Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]=O.[NH2:3][C:4]([CH3:16])([CH3:15])[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6]>C(OCC)C>[CH2:1]=[N:3][C:4]([CH3:16])([CH3:15])[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6]
Reactant: CC(C)(N)C(=O)OCc1ccccc1
Reactant: C=O
Solvent: CCOCC
Product: C=NC(C)(C)C(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 98.9 %

Procedure:
37% Aqueous formaldehyde solution (17.3 g) was added over 10 minutes to a stirred solution of benzyl 2-amino-2-methylpropanoate (28.0 g) in diethyl ether at ambient temperature. The two phase mixture was stirred for 21/2 hours then diluted with diethyl ether and washed with brine. The ethereal solution was dried (magnesium sulphate) and solvent evaporated under reduced pressure to give benzyl 2-(N-methyleneamino)-2-methylpropanoate (29.4 g) in equilibrium with its trimer 1,3,5-tri(1-benzyloxycarbonyl-1-methylethyl)hexahydrotriazine as a colourless oil, IR (liquid film) 2980(m), 1725(vs), 1250(m), 1135(vs).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]([C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=1)=[O:10].[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.N1C=CC=CC=1>C(Cl)Cl.CN(C=O)C>[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([C:15]([C:14]2[CH:13]=[CH:12][C:11]([C:9]([O:8][CH3:7])=[O:10])=[CH:19][CH:18]=2)=[O:17])[CH2:23][CH2:22]1
Reactant: CN1CCNCC1
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)N2CCN(C)CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.9 %

Procedure:
Oxalyl chloride (0.533 mL, 6.11 mmol) was added dropwise to a stirred suspension of 4-(methoxycarbonyl)benzoic acid (1 g, 5.55 mmol) in DCM (20 mL) under nitrogen. The resulting suspension was stirred at room temperature for 30 mins. DMF (0.05 mL) was added dropwise under nitrogen. The resulting suspension was stirred for 90 mins. A solution of 1-methylpiperazine (0.554 mL, 5.00 mmol) and pyridine (1.211 mL, 14.99 mmol) in DCM (15 mL) was added dropwise at 0° C., over a period of 60 mins under nitrogen. The resulting solution was stirred at room temperature for 3 h. The reaction mixture was evaporated to dryness to afford the crude product (1.791 g) as a dark orange solid. The solid was redissolved in DCM and washed with NaHCO3. The organic layer was evaporated to dryness to afford methyl 4-(4-methylpiperazine-1-carbonyl)benzoate (0.890 g, 61.1%) as an orange gum, which solidified on standing. Used without further purification.
Reaction SMILES: CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.[F:19][C:20]1[CH:27]=[C:26]([OH:28])[CH:25]=[C:24]([F:29])[C:21]=1[CH2:22][OH:23].Cl[CH2:31][C:32]1[C:33]([CH3:38])=[N:34][O:35][C:36]=1[CH3:37]>C(#N)C>[CH3:38][C:33]1[C:32]([CH2:31][O:28][C:26]2[CH:27]=[C:20]([F:19])[C:21]([CH2:22][OH:23])=[C:24]([F:29])[CH:25]=2)=[C:36]([CH3:37])[O:35][N:34]=1
Reactant: OCc1c(F)cc(O)cc1F
Reactant: Cc1noc(C)c1CCl
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CC#N
Product: Cc1noc(C)c1COc1cc(F)c(CO)c(F)c1
Reaction time: 0.08 h
Yield: 84.5 %

Procedure:
PS-BEMP (1.5 g, 2 eq) was added to a solution of 2,6-difluoro-4-hydroxybenzyl alcohol (400 mg, 1.5 eq) in acetonitrile (4 mL) and the mixture was shaken for 5 min. 4-(Chloromethyl)-3,5-dimethylisoxazole (210 uL, 1.67 mmol) was added and the resultant mixture was shaken at ambient temperature for 16 h. The mixture was filtered, the resin washed with dichloromethane (4×4 mL) and evaporated to afford the desired product (380 mg, 85%) as a white solid: NMR δH(400 MHz; d6-DMSO) 2.20 (3H, s), 2.40 (3H, s), 4.42 (2H, d, J 5.5 Hz), 5.95 (2H, s), 5.08 (1H, t, J 5.5 Hz) and 6.76–6.83 (2H, m); HPLC (XTERRA, 50/80, 220 nm) 94.5% (1.03 min).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:18][CH2:17][CH2:16][N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:27][N:28]([CH3:37])[C:29]1[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(O)C>[Br:1][C:2]1[C:3]([N:12]2[CH2:18][CH2:17][CH2:16][N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:33]([C:32]3[CH:35]=[CH:36][C:29]([N:28]([CH3:37])[CH3:27])=[CH:30][CH:31]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1ncc(Br)c(N2CCCN(Cc3ccc(F)cc3)CC2)c1[N+](=O)[O-]
Reactant: CN(C)c1ccc(C=O)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CN(C)c1ccc(-c2nc3c(N4CCCN(Cc5ccc(F)cc5)CC4)c(Br)cnc3[nH]2)cc1
Temperature: 70 °C

Procedure:
To a mixture of 5-bromo-4-(4-(4-fluorobenzyl)-1,4-diazepan-1-yl)-3-nitropyridin-2-amine (0.047 g, 0.11 mmol), ethanol (4 ml), and 4-dimethylaminobenzaldehyde (0.021 g, 0.14 mmol) was added a freshly prepared aqueous solution of Na2S2O4 (1M; 0.44 ml, 0.44 mmol). The reaction mixture was heated at 70° C. for 4.5 h, then allowed to cool to room temperature and the solvents were removed in vacuo. The residue was absorbed on silica gel and the free running powder was placed on a 10 g isolute silica column which was eluted with 0 to 5% methanol in ethyl acetate/dichloromethane (v/v; 1:1). The title compound was obtained as a yellow solid (0.020 g, 35%); 1H-NMR (500 MHz, DMSO-d6) 2.00 (m, 2H), 2.75-2.85 (m, 4H) and 3.86 (m, 4H) (homopiperazine protons), 2.99 (s, 6H, N(CH3)2), 3.66 (s, 2H, N—CH2), 6.82 (d, J=9.00 Hz, 2H) and 8.00 (d, J=8.84 Hz, 2H) (3,5-C6H4NMe2 and 2,6-C6H4—NMe2), 7.14 (t, J=8.93 Hz, 2H) and 7.39 (dd, J=8.13, 5.42 Hz, 2H) (3,5-ArH and 2,6-ArH), 8.11 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.08 (s, 1H, imidazo[4,5-b]pyridine N—H);
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[O:13]=[C:14]1[NH:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:10][O:9][C:7]([C:6]1[CH:11]=[CH:12][C:3]([CH2:2][N:19]2[CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:15][C:14]2=[O:13])=[CH:4][CH:5]=1)=[O:8]
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CN2CCN(C(=O)OC(C)(C)C)CC2=O)cc1

Procedure:
500 mg of methyl 4-(bromomethyl)benzoate was reacted with 480 mg of tert-butyl 3-oxopiperazine-1-carboxylate and 1 g of Cesium Carbonate in 9 mL of DMF at 45° C. Upon completion, the reaction was extracted in Ethyl Acetate 2 times saturated bicarbonate, dried over Magnesium Sulfate, filtered and concentrated to give tert-butyl 4-(4-(methoxycarbonyl)benzyl)-3-oxopiperazine-1-carboxylate. 613 mg of tert-butyl 4-(4-(methoxycarbonyl)benzyl)-3-oxopiperazine-1-carboxylate was hydrolyzed via Procedure M to give 4-((4-(tert-butoxycarbonyl)-2-oxopiperazin-1-yl)methyl)benzoic acid. 200 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-((4-(tert-butoxycarbonyl)-2-oxopiperazin-1-yl)methyl)benzoic acid via Procedure G. The crude product was extracted twice with saturated bicarbonate in Ethyl Acetate, dried over Magnesium Sulfate, filtered and concentrated to give crude tert-butyl 4-(4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzyl)-3-oxopiperazine-1-carboxylate. 4N HCl was subsequently added to crude tert-butyl 4-(4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzyl)-3-oxopiperazine-1-carboxylate and concentrated to give the HCl salt of N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((2-oxopiperazin-1-yl)methyl)benzamide. The reaction was purified by reverse phase HPLC to give pure N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((2-oxopiperazin-1-yl)methyl)benzamide. MS (Q1) 421.3 (M)+.
Reaction SMILES: [C:1]1([C@@H:7]([CH2:10][CH3:11])[CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:12][O:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16](Cl)=[O:17]>>[CH3:12][O:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16](=[O:17])[CH2:11][CH2:10][C@@H:7]([CH2:8][NH2:9])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccccc1C(=O)Cl
Reactant: CC[C@@H](CN)c1ccccc1
Product: COc1ccccc1C(=O)CC[C@@H](CN)c1ccccc1

Procedure:
The title compound was prepared from 0.2 gm of (R)-(−)-2-phenylbutyl amine and 2-mL of 4 methoxybenzoyl chloride according to procedures described in Example 2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[CH:11][C:10]([CH2:23][C:24]([OH:26])=[O:25])=[C:9]2[CH3:27])=[CH:4][CH:3]=1.[CH2:28](O)[CH2:29][CH2:30][CH2:31][OH:32]>>[OH:32][CH2:31][CH2:30][CH2:29][CH2:28][O:25][C:24](=[O:26])[CH2:23][C:10]1[CH:11]=[C:12]([C:13]2[CH:14]=[CH:15][C:16]([S:19]([CH3:22])(=[O:20])=[O:21])=[CH:17][CH:18]=2)[N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:9]=1[CH3:27]
Reactant: OCCCCO
Reactant: Cc1c(CC(=O)O)cc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(F)cc1
Product: Cc1c(CC(=O)OCCCCO)cc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(F)cc1
Yield: 66 %

Procedure:
Prepared from 6g and 1,4-butanediol similarly to example 1-II, yield 66%, m.p. 149-151° C., 1H NMR 200 MHz (CDCl3) δ (ppm): 1.57-1.65 (m, 2H), 1.68-1.75 (m, 2H), 2.02 (s, 3H), 2.97 (s, 3H), 3.46 (s, 2H), 3.62 (t, 2H, J=6.0), 4.15 (t, 2H, J=6.3), 6.45 (s, 1H), 7.11-7.15 (m, 6H), 7.60 (d, 2H, J=8.6). MS-ESI: m/z 482 (M+Na+).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([N:14]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25](Br)[CH:24]=2)[CH2:15][CH:16]([OH:21])[C:17]([F:20])([F:19])[F:18])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(B(O)O)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+].O(C1C=C(CC(NCC2C=C([C:73]3[CH:78]=[CH:77][CH:76]=[CH:75][C:74]=3[C:79]([F:82])([F:81])[F:80])C=CC=2)(O)C(F)(F)F)C=CC=1)C1C=CC=CC=1>CCO.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.O.CN(C=O)C.C1(C)C=CC=CC=1>[O:1]([C:8]1[CH:9]=[C:10]([N:14]([CH2:22][C:23]2[CH:24]=[C:25]([C:73]3[CH:78]=[CH:77][CH:76]=[CH:75][C:74]=3[C:79]([F:82])([F:81])[F:80])[CH:26]=[CH:27][CH:28]=2)[CH2:15][CH:16]([OH:21])[C:17]([F:20])([F:19])[F:18])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC(CN(Cc1cccc(Br)c1)c1cccc(Oc2ccccc2)c1)C(F)(F)F
Reactant: OC(Cc1cccc(Oc2ccccc2)c1)(NCc1cccc(-c2ccccc2C(F)(F)F)c1)C(F)(F)F
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: OB(O)c1ccccc1
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: OC(CN(Cc1cccc(-c2ccccc2C(F)(F)F)c1)c1cccc(Oc2ccccc2)c1)C(F)(F)F

Procedure:
To a toluene (8 mL) solution of 3-[(3-phenoxyphenyl)[[3-bromophenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol (0.51 g, 1.1 mmol) from EX-595B was added 2-tri-fluoromethyl)phenylboronic acid (0.33 g, 1.7 mmol) and DMF (3 Ml. The resulting solution was added K2CO3 (0.31 g, 2.2 mmol) and Pd(PPh3)4 (0.060 g, 0.05 mmol). The slurry was heated to reflux under argon for 18 h. The cooled mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4) and evaporated to an oil. Purification by flash chromatography on silica gel eluting with 20% ethyl acetate in hexane gave an oil which was dissolved in EtOH, stripped and dried in vacuo to give 0.32 g (55%) of the desired 3[(3-phenoxyphenyl) [[(2′-(trifluoromethyl)[1,1 ′-biphenyl ]-3-yl ]methyl ]amino ]-1,1,1-tri-fluoro-2-propanol product as a colorless oil. Anal. calcd. for C29H23NO2F6.0.8 EtOH: C, 64.67; H, 4.93; N, 2.46. Found: C, 64.53; H, 4.69; N, 2.49. HRMS calcd. 532.1711 [M+H]+, found: 532.1708. 1H NMR (C6D6) δ1.72 (d, 1H), 3.17 (dd, 1H), 3.46 (dd, 1H), 3.72 (m, 1H), 4.23 (s, 2H), 6.33 (dd, 1H), 6.43 (dd, 1H), 6.52 (t, 1H), 6.82 (m, 2H), 6.9-7.1 (m, 11H),7.43(d, 1H).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([N:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][OH:23])[CH2:17][CH2:16]2)[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=O)C.[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[CH:27][CH:26]=1>CN(C=O)C>[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH:30][C:4]([C:6]2[N:7]=[C:8]([N:15]3[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][OH:23])[CH2:17][CH2:16]3)[N:9]([CH3:14])[C:10](=[O:13])[C:11]=2[OH:12])=[O:3])=[CH:27][CH:26]=1
Reactant: NCc1ccc(F)cc1
Reactant: CCOC(=O)c1nc(N2CCN(CCO)CC2)n(C)c(=O)c1O
Solvent: CN(C)C=O
Product: Cn1c(N2CCN(CCO)CC2)nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O
Temperature: 70 °C
Reaction time: 2 h
Yield: 49.7 %

Procedure:
5-Hydroxy-2-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-1-methyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (0.024 g, 0.074 mmol) was dissolved in DMF (1 mL) to which was added 4-fluoro-benzyl amine (0.047 mL, 0.37 mmol). The mixture was stirred at 70° C. for 2 hours. The resulting mixture was purified by chromatography (YMC Combiprep ODS-A, 30 mm×50 mm, MeOH/H2O/0.1% TFA) to yield the title compound as a white powder (0.0149 g, 50% yield). 1H NMR (500 MHz, MeOD) δ: 8.81 (1H, bs), 7.40 (2H, dd, J=8.5, 5.5 Hz), 7.08 (2H, t, J=8.8 Hz), 4.59 (2H, d, J=6.1 Hz), 3.94 (2H, t, J=5.2 Hz), 3.70 (4H, d, J=11.3 Hz), 3.58 (3H, s), 3.47–3.35 (6H, m). HRMS (M+H) calcd for C19H25FN4O5: 406.18907. found: 406.1895.
Reaction SMILES: [F:1][C:2]1[C:3]([O:21][CH3:22])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[S:13][CH:14]=[C:15]([CH:17]([CH3:19])[CH3:18])[N:16]=1)[CH:8]=[C:7]2[OH:20].C(C1N=C(C2C=C(O[CH:42]3[CH2:59][CH:58]4[CH:44]([C:45](=[O:65])[N:46]([CH3:64])[CH2:47][CH2:48][CH2:49][CH2:50][CH:51]=[CH:52][CH:53]5[C:55]([C:61]([OH:63])=[O:62])([NH:56][C:57]4=[O:60])[CH2:54]5)[CH2:43]3)C3C(=C(C)C(OC)=CC=3)N=2)SC=1)(C)C>>[F:1][C:2]1[C:3]([O:21][CH3:22])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[S:13][CH:14]=[C:15]([CH:17]([CH3:18])[CH3:19])[N:16]=1)[CH:8]=[C:7]2[O:20][CH:42]1[CH2:59][CH:58]2[CH:44]([C:45](=[O:65])[N:46]([CH3:64])[CH2:47][CH2:48][CH2:49][CH2:50][CH:51]=[CH:52][CH:53]3[C:55]([C:61]([OH:63])=[O:62])([NH:56][C:57]2=[O:60])[CH2:54]3)[CH2:43]1
Reactant: COc1ccc2c(O)cc(-c3nc(C(C)C)cs3)nc2c1F
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)C4C3)cc(-c3nc(C(C)C)cs3)nc2c1C
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)C4C3)cc(-c3nc(C(C)C)cs3)nc2c1F

Procedure:
The title compound was prepared from 8-fluoro-4-hydroxy-2-(4-isopropylthiazole-2-yl)-7-methoxyquinoline (72) and alcohol 43 following the procedure (steps D-F) reported for the preparation of 17-[2-(4-isopropylthiazole-2-yl)-7-methoxy-8-methyl-quinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (46): m/z=651 (M+H)+.
Reaction SMILES: [CH2:1]1[O:3][CH2:2]1.[CH3:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=1.C(O)(=O)C(C)O>CCCCCCCCCC1C=CC(O)=CC=1.[OH-].[Na+]>[CH3:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][CH2:1][CH2:2][OH:3])=[CH:17][CH:18]=1
Reactant: CCCCCCCCCc1ccc(O)cc1
Reactant: C1CO1
Agent: CC(O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCCc1ccc(OCCO)cc1

Procedure:
In a stainless steel reactor having an inner volume of 1,000 ml and provided with a thermometer, a pressure gauge, and a stirrer, 200 g of nonylphenol (molecular weight 221), 0.6 g of sodium hydroxide as a catalyst, and 400 g of ethylene oxide were heated at 150° C. under pressure of 6.0 kg/cm2G of reaction. The resultant averagely 10-mole ethylene oxide adduct of nonylphenol and 2.7 g of an aqueous 50 wt% lactic acid solution added thereto were thoroughly stirred. The nonylphenol ethoxylate obtained as the result was tested for the effect of aging. The results are shown in Table 27.
Reaction SMILES: [NH:1]1[C:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][NH:4][C:3](=[O:12])[CH2:2]1.C(O)(=O)C.[Br:17]Br>CCCCCC>[Br:17][C:10]1[CH:9]=[N:8][C:7]2[NH:1][CH2:2][C:3](=[O:12])[NH:4][CH2:5][C:6]=2[CH:11]=1
Reactant: BrBr
Reactant: O=C1CNc2ncccc2CN1
Solvent: CCCCCC
Solvent: CC(=O)O
Product: O=C1CNc2ncc(Br)cc2CN1
Reaction time: 8 h

Procedure:
1,2,4,5-Tetrahydro-pyrido[2,3-e][1,4]diazepin-3-one (164 mg, 1.0 mmol) was dissolved into acetic acid (1 mL). Bromine (160 mg, 1.0 mmol) was added dropwise at room temperature and the solution was stirred overnight. Hexane (5 mL) was added and the orange precipitate was filtered and dried in vacuo. The title compound was isolated as an orange solid (190 mg, 78%). 1H NMR (300 MHz, DMSO-d6) δ 8.26 (t, J=5.7 Hz, 1H), 8.06 (d, J=2.1 Hz, 1H), 7.81 (d, J=2.1 Hz, 1H), 4.35 (d, J=5.7 Hz, 2H), 4.08 (s, 2H).
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)(Cl)=O.[CH2:11]([N:16]1[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:12][CH2:13][CH2:14][CH3:15]>O>[CH2:11]([N:16]1[C:17]2[CH:18]=[CH:19][C:20]([CH:3]=[O:4])=[CH:21][C:22]=2[C:23]2[C:28]1=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CN(C)C=O
Reactant: CCCCCn1c2ccccc2c2ccccc21
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCCn1c2ccccc2c2cc(C=O)ccc21
Reaction time: 1.5 h

Procedure:
Dimethylformamide (100 mL) is stirred and cooled in an ice bath while phosphorus oxychloride (35 mL, 58 g, 0.38 mol) is gradually added. 9-Pentylcarbazole (52 g, 0.22 mol) is introduced and the resulting mixture is heated on a steam bath with stirring for 1.5 hours. The entire mixture is cooled and added to water (200 mL) and the crude product is filtered off at the pump, washed with water (200 mL). The crude product is recrystallized to form 9-pentyl-3-carbazolecarboxaldehyde.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[F:17][C:18]1[CH:19]=[C:20]([CH:31]=[CH:32][CH:33]=1)[CH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[F:17][C:18]1[CH:19]=[C:20]([CH:31]=[CH:32][CH:33]=1)[CH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:14][CH2:13][CH2:12][C:6]2[C:5]3[C:9](=[CH:10][CH:11]=[C:3]([C:2]([F:15])([F:1])[F:16])[CH:4]=3)[NH:8][CH:7]=2)=[O:27])=[CH:24][CH:23]=1
Reactant: NCCc1c[nH]c2ccc(C(F)(F)F)cc12
Reactant: O=C(O)c1ccc(Cc2cccc(F)c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCCc1c[nH]c2ccc(C(F)(F)F)cc12)c1ccc(Cc2cccc(F)c2)cc1
Yield: 13.7 %

Procedure:
4-(3-Fluorobenzyl)-N-(2-(5-(trifluoromethyl)-1H-indol-3-yl)ethyl)benzamide was prepared according to Method A starting from 2-(5-(trifluoromethyl)-1H-indol-3-yl)ethanamine (0.080 g; 0.347 mmol), 4-(3-fluorobenzyl)benzoic acid (0.080 g, 0.347 mmol), HATU (0.132 g; 0.347 mmol) and N,N-diisopropylethylamine (0.149 mL; 0.869 mmol) in DMF (3 mL). The crude material was purified by preparative HPLC (method 2) to afford 0.021 g (14%) of the title compound as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)=[O:4].[CH2:13]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:14].C(N(C(C)C)CC)(C)C>C(#N)C>[CH2:13]([N:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)=[O:4])[CH3:14]
Reactant: CCNc1ccccc1
Reactant: O=C(CCl)Nc1ccc(O)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC(=O)Nc1ccc(O)cc1)c1ccccc1
Temperature: 60 °C
Reaction time: 12 h
Yield: 40.7 %

Procedure:
To a solution of compound 17a (250 mg, 1.35 mmol) and N-ethylaniline (0.326 mg, 2.69 mmol) in acetonitrile (6.0 mL) was added diisopropylethylamine (0.55 mL, 4.04 mmol) dropwise. After the addition was complete, the reaction was stirred at 60° C. for 12 hours. The reaction mixture was concentrated and purified by column chromatography to isolate the compound 17 as a colorless oil (150 mg, 0.55 mmol 41% yield). MS (ESI, positive) m/z calcd. for C16H19N2O2 [M+H]+: 271.14, found: 270.95. 1H NMR (CDCl3, 400 MHz) δ 8.34 (s, 1H), 7.27-7.31 (m, 4H), 6.88 (t, J=7.2 Hz, 1H), 6.80 (t, J=8.4 Hz, 4H), 3.96 (s, 2H), 3.53 (q, J1=J2=7.2, 2H), 2.20 (s, 1H), 1.24 (t, J=6.8 Hz, 3H).
Reaction SMILES: [C:1]([CH2:4][C:5](=[O:7])[CH3:6])(=[O:3])[CH3:2].[H-].[Na+].[Br:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Br)=[CH:13][CH:12]=1.[NH4+].[Cl-]>C1COCC1.CCOC(C)=O.CCCCCC>[Br:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][CH:4]([C:5](=[O:7])[CH3:6])[C:1](=[O:3])[CH3:2])=[CH:13][CH:12]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: CC(=O)CC(C)=O
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)C(Cc1ccc(Br)cc1)C(C)=O
Temperature: 50 °C

Procedure:
Acetylacetone (4.5 mL, 44 mmol) was added dropwise over 30 minutes to a cooled (ice/H2O bath) suspension of 95% NaH (0.95 g, 41 mmol) in anhydrous THF (150 mL). After H2 evolution had ceased, a solution of p-bromobenzyl bromide (10.2 g, 40.8 mmol) in anhydrous THF (20 mL) was added at once with stirring. The reaction mixture was heated to 50° C. (internal temperature) for 48 h, cooled to room temperature, and poured into saturated aqueous NH4Cl (250 mL). The organic phase was separated and the aqueous phase was extracted with EtOAc (3×125 mL). The combined organic extracts were dried (Na2SO4). The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure to give an oily residue. Flash column chromatography (EtOAc:hexane (1:8)) gave 4d as a clear amber oil which solidified upon standing at room temperature (9.01 g, 82%). 1H NMR (300 MHz, CDCl3): δ 7.42 (d, J=8.4 Hz, 2H, enol), 7.39 (d, J=8.4 Hz, 2H, keto), 7.03 (d, J=8.4 Hz, 2H, keto), 7.02 (d, J=8.4 Hz, 2H, enol), 3.95 (t, J=7.5 Hz, 1H, keto), 3.60 (s, 2H, enol), 3.10 (d, J=7.5 Hz, 2H, keto), 2.13 (s, 6H, keto), 2.05 (s, 6H, enol). 13C NMR (75 MHz, CDCl3): δ 203.3, 192.1, 138.9, 137.3, 132.0, 130.6, 129.4, 120.0, 120.9, 108.1, 70.0, 33.7, 32.6, 29.9, 23.5. IR (neat, cm−1): 3409, 3010, 3004, 2927, 1896, 1728, 1699, 1594, 1487, 1405, 1358, 1072, 1010. GC/MS (ET): m/z 268 (M+). Anal. Calcd. for C12H13BrO2: C, 53.55; H, 4.87; O, 11.89. Found: C, 53.27; H, 4.77; O, 11.61.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][O:8][C:7]([CH3:14])([CH3:13])[C:6]=2[CH:15]=1.Br[C:17]1[CH:18]=[C:19]([F:24])[CH:20]=[C:21]([Cl:23])[CH:22]=1>>[CH3:13][C:7]1([CH3:14])[O:8][CH2:9][C:10](=[O:12])[NH:11][C:5]2[CH:4]=[CH:3][C:2]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([F:24])[CH:18]=3)=[CH:15][C:6]1=2
Reactant: CC1(C)OCC(=O)Nc2ccc(Br)cc21
Reactant: Fc1cc(Cl)cc(Br)c1
Product: CC1(C)OCC(=O)Nc2ccc(-c3cc(F)cc(Cl)c3)cc21

Procedure:
Prepared from 7-bromo-5,5-dimethyl-1,5-dihydro-4,1-benzoxazepin-2(3H)-one and 3-bromo-5-chloro-1-fluorobenzene generally according to the coupling procedure described in examples 82 and 1. 1H NMR (DMSO-d6): δ 10.01 (s, 1H), 7.61-7.65 (m, 4H), 7.36-7.39 (m, 1H), 7.18 (d, J=8.54 Hz, 1H), 4.26 (s, 2H), 1.62 (s, 6H); MS (ESI) m/z 320/322 ([M+H]+); MS (ESI) m/z 318/320 ([M−H]−). Anal. calcd for C17H15ClFNO2: C: 63.86; H: 4.73; N: 4.38 Found: C: 62.53; H: 4.55; N: 3.50.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][CH:2]=1.[CH:7](=[O:10])[CH2:8][CH3:9]>>[N:1]1[CH:6]=[C:5]([C:7](=[O:10])[CH2:8][CH3:9])[N:4]=[CH:3][C:2]=1[C:7](=[O:10])[CH2:8][CH3:9]
Reactant: CCC=O
Reactant: c1cnccn1
Product: CCC(=O)c1cnc(C(=O)CC)cn1

Procedure:
The reaction of pyrazine and propionaldehyde is conducted on a 10 mmole scale using the Caronna et al procedure described in J. Chem. Soc., Perkin Trans. 2, 14, 2035-8 (1972). A 50% crude yield of 1,1'-(2,5-pyrazinediyl)bis-1-propanone is obtained.
Reaction SMILES: [NH2:1][CH:2]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)[C:3]([O:5]CC)=[O:4].[OH-].[Na+].CO>C(O)(=O)C>[NH2:1][CH:2]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(N)c1c[nH]c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: NC(C(=O)O)c1c[nH]c2ccccc12
Reaction time: 0.83 h

Procedure:
A mixture of 2 g of ethyl α-aminoindole-3-acetate, excess dilute NaOH solution, and a few mL of MeOH was stirred occasionally for 25 minutes. Since a solution had not been obtained, the mixture was heated on a steam bath for ten minutes. The resulting solution was allowed to stand at ambient temperature for 50 minutes. The solution was acidified with acetic acid. The solid which separated was collected by filtration and washed with H2O giving 1.50 g (86%) of the title compound as small buff plates, m.p. 217° (dec).