Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17].C(N(C(C)C)C(C)C)C.[O:30]=[C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33](=[O:40])[N:32]1[CH2:41][CH2:42][O:43][CH2:44][CH2:45][O:46][CH2:47][CH2:48][O:49][CH2:50][CH2:51][C:52](Cl)=[O:53]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:15]=[C:16]([NH:17][C:52](=[O:53])[CH2:51][CH2:50][O:49][CH2:48][CH2:47][O:46][CH2:45][CH2:44][O:43][CH2:42][CH2:41][N:32]2[C:31](=[O:30])[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:33]2=[O:40])[CH:18]=[CH:19][CH:20]=1
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(N)c2)C1
Reactant: O=C(Cl)CCOCCOCCOCCN1C(=O)c2ccccc2C1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(NC(=O)CCOCCOCCOCCN3C(=O)c4ccccc4C3=O)c2)C1
Temperature: 25 °C
Yield: 16 %

Procedure:
To 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenamine (intermediate 31.5) (600.0 mg, 1.95 mmol, 1.00 equiv) in anhydrous DCM (5.0 mL) was added N-ethyl-N,N-diisopropylamine (DIEA; 0.5 mL). Then a solution of 3-(2-(2-(2-(1,3-dioxoisoindolin-2-yl)ethoxy)ethoxy)ethoxy)propanoyl chloride (intermediate 179.5) (794 mg, 2.15 mmol, 1.10 equiv) was added dropwise with stirring at room temperature. The resulting solution was stirred for 2 h at ambient temperature and then concentrated under vacuum. The residue was applied onto a silica gel column with DCM/methanol (100˜50:1). This resulted in 870 mg (66%) of N-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl)-3-(2-(2-(2-(1,3-dioxoisoindolin-2-yl)ethoxy)ethoxy)ethoxy)propanamide as a pale yellow syrup. The other fractions was collected and evaporated to get an additional 200 mg of impure product.
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8]CC2C=CC=CC=2)=[CH:6][C:5]([O:16]CC2C=CC=CC=2)=[CH:4][C:3]=1[CH:24]1[NH:28][C:27](=[O:29])[NH:26][C:25]1=[O:30]>CO.[Pd]>[CH3:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([OH:16])=[CH:4][C:3]=1[CH:24]1[NH:28][C:27](=[O:29])[NH:26][C:25]1=[O:30]
Reactant: Cc1c(OCc2ccccc2)cc(OCc2ccccc2)cc1C1NC(=O)NC1=O
Agent: [Pd]
Solvent: CO
Product: Cc1c(O)cc(O)cc1C1NC(=O)NC1=O

Procedure:
A solution of 5-(2-methyl-3,5-dibenzyloxyphenyl)-hydantoin (1.13 g, 2.8 mmol) in methanol (100 ml) was shaken in a Parr hydrogenation apparatus at 60 p.s.i. over 10% Palladium/charcoal (120 mg) for 6 hours. The reaction suspension was filtered over celite and the filtrate evaporated in vacuo to give 5-(2-methyl-3,5-dihydroxyphenyl)-hydantoin as an off-white solid.
Reaction SMILES: [C:1]([Si:5]([CH3:23])([CH3:22])[O:6][CH:7]([CH:19]1[CH2:21][CH2:20]1)[CH2:8][O:9][C:10]1[C:11](Cl)=[N:12][C:13]([Cl:17])=[N:14][C:15]=1[Cl:16])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[C:1]([Si:5]([CH3:22])([CH3:23])[O:6][CH:7]([CH:19]1[CH2:21][CH2:20]1)[CH2:8][O:9][C:10]1[C:11]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[N:12][C:13]([Cl:17])=[N:14][C:15]=1[Cl:16])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)[Si](C)(C)OC(COc1c(Cl)nc(Cl)nc1Cl)C1CC1
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OC(COc1c(Cl)nc(Cl)nc1N1CCOCC1)C1CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.8 %

Procedure:
To a solution of 5-[2-(tert-butyl-dimethyl-silanyloxy)-2-cyclopropyl-ethoxy]-2,4,6-trichloro-pyrimidine (411 mg, 1.03 mmol) in IMS (5 mL) was added triethylamine (215 μL, 1.55 mmol) followed by morpholine (94 μL, 1.08 mmol). The reaction mixture was stirred at RT for 4 hours before being concentrated in vacuo. The resultant residue was purified by column chromatography (SiO2, gradient 0-20% ethyl acetate in cyclohexane) to afford 4-{5-[2-(tert-Butyl-dimethyl-silanyloxy)-2-cyclopropyl-ethoxy]-2,6-dichloro-pyrimidin-4-yl}-morpholine as a colorless gum (387 mg, 84%). LCMS: RT=5.22 min, [M+H]+=448/450/452.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I-].[Na+].Cl[C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=1.Cl[CH2:31][C:32]([O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:33]>CN(C)C=O.[Zn].[Ni](Cl)Cl>[C:32]([O:34][C:35]1[CH:40]=[CH:39][C:38]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)=[CH:37][CH:36]=1)(=[O:33])[CH3:31]
Reactant: Cc1ccc(Cl)cc1
Reactant: O=C(CCl)Oc1ccccc1
Agent: Cl[Ni]Cl
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccc(-c2ccc(C)cc2)cc1
Reaction time: 6 h

Procedure:
20 g of zinc dust, 20 go of triphenylphosphine, 3 g of sodium iodide and 1.3 of nickel(II) chloride in 150 ml of dimethylformamide were initially introduced into the reaction vessel under a nitrogen atmosphere. The mixture was kept at 60° C. for half an hour. A solution containing 12.3 g (0.1 mol) of 4-chlorotoluene, 17.1 g (0.1 mol) of 4-chloroacetoxybenzene and 50 ml of dimethylformamide was then added dropwise. After 6 hours at 80° C., the reaction mixture was filtered, the filtrate was concentrated, the residue was dissolved in 500 ml of chloroform and the mixture was extracted by shaking with water. After drying the organic phase over sodium sulphate and stripping off the solvent, the oily residue was analyzed by gas chromatography. The yield of 4-acetoxy-4'-methylbiphenyl was 40% of theory.
Reaction SMILES: C(OC([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:17][CH2:18][CH2:19][C:20]([F:23])([F:22])[F:21])[CH:14]=2)[CH2:9]1)=O)(C)(C)C.[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27]>>[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27].[F:23][C:20]([F:21])([F:22])[CH2:19][CH2:18][O:17][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH2:9][NH:8][CH2:16]2
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(OCCC(F)(F)F)cc2C1
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)CCOc1ccc2c(c1)CNC2

Procedure:
Prepared in analogy to Example A2(c) from 5-(3,3,3-trifluoro-propoxy)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and trifluoroacetic acid. Brown oil. MS (m/e): 232.1 ([M+H]+, 100%).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]3([CH2:14][CH2:13]3)[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH2:64]([N:66]1[CH2:71][CH2:70][N:69]([CH:72]2[CH2:77][CH2:76][CH:75]([NH2:78])[CH2:74][CH2:73]2)[CH2:68][CH2:67]1)[CH3:65]>CN(C=O)C>[CH:1]1([N:6]2[CH2:12][C:11]3([CH2:13][CH2:14]3)[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:78][C@H:75]5[CH2:74][CH2:73][C@H:72]([N:69]6[CH2:68][CH2:67][N:66]([CH2:64][CH3:65])[CH2:71][CH2:70]6)[CH2:77][CH2:76]5)=[O:28])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CC1)C(=O)N2C
Reactant: CCN1CCN(C2CCC(N)CC2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN1CCN([C@H]2CC[C@H](NC(=O)c3ccc(Nc4ncc5c(n4)N(C4CCCC4)CC4(CC4)C(=O)N5C)c(OC)c3)CC2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-(9′-Cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclopropane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-3-methoxybenzoic acid (Intermediate 5) (66 mg, 0.15 mmol, 1 eq), DIPEA (52 μl, 0.3 mmol, 2 eq) and TBTU (54 mg, 0.17 mmol, 1.1 eq) were added to 1.5 mL DMF and the resulting solution was stirred at rt for 20 min before the addition of 4-(4-ethylpiperazin-1-yl)cyclohexanamine (Intermediate 13) as the trihydrochloride salt (58 mg, 0.18 mmol, 1.2 eq) and DIPEA (78 μL, 0.45 mmol, 3 eq). The RM was then stirred at rt for 2 hours before purifying by preparative RP-HPLC-MS (Preparative—2) to provide 4-(9′-cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclopropane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-N-((trans)-4-(4-ethylpiperazin-1-yl)cyclohexyl)-3-methoxybenzamide (colourless glass, 26 mg, 28%).
Reaction SMILES: [CH3:1][N:2]([CH3:4])[CH3:3].[S:5]([C:9]1[CH:15]=[CH:14][C:12]([CH3:13])=[CH:11][CH:10]=1)([O-:8])(=[O:7])=[O:6].[C:16]1([CH3:22])C=CC=C[CH:17]=1>>[S:5]([C:9]1[CH:15]=[CH:14][C:12]([CH3:13])=[CH:11][CH:10]=1)([O-:8])(=[O:7])=[O:6].[OH:6][CH2:17][CH2:16][CH2:22][N+:2]([CH3:4])([CH3:3])[CH3:1]
Reactant: CN(C)C
Reactant: Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: C[N+](C)(C)CCCO
Reaction time: 72 h

Procedure:
7 ml of 18% trimethylamine in toluene was added to 2.0 g (9.2 mmole) of the above tosylate, and the mixture was allowed to stand at room temperature for 3 days. The crystals separated out were collected by filtration, washed with toluene and dried under reduced pressure to give 3-hydroxypropyltrimethylammonium tosylate as colorless needles. Melting point: 80° C. Yield: 2.3 g (yield: 92%).
Reaction SMILES: [CH3:1][CH2:2][C:3]1([CH2:12][CH3:13])[C:9](=[O:10])[N:8]=[C:7]([O-:11])[NH:6][C:4]1=[O:5].[Na+]>O>[CH3:1][CH2:2][C:3]1([CH2:12][CH3:13])[C:4](=[O:5])[NH:6][C:7](=[O:11])[NH:8][C:9]1=[O:10]
Reactant: CCC1(CC)C(=O)N=C([O-])NC1=O
Agent: [Na+]
Solvent: O
Product: CCC1(CC)C(=O)NC(=O)NC1=O

Procedure:
(41.2g sodium barbital in one liter of distilled water)
Reaction SMILES: O=[C:2]1[CH2:11][CH2:10][CH:9]2[CH:4]([CH2:5][CH:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:7]([C:12]([O:14][CH3:15])=[O:13])[CH2:8]2)[CH2:3]1.[CH2:21]([O:23][C:24](=[O:32])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([NH2:31])[CH:26]=1)[CH3:22].C(O)(=O)C.[Na]>CCCCCC.C(OCC)(=O)C>[CH2:21]([O:23][C:24]([C:25]1[CH:26]=[C:27]([NH:31][C@H:2]2[CH2:11][CH2:10][C@@H:9]3[C@@H:4]([CH2:5][C@@H:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:7]([C:12]([O:14][CH3:15])=[O:13])[CH2:8]3)[CH2:3]2)[CH:28]=[CH:29][CH:30]=1)=[O:32])[CH3:22]
Reactant: CCOC(=O)c1cccc(N)c1
Reactant: CCOC(=O)C1CC2CC(=O)CCC2CN1C(=O)OC
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CCCCCC
Product: CCOC(=O)c1cccc(N[C@H]2CC[C@H]3CN(C(=O)OC)[C@H](C(=O)OCC)C[C@H]3C2)c1
Yield: 91.1 %

Procedure:
Following the procedures from Example 1A, and using ethyl 6-oxo-2-(methoxycarbonyl)-decahydroisoquinoline-3-carboxylate (11.4 g, 40.28 mmol), 3-aminobenzoic acid ethyl ester (3.5 g, 21.2 mmol), glacial acetic acid (5.0 mL, 84.0 mmol), and sodium triacethoxyborohydride (12.58 g, 59.36 mmol) flash chromatography (silica gel, hexane-ethyl acetate 3:1) afforded 8.35 g (92% yield) of the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][N:5]=[C:6]([C:12]1([O:17][CH2:16][CH2:15][O:14]1)[CH3:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8].CC(C)([O-])C.[K+]>CS(C)=O.O1CCCC1>[CH:3]([O:4][N:5]=[C:6]([C:12]1([O:14][CH2:15][CH2:16][O:17]1)[CH3:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH2:2]
Reactant: CCOC(=O)C(=NOCCBr)C1(C)OCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: C=CON=C(C(=O)OCC)C1(C)OCCO1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 95 %

Procedure:
To a solution of ethyl 2-(2-bromoethoxyimino)-3,3-ethylenedioxybutyrate (syn isomer)(50 g) in dimethyl sulfoxide (50 ml) was dropwise added potassium tertbutoxide (21.7 g) in tetrahydrofuran (190 ml) under ice-cooling. The mixture was stirred at the same temperature for 10 minutes. The mixture was poured into ice-water and extracted with diethyl ether. The extract was washed with water, dried over magnesium sulfate and evaporated in vacuo to give ethyl 2-vinyloxyimino-3,3-ethylenedioxybutyrate (syn isomer) (35.1 g) as an oil.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[C:16]3[S:17][CH:18]=[CH:19][C:15]=3[O:14][N:13]=2)[CH:9]=[CH:10][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].[F:26][C:27]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:28]=1[CH2:29][NH2:30]>C(#N)C>[F:26][C:27]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:28]=1[CH2:29][NH:30][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[C:16]3[S:17][CH:18]=[CH:19][C:15]=3[O:14][N:13]=2)[CH:7]=1
Reactant: BrCCCOc1cccc(-c2noc3ccsc23)c1
Reactant: NCc1c(F)cccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Fc1cccc(F)c1CNCCCOc1cccc(-c2noc3ccsc23)c1

Procedure:
The title compound is prepared from 3-[3-(3-bromo-propoxy)-phenyl]-thieno[2,3-d]isoxazole, potassium carbonate, 2,6-difluorobenzylamine, and acetonitrile essentially as described above in example 56. Purity by LC/MS (APCI)=97%, [M+H]+=401.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([I:11])=[CH:9][N:8]([CH2:12][O:13][CH:14]([OH:18])[CH2:15][CH2:16][OH:17])[C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:19]C1C2C(Cl)=CN(COC(O)CCO)C=2N=CN=1>>[NH2:19][C:2]1[C:3]2[C:10]([I:11])=[CH:9][N:8]([CH2:12][O:13][CH:14]([OH:18])[CH2:15][CH2:16][OH:17])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1ncnc2c1c(Cl)cn2COC(O)CCO
Reactant: OCCC(O)OCn1cc(I)c2c(Cl)ncnc21
Product: Nc1ncnc2c1c(I)cn2COC(O)CCO

Procedure:
Compound 22c was prepared from 4-chloro-5-iodo-7-[(1,3-dihydroxypropoxy)methyl]pyrrolo[2,3-d]pyrimidine by the method described for 22a to yield 0.20 g (51%). mp=177°-177.5° C. 1H NMR (DMSO-d6): δ3.22-3.52 (m, 5); 4.58 (t, 2, exchanges with D2O, OH); 5.57 (s, 2, C-1'); 6.66 (bs, 2, exchanges with D2O, NH2); 7.55 (s, 1, C-6); 8.11 (s, 1, C-2). Anal. for C10H13N4O3I. (C,H,N).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]2[N:11]3[CH2:25][CH2:24][N:23]([CH3:26])[C:22](=[O:27])[C:12]3=[C:13]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:9]=2[C:8](=[O:28])[N:7]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[C:32]([Cl:37])[CH:31]=2)[N:6]=1)=[O:4].Cl.[NH2:39][NH:40][C:41]([NH2:43])=[O:42].C(N(C(C)C)CC)(C)C>C1COCC1>[CH2:15]([O:14][C:13]1[C:9]2[C:8](=[O:28])[N:7]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[C:32]([Cl:37])[CH:31]=3)[N:6]=[C:5]([C:3](=[O:4])[CH2:2][NH:39][NH:40][C:41]([NH2:43])=[O:42])[C:10]=2[N:11]2[CH2:25][CH2:24][N:23]([CH3:26])[C:22](=[O:27])[C:12]=12)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NNC(N)=O
Reactant: CN1CCn2c(c(OCc3ccccc3)c3c(=O)n(Cc4ccc(F)c(Cl)c4)nc(C(=O)CBr)c32)C1=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN1CCn2c(c(OCc3ccccc3)c3c(=O)n(Cc4ccc(F)c(Cl)c4)nc(C(=O)CNNC(N)=O)c32)C1=O

Procedure:
A solution of crude 4-bromoacetyl-10-(benzyloxy)-2-(3-chloro-4-fluorobenzyl)-8-methyl-7,8-dihydropyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyridazine-1,9(2H,6H)-dione (1.25 g, 2.13 mmol) in anhydrous THF, semicarbazide hydrochloride (0.35 g, 3.14 mmol), and diisopropylethylamine (0.66 mL, 3.77 mmol) was heated in a sealed tube at 100° C. for 30 minutes. The reaction mixture was concentrated under vacuum. The residue was dissolved in DMSO and subject to reverse phase preparative HPLC purification. Collection and lyophilization of appropriate fraction provided the intermediate 2-{2-[10-(benzyloxy)-2-(3-chloro-4-fluorobenzyl)-8-methyl-1,9-dioxo-1,2,6,7,8,9-hexahydropyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyridazin-4-yl]-2-oxoethyl}hydrazinecarboxamide as white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:10]2[C:5](=[CH:6][C:7]([CH3:11])=[CH:8][CH:9]=2)[C:4]([CH3:15])([CH:12]([CH3:14])[CH3:13])[CH2:3]1.[CH3:17][O:18]C(Cl)Cl>[Ti](Cl)(Cl)(Cl)Cl.C(Cl)Cl>[CH:17]([C:8]1[CH:9]=[C:10]2[C:5]([C:4]([CH3:15])([CH:12]([CH3:13])[CH3:14])[CH2:3][C:2]2([CH3:16])[CH3:1])=[CH:6][C:7]=1[CH3:11])=[O:18]
Reactant: Cc1ccc2c(c1)C(C)(C(C)C)CC2(C)C
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1cc2c(cc1C=O)C(C)(C)CC2(C)C(C)C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Next, 1,1,3,5-tetramethyl-3-isopropylindane (12.96 g) is placed in a 1 liter three-necked round bottom flask equipped with a reflux condenser, a stirrer and a dropping funnel. In accordance with the general procedures described in Organic Syntheses, Collective Vol. 5, pp. 49-50, by A. Rieche, H. Gross, and E. Hoft, edited by H.E. Baumgarten, John Wiley and Sons (New York, N.Y. 1973), methylene chloride (37.5 ml) is added to the flask. The solution is then cooled in an ice bath, and titanium tetrachloride (19.0 g) is added over a period of about 3 minutes. While the solution is stirred and cooled, α,α-dichloromethyl methyl ether (5.75 g) is added dropwise over a 25 minute period. After the addition is complete, the mixture is stirred for about 5 minutes in the ice bath, for about 30 minutes without cooling, and for about 15 minutes at about 35° C. The reaction mixture is then poured into a separatory funnel containing about 50 g of crushed ice and is shaken thoroughly. The organic layer is separated, and the aqueous solution is extracted with two 10 ml portions of methylene chloride. The combined organic solution is washed three times with 10 ml portions of water. A crystal of hydroquinone is added to the methylene chloride solution, which is then dried over anhydrous sodium sulfate. After evaporation of the solvent, the residue is distilled to yield as a crude product, 6-formyl-1,1,3,5-tetramethyl-3-isopropylindane. The 6 formyl-1,1,3,5 tetramethyl-3-isopropylindane is then further purified using standard fractional distillation techniques.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[C:14](=[O:31])[N:15]([C:18]4[CH:23]=[CH:22][C:21]([N:24]5[CH2:29][CH2:28][CH2:27][CH2:26][C:25]5=[O:30])=[CH:20][CH:19]=4)[CH2:16][CH2:17][C:12]=3[C:11]([C:32]([OH:34])=O)=[N:10]2)=[CH:5][CH:4]=1.C([N:37](CC)CC)C.ClC(OCC(C)C)=O.[OH-].[NH4+]>CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[C:14](=[O:31])[N:15]([C:18]4[CH:19]=[CH:20][C:21]([N:24]5[CH2:29][CH2:28][CH2:27][CH2:26][C:25]5=[O:30])=[CH:22][CH:23]=4)[CH2:16][CH2:17][C:12]=3[C:11]([C:32]([NH2:37])=[O:34])=[N:10]2)=[CH:5][CH:4]=1
Reactant: CCN(CC)CC
Reactant: COc1ccc(-n2nc(C(=O)O)c3c2C(=O)N(c2ccc(N4CCCCC4=O)cc2)CC3)cc1
Agent: CC(C)COC(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: COc1ccc(-n2nc(C(N)=O)c3c2C(=O)N(c2ccc(N4CCCCC4=O)cc2)CC3)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.9 %

Procedure:
Method A. A suspension of 1-(4-methoxy-phenyl)-7-oxo-6-[4-(2-oxo-piperidin-1-yl)-phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (61, 1.5 g, 3.3 mmol) in EtOAc (20 mL) was treated with triethylamine (TEA, 433 mg, 0.60 mL, 4.3 mmol, 1.3 equiv) at room temperature, and the resulting reaction mixture was treated dropwise with iso-butyl chloroformate (587 mg, 0.55 mL, 4.3 mmol, 1.3 equiv) at room temperature. The resulting reaction mixture was subsequently stirred at room temperature for an additional 30 min. When TLC and HPLC showed the mixed anhydride formation reaction was complete, the reaction mixture was poured into a cold (0-5° C.) ammonium hydroxide solution (NH4OH, 28% aqueous solution, 25 mL) with good stirring. The resulting mixture was stirred at room temperature for an additional 4 h. The solids were collected by filtration, washed with a mixture of methanol and water (1:1 v/v, 2×20 mL), and dried in vacuo at 40-45° C. for 12 h to afford the crude desired 1-(4-methoxy-phenyl)-7-oxo-6-[4-(2-oxo-piperidin-1-yl)-phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid amide (62, 1.06 g, 1.52 g theoretical, 70%) as off-white crystals. For 62, CIMS m/z 460 (M++H, C25H25N5O4).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([CH2:12]O)=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)=[C:17]([C:34]([F:37])([F:36])[F:35])[CH:16]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[CH3:52][NH2:53].Cl>ClCCl.C1COCC1.O=[Mn]=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([CH2:12][NH:53][CH3:52])=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])[CH2:23][CH2:22]2)=[C:17]([C:34]([F:37])([F:35])[F:36])[CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3c(CO)cnc4ccc(Cl)cc34)cc2C(F)(F)F)CC1
Reactant: CN
Agent: O=[Mn]=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: CNCc1cnc2ccc(Cl)cc2c1Nc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 4-(4-(6-chloro-3-(hydroxymethyl)quinolin-4-ylamino)-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate (400 mg, 0.74 mmol) in dichloromethane(10 mL) at room temperature was added MnO2 (2 g). The resultant solution was stirred for 3 h before filtering through celite and washing with dichloromethane (20 mL). After removal solvent in vacuo, the residue was redisolved in THF (5 mL), to which NaBH(OAc)3 (443 mg, 2.1 mmol) and CH3NH2.HCl (140 mg, 2.1 mmol) were added. The solution was stirred at room temperature overnight, quenched with NaHCO3 (sat. 10 mL), extracted with EtOAc (20 mL×3), and dried over Na2SO4. After removal of solvent in vacuo, the crude product was taken to next step without further purification. LC-MS: (M+H)=550.32
Reaction SMILES: [CH:1]([Sn](CCCC)(CCCC)CCCC)=[C:2]([CH3:4])[CH3:3].[NH2:18][C:19]1[CH:24]=[N:23][C:22](Br)=[CH:21][N:20]=1.C(N(CC)C(C)C)(C)C.[Cl-].[Li+]>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:18][C:19]1[CH:24]=[N:23][C:22]([CH:1]=[C:2]([CH3:4])[CH3:3])=[CH:21][N:20]=1
Reactant: CCCC[Sn](C=C(C)C)(CCCC)CCCC
Reactant: Nc1cnc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)=Cc1cnc(N)cn1
Temperature: 130 °C
Reaction time: 4 h
Yield: 25.6 %

Procedure:
A mixture of the crude isobutenyltri-n-butyltin (6.90 g, 58 purity), 2-amino-5-bromopyrazine (1.92 g, 11 mmol), and N,N-diisopropylethylamine (5 mL) in N,N-dimethylformamide (50 mL) was treated with lithium chloride (2.0 g) and tetrakis(triphenylphosphine)palladium(0) (381 mg, 0.33 mmol). The mixture was stirred at 130° C. for 4 h, at which time, thin layer chromatography indicated complete consumption of the starting material. The mixture was concentrated in vacuo. The residue was treated with a saturated aqueous potassium fluoride solution and then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 1.5/1 hexanes/ethyl acetate) afforded 2-amino-5-(2,2-dimethylvinyl)-pyrazine (420 mg, 26%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:12]([CH3:13])[C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:18]([O:20][C:21](=[O:28])[C@H:22]1[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]1)[CH3:19].C(=O)([O-])[O-].[Cs+].[Cs+].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>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[CH2:18]([O:20][C:21]([C@H:22]1[CH2:27][CH2:26][CH2:25][N:24]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:12]([CH3:13])[C:11]4[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=4[N:9]=3)[CH:3]=2)[CH2:23]1)=[O:28])[CH3:19]
Reactant: CCOC(=O)[C@H]1CCCNC1
Reactant: Cn1c(-c2cccc(Br)c2)nc2ccccc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@H]1CCCN(c2cccc(-c3nc4ccccc4n3C)c2)C1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 69.7 %

Procedure:
Method 1—Step c 2-(3-Bromo-phenyl)-1-methyl-1H-benzoimidazole (0.85 g, 2.96 mmol), (S)-(+)-Nipecotic acid ethyl ester (0.60 g, 3.85 mmol) and cesium carbonate (4.82 g, 14.80 mmol) were placed into a dry Schlenk tube under nitrogen. At the same time palladium acetate (0.14 g, 0.60 mmol), and rac-2,2′bis(diphenylphosphino)-1,1′-binaphtyl (BINAP) (0.57 g, 0.90 mmol) were placed into a dry 7 mL vial under nitrogen. Then dry toluene (5 mL) was added and the mixture was stirred 20 minutes under nitrogen before being added to the first flask. The reaction mixture was heated at 80° C. overnight, cooled to room temperature, filtered off, and the insoluble material was washed with EtOAC (3×10 mL). The organic solution was concentrated under reduced pressure and crude was purified by flash chromatography (eluent: cyclohexane:AcOEt gradient from 100% of cyclohexane to cyclohexane 4:AcOEt 1) to afford 0.75 g of the title compound (70%).