Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH:2]=[C:3]1[C:12]2([CH2:17][CH2:16][N:15]([C:18](=[O:31])[C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([C:27]([F:30])([F:29])[F:28])[CH:20]=3)[CH2:14][CH2:13]2)[O:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]1=O.[NH2:33][NH2:34]>C(O)C>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([C:18]([N:15]2[CH2:14][CH2:13][C:12]3([C:3]4[CH:2]=[N:34][NH:33][C:4]=4[C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=4[O:11]3)[CH2:17][CH2:16]2)=[O:31])=[CH:20][C:21]=1[C:27]([F:28])([F:29])[F:30]
Reactant: NN
Reactant: COc1ccc(C(=O)N2CCC3(CC2)Oc2ccccc2C(=O)C3=CO)cc1C(F)(F)F
Solvent: CCO
Product: COc1ccc(C(=O)N2CCC3(CC2)Oc2ccccc2-c2[nH]ncc23)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 3-(hydroxymethylene)-1′-[4-methoxy-3-(trifluoromethyl)-benzoyl]spiro[chromane-2,4′-piperidine]-4-one (54 mg, 0.12 mmol) and hydrazine (3.8 μL, 0.12 mmol) in ethanol (1.7 mL) was allowed to stir for 1 h at 25° C., then for 2.5 h at 50° C. The mixture was cooled and then concentrated in vacuo. The residue was taken up in DMF and was purified by reverse phase HPLC to give (4-methoxy-3-(trifluoromethyl)phenyl)(1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone. ESI-MS m/z calc. 443.2. found 444.1 (M+1)+; Retention time: 2.40 minutes (4 min run). 1H NMR (400 MHz, CDCl3) δ 9.15-8.90 (m, 1H), 7.73 (s, 1H), 7.67 (d, J=8.3 Hz, 1H), 7.58 (s, 1H), 7.52 (d, J=7.7 Hz, 1H), 7.33-7.18 (m, 1H), 7.04 (dd, J=18.8, 8.3 Hz, 2H), 6.91 (t, J=7.5 Hz, 1H), 6.05-5.60 (m, 1H), 4.50-4.05 (m, 2H), 4.08-3.55 (m, 3H), 3.97 (s, 3H), 2.50-2.32 (m, 2H).
Reaction SMILES: [CH3:1][N:2]([CH3:27])[C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][CH:26]=1)[C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:23])=[C:13]([CH:22]=1)[NH:14][C:15]1[CH:20]=[C:19](Cl)[N:18]=[CH:17][N:16]=1)=[O:7].[N:28]1([CH2:33][CH2:34][CH2:35][NH2:36])[CH2:32][CH2:31][CH2:30][CH2:29]1.C(N(CC)C(C)C)(C)C>C(O)CCC>[CH3:1][N:2]([CH3:27])[C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][CH:26]=1)[C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:23])=[C:13]([CH:22]=1)[NH:14][C:15]1[CH:20]=[C:19]([NH:36][CH2:35][CH2:34][CH2:33][N:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[N:18]=[CH:17][N:16]=1)=[O:7]
Reactant: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1Nc1cc(Cl)ncn1
Reactant: NCCCN1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1Nc1cc(NCCCN2CCCC2)ncn1

Procedure:
A mixture of 4-[5-(3-dimethylaminobenzamido)-2-methylanilino]-6-chloropyrimidine (0.114 g), 3-pyrrolidin-1-ylpropylamine (0.95 ml), N,N-di-isopropylethylamine (0.063 ml) and n-butanol (2 ml) was stirred and heated to reflux for 18 hours. The mixture was evaporated and the residue was purified by column chromatography on silica using a 10:1 mixture of ethyl acetate and methanol as eluent. There was thus obtained the title compound (0.124 g); NMR Spectrum: (DMSOd6) 1.59 (m, 6H), 2.15 (s, 3H), 2.34 (m, 6H), 2.93 (s, 6H), 3.14 (m, 2H), 6.72 (m, 1H), 6.89 (m, 1H), 7.2 (m, 4H), 7.3 (m, 1H), 7.5 (m, 1H), 7.72 (m, 1H), 7.96 (m, 1H), 8.16 (s, 1H), 10.02 (s, 1H); Mass Spectrum: M+H+ 474.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([Cl:22])[CH:16]=1)[C:9](=[O:14])N(OC)C)([CH3:4])([CH3:3])[CH3:2].Br[C:25]1[CH:38]=[CH:37][C:28]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])=[CH:27][CH:26]=1>>[C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([Cl:22])[CH:16]=1)[C:9]([C:25]1[CH:38]=[CH:37][C:28]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:31])[CH3:32])=[CH:27][CH:26]=1)=[O:14])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(Br)cc1
Reactant: CON(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(C)c(Cl)c1
Product: Cc1ccc(C(NC(=O)OC(C)(C)C)C(=O)c2ccc(O[Si](C)(C)C(C)(C)C)cc2)cc1Cl

Procedure:
The title compound was prepared from rac-[(3-chloro-4-methyl-phenyl)-(methoxy-methyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester (Intermediate 4) and (4-bromo-phenoxy)-tert-butyl-dimethyl-silane in analogy to Example 1a): MS (ISP): 374.3 ((M−Si(CH3)2C(CH3)3)+H)+ (100%).
Reaction SMILES: C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CCN(CC)CC.C[Si]([O:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37](Br)[CH:36]=1)(C)C.[C:42]1([C:48]#[CH:49])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[OH:34][C:35]1[CH:36]=[C:37]([C:49]#[C:48][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:38]=[CH:39][CH:40]=1
Reactant: C#Cc1ccccc1
Reactant: C[Si](C)(C)Oc1cccc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: O
Product: Oc1cccc(C#Cc2ccccc2)c1
Reaction time: 0.25 h

Procedure:
Palladium acetate (0.20 g, 8.9×10-4 mol) and tri-o-tolylphosphine (0.40 g, 1.31×10-3 mol) as well as 60 ml of NEt3 were placed in a 3-necked 100 ml round-bottomed flask equipped with a reflux condensor, a thermometer and a nitrogen adaptor. The resultant yellow mixture was then heated to reflux under N2. At about 70° C., the mixture turned deep-red but still maintained its homogeneity. While the mixture was still refluxing, 3-bromophenyl trimethylsilyl ether (7.10 g, 28.95 mmol) was introduced via the reflux column, allowing it to flow slowly along the wall of the column, into the reaction mixture. After about 15 minutes, degased phenylacetylene (3.11 g, 30.45 mmol) was added to the reaction mixture in a similar manner. As soon as the reactants were in contact, sudden rise in temperature and concomitant precipitation of white solids occurred. The color of reaction mixture became lighter as the reaction progressed. After about 3 hours, the reaction mixture was dark brown and no further change in color was observed even after 17 hours at 80° C. The cooled reaction mixture was poured into about 300 ml of water and extracted with ethyl ether (100 ml, 3×50 ml). The dark ethereal extract was subjected to rotary evaporation to afford a dark oil. About 20 ml of water was added to the dark oil and the mixture was rota-evaporated, in a 70° C-water bath for about 15 minutes. Then, 150 ml of methanol was added and rotary evaporation was resumed until all solvent was removed at 70° C. The resultant dark oil was then dried in vacuo at room temperature for 24 hrs and solidified into dark brown crude product (about 5.0g). Proton NMR (CDCl3): 5.18 (singlet, --OH), 6.71-7.67 (complex, aromatic H). The hydroxyl proton is readily exchanging with deuterium of D2O. IR(KBr): δ (OH) at 3350 cm-1 (strong and broad); δ (C≡C) at 2210 cm-1 (W). The crude product was used in the subsequent reaction without further purification.
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[CH3:16][O:17][C:18](=[O:28])[CH2:19][C:20]1[CH:25]=[C:24]([OH:26])[CH:23]=[C:22](O)[CH:21]=1.N1C=CC=CC=1>C(Cl)Cl>[CH3:16][O:17][C:18](=[O:28])[CH2:19][C:20]1[CH:25]=[C:24]([O:26][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:8])=[O:6])[CH:23]=[C:22]([O:6][S:7]([C:10]([F:11])([F:12])[F:13])(=[O:8])=[O:9])[CH:21]=1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)Cc1cc(O)cc(O)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)Cc1cc(OS(=O)(=O)C(F)(F)F)cc(OS(=O)(=O)C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
Trifluoromethanesulphonic anhydride (7.05 g, 25.0 mmol) was added dropwise to a solution of 3,5-dihydroxyphenyl acetic acid methyl ester (1.80 g, 10.0 mmol) and pyridine (4.9 mL, 60.0 mmol) in DCM (20 mL) at 0° C. The temperature was maintained at 0° C. for 15 mins before warming to room temperature and the mixture stirred for 18 hrs. The reaction was diluted with DCM washed with H2O, Na2CO3, dil. HCl, brine, dried (MgSO4) and evaporated under reduced pressure to give a yellow oil. The residue was purified by flash column chromatography (EtOAc:petroleum ether), yield 4.0 g (89%), 1H NMR (CDCl3) δ 7.31 (d, 2H), 7.17 (t, 1H), 3.74 (s, 3H), 7.73 (s, 2H).
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].O[CH2:8][S:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CCOCC>[Cl:2][CH2:8][S:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=C(SCO)c1ccccc1
Solvent: CCOCC
Product: O=C(SCCl)c1ccccc1

Procedure:
42 PARTS OF PHOSPHORUS PENTACHLORIDE IS COVERED WITH A LAYER OF ABSOLUTE ETHER. While stirring and cooling with ice, an ethereal solution of 33.6 parts of hydroxymethylbenzoyl sulfide is dripped in and the whole stirred for 2 hours at room temperature. The solution is filtered, the filtrate concentrated at 0.01 mm and a bath temperature of 40° C, the residue taken up in methylene chloride and washed with cold aqueous NaNHCO3 solution. The organic phase is dried over Na2SO4 and distilled 20 parts of chloromethylbenzoyl sulfide having a boiling point at 0.1 mm of 111° to 113° C is obtained.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:13][CH3:14])[CH2:4]1.C([O-])(=O)C.[Na+].[Br:20]Br>C(O)(=O)C>[NH2:2][C@@H:3]1[CH2:12][CH2:11][C:10]2[C:5](=[C:6]([Br:20])[CH:7]=[CH:8][C:9]=2[O:13][CH3:14])[CH2:4]1
Reactant: BrBr
Reactant: COc1cccc2c1CC[C@@H](N)C2
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(Br)c2c1CC[C@@H](N)C2
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
(R)-2-Amino-5-methoxy-1,2,3,4tetrahydronaphthalene hydrochloride (5.0 g, 23 mmol) was dissolved in acetic acid (300 mL) under nitrogen atmosphere. Sodium acetate (5.5 g, 70 mmol) was added and bromine (3.5 g, 23 mmol) was then added in one portion. The mixture was stirred for 5 minutes at room temperature. The solvent was removed in vacuo to give a solid residue which was partitioned between ethyl acetate and NaOH (2 M). The layers were separated and the aqueous phase was extracted twice with ethyl acetate. The organic layers were combined and dried (Na2SO4). The solvent was removed in vacuo to give a brown oily residue. The HCl salt was precipitated from diethyl ether/methylene chloride by the addition of HCl in diethyl ether (3 M): yield 7.7 g (94%). Recrystallization from methanol gave the title compound as needle crystals: mp 264-265° C.; [α]21D +54° (c 1, MeOH); EIMS (70 eV) m/z (relative intensity) 257 (30, M+, 81Br), 255 (31, M+, 79Br).
Reaction SMILES: [Cl-].C[C:3](C)([O-:5])C.[K+].[CH2:8]([CH:11]1[O:15][CH:14]([CH:16]2[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]2)[CH2:13][CH2:12]1)[CH2:9][CH3:10]>C1COCC1>[CH2:8]([CH:11]1[O:15][CH:14]([CH:16]2[CH2:21][CH2:20][CH:19]([CH:3]=[O:5])[CH2:18][CH2:17]2)[CH2:13][CH2:12]1)[CH2:9][CH3:10]
Reactant: CCCC1CCC(C2CCC(=O)CC2)O1
Reactant: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCC1CCC(C2CCC(C=O)CC2)O1
Temperature: -20 °C
Reaction time: 1 h
Yield: 76.2 %

Procedure:
Methoxymethyltriphenylphophnium chloride (55.23 g) and THF (300 ml) were placed in a reaction vessel, and the solution was cooled to −20° C. Potassium t-butoxide (16.0 g) was added, and the stirring was continued for another 1 hour. Then, 4-(5-propyltetrahydro-2-furanyl)cyclohexanone (15 g) in a THF (100 ml) solution was added dropwise, and the stirring was continued for another 1 hour. The reaction mixture was warmed to room temperature, and the mixture was separated after the addition of water (200 ml). The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (toluene:ethyl acetate=18:1), and the resultant product was dissolved in acetone (200 ml) and hydrochloric acid (6 M) (200 ml) was added, and then the stirring was continued at room temperature for another 1 hour. The mixture was extracted with toluene (100 ml) after the addition of water (200 ml). The solution was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to give 4-(5-propyltetrahydro-2-furanyl)cyclohexanecarboaldehyde (12.2 g)
Reaction SMILES: C(C(CC)CNCC1SC([C:12]2[CH:13]=[C:14]3[C:18](=[C:19]([C:21]([NH2:23])=O)[CH:20]=2)NC=C3C2CCN(S(CC)(=O)=O)CC2)=CC=1)C.[CH:37]([C:39]1[S:43][C:42]([B:44]([OH:46])[OH:45])=[CH:41][CH:40]=1)=O.C1(CN)CCCCC1.[BH3-]C#N.[Na+]>>[CH:19]1([CH2:21][NH:23][CH2:37][C:39]2[S:43][C:42]([B:44]([OH:46])[OH:45])=[CH:41][CH:40]=2)[CH2:20][CH2:12][CH2:13][CH2:14][CH2:18]1
Reactant: O=Cc1ccc(B(O)O)s1
Reactant: CCC(CC)CNCc1ccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)s1
Agent: NCC1CCCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Product: OB(O)c1ccc(CNCC2CCCCC2)s1

Procedure:
Following the general procedure of 5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol), (cyclohexylmethyl)amine (37 mg, 0.32 mmol), and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 30 mg of crude (5-{[(cyclohexylmethyl)amino]methyl}-2-thienyl)boronic acid. The crude (5-{[(cyclohexylmethyl)amino]methyl}-2-thienyl)boronic acid was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (65 mg, 0.157 mmol), K2CO3 (130 mg, 0.942 mmol), and tetrakis(triphenylphosphine)palladium(0) (9 mg, 0.0079 mmol). The crude product was purified once on an Agilent MDAP using the procedure shown in preparation of 5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide. The purified product was washed with a 20:4:1 mixture of hexanes/EtOAc/MeOH (2.5 mL), taken up in EtOAc (2 mL) and washed with saturated K2CO3 (1 mL). The organic layer was concentrated to give 4.7 mg of the title compound (6%).
Reaction SMILES: [CH:1]([NH:4][CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].Cl[CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:19]=[C:20]3[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][N:21]3[CH:27]=2)=[CH:14][CH:13]=1.BrCCCl>>[CH:1]([N:4]([CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:19]=[C:20]3[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][N:21]3[CH:27]=2)=[CH:14][CH:13]=1)[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)NC(C)C
Reactant: Cc1cccn2cc(-c3ccc(OCCCl)cc3)nc12
Solvent: ClCCBr
Product: Cc1cccn2cc(-c3ccc(OCCN(C(C)C)C(C)C)cc3)nc12

Procedure:
The title compound was prepared by condensing di-iso-propylamine with 2-(4-chloroethoxyphenyl)-8-methylimidazo[1,2-a]pyridine. 2-(4-Chloroethoxyphenyl)-8-methylimidazo[1,2-1]pyridine was prepared according the procedure described in Example 1 above using 1-bromo-2-chloroethane in place of 1-bromo-3-chloropropane. Analysis Calc'd for C22H29N3O 3HCl; C, 7.16; H, 55.18; N, 8.77. Found: C, 7.13; H, 55.56; N, 8.8.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH3:23])[CH2:12][CH2:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:26])=O>ClCCl>[Cl:26][C:18]([C:17]1[CH:21]=[CH:22][C:14]([CH2:13][CH2:12][N:11]([CH3:23])[C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:15][CH:16]=1)=[O:19]
Reactant: CN(CCc1ccc(C(=O)O)cc1)C(=O)OCc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CN(CCc1ccc(C(=O)Cl)cc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 4-(2-((benzyloxycarbonyl)(methyl)amino)ethyl)benzoic acid (2.0 g, 6.38 mmol) in anhydrous dichloromethane (30 mL) was added dropwise thionyl chloride (1.52 g, 12.76 mmol) at 0° C. After the addition, the solution was stirred at room temperature overnight. Solvent was removed in vacuum to give benzyl 4-(chlorocarbonyl)phenethyl(methyl)carbamate. To a stirred solution of methyl 3-amino-2-hydroxybenzoate (0.71 g, 4.25 mmol) and pyridine (0.19 mL, 10.2 mmol) in anhydrous toluene (20 mL) was added dropwise a solution of benzyl 4-(chlorocarbonyl)phenethyl(methyl)carbamate (1.7 g, 5.1 mmol) in anhydrous toluene (5 mL). After the addition, the mixture was stirred at room temperature 30 min, then 80° C. for 1 h. The mixture was diluted with toluene, washed with water (30 mL×3), 1N hydrochloric acid (30 mL×3), brine (30 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography ((silica gel, petroleum ether/ethyl acetate 15:1 to 4:1), to obtain methyl 3-(4-(2-((benzyloxycarbonyl)(methyl)amino)ethyl)benzamido)-2-hydroxybenzoate (1.9 g, yield 97%) as yellow oil. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 2.82-2.87 (m, 5H), 3.49-3.53 (t, J=7 Hz, 2H), 3.94 (s, 1H), 4.98-5.06 (d, J=32 Hz, 2H), 6.98-7.02 (t, J=8 Hz, 1H), 7.26-7.39 (m, 7H), 7.66-7.68 (d, J=7.6 Hz, 1H), 7.89-7.91 (m, 2H), 7.94-7.96 (d, J=8 Hz, 1H), 9.61 (s, 1H), 10.92 (s, 1H); LC-MS (ESI) m/z: 463 (M+1)+.
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]2[CH2:6][CH2:7][N:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:9][CH2:10][C:4]=2[CH:3]=1.[Br-:18].[Br-].[Br-].C[N+](C)(C)C1C=CC=CC=1.C[N+](C)(C)C1C=CC=CC=1.C[N+](C)(C)C1C=CC=CC=1>ClCCl.CO>[Br:18][C:17]1[C:2]([OH:1])=[CH:3][C:4]2[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][CH2:6][C:5]=2[CH:16]=1
Reactant: [Br-]
Reactant: CCOC(=O)N1CCc2ccc(O)cc2CC1
Agent: C[N+](C)(C)c1ccccc1
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)N1CCc2cc(O)c(Br)cc2CC1
Reaction time: 1 h
Yield: 171 %

Procedure:
Under an argon atmosphere, to a mixed solution of 5.0 g of ethyl 7-hydroxy-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate in 100 ml of dichloromethane and 20 ml of methanol was added portionwise 8.05 g of N,N,N-trimethylanilinium tribromide under ice-cooling, followed by stirring at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, the residue was extracted by the addition of ethyl acetate and water, and the organic layer was washed with 1 M aqueous hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure to obtain 6.67 g of ethyl 7-bromo-8-hydroxy-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate as a beige solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8](Cl)=[CH:7][N:6]=1)=[O:4].CCN(C(C)C)C(C)C.[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:7][N:6]=1)=[O:4]
Reactant: C1CCNCC1
Reactant: COC(=O)c1cnc(Cl)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(N2CCCCC2)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.2 %

Procedure:
To a solution of 5-chloro-pyrazine-2-carboxylic acid methyl ester (Preparation 41, 85 g, 492 mmol) in DMF (365 mL) was added DIPEA (129 mL, 738 mmol) and piperidine (58.4 mL, 591 mmol) and the resulting solution was stirred at room temperature for 18 hours. The reaction mixture was poured onto water (4 L) and the resulting precipitate was collected by filtration to give the title compound as a white solid (85.12 g) in a 78% yield.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15](OC(C)(C)C)=O)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH3:22][C:23]1(C)[CH2:25][O:24]1>ClCCl.FC(F)(F)C(O)=O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:10][CH2:11][N:12]([CH2:15][C:23]([CH3:25])([OH:24])[CH3:22])[CH2:13][CH2:14]2)=[CH:4][CH:3]=1
Reactant: CC1(C)CO1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)nc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(O)CN1CCC(Oc2ccc(Cl)nc2)CC1
Reaction time: 3 h
Yield: 85 %

Procedure:
To a stirred solution of tert-butyl 4-((6-chloropyridin-3-yl)oxy)piperidine-1-carboxylate (1.0 g, 3.2 mmol) in dichloromethane (10 mL), trifluoroacetic acid (3 mL) was added at 0° C. and stirred for 3 h. The reaction mixture was concentrated in vacuo and resultant residue was dissolved in MeOH (5 mL), 2,2-dimethyloxirane (0.246 g, 3.2 mmol) was added and stirred at room temperature for 10-12 h. The reaction mixture was concentrated in vacuo to give the title product (0.775, 85%); MS: 285.0 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[P:17]([O:24]CC)([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20]>[Ni](Br)Br>[F:16][C:13]1[CH:14]=[CH:15][C:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([P:17](=[O:24])([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])=[CH:3][CH:4]=2)=[O:9])=[CH:11][CH:12]=1
Reactant: CCOP(OCC)OCC
Reactant: O=C(c1ccc(F)cc1)c1ccc(Br)cc1
Agent: Br[Ni]Br
Product: CCOP(=O)(OCC)c1ccc(C(=O)c2ccc(F)cc2)cc1

Procedure:
(4-Bromophenyl)(4′-fluorophenyl)methanone (formula 28) (400 g, 1.43 mol) from Example 4A and anhydrous nickel bromide (35 g, 0.16 mol) are heated to 160° C. under an atmosphere of nitrogen. A green-blue colored melt is obtained. Then triethyl phosphite (304 g, 1.83 mol) is added over a period of 1 hour while maintaining the temperature between 160 and 165° C. The mixture is stirred at this temperature for an additional hour. Distillation of the mixture gave a pale yellow oil, b.p. 187-188° C./10-2 mbar. The yield is 304-326 g (63-68%).
Reaction SMILES: [NH2:1][C:2]1[C:6]2[C:7](=[O:11])[NH:8][CH:9]=[CH:10][C:5]=2[N:4]([C:12]([CH3:15])([CH3:14])[CH3:13])[N:3]=1.N1C=CC=CC=1.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1>[C:12]([N:4]1[C:5]2[CH:10]=[CH:9][NH:8][C:7](=[O:11])[C:6]=2[C:2]([NH:1][C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:3]1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)n1nc(N)c2c(=O)[nH]ccc21
Reactant: O=C(Cl)c1ccccc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(C)(C)n1nc(NC(=O)c2ccccc2)c2c(=O)[nH]ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-amino-1-tert-butyl-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one (20.0 mg) obtained in Example 264 and pyridine (0.016 ml) in THF (3 ml) was added benzoyl chloride (0.023 ml), and the mixture was stirred overnight at room temperature. The reaction mixture was extracted with water and ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/methanol) to give the title compound (28.8 mg).
Reaction SMILES: N1(CCC(O)=O)C=CN=C1.[CH3:11][N:12]([CH3:26])[CH2:13][CH2:14][CH2:15][NH:16][C:17](=O)[CH2:18][CH2:19][N:20]1[CH:24]=[CH:23][N:22]=[CH:21]1.B.[N:28]1[C:36]2[C:31]3[C:32](=[CH:37][CH:38]=[CH:39][C:30]=3[C:29]=1S)[CH:33]=[CH:34][CH:35]=2>O1CCCC1.C(O)C>[CH3:11][N:12]([CH3:26])[CH2:13][CH2:14][CH2:15][N:16]([CH2:17][CH2:18][CH2:19][N:20]1[CH:24]=[CH:23][N:22]=[CH:21]1)[C:29]1[C:30]2[CH:39]=[CH:38][CH:37]=[C:32]3[C:31]=2[C:36](=[CH:35][CH:34]=[CH:33]3)[N:28]=1
Reactant: CN(C)CCCNC(=O)CCn1ccnc1
Reactant: SC1=Nc2cccc3cccc1c23
Agent: B
Agent: O=C(O)CCn1ccnc1
Solvent: C1CCOC1
Solvent: CCO
Product: CN(C)CCCN(CCCn1ccnc1)C1=Nc2cccc3cccc1c23

Procedure:
3(1H-imidazol-1-yl)propanoic acid is converted to its acid chloride which upon reaction with 3-dimethylaminopropylamine leads to N-(3-dimethylaminopropyl)-3-(1H-imidazol-1-yl)propanamide. Reduction with borane in tetrahydrofuran solution then gives N-(3-dimethylaminopropyl-N-3-(1H-imidazol-1yl))propanamine. Treatment of the latter compound with molar equivalents of benz(cd)indol-2-thiol and mercuric acetate in refluxing ethanol under the conditions of Example 55 then leads to the title compound.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([N:10]3[CH2:14][CH2:13][C@H:12]([NH2:15])[CH2:11]3)[C:4]=2[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:23](Cl)(=[O:25])[CH3:24]>C(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([N:10]3[CH2:14][CH2:13][C@H:12]([NH:15][C:23](=[O:25])[CH3:24])[CH2:11]3)[C:4]=2[CH2:3][CH2:2]1
Reactant: N[C@H]1CCN(c2cccc3c2CCO3)C1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N[C@H]1CCN(c2cccc3c2CCO3)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(S)-N-(2,3-dihydrobenzofuran-4-yl)-3-(amino)pyrrolidine (0.1 mmol) and triethylamine (0.15 mmol) were dissolved in CH2Cl2. Acetylchloride (0.12 mmol) was added, and the reaction was stirred at room temperature for 16 hours. The organics were then washed with 1 N HCl, NaHCO3, and brine. The organic solution was dried over sodium sulfate, concentrated in vacuo, and purified by silica gel column chromatography eluting with 4% methanol in CH2Cl2 to yield the title compound.