Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[C:10]2[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]1=2.[CH3:23][C:24]1[CH:29]=[CH:28][C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][N:25]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.O.CCOC(C)=O.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>[CH3:22][N:19]1[CH2:20][CH2:21][C:9]2[N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[C:27]3[CH:26]=[N:25][C:24]([CH3:23])=[CH:29][CH:28]=3)[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]=2[CH2:18]1
Reactant: Cc1ccc2c(c1)c1c(n2-c2ccccc2Br)CCN(C)C1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
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: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: Cc1ccc2c(c1)c1c(n2-c2ccccc2-c2ccc(C)nc2)CCN(C)C1
Temperature: 90 °C
Reaction time: 0.75 h

Procedure:
To a de-aerated solution of 5-(2-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (200 mg, 0.564 mmol), 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (247 mg, 1.12 mmol) and K2CO3 (233.48 mg, 0.845 mmol) in DME-water (2:1) was added Pd(PPh3)4 (32.58 mg, 0.028 mmol). The reaction mixture was stirred at 90° C. for 45 min. The reaction mixture concentrated under reduced pressure. The residue obtained was dissolved in EtOAc (50 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to yield 2,8-dimethyl-5-(2-(6-methylpyridin-3-yl)phenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (TFA salt, CD3OD) δ (ppm): 8.18 (s, 1H), 7.74 (m, 4H), 7.38-7.58 (m, 2H), 7.28 (s, 1H), 6.93 (d, 1H), 6.78 (d, 1H), 4.4 (m, 2H), 3.7 (m, 2H), 3.1 (s, 3H), 2.8 (m, 2H), 2.57 (s, 3H), 2.38 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH:6]([C:7]#[C:8][Si](C)(C)C)[O:5][C:4](=[O:13])[NH:3]1.C([O-])([O-])=O.[K+].[K+]>CO>[CH3:1][C:2]1([CH3:14])[CH:6]([C:7]#[CH:8])[O:5][C:4](=[O:13])[NH:3]1
Reactant: CC1(C)NC(=O)OC1C#C[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#CC1OC(=O)NC1(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 4,4-Dimethyl-5-trimethylsilylethynyl-2-oxazolidinone (15.0 mmol) and K2CO3 (4.1 g, 30.0 mmol) in methanol (30.0 mL) was stirred at room temperature for 30 min. The solid was filtered off and washed with ether. The filtrate was concentrated, dissolved in ether (100 mL), washed with water (50 mL) and brine (50 mL), and dried over sodium sulfate. Solvent removal afforded 1.10 g (53%) of 4,4-Dimethyl-5-ethynyl-2-exazolidinone as a yellow oil: 1H NMR (CDCl3) δ 1.37 (s, 3H), 1.39 (s, 3H), 2.68 (s, 1H), 4.82 (s, 1H), 6.00 (br s, 1H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][CH2:13][CH3:14])[C:6]=2[N:7]=1.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>CS(C)=O>[CH2:13]([S:12][C:8]1[C:6]2[N:7]=[C:2]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[N:3]=[C:4]([N:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C:5]=2[N:11]=[CH:10][N:9]=1)[CH3:14]
Reactant: C1CNCCN1
Reactant: CCSc1ncnc2c(N3CCCCC3)nc(Cl)nc12
Solvent: CS(C)=O
Product: CCSc1ncnc2c(N3CCCCC3)nc(N3CCNCC3)nc12

Procedure:
Prepared analogously to Example 2 from 2-chloro-8-ethylthio-4-piperidino-pyrimido[5,4-d]pyrimidine and piperazine in dimethylsulphoxide.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH2:12][CH3:13])[N:5](COC)[C:6]=1[CH:7]=[O:8].[ClH:14]>>[Cl:14][C:2]1[N:3]=[C:4]([CH2:12][CH3:13])[NH:5][C:6]=1[CH:7]=[O:8]
Reactant: CCc1nc(Br)c(C=O)n1COC
Reactant: Cl
Product: CCc1nc(Cl)c(C=O)[nH]1
Temperature: 90 °C

Procedure:
4-Bromo-2-ethyl-1-(methoxymethyl)imidazole-5-carbaldehyde (365 g) was dissolved in 35% conc. hydrochloric acid (1.8 L), and the mixture was heated at 90° C. for 20 hr. The solvent was evaporated under reduced pressure, and sodium hydrogencarbonate was added to the residue under ice-cooling until the mixture assumed weak alkalinity. The mixture was extracted with chloroform, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and diisopropyl ether was added to the residue. The mixture was heated and allowed to cool. The precipitated crystals were collected by filtration and dried by heating under reduced pressure to give 4-chloro-2-ethylimidazole-5-carbaldehyde (211.5 g) as brown crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.C1(C)C=CC=CC=1.C(O)C.O.B([O-])([O-])O[C:46]1[CH:51]=[CH:50][C:49]([O:52][CH2:53][CH2:54][O:55][CH2:56][CH3:57])=[CH:48][CH:47]=1.C(=O)([O-])[O-].[K+].[K+]>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>[CH2:56]([O:55][CH2:54][CH2:53][O:52][C:49]1[CH:50]=[CH:51][C:46]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:12])(=[O:13])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([CH2:23][N:24]([CH3:31])[CH:25]5[CH2:26][CH2:27][O:28][CH2:29][CH2:30]5)=[CH:21][CH:22]=4)=[O:15])=[CH:7][C:6]=3[CH:32]=2)=[CH:47][CH:48]=1)[CH3:57]
Reactant: CCOCCOc1ccc(OB([O-])[O-])cc1
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
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: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.6 %

Procedure:
To 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (350 mg) was added toluene/ethanol/water (10/1/1, 13.6 ml) and then were added 4-(2-ethoxyethoxy)phenyl borate (226 mg) and potassium carbonate (205 mg), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (40 mg), and the mixture was stirred at 100° C. for 9 hours and cooled to room temperature. The mixture was added to water and the mixture was extracted with ethyl acetate/THF, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent, was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/ethanol=3/1) and recrystallized from ethanol to give 7-[4-(2-ethoxyethoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 84) (312 mg).
Reaction SMILES: [CH:1]1[S:2][CH:3]=[C:4]2[C:10]=1[C:9](=[O:11])[NH:8][C:7]1[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=1[NH:5]2.[H-].[Na+].[CH2:18](I)[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>CN(C)C=O>[CH2:18]([N:8]1[C:7]2[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=2[NH:5][C:4]2=[CH:3][S:2][CH:1]=[C:10]2[C:9]1=[O:11])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCI
Reactant: O=C1Nc2ccccc2Nc2cscc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCN1C(=O)c2cscc2Nc2ccccc21
Temperature: 0 °C
Reaction time: 8 h

Procedure:
An 11.8 g. portion of 4,9-dihydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-one is combined with 2.8 g. of 50% sodium hydride in mineral oil and 175 ml. of dimethylformamide and stirred for 2 hours. A 15.7 g. (11 ml.) portion of n-hexyl iodide is added and the mixture is stirred overnight. The reaction mixture is poured into ice water and the brown oil is separated and dissolved in methylene chloride. The dimethylformamide-water mixture is extracted twice with methylene chloride. All methylene chloride portions are combined, washed with water, dried over sodium sulfate, filtered and concentrated to a dark brown oil. This oil is dissolved in 10 ml. of methylene chloride and chromatographed on an alumina column. The column is eluted with 500 ml. of hexane followed by 30% methylene chloride in hexane for fractions 5-13 and methylene chloride:hexane (50:50) for fractions 14-19. Fraction 6 is concentrated to a dark brown viscous oil (A). Fractions 7-19 are combined and concentrated to dryness (B). (A) and (B) both crystallize in hexane and are combined, filtered, washed with hexane and dried. The product is dissolved with warming in 50 ml. of benzene and filtered. To the filtrate is added 100 ml. of hexane and the mixture is cooled overnight. The solid is collected, washed with ether and dried, giving the desired product, mp. 100°-102° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH2:18][N:19]3[CH:23]=[N:22][C:21]([NH2:24])=[N:20]3)[CH:11]=[N:12][C:13]=2[O:14][CH:15]([F:17])[F:16])[CH:5]=[CH:6][CH:7]=1.C=O.[C:27](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CC(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH2:18][N:19]3[CH:23]=[N:22][C:21]([NH:24][CH3:27])=[N:20]3)[CH:11]=[N:12][C:13]=2[O:14][CH:15]([F:17])[F:16])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Nc1ncn(Cc2cnc(OC(F)F)c(-c3cccc(Cl)c3)c2)n1
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CNc1ncn(Cc2cnc(OC(F)F)c(-c3cccc(Cl)c3)c2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 20.1 %

Procedure:
To a solution of 1-((5-(3-chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl)methyl)-1H-1,2,4-triazol-3-amine (Example 219, 120 mg, 0.34 mmol) in DCM (2 mL), was added formaldehyde (26 μL of 37 wt % solution, 0.35 mmol), sodium triacetoxyborohydride (145 mg, 0.68 mmol) and a few drops of AcOH. The mixture was stirred at room temperature for 16 h. Purification by reverse-phase PREP-HPLC gave the title compound (25 mg, 20%). 1H NMR (400 MHz, CD3OD) δ 8.19-8.11 (m, 1H), 7.82 (d, J=2.0 Hz, 1H), 7.71 (s, 1H), 7.53 (s, 1H), 7.47 (s, 1H), 7.41-7.28 (m, 3H), 5.21 (s, 2H), 2.72 (s, 3H). [M+H]=366.21.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH:11]=[C:10]([C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])[C:9]([NH2:20])=[N:8][C:6]=2[N:7]=1.S(=O)(=O)(O)N.N[CH2:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]1.C(=O)(O)[O-].[Na+]>O>[Cl:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([Cl:18])[C:12]=1[C:10]1[C:9]([NH2:20])=[N:8][C:6]2[N:7]=[C:2]([NH:1][CH2:27][CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]3)[N:3]=[CH:4][C:5]=2[CH:11]=1
Reactant: CN1CCN(CCCN)CC1
Reactant: Nc1ncc2cc(-c3c(Cl)cccc3Cl)c(N)nc2n1
Agent: NS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CN1CCN(CCCNc2ncc3cc(-c4c(Cl)cccc4Cl)c(N)nc3n2)CC1
Temperature: 150 °C

Procedure:
A mixture of 2,7-diamino-6-(2,6-dichlorophenyl)-pyrido[2,3-d]pyrimidine (3.0 g) from Example 1, sulfamic acid (1.9 g), and 1-(3-aminopropyl)-4-methylpiperazine (15 mL) was heated to approximately 150° C. for 24 hours After cooling, the residue was dissolved in water. The aqueous solution was made alkaline with a solution of saturated sodium bicarbonate and extracted with dichloromethane several times. The dichloromethane layers were combined, dried over magnesium sulfate, and concentrated in vacuo. The residue was recrystallized from ethyl acetate to give 2.0 g of 6-(2,6-dichlorophenyl)-N2 -[3-(4-methyl-piperazin-1-yl)-propyl]-pyrido[2,3-d]pyrimidine-2,7-diamine, CIMS (1% NH3 in CH4): 474=M+ +C2H5, 446=M+ +H (Base); mp 208-211° C.
Reaction SMILES: [Br:1][C:2]1[C:7]2[N:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:9]([C@@H:11]([NH2:13])[CH3:12])=[N:10][C:6]=2[CH:5]=[CH:4][C:3]=1[F:20].Cl[C:22]1[N:30]=[CH:29][N:28]=[C:27]2[C:23]=1[N:24]=[CH:25][N:26]2[CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][O:32]1.CCN(C(C)C)C(C)C>C(O)CCC>[Br:1][C:2]1[C:7]2[N:8]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:9]([C@@H:11]([NH:13][C:22]3[N:30]=[CH:29][N:28]=[C:27]4[C:23]=3[N:24]=[CH:25][N:26]4[CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][O:32]3)[CH3:12])=[N:10][C:6]=2[CH:5]=[CH:4][C:3]=1[F:20]
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: C[C@H](N)c1nc2ccc(F)c(Br)c2n1-c1ccccc1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc2c1ncn2C1CCCCO1)c1nc2ccc(F)c(Br)c2n1-c1ccccc1
Temperature: 90 °C
Yield: 77 %

Procedure:
A mixture of (S)-1-(7-bromo-6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethylamine (102 mg, 0.31 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (80 mg, 0.34 mmol) and DIPEA (104 μL, 0.61 mmol) in n-butanol (2 mL) was heated at 90° C. in a sealed vial for 18 h. After cooling to RT, the volatiles were removed in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-10% MeOH in EtOAc) to afford the title compound (128 mg, 78%). LCMS (Method C): RT 3.57 min [M+H]+ 536.3/538.3.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:13]([CH:14]=[O:15])[CH2:12][O:11][C:10]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:28][C:29]1[CH:34]=[C:33]([CH2:35][CH2:36][N+:37]([O-:39])=[O:38])[CH:32]=[C:31]([F:40])[CH:30]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[Na+]>O1CCCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[C@@H:13]([C@@H:14]([OH:15])[C@@H:36]([N+:37]([O-:39])=[O:38])[CH2:35][C:33]2[CH:34]=[C:29]([F:28])[CH:30]=[C:31]([F:40])[CH:32]=2)[CH2:12][O:11][C:10]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])CCc1cc(F)cc(F)c1
Reactant: CC(C)(C)OC(=O)N1CC(c2ccccc2)(c2ccccc2)OC[C@@H]1C=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(c2ccccc2)(c2ccccc2)OC[C@@H]1[C@@H](O)[C@H](Cc1cc(F)cc(F)c1)[N+](=O)[O-]
Reaction time: 0.33 h

Procedure:
To (R)-5-formyl-2,2-diphenylmorpholine-4-carboxylic acid tert-butyl ester (1.03 g, 2.80 mmol) and 1,3-difluoro-5-(2-nitroethyl)-benzene (0.577 g, 3.08 mmol) in tetrahydrofuran (5 mL) at −0° C. under nitrogen add tetrabutylammonium fluoride (3 mL, 3.0 mmol, 1.0 M in tetrahydrofuran). Stir 20 minutes and add half saturated aqueous sodium chloride (20 mL) and ethyl acetate (100 mL). Separate the layers and wash the organic layer with water and saturated aqueous sodium chloride. Dry (magnesium sulfate), filter and concentrate. Purify on silica gel, eluting with 0:100 to 50:50 ethyl acetate:hexanes, then re-crystallize from hexanes/dichloromethane to give the desired compound.
Reaction SMILES: Br[C:2]1[C:3]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH:10]2[C:15]([NH:17][CH:18]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([Cl:27])[CH:25]=3)[CH2:20][CH2:19]2)=[O:16])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C(O)(C)(C)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:8][C:5]1[N:6]=[CH:7][C:2]2[N:17]([CH:18]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([Cl:27])[CH:25]=4)[CH2:20][CH2:19]3)[C:15](=[O:16])[CH:10]3[CH2:11][O:12][CH2:13][CH2:14][N:9]3[C:3]=2[N:4]=1
Reactant: O=C(NC1CCc2ccc(Cl)cc21)C1COCCN1c1nc(Cl)ncc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CC(C)(C)O
Solvent: C1COCCO1
Product: O=C1C2COCCN2c2nc(Cl)ncc2N1C1CCc2ccc(Cl)cc21

Procedure:
The title compound was prepared in a manner similar to PREPARATION x35 using 4-(5-bromo-2-chloropyrimidin-4-yl)-N-(6-chloro-2,3-dihydro-1H-inden-1-yl)morpholine-3-carboxamide (PREPARATION x40, 567 mg, 1.201 mmol), Xantphos (52.1 mg, 0.090 mmol), palladium(II)acetate (13.48 mg, 0.060 mmol) and potassium phosphate (255 mg, 1.201 mmol) in dioxane (5 mL) and tert-butanol (1 mL). 1H NMR (400 MHz, DMSO-d6) δ 2.21-2.48 (m, 3H), 2.87-3.05 (m, 2H), 3.05-3.21 (m, 1H), 3.47-3.65 (m, 2H), 3.88-4.01 (m, 1H), 4.08-4.32 (m, 2H), 4.39-4.56 (m, 1H), 7.16-7.42 (m, 4H). ESI-MS m/z [M+H]+ calc'd for C18H16Cl2N4O2, 391.07. found 391.3.
Reaction SMILES: [C:1](=[S:3])=S.CP(=[N:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[N:15]1[CH2:20][CH2:19][CH2:18][C@H:17]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:16]1)(C)C>C1COCC1>[N:8]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[N:15]1[CH2:20][CH2:19][CH2:18][C@H:17]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27])[CH2:16]1)=[C:1]=[S:3]
Reactant: S=C=S
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccncc2N=P(C)(C)C)C1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccncc2N=C=S)C1
Reaction time: 0.25 h

Procedure:
tert-butyl ((3S)-1-(3-isothiocyanato-4-pyridinyl)-3-piperidinyl)carbamate. A dry, 3 neck, 100 mL Morton flask was configured as follows: opening 1: septa/Ar inlet; opening 2 (center): septa/PTFE addition needle; opening 3: septa. The flask was charged with tert-butyl ((3S)-1-(3-azido-4-pyridinyl)-3-piperidinyl)carbamate (3.25 g, 10.22 mmol), a stirbar, and dry THF (10 mL). The slurry was stirred for 10 min, and immersed into an ice-water bath. A syringe charged with 1.0 M PMe3 in THF (10.73 mL, 10.73 mmol, Aldrich) was fitted to the PTFE addition needle and added over a 15 min period via a syringe pump. The reaction was stirred for 15 min. The solution was charged to a dry 50 mL glass syringe via the PTFE addition needle to afford (S)-tert-butyl (1-(3-((trimethylphosphoranylidene)amino)pyridin-4-yl)piperidin-3-yl)carbamate. A dry, 250 mL, one neck round bottom flask was charged with dry THF (16 mL), carbon disulfide (6.17 mL, 102 mmol) and a stirbar. The flask was fitted with a septa/Ar inlet, and immersed into an ice-water bath. The solution was stirred for 15 min. The septa was pierced with the PTFE addition needle fitted to the 50 mL glass syringe containing the solution of (S)-tert-butyl (1-(3-((trimethylphosphoranylidene)amino)pyridin-4-yl)piperidin-3-yl)carbamate and the solution (19 mL) was added via syringe pump over a 1 h period. The reaction was stirred an additional 10 min and the solvent was removed in vacuo. The residue was further dried at <1 mm Hg at RT to afford tert-butyl ((3S)-1-(3-isothiocyanato-4-pyridinyl)-3-piperidinyl)carbamate. MS (ESI, pos. ion) m/z: 335.0 [M+H].
Reaction SMILES: [C:1]([CH:3]1[C:7](=O)[CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1)#[N:2].Cl.[NH2:17][NH2:18].C(=O)([O-])O.[Na+]>C(O)C>[NH2:2][C:1]1[NH:18][N:17]=[C:7]2[CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4][C:3]=12
Reactant: CC(C)(C)OC(=O)N1CC(=O)C(C#N)C1
Reactant: NN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1Cc2n[nH]c(N)c2C1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 1 g (4.76 mmol) of tert-butyl 3-cyano-4-oxopyrrolidine-1 carboxylate in ethanol (28 mL) was added 0.326 g (4.76 mmol) of hydrazine hydrochloride and the reaction mixture heated at ° C. for 3 h. The mixture was cooled to 0° C. and saturated aqueous sodium hydrogen carbonate (60 mL) added. The solvent was evaporated in vacuo and the aqueous phase extracted with ethyl acetate (10×10 mL). The combined organic fractions were dried (anhydrous sodium sulfate), filtered and the solvent evaporated in vacuo. The resulting residue was chromatographed on a Biotage Horizon® system (silica gel, 0 to 10% methanol/ethyl acetate gradient) to yield the title compound as a orange solid. LC/MS 225.2 (M+1).
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[CH:8]=[N:9][N:10]2[CH2:15][CH2:14][CH2:13][NH:12][C:11]=12.C(N(C(C)C)C(C)C)C.[C:25]([O:29][C:30]([NH:32][C:33]([NH:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=NS(C(F)(F)F)(=O)=O)=[O:31])([CH3:28])([CH3:27])[CH3:26]>C(Cl)Cl>[C:46]([O:45][C:43]([N:42]=[C:33]([NH:32][C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31])[NH:6][C:7]1[CH:8]=[N:9][N:10]2[CH2:15][CH2:14][CH2:13][NH:12][C:11]=12)=[O:44])([CH3:49])([CH3:48])[CH3:47]
Reactant: Nc1cnn2c1NCCC2
Reactant: CC(C)(C)OC(=O)NC(=NS(=O)(=O)C(F)(F)F)NC(=O)OC(C)(C)C
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)Nc1cnn2c1NCCC2
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 89.5 %

Procedure:
To a solution of 3-amino-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine sulfuric acid salt (2.96 g) and N-ethyldiisopropylamine (3.88 g) in methylene chloride (70 ml) was added 1,3-bis(tert-butoxycarbonyl)-2-(trifluoromethanesulfonyl)guanidine (3.91 g). The mixture was stirred at room temperature for 150 minutes. There action mixture was washed with saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 2% methanol/chloroform to give 3-[2,3-bis(tert-butoxycarbonyl)guanidino]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine (3.4 g) as a solid.
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:15])[C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][N:7]=1)=[O:5].FC(F)(F)C(O[I:21](C1C=CC=CC=1)OC(=O)C(F)(F)F)=O.II.OS([O-])=O.[Na+]>C(Cl)Cl>[I:21][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[NH:8][N:7]=[C:6]2[C:4]([N:3]([O:2][CH3:1])[CH3:15])=[O:5]
Reactant: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Reactant: CON(C)C(=O)c1n[nH]c2ccccc12
Agent: II
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CON(C)C(=O)c1n[nH]c2ccc(I)cc12
Reaction time: 1 h
Yield: 71.9 %

Procedure:
To N-methoxy-N-methyl-1H-indazole-3-carboxamide (CXI) (20 g, 97.4 mmol) in DCM (1 L) was added (Bis(trifluoroacetoxy)iodo)benzene (46 g, 107 mmol) followed by portionwise addition of iodine (14.84 g, 58.5 mmol) at room temperature. After 1 h, saturated aqueous NaHSO3 (600 mL) was added and a solid began to precipitate which was filtered and rinsed with excess DCM. The filtrate was washed with brine, dried over MgSO4, concentrated and the remaining solid was triturated with a minimal amount of DCM. The combined solids were dried under vacuum over KOH to produce 5-iodo-N-methoxy-N-methyl-1H-indazole-3-carboxamide (CXII) as a white solid (23.2 g, 70 mmol, 72% yield). 1H NMR (DMSO-d6) δ ppm 3.45 (s, 3H), 3.77 (s, 3H), 7.45-7.54 (m, 1H), 7.66 (dd, J=8.81, 1.51 Hz, 1H), 8.40 (d, J=1.01 Hz, 1H); ESIMS found for C10H10IN3O2 m/z 331 (M+H).
Reaction SMILES: F[C:2](F)(F)[C:3]([NH:5][C:6]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14](C(=O)C(F)(F)F)=[CH:13][CH:12]=2)[N:7]=1)=[O:4].[C:25](OC(=O)CC)(=O)CC>CN(C)C1C=CN=CC=1.ClCCl>[C:11]1([N:8]2[CH2:9][CH2:10][C:6]([NH:5][C:3](=[O:4])[CH2:2][CH3:25])=[N:7]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCC(=O)OC(=O)CC
Reactant: O=C(NC1=NN(c2ccc(C(=O)C(F)(F)F)cc2)CC1)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCC(=O)NC1=NN(c2ccccc2)CC1

Procedure:
A mixture of 10.0 g. of 3-amino-1-phenyl-2-pyrazoline (prepared as described in Example 8), 50 ml. of propionic anhydride and 200 mg. of 4-dimethylaminopyridine is kept at room temperature for 30 minutes. The mixture is cooled and filtered to give yellow crystals. The solid is dissolved in dichloromethane and is columnized and crystallized as for Example 10 (B) to yield 4.55 g. of the product of the Example as colorless crystals, m.p. 170.5°-171° C.