Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N1C=CC=CC=1.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[N:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: OB(O)c1ccccc1
Reactant: O=Cc1c(Cl)[nH]c2ccccc12
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: O=Cc1c(Cl)n(-c2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 96 h
Yield: 61.9 %

Procedure:
A mixture of 2-chloro-1H-indole-3-carboxaldehyde (5.00 g, 27.8 mmol), phenylboronic acid (6.79 g, 55.6 mmol), cupric acetate (10.11 g, 55.7 mmol), pyridine (4.40 g, 55.7 mmol), triethylamine (5.63 g, 55.6 mmol), 4 Å molecular sieves (15.0 g) dichloromethane (300 mL) is stirred at room temperature for 4 d. The reaction mixture is filtered through a pad of Celite and the filtrate is washed with water, with 2N aq hydrochloric acid, with sat aq sodium bicarbonate, with brine, dried, filtered and concentrated. The residue is purified by chromatography eluting with dichloromethane. Product containing fractions are combined and concentrated to afford 2-chloro-1-phenyl-1H-indole-3-carboxaldehyde (4.40 g, 88% yield) as a yellow solid. NMR (CDCl3) 12.30 (1H, s), 8.37 (1H, d), 7.58-7.70 (3H, m), 7.43 (2H, d), 7.23-7.40 (2H, m), 7.10 (1H, d).
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18](=[O:41])[NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][NH:27][C:28]3[C:37]4[C:32](=[C:33]([C:38](=[O:40])[NH2:39])[CH:34]=[CH:35][CH:36]=4)[N:31]=[CH:30][N:29]=3)[CH:21]=2)[CH:13]=1)C)(C)(C)C.Cl>O1CCOCC1>[CH3:6][NH:7][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:15]=[CH:16][CH:17]=1)[C:18]([NH:19][C:20]1[CH:21]=[C:22]([CH:23]=[CH:24][CH:25]=1)[CH2:26][NH:27][C:28]1[C:37]2[C:32](=[C:33]([C:38]([NH2:39])=[O:40])[CH:34]=[CH:35][CH:36]=2)[N:31]=[CH:30][N:29]=1)=[O:41]
Reactant: CN(CCOc1cccc(C(=O)Nc2cccc(CNc3ncnc4c(C(N)=O)cccc34)c2)c1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CNCCOc1cccc(C(=O)Nc2cccc(CNc3ncnc4c(C(N)=O)cccc34)c2)c1
Reaction time: 8 h

Procedure:
12 mq (0.11 mmol [2-(3-{3-[(8-Carbamoyl-quinazolin-4-ylamino)-methyl]-phenylcarbamoyl}-phenoxy)-ethyl]-methyl-carbamic acid tert-butyl ester were dissolved in 2 ml dioxane and 88 μl 4 N HCl in dioxane were added. The mixture was stirred overnight, filtered and washed with dioxane.
Reaction SMILES: [CH3:1][C@@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[S:15](N)([NH2:18])(=[O:17])=[O:16]>O1CCOCC1>[NH2:18][S:15]([N:7]1[CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[CH2:3][C@@H:2]1[CH3:1])(=[O:17])=[O:16]
Reactant: NS(N)(=O)=O
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Solvent: C1COCCO1
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1S(N)(=O)=O
Temperature: 110 °C

Procedure:
To a solution of tert-butyl (3S)-3-methylpiperazine-1-carboxylate (0.5 g) in dioxane (40 ml) was added sulfamide (0.29 g) and the reaction was heated at 110° C. for 18 h. The reaction mixture was then partitioned between DCM (150 ml) and H2O (150 ml). The organics were separated and the aqueous layer was re-extracted with DCM (2×150 ml). Organics were combined, dried (MgSO4) and reduced in vacuo to give the subtitle compound as a pale yellow oil. Yield: 0.66 g
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=3)[C:18]([NH2:21])=[N:19][CH:20]=2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si:31]([O:38][C:39]1[CH:44]=[CH:43][C:42]([CH2:45][C:46](Cl)=[O:47])=[CH:41][CH:40]=1)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32].O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[Si:31]([O:38][C:39]1[CH:40]=[CH:41][C:42]([CH2:45][C:46]([NH:21][C:18]2[C:17]([C:22]3[CH:23]=[CH:24][C:25]([N+:28]([O-:30])=[O:29])=[CH:26][CH:27]=3)=[N:16][C:15]([C:12]3[CH:11]=[CH:10][C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2])=[CH:14][CH:13]=3)=[CH:20][N:19]=2)=[O:47])=[CH:43][CH:44]=1)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2cnc(N)c(-c3ccc([N+](=O)[O-])cc3)n2)cc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Nc2ncc(-c3ccc(O[Si](C)(C)C(C)(C)C)cc3)nc2-c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 50 °C
Reaction time: 20 h
Yield: 48.1 %

Procedure:
Under an argon atmosphere, to a mixture of 5-[4-(tert-butyldimethylsilyloxy)phenyl]-3-(4-nitrophenyl)pyrazin-2-amine (7o) (317 mg, 751 μmol) and 4-(dimethylamino)pyridine (15.3 mg, 125 μmol) dissolved in anhydrous pyridine (15 mL) was added 2-[4-(tert-butyldimethylsilyl oxy)phenyl]acetyl chloride (10) prepared above at 0° C. and the mixture was heated with stirring at 50° C. for 20 hours. After cooling to room temperature, to this was added water and the product was extracted with ethyl acetate (100 mL×3). The combined organic extract was washed successively with water (200 mL) and brine (200 mL), followed by drying over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by column chromatography (silica gel 50 g, n-hexane/ethyl acetate=2/1) to give Compound 11o (242 mg, 361 μmol, 48.1%) as a yellow solid. Rf=0.30 (n-hexane/ethyl acetate=2/1); 1H NMR (400 MHz, DMSO-d6) δ 0.15 (s, 6H), 0.20 (s, 6H), 0.92 (s, 9H), 0.93 (s, 9H), 3.44 (s, 2H), 6.67-6.74 (AA′BB′, 2H), 6.94-7.07 (2AA′BB′, 4H), 7.80-7.86 (AA′BB′, 2H), 8.01-8.12 (2AA′BB′, 4H), 9.05 (s, 1H), 10.85 (s, 1H); 13C NMR (67.8 MHz, DMSO-d6) δ −4.5 (2C), −4.6 (2C), 17.9, 18.0, 25.50 (3C), 25.51 (3C), 41.6, 119.4 (2C), 120.4 (2C), 123.2 (2C), 127.4, 128.2, 128.52 (2C), 128.54 (2C), 130.4 (2C), 138.7, 143.0, 144.5, 145.0, 146.9, 147.9, 153.9, 156.9, 168.9; IR (KBr, cm−1) 700, 741, 781, 839, 914, 1169, 1265, 1348, 1443, 1508, 1603, 1670, 2857, 2930, 2955.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[C:6]([C:9]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:10]=1[N:11]([CH3:14])[CH:12]=[O:13])(=[O:8])[CH3:7].O>ClCCl>[Cl:4][CH2:7][C:6]([C:9]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:10]=1[N:11]([CH3:14])[CH:12]=[O:13])=[O:8]
Reactant: O=S(=O)(Cl)Cl
Reactant: CC(=O)c1ccc(F)cc1N(C)C=O
Solvent: ClCCl
Solvent: O
Product: CN(C=O)c1cc(F)ccc1C(=O)CCl
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of sulphuryl chloride (20.6 ml) in dichloromethane (30 ml) was added dropwise over a period of 45 minutes to the solution of 2'-acetyl-5'-fluoro-N-methylformanilide whilst maintaining the temperature below 2° with ice/water cooling under a nitrogen atmosphere. The mixture was stirred for 3 hours maintaining the temperature below 2°. Water (80 ml) was added dropwise over 15 minutes maintaining the temperature below 10°. The dichloromethane layer was separated and dried over magnesium sulphate to give a solution of 2'-(2-chloroacetyl)-5'-fluoro-N-methylformanilide.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[CH:7]([NH:16][C:17]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][N:20]=[C:19]([N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])[N:18]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:39][N:40]([CH3:44])[C:41](Cl)=[O:42]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6](=[O:31])[CH:7]([NH:16][C:17]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][N:20]=[C:19]([N:26]([CH2:27][CH3:28])[CH2:29][CH3:30])[N:18]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:41](=[O:42])[N:40]([CH3:44])[CH3:39])=[CH:11][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C(=O)Cl
Reactant: CCN(CC)c1ncc([N+](=O)[O-])c(NC(Cc2ccc(O)cc2)C(=O)OC(C)(C)C)n1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(CC)c1ncc([N+](=O)[O-])c(NC(Cc2ccc(OC(=O)N(C)C)cc2)C(=O)OC(C)(C)C)n1
Yield: 99.5 %

Procedure:
To a solution of 2-(2-diethylamino-5-nitropyrimidin-4-ylamino)-3-(4-hydroxy-phenyl)propionic acid t-butyl ester (31.86 g, 0.074 mol) in CH2Cl2 (600 mL) was added DMAP (9.00 g, 0.074 mol). After 5 minutes triethylamine (10.23 mL, 0.074 mol) was added dropwise. N,N-dimethylcarbamyl chloride (13.83 mL, 0.110 mol) was added dropwise, and the reaction was heated to reflux overnight. The reaction mixture was concentrated in vacuo and taken up in EtOAc (1 L). The organic phase was washed with 0.5 M citric acid (3×250 mL), sat. NaHCO3 (3×250 mL), brine (1×250 mL), dried (MgSO4), filtered, and concentrated in vacuo to yield 37.0 g (99%) the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH:13]2[O:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)[CH2:7]1)=[O:5])[CH3:2].[Li+].[CH3:24]C([N-]C(C)C)C.CI>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1([CH3:24])[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH:13]2[O:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CC(C)[N-]C(C)C
Reactant: CCOC(=O)C1CCCN(CC2COc3ccccc3O2)C1
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=O)C1(C)CCCN(CC2COc3ccccc3O2)C1
Reaction time: 1 h

Procedure:
To a solution of 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)piperidine-3-carboxylic acid ethyl ester (10.05 g, 32.90 mmol) in dry THF (100 ml) at −78° C. was slowly added LDA (20.1 ml, 1.8 M). The reaction mixture was stirred at this temperature for 1 h. Methyl iodide (2.25 ml, 36.21 mmol) was then added, the cooling bath removed and stirring was continued for 10 h. After addition of water, the reaction mixture was extracted with EtOAc (3×25 ml). The combined organic phases were dried over Na2SO4, filtered and the filtrate was evaporated to give the title compound, which was purified by column chromatography (EtOAc/heptane, 70:30).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[NH:4][C:3]1=[O:13].Cl[CH2:16][CH2:17][S:18][CH3:19].[Na]>C(O)(C)C>[CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[N:4]([CH2:16][CH2:17][S:18][CH3:19])[C:3]1=[O:13]
Reactant: CSCCCl
Reactant: CC1(C)C(=O)NC(=O)c2ccccc21
Agent: [Na]
Solvent: CC(C)O
Product: CSCCN1C(=O)c2ccccc2C(C)(C)C1=O

Procedure:
5.7 gm of 4,4-dimethyl-2H,4H-isoquinoline-1,3-dione and 3.3 gm of 1-chloro-2-methylmercapto-ethane were added to a solution of 0.7 gm of sodium in 200 ml of isopropanol. After refluxing the mixture for 3 hours the solvent was removed in vacuo, and the residue was taken up in water and chloroform. The separated organic phase was worked up as described in Example 1. Yield: 7 gm (88.6% of theory).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[CH:5]2.C([O-])([O-])=O.[K+].[K+].[C:23]1(C)C=CC=C[CH:24]=1>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>[O:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH:11]1[N:7]1[C:8]2[C:4](=[CH:3][C:2]([CH:23]=[CH2:24])=[CH:10][CH:9]=2)[CH:5]=[N:6]1
Reactant: Cc1ccccc1
Reactant: Brc1ccc2c(cnn2C2CCCCO2)c1
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: O
Product: C=Cc1ccc2c(cnn2C2CCCCO2)c1
Temperature: 110 °C
Yield: 74 %

Procedure:
To a solution of 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (0.5 g, 1.778 mmol) in toluene (10 mL) and water (10 mL) were added K2CO3 (0.492 g, 3.56 mmol), trivinylboroxin pyridine complex (0.514 g, 2.134 mmol), and Tetrakis (0.206 g, 0.178 mmol). The reaction mixture was heated at 110° C. for 4 h. The reaction mixture was concentrated and the residue was extracted with ethyl acetate and washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated to give 1-(tetrahydro-2H-pyran-2-yl)-5-vinyl-1H-indazole (0.3 g, 74%). LCMS (ES-API), m/z 144 (M-THP).
Reaction SMILES: [CH2:1]([C:4]1[N:5]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24]CC)=O)[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3].[CH3:27][NH2:28]>>[CH3:27][NH:28][C:22](=[O:24])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][N:5]1[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=[C:4]1[CH2:1][CH2:2][CH3:3]
Reactant: CN
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCCCC(=O)OCC
Product: CCCc1nc2cnc3ccccc3c2n1CCCCCC(=O)NC
Temperature: 70 °C
Reaction time: 8 h

Procedure:
The method described in Part D of Example 3 was used to treat ethyl 6-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)hexanoate (5.0 g, 14 mmol) with methylamine (8 mL of a 40% solution). The reaction was complete after being stirred overnight at 70° C. Following the work-up procedure, 3.42 g of N-methyl-6-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)hexanamide were obtained.
Reaction SMILES: B(Cl)(Cl)[Cl:2].C1[O:26][C:25]2[CH:24]=[CH:23][C:9]([CH2:10][NH:11][C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([Cl:22])[CH:20]=4)[N:15]=[CH:14][N:13]=3)=[CH:8][C:7]=2[O:6]1.CO>C(Cl)Cl.C(Cl)(Cl)Cl>[ClH:2].[OH:6][C:7]1[CH:8]=[C:9]([CH:23]=[CH:24][C:25]=1[OH:26])[CH2:10][NH:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([Cl:22])[CH:20]=2)[N:15]=[CH:14][N:13]=1
Reactant: Clc1ccc2ncnc(NCc3ccc4c(c3)OCO4)c2c1
Reactant: ClB(Cl)Cl
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cl
Product: Oc1ccc(CNc2ncnc3ccc(Cl)cc23)cc1O
Temperature: 25 °C

Procedure:
40 ml of a 1.0M solution of boron trichloride in methylene chloride was dropped into a solution of 2.00 g (6.37 mmol) of 4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline in 150 ml of chloroform under stirring at room temperature. The obtained mixture was stirred at room temperature for 2 days, followed by the addition of methanol, and the obtained mixture was distilled under a reduced pressure to remove the solvent. This procedure was repeated twice. The crystals thus precipitated were washed with methanol and recrystallized from ethanol to give 1.53 g of the title compound as a yellow crystal.
Reaction SMILES: Cl[C:2]1[N:3]=[N+:4]([O-:17])[C:5]2[C:14]([N:15]=1)=[CH:13][C:12]1[CH2:11][N:10]([CH3:16])[CH2:9][CH2:8][C:7]=1[CH:6]=2.[CH2:18]([NH2:20])[CH3:19]>COCCOC>[CH2:18]([NH:20][C:2]1[N:3]=[N+:4]([O-:17])[C:5]2[C:14]([N:15]=1)=[CH:13][C:12]1[CH2:11][N:10]([CH3:16])[CH2:9][CH2:8][C:7]=1[CH:6]=2)[CH3:19]
Reactant: CN1CCc2cc3c(cc2C1)nc(Cl)n[n+]3[O-]
Reactant: CCN
Solvent: COCCOC
Product: CCNc1nc2cc3c(cc2[n+]([O-])n1)CCN(C)C3
Temperature: 20 °C
Yield: 88.7 %

Procedure:
A solution of chloride 257 (500 mg, 2.0 mmol) and ethylamine (0.4 mL, 6.0 mmol) in DME (15 mL) was heated at 60° C. for 4 h in a sealed pressure tube. The solution was cooled to 20° C., the solid filtered off and solvent evaporated. The combined residue was purified by chromatography, eluting with a gradient (2-4%) of MeOH/DCM, to give 1-oxide 258 (460 mg, 88%) as a yellow solid: mp 193-196° C.; 1H NMR δ 8.03 (s, 1H, H-10), 7.27 (s, 1H, H-5), 5.07 (br s, 1H, NH), 3.69 (s, 2H, H-6), 3.53 (dq, J=7.2, 5.8 Hz, 2H, CH2N), 3.05 (t, J=6.0 Hz, 2H, H-8), 2.72 (t, J=6.0 Hz, 2H, H-9), 2.48 (s, 3H, NCH3), 1.29 (t, J=7.2 Hz, 3H, CH3); 13C NMR δ 158.6, 147.0, 144.4, 132.5, 129.6, 122.8, 119.3, 58.2, 52.6, 46.0, 36.3, 29.1, 14.8; MS (APCI) m/z 260 (MH+, 100%). Anal. calcd for C13H17N5O: C, 60.2; H, 6.6; N, 27.0. Found: C, 59.9; H, 6.6; N, 26.9%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[C:18]([O:22][C:23](=[O:26])[CH2:24]Br)([CH3:21])([CH3:20])[CH3:19].C(OCC)C>CN(C=O)C.O>[C:8]([C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[O:11][CH2:24][C:23]([O:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:26])(=[O:10])[CH3:9]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(=O)c1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(=O)c1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 1-(5-chloro-2-hydroxyphenyl)-ethanone (2 g), potassium carbonate (1.62 g) and tert-butylbromoacetate (1.73 ml) in DMF (5 ml) was stirred at ambient temperature for 16 h. Diethyl ether and water were added and the organic layer separated, it was washed with water, aqueous potassium carbonate solution, brine, dried (Na2SO4) and the solvent removed in vacuo to give the sub-title compound (2.84 g).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.CCCCCC.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:28]#[N:29].[CH3:36][N:37]([CH3:42])[CH2:38][CH2:39][CH2:40][Cl:41]>C1COCC1>[ClH:41].[CH3:36][N:37]([CH3:42])[CH2:38][CH2:39][CH2:40][C:27]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[O:20][CH3:19])([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:28]#[N:29]
Reactant: COc1ccccc1C(C#N)c1ccccc1
Reactant: CN(C)CCCCl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccccc1C(C#N)(CCCN(C)C)c1ccccc1
Product: Cl
Reaction time: 0.25 h
Yield: 37.7 %

Procedure:
To a solution of diisopropylamine (6.4 ml, 46 mmol) in anhydrous THF (50 ml) maintained at -70° under nitrogen was added n-BuLi/hexane (2.2M, 20 ml, 44 mmol). The solution was stirred at -70° for 15 minutes and brought to -30° C. A solution of alpha-(2-methoxyphenyl)-phenylacetonitrile (9.16 g, 40 mmol) in THF (50 ml) was added dropwise and the resultant solution was allowed to warm to 20° and stirred for 0.5 hour. Distilled 3-dimethylaminopropyl chloride (11.2 g, 92 mmol) was added dropwise and the mixture was refluxed 16 hours. The reaction mixture was cooled and quenched with H2O (5 ml), the volatiles were evaporated in vacuo and the residue was dissolved in dichloromethane (300 ml) and washed with H2O (3×100 ml) until the pH of the aqueous phase became 8. The organic solution was dried over Na2SO4, filtered, and evaporated in vacuo. The residue was dissolved in diethyl ether (300 ml) and saturated with gaseous HCl. The crude precipitated salt (10.4 g, 84%) was collected and dried. Analytically pure material (5.2 g, 38%) was obtained by recrystallization from acetonitrile, m.p. 194.0°-195.5°.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:31])[CH2:7][C:8]1[N:9]=[C:10]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[C:11]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:15][S:14][C:12]=2[N:13]=1)[CH3:4]>C(=O)(OCC)OCC>[CH2:3]([O:5][C:6](=[O:31])[CH:7]([C:8]1[N:9]=[C:10]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[C:11]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:15][S:14][C:12]=2[N:13]=1)[C:6]([O:5][CH2:3][CH3:4])=[O:31])[CH3:4]
Reactant: CCOC(=O)Cc1nc(NCc2ccccn2)c2c(-c3ccccc3)csc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(=O)OCC
Product: CCOC(=O)C(C(=O)OCC)c1nc(NCc2ccccn2)c2c(-c3ccccc3)csc2n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 126.7 %

Procedure:
Sodium hydride (60% dispersion in oil, 64 mg, 1.59 mmol) was treated with a solution of {5-phenyl-4-[(pyridin-2-ylmethyl)amino]thieno[2,3-d]pyrimidin-2-yl}acetic acid ethyl ester (0.43 g, 1.06 mmol) in diethyl carbonate (2.5 ml). The resulting suspension was stirred at ambient temperature for 5 hours and left to stand for 18 hours. The mixture was then quenched with aqueous ammonium chloride solution (50 ml) and extracted with diethyl ether (3×50 ml). The combined organic extracts were dried (MgSO4) and the solvent removed in vacuo to give the crude product. Purification by flash chromatography (silica) eluting with dichloromethane followed by dichloromethane and ethyl acetate (5:1) gave 2-{5-phenyl-4-[(pyridin-2-ylmethyl)amino]thieno[2,3-d]pyrimidin-2-yl}malonic acid diethyl ester as a colourless gum (0.32 g).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH:11]#[C:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH:19]([C:21]1[C:30]([CH3:31])=[C:29]([O:32][C:33](=[O:35])[CH3:34])[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([F:36])[CH:27]=2)[N:22]=1)=[O:20].O>CCCCCC.O1CCCC1>[OH:20][CH:19]([C:21]1[C:30]([CH3:31])=[C:29]([O:32][C:33](=[O:35])[CH3:34])[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([F:36])[CH:27]=2)[N:22]=1)/[CH:11]=[CH:12]/[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CC(=O)Oc1c(C)c(C=O)nc2ccc(F)cc12
Reactant: C#CCCCCCC
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCC/C=C/C(O)c1nc2ccc(F)cc2c(OC(C)=O)c1C
Temperature: 50 °C
Reaction time: 2 h
Yield: 57.5 %

Procedure:
10.8 ml of an n-hexane solution of 10.8 mmols of diisobutylaluminium hydride was added to a solution of 1.31 g (11.9 mmols) of 1-octyne in 20 ml of n-hexane in an atmosphere of nitrogen and stirred at 50° C. for 2 hours. The reaction solution was cooled to -78° C., to which a solution of 2.22 ml (9.00 mmols) of 2-formyl-3-methyl-4-acetoxy-6-fluoroquinoline in 30 ml of tetrahydrofuran was added. The reaction temperature was raised from -78° C. to room temperature and the reaction solution was stirred at room temperature for 30 minutes. The reaction solution was added to 100 ml of water and filtered through Celite, followed by extraction with ethyl acetate, washing with water and a saturated sodium chloride aqueous solution, and drying with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resultant residue was purified by silica gel column chromatography (solvent: n-hexane ethyl acetate=8:1) to obtain 1.86 g (yield 58 %) of 2-(trans-1-hydroxy-2-nonenyl)-3-methyl-4-acetoxy-6-fluoroquinoline.
Reaction SMILES: [H][H].[OH:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1.C(=O)C1C=CC=CC=1>CO>[OH:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: [H][H]
Solvent: O=Cc1ccccc1
Solvent: CO
Product: OCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A 1.0 g quantity of the catalyst (CuO/ZnO/Aluminium oxide) in 50 ml methanol was placed in a 300 ml capacity Parr reactor. The contents were treated with hydrogen at 170° C., under pressure of 400-500 psig for 2-3 hrs. Cooled to room temperature, depressurized, followed by the addition of 10.0 g of 4-hydroxybenzaldehyde, in 50 ml of methanol. Hydrogenation was carried out at 170° C., under a pressure of 400-500 psig, for 2-3 hrs. The conversion of benzaldehyde was 100% providing 100% selectivity of 4-hydroxybenzyl alcohol, the desired alcohol product.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:10]=O)[CH:8]=2)[CH:3]=[CH:2]1.[CH3:12][NH2:13].[BH4-].[Na+].O>CO>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:10][NH:13][CH3:12])[CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=Cc1ccc2cc[nH]c2c1
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CNCc1ccc2cc[nH]c2c1
Reaction time: 3 h
Yield: 98.7 %

Procedure:
Indole-6-carboxaldehyde (90 mg, 0.62 mmol) was dissolved in anhydrous methanol (3 mL). Methylamine (0.95 mL of 2M solution in methanol, 1.86 mmol) was added and the reaction was stirred for 3 hr. The solution was concentrated to a yellow oil and then dissolved into anhydrous methanol (3 mL). Sodium borohydride (24 mg, 0.62 mmol) was added and the mixture was stirred overnight. Water (1 mL) was added and the solution was concentrated. Sodium hydroxide (2 mL, 1N) was added and the indole was extracted with ethyl acetate (3×10 mL), dried over MgSO4 and concentrated to afford the title compound as a yellow oil (98 mg, 100%). 1H NMR (300 MHz, CDCl3) δ 9.02 (s, 1H), 7.57 (d, J=8.1 Hz, 1H), 7.29 (s, 1H), 7.12 (d, J=3.1 Hz, 1H), 7.04 (d, J=8.1 Hz, 1H), 6.49 (d, J=2.7 Hz, 1H), 3.81 (s, 2H), 2.50 (s, 3H).