Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11]([CH2:31][CH:32]([CH3:34])[CH3:33])[C:12](=[O:30])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)=[CH:17][C:16]([C:27](O)=[O:28])=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C([N:38]=C=NCCCN(C)C)C.[NH4+].ON1C2C=CC=CC=2N=N1.O>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11]([CH2:31][CH:32]([CH3:34])[CH3:33])[C:12](=[O:30])[C:13]2[C:18]([C:19]=1[C:20]1[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=1)=[CH:17][C:16]([C:27]([NH2:38])=[O:28])=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccc(Cl)cc2)c2cc(C(=O)O)ccc2c1=O
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccc(Cl)cc2)c2cc(C(N)=O)ccc2c1=O
Yield: 84.3 %

Procedure:
A solution of 3-[[(tert-butoxycarbonyl)amino]methyl]-4-(4-chlorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxylic acid (1.21 g, 2.5 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.96 g, 5 mmol) and 1-hydroxybenzotriazole ammonium salt (0.76 g, 5 mmol) in N,N-dimethylformamide (10 ml) was stirred at room temperature for 2 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from ethyl acetate-diisopropyl ether to give 3-[[(tert-butoxycarbonyl)amino]methyl]-4-(4-chlorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxamide (1.02 g, 85.0%) as crystals.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[N:10]1[C:14]([CH3:15])=[N:13][C:12]([NH:16][CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[N:11]1.Cl[C:24]1[S:28][N:27]=[C:26]([CH3:29])[N:25]=1>>[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[N:10]1[C:14]([CH3:15])=[N:13][C:12]([NH:16][CH:17]2[CH2:18][CH2:19][N:20]([C:24]3[S:28][N:27]=[C:26]([CH3:29])[N:25]=3)[CH2:21][CH2:22]2)=[N:11]1
Reactant: Cc1nsc(Cl)n1
Reactant: Cc1nc(NC2CCNCC2)nn1-c1ccc(Cl)cc1Cl
Agent: Cl
Product: Cc1nsc(N2CCC(Nc3nc(C)n(-c4ccc(Cl)cc4Cl)n3)CC2)n1

Procedure:
Prepared in analogy to example 1 step b) starting from [1-(2,4-dichloro-phenyl)-5-methyl-1H-[1,2,4]triazol-3-yl]-piperidin-4-yl-amine hydrochloride and 5-chloro-3-methyl-[1,2,4]thiadiazole (example 1 step a)). The title compound was obtained as slightly yellow solid (yield=10%).
Reaction SMILES: [C:1]1([O:7][CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:18]1[N:23]([CH3:24])[C:22](=[O:25])[NH:21][C:20](=[O:26])[CH:19]=1.C(N(CC)CC)C>C(O)(C)C>[CH3:24][N:23]1[C:18]([N:14]2[CH2:15][CH2:16][N:11]([CH2:10][CH2:9][CH2:8][O:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:12][CH2:13]2)=[CH:19][C:20](=[O:26])[NH:21][C:22]1=[O:25]
Reactant: c1ccc(OCCCN2CCNCC2)cc1
Reactant: Cn1c(Cl)cc(=O)[nH]c1=O
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: Cn1c(N2CCN(CCCOc3ccccc3)CC2)cc(=O)[nH]c1=O
Reaction time: 12 h
Yield: 68.1 %

Procedure:
1.3 g of 1-(3-phenyloxypropyl)piperazine and 0.5 g of 6-chloro-1-methyl-2,4(1H,3H)-pyrimidinedione were dissolved in 15 ml of isopropanol, and 2.7 ml of triethylamine was then added. Next, the solution was heated under reflux with stirring for 12 hours and then allowed to stand for cooling, and the solvent was distilled off. The resultant residue was dissolved in 100 ml of chloroform. The chloroform layer was washed with water, dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain an oily product. This oily product was purified through a silica gel column chromatograph (chloroform/methanol=30/1 in volume ratio), thereby obtaining 0.73 g of 1-methyl-6-[4-(3-phenoxypropyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH3:15])[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[CH2:21]([O:28][C:29]1[C:34]([C:35](=[O:37])[CH3:36])=[CH:33][CH:32]=[CH:31][C:30]=1[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:21]([O:28][C:29]1[C:34]([C:35]([C:2]2[CH:3]=[C:4]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[O:14][CH3:15])[CH:5]=[CH:6][CH:7]=2)([OH:37])[CH3:36])=[CH:33][CH:32]=[CH:31][C:30]=1[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(=O)c1cccc(-c2ccccc2)c1OCc1ccccc1
Reactant: COc1ccccc1-c1cccc(Br)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccccc1-c1cccc(C(C)(O)c2cccc(-c3ccccc3)c2OCc2ccccc2)c1
Reaction time: 1 h

Procedure:
A solution of 21 (0.7 g, 2.66 mmol) in anhydrous tetrahydrofuran (15 mL) was stirred under nitrogen at −78° C. and 2.5M n-butyllithium in hexanes (1.1 mL, 2.75 mmol) was added at such a rate that the temperature did not exceed −70° C. Stirring was continued at −78° C. for 1 hr when a solution of 20 (0.8 g, 2.66 mmol) in tetrahydrofuran (5 mL) was added at such a rate that the temperature did not exceed −65° C. Stirring was continued at −78° C. for 30 min., then for 2 hrs at room temperature. The reaction mixture was poured onto saturated ammonium chloride (120 mL) and extracted with ethyl acetate (150 mL). The organic extract was washed with water (2×80 mL), dried over sodium sulfate and stripped. The crude 22 was used as such in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[NH:11][NH:10][C:9]2=[O:19])=[CH:4][CH:3]=1.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][C:30](=O)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]>C(Cl)(Cl)Cl>[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([N:11]2[CH:12]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[CH:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[C:9](=[O:19])[NH:10]2)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: O=C1NNC(c2ccncc2)C1c1ccc(Cl)cc1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(N2NC(=O)C(c3ccc(Cl)cc3)C2c2ccncc2)CC1
Temperature: 25 °C

Procedure:
To a solution of 4-(4-Chloro-phenyl)-5-pyridin-4-yl-pyrazolidin-3-one 0.86 g and 4-Oxo-piperidine-1-carboxylic acid tert-butyl ester 0.75 g in chloroform 35 mL was added sodium triacetoxy boron hydride 0.75 g at 0° C., the reaction was warmed up to room temperature over two hours before heated to 50° C. for another two hours. The reaction was quenched with water 25 mL at 0° C., and the organic layer was collected, filtered, dried over MgSO4, concentrated to a yellow solid 0.42 g for being directly used for next step. MS (ES+): 457 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[C:14]1[N:15]([CH3:19])[N:16]=[CH:17][CH:18]=1.[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1>C(Cl)Cl>[CH3:20][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:29]([NH:28][C:25]2[CH:26]=[CH:27][C:22]([CH3:21])=[CH:23][CH:24]=2)=[O:30])=[CH:9][C:8]=1[C:14]1[N:15]([CH3:19])[N:16]=[CH:17][CH:18]=1
Reactant: Cc1ccc(N=C=O)cc1
Reactant: CN(C)CCCOc1ccc(N)cc1-c1ccnn1C
Solvent: ClCCl
Product: Cc1ccc(NC(=O)Nc2ccc(OCCCN(C)C)c(-c3ccnn3C)c2)cc1
Reaction time: 2 h
Yield: 90.8 %

Procedure:
To a solution of 4-(3-dimethylamino-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenylamine (45.9 mg, 0.167 mmol) in CH2Cl2 (2 mL) was added 4-methylphenyl isocyanate (0.24 μL, 0.191 mmol) and stirred for two hours. The resulting material was purified by solid phase extraction (SCX, 1 gram cartridge), eluting with methanol (30 mL) followed by 2M NH3 in methanol (30 mL). The NH3 containing fractions were dried in vacuo to afford Compound 130 as a colorless solid (61.8 mg, 91%). LCMS m/z (%)=408 (MH+) (100), 1H NMR (400 MHz, DMSO-d6) δ: 8.53 (bs, 1H), 8.52 (bs, 1H), 7.44 (d, J=1.77 Hz, 1H), 7.43 (dd, J=8.91, 2.73 Hz, 1H), 7.36 (d, J=2.70 Hz, 1H), 7.31 (d, J=8.43 Hz, 2H), 7.08 (d, J=8.92 Hz, 1H), 7.06 (d, J=8.32 Hz, 2H), 6.23 (d, J=1.82 Hz, 1H), 3.96 (t, 6.36 Hz, 2H), 3.65 (s, 3H), 2.23 (s, 3H), 2.19 (t, J=7.05 Hz, 2H), 2.07 (s, 6H), 1.77-1.69 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].Br[CH2:16][CH2:17]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[O:1]1[CH2:17][CH2:16][O:8][C:7]2[CH:6]=[CH:5][C:4]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:3][C:2]1=2
Reactant: BrCCBr
Reactant: CCOC(=O)Cc1ccc(O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1ccc2c(c1)OCCO2
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of Ethyl 2-(3,4-dihydroxyphenyl)acetate (1.11 g, 5.66 mmol) and 1,2-dibromoethane (1.07 g, 5.69 mmol) in DMF (5 mL) was added cesium carbonate (3.71 g, 11.4 mmol). The reaction mixture was stirred for 2 hrs at 80° C. then cooled to room temperature. The mixture was diluted with H2O and extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using EtOAc:hexanes (1:4-1:2) as eluant.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:6][C@@H:5]([C@H:7]2[O:11][C@@H:10]3[O:12][C:13]([CH3:16])([CH3:15])[O:14][C@@H:9]3[C@@H:8]2[OH:17])[CH2:4][O:3]1.[H-].[Na+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CO>CN(C)C=O>[CH3:1][C:2]1([CH3:18])[O:6][CH:5]([CH:7]2[O:11][CH:10]3[O:12][C:13]([CH3:16])([CH3:15])[O:14][CH:9]3[CH:8]2[O:17][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:4][O:3]1
Reactant: BrCc1ccccc1
Reactant: CC1(C)O[C@H]2O[C@H]([C@H]3COC(C)(C)O3)[C@@H](O)[C@H]2O1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CC1(C)OCC(C2OC3OC(C)(C)OC3C2OCc2ccccc2)O1
Reaction time: 1 h
Yield: 93 %

Procedure:
To a solution of 1,2:5,6-Di-O-isopropylidene-α-D-allofuranose (30A) (obtained from Pfanstiehl Laboratories Inc.) (40 g) in dimethylformamide at 0° C. was added sodium hydride in smaller portions. The reaction mixture was stirred for 1 h, benzyl bromide was added drop wise over a period of 1 h. The reaction mixture was stirred at room temperature for 16 h. Methanol was added to quench the reaction and dimethylformamide was removed under pressure. The syrup was extracted with ethyl acetate and washed with brine. Evaporation of the ethyl acetate layer yielded a semisolid (93%). Homogeneous by TLC.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@H:16]2[N:12]([N:13]=[C:14]([C:27]3[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[C:29]([Cl:35])[C:28]=3[CH3:36])[C@H:15]2[O:17][CH2:18][CH2:19][O:20]C2CCCCO2)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[Si:1]([O:8][C@@H:9]1[C@@H:16]2[N:12]([N:13]=[C:14]([C:27]3[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[C:29]([Cl:35])[C:28]=3[CH3:36])[C@H:15]2[O:17][CH2:18][CH2:19][OH:20])[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: Cc1c(C2=NN3CC[C@H](O[Si](C)(C)C(C)(C)C)[C@H]3[C@@H]2OCCOC2CCCCO2)ccc(C#N)c1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: Cc1c(C2=NN3CC[C@H](O[Si](C)(C)C(C)(C)C)[C@H]3[C@@H]2OCCO)ccc(C#N)c1Cl
Reaction time: 1 h

Procedure:
To a stirred solution of 4-((3S,3aR,4S)-4-((tert-butyldimethylsilyl)oxy)-3-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)-3a,4,5,6-tetrahydro-3H-pyrrolo[1,2-b]pyrazol-2-yl)-2-chloro-3-methylbenzonitrile (160 mg, 0.299 mmol) in methanol (5 mL) at room temperature was added p-toluenesulphonic acid and stirred for 1 h. Once the starting material had disappeared (monitored by TLC) methanol was removed from the reaction mixture and then extracted with EtOAc. Organic layer was washed with water, brine, dried over Na2SO4 and concentrated. Crude product was purified by column chromatography using 15% in ethylacetate in hexane as solvent.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=O)=[C:6]([NH:8][C:9]([NH2:11])=[O:10])[CH:7]=1.[OH-].[Na+]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N+:12]([O-:14])=[N:11][C:9](=[O:10])[NH:8][C:6]=2[CH:7]=1
Reactant: NC(=O)Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=c1n[n+]([O-])c2ccc(Cl)cc2[nH]1
Yield: 49 %

Procedure:
A suspension of N-(5-chloro-2-nitrophenyl)urea (1.558 g, 7.230 mmol) in an aqueous NaOH solution (4.34 g NaOH in 15 ml water) was heated at reflux for 0.5 h before cooling and treatment with water (100 ml). The mixture was then heated to reflux again and the hot mixture filtered through a Buchner funnel. The filtrate was then acidified with conc. HCl and the resultant solid was filtered, washed with water (20 ml) and dried in vacuo to give the desired product (700 mg, 49%).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)[C:9]([N:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C@H:12]1[C:20](=[O:30])[NH:21][C:22]1[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=1[F:29])=[O:10])(C)(C)C.[C:38]([OH:44])([C:40]([F:43])([F:42])[F:41])=[O:39]>C(Cl)Cl>[F:41][C:40]([F:43])([F:42])[C:38]([OH:44])=[O:39].[F:29][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]([F:28])[C:22]=1[NH:21][C:20]([C@@H:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:19][N:11]1[C:9](=[O:10])[C@@H:8]([NH2:7])[CH:31]1[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]1)=[O:30]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)N1Cc2ccccc2[C@H]1C(=O)Nc1c(F)cccc1F)C1CCCCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H](C(=O)N1Cc2ccccc2[C@H]1C(=O)Nc1c(F)cccc1F)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of {(S)-1-cyclohexyl-2-[(S)-1-(2,6-difluoro-phenylcarbamoyl)-1,3-dihydro-isoindol-2-yl]-2-oxo-ethyl}-carbamic acid tert-butyl ester (174 mg, 339 μmol, Eq: 1.00) in CH2Cl2 (3 mL) was added TFA (1 mL) dropwise. The reaction was stirred at RT for 1 h. The mixture was evaporated to afford (S)-2-((S)-2-amino-2-cyclohexyl-acetyl)-2,3-dihydro-1H-isoindole-1-carboxylic acid (2,6-difluoro-phenyl)-amide trifluoroacetate which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[NH2:8].C1N=CN([C:27](N2C=NC=C2)=[O:28])C=1>C1COCC1>[O:28]=[C:27]1[NH:8][C:7]2[CH:6]=[CH:5][C:4]([C:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]=3)=[CH:3][C:2]=2[NH:1]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(N)c(N)c2)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc3[nH]c(=O)[nH]c3c2)CC1
Temperature: 60 °C
Reaction time: 6 h
Yield: 68 %

Procedure:
A mixture of compound 18 (0.58 g, 2 mmol) and CDI (0.34 g, 2.1 mmol) in THF (10 mL) was stirred at 60° C. for 6 h. The solvent was removed in vacuo, the residue was triturated with diethyl ether, and the resultant off-white solid was filtered and washed with diethyl ether to obtain compound 13. Yield: 68%, off-white solid, mp 244-245° C. IR (KBr, cm1) 3433, 3191 (CONH), 3037 (Ar—H), 2978 (Alph-H), 1713, 1689 (C=0), 1604, 1433 (C═C), 1244 (C—N), 1178 (C-0); 1H NMR (500 MHz, DMSO d6)g 1.39 (s, 9H, OC(CH3)3), 2.48 (br. s, 2H, CH2), 3.54 (m, 2H, CH2), 3.93 (br. s, 2H, CH2), 5.97 (br. s, 1H, CH), 6.86 (d, J=8.2 Hz, 1H, H-7), 6.95 (d, J=2.4 Hz, 1H, H-4), 6.99 (dd, J=2.4, 8.2 Hz, 1H, H-6), 10.60 (br. s, 2FI, NH). 13C NMR (125.7 MHz, DMSO d6) δ 26.84 (CH2), 28.28 (OC(CH3)3), 32.33 (CH), 42.80 (CH2), 79.08 (OC(CH3)3), 105.16 (CH), 108.52 (C-4), 117.67 (C-7), 129.20 (C-6), 130.04 (C-8), 133.28 (C-5/C-9), 134.81 (C-5/C-9), 154.73 (CO), 155.67 (CO). Anal. Calcd for C17H21N3O3: C, 64.74; H, 6.71; N, 13.32%. Found: C, 64.68; H, 6.76; N, 13.24%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][CH:36]([F:38])[F:37])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][CH2:26][NH:27][CH2:28][CH:29]3[CH2:33][CH2:32][C:31](=[O:34])[O:30]3)[N:9]=2)[CH:7]=1.C=O.[BH3-][C:42]#N.[Na+]>CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][CH:36]([F:38])[F:37])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][CH2:26][N:27]([CH3:42])[CH2:28][CH:29]3[CH2:33][CH2:32][C:31](=[O:34])[O:30]3)[N:9]=2)[CH:7]=1
Reactant: O=C1CCC(CNCCn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)O1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CN(CCn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1)CC1CCC(=O)O1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[[(5-oxooxolan-2-yl)methyl]amino]ethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (140 mg, 0.26 mmol) in MeOH (20 mL) was added 37% formaldehyde in water (23 mg), followed by NaBH3CN (24.6 mg, 0.39 mmol). The resulting solution was stirred at room temperature for 3 h. The resulting mixture was concentrated under vacuum. The residue was passed through a short pad of silica gel eluting with 8% MeOH in DCM. The crude product (60 mg) was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-006(Waters)): Column, XSelect CSH Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, Water with 0.05% FA and MeCN (18.0% MeCN up to 36.0% in 8 min); Detector, 254/220. This resulted in 22.4 mg of the formic acid salt of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[methyl[(5-oxooxolan-2-yl)methyl]amino]ethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as a white solid. LCMS (Method 28) [M+H]+=560.2, RT=0.94 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.76 (s, 1H), 9.34 (dd, 1H, J=1.6, 7.2 Hz), 8.69-8.67 (m, 2H), 8.38 (s, 1H), 7.62 (dd, 1H, J=2.8, 8.8 Hz), 7.60 (d, 1H, J=2.4 Hz), 7.45 (d, 1H, J=8.8 Hz), 7.29 (dd, 1H, J=4.0, 6.8 Hz), 7.08 (t, 1H, J=73.2 Hz), 4.59-4.55 (m, 1H), 4.30-4.27 (m, 2H), 2.94-2.88 (m, 2H), 2.62 (d, 2H, J=5.6 Hz), 2.44-2.41 (m, 2H), 2.32 (s, 3H), 2.14-2.11 (m, 1H), 1.83-1.77 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([CH2:7][Cl:8])[N:3]=1.[F:9][C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=1)[CH2:13][N:14]=[C:15]=[O:16].O>CN(C1C=CN=CC=1)C.CN1C(=O)CCC1>[F:9][C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=1)[CH2:13][NH:14][C:15]([NH:1][C:2]1[S:6][N:5]=[C:4]([CH2:7][Cl:8])[N:3]=1)=[O:16]
Reactant: Nc1nc(CCl)ns1
Reactant: O=C=NCc1cccc(F)c1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C(NCc1cccc(F)c1)Nc1nc(CCl)ns1
Temperature: 25 °C

Procedure:
A solution of 5-Amino-3-(chloromethyl)-1,2,4-thiadiazole (Intermediate XXIV) (1 equivalent) and the 3-fluoro-benzyl isocyanate (1.2 equivalents) and DMAP (150 μmol) in NMP (12 ml) was heated in a microwave oven for 30 minutes at 150° C. After cooling to ambient temperature, the brown solution is poured into water (60 ml) and the mixture was extracted with ethyl acetate (5×20 ml). The combined organic layers were partitioned with water (2×20 ml), then brine, and dried over sodium sulphate, filtered and volatiles removed in vacuo. The crude material was first purified by normal phase column chromatography (silica gel, 12-75% ethyl acetate in heptane), followed by reversed phase column chromatography (C18, 10-100% methanol in water) to give a white solid. 1H NMR (300 MHz, d6-DMSO) δ 4.36 (d, 2H), 4.69 (s, 2H), 7.03-7.13 (m, 3H), 7.33-7.38 (m, 1H), 7.45 (t, br, 1H).
Reaction SMILES: C([N:8]1[CH2:20][C@H:19]2[C@H:11]([C:12](=[O:29])[C:13]3[C:18]2=[CH:17][C:16]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])=[CH:15][CH:14]=3)[CH2:10][CH2:9]1)C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[Cl:28][C:22]1[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:21]=1[C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:29])[C@H:11]1[C@@H:19]2[CH2:20][NH:8][CH2:9][CH2:10]1
Reactant: O=C1c2ccc(-c3ccc(Cl)cc3Cl)cc2[C@H]2CN(Cc3ccccc3)CC[C@@H]12
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: O=C1c2ccc(-c3ccc(Cl)cc3Cl)cc2[C@H]2CNCC[C@@H]12
Temperature: 20 °C
Reaction time: 15 h

Procedure:
To a solution of cis-3-benzyl-6-(2,4-dichloro-phenyl)-1,2,3,4,4a,9a-hexahydro-3-aza-fluoren-9-one (132 mg, 0.31 mmol) in MeOH (4.0 mL) was added Pd(OH)2 (26 mg, 20 wt %). The reaction mixture was stirred at 20° C. for 15 h under H2 atmosphere, filtered through celite and concentrated in vacuo to give the crude title compound.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][CH:3]=1.[CH:11]1([C:16](Cl)=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12]1.[N+](C)([O-])=O.[Cl-].[Al+3].[Cl-].[Cl-]>O>[CH:11]1([C:16]([C:3]2[S:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:2]=2[CH3:1])=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=C(Cl)C1CCCC1
Reactant: Cc1csc2ccccc12
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: C[N+](=O)[O-]
Product: Cc1c(C(=O)C2CCCC2)sc2ccccc12
Reaction time: 1.5 h
Yield: 93 %

Procedure:
To a mixture of 3-methyl-1-benzothiophene (1.00 g), cyclopentanecarbonyl chloride (903 μL) and nitromethane (10 mL) was added aluminum chloride (1.35 g) at 0° C., and the mixture was stirred for 1.5 hr. Water was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by NH-silica gel column chromatography (ethyl acetate) to give the title object compound (1.54 g, 93%) as a pale-brown oil.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[C:9]([CH3:11])[CH:8]=[C:7]([N:12]([CH3:14])[CH3:13])[N:6]=1)(=O)[CH3:2].Cl.[CH3:16][N:17](C)[CH2:18]CCl>>[CH3:16][N:17]([CH3:18])[CH2:2][CH2:1][NH:4][C:5]1[N:10]=[C:9]([CH3:11])[CH:8]=[C:7]([N:12]([CH3:14])[CH3:13])[N:6]=1
Reactant: CN(C)CCCl
Reactant: CC(=O)Nc1nc(C)cc(N(C)C)n1
Agent: Cl
Product: Cc1cc(N(C)C)nc(NCCN(C)C)n1

Procedure:
Following the procedure of Example 1, Part A 2-acetamido-4-methyl-6-dimethylaminopyrimidine and 2-dimethylaminoethyl chloride hydrochloride, 2-(2-dimethylaminoethylamino)-4-methyl-6-dimethylaminopyrimidine is obtained with a boiling point of 120°-124° C. at 0.03 mm.