Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[N:3]=1.[CH2:18](OCC)[CH3:19].Cl>C(O)C>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH2:18][CH3:19])=[O:9])[CH:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[N:3]=1
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)nc(Cl)n1
Reactant: CCOCC
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccc(Cl)cc2)nc(Cl)n1
Temperature: 20 °C
Reaction time: 24 h
Yield: 78 %

Procedure:
To a solution of 2-chloro-6-(4-chloro-phenyl)-pyrimidine-4-carboxylic acid (1.35 g, 5.0 mmol) in ethanol (50 mL) was added diethyl ether (10 mL) which had been saturated previously with hydrochloric acid gas. The reaction mixture was stirred for 24 h at 20° C. The solution was evaporated under reduced pressure and the residual oil was dissolved in ethyl acetate. The solution was washed with saturated sodium hydrogencarbonate solution and with brine, dried over sodium sulfate, and evaporated under reduced pressure. The residual material was crystallized from ethyl acetate/heptane to give the title compound (1.17 g, 78%) as light yellow solid. MS ISN (m/e): 297.1 [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=8.31 (s, 1H), 8.13 and 7.53 (2 d, 2×2H), 4.53 (q, 2H), 1.47 (t, 3H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[C:20]4[C:15](=[CH:16][C:17]([O:23][CH2:24][C@@H:25]5[CH2:27][O:26]5)=[C:18]([O:21][CH3:22])[CH:19]=4)[N:14]=[CH:13][N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[OH:26][C@@H:25]([CH2:27][N:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)[CH2:24][O:23][C:17]1[CH:16]=[C:15]2[C:20]([C:11]([O:10][C:6]3[CH:5]=[C:4]4[C:9](=[CH:8][CH:7]=3)[NH:1][CH:2]=[CH:3]4)=[N:12][CH:13]=[N:14]2)=[CH:19][C:18]=1[O:21][CH3:22]
Reactant: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1OC[C@@H]1CO1
Reactant: C1CCNCC1
Product: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1OC[C@@H](O)CN1CCCCC1
Yield: 74.1 %

Procedure:
Using an analogous procedure to that described in Example 297, (2S)-4-(indol-5-yloxy)-6-methoxy-7-(oxiran-2-ylmethoxy)quinazoline (100 mg, 0.28 mmol), (prepared as described for the starting material in Example 297), was reacted with piperidine (70 mg, 0.83 mmol), to give (2S)-7-(2-hydroxy-3-piperidinopropoxy)-4-(indol-5-yloxy)-6-methoxyquinazoline (93 mg, 73%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2].[N+:19]([O-])([OH:21])=[O:20]>>[C:1]([NH:4][C:5]1[C:14]([N+:19]([O-:21])=[O:20])=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(C(F)(F)F)cc1NC(C)=O
Reactant: O=[N+]([O-])O
Product: COC(=O)c1ccc(C(F)(F)F)c([N+](=O)[O-])c1NC(C)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 38 %

Procedure:
To an ice-cooled nitric acid (fuming) (20 ml) was added methyl 2-(acetylamino)-4-(trifluoromethyl)benzoate (7.30 g, 0.028 mol) portionwise and stirred for 30 min. The reaction mixture was poured into ice-water and extracted with ethyl acetate. The extracts were washed with aqueous saturated sodium bicarbonate and water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel with a 30% ethyl acetate/n-hexane to give 3.20 g (0.010 mol, 38%) of the title compound as a yellow powder.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[C:5]([N:14]2[C:18]([CH3:19])=[C:17]([C:20]([NH:22][C:23]3[CH:24]=[N:25][C:26]([CH:30]4[CH2:35][CH2:34][C:33](=[O:36])[CH2:32][CH2:31]4)=[C:27]([CH3:29])[CH:28]=3)=[O:21])[CH:16]=[N:15]2)=[N:6][CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1.O>CO>[F:3][C:4]1[C:5]([N:14]2[C:18]([CH3:19])=[C:17]([C:20]([NH:22][C:23]3[CH:24]=[N:25][C:26]([C@H:30]4[CH2:31][CH2:32][C@H:33]([OH:36])[CH2:34][CH2:35]4)=[C:27]([CH3:29])[CH:28]=3)=[O:21])[CH:16]=[N:15]2)=[N:6][CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1
Reactant: Cc1cc(NC(=O)c2cnn(-c3ncc(C(F)(F)F)cc3F)c2C)cnc1C1CCC(=O)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1cc(NC(=O)c2cnn(-c3ncc(C(F)(F)F)cc3F)c2C)cnc1[C@H]1CC[C@H](O)CC1
Reaction time: 0.5 h

Procedure:
Sodium borohydride (116.8 mg) was added under ice-cooling to a solution of 1-[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]-5-methyl-N-[5-methyl-6-(4-oxocyclohexan-1-yl)pyridin-3-yl]-1H-pyrazole-4-carboxamide (211 mg) described in Example F34 in methanol (3 ml) and stirred at the same temperature for 30 minutes. After the reaction, water was added and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting residue was fractionated with HPLC (water-acetonitrile:containing 0.05% trifluoroacetic acid). The obtained fraction was neutralized by the addition of 10% sodium carbonate, and the precipitates was filtered and dried at 60° C. under current of air to give the titled compound (92 mg) as a white solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[O:7]1[C:11]2[CH:12]=[CH:13][C:14]([CH:16]([C:32]3[C:40]4[C:35](=[CH:36][C:37]([C:41](OC)=[O:42])=[CH:38][CH:39]=4)[N:34]([CH3:45])[CH:33]=3)[C:17]([NH:19][S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=3[O:30][CH3:31])(=[O:22])=[O:21])=[O:18])=[CH:15][C:10]=2[O:9][CH2:8]1.C(OCC)(=O)C>O1CCCC1>[O:7]1[C:11]2[CH:12]=[CH:13][C:14]([CH:16]([C:32]3[C:40]4[C:35](=[CH:36][C:37]([CH2:41][OH:42])=[CH:38][CH:39]=4)[N:34]([CH3:45])[CH:33]=3)[C:17]([NH:19][S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=3[O:30][CH3:31])(=[O:22])=[O:21])=[O:18])=[CH:15][C:10]=2[O:9][CH2:8]1
Reactant: COC(=O)c1ccc2c(C(C(=O)NS(=O)(=O)c3ccc(C)cc3OC)c3ccc4c(c3)OCO4)cn(C)c2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(C)ccc1S(=O)(=O)NC(=O)C(c1ccc2c(c1)OCO2)c1cn(C)c2cc(CO)ccc12
Temperature: 25 °C
Yield: 62.2 %

Procedure:
Lithium aluminium hydride (15 mg, 0.2 mmol) was added slowly to a stirred solution of methyl 3-{1-(1,3-benzodioxol-5-yl)-2-[(2-methoxy-4-methylphenyl)sulfonamido]-2-oxo-ethyl}-1-methyl-1H-6-indolecarboxyate (from step (a), 200 mg, 0.4 mmol) in tetrahydrofuran at 0° C. under a nitrogen atmosphere. After 2 h a further 1 equivalent (30 mg) of lithium aluminium hydride was added and the mixture was warmed to room temperature. After 1 h ethyl acetate (10 ml) was carefully added and the product extracted from 1N hydrochloric acid with ethyl acetate (2×50 ml). The combined organic layers were dried (MgSO4) and concentrated in vacuo. Purification by flash column chromatography (elution with 95% dichloromethane /5% methanol) gave the product as a white solid (130 mg).
Reaction SMILES: [CH3:1][CH:2]([C:8]([O:10]CC)=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].N1C=CC=CC=1.[Cl:19][C:20]1[C:26]([F:27])=[CH:25][C:24]([F:28])=[CH:23][C:21]=1[NH2:22]>>[Cl:19][C:20]1[C:26]([F:27])=[CH:25][C:24]([F:28])=[CH:23][C:21]=1[NH:22][C:8](=[O:10])[CH:2]([CH3:1])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: Nc1cc(F)cc(F)c1Cl
Reactant: CCOC(=O)C(C)C(=O)OCC
Solvent: c1ccncc1
Product: CCOC(=O)C(C)C(=O)Nc1cc(F)cc(F)c1Cl

Procedure:
The ester was prepared according to Procedure A using diethyl 2-methylmalonate (6.31 mL, 36.7 mmol), pyridine (3.96 mL, 48.9 mmol) and 2-chloro-3,5-difluoroaniline (4.00 g, 24.46 mmol) over 3 days. The residue was purified by column chromatography on silica gel (0-30% EtOAc/hexanes) to give ethyl 3-(2-chloro-3,5-difluorophenylamino)-2-methyl-3-oxopropanoate as a red oil. Mass Spectrum (ESI) m/e=292.0 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:30]=[CH:29][C:8]([C:9]([N:11](C(=O)C2C=CC=C(C=O)C=2)[C:12]2[C:13]([NH2:18])=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:31]([OH:33])[CH3:32]>>[C:1]([C:5]1[CH:30]=[CH:29][C:8]([C:9]([NH:11][C:12]2[C:13]([NH:18][C:9](=[O:10])[C:8]3[CH:7]=[CH:6][CH:5]=[C:32]([CH2:31][OH:33])[CH:29]=3)=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CCO
Reactant: CC(C)(C)c1ccc(C(=O)N(C(=O)c2cccc(C=O)c2)c2ccccc2N)cc1
Product: CC(C)(C)c1ccc(C(=O)Nc2ccccc2NC(=O)c2cccc(CO)c2)cc1
Yield: 99 %

Procedure:
Using the procedure described in Example 57, N2-(4-tert-butylbenzoyl)-N2-(3-formylbenzoyl)-1,2-benzenediamine (230 mg, 0.57 mmol) was reacted in ethanol to yield 227 mg (99%) of the title compound as an off-white amorphous solid.
Reaction SMILES: [CH3:1][C:2]#[N:3].C([Li])CCC.C[O:10][C:11]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[N:18]([Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])[CH:17]=[CH:16]2)=O.Cl>C1(C)C=CC=CC=1.CCCCCC>[O:10]=[C:11]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[N:18]([Si:22]([CH:26]([CH3:28])[CH3:27])([CH:29]([CH3:31])[CH3:30])[CH:23]([CH3:24])[CH3:25])[CH:17]=[CH:16]2)[CH2:1][C:2]#[N:3]
Reactant: COC(=O)c1ccc2c(ccn2[Si](C(C)C)(C(C)C)C(C)C)c1
Reactant: CC#N
Agent: Cl
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(C(=O)CC#N)ccc21
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 95.9 %

Procedure:
To a solution of 393 μL of anhydrous CH3CN (7.5 mmol) in 6 mL of dry toluene cooled down to −78° C., 5.35 mL of butyllithium in hexane solution (1.6 N) were added dropwise. The mixture was left stirring at −78° C. for 20 minutes and then a solution of 500 mg of 1-triisopropylsilanyl-1H-indole-5-carboxylic acid methyl ester (1.5 mmol) in 2 mL of dry toluene were added and the reaction allowed to reach room temperature. Upon reaction completion after about 20 minutes the mixture was cooled down to 0° C. and HCl 2N was added to pH 2. The organic phase was separated, dried over Na2SO4 and concentrated under reduced pressure, affording 490 mg of title product which was used in the next step without further purification (yield=96%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@@H:15]3[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[NH:10]1.Br[CH2:24][CH2:25][C:26]([F:29])([F:28])[F:27].[I-].ClCCl>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@@H:15]3[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[N:10]1[CH2:24][CH2:25][C:26]([F:29])([F:28])[F:27]
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccc(F)cc3F)c(=O)c12
Reactant: FC(F)(F)CCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC1(C)[C@@H]2CC[C@@]1(C)c1c2c(=O)n(-c2ccc(F)cc2F)n1CCC(F)(F)F
Temperature: 100 °C
Yield: 17.4 %

Procedure:
A mixture of (4S,7R)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 14; 200 mg, 0.66 mmol), tetrabutylammonium iodide (190 mg, 0.51 mmol) and 3-bromo-1,1,1-trifluoropropane (Aldrich; 5.00 g, 28.25 mmol) in dimethylformamide (2 mL) was heated in a pressure tube in an oil-bath at 100° C. for 4 days. An additional portion of tetrabutylammoiun iodide (190 mg, 0.51 mmol) was added and the reaction mixture was heated at 100° C. for 3 days and then cooled to room temperature. Dichloromethane (150 mL) was added and the solution was washed with water (5×25 mL) and aqueous sodium thiosulfate (25 mL), dried (magnesium sulfate), filtered, evaporated and purified using an ISCO 40 g column, eluting with 30-100% ethyl acetate/hexanes. Fractions homogeneous for the product were evaporated and the residue was triturated with petroleum ether. The mixture was evaporated again and dried at 70° C. under high vacuum to give (4S,7R)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1-(3,3,3-trifluoro-propyl)-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (46 mg, 17%) as a light yellow solid. ES(+)-MS (M+H) 401.
Reaction SMILES: Br[C:2]1[C:3]([F:19])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1.[CH3:20][C:21]1[C:22]([C:27]([OH:31])([C:29]#[CH:30])[CH3:28])=[N:23][CH:24]=[CH:25][CH:26]=1>>[F:19][C:3]1[C:2]([C:30]#[C:29][C:27]([OH:31])([C:22]2[C:21]([CH3:20])=[CH:26][CH:25]=[CH:24][N:23]=2)[CH3:28])=[CH:18][C:6]2[C:7]3[N:8]([CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=3)[CH2:9][CH2:10][O:11][C:5]=2[CH:4]=1
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1OCC2
Reactant: C#CC(C)(O)c1ncccc1C
Product: Cc1cccnc1C(C)(O)C#Cc1cc2c(cc1F)OCCn1cc(C(N)=O)nc1-2
Yield: 7 %

Procedure:
Similar to as described in General Procedure G, 10-bromo-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with 2-(3-methylpyridin-2-yl)but-3-yn-2-ol to give the titled compound as a yellow solid (15.0 mg, 7%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:14]2[N:15]([C:19]([C:26](OCC)=[O:27])=[C:20]([C:22]([F:25])([F:24])[F:23])[N:21]=2)[CH:16]=[CH:17][CH:18]=1.B.[OH-].[Na+].O>C(OCC)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:14]2[N:15]([C:19]([CH2:26][OH:27])=[C:20]([C:22]([F:24])([F:23])[F:25])[N:21]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)c1c(C(F)(F)F)nc2c(OCCCc3ccc(Cl)cc3Cl)cccn12
Agent: B
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: OCc1c(C(F)(F)F)nc2c(OCCCc3ccc(Cl)cc3Cl)cccn12
Temperature: 25 °C
Reaction time: 42 h
Yield: 46.6 %

Procedure:
To a stirred solution of ethyl 8-[3-(2,4-dichlorophenyl)propoxy]-2-(trifluoro-methyl)imidazo[1,2-α]pyridine-3-carboxylate (0.223 g, 0.483 mmol, see example 35) in anhydrous diethyl ether (20 mL) was added dropwise borane-methyl sulfide complex (2.0 mL, 20 mmol). The reaction mixture was stirred at ambient temperature for 42 h under argon and then heated at reflux for 3.5 h. Excess borane was subsequently hydrolyzed by dropwise addition of 5M aq sodium hydroxide (4 mL) to the cold (0° C.) reaction mixture. The resultant solution was stirred for 30 min and water (50 mL) was added. After successive extraction of the solution with diethyl ether (2×30 mL) and dichloromethane (30 mL), the organic extracts were combined, dried over anhydrous sodium sulfate and concentrated in vacuo to yield the crude desired product as a white solid. Purification by chromatography with a mixture of ethyl acetate-hexanes (1:1 v/v, containing 0.5% v/v isopropylamine) yielded 94.3 mg (47% yield) of {8-[3-(2,4-dichlorophenyl)propoxy]-2-(trifluoromethyl)imidazo[1,2-α]pyridin-3-yl}methanol as a pale yellow solid (Rf=0.41 in ethyl acetate-hexanes, 1:1 v/v, containing 0.5% v/v isopropylamine). A stirred suspension of {8-[3-(2,4-dichlorophenyl)propoxy]-2-(trifluoromethyl)imidazo[1,2-α]pyridin-3-yl}methanol (0.142 g, 0.339 mmol) in anhydrous methanol (5 mL) was treated with ethereal hydrogen chloride to form the hydrochloride salt. Concentration of the solution in vacuo and trituration of the residue in anhydrous diethyl ether afforded the title compound as an off-white solid (0.144 g, 93% yield). 1H-NMR (400 MHz, CDCl3/CD3OD) δ 8.46 (d, 1H, Ar), 7.39–7.45 (m, 2H, Ar), 7.35 (d, 1H, Ar), 7.27 (d, 1H, Ar), 7.19 (dd, 1H, Ar), 5.09 (s, 2H, CH2OH), 4.36 (t, 2H, CH2O), 2.99 (t, 2H, CH2Ar), 2.26 (m, 2H, CH2CH2CH2); 13C-NMR (100 MHz, CDCl3/CD3OD, APT) δ 146.38 (+), 138.09 (+), 136.58 (+), 135.35 (+), 133.50 (+), 132.24 (−), 129.94 (−), 128.28 (+), 128.06 (−), 124.01 (+), 122.05/119.36 (+), 120.49 (−), 119.12 (−), 112.57 (−), 70.26 (+), 52.25 (+), 29.76 (+), 29.10 (+); LRMS-ES m/z: M+ 419.2 (100%); Anal. calcd for C18H15N2O2Cl2F3.HCl: C, 47.44; H, 3.54; N, 6.15%. found: C, 47.04; H, 3.54; N, 6.02%.
Reaction SMILES: [CH2:1]([S:8][CH:9]1[N:12]([CH2:13][C:14]([NH2:16])=[O:15])[C:11](=[O:17])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na].[C:19]1([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30](Cl)=[O:31])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[H-].[Na+]>C1COCC1>[C:19]1([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([NH:16][C:14](=[O:15])[CH2:13][N:12]2[CH:9]([S:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:10][C:11]2=[O:17])=[O:31])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NC(=O)CN1C(=O)CC1SCc1ccccc1
Reactant: O=C(Cl)CCCCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: C1CCOC1
Product: O=C(CCCCCc1ccccc1)NC(=O)CN1C(=O)CC1SCc1ccccc1
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 20.6 %

Procedure:
A solution of (4-benzylthio-2-oxoazetidin-1-yl)acetamide (0.63 g, 2.52 mmol) in dry THF (15 ml) was added to a suspension of sodium hyride (60% in oil, 0.10 g, 2.5 mmol) in dry THF at -10° C. under a nitrogen atmosphere. The reaction was stirred at -10° C. for 10 minutes and was then treated with a solution of 6-phenylhexanoyl chloride (0.58 g, 2.75 mmol) in dry THF (5 ml) dropwise over 2 minutes maintaining the temperature at -10° C. The cooling bath was removed an after stirring for 60 minutes the reaction was treated with sodium hydride (50 mg, 1.25 mmol) and 6-phenylhexanoyl chloride (0.29 g, 1.38 mmol) in dry THF (2 ml). The reaction was stirred for 60 minutes, poured into ice/brine (100 ml), extracted with ethyl acetate (2×50 ml). The organic extracts were combined, washed with aq. sat. NaHCO3 solution, brine, dried (MgSO4) and evaporated under reduced pressure to an orange oil. Purification by repeated column chromatography eluted with hexane:ethyl acetate (3:1 to 1:1) gave the product as a colourless oil (0.22 g, 21% yield, contains 10% 6-phenylhexanoic acid) 1H nmr δ (CDCl3) 1.3-1.7 (6H, m, 3×CH2), 2.44 (2H, t, J=7.4 Hz, NHCOCH2), 2.62 (2H, t, J=7.6 Hz, PhCH2), 2.96, 3.02 (1H, dd, J=2.4, 15.3 Hz, H3), 3.39, 3.45 (1H, dd, J=5.1, 15.3 Hz, H3), 3.61, 4.32 (each 1H, d, J=18.8 Hz, NCH2CO), 3.76 (2H, m, SCH2), 4.9 (1H, m, H4), 7.1-7.3 (10H, m, 2×Ph--H), 8.17 (1H, m, NH)
Reaction SMILES: [CH3:1][C:2]1[C:3]2[N:4]([C:8]([N:11]3[CH2:16][CH2:15][N:14]([CH:17]4[CH2:22][CH2:21][N:20]([C:23](=[O:25])[CH3:24])[CH2:19][CH2:18]4)[CH2:13][CH2:12]3)=[N:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1.[Br:26]N1C(=O)CCC1=O.O>ClCCl>[Br:26][C:10]1[N:9]=[C:8]([N:11]2[CH2:12][CH2:13][N:14]([CH:17]3[CH2:22][CH2:21][N:20]([C:23](=[O:25])[CH3:24])[CH2:19][CH2:18]3)[CH2:15][CH2:16]2)[N:4]2[CH:5]=[CH:6][N:7]=[C:2]([CH3:1])[C:3]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)N1CCC(N2CCN(c3ncc4c(C)nccn34)CC2)CC1
Solvent: ClCCl
Solvent: O
Product: CC(=O)N1CCC(N2CCN(c3nc(Br)c4c(C)nccn34)CC2)CC1
Yield: 74.5 %

Procedure:
To 1-(4-(4-(8-methylimidazo[1,5-a]pyrazin-3-yl)piperazin-1-yl)piperidin-1-yl)ethanone (0.102 mmol, 35 mg) in dichloromethane (1 ml) at room temperature was added N-bromosuccinimide (0.102 mmol, 18.19 mg). After stirring at room temperature for 5 minutes water was added and the mixture extracted three times with dichloromethane. The combined organic extracts were dried over a phase separation filter and concentrated in vacuo to give 1-(4-(4-(1-bromo-8-methylimidazo[1,5-a]pyrazin-3-yl)piperazin-1-yl)piperidin-1-yl)ethanone (32 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(N(CC)CC)C.[C:20](Cl)(=[O:25])[CH2:21][CH2:22][CH2:23][CH3:24]>C(Cl)Cl>[CH3:12][C:9]1[CH:10]=[CH:11][C:2]([NH:1][C:20](=[O:25])[CH2:21][CH2:22][CH2:23][CH3:24])=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(C)ccc1N
Reactant: CCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCC(=O)Nc1ccc(C)cc1C(=O)OC
Yield: 104.7 %

Procedure:
To a solution of methyl 2-amino-5-methylbenzoate (8.1 g) and triethylamine (6.0 g) in methylene chloride (50 ml) was added dropwise, while stirring under ice-cooling, valeryl chloride (6.5 g). The reaction was allowed to stir for two hours, then the reaction mixture was washed with an aqueous solution of sodium carbonate, dilute hydrochloric acid and water, followed by drying. The solvent was evaporated to dryness to give a pale brown oil (12.8 g, 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[N+:15]([O-])([OH:17])=[O:16].S(=O)(=O)=O.S(=O)(=O)(O)O>>[Cl:1][C:2]1[C:7]([N+:15]([O-:17])=[O:16])=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Product: O=[N+]([O-])c1cc(C(F)(F)F)cc([N+](=O)[O-])c1Cl

Procedure:
dinitrating said 4-chloro-3-nitrobenzotrifluoride organic layer with a fresh acid mixture of nitric acid, sulfur trioxide, and sulfuric acid to form 4-chloro-3,5-dinitrobenzotrifluoride product, and a partially spent acid mixture containing a portion of said product dissolved therein, said fresh acid mixture containing sufficient nitric acid to effect said nitration and to provide for said mononitration upon recycling of said partially spent acid mixture back to step (a),
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[CH:13][C:14]([OH:17])=[N:15][CH:16]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][O:27][C:28]2[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][C:29]=2[O:37][CH3:38])=[CH:22][CH:21]=1.C(#N)C.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH3:38][O:37][C:29]1[CH:30]=[C:31]([C:2]2[CH:3]=[C:4]3[C:10]([C:11]4[CH:12]=[CH:13][C:14]([OH:17])=[N:15][CH:16]=4)=[CH:9][NH:8][C:5]3=[N:6][CH:7]=2)[CH:32]=[CH:33][C:28]=1[O:27][CH2:26][C:23]1[CH:22]=[CH:21][C:20]([O:19][CH3:18])=[CH:25][CH:24]=1
Reactant: COc1ccc(COc2ccc(B(O)O)cc2OC)cc1
Reactant: Oc1ccc(-c2c[nH]c3ncc(Br)cc23)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COc1ccc(COc2ccc(-c3cnc4[nH]cc(-c5ccc(O)nc5)c4c3)cc2OC)cc1
Reaction time: 0.33 h
Yield: 46 %

Procedure:
To the 5-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-pyridin-2-ol, 4-(4-methoxyphenylmethoxy)-3-methoxyphenylboronic acid (1.3 equiv.), and 6 mol % of dichlorobis(triiphenylphosphino)palladium (II) in a Smith process vial was added a 3:2:1 mixture of acetonitrile, water and a 2 M aqueous solution of sodium carbonate (0.10 M). The reaction was run in a Personal Chemistry® microwave reactor at 165° C. for 1200 s. Water was added and the mixture was extracted three times with ethyl acetate Purification on silica gel with a gradient or methanol/dichloromethane by flash chromatography afforded 5-{5-[3-methoxy-4-(4-methoxy-benzyloxy)-phenyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-pyridin-2-ol as a tan solid (46% yield). 1H NMR (DMSO-d6): δ 11.86 (broad s, 1H), 11.67 (broad s, 1H), 8.51 (d, J=2.5 Hz, 1H), 8.22 (s, 1H), 7.89 (dd, J=2.5, 9;5 Hz, 1H), 7.75 (d, J=2.5 Hz, 1H), 7.72 (s, 1H), 7.38 (d, J=8.5 Hz, 2H), 7.30 (d, J=2.0 Hz, 1H), 7.20 (dd, J=2.0, 8.5 Hz, 1H), 7.11 (d, J=8.0 Hz, 1H), 6.94 (d, J=8.5 Hz, 2H), 6.44 (d, J=9.5 Hz, 1H), 5.03 (s, 2H), 3.85 (s, 3H), 3.75 (s, 3H); HPLC/MS m/z: 454.1 [MH]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].S(=O)(=O)(O)O.[CH2:17](O)[CH3:18]>>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH2:17][CH3:18])=[O:10]
Reactant: CCO
Reactant: O=C(O)Cc1ccccc1O
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1ccccc1O

Procedure:
2-Hydroxyphenylacetic acid (6.06 g, 39.8 mmol) was dissolved in ethanol (180 ml) and the solution was added with concentrated sulfuric acid (2 ml) and heated under reflux for 90 minutes. The reaction mixture was concentrated under reduced pressure and diluted with ethyl acetate. The mixture was washed with water and saturated brine, and dried over sodium sulfate. Insoluble solids were removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the title compound as orange oil (7.67 g, yield: quantitative).