Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17](O)=[O:18])[CH:15]=3)[N:10]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.Cl.[NH2:40][CH:41]1[CH2:46][CH2:45][CH2:44][C:43]([C:48]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)=[O:49])([OH:47])[CH2:42]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[C:48]([C:43]1([OH:47])[CH2:44][CH2:45][CH2:46][CH:41]([NH:40][C:17]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[N:10]([C:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:9]=[C:8]3[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=2)=[O:18])[CH2:42]1)(=[O:49])[C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1
Reactant: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(C(=O)O)cc23)ccn1
Reactant: NC1CCCC(O)(C(=O)c2ccccc2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(C(=O)NC4CCCC(O)(C(=O)c5ccccc5)C4)cc23)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A reaction mixture of 3-(2-methylpyridin-4-yl)-1-trityl-1H-indazole-5-carboxylic acid (0.1 mmol, 49.5 mg), HCl salt of (3-amino-1-hydroxycyclohexyl)(phenyl)methanone (0.1 mmol, 25.5 mg), HATU (0.1 mmol, 38 mg) and DIEA (0.15 mL) in DMA (0.65 mL) was stirred at room temperature for overnight. The product, N-(3-benzoyl-3-hydroxycyclohexyl)-3-(2-methylpyridin-4-yl)-1-trityl-1H-indazole-5-carboxamide, was obtained after rotary evaporation of solvent.
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][NH:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].C(OCC)(=O)C>CN(C=O)C>[CH2:29]([N:2]1[CH2:3][CH2:4][CH2:5][C:6]2[CH:11]=[C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)[CH:9]=[CH:8][C:7]=2[CH2:1]1)[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCCNC3)nc1
Reactant: CCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCCCN1CCCc2cc(Oc3ccc(C(N)=O)cn3)ccc2C1
Temperature: 50 °C

Procedure:
Mix 6-(2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy)nicotinamide (Example 447, Part E, 0.300 g, 1.06 mmol), K2CO3 (0.366 g, 2.65 mmol), and 1-bromoheptane (0.199 g, 1.11 mmol) in DMF (5.3 mL). Heat at 50° C. overnight, then increase the temperature to 80° C. for 3.5 hours. Cool the reaction mixture to room temperature and add ethyl acetate (100 mL). Wash with water (1×30 mL), brine (1×30 mL), dry the organic layer over Na2SO4, filter and concentrate. Purify by flash chromatography eluting with 6% to 15% (2.0 M NH3 in methanol) in ethyl acetate to give the title compound: MS ES+382.2 (M+H)+, HRMS calcd for C23H32N3O2 382.2495 (M+H)+, found 382.2489, time 0.46 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18 min], tR=12.6 min, 98.6% purity.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10]C(C)C)([CH3:3])[CH3:2].[CH3:14][C:15]([CH3:17])=O>>[CH:15]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH:1]([CH3:2])[CH3:3])[C:5]=1[OH:10])([CH3:17])[CH3:14]
Reactant: CC(C)=O
Reactant: CC(C)Oc1ccccc1C(C)C
Product: CC(C)c1cccc(C(C)C)c1O
Temperature: 150 °C

Procedure:
To 15 g of isopropyl (2-isopropylphenyl) ether was added 8 g of 1% fluorided alumina. The mixture was placed in a 300 cc stirred autoclave and the system was flushed with nitrogen and left under a nitrogen atmosphere. The autoclave was heated to 150° C. for 1 hour with stirring during which time the pressure reached 200 psig. The cooled reaction mixture was taken up in acetone, filtered, and the solvent was removed on a rotary evaporator. The residue was analyzed by gas-liquid phase chromatography (glpc) which showed the presence of 2-isopropylphenol (10%), isopropyl(2-isopropylphenyl) ether (28%), 2,6-diisopropylphenol (60%), and 2,4,6-triisopropylphenol (2%). Thus, the 2,6-diisopropylphenol was formed with 83% selectivity.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH2:9][CH2:10][C:11]([C:13]2[S:14][C:15]([CH2:24][CH3:25])=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:17]=2)=[O:12])=[CH:4][C:3]=1[CH3:26].Cl[CH2:28][C@@H:29]([OH:32])[CH2:30][OH:31]>CC(O)C.[OH-].[Na+].O>[OH:32][C@@H:29]([CH2:30][OH:31])[CH2:28][O:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH2:9][CH2:10][C:11]([C:13]2[S:14][C:15]([CH2:24][CH3:25])=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:17]=2)=[O:12])=[CH:4][C:3]=1[CH3:26]
Reactant: OC[C@H](O)CCl
Reactant: CCc1sc(C(=O)CCc2cc(C)c(O)c(C)c2)cc1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CCc1sc(C(=O)CCc2cc(C)c(OC[C@@H](O)CO)c(C)c2)cc1-c1ccccc1
Temperature: 70 °C
Reaction time: 15 h
Yield: 22.3 %

Procedure:
A solution of 3-(4-hydroxy-3,5-dimethyl-phenyl)-1-(5-ethyl-4-phenyl-thiophen-2-yl)-propan-1-one (52 mg, 0.143 mmol) in 2-propanol (1 mL) and 3 N aq. NaOH (0.3 mL) is treated with (S)-3-chloro-propane-1,2-diol (79 mg, 0.71 mmol) and the mixture is stirred at 70° C. for 15 h. The reaction mixture is diluted with water and extracted with DCM. The solvent of the organic extract is evaporated and the crude product is purified on prep. TLC plates with heptane:EA 1:3 to give 3-[4-((S)-2,3-dihydroxy-propoxy)-3,5-dimethyl-phenyl]-1-(5-ethyl-4-phenyl-thiophen-2-yl)-propan-1-one (14 mg) as a colourless resin; LC-MS: tR=1.03 min, [M+1]+=439.25; 1H NMR (CDCl3): δ 7.58 (s, 1H), 7.45-7.30 (m, 5H), 6.88 (s, 2H), 4.11-4.04 (m, 1H), 3.87-3.80 (m, 4H), 3.67-3.60 (m, 2H), 3.60-3.56 (m, 1H), 3.48-3.40 (m, 1H), 3.20-3.10 (m, 2H), 2.98-2.87 (m, 4H), 2.25 (s, 6H), 1.30 (t, J=7.6 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:21])[C:5]([NH:8][CH2:9][C:10]2[CH:20]=[CH:19][C:13]3[N:14]=[C:15]([S:17][CH3:18])[S:16][C:12]=3[CH:11]=2)=[CH:6][CH:7]=1.[CH:22](OCC)(OCC)OCC>C(O)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]([CH2:9][C:10]3[CH:20]=[CH:19][C:13]4[N:14]=[C:15]([S:17][CH3:18])[S:16][C:12]=4[CH:11]=3)[CH:22]=[N:21][C:4]=2[CH:3]=1
Reactant: CSc1nc2ccc(CNc3ccc(F)cc3N)cc2s1
Reactant: CCOC(OCC)OCC
Solvent: O=CO
Product: CSc1nc2ccc(Cn3cnc4cc(F)ccc43)cc2s1
Temperature: 100 °C
Yield: 67 %

Procedure:
A stirred mixture of 4-fluoro-N1-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)benzene-1,2-diamine (0.93 g, 2.93 mmol) from the previous step, formic acid (0.5 mL) and triethyl orthoformate (5 mL) was heated at 100° C. for 1 h. The reaction mixture was cooled to rt and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 3% MeOH in DCM to afford 6-((5-fluoro-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole (0.64 g, 67%) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 7.99 (s, 1H), 7.83 (d, J=8.1 Hz, 1H), 7.47-7.51 (m, 2H), 7.26 (m, 1H), 7.17 (m, 1H), 7.00 (dt, J=9.3, 2.4 Hz, 1H), 5.44 (s, 2H), 2.77 (s, 3H); LCMS (ESI) m/z 330 (M+H)+.
Reaction SMILES: [C:1]([NH:5][CH2:6][C:7]1[CH:8]=[C:9]([CH:18]=[CH:19][C:20]=1[OH:21])[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11])(=[O:4])[CH:2]=[CH2:3].[CH:22]1([N:28]=[C:29]=[O:30])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.C(N(CC)CC)C>C(C1C(O)=C(C(C)(C)C)C=C(C)C=1)(C)(C)C.CC(C)=O>[CH:22]1([NH:28][C:29](=[O:30])[O:21][C:20]2[CH:19]=[CH:18][C:9]([C:10](=[O:11])[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:8][C:7]=2[CH2:6][NH:5][C:1](=[O:4])[CH:2]=[CH2:3])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=C=NC1CCCCC1
Reactant: C=CC(=O)NCc1cc(C(=O)c2ccccc2)ccc1O
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: C=CC(=O)NCc1cc(C(=O)c2ccccc2)ccc1OC(=O)NC1CCCCC1
Yield: 31 %

Procedure:
A mixture of 30 g (0.107 mole) of 3-acrylamidomethyl-4-hydroxybenzophenone, 13.5 g (0.108 mole) of cyclohexyl isocyanate, 0.2 g of 2,6-di-tert-butyl-p-cresol, 1.5 g of triethylamine and 180 ml of acetone was refluxed for 3 hours and then left to stand. The crystals formed were filtered off, and 26.3 g of the desired product having a melting point of 142°-144° C. were obtained in this manner. A further 13.5 g of the desired carbamate were obtained by evaporating down the mother liquor.
Reaction SMILES: Cl[C:2]1[C:3](=[O:13])[N:4]([CH2:9][CH2:10][S:11][CH3:12])[CH:5]=[C:6]([Cl:8])[N:7]=1.Cl.[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:23](=[C:24]([CH3:26])[CH:25]=1)[NH:22][CH2:21][CH2:20]2>>[Cl:8][C:6]1[N:7]=[C:2]([N:22]2[C:23]3[C:19](=[CH:18][C:17]([O:16][CH3:15])=[CH:25][C:24]=3[CH3:26])[CH2:20][CH2:21]2)[C:3](=[O:13])[N:4]([CH2:9][CH2:10][S:11][CH3:12])[CH:5]=1
Reactant: CSCCn1cc(Cl)nc(Cl)c1=O
Reactant: COc1cc(C)c2c(c1)CCN2
Agent: Cl
Product: COc1cc(C)c2c(c1)CCN2c1nc(Cl)cn(CCSC)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[2-(methylthio)ethyl]-2(1H)-pyrazinone and 5-methoxy-7-methylindoline hydrochloride as the starting materials. mp 111–113° C.; 1H NMR (300 MHz, CDCl3): δ 6.80 (s, 1 H), 6.68 (d, J=2.2 Hz, 1 H), 6.59 (d, J=2.2 Hz, 1 H), 4.40 (t, J=7.7 Hz, 2 H), 4.04 (t, J=7.1 Hz, 2 H), 3.79 (s, 3 H), 3.04 (t, J=7.7 Hz, 2 H), 2.89 (t, J=7.2 Hz, 2 H), 2.18 (s, 3 H), 2.06 (s, 3 H); HRMS (CI) calcd for C17H20N3O2SCl (M+): 365.0965; found m/z 365.0967.
Reaction SMILES: [Cl:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]2[NH:6][C:7]([CH2:9][C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:23][C:24]([F:35])([F:34])[S:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=1>CN(C=O)C>[Cl:16][C:15]1[C:2]([Cl:1])=[CH:3][C:4]2[N:8]([CH2:30][C:29]3[CH:32]=[CH:33][C:26]([S:25][C:24]([F:35])([F:23])[F:34])=[CH:27][CH:28]=3)[C:7]([CH2:9][C:10]([F:12])([F:13])[F:11])=[N:6][C:5]=2[CH:14]=1
Reactant: FC(F)(F)Sc1ccc(CBr)cc1
Reactant: FC(F)(F)Cc1nc2cc(Cl)c(Cl)cc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(F)Cc1nc2cc(Cl)c(Cl)cc2n1Cc1ccc(SC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzimidazole (434 mg) in DMF (5 mL) was added potassium carbonate powder (669 mg) and 4-(trifluoromethylthio) benzyl bromide (596 mg). The resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched with water, extracted with EtOAc, and dried over Na2SO4. The crude product was purified by silica gel chromatography (10%-40% EtOAc/hexanes) to yield the title compound as a brown solid.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[C:20]([O:22][CH3:23])=[O:21].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(OCC)(=O)C>C(#N)C>[Br:1][CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)c1c(C)ccc2ccccc12
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1c(CBr)ccc2ccccc12
Yield: 54.2 %

Procedure:
N-Bromosuccinimide (0.748 g) was added to a solution of methyl 2-methylnapthalene-1-carboxylate (0.7 g) in acetonitrile (30 ml) and the mixture was heated to reflux. Benzoyl peroxide (0.093 g) was added and the reaction mixture was heated at reflux for 4 hours. After cooling, ethyl acetate was added and the solution was washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of DCM and pentane with a gradient of 7.5-25% to give methyl 2-bromomethylnaphthalene-1-carboxylate (0.529 g) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH2:5][Sn](CCCC)(CCCC)CCCC.C([Li])CCC.[C:24]([C:28]1[CH:33]=[CH:32][C:31]([S:34]([NH:37][C:38]2[C:43]([O:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=3[O:51][CH3:52])=[C:42]([O:53][CH2:54][CH2:55][OH:56])[N:41]=[C:40](S(C)(=O)=O)[N:39]=2)(=[O:36])=[O:35])=[CH:30][CH:29]=1)([CH3:27])([CH3:26])[CH3:25].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[C:24]([C:28]1[CH:33]=[CH:32][C:31]([S:34]([NH:37][C:38]2[C:43]([O:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=3[O:51][CH3:52])=[C:42]([O:53][CH2:54][CH2:55][OH:56])[N:41]=[C:40]([CH2:5][O:4][CH2:3][O:2][CH3:1])[N:39]=2)(=[O:35])=[O:36])=[CH:30][CH:29]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: CCCC[Sn](CCCC)(CCCC)COCOC
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(S(C)(=O)=O)nc1OCCO
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COCOCc1nc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c(Oc2ccccc2OC)c(OCCO)n1
Reaction time: 0.07 h

Procedure:
##STR150## (1) To a solution of methoxymethyloxymethyltributyltin (655 mg) in tetrahydrofuran (6 ml) is added dropwise a 1.63M solution of n-butyl lithium in n-hexane (1.09 ml) at -78° C. The mixture is stirred at the same temperature for four minutes, and thereto is added a solution of 4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxyphenoxy)-2-methylsulfonylpyrimidin-4-yl]benzenesulfonamide obtained in Reference Example 10-(1) (200 mg) in tetrahydrofuran (2 ml), and the mixture is stirred for 40 minutes. To the mixture is added an aqueous ammonium chloride solution, and the mixture is extracted with ethyl acetate. The ethyl acetate layer is washed, dried, and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography (solvent; chloroform:methanol=100:1~50:1) to give 4-tert-butyl-N-[6-(2-hydroxyethoxy)-2-methoxymethyloxymethyl-5-(2-methoxy-phenoxy)pyrimidin-4-yl]benzenesulfonamide (111 mg) as a colorless caramel.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][C@@H:11]([CH3:14])[C@@H:10]([N:15]3[C:19]4=[C:20]5[CH:26]=[CH:25][NH:24][C:21]5=[N:22][CH:23]=[C:18]4[NH:17][C:16]3=[O:27])[CH2:9]2)[CH:5]=[CH:4][N:3]=1.[C-]#N.[Na+].[N:31]12CCN(CC1)C[CH2:32]2.O>CS(C)=O>[CH3:14][C@@H:11]1[CH2:12][CH2:13][N:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:32]#[N:31])[N:7]=2)[CH2:9][C@@H:10]1[N:15]1[C:19]2=[C:20]3[CH:26]=[CH:25][NH:24][C:21]3=[N:22][CH:23]=[C:18]2[NH:17][C:16]1=[O:27]
Reactant: C[C@@H]1CCN(c2ccnc(Cl)n2)C[C@@H]1n1c(=O)[nH]c2cnc3[nH]ccc3c21
Reactant: C1CN2CCN1CC2
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: C[C@@H]1CCN(c2ccnc(C#N)n2)C[C@@H]1n1c(=O)[nH]c2cnc3[nH]ccc3c21
Temperature: 80 °C
Reaction time: 7 h
Yield: 245.7 %

Procedure:
To a solution of rel-1-[(3R,4R)-1-(2-chloro-4-pyrimidinyl)-4-methyl-3-piperidinyl]-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]-pyridin-2(1H)-one (60 mg) and sodium cyanide (38 mg) in DMSO (1 mL), 1,4-diazabicyclo[2.2.2]octane (5 mg) was added at ambient temperature. The temperature was raised to 80° C. and stirred for 7 hours. After cooling down to ambient temperature, water (15 mL) was added to the mixture and resulting precipitate was collected by filtration. The filtrate was purified by pre-packed column (chloroform:methanol=95:1 to 80:20) to afford rel-4-[(3R,4R)-4-methyl-3-(2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)-1-piperidinyl]-2-pyrimidinecarbonitrile (41 mg) as white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH2:11][CH:12]1[C:16](=[O:17])[N:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:14][CH:13]1[C:24]([O:26][CH2:27][CH3:28])=[O:25].C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:11][C@H:12]2[C:16](=[O:17])[N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:14][C@H:13]2[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:7])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1CN(c2ccccc2)C(=O)C1N
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@@H]1CN(c2ccccc2)C(=O)[C@@H]1NC(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.3 %

Procedure:
To a solution of p-chlorobenzoyl chloride (247 mg, 1.41 mmol) in CH2Cl2 (4 ml) was added a solution of aminopyrrolidinone of Example S (350 mg, 1.41 mmol) and triethylamine (0.4 ml, 2.82 mmol) in CH2Cl2 (4 ml) and the resulting solution was stirred for 18 h at room temperature. Concentration in vacuo gave an oil which was chromatographed on silica gel eluting with 5/95 EtOH/CH2Cl2 to give the title compound (378 mg, 68%) as a solid. Anal calcd for C20H19N2O4Cl: C, 62.10; H, 4.95; N, 7.24. Found: C, 62.07; H, 5.05; N, 7.18. MS calcd for C20H19N2O4Cl 386, found 386. DSC=215.2°-216.8° C. at 144.3 J/g.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]1[CH:8]=[C:7]([C:9]2[CH:10]=[N:11][N:12]([C:16]3[CH:31]=[CH:30][C:19]([C:20]([NH:22][CH2:23][CH:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[O:21])=[CH:18][N:17]=3)[C:13]=2[O:14]C)[CH:6]=[CH:5][N:4]=1.[Cl-].[Li+].CC(N(C)C)=O>CS(C)=O>[CH3:1][N:2]([CH3:32])[C:3]1[CH:8]=[C:7]([C:9]2[CH:10]=[N:11][N:12]([C:16]3[CH:31]=[CH:30][C:19]([C:20]([NH:22][CH2:23][CH:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[O:21])=[CH:18][N:17]=3)[C:13]=2[OH:14])[CH:6]=[CH:5][N:4]=1
Reactant: COc1c(-c2ccnc(N(C)C)c2)cnn1-c1ccc(C(=O)NCC2CCOCC2)cn1
Agent: [Cl-]
Agent: [Li+]
Solvent: CC(=O)N(C)C
Solvent: CS(C)=O
Product: CN(C)c1cc(-c2cnn(-c3ccc(C(=O)NCC4CCOCC4)cn3)c2O)ccn1
Temperature: 60 °C
Yield: 49.3 %

Procedure:
Combined 6-(4-(2-(dimethylamino)pyridin-4-yl)-5-methoxy-1H-pyrazol-1-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)nicotinamide from the above reaction and lithium chloride (42.7 mg, 1.008 mmol) and DMA (1 mL) and heated at 60° C. for 20 h. The reaction mixture was diluted with 0.2 mL DMSO and purified by prep HPLC (ammonium hydroxide conditions) to give the title compound (42 mg, 49.3% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.12-1.28 (m, 2H) 1.56-1.67 (m, 2H) 1.81 (ddt, J=14.9, 7.5, 3.8, 3.8 Hz, 1H) 3.05 (s, 6H) 3.17 (t, J=6.4 Hz, 2H) 3.28 (td, J=11.6, 1.8 Hz, 2H) 3.86 (dd, J=11.4, 2.5 Hz, 2H) 7.07 (d, J=4.5 Hz, 1H) 7.35 (br. s., 1H) 7.67 (d, J=6.1 Hz, 1H) 7.90 (s, 1H) 8.10-8.19 (m, 1H) 8.47-8.59 (m, 2H) 8.80 (d, J=2.0 Hz, 1H). MS m/z 423 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:3](C(=O)N)[N:4]=[CH:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH3:14])=[CH:9][CH:8]=1.[OH-].[Na+].O.Cl>CO>[NH2:1][C:2]1[C:6]([C:7]2[CH:8]=[CH:9][C:10]([C:13]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)([CH3:15])[CH3:14])=[CH:11][CH:12]=2)=[CH:5][NH:4][N:3]=1
Reactant: CC(C)(c1ccccc1)c1ccc(-c2cnn(C(N)=O)c2N)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(c1ccccc1)c1ccc(-c2c[nH]nc2N)cc1
Yield: 75.5 %

Procedure:
To a suspension of 3-amino-2-carbamoyl-4-[4-(2-phenylpropan-2-yl)phenyl]pyrazole (1.5 g) in methanol (20 ml) was added 5N sodium hydroxide solution (2 l), and the mixture was refluxed. To the mixture was added water (50 ml) under ice-cooling, and the mixture was neutralized (pH 7 to 8) with 10% hydrochloric acid solution, and was extracted with chloroform. The organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous potassium carbonate, and the solvent was distilled away under reduced pressure. The residue was separated and purified by using a silica-gel column chromatography (chloroform:methanol=1:3) to give the title compound (980 mg, 75.5%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][CH2:9][C:10]([OH:12])=[O:11])=O.[CH3:13][N:14]1[CH:18]=[C:17]([CH:19]=O)[C:16]([CH3:21])=[N:15]1.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>O>[CH3:13][N:14]1[CH:18]=[C:17]([CH:19]=[C:9]2[C:10](=[O:11])[O:12][C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[N:8]2)[C:16]([CH3:21])=[N:15]1
Reactant: Cc1nn(C)cc1C=O
Reactant: O=C(O)CNC(=O)c1cccs1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: Cc1nn(C)cc1C=C1N=C(c2cccs2)OC1=O
Temperature: 90 °C
Yield: 29.3 %

Procedure:
To a screw-capped test tube, N-(2-thienylcarbonyl)glycine (56 mg, 0.3 mmol), 1,3-dimethyl-1H-pyrazol-4-carboxaldehyde (41 mg, 0.3 mmol), sodium acetate (25 mg, 0.3 mmol) and acetic anhydride (0.3 mL) were added. The test tube was sealed, and it was then stirred at an external temperature of 90° C. Three hours later, the temperature of the reaction solution was returned to room temperature, and water (1.5 mL) was then added thereto. The obtained mixture was stirred at the same temperature as described above for 1.5 hours. Thereafter, the precipitated crystal was collected by filtration, and it was washed with water (5 mL) and was then dried under reduced pressure, so as to obtain 24 mg of the above-captioned compound.
Reaction SMILES: [CH2:1]([Mg]Cl)[CH3:2].[N+:5]([C:8]1[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[CH:10][CH:9]=1)([O-:7])=[O:6]>C1COCC1.O.[Cl-].[Cl-].[Zn+2].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>[N+:5]([C:8]1[CH:9]=[CH:10][C:11]([C:12](=[O:13])[CH2:1][CH3:2])=[CH:15][CH:16]=1)([O-:7])=[O:6]
Reactant: CC[Mg]Cl
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: O
Product: CCC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 40 %

Procedure:
A solution of 0.5M ZnCl2 in THF (60 mL, 30 mmol) in THF (20 mL) at room temperature was treated with 2M ethyl magnesium chloride in THF (15 mL, 30 mmol) dropwise via syringe, cooled with an ice bath for about 10 minutes, stirred at room temperature for 20 minutes, cooled to 0° C., and treated sequentially with Pd(PPh3)4 (1.73 g, 1.5 mmol) and a solution of 4-nitrobenzoyl chloride (6.12 g, 33 mmol) in THF (20 mL). The mixture was stirred at 0° C. for 40 minutes, diluted with water and extracted three times with ethyl acetate. The combined extracts were washed with saturated Na2CO3, water, and brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 6:1 hexanes/ethyl acetate to provide 2.17 g (40%) of the desired product. Rf=0.6 (3:1 hexanes/ethyl acetate).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH2:17][OH:18])[CH2:15][OH:16])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH2:15][O:16][S:28]([CH3:27])(=[O:30])=[O:29])[CH2:17][O:18][S:28]([CH3:27])(=[O:30])=[O:29])=[CH:10][CH:9]=1)=[O:19])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(CO)CO)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ccc(C(COS(C)(=O)=O)COS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of [4-(2-hydroxy-1-hydroxymethyl-ethyl)-phenyl]-carbamic acid tert-butyl ester (267 mg, 1.00 mmol, as prepared in the previous step) in DCM (10 mL) and Et3N (0.35 mL, 2.5 mmol), methanesulfonyl chloride (MsCl) (0.15 mL, 2.0 mmol) was added dropwise at 0° C. The resulting mixture was stirred at RT for 30 min, diluted with DCM (10 mL) and washed with satd NaHCO3 (20 mL). The organic layer was separated, dried (Na2SO4) and concentrated to afford methanesulfonic acid 2-(4-tert-butoxycarbonylamino-phenyl)-3-methanesulfonyloxy-propyl ester, which was dried in vacuo and directly used in next step: Mass spectrum, (ESI, m/z): Calcd. for C16H25NO8S2, 446.1 (M+Na). found 446.0.