Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[C:11]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[N:12][C:13]([CH2:17][CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[N:14][C:15]=1[CH3:16])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[CH:42][C:41]([CH2:44][O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])=[CH:40][CH:39]=2)=[CH:34][CH:33]=1.CC(C)([O-])C.[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:2]([O:9][C:10]1[C:11]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[N:12][C:13]([CH2:17][CH:18]2[CH2:23][CH2:22][N:21]([C:32]3[CH:33]=[CH:34][C:35]([C:38]4[CH:43]=[CH:42][C:41]([CH2:44][O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:47])[CH3:48])=[CH:40][CH:39]=4)=[CH:36][CH:37]=3)[CH2:20][CH2:19]2)=[N:14][C:15]=1[CH3:16])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(-c2ccc(Br)cc2)cc1
Reactant: Cc1nc(CC2CCNCC2)nc(C(=O)OC(C)(C)C)c1OCc1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1nc(CC2CCN(c3ccc(-c4ccc(CO[Si](C)(C)C(C)(C)C)cc4)cc3)CC2)nc(C(=O)OC(C)(C)C)c1OCc1ccccc1
Temperature: 25 °C
Yield: 60.9 %

Procedure:
tert-Butyl 5-(benzyloxy)-6-methyl-2-(piperidin-4-ylmethyl)pyrimidine-4-carboxylate hydrochloride (1.0 g, 2.3 mmol), [(4′-bromobiphenyl-4-yl)methoxy](tert-butyl)dimethylsilane (0.92 g, 2.4 mmol), sodium tert-butoxide (0.67 g, 7.0 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (X-PHOS) (0.11 g, 0.23 mmol) and tris(dibenzylideneacetone)dipalladium (0.11 g, 0.12 mmol) were suspended in toluene (50 mL), followed by heating to reflux for 3 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature, and filtered with celite, and subsequently the filtrate was concentrated under reduced pressure. The resulting residue was purified by chromatography on a silica gel column (Moritex Corporation, elution solvent: hexane/ethyl acetate), and a fraction corresponding to the Rf value=0.50 (hexane/ethyl acetate=2/1) by thin layer chromatography was concentrated under reduced pressure to afford the title compound (0.98 g, 1.4 mmol) as a yellow oil (yield 61%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH2:13](O)[CH2:14][OH:15].C1C=CC=CC=1>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:7]2[O:15][CH2:14][CH2:13][O:8]2)[CH:9]=1
Reactant: OCCO
Reactant: O=Cc1cc(Cl)ccc1[N+](=O)[O-]
Solvent: c1ccccc1
Solvent: O
Product: O=[N+]([O-])c1ccc(Cl)cc1C1OCCO1
Yield: 94.9 %

Procedure:
Prepared as described by D. E. O'Brien et al, J. Het. Chem., 7, 102 (1970) as follows. A mixture of 5-chloro-2-nitrobenzaldehyde (18.3 g, 0.1 mole), ethylene glycol (7.0 g, 0.11 mole) p-toluenesulfonic acid (0.5 g) and benzene (850 mL) was stirred and refluxed with continuous removal of water via a Dean and Stark trap for 24 hours. The solvent was removed, the residue dissolved in dichloromethane and filtered through a plug of silica gel (6" deep). Evaporation of the solvent afforded 2-(5-chloro-2-nitrophenyl)-1,3-dioxolane (21.8 g, 97%) as an oil.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[C:11]([CH2:13][S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])[N:10]=[C:9]([C:23]3[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=3)[N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(=O)(O)[O-].[Na+].Cl[C:36]([O:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:37]>O1CCOCC1>[N:1]1([C:7]2[CH:12]=[C:11]([CH2:13][S:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)(=[O:15])=[O:16])[N:10]=[C:9]([C:23]3[CH:24]=[CH:25][C:26]([NH:29][C:36](=[O:37])[O:38][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)=[CH:27][CH:28]=3)[N:8]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: Nc1ccc(-c2nc(CS(=O)(=O)c3ccccc3)cc(N3CCOCC3)n2)cc1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(Nc1ccc(-c2nc(CS(=O)(=O)c3ccccc3)cc(N3CCOCC3)n2)cc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61 %

Procedure:
(4-{4-Morpholin-4-yl-6-[(phenylsulfonyl)methyl]pyrimidin-2-yl}phenyl)amine (1 g, 2.44 mmol) was dissolved in dioxane (10 mL). Sodium bicarbonate (307 mg, 3.65 mmol) was added, followed by phenyl chloroformate (0.307 mL, 2.44 mmol) and the reaction stirred at room temperature for 2 hours. The solvent was removed in vacuo, and the resultant oil partitioned between 10 mL DCM and 10 mL water. The organic phase was dried over magnesium sulphate, filtered and concentrated in vacuo. The cream solid obtained was chromatographed on silica, eluting with 0-50% ethyl acetate in DCM, to give the desired material as a white solid (790 mg).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:19])[CH2:14][C@H:13]2[CH3:26])=[N:4][N:3]=1.[O:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]1[O:33][CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:26][C@H:13]1[N:12]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]([C:39]3[CH:40]=[CH:41][C:36]([CH2:35][CH2:34][O:33][CH:28]4[CH2:29][CH2:30][CH2:31][CH2:32][O:27]4)=[CH:37][CH:38]=3)=[N:3][N:4]=2)[CH2:17][CH2:16][N:15]([C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:19])[CH2:14]1
Reactant: OB(O)c1ccc(CCOC2CCCCO2)cc1
Reactant: C[C@@H]1CN(C(=O)c2ccccc2)CCN1c1nnc(Cl)c2ccccc12
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C[C@@H]1CN(C(=O)c2ccccc2)CCN1c1nnc(-c2ccc(CCOC3CCCCO3)cc2)c2ccccc12
Temperature: 100 °C

Procedure:
(R)-(4-(4-chlorophthalazin-1-yl)-3-methylpiperazin-1-yl)(phenyl)methanone (JK-5) (200 mg, 0.545 mmol), 4-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)phenylboronic acid (136 mg, 0.545 mmol) and tetrakis(triphenylphosphine)palladium (0) (31.5 mg, 0.0273 mmol) were dissolved in toluene (4 mL) and aqueous sodium carbonate (2.0M, 0.400 mL) under an atmosphere of argon. The reaction was heated at 100° C. for 15 hours, cooled to rt, and taken up in ethyl acetate (80 mL). After washing with aqueous K2CO3 (10%), water, and saturated sodium chloride, the organics were dried (MgSO4) and evaporated to give a yellow oil. Chromatography over silica gel with a gradient of hexanes/0-100% ethyl acetate gave a pale yellow solid, compound 83. MS (M+H)+=537.4.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH2:21])=[N:8][CH:9]=[C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][CH:16]=[CH:15]3)[CH:11]=1.FC(F)(F)C(O)=O.[CH3:34][N:35]1[CH2:40][CH2:39][C:38](=O)[CH2:37][CH2:36]1>C(O)(=O)C>[Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH2:21])=[N:8][CH:9]=[C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][CH:16]=[C:15]3[C:38]2[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH:37]=2)[CH:11]=1
Reactant: CN1CCC(=O)CC1
Reactant: Nc1ncc(-c2ccc3[nH]ccc3c2)cc1OCc1c(Cl)cccc1Cl
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CN1CC=C(c2c[nH]c3ccc(-c4cnc(N)c(OCc5c(Cl)cccc5Cl)c4)cc23)CC1
Yield: 41 %

Procedure:
To a solution of 3-(2,6-Dichloro-benzyloxy)-5-(1H-indol-5-yl)-pyridin-2-ylamine (example I-58, 200 mg, 0.52 mmol) in acetic acid (4 mL) and trifluoroacetic-acid (1 mL) was added 1-methyl-4-piperidone (0.32 mL, 2.6 mmol). The solution was refluxing for over night, and evaporated. The residue was dissolved in ethyl acetate, washed with saturated NaHCO3 and brine, dried over Na2SO4, and condensed. The crude product was purified on a silica gel column eluting with dichloromethane-methanol-triethyl amine (95:5:0.1) to provide 3-(2,6-dichloro-benzyloxy)-5-[3-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indol-5-yl]-pyridin-2-ylamine (103.5 mg, 41% yield) as an orange crystalline solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:13]([OH:15])=O)=[N:4][C:5]([Br:12])=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=1.CCN(CC)CC.[NH2:23][C:24]1[NH:28][N:27]=[C:26]([C:29]([O:31][CH3:32])=[O:30])[N:25]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCOC(C)=O.CCCC(C)C>C(Cl)Cl.CC#N.O>[NH2:1][C:2]1[C:3]([C:13]([NH:23][C:24]2[NH:28][N:27]=[C:26]([C:29]([O:31][CH3:32])=[O:30])[N:25]=2)=[O:15])=[N:4][C:5]([Br:12])=[C:6]([C:8]([F:9])([F:10])[F:11])[N:7]=1
Reactant: Nc1nc(C(F)(F)F)c(Br)nc1C(=O)O
Reactant: COC(=O)c1n[nH]c(N)n1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: ClCCl
Product: COC(=O)c1n[nH]c(NC(=O)c2nc(Br)c(C(F)(F)F)nc2N)n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 3-amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid (Intermediate 2) (300 mg, 1.049 mmol) in dry DCM (10 ml) was added NEt3 (0.322 ml, 2.308 mmol) followed by methyl 5-amino-1H-1,2,4-triazole-3-carboxylate (149 mg, 1.049 mmol). After stirring at RT for 5 minutes the reaction mixture was treated with PyBOP (546 mg, 1.049 mmol) and stirred for 3 hours. The mixture was partitioned between DCM (20 ml) and water (20 ml), shaken and separated. The organic portion was washed with water (20 ml), dried over MgSO4, filtered and concentrated in vacuo to give an orange oil. Purification of the crude residue by chromatography on silica eluting with 0-100% EtOAc in iso-hexane, followed by 0-35% MeOH in EtOAc afforded a yellow oil. Trituration of the oil with EtOAc/iso-hexane followed by MeCN/water afforded the title compound as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1([C:5]([NH2:7])=[O:6])[CH2:4][CH2:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[C:19]([O:21][C:22]([CH3:24])=[CH2:23])=[O:20]>C1COCC1>[CH3:1][C:2]1([C:5]([NH:7][C:19](=[O:20])[O:21][C:22]([CH3:24])=[CH2:23])=[O:6])[CH2:4][CH2:3]1
Reactant: C=C(C)OC(=O)Cl
Reactant: CC1(C(N)=O)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C(C)OC(=O)NC(=O)C1(C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 116.4 %

Procedure:
A −78° C. solution of 1-methylcyclopropanecarboxamide (1.35 g, 13.6 mmol) in THF (30 mL) was treated drop-wise with lithium bis(trimethylsilyl)amide (1M THF, 17.7 mL, 17.7 mmol), stirred for 0.5 h, treated drop-wise with a solution of isopropenyl chloroformate (1.94 mL, 17.7 mmol) in THF (5 mL), stirred at −78° C. for 1 h, then allowed to warm to RT and stirred for 1 h. The mixture was quenched with satd. NaHCO3, extracted with EtOAc (3×) and the combined organics were dried over Na2SO4 and concentrated to dryness to afford crude prop-1-en-2-yl (1-methylcyclopropanecarbonyl)carbamate (2.9 g, 116%) which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[S:10][C:9]([O:11][CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[N:8][C:5]2=[N:6][CH:7]=1.Cl[C:19]1[N:24]=[CH:23][C:22]([CH2:25][CH2:26][CH3:27])=[CH:21][N:20]=1.BrC1C=CC2N=C(OC3CCN(C4N=CC(CCC)=CN=4)CC3)SC=2C=1>>[Br:1][C:2]1[CH:3]=[C:4]2[S:10][C:9]([O:11][CH:12]3[CH2:17][CH2:16][N:15]([C:19]4[N:24]=[CH:23][C:22]([CH2:25][CH2:26][CH3:27])=[CH:21][N:20]=4)[CH2:14][CH2:13]3)=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: CCCc1cnc(Cl)nc1
Reactant: Brc1cnc2nc(OC3CCNCC3)sc2c1
Agent: CCCc1cnc(N2CCC(Oc3nc4ccc(Br)cc4s3)CC2)nc1
Product: CCCc1cnc(N2CCC(Oc3nc4ncc(Br)cc4s3)CC2)nc1

Procedure:
Compound 21D was prepared from Compound 21C and 2-chloro-5-propylpyrimidine in a similar manner to the procedure described for Compound 1C in Example 1. 1H NMR (400 MHz, chloroform-d) δ ppm 8.55 (d, J=2.2 Hz, 1H), 8.16 (s, 2H), 8.08 (d, J=2.2 Hz, 1H), 5.58 (dt, J=8.2, 4.1 Hz, 1H), 4.20-4.34 (m, 2H), 3.52-3.65 (m, 2H), 2.40 (t, J=7.7 Hz, 2H), 2.16-2.28 (m, 2H), 1.84-2.01 (m, J=12.9, 8.7, 8.7, 3.8 Hz, 2H), 1.49-1.64 (m, J=7.5, 7.5, 7.5, 7.3, 7.1 Hz, 2H), 0.93 (t, J=7.1 Hz, 3H). LC/MS (m/z)=435 (M+H)+.
Reaction SMILES: [C:1]([Cl:6])(=O)[C:2](Cl)=O.[CH2:7]([N:14]1[C:18]2[NH:19][C:20]([C:24]([CH3:27])([CH3:26])[CH3:25])=[N:21]C(=O)C=2[N:16]=[N:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C([O-])(O)=O.[Na+]>ClCCl.CN(C=O)C>[CH2:7]([N:14]1[C:18]2[N:19]=[C:20]([C:24]([CH3:27])([CH3:26])[CH3:25])[N:21]=[C:1]([Cl:6])[C:2]=2[N:16]=[N:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(C)c1nc(=O)c2nnn(Cc3ccccc3)c2[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3)c2n1
Temperature: 35 °C
Reaction time: 0.75 h
Yield: 114.2 %

Procedure:
DMF over MS(105 g, 110 ml, 1.43 mol, Eq: 2.56) was charged in the reactor followed by Dichlormethane (1.46 kg, 1.1 l). The solution was heated to 35° C. and oxalylchloride (144 g, 97.6 ml, 1.11 mol, Eq: 2) was added over 1 h. After 45 min, a fine suspension of 3-benzyl-5-tert-butyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(4H)-one (161 g, 557 mmol, Eq: 1.00) in a mixture of dichlormethane (877 g, 662 ml) and DMF (41.8 g, 44.1 ml) was added over of 20 min. After 3 h, the reaction mixture was cooled to RT and slowly added to a cold (0-5° C.) half saturated aqueous NaHCO3 (1.76 l). The organic phase was separated and washed again with half saturated NaHCO3 (662 ml) followed by water (662 g, 662 ml). Then the org. phase was dried over MgSO4 and was concentrated under reduced pressure at 50° C./down to 10 mbar to give 192 g of a crude oil which does crystallize on standing. The crude 3-benzyl-5-tert-butyl-7-chloro-triazolo[4,5-d]pyrimidine was introduced in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].FC(F)(F)S(O[CH2:18][CH:19]([F:21])[F:20])(=O)=O>>[Cl:1][C:2]1[N:10]=[C:9]([O:11][CH2:18][CH:19]([F:20])[F:21])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH2:18][CH:19]([F:21])[F:20])=[O:5]
Reactant: O=C(O)c1ccc(O)nc1Cl
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Product: O=C(OCC(F)F)c1ccc(OCC(F)F)nc1Cl
Yield: 92 %

Procedure:
The title compound is prepared in 92% yield (2.9 g, clear colorless oil) from 2-chloro-6-hydroxynicotinic acid (1.8 g, 11 mmol) and 2,2-difluoroethyl trifluoromethanesulfonate instead of 2,2,2-trifluoroethyl trifluoromethanesulfonate by the similar manner in Step-3 of Amine-13.
Reaction SMILES: O1C2([CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[C:15]([NH2:17])[N:14]4[N:18]=[CH:19][CH:20]=[C:13]4[N:12]=3)[CH2:7][CH2:6]2)OCC1.ClC1N2N=CC=C2N=C(C2CC[N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])CC2)C=1.ClC1N2N=CC=C2N=C(C2CCC3(OCCO3)CC2)C=1>>[NH2:17][C:15]1[N:14]2[N:18]=[CH:19][CH:20]=[C:13]2[N:12]=[C:11]([CH:8]2[CH2:7][CH2:6][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:10][CH2:9]2)[CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(Cl)n3nccc3n2)CC1
Reactant: Nc1cc(C2CCC3(CC2)OCCO3)nc2ccnn12
Agent: Clc1cc(C2CCC3(CC2)OCCO3)nc2ccnn12
Product: CC(C)(C)OC(=O)N1CCC(c2cc(N)n3nccc3n2)CC1

Procedure:
tert-Butyl 4-(7-aminopyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1-carboxylate was synthesized in a manner similar to the synthesis of 5-(1,4-dioxaspiro[4.5]decan-8-yl)pyrazolo[1,5-a]pyrimidin-7-amine, but tert-butyl 4-(7-chloropyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1-carboxylate substituted for 7-chloro-5-(1,4-dioxaspiro[4.5]decan-8-yl)pyrazolo[1,5-a]pyrimidine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][C:17]2[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:26][OH:27].[OH-].[Na+].Cl>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][C:17]2[CH:24]=[CH:23][C:20]([CH:21]=[N:26][OH:27])=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CCOc2ccc(C=O)cc2)CC1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(CCOc2ccc(C=NO)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-[2-(N-t-butyloxycarbonylpiperidin-4-yl)ethoxy]benzaldehyde (3.16 g, 9.48 mmol) in MeOH (20 mL) was added hydroxylamine hydrochloride (1.27 g, 18.3 mmol) and 2M NaOH (7 mL, 14 mmol). The resulting suspension was stirred overnight at room temperature (18 hours). The mixture was brought to pH 4 using 1M HCl, followed by filtration and water wash. The crystals were dried under vacuum over P205, affording 2.88 g (87%); mp: 114.4°-116.1° C.; 1H NMR (300 MHz, CDCl3) δ 8.09 (s, 2H), 7.51 (d, J=8.8 Hz, 2H), 6.89 (d, J=8.8 Hz, 2H), 4.10 (b, 2H), 4.03 (t, J=6.2 Hz 2H), 2.71 (bt, 2H), 1.73 (m, 4H), 1.46 (s, 9H), 1.19 (m, 2H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(N(C(C)C)CC)(C)C.[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]2[CH2:21][NH:22][CH2:23][C:16]=12>C(Cl)Cl>[CH3:1][S:2]([N:22]1[CH2:21][C:17]2[C:16](=[N:15][CH:20]=[CH:19][CH:18]=2)[CH2:23]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: c1cnc2c(c1)CNC2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)N1Cc2cccnc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methanesulfonyl chloride (0.97 mL, 12.4 mmol) was added dropwise to a −10° C. solution of diisopropyl-ethylamine (5.16 mL, 31.1 mmol) and 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine (2.0 g, 10.0 mmol) in CH2Cl2 (20 mL). The mixture was stirred overnight at rt diluted with CH2Cl2 (300 mL) and washed with saturated aqueous sodium bicarbonate. The organic phase was separated, dried (MgSO4) and filtered through a short silica gel pad with EtOAc rinse. The filtrate was concentrated to yield 2.15 g (quantitative) of Ex 10-Step 1 product as a solid which was used without further purification: LCMS m/z 199.2 (M+1); 1H NMR (400 MHz, CDCl3) δ 8.54 (d, J=4.9, 1H), 7.61 (d, J=7.8, 1H), 7.25 (dd, J=7.8, 5.1, 1H), 4.75 (AB quartet, JAB=2.1, ΔvAB=7.8, 4H), 2.94 (s, 3H).
Reaction SMILES: [CH2:1]([S:8][C:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([N:19]2[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]2)[N:12]=[C:11](Cl)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:27]1[CH:28]=[CH:29][N:30]2[CH2:35][CH2:34][NH:33][CH2:32][C:31]=12.C(N(CC)CC)C.CN(C)C(=O)C>C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH2:1]([S:8][C:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([N:19]2[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]2)[N:12]=[C:11]([N:33]2[CH2:34][CH2:35][N:30]3[CH:29]=[CH:28][N:27]=[C:31]3[CH2:32]2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1cn2c(n1)CNCC2
Reactant: COC(=O)c1c(SCc2ccccc2)nc(Cl)nc1N1CCC(O)CC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: COC(=O)c1c(SCc2ccccc2)nc(N2CCn3ccnc3C2)nc1N1CCC(O)CC1
Temperature: 10 °C
Reaction time: 3 h

Procedure:
A mixture of 4-benzylthio-5-methoxycarbonyl-6-(4-hydroxypiperidine-1-yl)-2-chloropyrimidine (prepared in the above (4)) 120 mg, 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine 70 mg, triethylamine 57 mg and N,N-dimethylacetamide 3 ml is stirred at 10° C. for 3 hours. The reaction mixture is diluted with an aqueous citric acid solution and extracted with ethyl acetate. The water layer is made basic with an aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer is washed, dried and concentrated in vacuo to give 4-benzylthio-5-methoxycarbonyl-6-(4-hydroxypiperidin-1-yl)-2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)pyrimidine as a colorless foam, 105 mg.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH2:16])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1.[CH3:24][N:25]1[CH:29]=[C:28]([C:30](O)=[O:31])[C:27]([CH3:33])=[N:26]1>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH:16][C:30]([C:28]3[C:27]([CH3:33])=[N:26][N:25]([CH3:24])[CH:29]=3)=[O:31])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1
Reactant: NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1nc(N)sc1-c1cccc(F)c1
Reactant: Cc1nn(C)cc1C(=O)O
Product: Cc1nn(C)cc1C(=O)NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1nc(N)sc1-c1cccc(F)c1

Procedure:
prepared by reaction of [2-amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl)-methanone with 1,3-dimethyl-1H-pyrazole-4-carboxylic acid. LC-MS (basic): tR=0.71 min; [M+H]+=455.2.
Reaction SMILES: [O:1]=[S:2]1(=[O:18])[CH2:6][CH2:5][N:4]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-])=O)[CH:10]=2)=[O:8])[CH2:3]1>CO.[Pd]>[NH2:15][C:11]1[CH:10]=[C:9]([C:7]([N:4]2[CH2:5][CH2:6][S:2](=[O:18])(=[O:1])[CH2:3]2)=[O:8])[CH:14]=[CH:13][CH:12]=1
Reactant: O=C(c1cccc([N+](=O)[O-])c1)N1CCS(=O)(=O)C1
Agent: [Pd]
Solvent: CO
Product: Nc1cccc(C(=O)N2CCS(=O)(=O)C2)c1
Yield: 86.2 %

Procedure:
A solution of (1,1-dioxidothiazolidin-3-yl)(3-nitrophenyl)methanone (3 g, 11.10 mmol) in MeOH (30 ml) and 10% Pd—C (300 mg) was stirred under H2 (1 atm) for overnight. Reaction mixture was filtered through celite pad and the filtrate was evaporated under vacuum to afford the titled compound (2.3 gm).
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]2[C:33]3[CH2:34][CH2:35][N:36]4[C:41]([C:32]=3[NH:31][C:28]2=[CH:29][CH:30]=1)=[C:40]([CH2:42][CH3:43])[CH2:39][CH2:38][C:37]4=O>C1(C)C=CC=CC=1>[CH3:23][O:24][C:25]1[CH:26]=[C:27]2[C:33]3[CH2:34][CH2:35][N:36]4[C:41]([C:32]=3[NH:31][C:28]2=[CH:29][CH:30]=1)=[C:40]([CH2:42][CH3:43])[CH2:39][CH2:38][C:37]4=[S:10]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCC1=C2c3[nH]c4ccc(OC)cc4c3CCN2C(=O)CC1
Solvent: Cc1ccccc1
Product: CCC1=C2c3[nH]c4ccc(OC)cc4c3CCN2C(=S)CC1
Yield: 60 %

Procedure:
Lawesson's reagent (0.5 nimol) is added portionwise, at 110° C., to a solution of 9-metlioxy-1-ethyl-2,3,4,6,7,12-hexahydroindolo[2,3-a]quinoIizin-4-one (300 mg, 1.01 mmol) in anhydrous toluene (15 mL). After refluxing for 30 min. and evaporation of the toluene, the product is chromatographed on silica gel (99/1 chloroform/methanol eluent) and 9-methoxy-1-ethyl-2,3,4,6,7,12-hexahydroindolo[2,3-alquinolizine-4-thione is thus recovered (60% yield).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[C:23]([O:27][C:28](=[O:40])[NH:29][C:30]1[O:34][N:33]=[C:32]([C:35]([CH3:39])([CH3:38])[CH2:36][OH:37])[CH:31]=1)([CH3:26])([CH3:25])[CH3:24]>C(Cl)Cl>[C:23]([O:27][C:28](=[O:40])[NH:29][C:30]1[O:34][N:33]=[C:32]([C:35]([CH3:39])([CH3:38])[CH:36]=[O:37])[CH:31]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)Nc1cc(C(C)(C)CO)no1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1cc(C(C)(C)C=O)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.2 %

Procedure:
Dess-Martin periodinane (1.39 g, 3.29 mmol) is added to a solution of [3-(2-hydroxy-1,1-dimethyl-ethyl)-isoxazol-5-yl]-carbamic acid tert-butyl ester (602.0 mg, 2.35 mmol) in DCM (20 mL). The reaction mixture is stirred at room temperature for 1 h. After this time, the reaction mixture is quenched with 50 mL (1:1) of saturated aqueous NaHCO3 solution and saturated aqueous sodium thiosulfate solution and stirred at room temperature for 2 h then extracted with DCM twice. The organic extracts are combined and washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to provide 587.0 mg of the title compound. Yield: 98.3% 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.45 (6H, s), 1.55 (9H, s), 6.05 (1H, s), 7.25 (1H, s), 9.65 (1H, s).