Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=[C:3]1[CH2:8]C2C[CH:4]1C=C2)[CH3:2].[CH3:10][O:11][C:12](=[O:15])[CH:13]=[CH2:14].C1CC=CC=1>CCOCC>[CH3:10][O:11][C:12]([CH:13]1[CH2:4][CH:3]2[CH2:8][CH:14]1[CH:2]=[CH:1]2)=[O:15]
Reactant: C=CC(=O)OC
Reactant: CC=C1CC2C=CC1C2
Agent: C1=CCC=C1
Solvent: CCOCC
Product: COC(=O)C1CC2C=CC1C2

Procedure:
Commercially available ethylidenenorbornene (called "EN" hereinafter) was used as the third comonomer. 82.5 g of methyl-acrylate was reacted with 54 g of cyclopentadiene in ether, and the product was purified by distillation to produce 91 g of 5-methoxycarbonylnorbornene (called "MCN" hereinafter) which was also used as the third comonomer.
Reaction SMILES: CN(C)C=O.[F:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[N:24]=[CH:23][NH:22][C:21](=[O:25])[N:20]=3)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1.[Cl:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][N:22]2[CH:23]=[N:24][C:19]([N:16]3[CH2:15][CH2:14][N:13]([C:10]4[CH:11]=[CH:12][C:7]([F:6])=[CH:8][CH:9]=4)[CH2:18][CH2:17]3)=[N:20][C:21]2=[O:25])=[CH:29][CH:28]=1
Reactant: O=c1nc(N2CCN(c3ccc(F)cc3)CC2)nc[nH]1
Reactant: Clc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1nc(N2CCN(c3ccc(F)cc3)CC2)ncn1Cc1ccc(Cl)cc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 52.7 %

Procedure:
To an N,N-dimethylformamide solution (170 mL) of 4-[4-(4-fluorophenyl)piperazin-1-yl]-1,3,5-triazin-2(1H)-one (8.48 g, 30.8 mmol) synthesized in Reference Synthesis Example 3, 4-chlorobenzyl bromide (6.32 g, 30.9 mmol) and potassium carbonate (5.11 g, 37.0 mmol) were added and the resultant mixture was stirred at 50° C. for 1 hour and at 70° C. for 3 hours. To the reaction solution, 4-chlorobenzyl bromide (1.90 g, 9.25 mmol) and potassium carbonate (2.13 g, 15.4 mmol) were added and the resultant reaction solution was stirred at 70° C. further for 2 hours. After the completion of the reaction, water was added to the reaction solution and a resultant solid was filtered and was dried under reduced pressure. The resultant solid was suspended in ethyl acetate and the suspension was stirred at room temperature for 10 minutes. The solid was filtered and was dried under reduced pressure. These operations from suspending of the solid to the second drying of the solid were performed twice to obtain the title compound (6.49 g, yield: 53%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[N+:17]([O-])[CH:18]=[C:19]([Cl:21])[CH:20]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:23]([N:25](CC)CC)C.C[Si](C#N)(C)C.[OH-].[Na+]>C(#N)C.C(OCC)(=O)C>[Cl:21][C:19]1[CH:20]=[C:15]([O:14][CH2:13][C@H:9]2[CH2:10][CH2:11][CH2:12][N:8]2[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:16]([C:23]#[N:25])=[N:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cc(Cl)c[n+]([O-])c1
Reactant: CCN(CC)CC
Agent: C[Si](C)(C)C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cc(Cl)cnc1C#N
Temperature: 80 °C
Reaction time: 15 h
Yield: 58.1 %

Procedure:
To a stirred solution of (R)-3-((1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methoxy)-5-chloropyridine 1-oxide (610 mg, 1.855 mmol, EXAMPLE 29 Step 2) and triethylamine (1.56 mL, 11.13 mmol) in acetonitrile was added trimethylsilyl cyanide (TMSCN) (1.24 mL, 9.28 mmol) at ambient temperature and the mixture was heated at 80° C. After being stirred at 80° C. for 15 h, the mixture was cooled to room temperature. 1.24 mL of TMSCN (9.28 mmol) and 1.56 mL of triethylamine (11.13 mmol) were added to the mixture and the mixture was heated at 80° C. further 6 h. After cooling to room temperature, the mixture was concentrated in vacuo to give a dark brown oil. The residual oil was dissolved with ethyl acetate and 2 N aq. sodium hydroxide. The mixture was extracted with ethyl acetate twice and washed with water, 2 N hydrochloric acid, and brine. The extracts were combined and dried over sodium sulfate and concentrated in vacuo to afford an oil. The residual oil was purified by silica gel column chromatography (hexane to ethyl acetate/hexane 1:4) to afford 364 mg (58%) of the title compound as a waxy solid.
Reaction SMILES: OO.C(OC(C(F)(F)F)=O)(C(F)(F)F)=[O:4].[CH3:16][N:17]([CH3:35])[CH2:18][CH2:19][NH:20][C:21]1[N:22]=[N+:23]([O-:34])[C:24]2[CH:33]=[C:32]3[C:28]([CH2:29][CH2:30][CH2:31]3)=[CH:27][C:25]=2[N:26]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.C(Cl)(Cl)Cl.N>[O-:34][N+:23]1[C:24]2[CH:33]=[C:32]3[C:28](=[CH:27][C:25]=2[N+:26]([O-:4])=[C:21]([NH:20][CH2:19][CH2:18][N:17]([CH3:35])[CH3:16])[N:22]=1)[CH2:29][CH2:30][CH2:31]3
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CN(C)CCNc1nc2cc3c(cc2[n+]([O-])n1)CCC3
Agent: N
Agent: OO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CN(C)CCNc1n[n+]([O-])c2cc3c(cc2[n+]1[O-])CCC3
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 54.4 %

Procedure:
H2O2 (70%, 0.54 mL, ca. 10.8 mmol) was added dropwise to a stirred solution of TFAA (1.5 mL, 10.8 mmol) in DCM (10 mL) at 0° C. The solution was stirred at 0° C. for 5 min, warmed to 20° C. for 10 min, then cooled to 0° C. and added to a stirred solution of 1-oxide 22 (294 mg, 1.1 mmol) and TFA (0.17 mL, 2.2 mmol) in CHCl3 (15 mL) at 0° C. The solution was stirred at 20° C. for 6 h, diluted with dilute aqueous NH3 solution (10 mL) and extracted with CHCl3 (4×50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1,4-dioxide 23 (173 mg, 55%) as a red solid: mp (MeOH/EtOAc) 150-153° C.; 1H NMR δ 8.12 (s, 1H, H-9), 8.10 (s, 1H, H-5), 7.40 (br s, 1H, NH), 3.62-3.67 (m, 2H, CH2N), 3.03-3.13 (m, 4H, H-6, H-8), 2.63 (t, J=6.0 Hz, 2H, CH2N), 2.31 [s, 6H, N(CH3)2], 2.17-2.23 (m, 2H, H-7); 13C NMR δ 155.6, 149.5, 145.8, 138.0, 129.7, 115.7, 111.6, 57.5, 45.2 (2), 38.8, 33.6, 32.4, 25.6; MS m/z 289 (M+, 0.5%), 272 (5), 58 (100); HRMS calcd for C14H19N5O2 (M+) m/z 289.1539, found 289.1536. The hydrochloride salt was crystallised from MeOH/EtOAc. Anal. calcd for C14H20CIN5O2.½CH3OH: C, 49.7; H, 6.8; N, 19.3. Found: C, 49.4; H, 7.0; N, 19.8%.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[C:10]([NH:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=1[CH3:24])[C:17]([O:19][CH3:20])=[O:18])(=[O:12])[CH3:11]>>[C:10]([NH:13][C:14]1[C:23]([CH3:24])=[CH:22][C:21]([N+:1]([O-:4])=[O:2])=[C:16]([CH:15]=1)[C:17]([O:19][CH3:20])=[O:18])(=[O:12])[CH3:11]
Reactant: COC(=O)c1ccc(C)c(NC(C)=O)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(NC(C)=O)c(C)cc1[N+](=O)[O-]
Temperature: 5 °C
Yield: 84.3 %

Procedure:
a mixture of fuming nitric acid (8.4 g) and conc. sulfuric acid (260 g) was cooled to 0-10° C. and the known methyl 3-acetylamino-4-methylbenzoate (26.3 g, 127 mmol) was added portionwise with stirring. After stirring for several hours, the mixture was poured onto ice which subsequently melted. The product was collected by suction filtration, washed with water and dried. The solid was recrystallized from isopropanol to give 27 g of yellow powder.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11](Cl)(=[O:13])=[O:12])(=[O:4])=[O:3].[CH3:15][N:16]([CH3:18])[NH2:17]>O1CCCC1>[CH3:15][N:16]([CH3:18])[NH:17][S:11]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[S:2]([NH2:1])(=[O:4])=[O:3])(=[O:13])=[O:12]
Reactant: CN(C)N
Reactant: NS(=O)(=O)c1ccccc1S(=O)(=O)Cl
Solvent: C1CCOC1
Product: CN(C)NS(=O)(=O)c1ccccc1S(N)(=O)=O
Temperature: 25 °C

Procedure:
A solution of 1.28 g of 2-(aminosulfonyl)benzenesulfonyl chloride in 12 mL of dry tetrahydrofuran (THF) was cooled to -65° C. and a solution of 0.88 mL of 1,1-dimethylhydrazine in 12 mL of dry THF added dropwise. The resulting mixture was allowed to warm to room temperature, filtered, and the filtrate concentrated in vacuo. The solid residue was partitioned between water and ethyl acetate, the organic phase was separated, washed with water, washed with brine, dried (MgSO4), concentrated in vacuo, and the residue triturated with 1-chlorobutane to provide 1.07 g of the subject compound, m.p. 122°-124° C. (dec).
Reaction SMILES: C([O:5][C:6]([CH2:8][S:9][C:10]1[C:19]2[C:14](=[C:15]([NH:20][C:21](=[O:30])[C:22]3[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:29])[CH:16]=[CH:17][CH:18]=2)[N:13]=[CH:12][C:11]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:7])(C)(C)C.Cl>C(OCC)(=O)C>[C:6]([CH2:8][S:9][C:10]1[C:19]2[C:14](=[C:15]([NH:20][C:21](=[O:30])[C:22]3[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:29])[CH:16]=[CH:17][CH:18]=2)[N:13]=[CH:12][C:11]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32])([OH:7])=[O:5]
Reactant: CCOC(=O)c1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1SCC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1SCC(=O)O
Reaction time: 1 h
Yield: 87.8 %

Procedure:
A solution of 4-(tert-butoxycarbonylmethylthio)-8-(2,6-dichlorobenzoylamino)-3-ethoxycarbonylquinoline (140 mg) in 4N solution of hydrogen chloride in ethyl acetate was allowed to stand for 1 hour at ambient temperature. The mixture was concentrated in vacuo, and the residue was dissolved in ethyl acetate. The solution was washed with brine, dried over magnesium sulfate and evaporated in vacuo to give 4-carboxymethylthio-8-(2,6-dichlorobenzoylamino)-3-ethoxycarbonylquinoline (110 mg).
Reaction SMILES: [BH4-].[Na+].[Cl-].[Ca+2].[Cl-].[OH:6][C:7]([C:38]1[CH:47]=[CH:46][C:45]2[C:40](=[CH:41][CH:42]=[C:43]([C:48]([NH:50][CH3:51])=[O:49])[CH:44]=2)[CH:39]=1)([C:14]1[N:15]=[CH:16][N:17]([C:19]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=1)[CH2:8][C:9](OCC)=[O:10].Cl>C1COCC1.O.C(O)C>[OH:6][C:7]([C:38]1[CH:39]=[C:40]2[C:45](=[CH:46][CH:47]=1)[CH:44]=[C:43]([C:48]([NH:50][CH3:51])=[O:49])[CH:42]=[CH:41]2)([C:14]1[N:15]=[CH:16][N:17]([C:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=1)[CH2:8][CH2:9][OH:10]
Reactant: CCOC(=O)CC(O)(c1ccc2cc(C(=O)NC)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: Cl
Agent: [BH4-]
Agent: [Ca+2]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)c1ccc2cc(C(O)(CCO)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2c1
Reaction time: 0.5 h
Yield: 98 %

Procedure:
360 mL of ethanol and 156 mL of THF were added to 26.7 g (0.71 mol, 8eq) of sodium borohydride. 39.3 g (0.35 mol, 4 eq) of calcium chloride was added at 0° C., and the mixture was stirred at 1˜3° C. for 30 minutes. A solution of 60 g (98 mmol) of ethyl 3-hydroxy-3-{6-[(methylamino)carbonyl]-2-naphthyl}-3-(1-trityl-1H-imidazol-4-yl)propanoate in 204 mL of THF was added dropwise at 0° C. The mixture was stirred at 0˜10° C. for 30 minutes, and at 20˜26° C. for 5 hours. 360 mL of water, and 1.44 liters of 1N hydrochloric acid were successively added dropwise. The mixture was stirred at 25° C. for 1 hour. Crystals were filtered, and washed with 500 mL of water two times. Vacuum drying (50° C.) to a constant weight afforded 54.5 g of 6-[1,3-dihydroxy-1-(1-trityl-1H-imidazol-4-yl)propyl]-N-methyl-2-naphthamide (yield 87%).
Reaction SMILES: [ClH:1].Cl.[C@H]1([CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[CH:39]=[CH:40][CH:41]=[C:42]([O:43][CH3:44])[C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:16][CH2:15]2)[C@@H]2N(CCCC2)CCC1.Cl.Cl.Cl.NC1CCN([CH2:55][C@@H:56]([N:58]2[CH2:63][CH2:62][CH:61]([OH:64])[CH2:60][CH2:59]2)C)CC1>>[ClH:1].[ClH:1].[OH:64][CH:61]1[CH2:62][CH2:63][N:58]([C@@H:56]([CH3:55])[CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[CH:39]=[CH:40][CH:41]=[C:42]([O:43][CH3:44])[C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:16][CH2:15]2)[CH2:59][CH2:60]1
Reactant: COc1cccc2c(COc3cccc4[nH]c(C(=O)NC5CCN(C[C@@H]6CCCN7CCCC[C@H]67)CC5)cc34)coc12
Reactant: C[C@@H](CN1CCC(N)CC1)N1CCC(O)CC1
Agent: Cl
Product: COc1cccc2c(COc3cccc4[nH]c(C(=O)NC5CCN(C[C@H](C)N6CCC(O)CC6)CC5)cc34)coc12

Procedure:
This compound is synthesized from 4-(7-methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (119, see example 80) and amine 50 analogously to the method described in example 1.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[CH:10]=[N:9][C:8]([S:12][CH3:13])=[N:7][C:6]=2[N:5]([CH:14]2[CH2:17][CH2:16][CH2:15]2)[C:4](=[O:18])[C:3]=1Br.[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.CCO.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>[NH2:1][C:2]1[C:11]2[CH:10]=[N:9][C:8]([S:12][CH3:13])=[N:7][C:6]=2[N:5]([CH:14]2[CH2:17][CH2:16][CH2:15]2)[C:4](=[O:18])[C:3]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CSc1ncc2c(N)c(Br)c(=O)n(C3CCC3)c2n1
Reactant: OB(O)c1ccccc1
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: O=C([O-])[O-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CSc1ncc2c(N)c(-c3ccccc3)c(=O)n(C3CCC3)c2n1
Temperature: 100 °C
Yield: 78.8 %

Procedure:
To a mixture of 5-amino-6-bromo-8-cyclobutyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (50 mg, 0.15 mmol), phenylboronic acid (28 mg, 0.22 mmol), tetrakis(triphenylphosphine)palladium(0) (17 mg, 0.015 mmol) in 0.6 mL toluene and 0.6 mL EtOH was added cesium carbonate (0.17 g, 0.52 mmol). The resulting mixture was heated at 100° C. in a microwave reactor for 30 min. The reaction mixture was cooled, NaHCO3 (sat'd aq) added and the mixture extracted with EtOAc (3×20 mL). The combined organic layers were washed with water (2×10 mL) and evaporated under reduced pressure. The crude residue was purified by preparative TLC (Hexanes:EtOAc, 2:1) to afford 40 mg of 5-amino-8-cyclobutyl-2-methylsulfanyl-6-phenyl-8H-pyrido[2,3-d]pyrimidin-7-one as a solid.
Reaction SMILES: [NH2:1][C@@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[OH:6].[OH-].[K+].[O:13](C(OC(C)(C)C)=O)[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=O>O.O1CCOCC1>[NH:1]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:13])[C@@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:6])[OH:7]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: N[C@H](CCC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@H](CCC(=O)O)C(=O)O

Procedure:
14.7 g (0.1 Mol) of H-D-Glu-OH was dissolved in 200 ml of distilled water, and the pH was adjusted to 10.2 with 0.1 M potassium hydroxide. 33.0 g (0.3 Mol) of BOC2O in dioxane was added with intensive mixing. The pH was controlled using a pH-stat. After completion of the reaction, the mixture was transferred to a separating funnel, and extraction was carried out from the alkaline solution with ethyl acetate (3×150 ml). The pH of the aqueous phase was adjusted to 3.0 using 0.2% sulphuric acid, and Boc-D-Glu-OH was extracted from the organic phase (3×200 ml). The organic phase was washed three times with 200 ml of Na2SO4 saturated solution to neutral pH, and dried over Na2SO4, and evaporated to oil under vacuum. The yield was 16.7 g (68%).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[S:9]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([CH2:21][C:22]([CH3:26])([CH3:25])[C:23]#[N:24])[C:16](=O)[C:15]12[O:32]CCCO1)(=[O:11])=[O:10].N>[Ni].CCO>[CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[S:9]([C:12]1[CH:20]=[CH:19][C:18]2[N:17]3[CH2:21][C:22]([CH3:25])([CH3:26])[CH2:23][N:24]=[C:16]3[C:15](=[O:32])[C:14]=2[CH:13]=1)(=[O:10])=[O:11]
Reactant: COC[C@@H]1CCCN1S(=O)(=O)c1ccc2c(c1)C1(OCCCO1)C(=O)N2CC(C)(C)C#N
Agent: [Ni]
Agent: N
Solvent: CCO
Product: COC[C@@H]1CCCN1S(=O)(=O)c1ccc2c(c1)C(=O)C1=NCC(C)(C)CN12
Temperature: 135 °C
Yield: 103.7 %

Procedure:
3-[5′-{[(2S)-2-(Methoxymethyl)pyrrolidin-1-yl]sulfonyl}-2′-oxospiro[1,3-dioxane-2,3′-indol]-1′ (2′H)-yl]-2,2-dimethylpropanenitrile (1.92 g, 4.14 mmol), wet Raney Nickel (3.59 g), 2M EtOH.NH3 (175 mL) were combined in a Parr Bottle (500 mL) and hydrogenated at 52 lb/in2 H2 for 18 hours. The Raney Nickel was removed by filtration through Sulka Floc and the filter pad was washed well with 2M EtOH.NH3. The filtrate was poured into a steel pressure vessel and heated at 135° C. for 21 hours. The mixture was cooled to room temperature and the solvents were removed. The crude product was purified on Biotage KP silica gel eluting with CH2Cl2/CH3OH/NH4OH (95.5/3/1.5) to give the title compound as a white solid (1.68 g, 90% yield). Anal: Calc'd. for C22H31N3O5S : C, 58.78; H, 6.95; N, 9.35; Found: C, 58.50; H, 7.02; N, 9.22. NMR: consistent. MS; (ES+) m/z 450 [M+H]. IR: consistent. m.p.: 167-169° C. Opt. Rotation: −80.62(calculated) at 25° C. in CH2Cl2 (1% concentration), wavelength 589.
Reaction SMILES: [CH2:1]([N:5]1[C:9]2=[C:10](Cl)[N:11]=[N:12][CH:13]=[C:8]2[C:7]([CH3:15])=[C:6]1[CH3:16])[CH:2]=[CH:3][CH3:4].[F:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][SH:25])=[CH:20][CH:19]=1>>[CH2:1]([N:5]1[C:9]2=[C:10]([S:25][CH2:24][C:21]3[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=3)[N:11]=[N:12][CH:13]=[C:8]2[C:7]([CH3:15])=[C:6]1[CH3:16])[CH:2]=[CH:3][CH3:4]
Reactant: Fc1ccc(CS)cc1
Reactant: CC=CCn1c(C)c(C)c2cnnc(Cl)c21
Product: CC=CCn1c(C)c(C)c2cnnc(SCc3ccc(F)cc3)c21
Yield: 64.9 %

Procedure:
The title compound (cis/trans=20:80) was prepared as a pale yellow powder in 64.9% yield in a similar procedure to that described in Example 1 by using 1-(2-butenyl)-7-chloro-2,3-dimethylpyrrolo[2,3-d]pyridazine (cis/trans=23/77) and 4-fluorophenylmethanethiol.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8](Br)[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([O:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[Cl:25])[CH:10]=2)=[O:5])[CH3:2].[C:27]([Cu])#[N:28].N#N.Cl>C(Cl)Cl.CN1C(=O)CCC1>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:27]#[N:28])[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([O:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[Cl:25])[CH:10]=2)=[O:5])[CH3:2]
Reactant: N#C[Cu]
Reactant: CCOC(=O)c1nc(Br)c2cc(Oc3ccc(F)cc3Cl)ccc2c1O
Agent: Cl
Agent: N#N
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: CCOC(=O)c1nc(C#N)c2cc(Oc3ccc(F)cc3Cl)ccc2c1O
Temperature: 130 °C
Reaction time: 3 h
Yield: 77.9 %

Procedure:
A 20-mL scintillation vial was charged with 1-bromo-4-hydroxy-7-(4-fluoro-2-chloro-phenoxy)-isoquinoline-3-carboxylic acid ethyl ester (340 mg, 0.77 mmol), CuCN (138 mg, 1.54 mmol) and NMP (1.8 mL). It was filled with N2 gas and close-capped. The mixture was stirred in a 130° C. oil bath for 3 h. Reaction mixture was diluted with CH2Cl2 (100 mL) and stirred at room temperature for 3 days. To the mixture was added 100 mL of 0.5 N HCl aq. solution. It was stirred vigorously for 3 min. Two phases were separated. Organic layer was washed with brine, dried over MgSO4, filtered and concentrated. Crude product was purified by silica gel chromatography, eluting with 5-50% EtOAc/hexanes to provide the title compound 231 mg (0.60 mmol) in 78% yield. 1H NMR (200 MHz) in CDCl3, δ ppm: 12.42 (s, 1H), 8.45 (d, J=8.8 Hz, 1H), 7.54 (dd, J=9.2, 2.6 Hz, 1H), 7.40-7.10 (m, 4H), 4.58 (q, J=7.0 Hz, 2H), 1.51 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])/[CH:5]=[CH:6]/[C:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[N:9]([C:19]2[CH:24]=[CH:23][C:22]([S:25](=[O:28])(=[O:27])[NH2:26])=[CH:21][CH:20]=2)[N:8]=1)[CH3:2]>CCOC(C)=O.[Pd]>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][C:7]1[CH:11]=[C:10]([C:12]2[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=2)[N:9]([C:19]2[CH:20]=[CH:21][C:22]([S:25](=[O:27])(=[O:28])[NH2:26])=[CH:23][CH:24]=2)[N:8]=1)[CH3:2]
Reactant: CCOC(=O)/C=C/c1cc(-c2ccc(C)cc2)n(-c2ccc(S(N)(=O)=O)cc2)n1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1cc(-c2ccc(C)cc2)n(-c2ccc(S(N)(=O)=O)cc2)n1
Reaction time: 2 h

Procedure:
To a solution of 16c (0.13 g, 0.32 mmol) in 5 mL of EtOAc was added 10% palladium on carbon. The solution was filled with H2 and the reaction mixture was stirred for 2 hours. After the solution was filtered through Celite, the filtrate was concentrated in vacuo. Purification by column chromatography (3:7 EtOAc-haxanes) gave the title compound, 0.11 g (84%) as a white solid. mp 116.5-117.2° C. 1H NMR (300 MHz, CDCl3): δ 7.79 (d, J=9 Hz, 2H), 7.36 (d, J=9 Hz, 2H), 7.17-7.04 (m, 4H), 6.32 (s, 1H), 5.23 (s, 2H), 4.17 (q, J=7 Hz, 2H), 3.05 (t, J=8 Hz, 2H), 2.76 (t, J=8 Hz, 2H), 2.35 (s, 3H), 1.26 (t, J=7 Hz, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].S(=O)(=O)(O)O.[CH3:19]O>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11]([O:13][CH3:19])=[O:12])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CO
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc([N+](=O)[O-])cc1
Yield: 96 %

Procedure:
A 1-L single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with 4-nitrophenylacetic acid (14.1 g, 77.5 mmol), anhydrous methanol (130 mL) and concentrated sulfuric acid (12.0 mL, 216 mmol), and the reaction mixture was heated at reflux for 16 h. After this time, the reaction was concentrated to dryness under reduced pressure. The resulting residue was partitioned between water (500 mL) and diethyl ether (200 mL) and the layers separated. The aqueous phase was extracted with diethyl ether (100 mL). The combined organic phases were washed with saturated aqueous sodium carbonate and dried over magnesium sulfate, and the drying agent was removed by filtration. The filtrate was concentrated under reduced pressure and dried to a constant weight under vacuum to afford a 96% yield of 1 (14.6 g) as a white solid: mp 45-46° C.; 1H NMR (500 MHz, CDCl3) δ 8.19 (d, 2H, J=8.5 Hz), 7.46 (d, 2H, J=8.5 Hz), 3.75 (s, 2H), 3.73 (s, 3H). Reference: Tetrahedron 2002, 58, 10113.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:9]1[N:14]=[C:13]([CH:15]2[CH2:17][CH2:16]2)[N:12]=[C:11]([NH:18][CH:19]2[CH2:21][CH2:20]2)[C:10]=1[CH3:22]>COCC(O)C.ClCCl>[CH:1]1([NH:7][C:9]2[C:10]([CH3:22])=[C:11]([NH:18][CH:19]3[CH2:21][CH2:20]3)[N:12]=[C:13]([CH:15]3[CH2:16][CH2:17]3)[N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: Cc1c(Cl)nc(C2CC2)nc1NC1CC1
Solvent: COCC(C)O
Solvent: ClCCl
Product: Cc1c(NC2CCCCC2)nc(C2CC2)nc1NC1CC1
Temperature: 125 °C
Reaction time: 120 h
Yield: 17.5 %

Procedure:
A mixture of cyclohexylamine (1.78 g, 18 mmol) and 6-chloro-N,2-dicyclopropyl-5-methyl-4-pyrimidinamine 33 (0.70 g, 3 mmol) in 1-methoxy-2-propanol (2 ml) is stirred at 125° C. for 120 hours. After cooling, the brown solution is diluted with dichloromethane, washed two times with a saturated sodium bicarbonate solution. The combined organic layers are dried over magnesium sulfate and concentrated under high vacuum to afford a brown oil. The crude oil is purified by column chromatography (dichloromethane/methanol: 97.3/2.7) to give pure N4-cyclohexyl-N6,2-dicyclopropyl-5-methyl-4,6-pyrimidinediamine 141 (0.150 g, 17%).