t-butyl-5-(3-(2,3-dichlorophenyl)ureido)-1H-pyrazol-1-yl)-1H-indazole-1-carboxylate (115.5 mg, 50% yield). 1H NMR (DMSO-d6): δ 9.25 (s, 1H), 8.73 (s, 1H), 8.53 (brs, 1H), 8.22-8.19 (m, 1H), 8.06-8.01 (m, 2H), 7.79-7.76 (m, 1H), 7.33-7.29 (m, 2H), 6.43 (s, 1H), 1.67 (s, 9H), 1.30 (s, 9H); MS (ESI) m/z: 543.0 (M+H+), 545.0 (M+2+H+).
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[CH3:11].[CH3:12][C:13]([S@:16]([NH2:18])=[O:17])([CH3:15])[CH3:14]>C1(C)C=CC=CC=1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Cl:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5](/[CH:6]=[N:18]/[S@@:16]([C:13]([CH3:15])([CH3:14])[CH3:12])=[O:17])=[CH:4][C:3]=1[CH3:11]
Reactant: Cc1cc(C=O)cc(C)c1Cl
Reactant: CC(C)(C)[S@](N)=O
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: Cc1ccccc1
Product: Cc1cc(/C=N/[S@](=O)C(C)(C)C)cc(C)c1Cl
Temperature: 50 °C
Reaction time: 24 h

Procedure:
A solution of 4-chloro-3,5-dimethyl-benzaldehyde (6.04 g, 35.8 mmol) and (R)-2-methylpropane-2-sulfinamide (4.78 g, 39.4 mmol) in toluene (110 mL) was treated with titanium(IV) isopropoxide (15.74 mL, 53.7 mmol). The mixture was stirred at 50° C. for 24 hours. It was then quenched with 10% aqueous sodium bicarbonate solution (100 mL) and filtered through Celite. The filter cake was washed with Et2O (250 mL). The organic layers were washed with water and brine, dried over sodium sulfate, filtered and concentrated. The crude was purified by chromatography on silica gel (cyclohexane/EtOAc).
Reaction SMILES: [C:1]([CH2:9][C:10]([O:12]CC)=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][NH:16][NH2:17]>C(O)(C)C>[CH3:15][N:16]1[C:10](=[O:12])[CH2:9][C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:17]1
Reactant: CNN
Reactant: CCOC(=O)CC(=O)c1ccccc1
Solvent: CC(C)O
Product: CN1N=C(c2ccccc2)CC1=O
Temperature: 20 °C
Reaction time: 2 h

Procedure:
Ethyl benzoylacetate (1,538 g, 8 moles) dissolved in isopropanol (6 l ) is placed in a 12 l flask under an atmosphere of nitrogen. Methylhydrazine (410 g, 8.7 moles, 98%) in isopropanol (800 ml) is added with stirring in a dropwise manner to the ethyl benzoylacetate solution prewarmed to about 80°C. During the addition the external heating is removed. Seeding of the reaction mixture with the product at the point of one-third addition of methylhydrazine causes a copious precipitate of product. This procedure eliminates a large exotherm from occurring at a later stage. After the addition is complete, the reaction mixture is held at about 80°C. for 2 hours. Cooling the slurry to 20°C. and filtering off the solid, a yield of 1,131 g (81%) of product after drying with a melting point equal to 211° C. is obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH:4]=[C:5]=[CH:6][C:7]([O:9][CH3:10])=[O:8].C([O:14][C:15](O[Si](C)(C)C)=[CH:16][C:17]([O:21][Si](C)(C)C)=[CH:18][CH2:19][CH3:20])C.C(O)C.[F-].[NH4+]>O>[CH3:10][O:9][C:7](=[O:8])[C:6]1[C:15]([OH:14])=[CH:16][C:17]([OH:21])=[C:18]([CH2:19][CH3:20])[C:5]=1[CH2:4][C:3]([O:2][CH3:1])=[O:11]
Reactant: COC(=O)C=C=CC(=O)OC
Reactant: CCC=C(C=C(OCC)O[Si](C)(C)C)O[Si](C)(C)C
Agent: [F-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CCc1c(O)cc(O)c(C(=O)OC)c1CC(=O)OC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 39.8 %

Procedure:
The above-obtained penta-2,3-dienedioic acid dimethyl ester (4.6 g, 30 mmol) and 1-ethoxy-1,3-bis(trimethylsiloxy)hexa-1,3-diene (13 g, 41 mmol) were mixed and stirred at a room temperature for 1.5 hours. The reaction mixture was added with ethanol (100 mL) and ammonium fluoride (5.4 g) and stirred at a room temperature for 2 hours. The reaction mixture was further added with water and extracted with ethyl acetate 3 times. The organic layers were combined, sequentially washed with water and saturated brine, dried over anhydrous sodium sulfate and then the solvent was evaporated under reduced pressure. The residue was triturated with hexane (50 mL) to obtain Compound 23 (3.2 g, 40%).
Reaction SMILES: [CH3:1][O:2][CH2:3][NH:4][CH2:5][CH2:6][C:7]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:8].CC(C)([O-])C.[K+].[H][H]>CO>[CH3:1][O:2][CH2:3][NH:4][CH2:5][CH2:6][C@@H:7]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)[OH:8]
Reactant: [H][H]
Reactant: COCNCCC(=O)c1cccs1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Product: COCNCC[C@H](O)c1cccs1
Reaction time: 12 h

Procedure:
4 mL of degassed methanol solution containing 10 mg of RuCl2((R)-3,5-xylylBINAP) ((2R)-DAIPEN), 160 mg of 3-methoxymethylamino-1-(2-thienyl)-1-propanone, 100 mg of potassium tert-butoxide and 10 mL of methanol were charged in a glass autoclave under an argon gas flow. After deaeration and replacement by argon, hydrogen was introduced to a predetermined pressure. The resulting solution was hydrogenated at 20□ for 12 hours. Upon completion of hydrogenation the reaction mixture was concentrated, and then the desired compound is obtained as an oily product (161 mg, 95.8% by HPLC assay, 95% ee). 1H NMR (400 MHz, CDCl3) δ (ppm) 3.0 (s, 3H), 3.0-3.1 (m, 1H), 4.1 (s, 3H), 4.0-4.1 (m, 3H), 6.1 (dt,J=7.4, 15.4 Hz, 1H), 6.9 (d,J=15.7 Hz, 1H), 7.0 (dd, J=3.7, 5.0 Hz, 1H), 7.1 (d, J=3.4 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:19][C:20]2[C:21]3[N:28]([CH2:29][C:30]([O:32]CC)=[O:31])[CH:27]=[CH:26][C:22]=3[N:23]=[CH:24][N:25]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1.Cl>O1CCCC1.C(O)C.[OH-].[Na+]>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][C:20]2[C:21]3[N:28]([CH2:29][C:30]([OH:32])=[O:31])[CH:27]=[CH:26][C:22]=3[N:23]=[CH:24][N:25]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:16])([F:18])[F:17])[CH:10]=1
Reactant: CCOC(=O)Cn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)Cn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.4 %

Procedure:
Ethyl [4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]acetate (221.2 mg) was dissolved in a mixed solvent of tetrahydrofuran (1.5 mL)/ethanol (1.5 mL), 1N aqueous sodium hydroxide solution (0.6 mL) was added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was adjusted to pH 2-3 with 1N hydrochloric acid and extracted with a mixed solvent of ethyl acetate/tetrahydrofuran=1/1. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was collected by filtration and dried to give the title compound (169.8 mg) as a yellow powder.