Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].Br[CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[Si:12]([O:19][C@@H:20]([C@@H:22]1[C@@H:25]([C@H:26]([C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[S:29])[CH3:27])[NH:24][C:23]1=[O:36])[CH3:21])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].P(=O)(O)(O)O>CN(C)C=O.C(OCC)C>[Si:12]([O:19][C@@H:20]([C@@H:22]1[C@@H:25]([C@H:26]([C:28]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[S:29])[CH3:27])[N:24]([CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[C:23]1=[O:36])[CH3:21])([C:15]([CH3:16])([CH3:17])[CH3:18])([CH3:14])[CH3:13]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1[C@@H](C)C(=S)c1ccccc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=P(O)(O)O
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N(CC(=O)OC(C)(C)C)[C@@H]1[C@@H](C)C(=S)c1ccccc1

Procedure:
To a suspension of sodium hydride (31 mg) in dry dimethylformamide (4.3 ml), there were added successively t-buty alpha-bromoacetate (835 mg) and (3S,4S)-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-4-[(1R)-1-phenylthiocarbonylethyl]azetidin-2-one (0.42 g), and the resultant mixture was stirred at room temperature for 1 hour under a nitrogen stream. The reaction mixture was diluted with diethyl ether and adjusted to pH 6.86 with a phosphoric acid buffer solution. The aqueous layer was separated from the organic layer and extracted with diethyl ether three times. The extracts were combined with the organic layer, washed three times with brine, dried over sodium sulfate and evaporated. The residue was purified by silica gel chromatography to give (3S,4S)-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-4-[(1R)-1-phenylthiocarbonylethyl]-1-(t-butyloxycarbonylmethyl)azetidin-2-one.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:24]=[CH:23][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:19](=[O:20])[CH:18]=[C:17]([CH3:21])[NH:16][C:15]=3[CH3:22])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[Br:27]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:27][C:18]1[C:19](=[O:20])[C:14]([C:11]2[CH:12]=[CH:13][C:8]([O:7][C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:25])[F:26])=[CH:24][CH:23]=3)=[CH:9][CH:10]=2)=[C:15]([CH3:22])[NH:16][C:17]=1[CH3:21]
Reactant: Cc1cc(=O)c(-c2ccc(Oc3ccc(C(F)(F)F)cc3)cc2)c(C)[nH]1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: Cc1[nH]c(C)c(-c2ccc(Oc3ccc(C(F)(F)F)cc3)cc2)c(=O)c1Br
Yield: 43.4 %

Procedure:
To a stirred suspension of 3-(4-(4-trifluoromethylphenoxy)phenyl)-2,6-dimethyl pyridin-4(1H)-one (4.12 g) in chloroform (50 ml) at room temperature was added N-bromosuccinimide (2.25 g). After 2 hr the mixture was filtered and the solid washed with chlorofrom and dried in vacuo. Recrystallisation from DMF afforded the title compound (2.18 g), m.p. 304°-305°, NMR δH (d6 -DMSO) 7.70 (2H, dd, J 5, 0.5 Hz), 7.0-7.3 (6H, m), 2.42 (3H, s), 2.1 (3H, s).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[OH-].[Na+].[CH3:12][S:13](Cl)(=[O:15])=[O:14]>>[CH3:12][S:13]([CH:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH2:1])[C:7]([OH:9])=[O:8])(=[O:15])=[O:14]
Reactant: CS(=O)(=O)Cl
Reactant: NCCCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Product: CS(=O)(=O)C(CCCCN)C(=O)O

Procedure:
Analogously to Example 20a, 65.6 g of ε-aminocaproic acid are reacted with 40 ml of methanesulfonyl chloride in the presence of 2N NaOH and the mixture is worked up. The DCA salt is prepared, and 42.3 g of melting point 134° are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[CH:6][C:3]=1[CH2:4][OH:5].C(N(C(C)C)CC)(C)C.[CH3:21][O:22][CH2:23]Cl.O>ClCCl>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[CH:6][C:3]=1[CH2:4][O:5][CH2:21][O:22][CH3:23]
Reactant: N#Cc1ccc(Br)c(CO)c1
Reactant: COCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: COCOCc1cc(C#N)ccc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.4 %

Procedure:
To a solution of 2-bromo-5-cyanobenzyl alcohol (4.59 g, 21.7 mmol) in dichloromethane (80 mL) were added diisopropylethylamine (5.6 mL, 32 mmol) and chloromethyl methyl ether (2.3 mL, 30 mmol) at 0° C., and the reaction mixture was stirred at room temperature overnight. Water was added, and the mixture was extracted with chloroform. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (6:1 hexane/ethyl acetate) to give 18f (4.08 g, 71%): 1H NMR (300 MHz, CDCl3) δ (ppm) 3.43 (s, 3H), 4.65 (s, 2H), 4.80 (s, 2H), 7.43 (dd, J=8.2, 4.1 Hz, 1H), 7.66 (d, J=8.2 Hz, 1H), 7.82 (d, J=4.1 Hz, 1H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[N:11]([CH2:13][CH:14]=[CH2:15])[CH:10]=[CH:9]2)([OH:3])=O.N1C2C(=CC=CC=2C([N:27]2[CH2:31][C@@H:30]([CH:32]3[CH2:34][CH2:33]3)[C@H:29]([CH2:35][N:36]3[CH2:41][CH2:40][CH:39]([C:42]4[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=4)[CH2:38][CH2:37]3)[CH2:28]2)=O)C=C1>>[CH2:13]([N:11]1[C:12]2[C:8](=[CH:7][CH:6]=[CH:5][C:4]=2[C:1]([N:27]2[CH2:31][C@@H:30]([CH:32]3[CH2:33][CH2:34]3)[C@H:29]([CH2:35][N:36]3[CH2:37][CH2:38][CH:39]([C:42]4[CH:43]=[CH:44][C:45]([F:48])=[CH:46][CH:47]=4)[CH2:40][CH2:41]3)[CH2:28]2)=[O:3])[CH:9]=[CH:10]1)[CH:14]=[CH2:15]
Reactant: O=C(c1cccc2cc[nH]c12)N1C[C@@H](CN2CCC(c3ccc(F)cc3)CC2)[C@H](C2CC2)C1
Reactant: C=CCn1ccc2cccc(C(=O)O)c21
Product: C=CCn1ccc2cccc(C(=O)N3C[C@@H](CN4CCC(c5ccc(F)cc5)CC4)[C@H](C4CC4)C3)c21

Procedure:
The title compound was prepared from 7-carboxy-N-allylindole and 3-(S)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(S)-(cyclopropyl)pyrrolidine (Example 11) as described in Example 11. Mass Spectrum (EI) m/e 486 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)#[CH:2].[CH2:9]([Li])[CH2:10][CH2:11][CH3:12].[CH3:14][SiH:15](Cl)[CH3:16]>O1CCCC1>[C:3]1([C:1]#[C:2][Si:15]([C:9]#[C:10][C:11]2[CH:12]=[CH:4][CH:3]=[CH:1][CH:2]=2)([CH3:16])[CH3:14])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C[SiH](C)Cl
Reactant: [Li]CCCC
Reactant: C#Cc1ccccc1
Solvent: C1CCOC1
Product: C[Si](C)(C#Cc1ccccc1)C#Cc1ccccc1
Reaction time: 1 h

Procedure:
To 50 ml of tetrahydrofuran (THF) solution containing 6 ml of ethynylbenzene, 33 ml of 1.6N normal-butyl lithium was added dropwise under a nitrogen gas flow at 0° C. After stirring for 1 hour, 33.3 ml of THF solution containing 3 ml of dimethylsilyl chloride was added. After stirring at the room temperature for one night, the deposited solid was filtered and thereafter the obtained reaction solution was concentrated. Water was added to the solution, and then the solution was extracted with diethyl ether. Furthermore, the said diethyl ether layer was washed with water, thereafter dried with magnesium sulfate and concentrated. Then it was recrystallized from hexane, to obtain 5.02 g of bisphenylethynyldimethylsilane.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1)[C:6]([N:19]1[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]1)=[N:5]2.C(N(CC)CC)C.[C:33]1([CH3:43])[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1>C(Cl)(Cl)Cl>[CH3:18][N:15]1[CH2:16][CH2:17][N:12]([C:7]2[C:6]([N:19]3[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]3)=[N:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([NH:1][S:39]([C:36]4[CH:37]=[CH:38][C:33]([CH3:43])=[CH:34][CH:35]=4)(=[O:41])=[O:40])[CH:3]=3)[N:8]=2)[CH2:13][CH2:14]1
Reactant: CN1CCN(c2nc3ccc(N)cc3nc2N2CCN(C)CC2)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)Nc2ccc3nc(N4CCN(C)CC4)c(N4CCN(C)CC4)nc3c2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A 6.41 g. (.020 mole) portion of 6-amino-2,3-bis-(4-methyl-1-piperazinyl)quinoxaline (prepared as in Example 1) is dissolved in 200 ml. of chloroform. Then 3.0 ml. (0.021 mole) of triethylamine is added plus 3.81 g. (0.020 mole) of p-toluenesulfonyl chloride. The resulting solution is stirred at room temperature for three hours and is left standing in a sealed flask for 18 hours. It is washed with two 50 ml. portions of distilled water and is dried over anhydrous sodium sulfate and anhydrous calcium sulfate. The solution is stripped of solvent by water pump evacuation to give a yellow solid which is dissolved in 100 ml. of hot benzene and filtered. A 200 ml. portion of cyclohexane is added to the filtrate and the resulting suspension is cooled at 4° C. and then is filtered. The collected solid is dried in vacuo at 78° C. over phosphorous pentoxide, dissolved in 475 ml. of hot acetonitrile and is filtered hot. The filtrate is cooled at -10° C. to recrystallize 3.2 g. of the final product which is collected by filtration, m.p. 234°-237° C.
Reaction SMILES: ClC([O:4][C:5](Cl)(Cl)Cl)=O.[CH3:9][C:10]1[NH:14][N:13]=[C:12]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)[CH:11]=1.Cl.[CH2:27]([O:29][NH2:30])[CH3:28].C(N(CC)CC)C>C(OCC)(=O)C>[CH2:27]([O:29][NH:30][C:5]([N:14]1[C:10]([CH3:9])=[CH:11][C:12]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:23])[F:24])[CH:17]=2)=[N:13]1)=[O:4])[CH3:28]
Reactant: CCON
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: Cc1cc(Oc2cccc(C(F)(F)F)c2)n[nH]1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCONC(=O)n1nc(Oc2cccc(C(F)(F)F)c2)cc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 45.6 %

Procedure:
Trichloromethyl chloroformate (0.59 g, 3.0 mmol) was added to a solution of 5-methyl-3-(3-trifluoromethylphenyloxy)pyrazole (0.48 g, 2.0 mmol) in ethyl acetate (10 ml) at 0° C., and while the mixture was allowed to have room temperature gradually, the mixture was further stirred at room temperature for 3 hours. To the reaction mixture were added O-ethylhydroxylamine hydrochloride (0.98 g, 10.0 mmol) and triethylamine (0.61 g, 6.0 mmol), and the resulting mixture was refluxed under heating. After completion of the reaction, the reaction mixture was poured into ice water, and the mixture was extracted with ethyl acetate (20 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/10), to give a yellowish viscous substance of N-ethoxy-5-methyl-3-(3-trifluoromethylphenyloxy)pyrazole-1-carboxamide (0.30 g, yield: 45.4%). 1H-NMR (CDCl3, TMS, ppm): δ 1.31 (t, J=7.0 Hz, 3H), 2.61 (d, J=0.8 Hz, 3H), 4.05 (q, J=7.0 Hz, 2H), 5.78 (q, J=0.8 Hz, 1H), 7.33-7.37 (m, 1H), 7.42-7.50 (m, 3H), 9.25 (br s, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:30])[C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][CH:22]=3)[CH:12]=2)=[O:10])=[CH:3][CH:2]=1.C(O)(C)C.[H][H]>[Ni].O1CCOCC1>[N:1]1[CH:2]=[CH:3][C:4]([NH:7][C:8](=[O:30])[C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([NH2:27])=[CH:25][CH:26]=3)[CH:12]=2)=[O:10])=[CH:5][CH:6]=1
Reactant: O=C(Nc1ccncc1)C(=O)c1cn(Cc2ccc([N+](=O)[O-])cc2)c2ccccc12
Reactant: [H][H]
Agent: [Ni]
Solvent: CC(C)O
Solvent: C1COCCO1
Product: Nc1ccc(Cn2cc(C(=O)C(=O)Nc3ccncc3)c3ccccc32)cc1
Reaction time: 3 h

Procedure:
A mixture of 200 mg of Raney nickel in 50 ml of dioxane is treated with a suspension of 320 mg (0.8 mmol) of N-(pyridin-4-yl)-[1-(4-nitrobenzyl)indol-3-yl]glyoxyl-amide in a solvent mixture of 150 ml of dioxane and 20 ml of isopropanol. Hydrogen is passed into this suspension with shaking at a gas pressure of 5 bar and the temperature is kept at 30-35° C. After about 3 hours, a further 400 mg of Raney nickel are added and the hydrogenation is continued at 35° C. and 5 bar for a further 8 hours with vigorous shaking. The catalyst is filtered off under an N2 atmosphere, the filtrate is concentrated to dryness in vacuo and the residue is dried in vacuo at 40° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][C:11](=[S:13])[N:12]=2)=[CH:4][CH:3]=1.[Na].Br[C:16]1[S:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][N:20]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[C:11]([S:13][C:16]3[S:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][N:20]=3)[NH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cnc(Br)s1
Reactant: S=C1N=NC(c2ccc(Cl)cc2)=N1
Agent: [Na]
Product: O=[N+]([O-])c1cnc(Sc2nc(-c3ccc(Cl)cc3)n[nH]2)s1

Procedure:
The title compound was prepared in the manner described in Example 1. Substituting 4-chlorobenzoyl chloride for the benzoyl chloride in Example 1 gave 4-chlorobenzoyl thiosemicarbazide and then 3-(4-chlorophenyl)-1,2,4-triazole-5-thione. Reaction of 2.34 g of the sodium salt of 3-(4-chlorophenyl)1,2,4-triazole-5-thione with 2.09 g of 2-bromo-5-nitrothiazole as in Example 1 yielded 1.5 g of 3-(4-chlorophenyl)-5-[(5-nitrothiazol-2-yl)mercapto]-1,2,4-triazole, a light brown solid, MP 181-184° C.
Reaction SMILES: [O:1]=[C:2]1[CH:11]2[CH2:12][CH2:13]O[C:10]2=[C:9]2[C:4]([C:5]([O:15][CH3:16])=[CH:6][CH:7]=[CH:8]2)=[N:3]1.C[C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH2:20].C(O)[CH2:26][O:27]CCO>O>[CH3:26][O:27][C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[N:20]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([O:15][CH3:16])[C:4]=3[NH:3][C:2](=[O:1])[C:11]=2[CH2:12][CH2:13]1
Reactant: OCCOCCO
Reactant: COc1cccc2c1=NC(=O)C1CCOC=21
Reactant: Cc1ccccc1N
Solvent: O
Product: COc1ccccc1N1CCc2c1c1cccc(OC)c1[nH]c2=O
Temperature: 250 °C

Procedure:
4-Oxo-6-methoxy-2,3-dihydrofuro[3,2-c]quinoline (217 mg, 1.0 mmol) was dissolved in 10 ml of diethylene glycol in a pressure tube and of 2-methylaniline (282 μl, 2.5 mmol) was added under nitrogen. The reaction mixture was heated at 250° C. for 15 hours. The reaction mixture was diluted with 20 ml of salt water and the aqueous layer was extracted with methylene chloride (15 ml×3). After layer with water (15 ml×3), the organic layer was dried with anhydrous magnesium sulfate and filtrated to be concentrated under reduced pressure. The residue was purified with ethyl acetate as a development solution according to silica gel chromatography to obtain 260 mg of desired compound as solid in 81% of yield.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([Cl:9])[CH:3]=1.[Mg].II.[C:13]([N:20]1[CH2:24][CH2:23][C:22](=[O:25])[CH2:21]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]>O1CCCC1>[Cl:9][C:4]1[CH:3]=[C:2]([C:22]2([OH:25])[CH2:23][CH2:24][N:20]([C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14])[CH2:21]2)[CH:7]=[C:6]([F:8])[CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Reactant: Fc1cc(Cl)cc(Br)c1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2cc(F)cc(Cl)c2)C1
Yield: 27.8 %

Procedure:
Preparation according to Preparation 1. 1-Bromo-3-chloro-5-fluorobenzene (5 g, 23.9 mmol) in dry tetrahydrofuran (100 ml), magnesium turnings (0.57 g, 23.9 mmol) and one crystal of iodine. 1-N-boc-3-pyrrolidone (4.41 g, 23.9 mmol) in dry tetrahydrofuran (50 ml). The crude product was purified by flash column chromatography on silica gel (ethyl acetate/isooctane, 1:9 to 1:1) gave the title compound (2.1 g, 28%). MS m/z (rel. intensity, 70 eV) 259 (45), 214 (69), 184 (35), 143 (37), 57 (bp).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[N:24]=[CH:23][C:22]3[CH2:21][C@@H:20]([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=4)[C:19]4[CH:32]=[CH:33][CH:34]=[CH:35][C:18]=4[C:17]=3[N:16]=2)=[CH:10][CH:9]=1)(=O)=O.[CH3:36][NH:37][CH2:38][CH2:39][CH2:40][CH3:41]>C(N(CC)CC)C>[ClH:31].[CH2:38]([N:37]([CH3:36])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[N:24]=[CH:23][C:22]3[CH2:21][C@@H:20]([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=4)[C:19]4[CH:32]=[CH:33][CH:34]=[CH:35][C:18]=4[C:17]=3[N:16]=2)=[CH:10][CH:9]=1)[CH2:39][CH2:40][CH3:41]
Reactant: CCCCNC
Reactant: CS(=O)(=O)OCCc1ccc(Nc2ncc3c(n2)-c2ccccc2[C@H](c2ccc(Cl)cc2)C3)cc1
Solvent: CCN(CC)CC
Product: CCCCN(C)CCc1ccc(Nc2ncc3c(n2)-c2ccccc2[C@H](c2ccc(Cl)cc2)C3)cc1
Product: Cl

Procedure:
This was synthesized by using (S)-4-(6-(4-chlorophenyl)-5,6-dihydrobenzo[h]quinazolin-2-ylamino)phenethyl methanesulfonate, N-methylbutan-1-amine and triethylamine as described in general procedure 2 to give a yellow solid. M.p.=75-77° C. 1H NMR 400 MHz (DMSO-d6) δ 9.90 (s, br, 1H), 9.59 (s, 1H), 8.30 (m, 2H), 7.79 (d, J=8.4 Hz, 2H), 7.50-7.44 (m, 2H), 7.31 (m, 2H), 7.22 (d, J=8.8 Hz, 2H), 7.10 (m, 4H), 4.42 (t, J=5.6 Hz, 1H), 3.28-2.86 (m, 8H), 2.78 (d, J=5.2 Hz, 3H), 1.67-1.59 (m, 2H), 1.33-1.27 (m, 2H), 0.90 (t, J=7.2 Hz, 3H). LCMS m/e 497 (M+H).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[C:7]([C:10]1[C:18]2[CH:17]=[C:16](B(O)O)[S:15][C:14]=2[CH:13]=[CH:12][CH:11]=1)([OH:9])=[O:8].[Cl:22][C:23]1[N:28]=[C:27](Cl)[CH:26]=[C:25](Cl)[N:24]=1.[ClH:31]>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:22][C:23]1[N:28]=[C:27]([C:16]2[S:15][C:14]3[CH:13]=[CH:12][CH:11]=[C:10]([C:7]([OH:9])=[O:8])[C:18]=3[CH:17]=2)[C:26]([Cl:31])=[CH:25][N:24]=1
Reactant: Cl
Reactant: O=C(O)c1cccc2sc(B(O)O)cc12
Reactant: Clc1cc(Cl)nc(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O=C(O)c1cccc2sc(-c3nc(Cl)ncc3Cl)cc12
Temperature: 100 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
An aqueous Na2CO3 solution (2 M, 500 mL) is added dropwise to a stirred solution of (4-carboxy-benzo[b]thiophen-2-yl)boronic acid (56 g, 0.25 mol) and 2,4,6-trichloro-pyrimidine (42.1 g, 0.230 mol) in ethyleneglycol dimethyl ether (620 mL) at room temperature under nitrogen atmosphere. Upon the completion of addition, PdCl2(PPh3)2 (5.31 g, 3% mol) is added in one portion, then the reaction mixture is heated at 100° C. overnight. The mixture is cooled to 10° C., then 37% HCl (150 mL) is added in portions to form a suspension. After filtration and washing with water (300 mL×3) the solid is dried under vacuum. Then the solid is suspended in 1 L of dichloromethane/ethanol (10:1) and stirred overnight. After another round of filtration and drying, the first crop of title compound (28.0 g, 38% yield) is obtained. Mother liquor is concentrated and the residue is suspended in acetone (1 mL) and stirred overnight. After filtration, the solid is re-suspended in 200 mL of dichloromethane/ethanol (ethanol) (3:1) and stirred for 2 hours. Additional 5 g of the title compound is obtained after filtration and drying. Overall yield is 44%.
Reaction SMILES: C(Cl)(Cl)Cl.[Cl:5][C:6]1[C:11]([S:12](Cl)(=[O:14])=[O:13])=[CH:10][C:9]([C:16]2[C:17](=[O:27])[N:18]([CH3:26])[C:19]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:21]=2)=[C:8]([F:28])[CH:7]=1.Cl.CN.[CH2:32]([N:34](CC)CC)C>O>[Cl:5][C:6]1[C:11]([S:12](=[O:14])(=[O:13])[NH:34][CH3:32])=[CH:10][C:9]([C:16]2[C:17](=[O:27])[N:18]([CH3:26])[C:19]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:21]=2)=[C:8]([F:28])[CH:7]=1
Reactant: Cn1c(C(F)(F)F)ccc(-c2cc(S(=O)(=O)Cl)c(Cl)cc2F)c1=O
Reactant: CCN(CC)CC
Agent: CN
Agent: Cl
Solvent: O
Solvent: ClC(Cl)Cl
Product: CNS(=O)(=O)c1cc(-c2ccc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 25 ml of chloroform, 0.6 g (1.5 mmol) of 3-(4-chloro-5-chlorosulfonyl-2-fluorophenyl)-1-methyl-6-trifluoromethyl-2(1H)-pyridone and 1.8 g (26.7 mmol) of methylamine hydrochloride were added, and 6.0 g (59.4 mmol) of triethylamine was dropwise added thereto under cooling with ice, followed by stirring at room temperature for 2 hours. This reaction solution was poured into water and extracted with chloroform. After washing with water and a 10% citric acid aqueous solution, the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. Then, the obtained residue was purified by silica gel column chromatography to obtain 0.4 g (yield:67) of the desired product. Melting point: 150-151° C.
Reaction SMILES: [CH2:1]1[C:7]2=[C:8]3[C:12](=[CH:13][CH:14]=[C:6]2[O:5][CH2:4][CH2:3][N:2]1C(OC(C)(C)C)=O)[NH:11][CH:10]=[CH:9]3.[H-].[Na+].CN(C=O)C.[S:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[CH:31]=[C:30]1[S:38](Cl)(=[O:40])=[O:39]>N.CO>[S:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[CH:31]=[C:30]1[S:38]([N:11]1[C:12]2[C:8](=[C:7]3[CH2:1][NH:2][CH2:3][CH2:4][O:5][C:6]3=[CH:14][CH:13]=2)[CH:9]=[CH:10]1)(=[O:40])=[O:39]
Reactant: O=S(=O)(Cl)c1cc2ccccc2s1
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc3[nH]ccc3c2C1
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: O=S(=O)(c1cc2ccccc2s1)n1ccc2c3c(ccc21)OCCNC3
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 9.9 %

Procedure:
tert-Butyl 1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 18, 14 mg, 0.050 mmol), NaH (60% in mineral oil, 6.4 mg, 0.10 mmol) and dry DMF (0.2 mL) were shaken at room temperature for 10 minutes. 1-Benzothiophene-2-sulfonyl chloride (23 mg, 0.10 mmol, in 0.15 mL of dry DMF) was added to the solution. The reaction mixture was shaken at room temperature for another 20 minutes and a mixture of MeOH/1 M HCl (3:1, 1 mL) was added. The reaction mixture was stirred overnight and evaporated. The residue was dissolved in 1 M NH3 in MeOH (1 mL, 1 mmol) and MeOH (1 mL). The crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give the title compound as an off-white solid (1.9 mg). MS m/z 385 [M+H]+.
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][CH:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11]1)=[O:7])(C)(C)C.[C:18]1([N:24]=[C:25]=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[NH2:27][C:28]1[C:36]([Cl:37])=[CH:35][C:31](C(O)=O)=[C:30]([O:38][CH3:39])[CH:29]=1>>[NH2:27][C:28]1[C:36]([Cl:37])=[CH:35][C:31]([C:6]([NH:8][CH2:9][CH:10]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH:17][C:25]([NH:24][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:26])[CH2:11]2)=[O:7])=[C:30]([O:38][CH3:39])[CH:29]=1
Reactant: CC(C)(C)OC(=O)NCC1CCN(CCN)C1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: O=C=Nc1ccccc1
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCNC(=O)Nc2ccccc2)C1

Procedure:
2-(3-tert-Butoxycarbonylaminomethylpyrrolidin-1-yl)ethylamine (1 g) as starting compound was reacted and treated in the same manner as in Example 34 using phenyl isocyanate (0.40 ml) and 4-amino-5-chloro-2-methoxybenzoic acid (0.83 g) to give 4-amino-5-chloro-2-methoxy-N-(1-(2-(3-phenylureido)ethyl)pyrrolidin-3-ylmethyl)benzamide.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([Cl:15])=[CH:10][C:9]=2[CH2:16][N:17]([CH3:19])[CH3:18])=[O:5])C.O[Li].O.Cl>C1COCC1.CCO.O>[Cl:15][C:11]1[CH:12]=[C:13]2[C:8](=[C:9]([CH2:16][N:17]([CH3:18])[CH3:19])[CH:10]=1)[NH:7][C:6]([C:4]([OH:5])=[O:3])=[CH:14]2
Reactant: CCOC(=O)c1cc2cc(Cl)cc(CN(C)C)c2[nH]1
Agent: Cl
Agent: [Li]O
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CN(C)Cc1cc(Cl)cc2cc(C(=O)O)[nH]c12
Temperature: 45 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
To a solution of 90 mg (0.32 mmol) of 5-chloro-7-dimethylaminomethyl-1H-indole-2-carboxylic acid ethyl ester in THF/EtOH/H2O (5 ml) at RT was added 23 mg of LiOH.H2O. The reaction mixture was stirred at 45° C. for one hour and then acidified with aqueous HCl 1M. The product was extracted with EtOAc and concentrated under vacuo to afford 34 mg (42%) of 5-chloro-7-dimethylaminomethyl-1H-indole-2-carboxylic acid as a white solid. ES-MS m/e (%): 251.3 (M−H+).
Reaction SMILES: [Br:1]Br.Br.[CH3:4][C:5]1[CH:6]=[CH:7][C:8]([CH3:11])=[CH:9][CH:10]=1>>[Br:1][C:6]1[CH:7]=[C:8]([CH3:11])[CH:9]=[CH:10][C:5]=1[CH3:4]
Reactant: Cc1ccc(C)cc1
Reactant: BrBr
Agent: Br
Product: Cc1ccc(C)c(Br)c1

Procedure:
This experiment was carried out in two successive steps. In the first stage the total p-xylene was divided into two parts and one-half of the p-xylene was added to the reaction vessel with the catalyst. The other half of the p-xylene and the bromine were then added simultaneously but in separate streams to the flask while maintaining the temperature of the reacting mixture at 20°-25°C. When the reaction was completed as evidenced by no further hydrogen bromide evolution, the resulting mixture was distilled. An initial fraction of monobromo-p-xylene was taken off at 75°-103° (9mm). The 2,5-dibromo-p-xylene was recovered by distillation at 122°-126° (10 mm) as a water-white liquid which solidified to a white, fused, crystalline mass.