Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16]([NH:19][C:20]2[CH:21]=[C:22]3[C:31](=[CH:32][C:33]=2Br)[O:30][CH2:29][C:28]2[N:23]3[CH:24]([CH3:36])[C:25](=[O:35])[NH:26][N:27]=2)([CH3:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:37]([O-])([O-])=O.[K+].[K+].CB1OB(C)OB(C)O1>O.O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:1]([N:14]1[CH2:17][C:16]([NH:19][C:20]2[CH:21]=[C:22]3[C:31](=[CH:32][C:33]=2[CH3:37])[O:30][CH2:29][C:28]2[N:23]3[CH:24]([CH3:36])[C:25](=[O:35])[NH:26][N:27]=2)([CH3:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CC1C(=O)NN=C2COc3cc(Br)c(NC4(C)CN(C(c5ccccc5)c5ccccc5)C4)cc3N21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CB1OB(C)OB(C)O1
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc2c(cc1NC1(C)CN(C(c3ccccc3)c3ccccc3)C1)N1C(=NNC(=O)C1C)CO2
Temperature: 120 °C
Reaction time: 8 h
Yield: 56.7 %

Procedure:
A mixture of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.0598 g, 0.073 mmol), 6-(1-benzhydryl-3-methyl-azetidin-3-ylamino)-7-bromo-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (Example #79, Step B, 0.20 g, 0.366 mmol), K2CO3 (0.152 g, 1.098 mmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (0.138 g, 1.098 mmol) in water (1 mL) and dioxane (6 mL) was stirred at 120° C. overnight. The reaction mixture was cooled to ambient temperature and the solvent was removed in vacuo. The residue was purified by preparative HPLC (Table 3, Method 13) to give 6-(1-benzhydryl-3-methyl-azetidin-3-ylamino)-4,7-dimethyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (0.10 g, 56%). LC/MS (Table 1, Method 2) Rt=0.959 min; MS m/z: 482 [M+H]+.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:7]([N:31]2[CH2:43][CH2:42][N:34]3[C:35]4[CH2:36][CH2:37][CH2:38][CH2:39][C:40]=4[CH:41]=[C:33]3[C:32]2=[O:44])=[N:8][CH:9]=[CH:10][C:11]=1C1C=C(NC2C=C3CN(C)CCN3N=2)C(=O)N(C)C=1)(=[O:3])[CH3:2].Br[C:46]1[CH:47]=[C:48]([NH:54][C:55]2[CH:60]=[CH:59][C:58]([N:61]3[CH2:66][C@@H:65]([CH3:67])[N:64]([CH:68]4[CH2:71][O:70][CH2:69]4)[CH2:63][C@@H:62]3[CH3:72])=[CH:57][N:56]=2)[C:49](=[O:53])[N:50]([CH3:52])[CH:51]=1.C(OCC1C(N2CCN3C4CCCCC=4C=C3C2=O)=NC=CC=1B1OC(C)(C)C(C)(C)O1)(=O)C>>[C:1]([O:4][CH2:5][C:6]1[C:7]([N:31]2[CH2:43][CH2:42][N:34]3[C:35]4[CH2:36][CH2:37][CH2:38][CH2:39][C:40]=4[CH:41]=[C:33]3[C:32]2=[O:44])=[N:8][CH:9]=[CH:10][C:11]=1[C:46]1[CH:47]=[C:48]([NH:54][C:55]2[CH:60]=[CH:59][C:58]([N:61]3[CH2:66][C@@H:65]([CH3:67])[N:64]([CH:68]4[CH2:71][O:70][CH2:69]4)[CH2:63][C@@H:62]3[CH3:72])=[CH:57][N:56]=2)[C:49](=[O:53])[N:50]([CH3:52])[CH:51]=1)(=[O:3])[CH3:2]
Reactant: C[C@@H]1CN(c2ccc(Nc3cc(Br)cn(C)c3=O)nc2)[C@@H](C)CN1C1COC1
Reactant: CC(=O)OCc1c(-c2cc(Nc3cc4n(n3)CCN(C)C4)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(N4C[C@@H](C)N(C5COC5)C[C@@H]4C)cn3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Yield: 41 %

Procedure:
Following the procedures as described for compound 113j, reaction of 122e (723 mg, 1.62 mmol) and 3-(acetoxymethyl)-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)pyridin-4-ylboronic acid 113i (613 mg, 1.62 mmol) afforded 122f as a yellow solid (464 mg, 41%). LCMS: [M+H]+ 707
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:20])[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=1[NH:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)(=[O:12])=[O:11].[C:21](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(=O)CC>[CH3:21][O:20][C:3]1[C:2](=[O:1])[C:8]([NH:9][S:10]([C:13]2[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=2)(=[O:12])=[O:11])=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(S(=O)(=O)Nc2ccccc(=O)c2O)cc1
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CCC(C)=O
Product: COc1ccccc(NS(=O)(=O)c2ccc(C)cc2)c1=O

Procedure:
A mixture of 2-hydroxy-3-[N-[(4-methylphenyl)sulfonyl]-amino]-2,4,6-cycloheptatrien-1-one (14.5 g), potassium carbonate (12.5 g), dimethyl sulfate (12.5 g) and 2-butanone (145 ml) is heated at reflux for 1 hour. The mixture is filtered and the precipitate is washed with water and suspended in ethyl actate. Hydrochloric acid (10%) is added until the solution is acidic. The organic phase is collected and dried over sodium sulfate. Evaporation of the solvent and crystallization of the residue from ethyl acetate-hexane gives 2-methoxy-7-[N-[(4-methylphenyl)sulfonyl]amino]-2,4,6-cycloheptatrien-1-one, mp 163°-164° C. The above filtrate is evaporated and the residue is subjected to chromatography on silica gel using ethyl acetate-hexane (3:1). Evaporation of the eluates are crystallization of the residue from ethyl acetate gives 2-methoxy-3-[N-[(4-methylphenyl)sulfonyl]-N-methylamino]-2,4,6-cycloheptatrien-1-one, mp 101°-102° C and 2-methoxy-7-[N-[(4-methylphenyl)sulfonyl]-N-methylamino]-2,4,6-cycloheptatrien-1-one, mp 94.5° C.
Reaction SMILES: C(=CC(=O)C)C1C=CC=CC=1.[CH:12](=[CH:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:21])C1C=CC=CC=1>>[C:20]([CH:19]=[CH2:12])(=[O:21])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(C=Cc1ccccc1)c1ccccc1
Agent: CC(=O)C=Cc1ccccc1
Product: C=CC(=O)c1ccccc1

Procedure:
Benzalacetone and benzalacetophenone
Reaction SMILES: [OH:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[CH:10]1([NH2:13])[CH2:12][CH2:11]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C.[OH-].[Na+]>ClCCCl>[CH:10]1([NH:13][CH:5]2[CH2:6][CH2:7][C:2]([CH3:9])([OH:1])[CH2:3][CH2:4]2)[CH2:12][CH2:11]1
Reactant: CC1(O)CCC(=O)CC1
Reactant: NC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC1(O)CCC(NC2CC2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 71.8 %

Procedure:
4-Hydroxy-4-methylcyclohexanone (440 mg, 3.43 mmol) was dissolved in 1,2-dichloroethane (15 ml), followed by sequential addition of cyclopropylamine (0.26 ml, 3.78 mmol), NaBH(OAc)3 (1.16 g, 5.49 mmol), and acetic acid (0.20 ml, 3.43 mmol), and then the resulting mixture was stirred at room temperature under nitrogen stream for 20 hours. The resulting reaction liquid was neutralized by addition of 10% aqueous NaOH solution, and extracted with 5% MeOH/MC (15 ml×4). The organic layer was dried over anhydrous sodium sulfate, followed by filtration, concentration, and vacuum drying, to obtain 417 mg of yellow solid (72%).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.Cl.[NH2:14][OH:15].O.[OH-].[Na+]>C(O)C.CCOCC>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[N:14][OH:15])=[CH:5][CH:4]=1
Reactant: NO
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CCOCC
Product: ON=Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.4 %

Procedure:
The first step of the process of the present invention was conducted as follows. At first, 8.79 g (50.5 mmol) of 4-trifluoromethylbenzaldehyde and 3.83 g (55.1 mmol) of hydroxylamine hydrochloride were dissolved in 12.5 ml of ethanol and 34 ml of water followed by the addition of 2.5 g of sodium hydroxide and stirring for 1 hour at room temperature. After adding ether and washing with dilute hydrochloric acid, the reaction liquid was further washed with saturated brine followed by drying with mirabilite and concentrating to obtain 9.25 g (48.2 mmol) of 4-trifluoromethylbenzaldehyde oxime (yield: 95.5%).
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:6]=1[CH3:7].C([Mg]Br)C.Br[C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1>C1COCC1.[Cl-].[Zn+2].[Cl-].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>[CH3:7][C:6]1[NH:5][CH:4]=[N:3][C:2]=1[C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1
Reactant: Brc1cccnc1
Reactant: Cc1c(I)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC[Mg]Br
Agent: [Cl-]
Solvent: C1CCOC1
Product: Cc1[nH]cnc1-c1cccnc1
Reaction time: 1.5 h
Yield: 92 %

Procedure:
To a solution of 4-Iodo-5-methyl-1-trityl-1H-imidazole (1 eq) in THF at room temperature was added ethylmagnesium bromide (1.2 eq) under dry conditions. After stirring for 90 minutes, zinc chloride (1.2 eq) was added to the reaction mixture. After stirring for another 90 minutes, tetrakis(triphenylphosphine)palladium (10%) and 3-bromopyridine (1.2 eq) were added to the reaction mixture. Subsequent reaction conditions were performed as in Example 73 to give 3-(5-methyl-1H-imidazol-4-yl)-pyridine (92%). MH+(160).
Reaction SMILES: [O:1]1[C@H:3]([CH3:4])[CH2:2]1.[CH2:5]([Mg]Br)[CH2:6][CH2:7][CH:8]=[CH2:9]>C1COCC1>[CH3:4][C@@H:3]([OH:1])[CH2:2][CH2:9][CH2:8][CH2:7][CH:6]=[CH2:5]
Reactant: C=CCCC[Mg]Br
Reactant: C[C@@H]1CO1
Solvent: C1CCOC1
Product: C=CCCCC[C@@H](C)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 63.4 %

Procedure:
(R)-(+)-1,2-epoxypropane (1.12 ml, 16.0 mmol) is dissolved in dry THF (23 ml) and CuBr (230 mg, 1.6 mmol) is added therein, after which the temperature is reduced −78° C. The 1M 4-pentenylmagnesium bromide solution (23 ml, 23.5 mmol) prepared in the reaction (1) is added to reaction mixture. The temperature is gradually increased to a room temperature and the mixture is stirred for 4 hours. The reaction is finished with saturated NH4 Cl solution (10 ml). An obtained product is extracted with Et2O (20 ml×2) and it is washed by water (10 ml). An organic layer is dried using anhydrous MgSO4. The solution is vacuum concentrated, and then the compound (III) (1.3 g, 65%) is isolated using flash column chromatography (Et2O/n-pentene, 5:1, v/v):
Reaction SMILES: [CH3:1][NH2:2].Cl[CH2:4][C:5]1[N:6]=[C:7]([CH:10]([CH3:12])[CH3:11])[O:8][CH:9]=1>O1CCOCC1.O>[CH:10]([C:7]1[O:8][CH:9]=[C:5]([CH2:4][NH:2][CH3:1])[N:6]=1)([CH3:12])[CH3:11]
Reactant: CN
Reactant: CC(C)c1nc(CCl)co1
Solvent: O
Solvent: C1COCCO1
Product: CNCc1coc(C(C)C)n1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 71 %

Procedure:
To 40% aqueous methylamine (100 mL) was added dropwise a suspension of 4-chloromethyl-2-isopropyloxazole (4.20 g, 0.0263 mol) in p-dioxane/H2O (1:1 (v/v), 20 mL) over a 25 min period. After stirring for 45 min at ambient temperature, the volume was reduced to ca. 50 mL by rotary evaporation in vacuo, and NaCl was added. The aqueous was extracted with CHCl3 (4×100 mL), and the combined extract was dried over Na2SO4 and concentrated in vacuo. The resulting brown liquid was chromatographed on a 200 g SiO2 flash column with 2% /PrNH2 /CH2Cl2 followed by a gradient of /PrNH2 /MeOH/CH2Cl2 (0.5:2:97.5, 0.5:4:95.5). Concentration in vacuo of the product-containing fractions afforded the desired compound as a golden oil (2.89 g, 0.0187 mol, 71%): 1H NMR (CDCl3) δ 1.33 (d, J=6.9 Hz, 6H), 2.46 (s, 3H), 2.99-3.14 (m, 1H), 3.64 (s, 2H), 7.42 (s, 1H). Mass spectrum: (M+H)+ =155, (M+NH4)+ =172.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1B(O)O.C(=O)(O)[O-].[Na+].[C:14]([O:17][C:18]1[CH:42]=[CH:41][C:40](Br)=[CH:39][C:19]=1[C:20]([NH:22][C:23]1[CH:32]=[C:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:30]=[CH:29][C:24]=1[C:25]([O:27][CH3:28])=[O:26])=[O:21])(=[O:16])[CH3:15]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C.O.COCCOC>[C:14]([O:17][C:18]1[CH:42]=[CH:41][C:40]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[CH:39][C:19]=1[C:20]([NH:22][C:23]1[CH:32]=[C:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:30]=[CH:29][C:24]=1[C:25]([O:27][CH3:28])=[O:26])=[O:21])(=[O:16])[CH3:15]
Reactant: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(Br)ccc1OC(C)=O
Reactant: OB(O)c1ccco1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(-c2ccco2)ccc1OC(C)=O
Temperature: 25 °C
Yield: 53.6 %

Procedure:
Water (0.42 mL), 2-furanboronic acid (0.040 g), sodium bicarbonate (0.060 g), and bis(triphenylphosphine)palladium(II) dichloride (4 mg) were added to an ethylene glycol dimethyl ether (1.4 mL) suspension of methyl 2-(2-acetoxy-5-bromobenzamido)-4-phenylbenzoate (0.14 g), followed by heating to reflux under a nitrogen atmosphere for 1 hour and 10 minutes. The reaction mixture was cooled to room temperature, and water and ethyl acetate were added thereto. The insoluble substance was removed by filtration. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 95-70% hexane/ethyl acetate] and further purified by silica gel column chromatography [eluent: 90-70% hexane/ethyl acetate] to obtain 0.073 g of methyl 2-(2-acetoxy-5-(furan-2-yl)benzamido)-4-phenylbenzoate.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]([CH3:13])[C:7](=[O:12])[NH:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.[CH3:16]CN(C(C)C)C(C)C.CI>CN(C=O)C.O>[Br:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]([CH3:13])[C:7](=[O:12])[N:8]([CH3:16])[S:9](=[O:10])(=[O:11])[C:4]=2[CH:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CN1C(=O)NS(=O)(=O)c2cc(Br)ccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: CN1C(=O)N(C)S(=O)(=O)c2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 7-bromo-4-methyl-2H-benzo[e][1,2,4]thiadiazin-3(4H)-one 1,1-dioxide (262 mg, 0.902 mmol), in DMF (3 mL), DIEA (233 μL, 1.35 mmol) was added. The resulting mixture was stirred at rt for 10 min and MeI (56.0 μL, 0.902) was added. The reaction mixture was stirred at rt overnight and diluted with 20 mL of water. The solid formed was collected by suction filtration and washed with water (2×20 mL) to obtain compound 41a. Mass Spectrum (LCMS, ESI pos.) Calcd. For C9H9BrN2O3S: 304.9 (M+H). Found 305.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH3:15])=[N:8][C:7]([OH:16])=[CH:6]2.[OH-].[K+].Br[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:22]=1>C1(C)C=CC=CC=1.O.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH3:15])=[N:8][C:7]([OH:16])=[C:6]2[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:22]=1
Reactant: COc1cc2cc(O)nc(C)c2cc1OC
Reactant: BrCc1cccc(Oc2ccccc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc2c(C)nc(O)c(Cc3cccc(Oc4ccccc4)c3)c2cc1OC
Temperature: 130 °C
Reaction time: 0.75 h

Procedure:
To a solution of 6,7-dimethoxy-1-methylisoquinolin-3-ol CCH 18060 (152 mg, 693 μmol) in toluene (15 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added a 2 N aq. KOH solution (0.38 mL, 0.76 mmol) at RT followed by 1-(bromomethyl)-3-phenoxybenzene (191 mg, 726 μmol) and the mixture was stirred at 130° C. for 45 min under microwave irradiation. After cooling to RT, the mixture was diluted with H2O (10 mL) before extraction with EtOAc (50 mL). The organic phase was isolated and the aqueous phase was further extracted with CH2Cl2 (50 mL). Both organic phases were washed with brine (10 mL), combined, dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 95:3) gave 28 mg of 6,7-dimethoxy-1-methyl-4-(3-phenoxybenzyl)isoquinolin-3-ol. This free base was dissolved in MeOH (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.09 M HCl solution in MeOH (2 mL). The reaction mixture was stirred for 5 min at RT and concentrated at 40° C. under vacuum to afford 6,7-dimethoxy-1-methyl-4-(3-phenoxybenzyl)isoquinolin-3-ol hydrochloride 4 as a brown solid (31 mg, 10% yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]([C:13]#[N:14])=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2]>C1C=CC=CC=1.[Pd]>[CH2:1]([O:3][C:4](=[O:15])[CH:5]([C:13]#[N:14])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(C#N)=Cc1ccccc1
Agent: [Pd]
Solvent: c1ccccc1
Product: CCOC(=O)C(C#N)Cc1ccccc1
Yield: 92.5 %

Procedure:
A solution of 4.56 g of the ester obtained in 30 ml of benzene was hydrogenated over 0.45 g of a 10% palladium/charcoal under a hydrogen atmosphere at room temperature for 4 hours. After filtration of the catalyst, the reaction mixture was concentrated under reduced pressure to obtain 4.26 g of 2-cyano-3-phenylpropionic acid ethyl ester as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=CNN=1.CO[C:9]([C:11]1[S:12][C:13]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:14][CH:15]=1)=[O:10]>>[C:16]([C:13]1[S:12][C:11]([C:9](=[O:10])[CH2:6][C:2]#[N:1])=[CH:15][CH:14]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: COC(=O)c1ccc(C(C)(C)C)s1
Reactant: Nc1cc[nH]n1
Product: CC(C)(C)c1ccc(C(=O)CC#N)s1
Yield: 86 %

Procedure:
The product was prepared according to the general procedure for aminopyrazole synthesis (route A1) from 5-tert-Butyl-thiophene-2-carboxylic acid methyl ester (3.0 g, 15.0 mmol, 1.0 eq). The crude product was extracted with DCM and used in the following step without further purification (2.7 g, yield: 86%).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[N:14]=[C:13](Cl)[C:12]([C:16](=O)[CH2:17][CH:18]2[CH2:22][O:21][C:20]([CH3:24])([CH3:23])[O:19]2)=[C:11]([Cl:26])[N:10]=1.Cl.[CH3:28][O:29][C:30]1[CH:38]=[CH:37][C:33]([CH2:34][NH:35][NH2:36])=[CH:32][CH:31]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl>[Cl:26][C:11]1[N:10]=[C:9]([NH2:8])[N:14]=[C:13]2[N:35]([CH2:34][C:33]3[CH:37]=[CH:38][C:30]([O:29][CH3:28])=[CH:31][CH:32]=3)[N:36]=[C:16]([CH2:17][CH:18]3[CH2:22][O:21][C:20]([CH3:24])([CH3:23])[O:19]3)[C:12]=12
Reactant: CC1(C)OCC(CC(=O)c2c(Cl)nc(N)nc2Cl)O1
Reactant: COc1ccc(CNN)cc1
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(Cn2nc(CC3COC(C)(C)O3)c3c(Cl)nc(N)nc32)cc1
Reaction time: 17 h
Yield: 91.4 %

Procedure:
Triethylamine (83.68 ml) was added to a mixture composed of the above 1-(2-amino-4,6-dichloropyrimidin-5-yl)-2-(2,2-dimethyl-[1,3]dioxolan-4-yl)ethan-1-one (61.23 g), (4-methoxybenzyl)-hydrazine hydrochloride (41.50 g) produced by the method described in U.S. Patent No. US2003/18197, and dichloromethane (600 ml) over 30 minutes under cooling in an ice bath. Thereafter, while the temperature of the reaction solution was gradually raised, it was stirred for 17 hours. Thereafter, a 10% citric acid aqueous solution was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and was then concentrated under reduced pressure. A 5% citric acid aqueous solution was added to the resulting residue, and the precipitate was then collected by filtration. The resultant was washed with water, so as to obtain the title compound (73.84 g) as a solid.
Reaction SMILES: C(C1C=C(C(C)C)C=C(C(C)C)C=1S(NN=[C:21]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:22][CH:23]([N:26]([CH3:28])[CH3:27])OC)(=O)=O)(C)C.[CH:35](=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[CH:36]1([CH:35]([OH:42])[C:21]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[CH:22][CH2:23][N:26]([CH3:27])[CH3:28])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: COC(CC(=NNS(=O)(=O)c1c(C(C)C)cc(C(C)C)cc1C(C)C)c1ccccc1)N(C)C
Reactant: O=Cc1ccccc1
Product: CN(C)CC=C(c1ccccc1)C(O)C1CCCCC1

Procedure:
By using a method similar to that described in Example 22, but starting from β-dimethylamino-3-methoxypropiophenone 2,4,6-triisopropylbenzenesulphonylhydrazone (21.7 g) and from benzaldehyde (5.4 cc), 4-dimethylamino-2-(3-methoxyphenyl)-1-phenyl-2-buten-1-ol (Z) hydrochloride (11.9 g) is obtained in the form of a white solid melting at 166° C. after recrystallisation from isopropanol (100 cc).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([CH2:12][NH:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].O1CCOCC1.[OH-].[Li+].Cl>O>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]([CH2:12][NH:13][C:14](=[O:19])[C:15]([CH3:17])([CH3:16])[CH3:18])=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1cc(CNC(=O)C(C)(C)C)ccc1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.7 %

Procedure:
Add methyl 2-chloro-5-[(2,2-dimethylpropanoylamino)methyl]benzoate (1.05 kg, 3.7 mol), 1,4-dioxane (5.25 L) and water (3.15 L) together and then add lithium hydroxide (407.8 g, 9.6 mol). Stir the resulting suspension at room temperature for one hour. Acidify the mixture to pH 1 with 5 N aqueous HCl in a dropwise fashion at a rate such that the internal temperature does not exceed 30° C. Concentrate the solution to remove approximately 6 L of solvent, and cool the resulting suspension to 10° C. Filter, wash the resulting solid material with water (8 L), and allow to dry on the sinter for 3 h. Collect the solid, and dry the material in a vacuum oven at 40° C. for 48 h to give the title compound as a free-flowing white solid (775 g, 77.7%). MS (m/z) (35Cl/37Cl) 270/272 (M+1).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:9][CH2:10][CH3:11])[C:5](=[NH:8])OC)[CH3:2].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH2:22][NH2:23])[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]>CO>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH2:22][NH:23][C:5](=[NH:8])[CH:4]([O:3][CH2:1][CH3:2])[O:9][CH2:10][CH3:11]
Reactant: COc1ccc(CN)cc1OC
Reactant: CCOC(OCC)C(=N)OC
Solvent: CO
Product: CCOC(OCC)C(=N)NCc1ccc(OC)c(OC)c1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A mixture of methyl 2,2-diethoxyacetimidate (294 mg, 1.824 mmol), (3,4-dimethoxyphenyl)methanamine (312 mg, 1.866 mmol), and MeOH (1.5 mL) was heated with stirring in an oil bath at 70° C. for 2 hrs and allowed to cool to room temperature. The volatile components were removed in vacuo. The residue was carried on without further purification. LCMS RT 0.96 min, MH+=297.2, 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 6.79-6.93 (3H, m), 4.94 (1H, s), 4.41 (2H, s), 3.84-3.90 (6H, m), 3.52-3.70 (4H, m), 1.19-1.28 (6H, m).
Reaction SMILES: [OH-].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][Si](C)(C)C)=[C:9]([C:19]#[C:20][Si](C)(C)C)[CH:8]=1)([CH3:6])([CH3:5])[CH3:4]>CO.CCCCCCC.C(OCC)(=O)C>[C:3]([C:7]1[CH:12]=[CH:11][C:10]([C:13]#[CH:14])=[C:9]([C:19]#[CH:20])[CH:8]=1)([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)c1ccc(C#C[Si](C)(C)C)c(C#C[Si](C)(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCCCCCC
Product: C#Cc1ccc(C(C)(C)C)cc1C#C
Reaction time: 0.5 h

Procedure:
Sodium hydroxide (1N) was added to the crude (4-tert-butyl-1,2-phenylene)bis(ethyne-2,1-diyl)bis(trimethylsilane) in methanol to remove the trimethylsilane groups. Stirring for 30 minutes resulted in the crude final product mixture. Column chromatography using heptane:ethyl acetate (99:1) as eluent provided the desired compound, 4-tert-butyl-1,2-diethynylbenzene, as a brown oil (1.08 g, 5.9 mmol). 1H-NMR (CDCl3) δ 1.30 (s, 9H) 3.28 (s, 1H) 3.30 (s, 1H) 7.33 (d, 1H) 7.43 (d, 1H) 7.51 (d, 1H)