Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(C1NN=C(CCC)C=1)=O)C.ClC1C=C(C=CC=1Cl)CBr.[Cl:24][C:25]1[CH:26]=[C:27]([CH:40]=[CH:41][C:42]=1[Cl:43])[CH2:28][N:29]1[C:33]([C:34]([OH:36])=[O:35])=[CH:32][C:31]([CH2:37][CH2:38][CH3:39])=[N:30]1.[NH2:44][C:45]1[S:46][CH:47]=[CH:48][N:49]=1>>[Cl:24][C:25]1[CH:26]=[C:27]([CH:40]=[CH:41][C:42]=1[Cl:43])[CH2:28][N:29]1[C:33]([C:34]([OH:36])=[O:35])=[CH:32][C:31]([CH2:37][CH2:38][CH3:39])=[N:30]1.[S:46]1[CH:47]=[CH:48][N:49]=[C:45]1[NH:44][C:34]([C:33]1[N:29]([CH2:28][C:27]2[CH:40]=[CH:41][C:42]([Cl:43])=[C:25]([Cl:24])[CH:26]=2)[N:30]=[C:31]([CH2:37][CH2:38][CH3:39])[CH:32]=1)=[O:36]
Reactant: Nc1nccs1
Agent: CCCc1cc(C(=O)O)n(Cc2ccc(Cl)c(Cl)c2)n1
Agent: CCCc1cc(C(=O)OCC)[nH]n1
Agent: Clc1ccc(CBr)cc1Cl
Product: CCCc1cc(C(=O)Nc2nccs2)n(Cc2ccc(Cl)c(Cl)c2)n1

Procedure:
2-(3,4-Dichlorobenzyl)-5-propyl-2H-pyrazole-3-carboxylic acid (0.84 g) was prepared from 5-propyl-2H-pyrazole-3-carboxylic acid ethyl ester (0.91 g, 5.0 mmol) and 3,4-dichlorobenzyl bromide (1.32 g, 5.5 mmol) following the general procedures D and E. 2-(3,4-dichlorobenzyl)-5-propyl-2H-pyrazole-3-carboxylic acid thiazol-2-ylamide (63 mg) was prepared from 2-(3,4-dichlorobenzyl)-5-propyl-2H-pyrazole-3-carboxylic acid (78 mg, 0.25 mmol) and 2-aminothiazole (25 mg, 0.25 mmol) following the general procedure F.
Reaction SMILES: CC(C[AlH]CC(C)C)C.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20](/[CH:23]=[CH:24]/[C:25](OC)=[O:26])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].CO>C(Cl)Cl>[OH:26][CH2:25]/[CH:24]=[CH:23]/[CH:20]1[CH2:21][CH2:22][N:17]([C:15]([O:14][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:16])[CH2:18][CH2:19]1
Reactant: COC(=O)/C=C/C1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)C[AlH]CC(C)C
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(/C=C/CO)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
1 M DiBAl—H in dichloromethane (42 mL, 2.2 eq.) was added slowly, via an addition funnel, over 20 min to a well stirred solution of the α,β-unsaturated ester from step 1 of this example (5.14 gram, 1 eq.) in anhydrous DCM (100 mL) under argon atmosphere at −78° C. The resulting solution was warmed to 0° C. after completion of addition and was kept at that temperature for 30 min. The reaction was cooled back to −78° C. and 4 mL MeOH was added slowly to quench the excess DiBAl-H. The cold solution was further stirred at −78° C. for 10 min before pouring into 150 mL saturated aqueous Rochelle (sodium potassium tartrate) salts solution. The mixture was vigorously stirred at room temperature for 3 hours until it turned clear. The organic layer was separated, dried over sodium sulfate, filtered and concentrated i. vac. The residue was further purified by column chromatography using acetone/hexanes (20%, isocratic) to give the desired product as colorless oil.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[S:10][C:11]=2[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:31])C=1>C(#N)C>[O-:31][N+:20]1[CH:19]=[CH:18][C:17]([C:9]2[S:10][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=2)=[CH:22][CH:21]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)c1sc(-c2ccncc2)nc1-c1ccccc1
Solvent: CC#N
Product: CCOC(=O)c1sc(-c2cc[n+]([O-])cc2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 72.1 %

Procedure:
To a suspension of ethyl 4-phenyl-2-pyridin-4-yl-1,3-thiazole-5-carboxylate (2.6 g, 8.5 mmol) produced above in acetonitrile (300 mL) was added m-chloroperbenzoic acid (containing water, about 70%, 3.9 g, about 16.0 mmol), and the mixture was stirred at room temperature for 2 days. The reaction solution was concentrated under reduced pressure to about 100 mL, and the obtained suspension was diluted with ethyl acetate (300 mL), and washed successively with saturated aqueous sodium bisulfite solution (150 mL×2) and saturated aqueous sodium carbonate solution (150 mL×2). The combined aqueous layer was extracted with ethyl acetate (200 mL×2). The combined organic layer was dried over anhydrous magnesium sulfate, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained solid was washed with ethyl acetate, and collected by filtration to give the title compound (2.0 g, 72%) as a yellow solid.
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH3:6][N+:7]1[C:12](Cl)=[CH:11][C:10]([NH2:14])=[CH:9][N:8]=1.C(#N)C.[C:18]1([OH:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>N1C=CC=CC=1>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH3:6][N+:7]1[C:12]([O:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:11][C:10]([NH2:14])=[CH:9][N:8]=1
Reactant: Oc1ccccc1
Reactant: C[n+]1ncc(N)cc1Cl
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: c1ccncc1
Solvent: CC#N
Product: C[n+]1ncc(N)cc1Oc1ccccc1

Procedure:
12.2 parts of 1-methyl-4-amino-6-chloropyridazinium perchlorate in 150 parts of acetonitrile is stirred with 5 parts of phenol and 4 parts of pyridine for 4 hours at 80°C. The reaction mixture is filtered and the filtrate is concentrated at subatmospheric pressure. About 200 parts of water is added. 5.5 parts (36.6% of theory) of 1-methyl-4-amino-6-phenoxypyridazinium perchlorate is obtained; C11H12O5N3Cl, melting point 182° to 184°C after having been recrystallized from water.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=1.[C:9]([N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)(=[O:11])[CH3:10].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[C:9]([N:12]1[CH2:17][CH2:16][N:15]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=2)[CH2:14][CH2:13]1)(=[O:11])[CH3:10]
Reactant: CC(=O)N1CCNCC1
Reactant: Fc1cccc(F)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(=O)N1CCN(c2cccc(F)n2)CC1
Yield: 99.9 %

Procedure:
A solution of 2,6-difluoropyridine (9.0 g), 1-acetylpiperazine (5.0 g) and potassium carbonate (8.1 g) in acetonitrile (100 ml) was refluxed under heating for 18 hr. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a pale-brown solid (8.7 g). The obtained pale-brown solid was crystallized from ethyl acetate-hexane to give the title compound (5.5 g) as pale-brown crystals.
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:12][CH3:13])[CH:9]=2)[CH:4]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[O:3]1.[OH-:23].[Na+].Cl>CS(C)=O.CN(C=O)C>[OH:23][C:4]1([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[C:5]2[C:10](=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2)[CH2:11][CH:2]([CH3:1])[O:3]1
Reactant: COc1ccc2c(c1)CC(C)OC2c1ccc([N+](=O)[O-])cc1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: COc1ccc2c(c1)CC(C)OC2(O)c1ccc([N+](=O)[O-])cc1
Reaction time: 5 h

Procedure:
A solution of 3 (1.3 g) in 4 ml of DMSO and 24 ml of DMF was cooled to 8-12° C. and air was passed through the mixture. To the solution was added 1.2 ml of 50% aqueous sodium hydroxide in one portion and the resulting mixture was stirred for 5 hours. HCl (1 N) was added, and extracted with ethyl acetate three times. The combined organic phase was washed with water in order to remove DMF, dried over Na2SO4. Removal of the solvent afforded syrup crude product (1.6 g), which was used directly for the next step.
Reaction SMILES: N#N.[F:3][C:4]1[CH:21]=[CH:20][C:7]([CH2:8][C:9]2[NH:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[CH:10]=2)=[CH:6][CH:5]=1.[H-].[Na+].Br[CH2:25][C:26]([O:28][CH3:29])=[O:27]>C1COCC1>[F:3][C:4]1[CH:21]=[CH:20][C:7]([CH2:8][C:9]2[N:13]([CH2:25][C:26]([O:28][CH3:29])=[O:27])[N:12]=[C:11]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[CH:10]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)CBr
Reactant: Fc1ccc(Cc2cc(-c3ccncc3)n[nH]2)cc1
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)Cn1nc(-c2ccncc2)cc1Cc1ccc(F)cc1
Temperature: 5 °C
Reaction time: 1.5 h
Yield: 47.5 %

Procedure:
A 22 liter, three-neck, round bottom flask equipped with a mechanical stirrer, Claisen adapter with a thermocouple and N2 inlet adapter, and a 250 ml addition funnel was charged with THF (10 L), and 4-[5-(4-fluorobenzyl)-1H-pyrazol-3-yl]pyridine (385.5 g, 1.52 mol). The resulting solution was cooled to 5° C. using a water/ice/salt bath. Sodium hydride (60% dispersion in mineral oil, 66.9 g, 1.67 mol) was then added in several portions at such that the internal temperature did not exceed 15° C. The resulting red mixture was stirred at 5° C. for 1.5 hours. Methyl bromoacetate (254 g, 1.67 mol) was then added drop-wise at such a rate that the temperature did not exceed 15° C. The mixture was then allowed to slowly reach room temperature overnight. The mixture was then filtered through celite, and the celite was washed with ethyl acetate. The majority of the THF was removed by rotary evaporation. Ethyl acetate (4 L) and water (4 L) were then added. The layers were separated and the aqueous layer was extracted with ethyl acetate (2×3 L). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The mixture of isomers (80:20 by GC-MS) was then eluted through silica gel using 100% ethyl acetate. The fractions that contained the isomers were concentrated and the solid suspended in ether (3 L). After heating to boiling, ethyl acetate (2 L) was added until the solid dissolved, followed by hexanes (4 L). After cooling overnight, the solid was filtered and dried under reduced vacuum to give the title compound as a red solid (235 g, 47%). 1H NMR (400 MHz, CD2Cl2) δ ppm 8.56 (d, 2 H) 7.61 (d, 2 H) 7.20 (t, 2 H) 7.03 (t, 2 H) 6.42 (s, 1 H) 4.86 (s, 2 H) 3.96 (s, 2 H) 3.71 (s, 3 H); m/z (APCI+) for C18H16N3O2F 326.1 (M+H)+.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[C:7]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[C:6]([CH3:15])=[CH:5][C:4]=1[NH:16][C:17]1[N:22]=[C:21]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)[C:20]([CH3:30])=[CH:19][N:18]=1.[F:31][C:32]([F:37])([F:36])[C@@H:33]1[CH2:35][O:34]1>CN(C=O)C>[CH3:15][C:6]1[CH:5]=[C:4]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C:24]3[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=3)[C:20]([CH3:30])=[CH:19][N:18]=2)[C:3]([CH3:2])=[CH:8][C:7]=1[CH:9]1[CH2:14][CH2:13][N:12]([CH2:35][C@H:33]([OH:34])[C:32]([F:37])([F:36])[F:31])[CH2:11][CH2:10]1
Reactant: FC(F)(F)[C@@H]1CO1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3C)ncc2C)n[nH]1
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCN(C[C@H](O)C(F)(F)F)CC4)cc3C)ncc2C)n[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N2-(2,5-dimethyl-4-(piperidin-4-yl)phenyl)-5-methyl-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine hydrochloride (36.0 mg, 0.084 mmol) in DMF (0.5 mL) were added TEA (23.4 μL, 0.168 mmol) and (S)-2-(trifluoromethyl) oxirane (72.8 μL, 0.84 mmol). The reaction mixture was stirred at room temperature overnight, and purified by preparative RP-HPLC to provide (S)-3-(4-(2,5-dimethyl-4-(5-methyl-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)phenyl)piperidin-1-yl)-1,1,1-trifluoropropan-2-ol; ESMS m/z 504.3 (M+H+).
Reaction SMILES: C([N:8]1[CH2:16][CH:15]2[CH:10]([C:11](OC)(OC)[CH2:12][CH2:13][C:14]2(C2C=CC=CC=2OC)O)[CH2:9]1)C1C=CC=CC=1.C(N(CC)CC)C.FC(F)(F)C(O)=[O:40].[OH-].[Na+]>ClCCl>[C:9]1(=[O:40])[CH:10]2[CH:15]([CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:16][NH:8]1
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccccc1C1(O)CCC(OC)(OC)C2CN(Cc3ccccc3)CC21
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1NCC2CCCCC12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 7 g of (3aRS,4RS,7aSR)-2-benzyl-7,7-dimethoxy -4-(2-methoxyphenyl)-4-perhydroisoindolol in 70 cm3 of dry dichloromethane are added 6.5 cm3 of triethylamine and 6.5 cm3 of trifluoroacetic acid. After stirring for 3 hours at room temperature, the reaction mixture, cooled to +5° C., is basified with 50 cm3 of 1N sodium hydroxide. The organic phase is separated out, washed with water, dried over magnesium sulphate and then concentrated to dryness under reduced pressure (2.7 kPa). The oil obtained is crystallized in diisopropyl ether. The solid, washed with petroleum ether, is then drained and dried under reduced pressure at 40° C. 3.4 g of (3aRS,7RS,7aSR)-2-benzyl-7-hydroxy -7-(2-methoxyphenyl)-4)-perhydroisoindolone are obtained, in the form of a cream-coloured solid. M.p.=96C.
Reaction SMILES: [CH3:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][NH2:4].[C:11](Cl)(=O)[CH3:12]>>[CH3:11][CH:12]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:2]([CH3:1])[CH2:3][NH:4]1
Reactant: CC(CN)c1ccccc1
Reactant: CC(=O)Cl
Product: CC1CNC(C)c2ccccc21

Procedure:
In accordance with the same procedures as in Preparation 1-1, except that 14.5 ml of β-methylphenethyl-amine(0.1M) and 7.8 ml of acetyl chloride(0.11M) were used as starting materials, 6.6 g of the title compound was prepared.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:11][CH2:12][C:13]2[CH:14]=[C:15]([CH:19]([OH:24])[CH2:20][CH2:21][CH2:22][CH3:23])[CH:16]=[CH:17][CH:18]=2)[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:32](Cl)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>ClCCl>[C:32]([O:24][CH:19]([C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([CH2:12][O:11][C:9]2[CH:8]=[CH:7][CH:6]=[C:5]3[C:10]=2[N:1]=[CH:2][CH:3]=[CH:4]3)[CH:14]=1)[CH2:20][CH2:21][CH2:22][CH3:23])(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCCC(O)c1cccc(COc2cccc3cccnc23)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCC(OC(=O)c1ccccc1)c1cccc(COc2cccc3cccnc23)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3.2 g (10 mmol) of 1-[3-(quinolin-8-yloxymethyl)phenyl]-pentanol are dissolved in 50 ml of dichloromethane. After the addition of 2.8 ml of triethylamine and 1.16 ml of benzoyl chloride, the mixture is stirred for 2 hours at 25° C. and then heated under reflux for 5 hours. The reaction mixture is washed three times with water, dried over sodium sulphate and evaporated down. The residue is chromatographed over silica gel 60 (mobile phase: 100:2 dichloromethane/methanol). An oil is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:17])=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:7]=1.Cl[C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=1.C1(C)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>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.CCO>[CH3:17][C:5]1[CH:4]=[CH:3][C:2]([NH2:1])=[CH:7][C:6]=1[C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=1
Reactant: Cc1ccc(Cl)nc1
Reactant: Cc1ccc(N)cc1B1OC(C)(C)C(C)(C)O1
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: CCO
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2cc(N)ccc2C)nc1
Temperature: 90 °C
Reaction time: 18 h

Procedure:
To a round-bottom flask containing 5-amino-2-methyl-phenylboronic acid pinacol ester (348 mg, 1.5 mmol), 2-chloro-5-methylpyridine (381 mg, 3 mmol), Pd(PPh3)4 (192 mg, 0.15 mmol) is added toluene (12 ml), EtOH (3 ml) and 2M aqueous Na2CO3 solution (3 ml). The flask is purged with argon and sealed. The mixture is stirred at 90° C. for 18 hours, cooled to room temperature and then water (20 ml) and ethyl acetate (20 ml) are added. The organic layer is separated, washed with brine, dried over MgSO4 and concentrated. The residue is purified by silica gel flash chromatography, eluted with 2% methanol in dichloromethane to afford 4-Methyl-3-(5-methylpyridin-2-yl)aniline as a brown oil. LC-MS m/z: 199.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[CH:3]=1.[Br:10][CH2:11][C:12](Br)=[O:13].[Cl-].[Al+3].[Cl-].[Cl-].O>C(OCC)(=O)C>[Br:10][CH2:11][C:12]([C:7]1[C:2]([Cl:1])=[CH:3][C:4]([Cl:9])=[CH:5][C:6]=1[Cl:8])=[O:13]
Reactant: O=C(Br)CBr
Reactant: Clc1cc(Cl)cc(Cl)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(CBr)c1c(Cl)cc(Cl)cc1Cl
Temperature: 80 °C
Yield: 69 %

Procedure:
A mixture of 1,3,5-trichlorobenzene (10.0 g, 55.1 mmol), 2-bromoacetyl bromide (5.0 mL, 57.8 mmol, 1.05 eq), and aluminum chloride (7.7 g, 57.8 mmol, 1.05 eq) was heated neat at 80° C. under argon for 17 h until a black precipitate is formed. The reaction was cooled to room temperature, and the resultant black mass was dissolved in ethyl acetate (500 mL). Water (200 mL) was added slowly at 0° C. to quench the reaction, and the biphasic layers were separated. The organic layer was then washed with water (2×150 mL) and brine (1×150 mL), dried (MgSO4), filtered, and evaporated in vacuo. Recrystallization from hexane gave 11.5 g (69.3%) of 2-bromo-1-(2,4,6-trichlorophenyl)ethanone as a fluffy white solid. 1H-NMR (DMSO-d6) δ 7.86 (s, 2H), 4.78 (s, 2H); Rf=0.28, 2% ethyl acetate-hexane.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:13]([O:14][CH3:15])=[CH:12][C:6]2[CH2:7][CH2:8][NH:9][CH2:10][CH2:11][C:5]=2[CH:4]=1.C(N(CC)CC)C.Cl[C:24]([O:26][CH2:27][CH3:28])=[O:25]>C1(C)C=CC=CC=1>[C:24]([N:9]1[CH2:10][CH2:11][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:13]([O:14][CH3:15])=[CH:12][C:6]=2[CH2:7][CH2:8]1)([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCOC(=O)Cl
Reactant: COc1cc2c(cc1OC)CCNCC2
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCc2cc(OC)c(OC)cc2CC1

Procedure:
To a stirred solution of 42.6 g. (0.206 mole) of 7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepine in 1 l. of toluene were added 35.7 ml. of triethylamine (0.256 mole) and 24.5 ml. of ethyl chloroformate (0.256 mole), at room temperature, and the mixture was refluxed for 12 hours. The reaction mixture was filtered to remove triethylamine hydrochloride and the filtrate was concentrated. The solid residue (57 g.) was recrystallized from ethyl acetate to give 3-carboethoxy-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepine, m.p. 91°-93° C.
Reaction SMILES: [C:1]1([O-:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].Cl[CH2:10][CH2:11][CH2:12][NH:13][CH2:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH:20]=1.OCCCN.ClCC1C=NC=C(C2C=CC(F)=CC=2)C=1.P(Cl)(Cl)Cl>C(#N)C>[O:7]([CH2:10][CH2:11][CH2:12][NH:13][CH2:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([C:21]2[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=2)[CH:20]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Fc1ccc(-c2cncc(CNCCCCl)c2)cc1
Reactant: [O-]c1ccccc1
Agent: Fc1ccc(-c2cncc(CCl)c2)cc1
Agent: NCCCO
Agent: [Na+]
Solvent: CC#N
Solvent: ClP(Cl)Cl
Product: Fc1ccc(-c2cncc(CNCCCOc3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Analogously to Example 7 a solution of 2.3 g sodium phenolate and 2.5 g N-3-chloropropyl-N-[5-(4-fluorophenyl)-3-pyridylmethyl]-amine [obtainable by reaction of 3-hydroxypropylamine with 3-chloromethyl-5-(4-fluorophenyl)-pyridine and subsequent transformation of the product to the 3-chloropropyl-compound by reaction with PCl3 ] in 200 ml of acetonitrile is stirred for 5 hours at room temperature and worked up in a conventional manner to give N-(3-phenoxy-propyl)-N-[5-(4-fluorophenyl)-3-pyridyl-methyl]-amine. Stirring with Q5 equivalents of oxalic acid in 100 ml ethanol/water mixture gives the oxalate-hemihydrate, m.p. 217°.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:16])[CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1.[CH3:17]I>CN(C=O)C>[CH3:3][O:4][C:5](=[O:16])[CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH3:17])[CH:8]=1
Reactant: COC(=O)Cc1c[nH]c2ccccc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)Cc1cn(C)c2ccccc12
Reaction time: 1 h
Yield: 18.9 %

Procedure:
To a suspension of sodium hydride (104 mg, 7.61 mmol) in DMF (11 mL) was added a solution of 1H-indol-3-yl-acetic acid methyl ester (0.50 g, 2.6 mmol) in DMF (5.0 mL). The mixture was stirred for 1 h followed by addition of methyl iodide (1.1 g, 7.8 mmol). The reaction mixture was stirred for an additional 18 h, quenched, diluted with saturated ammonium chloride (200 mL), and then extracted with diethyl ether (3×100 mL). The combined organic layers were dried with Na2SO4, and the solvent was removed under reduced pressure. The crude residue was purified by flash chromatography (EtOAc/hexanes) giving 100 mg (19%) of (1-methyl-1H-indol-3-yl)-acetic acid methyl ester after purification. HPLC: Rt=8.91 (Method A). MS (ES+): mass calculated for C12H13NO2, 203.09; m/z found 204.09 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.60 (d, J=7.9 Hz, 1H), 7.30 (d, J=8.2 Hz, 1H), 7.23 (t, J=8.2 Hz, 1H), 7.13 (t, 7.4 Hz, 1H), 7.04 (s, 1H), 3.77 (s, 2H), 3.76 (s, 3H), 3.69 (s, 3H).
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]([C:8]1[O:9][C:10]2[CH:20]=[C:19]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])[C:18]([Br:27])=[CH:17][C:11]=2[C:12]=1[C:13]([NH:15][CH3:16])=[O:14])=[O:7])(=O)[CH3:2].CCN(CC)CC>C(Cl)Cl>[Br:27][C:18]1[C:19]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:23])=[O:24])=[CH:20][C:10]2[O:9][C:8]([C:6]3[O:7][C:1]([CH3:2])=[N:4][N:5]=3)=[C:12]([C:13]([NH:15][CH3:16])=[O:14])[C:11]=2[CH:17]=1
Reactant: CNC(=O)c1c(C(=O)NNC(C)=O)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=O)c1c(-c2nnc(C)o2)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Yield: 99.8 %

Procedure:
A mixture of compound 2-(2-acetylhydrazinecarbonyl)-5-bromo-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (150 mg, 0.33 mmol), p-TsCl (124 mg, 0.66 mmol) and Et3N (108 mg, 0.98 mmol) in CH2Cl2 (6 mL) was refluxed for 5 h. After concentration in vacuo, the residue was purified with prep-TLC (DCM:MeOH=100:1) to give the product 5-bromo-N-methyl-2-(5-methyl-1,3,4-oxadiazol-2-yl)-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (146 mg, yield: 63%). 1H-NMR (CDCl3, 400 MHz) δ 9.80 (br s, 1H), 8.96 (s, 1H), 7.77 (s, 1H), 3.36 (s, 3H), 3.13˜3.06 (m, 6H), 2.75 (s, 3H). MS (M+H)+: 443/445.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:5]=[N:6][CH:7]=[N:8][CH:9]=1.[C:11]([C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[CH:14]=1)#[CH:12].N>>[F:19][C:17]1[CH:18]=[C:13]([C:11]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[N:8][CH:9]=3)[CH:12]=2)[CH:14]=[C:15]([F:20])[CH:16]=1
Reactant: ON=C(Cl)c1cncnc1
Reactant: C#Cc1cc(F)cc(F)c1
Agent: N
Product: Fc1cc(F)cc(-c2cc(-c3cncnc3)no2)c1

Procedure:
The titled compound was prepared as the hydrochloride salt according to Method CB using the product of Example 44B (79 mg, 0.5 mmol) and 1-ethynyl-3,5-difluorobenzene (Apollo, 69 mg, 0.5 mmol). 1H NMR (300 MHz, DMSO-d6) δ 7.52 (tt, J=9.5, 2.4 Hz, 1H), 7.62-7.78 (m, 2H), 7.93 (s, 1H), 9.30 (s, 2H), 9.36 (s, 1H) ppm; MS (DCI/NH3) m/z 260 (M+H)+.