Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[NH:4][C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([Br:12])=[CH:7][C:6]=1I.[CH3:15][Si:16]([CH3:27])([O:23][CH2:24][C:25]#[CH:26])[C:17]([CH3:22])([CH3:21])[CH:18]([CH3:20])[CH3:19]>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:14])[NH:4][C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([Br:12])=[CH:7][C:6]=1[C:26]#[C:25][CH2:24][O:23][Si:16]([CH3:27])([CH3:15])[C:17]([CH3:22])([CH3:21])[CH:18]([CH3:20])[CH3:19]
Reactant: COC(=O)Nc1cc(C)c(Br)cc1I
Reactant: C#CCO[Si](C)(C)C(C)(C)C(C)C
Solvent: CCN(CC)CC
Product: COC(=O)Nc1cc(C)c(Br)cc1C#CCO[Si](C)(C)C(C)(C)C(C)C
Yield: 43.6 %

Procedure:
To a solution of 3.70 g (4-bromo-2-iodo-5-methyl-phenyl)-carbamic acid methyl ester and 0.070 g bis-triphenylphosphine palladium dichloride and 0.038 g cuprous iodide in 25 ml triethylamine was added 2.38 g dimethyl (2-propynyloxy)(1,1,2-trimethylpropyl)-silane and the mixture was heated 2 h at reflux. The reaction mixture was partitioned between water and ethyl acetate. The phases were separated and the organic phase was washed with 1N hydrochloric acid, sodium bicarbonate and brine, dried with magnesium sulfate and purified by chromatography on silica gel with hexane:ethyl acetate=4:1 to yield 1.92 g (4-bromo-2-{3-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxy]-prop-1-ynyl}-5-methyl-phenyl)-carbamic acid methyl ester as a light brown oil. MS: M+NH4+=457.0 M+Na+=462.2
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([N:14]([CH3:16])[CH3:15])[CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7].C(OP(OCC)OCC)C.C[O-].[Na+].[CH3:30][O:31][CH2:32][O:33][C:34]1[C:41]([CH3:42])=[CH:40][C:37]([CH:38]=O)=[CH:36][C:35]=1[CH3:43]>CCOC(C)=O.CCO.CN(C=O)C>[CH3:15][N:14]([CH3:16])[C:12]1[CH:11]=[C:5]([CH:4]=[C:3](/[CH:2]=[CH:38]/[C:37]2[CH:40]=[C:41]([CH3:42])[C:34]([O:33][CH2:32][O:31][CH3:30])=[C:35]([CH3:43])[CH:36]=2)[CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: COCOc1c(C)cc(C=O)cc1C
Reactant: CCOC(=O)c1cc(CCl)cc(N(C)C)c1
Agent: CCOP(OCC)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(/C=C/c2cc(C)c(OCOC)c(C)c2)cc(N(C)C)c1
Temperature: 0 °C
Reaction time: 18 h
Yield: 67.1 %

Procedure:
Compound 3 (1.224 g, 4.277 mmol) and triethylphosphite (1.512 mL, 8.555 mmol) were heated to 150° C. for 3 hours. The reaction mixture was cooled to 0° C. and then 6 mL of DMF and 6 mL of EtOH were added. NaOMe (486 mg, 8.554 mmol) and 4-(methoxymethoxy)-3,5-dimethylbenzaldehyde (0.831 g, 4.277 mmol) were added to the solution. After 18 hours, the mixture was diluted with EtOAc and the solution was washed with brine. After drying on Na2SO4, the organic layer was filtered and concentrated under reduced pressure. The residue was subjected to chromatography over silica gel (Hexanes/EtOAc=9/1) to give Compound 4 (1.10 g, 67%). 1H-NMR (500 MHz, CDCl3) δ 7.56 (s, 1H), 7.30 (m, 1H), 7.20 (s, 2H), 7.06 (d, J=16.3 Hz, 1H), 6.99 (d, J=16.3 Hz, 1H), 6.97 (s, 1H), 4.96 (s, 2H), 4.39 (q, J=7.1 Hz, 2H), 3.62 (s, 3H), 3.03 (s, 6H), 2.32 (s, 6H), 1.42 (t, J=7.1 Hz, 3H); 13C-NMR (125 MHz, CDCl3) δ 167.23, 154.65, 150.72, 138.36, 133.12, 131.48, 131.24, 128.70, 127.78, 127.07, 115.70, 114.53, 112.47, 99.11, 60.92, 57.39, 40.65, 16.99, 14.40; ESI-MS: m/z (MH+): 384.2169 (calc'd), 384.2173 (found).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.Cl.[CH:13]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:13]([N:16]1[CH2:21][CH2:20][N:19]([C:2]2[S:3][C:4]3[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:5]=3[N:6]=2)[CH2:18][CH2:17]1)([CH3:15])[CH3:14]
Reactant: CC(C)N1CCNCC1
Reactant: Oc1ccc2nc(Br)sc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)N1CCN(c2nc3ccc(O)cc3s2)CC1
Temperature: 100 °C
Reaction time: 18 h
Yield: 18 %

Procedure:
2-Bromo-6-hydroxybenzothiazole (345 mg, 1.5 mmol), 1-isopropyl-piperazine hydrochloride (271 mg, 1.65 mmol) and dry potassium carbonate (828 mg, 6.00 mmol), were dissolved in 6 mL, of dry N,N-dimethylformamide. The resulted pale brown solution was stirred at 100° C. for 18 h in a closed vial. The reaction mixture was evaporated, suspended in 20 mL of water and extracted with dichloromethane (3×15 mL). The combined organic layers were washed with saturated sodium bicarbonate and brine, then dried over MgSO4. After evaporation the residue was purified by column chromatography (Kieselgel 60) using chloroform-methanol 49:1 as the eluent. The title compound (76 mg, 0.27 mmol, 18%) was obtained as a white solid.
Reaction SMILES: [CH2:1]1[C:6]2([C:15](=[O:16])[NH:14][C:8]3([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:17]1([N:27]=[C:28]=[O:29])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1.N12CCN(CC1)CC2>C1(C)C=CC=CC=1>[C:17]1([NH:27][C:28]([N:14]2[C:15](=[O:16])[C:6]3([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5]3)[NH:7][C:8]32[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)=[O:29])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: O=C1NC2(CCCCC2)NC12CCCCC2
Reactant: O=C=Nc1cccc2ccccc12
Agent: C1CN2CCN1CC2
Solvent: Cc1ccccc1
Product: O=C(Nc1cccc2ccccc12)N1C(=O)C2(CCCCC2)NC12CCCCC2

Procedure:
11.1 Parts of 7,14-diazadispiro[5.1.5.2]pentadecan-15-one, 8.50 parts of 1-naphthyl isocyanate and a trace of 1,4-diazabicyclo[2.2.2]octane in 125 parts of dry toluene were heated at reflux for 24 hours. After removal of the toluene by distillation under reduced pressure the residue was twice recrystallised from benzene to give 7.0 parts of 14-naphthylcarbamoyl-7,14-diazadispiro[5.1.5.2]pentadecan-15-one having a melting point of 157° to 160°C and the following elemental analysis by weight:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1F)[O:8][CH:7]([C:13]([F:16])([F:15])[F:14])[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5]2.[CH2:22]([NH2:25])[CH2:23][CH3:24].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[NH:25][CH2:22][CH2:23][CH3:24])[O:8][CH:7]([C:13]([F:16])([F:15])[F:14])[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5]2
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Reactant: CCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCNc1cc2c(cc1Cl)C=C(C(=O)OCC)C(C(F)(F)F)O2
Temperature: 90 °C
Yield: 78.5 %

Procedure:
A mixture of ethyl 6-chloro-7-fluoro-2-(trifluoromethyl)-2H-chromene-3-carboxylate (Example 7a, Step 2) (0.5 g, 1.54 mmole) and propylamine (0.13 mL, 1.54 mmole) was dissolved in anhydrous DMF (5 mL), which was warmed to 90° C. and treated with K2CO3 (0.25 g, 1.84 mmole). The mixture was maintained at 90° C. for 24 hrs, cooled to room temperature, filtered through celite and condensed to a viscous oil. The oil was purified by flash chromatography (silica gel) with 40% methylene chloride in hexane to give a light yellow oil (0.44 g, 79%): GCMS m/z 363.00 (M+). 1H NMR (CDCl3/400 MHz) 7.57 (s, 1H), 7.08 (s, 1H), 6.23 (s, 1H), 5.63 (q, 1H, J=7.0 Hz), 4.73 (brs, 1H), 4.26 (m, 2H), 3.14 (m, 2H), 1.66 (m, 2H), 1.31 (m, 3H), 1.01 (m, 3H).
Reaction SMILES: BrC1C=CC([N:8]2[C:12]3[N:13]=[C:14]([N:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)[N:15]=[C:16]([C:17]4[CH:18]=[N:19][C:20]([N:23]([CH2:33][C:34]5[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=5)[CH2:24][C:25]5[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=5)=[N:21][CH:22]=4)[C:11]=3[CH2:10][CH2:9]2)=NC=1.FC1N=CC(N2C3N=C(N4CCOCC4)N=C(C4C=NC(N(CC5C=CC(OC)=CC=5)CC5C=CC(OC)=CC=5)=NC=4)C=3CC2)=CC=1>FC1C=CC(Br)=CN=1>[CH3:41][O:40][C:37]1[CH:36]=[CH:35][C:34]([CH2:33][N:23]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)[C:20]2[N:21]=[CH:22][C:17]([C:16]3[C:11]4[CH2:10][CH2:9][NH:8][C:12]=4[N:13]=[C:14]([N:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)[N:15]=3)=[CH:18][N:19]=2)=[CH:39][CH:38]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(Br)cn3)cn2)cc1
Agent: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(F)nc3)cn2)cc1
Agent: Fc1ccc(Br)cn1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1

Procedure:
From bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (81 mg) and 2-fluoro-5-bromopyridine (30 μl), in the same manner as Step B in Example 1-D-25, crude products of {5-[7-(5-bromo-pyridin-2-yl)-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]-pyrimidin-2-yl}-bis-(4-methoxy-benzyl)-amine and {5-[7-(6-fluoro-pyridin-3-yl)-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]-pyrimidin-2-yl}-bis-(4-methoxy-benzyl)-amine were obtained, and then for each products the PMB groups were removed according to Deprotection method 3, to obtain the desired compound (D-36) as a colorless powder (5 mg, 32%) and as a colorless powder (D-37: 7 mg, 63%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C=O)C.C(Cl)(=O)C(Cl)=O.[NH:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[C:31]1[Zn]>C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([C:32]2[C:33]3[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=3)[NH:30][CH:31]=2)=[O:16])=[CH:17][CH:18]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: [Zn]c1cc2ccccc2[nH]1
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1ccc(C(=O)c2c[nH]c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.8 %

Procedure:
To a 0° C. solution of 4-(N-tert-butoxycarbonylaminomethyl)benzoic acid (5.07 g, 20.2 mmol) in CHCl3 was added DMF (200 μL) and oxalyl chloride (1.94 mL, 22.2 mmol). The cold bath was removed and the reaction mixture was stirred for 2 hours at ambient temperature, after which it was concentrated in vacuo. The residue was taken up in CH2Cl2 and added to a solution of indolylzinc (50.5 mmol, prepared as described in Example 1, step 4, except substituting indole for 6-(4-fluorophenyl)indole). The reaction mixture was stirred for 16 hours at ambient temperature, then quenched with saturated aqueous NH4Cl and partitioned between CH2Cl2 and saturated aqueous NH4Cl. The solids were filtered off and rinsed with CH2Cl2. The layers were separated and the organic phase was dried over MgSO4, filtered, and concentrated in vacuo. Pure 3-[4-(N-tert-butoxycarbonylaminomethyl)benzoyl]indole (3.10 g) was obtained by chromatography on silica gel (60% ether/hexanes, then 60% ethyl acetate/hexanes).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][NH:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH:21][C:22]2[N:27]=[C:26]([CH3:28])[CH:25]=[C:24]([CH3:29])[N:23]=2)(=[O:20])=[O:19])=[CH:14][CH:13]=1.[C:30](Cl)(=[O:32])[CH3:31]>N1C=CC=CC=1.ClCCl>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([C:12]1[CH:17]=[CH:16][C:15]([S:18](=[O:20])(=[O:19])[NH:21][C:22]2[N:23]=[C:24]([CH3:29])[CH:25]=[C:26]([CH3:28])[N:27]=2)=[CH:14][CH:13]=1)[C:30](=[O:32])[CH3:31]
Reactant: Cc1cc(C)nc(NS(=O)(=O)c2ccc(NCc3nc4ccccc4[nH]3)cc2)n1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N(Cc1nc2ccccc2[nH]1)c1ccc(S(=O)(=O)Nc2nc(C)cc(C)n2)cc1
Yield: 30 %

Procedure:
18 mg (0.044 mmol) 4-[(1H-benzimidazol-2-ylmethyl)-amino]-N-(4,6-dimethylpyrimidin-2-yl)-benzenesulfonamide was dissolved in 2 ml of 15% pyridine in dichloromethane. Acetyl chloride (31 μl, 0.44 mmol) was diluted with 1 ml dichloromethane and solution was added to the reaction mixture. After three hours reaction mixture was washed with acidic water and organic layer was evaporated to dryness. Crystals were purified on silica using gradient elution (chloroform to 5% methanol in chloroform) to obtain white crystals with 30% yield. 1H NMR (DMSO-d6, 500 MHz): 7.97 (2H, m), 7.60 (2H, m), 7.48 (2H, m), 7.14 (2H, m), 6.68 (1H, s), 5.08 (2H, s), 2.18 (6H, s), 1.93 (3H, s); MS (ESI+): m/z 473 (M+Na)+, 451 (M+H)+.
Reaction SMILES: C([O-])=O.[NH4+].C([O:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([C:20]2[NH:29][C:28](=[O:30])[C:27]3[C:22](=[CH:23][C:24]([O:32][CH3:33])=[CH:25][C:26]=3[OH:31])[N:21]=2)=[CH:15][C:14]=1[CH3:34])C1C=CC=CC=1>CN(C=O)C.[C].[Pd]>[OH:31][C:26]1[CH:25]=[C:24]([O:32][CH3:33])[CH:23]=[C:22]2[C:27]=1[C:28](=[O:30])[NH:29][C:20]([C:16]1[CH:17]=[C:18]([CH3:19])[C:13]([OH:12])=[C:14]([CH3:34])[CH:15]=1)=[N:21]2
Reactant: COc1cc(O)c2c(=O)[nH]c(-c3cc(C)c(OCc4ccccc4)c(C)c3)nc2c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COc1cc(O)c2c(=O)[nH]c(-c3cc(C)c(O)c(C)c3)nc2c1
Temperature: 85 °C
Reaction time: 14 h
Yield: 73 %

Procedure:
A mixture of 2-(4-benzyloxy-3,5-dimethyl-phenyl)-5,7-dimethoxy-3H-quinazolin-4-one (1.2 g, 2.92 mmol) and magnesium bromide (0.644 g, 3.5 mmol) in pyridine (50 mL) was stirred at reflux for 12 h. The mixture was concentrated and the solid residue was made into slurry with HCl (2 N, 100 mL). The solid was collected by filtration, washed with water and hexanes to yield 2-(4-benzyloxy-3,5-dimethyl-phenyl)-5-hydroxy-7-methoxy-3H-quinazolin-4-one as a white solid (0.76 g, 65%). A solution of ammonium formate (0.945 g, 15 mmol) and 2-(4-benzyloxy-3,5-dimethyl-phenyl)-5-hydroxy-7-methoxy-3H-quinazolin-4-one (0.1 g, 0.25 mmol) in DMF (50 mL) was mixed with palladium carbon (0.1 g) and stirred at 85° C. for 14 h. The resulting suspension was cooled to room temperature, passed through a Celite pad, and washed with DCM. The filtrate was concentrated and the residue was diluted with water (20 mL). The resulting solid was collected by filtration and washed with hexanes to afford 5-hydroxy-2-(4-hydroxy-3,5-dimethylphenyl)-7-methoxyquinazolin-4(3H)-one (57 mg, 74%) as light yellow solid. Selected data: MS (ES) m/z: 312.94; MP 291.3-293° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:10]2[C:5](=[C:6]([NH2:11])[CH:7]=[CH:8][CH:9]=2)[C@H:4]([CH3:12])[CH2:3]1.C(N(CC)CC)C.[CH3:21][N:22]1[C:26]([CH3:27])=[C:25]([C:28](Cl)=[O:29])[C:24]([CH3:31])=[N:23]1>CN(C)C1C=CN=CC=1.C1COCC1>[CH3:1][C:2]1([CH3:13])[C:10]2[C:5](=[C:6]([NH:11][C:28]([C:25]3[C:24]([CH3:31])=[N:23][N:22]([CH3:21])[C:26]=3[CH3:27])=[O:29])[CH:7]=[CH:8][CH:9]=2)[C@H:4]([CH3:12])[CH2:3]1
Reactant: Cc1nn(C)c(C)c1C(=O)Cl
Reactant: C[C@@H]1CC(C)(C)c2cccc(N)c21
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1nn(C)c(C)c1C(=O)Nc1cccc2c1[C@H](C)CC2(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 63.8 %

Procedure:
Into a solution composed of 0.15 g of (R)-1,1,3-trimethyl-4-aminoindane (optical purity: 99% ee), 0.13 g of triethylamine, 5 mg of 4-dimethylaminopyridine and 1 mL of THF, a solution of 0.15 g of 1,3,5-trimethylpyrazole-4-carbonyl chloride in THF was dropped under ice cool. The mixture was stirred at room temperature for 15 minutes, then, to the reaction mixture was added ice water, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium hydrogen carbonate aqueous solution and saturated saline sequentially, then, dried over magnesium sulfate and concentrated under reduced pressure. The resultant residue was subjected to silica gel column chromatography to obtain 0.17 g of (R)-(−)-N-(1,1,3-trimethylindan-4-yl)-1,3,5-trimethylpyrazole-4-carboxamide (hereinafter, referred to as present carboxamide compound (3)) (optical purity: 99% ee).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1[CH2:9][CH:10]2[C:17](=O)[O:16][C:14](=[O:15])[CH:11]2[CH2:12][CH:13]=1.C(OCC)(=O)C.C(O)(C)C>O1CCCC1.O>[CH3:7][C:8]1[CH2:9][C@H:10]([CH2:17][OH:16])[C@H:11]([CH2:14][OH:15])[CH2:12][CH:13]=1
Reactant: CC1=CCC2C(=O)OC(=O)C2C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC1=CC[C@@H](CO)[C@@H](CO)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 300 ml of tetrahydrofuran at 0° C. was added 16.0 g (0.42 mol) lithium aluminum hydride portionwise keeping the reaction temperature between 0° C. and 5° C. A solution of 33.0 g (0.20 mol) of 4-methyl-4-cyclohexene-1,2dicarboxylic anhydride in 100 ml of tetrahydrofuran was added dropwise over 2 hours keeping the temperature between 0° C. and 10° C. The reaction mixture was warmed to ambient temperature and stirred for 2 hours. The reaction was cooled to 0° C. and 35 ml of ethyl acetate was added. dropwise, followed by dropwise addition of 35 ml isopropanol and 35 ml water. The reaction mixture was filtered through celite using acetone, dried with MgSO4, filtered, and concentrated to 33.0 g of oil. Flash chromatography in 3:1 hexanes-ethylacetate, followed by 1:1 hexanes-ethylacetate and finally ethylacetate alone yielded 18.2 g of oil. NMR (CDCl3): 5.35 (br s,1H), 3.68 (m,2H), 3.60 (m,2H), 3.10 (br s,2H), 2.05 (br s,6H), 1.64 (s,3H). IR (neat): 3500-3100, 1730w, 1440, 1010. MS (CI): 157 (M+I), 139,121.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][NH2:13])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.C[Si](C)(C)N[Si](C)(C)C.[O:23]1[CH:25]([CH2:26][O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH3:34])[CH2:24]1.[ClH:35].[OH-].[Na+]>CS(C)=O.O>[ClH:35].[ClH:35].[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([CH2:12][NH:13][CH2:24][CH:25]([OH:23])[CH2:26][O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])=[CH:10][CH:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Cc1ccccc1OCC1CO1
Reactant: NCc1ccc(-n2ccnc2)cc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccccc1OCC(O)CNCc1ccc(-n2ccnc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Dissolve 1.74 g (10.04 mmol) of 4-(1H-imidazol-1-yl)-benzenemethanamine in 20 mL of dry DMSO under nitrogen. Add 2.44 mL (11.55 mmol) of hexamethyldisilazane and stir at room temperature for 30 min. After this time, add a solution of 1.73 g (10.54 mmol) of 1,2-epoxy-3-(2-methylphenoxy)propane in 10 mL of DMSO and heat in an oil bath at 60° C. for 42 h. Follow the progress of the reaction by thin-layer chromatography on silica gel (acetonitrile: ammonia (aq), 90:10). At the completion of the reaction, add 6 N hydrochloric acid to pH=1 and then add 4 N sodium hydroxide to pH=12. Dilute this basic mixturewith 20 mL of water and extract with 3×75 mL of methylene chloride. Remove the solvent on the rotary evaporator. Purify this residue by flash chromatography using flash silica gel (Baker) and eluting with a solution of acetonitrile: ammonia hydroxide 98:2. Combine pure fractions and removethe solvent on the rotary evaporator. Dissolve this residue in 50 mL of acetonitrile and remove the solvent on the rotary evaporator. Dissolve this residue in 10 mL of methanol and bubble hydrogen chloride through thesolution until pH=1 is reached. Remove the solvent on the rotary evaporatorand recrystallize the solid from 20 mL of isopropanol to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[C:4]([N+:22]([O-])=O)[C:3]=1[O:25][CH3:26].O>C(O)(=O)C.[Fe]>[NH2:22][C:4]1[C:3]([O:25][CH3:26])=[C:2]([Cl:1])[CH:7]=[C:6]([F:8])[C:5]=1[N:9]1[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]1=[O:21]
Reactant: COc1c(Cl)cc(F)c(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: COc1c(Cl)cc(F)c(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c1N
Temperature: 25 °C
Reaction time: 6 h
Yield: 97.9 %

Procedure:
3-(4-Chloro-6-fluoro-3-methoxy-2-nitrophenyl)-1-methyl-6-trifluoromethyl-2,4(1H, 3H)-pyrimidinedione (7.5 g, 18.9 mmol) was dissolved in acetic acid (75 ml) and 4.2 g (75.6 mmol) of iron powder was added. The solution was stirred at ambient temperature under nitrogen atmosphere for 6 hr and water was added. Extraction was carried out with ethyl acetate. Organic layer was washed with water, brine, and dried with anhydrous sodium sulfate followed by evaporation to afford the title compound (6.8 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]3[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]2=3)[CH:5]=[CH:6][CH:7]=1.[CH3:23][C:24]1[CH:28]=[CH:27][S:26][C:25]=1B1OC(C)(C)C(C)(C)O1.C([O-])([O-])=O.[K+].[K+].O>COCCOC.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>[CH3:22][N:19]1[CH2:20][CH2:21][C:9]2[N:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([C:25]4[S:26][CH:27]=[CH:28][C:24]=4[CH3:23])[CH:3]=3)[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]=2[CH2:18]1
Reactant: Cc1ccc2c(c1)c1c(n2-c2cccc(Br)c2)CCN(C)C1
Reactant: Cc1ccsc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2-c2cccc(-c3sccc3C)c2)CCN(C)C1
Temperature: 90 °C
Reaction time: 0.75 h

Procedure:
To a de-aerated solution of 5-(3-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.281 mmol), 3-methylthiophene-2-boronic acid pinacol ester (125 mg, 0.557 mmol) and K2CO3 (120 mg, 0.845 mmol) in DME (4 mL)-water (2 mL) was added Pd(PPh3)4 (16 mg, 0.013 mmol). The reaction mixture was stirred at 90° C. for 45 min. The solvent was removed under reduced pressure, residue diluted with water (20 mL) and extracted with EtOAc (50 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to yield 2,8-dimethyl-5-(3-(3-methylthiophen-2-yl)phenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (TFA salt, CD3OD) δ (ppm): 7.52-7.71 (m, 2H), 7.42 (s, 1H), 7.4 (m, 2H), 7.35 (s, 1H), 7.18 (d, 1H), 7.04 (d, 1H), 6.97 (d, 1H), 4.7 (m, 1H), 4.4 (m, 1H), 3.82 (m, 1H), 3.58 (m, 1H), 3.2 (m, 4H), 3.0 (m, 1H), 2.42 (s, 3H), 2.38 (s, 3H).
Reaction SMILES: C1(CCN2C3C(=CC=CC=3)C(=O)C2=O)CC1.[C:17]1([CH:23]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26](=[O:33])[C:25]2=[O:34])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O1C2C=CC(O)=CC=2OC1.[F:51][C:52]([F:62])([F:61])[O:53][C:54]1[CH:55]=[C:56]([OH:60])[CH:57]=[CH:58][CH:59]=1>>[C:35]1([CH:23]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]([OH:33])([C:57]3[CH:58]=[CH:59][C:54]([O:53][C:52]([F:61])([F:62])[F:51])=[CH:55][C:56]=3[OH:60])[C:25]2=[O:34])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: Oc1cccc(OC(F)(F)F)c1
Reactant: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Agent: O=C1C(=O)N(CCC2CC2)c2ccccc21
Agent: Oc1ccc2c(c1)OCO2
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C1(O)c1ccc(OC(F)(F)F)cc1O

Procedure:
Following the procedure as described in PREPARATION 2B, and making non-critical variations to replace 1-(2-cyclopropylethyl)-1H-indole-2,3-dione with 1-(diphenylmethyl)-1H-indole-2,3-dione, and 1,3-benzodioxol-5-ol with 3-(trifluoromethoxy)phenol, the title compound was obtained (75%): MS (ES+) m/z 514.5 (M+23).