Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([CH2:8][C:9]1[CH:14]=[C:13](I)[C:12]([NH2:16])=[C:11]([Cl:17])[CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(N(CC)CC)C.[CH3:25][Si:26]([C:29]#[CH:30])([CH3:28])[CH3:27]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I.O>[NH2:1][C@H:2]([CH2:8][C:9]1[CH:14]=[C:13]([C:30]#[C:29][Si:26]([CH3:28])([CH3:27])[CH3:25])[C:12]([NH2:16])=[C:11]([Cl:17])[CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: C#C[Si](C)(C)C
Reactant: CCOC(=O)[C@H](N)Cc1cc(Cl)c(N)c(I)c1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)[C@H](N)Cc1cc(Cl)c(N)c(C#C[Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Under protective argon gas a mixture of 235 mg (0.64 mmol) ethyl (R)-2-amino-3-(4-amino-3-chloro-5-iodo-phenyl)-propionate, 45.9 mg (0.064 mmol) bis-(triphenylphosphine)-palladium(II)-dichloride, 6.0 mg (0.032 mmol) copper(I)- iodide and 15 ml triethylamine was combined with 0.19 ml (1.32 mmol) trimethylsilylacetylene and stirred for 3 hours at ambient temperature. The reaction mixture was combined with 30 ml of water and extracted with 40 ml of ethyl acetate. The organic phase was dried over sodium sulphate, evaporated down under reduced pressure and the residue was purified by column chromatography through silica gel.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[N+:10]([O-])=O.[C:13]([O:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[CH2:22])=[CH:19][CH:18]=1)(=[O:15])[CH3:14]>>[NH2:10][C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[CH:22]=[CH:21][C:20]1[CH:23]=[CH:24][C:17]([O:16][C:13](=[O:15])[CH3:14])=[CH:18][CH:19]=1
Reactant: COc1ccc(Br)c([N+](=O)[O-])c1
Reactant: C=Cc1ccc(OC(C)=O)cc1
Product: COc1ccc(C=Cc2ccc(OC(C)=O)cc2)c(N)c1

Procedure:
Synthesized from 4-bromo-3-nitroanisole (2.3 g) and 4-acetoxystyrene (1.7 ml) according to an analogous synthetic method to Example 107, the title compound (1.2 g) was obtained.
Reaction SMILES: Cl.Cl.Cl.N1C=C(C[N:10]2[C:16]3[CH:17]=CC(C4C=NC=CC=4)=[CH:20][C:15]=3[CH2:14][N:13]([C:27](=[O:32])[C:28](F)(F)F)[CH:12]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:11]2)N=C1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[C:11]([C:12]1[CH:33]=[CH:17][C:16]2[NH:10][CH2:11][C@@H:12]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:13]([C:27](=[O:32])[CH2:28][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:14][C:15]=2[CH:20]=1)#[N:10]
Reactant: O=C(N1Cc2cc(-c3cccnc3)ccc2N(Cc2c[nH]cn2)CC1Cc1ccccc1)C(F)(F)F
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc2c(c1)CN(C(=O)Cc1ccccc1)[C@H](Cc1ccccc1)CN2
Yield: 131.1 %

Procedure:
A solution of Compound B (1.1g, 2.8 mmol) in TFA (8 mL) and methylene chloride (8 mL) was stirred for 3 h and concentrated. Trituration with ethyl ether and drying under vacuum afforded 700 mg (74%) of Compound C as a white solid. MS (M+H)+ 337.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Br:19][CH:20]([CH3:24])[C:21](Br)=[O:22]>C1(C)C=CC=CC=1>[CH2:1]([O:8][CH2:9][CH2:10][O:11][C:21](=[O:22])[CH:20]([Br:19])[CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(Br)C(=O)Br
Reactant: OCCOCc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(Br)C(=O)OCCOCc1ccccc1
Temperature: -5 °C

Procedure:
15.2 g of 2-benzyloxyethanol and 10.6 g of triethylamine were dissolved in 150 ml of toluene, and the solution was cooled to -5° C. A solution of 21.6 g of 2-bromopropionylbromide in 30 ml of toluene was added dropwise thereto at -5° to 0° C. with stirring. The reaction mixture was further maintained at room temperature for two hours. The mixtue was then washed successively with 1% strength by weight sodium hydroxide solution and water, and the toluene solution was then dried and filtered. The toluene was distilled off under reduced pressure, and the end product of 2-benzyloxyethyl-2-bromopropionate was obtained in a yield of 26.7 g (nD20.5 1.5182)
Reaction SMILES: Br[C:2]1[C:6]([CH3:8])([CH3:7])[O:5]/[C:4](=[C:9]2/[C:10](=[O:19])[NH:11][C:12]3[C:17]/2=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=3)/[CH:3]=1.[CH:20]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)=[O:21].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C1COCC1>[F:18][C:14]1[CH:13]=[C:12]2[C:17](/[C:9](=[C:4]3/[CH:3]=[C:2]([C:25]4[CH:26]=[CH:27][C:22]([CH:20]=[O:21])=[CH:23][CH:24]=4)[C:6]([CH3:8])([CH3:7])[O:5]/3)/[C:10](=[O:19])[NH:11]2)=[CH:16][CH:15]=1
Reactant: CC1(C)O/C(=C2/C(=O)Nc3cc(F)ccc32)C=C1Br
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1(C)O/C(=C2/C(=O)Nc3cc(F)ccc32)C=C1c1ccc(C=O)cc1
Temperature: 65 °C
Yield: 51 %

Procedure:
To a mixture of (3E)-3-(4-bromo-5,5-dimethylfuran-2(5H)-ylidene)-6-fluoro-1,3-dihydro-2H-indol-2-one (2.0 g, 6.17 mmol), 4-formyl phenylboronic acid (1.85 g, 12.3 mmol), aqueous potassium carbonate (1M, 31 mL, 31 mmol) in THF (120 mL) under a nitrogen atmosphere, was added palladium(O) tetrakis(triphenylphosphine) (356 mg, 0.3 mmol, 5 mol %). The mixture was heated at 65° C. overnight (20 h). The reaction was cooled to room temperature and ethyl acetate (500 mL) was added. The organic phase was washed with water (100 mL×2), dried over sodium sulfate, and evaporated. The residue was purified by silica gel column chromatography (5% CH3OH/CH2Cl2 elution). Trituration of the product obtained from the column chromatography with ethyl acetate/hexane (1/1), followed by isolation of the precipitate by filtration, provided 4-[(5E)-5-(6-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]benzaldehyde as a red orange solid (1.1 g, yield 51%).
Reaction SMILES: C([C@@:3]([C:12]([O-])=O)([OH:11])[C@@:4]([CH2:9][CH3:10])(O)[C:5]([O-:7])=O)C.[C:15]([NH:34][C@@H]1CC(CO)=CC1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(OO)(C)(C)C>C(Cl)Cl.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[C:15]([NH:34][C@H:10]1[CH2:12][C@H:3]2[C@:4]([CH2:5][OH:7])([O:11]2)[CH2:9]1)([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC[C@](O)(C(=O)[O-])[C@](O)(CC)C(=O)[O-]
Reactant: OCC1=CC[C@H](NC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Agent: [Ti+4]
Agent: CC(C)(C)OO
Agent: CC(C)[O-]
Solvent: ClCCl
Product: OC[C@@]12C[C@@H](NC(c3ccccc3)(c3ccccc3)c3ccccc3)C[C@@H]1O2
Temperature: -35 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
A reactor was charged with (+)-diethyl-L-tartrate (2.23 L, 13.0 mol) and methylene chloride (10.5 L). Stirring was started and the mixture was cooled to −30 to −40° C. Titanium (IV) isopropoxide (3.93 L, 13.4 mol) was slowly added while maintaining the internal temperature between −30 to −40° C. A solution of [(4S)-4-(tritylamino)cyclopent-1-en-1-yl]methanol (4.2 kg, 11.8 mol) in methylene chloride (19 L) was slowly added to the reaction mixture, while maintaining the temperature between −30 to −40° C. After stirring for 20 minutes, t-butyl hydroperoxide (5-6 M in decane, 3.3 L, 16.3 mol) was slowly added while maintaining the temperature between −30 to −40° C. Upon completion of the addition, the reaction mixture was analyzed by HPLC, which confirmed the formation of the product and presence of 3% (AUC) of the starting material. The reaction mixture was carefully quenched into a 100-L reactor containing a cold aqueous solution (0 to 5° C.) of iron (II) sulfate heptahydrate (10.5 kg) and tartaric acid (6.3 kg) in DI water (42 L). After stirring for 15 minutes, the organic phase was separated and filtered through a pad of diatomaceous earth. The pad was washed with methylene chloride (2×2 L), and the filtrate was transferred into a 100-L reactor. A cold solution (0 to 5° C.) of solid sodium hydroxide (3.36 kg) in brine (42 L) was slowly added to the gently stirred reaction mixture. After 1 h, the organic phase was separated, dried over anhydrous sodium sulfate, filtered through a pad of diatomaceous earth and concentrated under reduced pressure to give a brown oil. This was purified via silica-gel chromatography using five columns. Each column was performed as follows. A 20 cm diameter glass column was loaded with a slurry of silica gel (5 kg) in 30% ethyl acetate/heptane with 0.5% triethylamine added. Crude product (˜1.2 kg) was adsorbed onto silica gel (1.5 kg) and loaded on the column. Polarity was gradually increased from 30% to 40% ethyl acetate/heptane with 0.5% triethylamine. Combined purified material from all columns afforded the title compound (3.93 kg, 89% yield) as an amber oil. 1H NMR (300 MHz, CDCl3, δ) 7.54-7.50 (m, 5H), 7.32-7.18 (m, 10H), 3.80-3.76 (d, J=12.5 Hz, 1H), 3.65-3.61 (d, J=12.5 Hz, 1H), 3.31 (s, 1H), 3.03-2.92 (m, 1H), 1.77-1.69 (m, 2H) and 1.37-1.13 (m, 2H).
Reaction SMILES: CO.[Na].CO[C:6](=[O:17])[C:7]1[C:8](=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:9]([O:11]C)=O.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([C:25](=[O:27])[CH3:26])=[CH:21][CH:20]=1>C1C=CC=CC=1>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([CH:26]2[C:6](=[O:17])[C:7]3[C:8](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:9]2=[O:11])=[O:27])=[CH:21][CH:20]=1
Reactant: CC(=O)c1ccc(Br)cc1
Reactant: COC(=O)c1ccccc1C(=O)OC
Agent: [Na]
Solvent: CO
Solvent: c1ccccc1
Product: O=C(c1ccc(Br)cc1)C1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methanol (8.5 ml) was treated with sodium (4.8 g) in benzene (90 mL). The reaction mixture was refluxed overnight, allowed to cool to room temperature, and treated with phthalic acid dimethyl ester (38.84 g) and 1-(4-bromophenyl)ethanone (39.81 g) in benzene (50 mL). Distillation of the reaction mixture was performed at 80° C. overnight to remove methanol. The reaction mixture was poured into diluted HCl and filtered. The filter cake was collected and recrystallized from ethanol to provide the title compound.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].N1C=CC=CC=1.[N+:13]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][N:20]=[C:19]2[OH:25])([O-:15])=[O:14].Cl>O>[OH:25][C:19]1[C:18]2[C:22](=[CH:23][CH:24]=[C:16]([N+:13]([O-:15])=[O:14])[CH:17]=2)[N:21]([C:2]([O:4][CH2:5][CH3:6])=[O:3])[N:20]=1
Reactant: O=[N+]([O-])c1ccc2[nH]nc(O)c2c1
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)n1nc(O)c2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Ethyl chloroformate (5 ml) was added to a pyridine (30 ml) solution containing 5-nitro-1H-indazol-3-ol (5.42 g) obtained in the 1st step, followed by stirring at room temperature for 1.5 hours. Water and concentrated hydrochloric acid (32 ml) were added dropwise to the reaction solution and a solid precipitate was collected by filtration. The obtained residue was washed with water. A brown solid of ethyl 3-hydroxy-5-nitro-1H-indazol-1-carboxylate (7.5 g) was thus obtained.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][C:8]([O:15][CH2:16][C:17]([OH:19])=O)=[CH:9][C:10]([C:11]([F:14])([F:13])[F:12])=[C:5]2[C:4]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:3]1.CC(C)N=C=NC(C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:45][O:46][C:47]1[CH:55]=[CH:54][C:50]([C@@H:51]([NH2:53])[CH3:52])=[CH:49][CH:48]=1>CN(C=O)C>[CH3:45][O:46][C:47]1[CH:55]=[CH:54][C:50]([C@@H:51]([NH:53][C:17](=[O:19])[CH2:16][O:15][C:8]2[N:7]=[C:6]3[N:2]([CH3:1])[N:3]=[C:4]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:5]3=[C:10]([C:11]([F:13])([F:14])[F:12])[CH:9]=2)[CH3:52])=[CH:49][CH:48]=1
Reactant: COc1ccc([C@H](C)N)cc1
Reactant: Cn1nc(-c2ccccc2)c2c(C(F)(F)F)cc(OCC(=O)O)nc21
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COc1ccc([C@H](C)NC(=O)COc2cc(C(F)(F)F)c3c(-c4ccccc4)nn(C)c3n2)cc1
Reaction time: 12 h
Yield: 63.2 %

Procedure:
A solution of (1-Methyl-3-phenyl-4-trifluoromethyl-1H-pyrazolo[3,4-b]pyridin-6-yloxy)-acetic acid (350 mg, 0.996 mmol), DIC (189 mg, 1.494 mmol) and HOBt (175 mg, 1.295 mmol) in DMF (10 ml) was stirred at rt for 10 min. (S)-(−)-4-methoxy-α-methyl benzyl amine (166 mg, 1.096 mmol) was added to the reaction mixture at rt and stirring was continued for 12 h at rt. After completion of the reaction, the reaction mixture was poured into rapidly stirred ice-cold water to obtain the crude product as a solid. The solid was collected by filtration and dried under vacuum. The product was further purified by flash column chromatography [(eluent: EtOAc/hexane (1:3)] to yield the title compound as a white solid (305 mg, 63%). [1H-NMR (CDCl3, 300 MHz) δ 7.58-7.39 (m, 5H), 7.32-7.21 (m, 2H), 6.99 (s, 1H), 6.85 (d, 2H), 6.51 (d, 1H), 5.31-5.22 (m, 1H), 5.0 (s, 2H), 4.05 (s, 3H), 3.8 (s, 3H), 1.52 (d, 3H); HPLC RtB=5.933 min. (98%); LCMS RtA=1.785, [M+H]+=485.1; Mp=172-174° C.]
Reaction SMILES: Cl[C:2]([C:4]1[CH:5]=[CH:6][C:7]([N+:14]([O-:16])=[O:15])=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10])=[O:3].C(N(CC)CC)C.[CH:24]1[N:25]=[CH:26][N:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=12>ClCCCl>[CH:24]1[N:25]=[C:26]([C:2]([C:4]2[CH:5]=[CH:6][C:7]([N+:14]([O-:16])=[O:15])=[C:8]([CH:13]=2)[C:9]([O:11][CH3:12])=[O:10])=[O:3])[N:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=12
Reactant: COC(=O)c1cc(C(=O)Cl)ccc1[N+](=O)[O-]
Reactant: c1ccn2cncc2c1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(C(=O)c2ncc3ccccn23)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
5.6 g (0.023 mol) of methyl 5-(chlorocarbonyl)-2-nitrobenzoate and 3.4 ml (0.024 mol) of triethylamine are added to 1.3 g (0.011 mol) of imidazo[1,5-a]pyridine [described in J. Chem. Soc., (1955), 2834-2836] dissolved in 100 ml of 1,2-dichloroethane. The mixture is stirred at ambient temperature for 4 hours. The reaction medium is concentrated under reduced pressure and then the residue is taken up in dichloromethane and a saturated aqueous sodium bicarbonate solution. The organic phase is separated by settling, washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. The product is purified by column chromatography on silica gel, elution being carried out with dichloromethane. After evaporation, 3.1 g of a yellow solid are collected. Melting point: 151° C.; 1H NMR (d6-DMSO): 3.92 (3H, s), 7.39-7.42 (1H, m), 7.50-7.54 (1H, m), 8.00 (1H, s), 8.10 (1H, d), 8.25 (1H, d), 8.69 (1H, d), 8.76 (1H, s), 9.78 (1H, d)
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9](Cl)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+].[CH3:21][NH:22][CH3:23]>>[NH2:1][C:2]1[N:10]=[C:9]([N:22]([CH3:23])[CH3:21])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CNC
Reactant: Nc1nc(Cl)nc2c1ncn2Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: CN(C)c1nc(N)c2ncn(Cc3ccccc3)c2n1
Yield: 87 %

Procedure:
6-Amino-9-benzyl-2-chloropurine (100 mg, 0.385 mmol) and aqueous dimethylamine (30 ml) were heated at 120° C. for 15 hours in autoclave. The reaction mixture was condensed in vacuo. To the residue was added 5N aqueous sodium hydroxide and the solution was extracted with chloroform. The organic layer was dried on sodium sulfate, filtered and the solvent in the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (2% methanol/chloroform) to give the subject compound (90 mg, yield 87%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:12])=[CH:4][C:5]2[CH:9]=[CH:8][S:7][C:6]=2[C:10]=1[Cl:11].C([Li])CCC.[CH:18](=[O:21])[CH2:19][CH3:20]>O1CCCC1.CCCCCC>[Cl:1][C:2]1[C:3]([OH:12])=[CH:4][C:5]2[CH:9]=[C:8]([CH:18]([CH2:19][CH3:20])[OH:21])[S:7][C:6]=2[C:10]=1[Cl:11]
Reactant: CCC=O
Reactant: Oc1cc2ccsc2c(Cl)c1Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCC(O)c1cc2cc(O)c(Cl)c(Cl)c2s1
Reaction time: 4 h

Procedure:
A solution of 7.0 g of 6,7-dichloro-5-hydroxybenzo[b]thiophene in 50 ml of dry tetrahydrofuran is cooled to -30°, using a dry ice-carbon tetrachloride bath and to the mixture is added dropwise, 35 ml of 2.2M n-butyllithium in hexane while the temperature is maintained below -20°. Following the addition, the bath is replaced with an ice-water bath and the reaction is stirred for 4 hrs at a temperature of 0°-5°. To the mixture is added dropwise solution of 3 ml of freshly distilled proprionaldehyde in 5 ml of tetrahydrofuran. The bath is removed. The reaction mixture is stirred for 20 mins and poured onto cold 10% hydrochloric acid. The mixture is extracted 3 times with ethyl ether. The combined ether extracts are washed, dried and the solvent is removed to give a solid. Recrystallization from ethyl ether and hexane gives 5.9 g of 6,7-dichloro-5-hydroxy-α-ethylbenzo[b]thiophene-2-methanol, mp 145°-145.5°.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:6]=[CH:7][C:8]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]3)[C:9]=2[CH:27]=1)[CH3:3].FC(F)(F)C(O)=O>ClCCl>[CH3:3][CH:2]([O:4][C:5]1[CH:6]=[CH:7][C:8]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]3)[C:9]=2[CH:27]=1)[CH3:1]
Reactant: CC(C)Oc1ccc2[nH]c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)Oc1ccc2[nH]c(=O)n(C3CCNCC3)c2c1
Reaction time: 1 h
Yield: 89.4 %

Procedure:
A solution of 1,1-dimethylethyl 4-{6-[(1-methylethyl)oxy]-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl}-1-piperidinecarboxylate (D49, 351 mg, 0.93 mmol) in dichloromethane (5 ml) was treated with trifluoroacetic acid (3 ml) and stirred under argon for 1 hr. The mixture was concentrated under vacuum and the residue treated with 10% Na2CO3 solution and extracted with ethyl acetate (×3). The combined extract was concentrated under vacuum to leave the title compound as an orange oil (229 mg, 89%). M++H=276.1.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][C:3]=1[CH3:10].C(N(CC)CC)C.[CH:18](OCC)=[O:19]>>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][CH:18]=[O:19])=[CH:4][C:3]=1[CH3:10]
Reactant: CCOC=O
Reactant: Cc1cc(CN)ccc1Br
Solvent: CCN(CC)CC
Product: Cc1cc(CNC=O)ccc1Br

Procedure:
To a solution of 4-bromo-3-methyl-benzylamine (Example 10.1) (15.11 g) in ethyl formate (150 ml) was added triethylamine (1.5 ml) at ambient temperature. The reaction mixture was stirred at reflux for 16 hours. The reaction mixture was concentrated and the residue was triturated with diisopropyl ether/heptane (1:1) (100 ml) to give N-(4-bromo-3-methyl-benzyl)-formamide (14.04 g) as a white solid. 1H-NMR (400 MHz, CDCl3): 8.28 (s, 1H), 7.49 (m, 1H), 7.16 (s, 1H), 6.97 (m, 1H), 5.85 (s, 1H), 4.42 (m, 2H), 2.39 (s, 3H) ppm.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[O:6][C:7]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:8]=1[C:9]#[N:10])=O.CN.[C:21]([BH3-])#[N:22].[Na+].[C:25]([OH:32])(=[O:31])/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29]>C(O)(=O)C.CO>[C:25]([OH:32])(=[O:31])/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29].[CH3:15][C:13]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([O:6][C:5]2[CH:16]=[CH:17][CH:18]=[C:3]([CH2:1][NH:22][CH3:21])[CH:4]=2)[CH:14]=1
Reactant: Cc1ccc(C#N)c(Oc2cccc(C=O)c2)c1
Reactant: [BH3-]C#N
Agent: CN
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CNCc1cccc(Oc2cc(C)ccc2C#N)c1
Yield: 19.2 %

Procedure:
2-(3-Formyl-phenoxy)-4-methyl-benzonitrile (0.26 g, 1.1 mmol), methylamine (2M in methanol, 2.5 mL, 5.0 mmol) and sodium cyanoborohydride (80 mg, 1.3 mmol) were stirred at ambient temperature in a 1% acetic acid/methanol solution (30 mL) for 18 h. The solvent was removed in vacuo. The residue was treated with 10% sodium carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was separated and fumaric acid (0.12 g, 1.1 mmol) was added. After the solvent was removed in vacuo, the residue was triturated with ethyl acetate overnight, collected by filtration, and dried to give 4-methyl-2-(3-methylaminomethyl-phenoxy)-benzonitrile fumarate (78 mg, 20%) as a tan solid.
Reaction SMILES: CS[C:3]1[C:12]2[C:7]([CH:8]=[N:9][CH2:10][N:11]=2)=[CH:6][C:5]2=[N:13][CH:14]=[N:15][C:4]=12.[C:16]([C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21])#[CH:17].[ClH:25].N1C=CC=CC=1>C(O)(C)(C)C>[ClH:25].[C:16]([C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH:21][CH:6]1[C:7]2[N:8]=[CH:9][N:10]=[CH:11][C:12]=2[CH:3]=[C:4]2[N:15]=[CH:14][N:13]=[C:5]12)#[CH:17]
Reactant: C#Cc1cccc(N)c1
Reactant: CSc1c2c(cc3c1=NCN=C3)=NC=N2
Agent: Cl
Solvent: CC(C)(C)O
Solvent: c1ccncc1
Product: C#Cc1cccc(NC2C3=NC=NC3=Cc3cncnc32)c1
Temperature: 25 °C

Procedure:
A mixture of 4-methylthio-6H-imidazo[4,5-g]quinazoline (0.0455 g, 0.210 mmol), prepared as described in Leonard, N. J.; Morrice, A. G.; Sprecker, M. A., J. Org. Chem., 1975, 40 (3), 356-363, 3-ethynylaniline (0.0672 g, 0.574 mmol) and pyridine hydrochloride (0.0274 g, 0.237 mmol) in t-butanol (5 mL) was heated to reflux for 6 hours then cooled to room temperature. Precipitate was collected and washed with t-butanol to give 4-(3-ethynylanilino)-imidazo[4,5-g]-quinazoline hydrochloride as a yellow solid: 0.0349 g (58%); 1H NMR (DMSO-d6) δ4.34 (1H, s), 7.48 (1H, m), 7.53 (1H, m), 7.82 (1H, m), 7.98 (1H, s), 8.13 (1H, s), 8.81 (1H, s), 8.99 (1H, s), 9.24 (1H, s), 11.49 (1H, br s ); m/e 286 (M+1).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH2:9][CH2:10][CH2:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13].Cl.Cl.[NH2:22][C:23]1[C:38]([Cl:39])=[CH:37][C:26]([C:27]([NH:29][CH2:30][CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[O:28])=[C:25]([O:40][CH3:41])[CH:24]=1.O>CN(C)C=O>[NH2:22][C:23]1[C:38]([Cl:39])=[CH:37][C:26]([C:27]([NH:29][CH2:30][CH:31]2[CH2:32][CH2:33][N:34]([CH2:8][CH2:9][CH2:10][CH2:11][C:12](=[O:13])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:35][CH2:36]2)=[O:28])=[C:25]([O:40][CH3:41])[CH:24]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: O=C(CCCCBr)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCC(=O)c2ccccc2)CC1
Reaction time: 7.5 h
Yield: 52.6 %

Procedure:
Potassium carbonate (0.57 g) and 5-bromo-1-phenyl-1-pentanone (0.80 g) were added to a solution (45 ml) of 4-amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (1.5 g) in dimethylformamide, and the mixture was stirred at 70°-80° C. for 7.5 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated aqueous sodium chloride solution, dried and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give crystals. The obtained crystals were recrystallized from ethyl acetate to give 0.80 g of 4-amino-5-chloro-2-methoxy-N-((1-(5-oxo-5-phenylpentyl)piperidin-4-yl)methyl)benzamide.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][CH:7]([CH2:13][CH2:14][CH3:15])[C:8]2=[O:12])=[CH:4][C:3]=1[O:16][CH3:17].[H-].[Na+].Cl[CH2:21][CH:22]=[C:23]([Cl:25])[CH3:24]>C1(C)C=CC=CC=1.CN(C)C=O>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH2:21][CH:22]=[C:23]([Cl:25])[CH3:24])([CH2:13][CH2:14][CH3:15])[C:8]2=[O:12])=[CH:4][C:3]=1[O:16][CH3:17]
Reactant: CCCC1Cc2cc(OC)c(Cl)c(Cl)c2C1=O
Reactant: CC(Cl)=CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCCC1(CC=C(C)Cl)Cc2cc(OC)c(Cl)c(Cl)c2C1=O
Temperature: 30 °C
Reaction time: 0.5 h
Yield: 80.2 %

Procedure:
6,7-Dichloro-2,3-dihydro-5-methoxy-2-propyl-1H-inden-1-one (13.66 g, 0.05 mole) dissolved in toluene (80 ml) was added over 15 minutes with stirring under N2 to a suspension of 56% sodium hydride (2.36 g, 0.055M) in dimethylformamide (65 ml) and toluene (15 ml) at 25°. The mixture was stirred without external heat for 11/2 hours, at 50° C. for 1/2 hour and then cooled to 30° C. A solution of 1,3-dichloro-2-butene (7.81 g, 0.0625 mole) in toluene (10 ml) was added, and the mixture was heated at 50°-55° for 2 hours, poured into ice water, and extracted with diethyl ether. The organic extracts were washed with water, dried over MgSO4, concentrated under vacuum and chromatographed on silica with elution with 1/1 hexane/methylene chloride to obtain 14.5 g of product as an oil which was a mixture of cis-trans isomers.