Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[CH3:27][N:28]([C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])[C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH2:34])=[CH:31][CH:30]=1>C1(C)C=CC=CC=1.O1CCOCC1>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:34][CH2:33][C:32]1[CH:31]=[CH:30][C:29]([N:28]([C:37](=[O:42])[C:38]([CH3:40])([CH3:39])[CH3:41])[CH3:27])=[CH:36][CH:35]=1
Reactant: CN(C(=O)C(C)(C)C)c1ccc(CN)cc1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CN(C(=O)C(C)(C)C)c1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1
Yield: 89.4 %

Procedure:
Use a method similar to the General Procedure 1-2 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.23 g, 0.53 mmol) with a solution of 4-(N-methyl-2,2-dimethyl-propionylamino)-benzylamine (0.23 g, 1.06 mmol) in anhydrous toluene/dioxane (4:1, 7 mL). Purify by chromatography on silica gel eluting with hexane/EtOAc (1:0 to 17:3 gradient over 30 min, 17:3 over 30 min, 17:3 to 7:3 gradient over 30 min and 7:3 over 30 min; 35 mL/min) to obtain 7-chloro-6-[4-(N-methyl-2,2-dimethyl-propionylamino)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]-azepine as a yellow oil (0.235 g, 90%).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.[N:10]1([C:16]2[N:17]=[C:18]([CH2:23][C:24](OCC)=[O:25])[NH:19][C:20](=[O:22])[CH:21]=2)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.C[Al](C)C>C1(C)C=CC=CC=1.O1CCCC1>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][N:2]1[C:24](=[O:25])[CH2:23][C:18]1[NH:19][C:20](=[O:22])[CH:21]=[C:16]([N:10]2[CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)[N:17]=1
Reactant: CCOC(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: c1ccc2c(c1)CNC2
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)N1Cc2ccccc2C1
Yield: 23.5 %

Procedure:
The product is prepared according to the procedure described in example 70, using 250 mg of isoindoline, 267 mg of ethyl [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 1 of example 1 and 1.15 ml of a 2M solution of trimethylaluminium, in a mixture of 20 ml of toluene and 10 ml of tetrahydrofuran. 80 mg of 2-[2-(1,3-dihydro-2H-isoindol-2-yl)-2-oxoethyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one are thus obtained in the form of a white powder, the characteristics of which are the following:
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[CH2:15][CH2:14][N:13]([C:16]2[N:25]=[C:24]([NH2:26])[C:23]3[C:18](=[CH:19][C:20]([O:29][CH3:30])=[C:21]([O:27][CH3:28])[CH:22]=3)[N:17]=2)[CH2:12][CH2:11]1.[CH3:31]I>CS(C)=O>[CH3:28][O:27][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][C:20]=1[O:29][CH3:30])[N:17]=[C:16]([N:13]1[CH2:14][CH2:15][N:10]([C:2]3[N:3]([CH3:31])[C:4]4[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=4[N:1]=3)[CH2:11][CH2:12]1)[N:25]=[C:24]2[NH2:26]
Reactant: COc1cc2nc(N3CCN(c4nc5ccccc5[nH]4)CC3)nc(N)c2cc1OC
Reactant: CI
Solvent: CS(C)=O
Product: COc1cc2nc(N3CCN(c4nc5ccccc5n4C)CC3)nc(N)c2cc1OC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 2-[4-(1H-2-benzimidazolyl)-1-piperazinyl]-6,7-dimethoxy-4-quinazolinamine (0.75 g, described in Example 10) and methyl iodide (1.0 ml) in dimethyl sulfoxide (10 ml) was stirred at room temperature for 4 hr and poured into ice. The resulting mixture was extracted with chloroform. The organic extract was washed with water, dried over sodium sulfate and evaporated. The residue was chromatographed through silica gel using 4% methanol in chloroform. The appropriate fractions were combined and evaporated to give a residue (0.42 g) of the title compound. The latter residue was crystallized from hexane-chloroform: mp 249°-251° C.; ir (CHCl3) 3400 and 3300 cm-1 ; uv max (MeOH) 213 (ε=49,870), 250 (ε=64,830); 284 (ε=26,545) and 341 nm (ε=6,565); and Anal. Calcd. for C22H25N7O2 : C, 62.99% H, 6.01% N, 23.37% and Found: C, 62,81% H, 6.18% N, 23.71%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([Cl:8])[CH:3]=1.C([N-]C(C)C)(C)C.[Li+].[CH3:17][O:18][C:19](Cl)=[O:20]>C1COCC1>[CH3:17][O:18][C:19](=[O:20])[C:3]1[C:2]([Br:1])=[CH:7][CH:6]=[N:5][C:4]=1[Cl:8]
Reactant: Clc1cc(Br)ccn1
Reactant: COC(=O)Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1c(Br)ccnc1Cl
Temperature: -80 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-bromo-2-chloro-pyridine (4.5 mL, 41 mmol) in anhydrous THF (60 mL) was added dropwise to a stirred solution of lithium diisopropylamide (1.8 M in THF, 25 mL, 45 mmol) in anhydrous THF (60 mL) at −85° C. After stirring for 30 min at −80° C., the reaction mixture was added dropwise via cannula to a stirred solution of methylchloroformate (31 mL, 400 mmol) in anhydrous THF at −80° C. After stirring for 50 min at −80° C., the reaction was quenched by the addition of concentrated aqueous NaHCO3 (90 mL), and subsequently diluted with EA (250 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (elution with hexane/EA 4:1) to give the title compound. MS (m/z): 252.0.1 [M+H+].
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][N:5]2[C:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18]([NH:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[O:19])[CH:14]=[CH:15][CH:16]=3)=[CH:9][N:10]=[C:4]2[CH:3]=1.CC1(C)C(C)(C)OB([C:34]2[CH:35]=[N:36][N:37](C(OC(C)(C)C)=O)[CH:38]=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.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>[NH:36]1[CH:35]=[C:34]([C:2]2[CH:7]=[N:6][N:5]3[C:8]([C:11]4[CH:12]=[C:13]([NH:17][C:18]([NH:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[O:19])[CH:14]=[CH:15][CH:16]=4)=[CH:9][N:10]=[C:4]3[CH:3]=2)[CH:38]=[N:37]1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(Cl)cnn23)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(-c4cn[nH]c4)cnn23)c1
Temperature: 100 °C

Procedure:
A mixture of N-[3-(7-chloroimidazo[1,2-b]pyridazin-3-yl)phenyl]-N′-(2,2,2-trifluoroethyl)urea (0.30 g, 0.81 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (0.29 g, 0.97 mmol), tetrakis(triphenylphosphine)palladium(0) (46.9 mg, 0.0406 mmol) and K3PO4 (0.43 g, 2.0 mmol) in 1,4-dioxane (4.0 mL) and water (2 mL) was heated at 100° C. under an atmosphere of nitrogen for 3 h. After cooling, the reaction mixture was extracted with ethyl acetate (3×30 mL), and washed with brine. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with methanol in dichloromethane (0-15%) to afford the desired product. LCMS (M+H)+: m/z=402.1.
Reaction SMILES: [F:1][CH:2]([F:31])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[C:17]([O:25][CH2:26][C:27]([F:30])([F:29])[F:28])[CH:16]=2)[CH:4]=1.[CH3:32][S:33]([C:36]1[CH:37]=[C:38]([NH2:42])[CH:39]=[CH:40][CH:41]=1)(=[O:35])=[O:34].Cl>>[CH3:32][S:33]([C:36]1[CH:37]=[C:38]([NH:42][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:31])[F:1])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[C:17]([O:25][CH2:26][C:27]([F:30])([F:28])[F:29])[CH:16]=4)=[N:6][C:7]=23)=[O:13])[CH:39]=[CH:40][CH:41]=1)(=[O:34])=[O:35]
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)c(OCC(F)(F)F)c3)nc12
Reactant: CS(=O)(=O)c1cccc(N)c1
Agent: Cl
Product: CS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)c(OCC(F)(F)F)c4)nc23)c1

Procedure:
The title compound was prepared from 7-difluoromethyl-5-[3-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.13) and 3-methanesulfonyl-phenylamine [commercially available as hydrochloride] according to general procedure II. Yellow solid. MS (EI) 608.3 [M]; mp 207° C.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:23]3[N:24]=[C:25]([CH3:28])[S:26][CH:27]=3)[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[CH:12]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH:29]1([NH2:34])[CH2:33][CH2:32][CH2:31][CH2:30]1>C(OCC)(=O)C>[CH:29]1([NH:34][C:2]2[N:7]3[N:8]=[C:9]([C:23]4[N:24]=[C:25]([CH3:28])[S:26][CH:27]=4)[C:10]([C:11]4[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]5[CH2:22][CH2:21][CH2:20][CH2:19]5)[CH:12]=4)=[C:6]3[CH:5]=[CH:4][CH:3]=2)[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: NC1CCCC1
Reactant: Cc1nc(-c2nn3c(Cl)cccc3c2-c2ccnc(NC3CCCC3)c2)cs1
Solvent: CCOC(C)=O
Product: Cc1nc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccnc(NC3CCCC3)c2)cs1
Temperature: 80 °C
Yield: 120 %

Procedure:
To 4-[7-chloro-2-(2-methyl-1,3-thiazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyridinamine from previous reaction was added cyclopentylamine and the resulting mixture heated to 80° C. for 3 days. The resultant solution was cooled to room temperature, diluted with ethyl acetate and washed with water, brine and dried over magnesium sulfate. Filtration and concentration followed by flash chromatography (1:19 methanol/dichloromethane) gave N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyridinyl]-2-(2-methyl-1,3-thiazol-4-yl)pyrazolo[1,5-a]pyridin-7-amine (20 mg, 120% for two steps) as a brown foam. 1H NMR (CDCl3): δ 8.09 (d, 1H), 7.56 (d, 1H), 7.34 (s, 1H), 7.15 (t, 1H), 6.98 (d, 1H), 6.64 (d, 1H), 6.45 (s, 1H), 5.60 (d, 1H), 4.80 (b, 1H), 3.94 (m, 1H), 3.87 (m, 1H), 2.76 (s, 3H), 1.98–1.45 (m, 16H). MS m/z 459 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=2[CH3:18])=[CH:4][N:3]=1.[H][H]>C(O)C.[Pd]>[CH3:18][C:10]1[CH:11]=[C:12]([NH2:15])[CH:13]=[CH:14][C:9]=1[O:8][C:5]1[CH:4]=[N:3][C:2]([CH3:1])=[CH:7][CH:6]=1
Reactant: [H][H]
Reactant: Cc1ccc(Oc2ccc([N+](=O)[O-])cc2C)cn1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(Oc2ccc(N)cc2C)cn1
Yield: 98.9 %

Procedure:
The solution of 2-Methyl-5-(2-methyl-4-nitro-phenoxy)-pyridine (6.4 g, 26.2 mmol), 10 wt % Pd/C (0.50 g) in ethanol (100 mL) was stirred under 1 atm hydrogen at rt for 24 h. Then the Pd/C catalyst was removed by filtration through a layer of celite. Removal of the solvent gave the desired product as an off-white solid (5.55 g, 99%). 1H-NMR (DMSO-d6) δ 8.04 (d, J=2.7 Hz, 1H), 7.13 (d, J=5.4 Hz, 1H), 7.02 (dd, J=8.7, 3.1 Hz, 1H), 6.68 (d, J=8.7 Hz, 1H), 6.49 (d, J=2.6 Hz, 1H), 6.42 (dd, J=8.4, 2.8 Hz, 1H), 4.96 (br, 2H), 2.39 (s, 3H), 1.97 (s, 3H). LCMS RT=1.04 min; [M+H]+=215.2.
Reaction SMILES: [CH2:1]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][NH:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+].Br[C:69]1[CH:74]=[CH:73][C:72]([F:75])=[CH:71][CH:70]=1>O1CCOCC1>[CH2:1]([N:8]1[C@H:13]2[CH2:14][CH2:15][C@@H:9]1[CH2:10][N:11]([C:69]1[CH:74]=[CH:73][C:72]([F:75])=[CH:71][CH:70]=1)[CH2:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2C3CCC2CNC3)cc1
Reactant: Fc1ccc(Br)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: C1COCCO1
Product: Fc1ccc(N2C[C@H]3CC[C@@H](C2)N3Cc2ccccc2)cc1
Temperature: 100 °C
Reaction time: 15 h
Yield: 65.5 %

Procedure:
To a stirred solution of 8-benzyl-3,8-diazabicyclo[3.2.1]octane (2.5 g, 12.36 mmol) in 1,4-dioxane (15 ml) in sealed tube at 25° C. was added 2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl (0.770 g, 1.23 mmol), sodium tert-butoxide (2.37 g, 24.72 mmol), 1-bromo-4-fluorobenzene (1.63 ml, 14.83 mmol) and tris(dibenzyllideneacetone)dipalladium (0) [Pd2(dba)3] (0.566 g, 0.618 mmol). The resulting reaction mixture was purged with nitrogen for 10 min and stirred at 100° C. for 15 h. The reaction mixture was then cooled to 25° C., filtered through a celite bed, and the celite bed was washed with ethyl acetate (2×20 ml). The combined filtrate was concentrated under reduced pressure to get crude compound. The resulting crude compound was purified by using flash column chromatography over silica gel (100-200 mesh) using 10% ethylacetate in hexane to obtain title compound (2.4 g 66%).
Reaction SMILES: Br[CH2:2][C:3]1[S:7][CH:6]=[N:5][C:4]=1[Cl:8].[CH3:9][C:10]1[N:15]=[C:14]([SH:16])[N:13]=[C:12]([OH:17])[CH:11]=1.C(N(CC)CC)C>C(O)C>[Cl:8][C:4]1[N:5]=[CH:6][S:7][C:3]=1[CH2:2][S:16][C:14]1[N:13]=[C:12]([OH:17])[CH:11]=[C:10]([CH3:9])[N:15]=1
Reactant: Clc1ncsc1CBr
Reactant: Cc1cc(O)nc(S)n1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(O)nc(SCc2scnc2Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.9 %

Procedure:
A mixture of 5-(bromomethyl)-4-chloro-1,3-thiazole (8.4 mmol), 6-methyl-2-sulfanylpyrimidin-4-ol (850 mg, 6.0 mmol), and triethylamine (3.5 mL, 25 mmol) in absolute ethanol (45 mL) was stirred at room temperature overnight. The mixture was evaporated to dryness and then co-evaporated with EtOAc (20 mL). The residue was treated with water (100 mL). The solid material was recovered by filtration and washed with water (3×25 mL), diethyl ether (2×25 mL), and hexanes (2×25 mL). The solid material was dried in vacuo. The crude product was purified by flash chromatography (0-4% MeOH/DCM), affording the title compound (491 mg, 31% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.15 (s, 3H), 4.62 (s, 2H), 6.05 (s, 1H), 8.82 (s, 1H); M+ 274.
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]([C:12]#[N:13])[C:7](=[CH:10][CH:11]=1)[C:8]#[N:9])([O-])=O.[CH2:14]([SH:22])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C(=O)C>[CH2:14]([S:22][C:4]1[CH:5]=[C:6]([C:12]#[N:13])[C:7](=[CH:10][CH:11]=1)[C:8]#[N:9])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: N#Cc1ccc([N+](=O)[O-])cc1C#N
Reactant: CCCCCCCCS
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCCCCCCCSc1ccc(C#N)c(C#N)c1
Reaction time: 1 h
Yield: 67.9 %

Procedure:
While cooling a reaction vessel on a water bath, were mixed 17.3 g (100 mmol) of 4-nitrophthalonitrile, 15.7 g (110 mmol) of 1-octanethiol, 20.7 g (150 mmol) of potassium carbonate and 80 ml of N,N-dimethylacetamide. The resultant mixture was stirred for 7 hours at room temperature and then for 1 hour at 40° C. The thus-obtained reaction mixture was poured into 600 ml of a 3% hydrochloric acid. The resultant precipitates were separated by a filtration under reduced pressure, and then washed with water and dried. Thereafter, by recrystallization from a mixed solvent of methanol (190 ml)/water (9 ml), there was obtained 18.5 g (Yield: 68%) of white powder synthesis intermediate (A-1) (Melting point=37 to 38° C.).
Reaction SMILES: Cl[CH:2]1[C:8]2=[N:9][C:10]3[N:15]([CH2:16][CH3:17])[N:14]=[CH:13][C:11]=3[CH:12]=[C:7]2[CH2:6][CH2:5][C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2.[CH3:22][N:23]([CH3:28])[CH2:24][CH2:25][CH2:26][NH2:27]>>[CH3:22][N:23]([CH3:28])[CH2:24][CH2:25][CH2:26][NH:27][CH:2]1[C:8]2=[N:9][C:10]3[N:15]([CH2:16][CH3:17])[N:14]=[CH:13][C:11]=3[CH:12]=[C:7]2[CH2:6][CH2:5][C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2
Reactant: CN(C)CCCN
Reactant: CCn1ncc2cc3c(nc21)C(Cl)c1ccccc1CC3
Product: CCn1ncc2cc3c(nc21)C(NCCCN(C)C)c1ccccc1CC3
Yield: 76 %

Procedure:
11.8 g. of 11-chloro-1-ethyl-1,5,6,11-tetrahydrobenzo[5,6]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridine (0.04 mol.), from example 44(a), and 75 ml. of 3-(dimethylamino)propylamine are heated at 120°-125° (bath temperature) for 5.5 hours. Following the procedure of example 44(b), 11 g. (76%) of oily N-[3-(dimethylamino)propyl]-1-ethyl-1,5,6,11-tetrahydrobenzo[5,6]-cyclohepta-[1,2-b]pyrazolo[4,3-e]pyridin-11-amine are obtained. Treatment with ethereal hydrochloric acid yields N-[3-(dimethylamino)propyl]-1-ethyl-1,5,6,11-tetrahydrobenzo[5,6]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridin-11-amine, hydrochloride (1:2), hydrate (1:2); m.p. 125° (dec.).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:18])[CH2:13][CH2:12]2)=[CH:6][CH:5]=1.C([Si]([O:43][C:44]1[CH:49]=[CH:48][C:47]([O:50][CH2:51][CH:52]2[CH2:54][O:53]2)=[CH:46][CH:45]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>>[CH2:20]([NH:19][C:17]([N:14]1[CH2:15][CH2:16][CH:11]([S:10][C:7]2[CH:6]=[CH:5][C:4]([CH2:3][CH2:2][NH:1][CH2:54][C@H:52]([OH:53])[CH2:51][O:50][C:47]3[CH:48]=[CH:49][C:44]([OH:43])=[CH:45][CH:46]=3)=[CH:9][CH:8]=2)[CH2:12][CH2:13]1)=[O:18])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCNC(=O)N1CCC(Sc2ccc(CCN)cc2)CC1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Product: CCCCCCNC(=O)N1CCC(Sc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 35.3 %

Procedure:
4-{[4-(2-Aminoethyl)phenyl]sulfanyl}-N-hexyl-1-piperidinecarboxamide (0.588 g, 1.617 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenylsilane (0.589 g, 1.455 mmol) according to Procedure G to give the title compound (eluant: 20/1 chloroform-methanol) (0.395 g, 0.514 mmol).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1[N:7]=[C:8]([C:16]([F:19])([F:18])[F:17])[N:9]2[CH2:14][CH2:13][NH:12][CH:11]([CH3:15])[C:10]=12)=[O:5].[C:20]([O:24][C:25]([NH:27][C@H:28]([CH2:33][C:34]1[CH:39]=[C:38]([F:40])[C:37]([F:41])=[CH:36][C:35]=1[F:42])[CH2:29][C:30](O)=[O:31])=[O:26])([CH3:23])([CH3:22])[CH3:21].C(N(CC)CC)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>ClCCl>[CH3:2][O:3][C:4]([C:6]1[N:7]=[C:8]([C:16]([F:19])([F:18])[F:17])[N:9]2[CH2:14][CH2:13][N:12]([C:30](=[O:31])[CH2:29][CH:28]([NH:27][C:25]([O:24][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:26])[CH2:33][C:34]3[CH:39]=[C:38]([F:40])[C:37]([F:41])=[CH:36][C:35]=3[F:42])[C@H:11]([CH3:15])[C:10]=12)=[O:5]
Reactant: COC(=O)c1nc(C(F)(F)F)n2c1C(C)NCC2
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)c(F)cc1F
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1nc(C(F)(F)F)n2c1[C@@H](C)N(C(=O)CC(Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C)CC2
Yield: 77.2 %

Procedure:
8-Methyl-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid methyl ester hydrochloride 39c crude product (0.289 g, 0.96 mmol) and (R)-3-tert-butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyric acid 1f (0.353 g, 1.06 mmol) were dissolved in 10 mL of dichloromethane, followed by addition of triethylamine (0.4 mL, 2.9 mmol) and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.368 g, 1.45 mmol) under stirring. The reaction mixture was stirred at room temperature overnight and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-7-[3-tert-butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-8-methyl-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid methyl ester 39d (0.43 g, yield 77.2%) as a yellow oil.
Reaction SMILES: [C:1]([C:4]1[CH:36]=[CH:35][C:7]([O:8][CH2:9][CH:10]([OH:34])[CH2:11][O:12][C:13]2[CH:30]=[CH:29][C:16]3[C:17](=[O:28])[CH:18]=[C:19](/[CH:21]=[CH:22]/[C:23]([O:25]CC)=[O:24])[O:20][C:15]=3[C:14]=2[CH2:31][CH2:32][CH3:33])=[C:6]([CH2:37][CH2:38][CH3:39])[C:5]=1[OH:40])(=[O:3])[CH3:2].C(=O)([O-])O.[Na+].C(Cl)(Cl)(Cl)Cl>C(O)C>[C:1]([C:4]1[CH:36]=[CH:35][C:7]([O:8][CH2:9][CH:10]([OH:34])[CH2:11][O:12][C:13]2[CH:30]=[CH:29][C:16]3[C:17](=[O:28])[CH:18]=[C:19](/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24])[O:20][C:15]=3[C:14]=2[CH2:31][CH2:32][CH3:33])=[C:6]([CH2:37][CH2:38][CH3:39])[C:5]=1[OH:40])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCC(O)COc2ccc3c(=O)cc(/C=C/C(=O)OCC)oc3c2CCC)ccc(C(C)=O)c1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: ClC(Cl)(Cl)Cl
Product: CCCc1c(OCC(O)COc2ccc3c(=O)cc(/C=C/C(=O)O)oc3c2CCC)ccc(C(C)=O)c1O
Yield: 39.2 %

Procedure:
A solution of trans-ethyl 3-[7-[3-(4-acetyl-3-hydroxy-2-n-propylphenoxy)-2-hydroxypropyloxy]-4-oxo-8-n-propyl-4H-1-benzopyran-2-yl]acrylate (1.56 g) and sodium hydrogen carbonate (1.56 g) in aqueous ethanol was refluxed for 1 hour. Ethanol was removed by distillation and the residual aqueous solution cooled. Acidification afforded a gum which solidified on prolonged treatment with refluxing carbon tetrachloride. Crystallisation from acetone-carbon tetrachloride yielded trans-3[7-[3-(4-acetyl-3-hydroxy-2-n-propylphenoxy)-2-hydroxypropyloxy]-4-oxo-8-n-propyl-4H-1-benzopyran-2-yl]acrylic acid (0.58 g) mp 101°-103° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12](B3OC(C)(C)C(C)(C)O3)=[CH:13][CH:14]=2)[C:9]([C:25]([F:28])([F:27])[F:26])=[N:8]1.B1([O-])O[O:30]1.O.O.O.O.[Na+]>C1COCC1.O>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([OH:30])=[CH:13][CH:14]=2)[C:9]([C:25]([F:28])([F:27])[F:26])=[N:8]1
Reactant: CC1(C)OB(c2ccc3c(c2)c(C(F)(F)F)nn3C2CCCCO2)OC1(C)C
Reactant: [O-]B1OO1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Oc1ccc2c(c1)c(C(F)(F)F)nn2C1CCCCO1
Temperature: 50 °C
Yield: 85.1 %

Procedure:
To a solution of 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)-1H-indazole (415 mg, 1.047 mmol) in THF (4 mL) and water (4.00 mL) was added sodium perborate tetrahydrate (483 mg, 3.14 mmol). The reaction mixture was heated at 50° C. for 2 h. The organic solvents were evaporated, extracted with EtOAc and washed with water and brine solution, then dried over Na2SO4 and concentrated. The crude product was purified by flash chromatography on silica gel using 50% EtOAc/Petroleum Ether to give 1-(tetrahydro-2H-pyran-2-yl)-3-(trifluoromethyl)-1H-indazol-5-ol (255 mg, 85%). 1HNMR 400 MHz, CDCl3: 6 ppm 1.68-1.75 (m, 4H), 2.05-2.17 (m, 2H), 2.46-2.52 (m, 1H), 3.71-3.77 (m, 1H), 3.98-4.01 (m, 1H), 4.89 (s, 1H), 5.74 (dd, J=2.40, 9.00 Hz, 1H), 7.08 (dd, J=2.40, 9.00 Hz, 1H), 7.13 (d, J=0.80 Hz, 1H), 7.59 (d, J=0.40 Hz, 1H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[N:11]=[C:10]([CH2:12][CH:13]3[CH2:18][CH2:17][N:16]([C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH2:15][CH2:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[Si]([N:37]1[C:45]2[C:40](=[C:41](B3OC(C)(C)C(C)(C)O3)[C:42]([F:46])=[CH:43][CH:44]=2)[CH:39]=[CH:38]1)(C(C)(C)C)(C)C>>[F:46][C:42]1[C:41]([C:2]2[N:3]=[C:4]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:5]3[N:11]=[C:10]([CH2:12][CH:13]4[CH2:18][CH2:17][N:16]([C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH2:15][CH2:14]4)[CH:9]=[CH:8][C:6]=3[N:7]=2)=[C:40]2[C:45](=[CH:44][CH:43]=1)[NH:37][CH:38]=[CH:39]2
Reactant: CC(C)C(=O)N1CCC(Cc2ccc3nc(Cl)nc(N4CCOCC4)c3n2)CC1
Reactant: CC1(C)OB(c2c(F)ccc3c2ccn3[Si](C)(C)C(C)(C)C)OC1(C)C
Product: CC(C)C(=O)N1CCC(Cc2ccc3nc(-c4c(F)ccc5[nH]ccc45)nc(N4CCOCC4)c3n2)CC1

Procedure:
1-(4-((2-Chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)piperidin-1-yl)-2-methylpropan-1-one (60 mg) was reacted with 1-(tert-butyldimethylsilyl)-5-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole via General Procedure A to produce 19.9 mg of 149 following reverse phase HPLC purification. MS (Q1) 517.3 (M)+