Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O>[CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:9][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:8])=[CH:5][CH:4]=1)=[O:2]
Reactant: BrCc1ccccc1
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(C(=O)OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 104.7 %

Procedure:
304 g (2 mol) of 4-formylbenzoic acid were dissolved in 1 l of dimethylformamide (DMF), 304 g (2.2 mol) of potassium carbonate were added and then over a period of 30 min 261 ml (2.2 mol) of benzyl bromide were added at about 40° C. (exothermic reaction). The mixture was stirred for further 4 h at 40° C. to 45° C. Then the reaction mixture was poured into 3 l of ice-water and extracted for times with 1 l each of ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and the ethyl acetate removed in a rotary evaporator at reduced pressure. 503 g of an oil were obtained. The crude product was used directly in the next reaction step.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:17]=[C:16]([CH:18]([OH:20])[CH3:19])[CH:15]=[C:7]([C:8]([N:10]([CH3:14])[CH2:11][CH2:12][CH3:13])=[O:9])[CH:6]=1)[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:17]=[C:16]([C:18](=[O:20])[CH3:19])[CH:15]=[C:7]([C:8]([N:10]([CH3:14])[CH2:11][CH2:12][CH3:13])=[O:9])[CH:6]=1)[CH3:2]
Reactant: CCCN(C)C(=O)c1cc(C(=O)OCC)cc(C(C)O)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CCCN(C)C(=O)c1cc(C(C)=O)cc(C(=O)OCC)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 79.1 %

Procedure:
Treat a solution of 5-(1-hydroxyethyl)-N-methyl-N-propyl-isophthalamic acid ethyl ester (250 mg, 0.85 mmol) in dichloromethane (10 mL) with Dess-Martin periodinane (470 mg, 1.11 mmol). Stir at room temperature for 2.5 h, quench with 10% aqueous sodium sulfate, extract with ethyl acetate (50 mL). Wash with 10% aqueous sodium sulfate solution, saturated aqueous sodium chloride, dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with 50:50 ethyl acetate:hexanes) to give the title compound (196 mg, 78%).
Reaction SMILES: [N+:1]([C:4]1[CH:41]=[CH:40][C:7]([C:8]([O:10][C@@:11]([C:18]2[N:19]=[N:20][N:21]([CH2:23][C:24]3[CH:33]=[C:32]4[C:27]([C:28]([C:36](=O)[CH2:37]Br)=[CH:29][C:30]([C:34]#[N:35])=[N:31]4)=[CH:26][CH:25]=3)[CH:22]=2)([C:14]([F:17])([F:16])[F:15])[CH2:12][CH3:13])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:42]([NH2:45])(=[S:44])[CH3:43]>CN(C=O)C.C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([O:10][C@@:11]([C:18]2[N:19]=[N:20][N:21]([CH2:23][C:24]3[CH:33]=[C:32]4[C:27]([C:28]([C:36]5[N:45]=[C:42]([CH3:43])[S:44][CH:37]=5)=[CH:29][C:30]([C:34]#[N:35])=[N:31]4)=[CH:26][CH:25]=3)[CH:22]=2)([C:14]([F:16])([F:17])[F:15])[CH2:12][CH3:13])=[O:9])=[CH:40][CH:41]=1)([O-:3])=[O:2]
Reactant: CC[C@](OC(=O)c1ccc([N+](=O)[O-])cc1)(c1cn(Cc2ccc3c(C(=O)CBr)cc(C#N)nc3c2)nn1)C(F)(F)F
Reactant: CC(N)=S
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC[C@](OC(=O)c1ccc([N+](=O)[O-])cc1)(c1cn(Cc2ccc3c(-c4csc(C)n4)cc(C#N)nc3c2)nn1)C(F)(F)F

Procedure:
A solution of 1-(1-{[4-(bromoacetyl)-2-cyanoquinolin-7-yl]methyl}-1H-1,2,3-triazol-4-yl)-1-(trifluoromethyl)propyl 4-nitrobenzoate (see Example 52, Step 2) (65 mg, 0.1 mmol) and thioacetamide (9 mg, 0.11 mmol) in DMF (1 mL) was stirred at 100° C. overnight. The reaction mixture was diluted in ethyl acetate, washed with water, brine and dried over MgSO4. The crude compound was purified on silica gel (eluting solvent: 3% acetone in dichloromethane) to give the desired product. 1H NMR (acetone-d6): δ 8.85 (d, 1H), 8.52 (s, 1H), 8.42 (d, 2H), 8.30 (d, 2H), 8.17 (d, 2H), 8.05 (s, 1H), 7.75 (d, 1H), 6.05 (s, 2H), 3.05 (m, 1H), 2.85 (s, 3H), 2.85 (m, 1H), 1.15 (t, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.Cl[CH2:10][CH:11]1[O:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:12]2[O:13][CH:11]2[CH3:10])=[CH:4][CH:3]=1
Reactant: ClCC1CO1
Reactant: Sc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC1OC1Sc1ccc(Br)cc1

Procedure:
A suspension containing 9.45 g of 4-bromothiophenol, 14.45 g of 1-chloro-2,3-epoxypropane and 13.8 g of potassium carbonate in 100 ml of butanone is refluxed for 12 hours. The inorganic salts formed are filtered off and drained and the solvent and excess 1-chloro-2,3-epoxypropane are then evaporated off under vacuum. The residual oil is distilled at between 130° C. and 140° C. under 0.01 mm of mercury.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.CS(O[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)[CH3:12])(=O)=O>C(#N)C>[N+:19]([C:16]1[CH:17]=[CH:18][C:13]([CH:11]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH3:12])=[CH:14][CH:15]=1)([O-:21])=[O:20]
Reactant: c1c[nH]cn1
Reactant: CC(OS(C)(=O)=O)c1ccc([N+](=O)[O-])cc1
Solvent: CC#N
Product: CC(c1ccc([N+](=O)[O-])cc1)n1ccnc1
Yield: 63.3 %

Procedure:
(a-2) A mixture of 37.5 parts of 1H-imidazole, 61.3 parts of [1-(4-nitrophenyl)ethyl] methanesulfonate and 200 parts of acetonitrile was stirred and refluxed for 2.50 hours. After cooling, the whole was filtered and the filtrate was evaporated. 150 Parts of water were added and the product was extracted three times with 130 parts of dichloromethane. The combined extracts were dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 34.4 parts (63.3%) of 1-[1-(4-nitrophenyl)ethyl]-1H-imidazole as a solid residue (int. 113).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[N:3]=1.[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([NH:25][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]([C:11]#[N:12])=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-n2cccn2)c1C#N
Reactant: NCc1ccccc1
Solvent: COCCOC
Product: N#Cc1c(NCc2ccccc2)nc(N)nc1-n1cccn1

Procedure:
From 2-amino-4-methanesulfinyl-6-pyrazol-1-yl-pyrimidine-5-carbonitrile and benzylamine in DME. ES-MS m/e (%): 292 (M+H+, 100).
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[S:13][CH:14]=[CH:15][CH:16]=3)=[CH:10][C:9]([CH2:17][CH2:18][CH:19]=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)[N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:24][CH:23]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[F:41][C:38]1[CH:37]=[CH:36][C:35]([CH:28]([C:25]2[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=2)[N:29]2[CH2:30][CH2:31][N:32]([CH2:19][CH2:18][CH2:17][C:9]3[CH:10]=[C:11]([C:12]4[S:13][CH:14]=[CH:15][CH:16]=4)[N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:8]=3)[CH2:33][CH2:34]2)=[CH:40][CH:39]=1
Reactant: O=CCCc1cc(-c2cccs2)n(-c2ccccc2)n1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc(C(c2ccc(F)cc2)N2CCN(CCCc3cc(-c4cccs4)n(-c4ccccc4)n3)CC2)cc1

Procedure:
65 mg (78%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-phenyl-5-(thiophene-2-yl)-1H-pyrazol-3-yl)-propanal (40 mg, 0.142 mmol), 1-(bis(4-fluorophenyl)methyl)piperazine (41 mg, 0.142 mmol), DIPEA (0.040 mL, 0.213 mmol) and NaBH(OAc)3 (90 mg, 0.573 mmol).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=1.[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]([C:16]2[CH:15]=[CH:14][C:13]([Cl:12])=[CH:18][C:17]=2[Cl:19])=[CH:6][CH:5]=1)=[O:11]
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: COC(=O)c1ccc(Br)cc1
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: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COC(=O)c1ccc(-c2ccc(Cl)cc2Cl)cc1

Procedure:
4-Bromo-benzoic acid methyl ester (3 g) was dissolved in a mixture of toluene (20 mL) and ethanol (20 mL). 2,4-Dichloro-phenyl boronic acid (3 g) was added followed by 2 M Na2CO3 (20 mL). The mixture was stirred vigorously under N2 and (PPh3)4Pd (0.5 g) added. The mixture was refluxed with stirring for 3 hours under an atmosphere of N2. The solvent was removed under vacuum, the residue was dissolved in ethyl acetate, and washed with water and saturated NaCl solution. After drying (Na2SO4), the solvent was evaporated and the resultant oil purified by column chromatography to give a fluffy white powder, which was recrystallised from ethanol to give the title compound as long needles. 13C NMR (CDCl3): δ 52.3, 127.3, 129.5, 129.5, 129.6, 129.9, 131.9, 133.1, 134.4, 138.1, 142.8 and 166.8. 1H NMR (CDCl3): δ 3.93 (3H, s), 7.27 (2H, m), 7.47 (2H, d, J=8.5 Hz), 7.49 (1H, s) and 8.09 (2H, d, J=8.2 Hz).
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[O:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:19]([O:23][C:24](=[O:45])[NH:25][C:26]1([C:30]2[CH:35]=[CH:34][C:33](B3OC(C)(C)C(C)(C)O3)=[CH:32][CH:31]=2)[CH2:29][CH2:28][CH2:27]1)([CH3:22])([CH3:21])[CH3:20]>C1(C)C=CC=CC=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>[C:19]([O:23][C:24](=[O:45])[NH:25][C:26]1([C:30]2[CH:31]=[CH:32][C:33]([C:2]3[C:7](=[O:8])[C:6]4[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=4[O:4][C:3]=3[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:34][CH:35]=2)[CH2:27][CH2:28][CH2:29]1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CCC1
Reactant: O=c1c(Br)c(-c2ccccc2)oc2ccccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccccc4c3=O)cc2)CCC1
Temperature: 80 °C
Reaction time: 21 h
Yield: 29 %

Procedure:
To a round-bottom flask was added 3-bromo-2-phenyl-1-benzopyran-4-one (27.1 mg, 0.09 mmol) and {1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (50.4 mg, 0.135 mmol) in toluene:ethanol (4:1, 2.5 mL) and 2 M aqueous sodium carbonate (1 mL). The solution was degassed for 20 minutes, after which time, tetrakis(triphenylphosphine) palladium (5.2 mg, 5 mol %) was added. The reaction mixture was heated to 80° C. using an oil bath with a water cooled reflux condenser, while stirring for 21 hours. The reaction mixture cooled to RT, suspended in ethyl acetate and washed with brine, dried (MgSO4), filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (10:1 to 5:1 hexane:EtOAc gradient) to give a white solid (12.2 mg, 94%). 1H-NMR (400 MHz, CDCl3) δ 8.30 (d, 1H), 7.66 (dd, 1H), 7.53 (dd, 1H), 7.38-7.45 (m, 3H), 7.30-7.36 (m, 3H), 7.27 (d, 2H), 7.19 (d, 2H), 5.11 (bs, 1H), 2.35-2.58 (m, 4H), 1.91-2.09 (m, 1H), 1.77-1.88 (m, 1H), 1.38 (bs, 9H).
Reaction SMILES: [OH:1][C:2]1[C:3]([OH:18])=[CH:4][C:5]2[O:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[CH3:16])[C:6]=2[CH:17]=1.C(=O)([O-])[O-].[K+:23].[K+].Cl[CH:26](Cl)[C:27]([O:29]C)=[O:28].O>CN(C)C=O>[K+:23].[C:11]1([CH3:16])[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:7]1[C:6]2[CH:17]=[C:2]3[O:1][CH:26]([C:27]([O-:29])=[O:28])[O:18][C:3]3=[CH:4][C:5]=2[O:9][N:8]=1
Reactant: COC(=O)C(Cl)Cl
Reactant: Cc1ccccc1-c1noc2cc(O)c(O)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccccc1-c1noc2cc3c(cc12)OC(C(=O)[O-])O3
Reaction time: 1.5 h
Yield: 47.4 %

Procedure:
A mixture of 5,6-dihydroxy-3-(o-tolyl)-1,2-benzisoxazole (4.7 g), potassium carbonate (12.1 g), methyl dichloroacetate (4.2 g) in N,N-dimethylformamide (40 ml) was stirred at 90°-95° C. for 1.5 hours. After cooling, water (10 ml) was added to the mixture followed by stirring at 80°-90° C. for 10 minutes. After cooling the mixture was extracted with ether, and then the ether layer was washed with water, dried and evaporated to remove the solvent. The residue was dissolved in a potassium bicarbonate aqueous solution, and then ethanol was added to the solution. The resulting precipitate was collected by filtration, washed with ethanol and dried in air to give 3.1 g of 3-(o-tolyl)-1,3-dioxolo [4,5-f]-1,2-benzisoxazole-6-carboxylic acid potassium salt. The resulting potassium salt was dissolved in a small amount of water, and after acidifying it with hydrochloric acid, was extracted with ether. The ether layer was washed with water, dried and evaporated to remove the solvent. The residue was recrystallized from acetonitrile to give 1.9 g of 3-(o-tolyl)-1,3-dioxolo[4,5-f]-1,2-benzisoxazole-6-carboxylic acid. m.p.: 166-170 (decomposition)
Reaction SMILES: Cl.[CH:2]([NH:5][OH:6])([CH3:4])[CH3:3].[OH-].[Na+].[Br:9][CH:10]([CH2:14][CH2:15]Br)[C:11](Cl)=[O:12]>C(Cl)Cl.O>[Br:9][CH:10]1[CH2:14][CH2:15][O:6][N:5]([CH:2]([CH3:4])[CH3:3])[C:11]1=[O:12]
Reactant: O=C(Cl)C(Br)CCBr
Reactant: CC(C)NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC(C)N1OCCC(Br)C1=O
Temperature: 5 °C
Yield: 10.5 %

Procedure:
To a stirred mixture of 5.3 g (47 mmol) of N-isopropylhydroxylamine hydrochloride in 100 ml of methylene chloride cooled to 5° C. was added 3.8 g (47 mmol) of 50% sodium hydroxide solution in 20 ml of water. To this mixture was added with stirring 12.4 g (47 mmol) of 2,4-dibromobutyrylchloride and twenty minutes later an additional 7.6 g (94 mmol) of 50% sodium hydroxide solution was added. After twenty hours the organic phase was separated, dried over anhydrous magnesium sulfate and concentrated to an oil. This oil was chromatographed on silica gel with 40% ethyl acetate-hexane to afford 1.1 g of oily dihydro-4-bromo-2-isopropyl-2H-1,2-oxazin-3(4H)-one.
Reaction SMILES: Cl.[CH:2]1([NH:8][C:9]2[C:10]3[CH:27]=[N:26][N:25]([CH2:28][CH3:29])[C:11]=3[N:12]=[CH:13][C:14]=2[C:15]2[CH2:19][C:18]3([CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[O:17][N:16]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[C:37](Cl)(=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39]>ClCCl>[CH:2]1([NH:8][C:9]2[C:10]3[CH:27]=[N:26][N:25]([CH2:28][CH3:29])[C:11]=3[N:12]=[CH:13][C:14]=2[C:15]2[CH2:19][C:18]3([CH2:24][CH2:23][N:22]([C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:21][CH2:20]3)[O:17][N:16]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: CCn1ncc2c(NC3CCCCC3)c(C3=NOC4(CCNCC4)C3)cnc21
Reactant: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCn1ncc2c(NC3CCCCC3)c(C3=NOC4(CCN(C(=O)C(C)(C)C)CC4)C3)cnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
N-Cyclohexyl-1-ethyl-5-(1-oxa-2,8-diazaspiro[4.5]dec-2-en-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine hydrochloride salt (70 mg, 0.00016 mole) (example 22) was taken in dichloromethane (10 ml). Triethyl amine (0.07 ml, 0.00050 mole) and pivaloyl chloride (0.030 ml, 0.00025 mole) were added at 0° C. The reaction mixture was stirred at room temperature overnight. It was diluted with dichloromethane, washed with sodium bicarbonate solution, extracted with brine, dried over anhydrous sodium sulphate and concentrated in vacuo. The crude product obtained was purified by preparative thin layer chromatography.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.Cl.[CH3:12]O>>[CH3:12][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([NH2:1])=[CH:3][CH:4]=1
Reactant: CO
Reactant: Nc1ccc(C(=O)O)cc1
Agent: Cl
Product: COC(=O)c1ccc(N)cc1

Procedure:
To a solution of 4-amino benzoic acid (100 grams, 729.18 mmol) in methanol (1000 mL) at 0° C. is passed dry HCl for 3 hours. The solution is then refluxed for 10 hours. Excess methanol is distilled, and water (1000 mL) is added. The solution is neutralized with dilute ammonia, filtered, and purified from an appropriate solvent.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:4]=1.BrC[CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>>[CH2:27]([O:26][C:24]([CH2:23][CH2:22][CH2:21][CH2:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:4]=1)=[O:25])[CH3:28]
Reactant: COc1nc(-c2ccccc2)nc2ccccc12
Reactant: CCOC(=O)CCCCBr
Product: CCOC(=O)CCCCOc1nc(-c2ccccc2)nc2ccccc12
Yield: 79.4 %

Procedure:
According to the preparation of 69, ethyl 5-bromovalerate (1.88 g, 9.00 mmol) was used to yield 73 (1.25 g, 79.4%) as colorless powder.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.[Br:9]N1C(=O)CCC1=O>ClCCl>[Br:9][C:4]1[C:5](=[O:8])[NH:6][CH:7]=[C:2]([CH3:1])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(=O)[nH]c1
Solvent: ClCCl
Product: Cc1c[nH]c(=O)c(Br)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 63.6 %

Procedure:
5-Methyl-2(1H)-pyridinone (50 g, 0.46 mol) was suspended in dichloromethane (500 mL). N-bromosuccinimide (82 g, 0.46 mol) was added in portions with cooling. Addition was finished after 15 min; the mixture was stirred for 1 h at room temperature and afterwards partitioned between dichloromethane and water. Organic phases were pooled, dried with Na2SO4 and the solvent was evaporated. The residue was purified by crystallization from ethyl acetate to yield 55 g of the title compound as a light yellow solid, mp 156–161° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:14]Br>C(Cl)(Cl)Cl>[Br:14][C:4]1[CH:5]=[CH:6][C:1]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[CH:2][CH:3]=1
Reactant: CCCCCCCc1ccccc1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: CCCCCCCc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 37921.8 %

Procedure:
Phenylheptane (100 g, 0.57 mol) was dissolved in 900 mL of chloroform, and ferric chloride (1.41 g, 9 mmol) was added. The mixture was cooled to 0° C. and bromine (32 mL, 0.62 mmol) was added dropwise through an additional funnel. The reaction was kept in dark to prevent the bromination of the aliphatic side chain. After stirring at room temperature overnight, the reaction was quenched with 1N KOH. After extraction, the organic phase was washed with water and dried over MgSO4. The crude product was a brown oil and was purified by column chromatography on silica gel using heptane as an eluent to give 60 g of pure product as light yellow oil at 42% yield. 1H NMR (CDCl3) δ (ppm): 0.88 (t, J=6.9 Hz, 3H), 1.26-1.31 (m, 8H), 1.54-1.59 (m, 2H), 2.54 (t, J=7.8 Hz, 2H), 7.04 (d, J=8.2 Hz, 2H), 7.38 (d, J=8.2 Hz, 2H). FD-MS: m/z 255 (M+).
Reaction SMILES: [CH2:1]([C:3]1([C:16]2[N:17]=[CH:18][NH:19][CH:20]=2)[CH2:11][C:10]2[C:5](=[CH:6][C:7]([N+:12]([O-])=O)=[CH:8][CH:9]=2)[C:4]1=[O:15])[CH3:2].[H][H]>C(O)C.[Pd]>[NH2:12][C:7]1[CH:6]=[C:5]2[C:10]([CH2:11][C:3]([CH2:1][CH3:2])([C:16]3[N:17]=[CH:18][NH:19][CH:20]=3)[C:4]2=[O:15])=[CH:9][CH:8]=1
Reactant: CCC1(c2c[nH]cn2)Cc2ccc([N+](=O)[O-])cc2C1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCC1(c2c[nH]cn2)Cc2ccc(N)cc2C1=O
Yield: 93.2 %

Procedure:
To 7.20 g (0.0265 mol) of 2-ethyl-2,3-dihydro-2-(1H-imidazol-4-yl)-6-nitro-1H-inden-1-one dissolved in 70 ml of ethanol was added 0.7 g of 10% palladium on carbon and the mixture was shaken in an atmosphere of hydrogen at the room temperature. When the reduction came to a standstill the catalyst was removed. The filtrate was concentrated to give 6-amino-2-ethyl-2,3-dihydro-2-(1H-imidazol-4-yl)-1H-inden-1-one (5.96 g, 93%). The product was purified by flash chromatography eluting with methylene chloride--methanol mixture (9.5:0.5).
Reaction SMILES: Cl[C:2]1[C:3]2[S:10][C:9]3[N:11]=[CH:12][CH:13]=[CH:14][C:8]=3[C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].C(OCCO)C>>[Cl:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH:19][C:2]1[C:3]2[S:10][C:9]3[N:11]=[CH:12][CH:13]=[CH:14][C:8]=3[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2c1sc1ncccc12
Reactant: Nc1cccc(Cl)c1
Solvent: CCOCCO
Product: Clc1cccc(Nc2ncnc3c2sc2ncccc23)c1
Reaction time: 3 h
Yield: 29.4 %

Procedure:
A mixture of 4-chloropyrido [3',2'; 4,5]thieno[3,2-d]pyrimidine (0.12 g, 0.54 mmol), 3-chloroaniline (0.06 mL, 0.5 mmol) and 2-ethoxyethanol (5 mL) is heated under N2 with stirring at 135 C. for 3 h. Upon cooling a solid precipitates. The solid is collected by filtration, washed with acetone and dried in a vacuum oven at ~80 C. to give 4-(3-chloroanilino)pyrido[3',2'; 4,5]thieno[3,2-d]pyrimidine (46 mg, 27%). 1H NMR (DMSO) δ9.97 (1H, s), 8.88 (1H, dd, J=4.6, 1.7 Hz), 8.85 (1H, s), 8.72 (1H, dd, J=8.0, 1.7 Hz), 8.08 (2H, t, J=2.0 Hz), 7.79 (1H, ddd, J=8.3, 2.0, 0.8 Hz), 7.69 (1H, dd, J=8.0, 4.6 Hz), 7.43 (1H, t, J=8.0 Hz), 7.19 (1H, ddd, J=8.0, 2.0, 0.8 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>S(=O)(=O)(O)O>[C:12]([O:11][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)c1cc(Cl)ccc1O
Agent: O=S(=O)(O)O
Product: CC(=O)Oc1ccc(Cl)cc1C(=O)O
Temperature: 40 °C

Procedure:
A mixture of 86 g (0.5 mole) of 5-chloro salicylic acid and 102 g (1.0 mole) of acetic anhydride are warmed to 40° C. With stirring, 5 drops of conc. sulfuric acid are added, which causes an exothermic reaction. The mixture is stirred for 1/2 hour at 60° C. then poured into ice. The solid is filtered, washed with water and air dried, mp 146°-8° C, and is used as is for the next step. ##STR5##
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[Cl:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:31][C:32]1[CH:37]=[C:36]([N:11]2[C:12]3[C:17](=[CH:16][C:15]([C:19]([N:21]4[CH2:22][CH2:23][N:24]([CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:26]4)=[O:20])=[CH:14][CH:13]=3)[CH:18]=[C:10]2[C:8]([N:5]2[CH2:6][CH2:7][C:2]([F:1])([F:30])[CH2:3][CH2:4]2)=[O:9])[CH:35]=[CH:34][CH:33]=1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Reactant: OB(O)c1cccc(Cl)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3-c2cccc(Cl)c2)CC1
Yield: 37 %

Procedure:
The title compound was synthesized in analogy to example 66, from (4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone (example 32), 3-chlorphenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a colorless foam (37%).