Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15](CC3C=CC(OC)=CC=3OC)[C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:32][O:33][CH2:34][C@H:35]1[CH2:39][CH2:38][CH2:37][NH:36]1.CCN(C(C)C)C(C)C.C(O)(C(F)(F)F)=O>CN(C=O)C>[CH3:32][O:33][CH2:34][C@H:35]1[CH2:39][CH2:38][CH2:37][N:36]1[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([NH:15][C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Cl)ncnc3c2)c(OC)c1
Reactant: COC[C@H]1CCCN1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: COC[C@H]1CCCN1c1ncnc2cc(S(=O)(=O)Nc3nccs3)ccc12
Temperature: 25 °C
Reaction time: 0.01 h

Procedure:
A vial was charged with 4-chloro-N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)quinazoline-7-sulfonamide (Intermediate KKKK; 0.075 g, 0.157 mmol) and DMF (0.786 ml). (R)-2-(methoxymethyl)pyrrolidine (0.036 ml, 0.314 mmol) was added followed by Hunig's base (0.082 ml, 0.472 mmol). The reaction was stirred for 30 seconds at room temperature. TFA (0.2 ml, 2.60 mmol) was added and the reaction was stirred overnight at room temperature. The reaction was filtered through a frit, concentrated, and purified via Gilson HPLC (5-50% MeCN:H2O w/ 0.1% TFA modifier). The product fractions were passed through an Isolute SCX ion exchange column (pre-wetted with methanol). The column was flushed with methanol, then the product was liberated by flushing the column several times with 2.0 M ammonia in methanol. The product-containing filtrate was concentrated to afford (R)-4-(2-(methoxymethyl)pyrrolidin-1-yl)-N-(thiazol-2-yl)quinazoline-7-sulfonamide as an off-white solid. (ESI) 406.2 (M+H)+.
Reaction SMILES: [C:1]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)=[C:11]([OH:23])[CH:10]=1)=[O:8])([CH3:4])([CH3:3])[CH3:2].[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[N:27][CH:26]=1>>[C:1]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)=[C:11]([O:23][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[N:27][CH:26]=2)[CH:10]=1)=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)c1cccnc1
Reactant: Cc1ccc(Oc2ccc(C(=O)CNC(C)(C)C)cc2O)cc1
Product: Cc1ccc(Oc2ccc(C(=O)CNC(C)(C)C)cc2OC(=O)c2cccnc2)cc1

Procedure:
Following a procedure similar to that described above in Example 30A, when 3-hydroxy-4-(p-toluyloxy)phenyl tert-butylaminomethyl ketone is interacted with nicotinoyl chloride, there is obtained 3-(nicotinoyloxy)-4-(p-toluyloxy)phenyl tert-butylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using the procedure described above in Example 30B, there is obtained 3-nicotinoyloxy-4-(p-toluyloxy)-alpha-(tert-butylaminomethyl)-benzyl alcohol hydrochloride.
Reaction SMILES: Br[CH2:2][C:3](Br)=[O:4].[CH2:6]([NH:13][CH2:14][CH3:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH:24][S:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH3:34])(=[O:27])=[O:26]>>[CH2:6]([N:13]([CH2:14][CH3:15])[C:3](=[O:4])[CH2:2][N:24]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[O:17][CH3:16])[S:25]([C:28]1[C:29]([CH3:34])=[CH:30][CH:31]=[CH:32][CH:33]=1)(=[O:27])=[O:26])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(Br)CBr
Reactant: COc1ccccc1NS(=O)(=O)c1ccccc1C
Reactant: CCNCc1ccccc1
Product: CCN(Cc1ccccc1)C(=O)CN(c1ccccc1OC)S(=O)(=O)c1ccccc1C

Procedure:
prepared by reaction of 2-bromoacetyl bromide with N-benzyl-N-ethylamine and N-(2-methoxy-phenyl)-2-methyl-benzenesulfonamide
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C:18](=O)[CH2:17][CH2:16][CH2:15]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23]([CH2:25]P(=O)(OCC)OCC)#[N:24].[H-].[Na+].O>O1CCCC1>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C:18](=[CH:25][C:23]#[N:24])[CH2:17][CH2:16][CH2:15]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCCc2cc(OCCCCc3ccccc3)ccc21
Reactant: CCOP(=O)(CC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: N#CC=C1CCCc2cc(OCCCCc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 64 %

Procedure:
To a solution of 6-(4-phenylbutoxy)-3,4-dihydronaphthalen-1(2H)-one (300 mg) in tetrahydrofuran (10 mL), diethyl cyanomethylphosphonate (199 mg) and sodium hydride (60%, 97.8 mg) were added, followed by stirring at room temperature for 24 hours. After adding water, the reaction, mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, concentrated and then purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to thereby give the title compound (E/Z mixture, 207 mg) having the following physical properties.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13]C(CCNC)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:19]([F:22])([F:21])[F:20].[CH3:23]CN(C(C)C)C(C)C.[N:32]1([C:37](=[NH:39])[NH2:38])[CH:36]=[CH:35][CH:34]=N1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:34]([CH2:35][CH2:36][N:32]([CH3:23])[C:37]([NH2:38])=[NH:39])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:19]([F:20])([F:21])[F:22]
Reactant: N=C(N)n1cccn1
Reactant: CCN(C(C)C)C(C)C
Reactant: CNCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Solvent: CN(C)C=O
Product: CN(CCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1)C(=N)N
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.1 %

Procedure:
To a solution of 2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)-N-methylethanamine (300 mg, 0.910 mmol) and DIPEA (0.477 mL, 2.73 mmol) in DMF (5 mL) was added 1H-pyrazole-1-carboximidamide (150 mg, 1.365 mmol). The reaction mixture was stirred at room temperature overnight. Purification via a reverse phase Biotage then afforded the title compound (315 mg, 93% yield) as a white powder. LCMS: rt=2.88 min, [M+H+]=371.9
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:16]=[CH:17][N:18]([C:20]3[N:25]=[C:24]([CH3:26])[CH:23]=[C:22]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([CH3:34])[CH:28]=4)[N:21]=3)[CH:19]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([C:22]2[CH:23]=[C:24]([CH3:26])[N:25]=[C:20]([N:18]3[CH:19]=[C:15]([C:11]4[CH:10]=[C:9]([S:6]([NH2:5])(=[O:7])=[O:8])[CH:14]=[CH:13][CH:12]=4)[N:16]=[CH:17]3)[N:21]=2)=[CH:28][C:29]=1[CH3:34]
Reactant: Cc1cc(-c2ccc(Cl)c(C)c2)nc(-n2cnc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)c2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2ccc(Cl)c(C)c2)nc(-n2cnc(-c3cccc(S(N)(=O)=O)c3)c2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 63.8 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-3-{1-[6-(4-chloro-3-methyl-phenyl)-4-methyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-benzenesulfonamide (0.53 g) in dichloromethane (5 ml) was added TFA (5 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (10 ml), diethylether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration, washed with water and heptane and dried. Further purification by flash chromatography on silica gel (ethyl acetate/heptane) and crystallization (THF/heptane) yielded the title compound as a white solid (0.3 g, 68%). MS (ISP) 440.1 [(M+H)+]; mp 219° C. (dec.).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Cl:7][C:8]1[CH:22]=[CH:21][C:11]([CH2:12][CH:13]2[CH2:18][CH2:17][N:16]([N:19]=O)[CH2:15][CH2:14]2)=[CH:10][CH:9]=1.CCOCC.O>C1COCC1>[NH2:19][N:16]1[CH2:17][CH2:18][CH:13]([CH2:12][C:11]2[CH:10]=[CH:9][C:8]([Cl:7])=[CH:22][CH:21]=2)[CH2:14][CH2:15]1
Reactant: O=NN1CCC(Cc2ccc(Cl)cc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: NN1CCC(Cc2ccc(Cl)cc2)CC1
Temperature: 25 °C

Procedure:
A suspension of LiAlH4 (535 mg, 14.1 mmol) in dry THF (10 mL) was heated to refux with stirring. The mixture was removed from the heat source and a solution of 4-(4-chlorobenzyl)-1-nitrosopiperidine (1.68 g, 7.04 mmol) in dry THF (10 mL) was added with stirring so as to maintain a gentle reflux. After addition, the reaction was allowed to stir at reflux for 10 min. The reaction was allowed to cool to 25° C. and ether (60 mL) was added. Water (10 mL) was slowly added with stirring so as to destroy the excess hydride. The ether layer was separated and the aqueous portion was washed with ether. The combined ether portion was dried over Na2SO4 and the solvent was removed to give a near colorless liquid. This was filtered through a column of silica gel (2.5×10 cm) with 2% EtOH/98% CHCl3 elution to remove a low TLC Rf impurity. Solvent removal and drying in vacuo (0.005 Torr, 25° C.) gave a colorless liquid that solidified with scratching (1.20 g, 76%): mp 49-51° C.; 1H NMR (CDCl3) 1.24-1.52 (m, 3H), 1.56-1.68 (m, 2H), 2.00 (t, J=10, 2H), 2.48 (d, J=6.6, 2H), 2.86 (bs, 2H), 3.08 (d, J=11, 2H), 7.05 (d, J=8.4, 2H), 7.23 (d, J=8.4, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:13])[N:4]([CH2:10][CH2:11][CH3:12])[C:5](=[O:9])[NH:6][C:7]=1[NH2:8].[CH:14]1([C:19](O)=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15]1.Cl.C(N=C=NCCCN(C)C)C>CO>[NH2:8][C:7]1[NH:6][C:5](=[O:9])[N:4]([CH2:10][CH2:11][CH3:12])[C:3](=[O:13])[C:2]=1[NH:1][C:19]([CH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:20]
Reactant: O=C(O)C1CCCC1
Reactant: CCCn1c(=O)[nH]c(N)c(N)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CO
Product: CCCn1c(=O)[nH]c(N)c(NC(=O)C2CCCC2)c1=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of 5,6-diamino-3-propyl-1H-pyrimidine-2,4-dione (0.6 g, 2.72 mmol) in methanol (50 ml) was added cyclopentane carboxylic acid (0.310 g, 2.72 mmol). The reaction mixture was cooled to 0° C. and then 1-ethyl-3(3′-dimethylaminopropyl) carbodiimide hydrochloride (EDCI.HCl) (0.78 g, 4.1 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water. The solid was filtered and washed thoroughly with water followed by diethyl ether. The product obtained was dried under high vacuum. The crude product (0.40 g) was used for the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(O[C@@H:13]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:14]([O:16][CH3:17])=[O:15])(=O)=O>CC#N>[C:18]1([C@@H:13]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:14]([O:16][CH3:17])=[O:15])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1ccccc1
Reactant: COC(=O)[C@@H](OS(C)(=O)=O)c1ccccc1
Solvent: CC#N
Product: COC(=O)[C@H](Nc1ccccc1)c1ccccc1
Temperature: 120 °C
Yield: 91.4 %

Procedure:
Aniline (16.8 mL, 184 mmol) is added to a solution of (S)-methyl 2-(methylsulfonyloxy)-2-phenylacetate (I5) (22.4 g, 92.0 mmol) in CH3CN (50 mL). The mixture is heated under MW irradiation at 120° C. for 5 minutes (UPLC-MS monitoring: complete conversion). The resulting crude is partitioned between EtOAc (200 mL) and 1N HCl (200 mL) and the aqueous phase is extracted with EtOAc (3×200 mL). The combined organic layers are dried over Na2SO4, filtered and evaporated under vacuum to obtain 20.3 g of a pale yellow solid (92% yield), which is used in the next step without any additional purification.
Reaction SMILES: [OH-:1].[Na+].[CH2:3]([CH:5]([CH2:9][CH2:10][CH2:11][CH3:12])[C:6](Cl)=[O:7])[CH3:4].[CH3:13][C:14]([O:23][OH:24])([CH2:16][CH2:17][C:18]([CH3:22])([O:20][OH:21])[CH3:19])[CH3:15]>>[CH3:15][C:14]([O:23][O:24][C:6](=[O:1])[CH:5]([CH2:3][CH3:4])[CH2:9][CH2:10][CH2:11][CH3:12])([CH2:16][CH2:17][C:18]([CH3:22])([O:20][O:21][C:6](=[O:7])[CH:5]([CH2:3][CH3:4])[CH2:9][CH2:10][CH2:11][CH3:12])[CH3:19])[CH3:13]
Reactant: CCCCC(CC)C(=O)Cl
Reactant: [OH-]
Reactant: CC(C)(CCC(C)(C)OO)OO
Agent: [Na+]
Product: CCCCC(CC)C(=O)OOC(C)(C)CCC(C)(C)OOC(=O)C(CC)CCCC
Temperature: 30 °C

Procedure:
Sodium hydroxide (25% aqueous solution), 2-ethylhexanoyl chloride (93%), 2,5-dimethyl-2,5-dihydroperoxyhexane (70%) are introduced into the mixing reactor (21) along with an aliphatic organic solvent (hexane, heptane etc.) at the rate of 51 lbs/hr, 31 lbs/hr and 38 lbs/hr respectively. The temperature in the reaction zone 21 is maintained at about 30° C and that in the after reaction zone 22 at about 20° C. The product 2,5-dimethyl-2,5-di(2-ethylhexanoylperoxy)hexane is obtained at the rate of about 50 lbs/hr.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[NH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:4]1(=[O:6])[N:12]([CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]12
Reactant: O=C1OC(=O)c2ccccc21
Reactant: NCCCC(=O)O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(O)CCCN1C(=O)c2ccccc2C1=O

Procedure:
To a mixture of phthalic anhydride (14.8 g, 100 mmole) and 4-aminobutyric acid (10.3 g, 100 mmole) in 150 mL of dry toluene was added triethylamine (1.3 mL, 9.3 mmole). The reaction mixture was heated to reflux in a flask equipped with a Dean Stark trap and condensor. After refluxing for 2.5 hours, the reaction solution was cooled in an ice bath which resulted in the formation of a white precipitate. The solid was isolated by filtration and washed with 5% HCl (3×80 mL) followed by cold water (2×70 mL). 4-Phthalimidobutyric acid was obtained as a white powder (16.8 g, 72%). m.p.: 118-118.6° C.
Reaction SMILES: C[Al](C)C.[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=1.[Si:13]([O:30][CH2:31][CH2:32][O:33][CH2:34][C@H:35]([OH:40])[C:36](OC)=[O:37])([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1.O>[Si:13]([O:30][CH2:31][CH2:32][O:33][CH2:34][C@H:35]([OH:40])[C:36]([NH:12][C:9]1[CH:8]=[CH:7][C:6]([Cl:5])=[CH:11][N:10]=1)=[O:37])([C:26]([CH3:29])([CH3:27])[CH3:28])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Nc1ccc(Cl)cn1
Reactant: COC(=O)[C@@H](O)COCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: C[Al](C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](OCCOC[C@H](O)C(=O)Nc1ccc(Cl)cn1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 61.3 %

Procedure:
Trimethylaluminium (2M in toluene) (4.97 mL, 9.94 mmol) was added carefully to 5-chloropyridin-2-amine (1.277 g, 9.94 mmol) in toluene (10 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 15 minutes. (S)-Methyl 3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-hydroxypropanoate (Intermediate AB3) (2 g, 4.97 mmol) in toluene (2 mL) was added. The reaction was heated to 120° C. for 2 hours in the microwave reactor. The reaction mixture was allowed to cool. The residue was neutralised with citric acid (1M, aq) and then diluted with water and extracted with EtOAc. The combined organics were dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 50% EtOAc in isohexane to afford the product (1.52 g, 61.3%). 1H NMR (400 MHz, CDCl3) δ 1.04 (9H, s), 3.63-3.68 (3H, m), 3.79-3.83 (2H, m), 3.85 (2H, d), 4.33 (1H, q), 7.34-7.46 (6H, m), 7.63-7.69 (5H, m), 8.18-8.25 (2H, m), 9.19 (1H, s); m/z (ES+) (M+H)+=499.55; HPLC tR=3.43 min.
Reaction SMILES: [CH2:1]([N:4]([C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH:5]=[O:6])[C:2]#[CH:3].[CH2:15]=O.[CH2:17]([NH:19][CH2:20][CH3:21])[CH3:18].Cl>O1CCOCC1>[CH2:17]([N:19]([CH2:20][CH3:21])[CH2:15][C:3]#[C:2][CH2:1][N:4]([C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH:5]=[O:6])[CH3:18]
Reactant: CCNCC
Reactant: C=O
Reactant: C#CCN(C=O)C(=O)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: CCN(CC)CC#CCN(C=O)C(=O)c1ccccc1
Temperature: 75 °C
Yield: 74.5 %

Procedure:
N-(2-propynyl)benzoylformamide (0.36 g), 80% paraformaldehyde (90 mg) and diethylamine (162 mg) were added to anhydrous dioxane, 4 mg cuprous chloride was further added, and the mixture was heated at 70 to 80° C. for 1.5 hours with stirring. After cooling to room temperature, the reaction mixture was acidified with 5% hydrochloric acid. The separated aqueous layer was collected and washed with diethyl ether, 5% aqueous solution of caustic soda was added under ice cooling to make the solution weakly alkaline, and the alkaline solution was extracted with diethyl ether. The etheral extract was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The oily residue thus obtained was purified by silica gel column chromatography (Wako Gel C-200; chloroform), giving 0.39 g of the objective compound.
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[CH:9][CH:10]=2)[C:5]1=O.O.[NH2:18][CH2:19][C@H:20]([OH:22])[CH3:21]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:15][O:14][C:8]1[CH:9]=[CH:10][C:11]2[CH2:12][CH2:13][C:4]3[CH:3]=[CH:2][N:18]([CH2:19][C@H:20]([OH:22])[CH3:21])[C:5]=3[C:6]=2[CH:7]=1
Reactant: COc1ccc2c(c1)C(=O)C(CC=O)CC2
Reactant: C[C@@H](O)CN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)-c1c(ccn1C[C@@H](C)O)CC2
Reaction time: 0.5 h
Yield: 95.4 %

Procedure:
A solution of 2 g of (RS)-2-(2-oxoethyl)-7-methoxy-1-tetralone and 100 mg of p-toluenesulfonic acid in 90 ml of anhydrous toluene was heated on a water separator. A solution of 2.78 g of (R)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 30 minutes, during which the solvent was reduced to a volume of 25 ml. The cooled reaction mixture was purified by column chromatography on silica gel (ethyl acetate/toluene 1:1). 2.25 g (94%) of (R)-1-(4,5-dihydro-8-methoxy-1H-benz[g]indol-1-yl)-propan-2-ol were obtained as a brown oil which was used directly in the next reaction.
Reaction SMILES: [CH:1]([NH2:5])([CH2:3][CH3:4])[CH3:2].Cl[C:7]1[C:8]([N+:18]([O-:20])=[O:19])=[C:9]([CH3:17])[C:10]([CH3:16])=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14]>C(O)C>[CH:1]([NH:5][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:10]([CH3:16])=[C:9]([CH3:17])[C:8]=1[N+:18]([O-:20])=[O:19])([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)N
Reactant: Cc1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1C
Solvent: CCO
Product: CCC(C)Nc1c([N+](=O)[O-])cc(C)c(C)c1[N+](=O)[O-]

Procedure:
(-)-sec-Butylamine [prepared according to L. Verbit and P. J. Heffron, Journal of Organic Chemistry 32, 3199 (1967)] was reacted with 4-chloro-3,5-dinitro-o-xylene as by the general procedure of Example 5 to give a yellow-orange solid with melting point 37° C. to 38.5° C., [α]D25° =-51.38° (c 2.071, ethanol). Concentrations, abbreviated c herein, are measured in grams per 100 ml. of solution.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[N+:11]([C:14]1[CH:15]=[C:16]([OH:23])[CH:17]=[CH:18][C:19]=1[N+:20]([O-:22])=[O:21])([O-:13])=[O:12]>[OH-].[Na+].C(Cl)Cl>[N+:11]([C:14]1[CH:15]=[C:16]([CH:17]=[CH:18][C:19]=1[N+:20]([O-:22])=[O:21])[O:23][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12)([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1ccc(O)cc1[N+](=O)[O-]
Reactant: Clc1ccnc2[nH]ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(Oc2ccnc3[nH]ccc23)cc1[N+](=O)[O-]
Temperature: 150 °C

Procedure:
A mixture of 4-chloro-1H-pyrrolo[2,3-b]pyridine (Step B, 1.0 g, 6.5 mmol) and 3,4-dinitrophenol (1.41 g, 7.6 mmol) was heated at 150° C. for 8 h. The resulting crude solid was dissolved in NaOH (12N) and CH2Cl2. The aqueous layer was extracted several times with CH2Cl2. The insoluble material was solubilized in acetone. The acetone solution was diluted with CH2Cl2 and washed with water. The combined CH2Cl2 layers were dried and concentrated under vacuum. The crude material was purified on silica gel using a CH2Cl2/EtOH gradient (100/0 to 90/10) to give 4-(3,4-dinitro-phenoxy)-1H-pyrrolo[2,3-b]pyridine.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12](F)[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[N+:19]([O-:21])=[O:20])([CH3:4])([CH3:3])[CH3:2].[CH3:23][NH:24][CH3:25]>CS(C)=O>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:24]([CH3:25])[CH3:23])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[N+:19]([O-:21])=[O:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: CNC
Solvent: CS(C)=O
Product: CN(C)c1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1C(F)(F)F

Procedure:
The title compound was prepared from (5-fluoro-2-nitro-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example A2) (1.62 g, 5.0 mmol) and dimethylamine (5.6 N in EtOH, 4.47 mL, 25.0 mmol) in DMSO (10 mL) at 23° C. according to the general procedure C and obtained as a yellow solid (1.48 g).
Reaction SMILES: [CH3:1][N:2]([CH:4]=O)[CH3:3].[CH2:6]([O:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[CH:22][C:23]3[N:29]([CH2:30][C:31]4[O:32][CH:33]=[CH:34][CH:35]=4)[CH2:28][CH2:27][C:26]([C:36](O)=[O:37])=[CH:25][C:24]=3[CH:39]=2)=[CH:16][CH:15]=1)[CH2:7][CH2:8][CH3:9].S(Cl)(Cl)=O>O1CCCC1>[CH2:6]([O:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[CH:22][C:23]3[N:29]([CH2:30][C:31]4[O:32][CH:33]=[CH:34][CH:35]=4)[CH2:28][CH2:27][C:26]([C:36]([NH:29][C:23]4[CH:24]=[CH:39][C:20]([CH2:4][N:2]([CH3:1])[CH:3]5[CH2:12][CH2:11][O:10][CH2:6][CH2:7]5)=[CH:21][CH:22]=4)=[O:37])=[CH:25][C:24]=3[CH:39]=2)=[CH:16][CH:15]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2ccco2)cc1
Reactant: CN(C)C=O
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3Cc2ccco2)cc1
Reaction time: 1 h

Procedure:
One droplet of DMF was added to a solution of 7-(4-butoxyethoxyphenyl)-1-(2-furylmethyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (200 mg) in tetrahydrofuran (10 ml). Then, thionyl chloride (155 mg) was added at 0° C., the temperature was returned to room temperature, and the mixture was stirred under nitrogen atmosphere for 1 hour. Then, the solvent and excess thionyl chloride were evaporated, and the resulting residue was suspended in tetrahydrofuran (15 ml) and added to a solution of 4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]aniline (115 mg) and triethylamine (1.1 g) in tetrahydrofuran (10 ml) at 0° C. The mixture was stirred under nitrogen atmosphere at room temperature for 2.5 hours, to the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was separated and purified with silica gel column chromatography (methanol:ethyl acetate=1:8), which was recrystallized from hexane-ethyl acetate to give 7-(4-butoxyethoxyphenyl)-1-(2-furylmethyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 72) (199 mg) as yellow crystals.