Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]([C:6]([NH:8][C@H:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([N:18]4[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][C:19]4=O)[CH:16]=3)[CH2:11][C@@H:10]2[OH:32])=[O:7])=[CH:4][CH:3]=1.O.C(=O)(O)[O-].[Na+]>O1CCCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][C@H:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([N:18]4[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:25])[CH2:20][CH2:19]4)[CH:16]=3)[CH2:11][C@@H:10]2[OH:32])=[O:7])=[CH:33][CH:34]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3c(c2)[C@H](NC(=O)c2ccc(F)cc2)[C@@H](O)C3)C(=O)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3c(c2)[C@H](NC(=O)c2ccc(F)cc2)[C@@H](O)C3)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 79 %

Procedure:
Cool a solution of tert-butyl 4-[(2S,3S)-3-[(4-fluorobenzoyl)amino]-2-hydroxy-indan-5-yl]-3-oxo-piperazine-1-carboxylate (8.85 g, 18.9 mmol) in anhydrous tetrahydrofuran (40 mL) in an ice bath for 30 min. and add borane-dimethyl sulfide complex (2 M, 37.7 mL, 75.40 mmol) under nitrogen. Warm the mixture to room temperature and stir for 1.5 hr. Add a second portion of borane-dimethyl sulfide complex (2 M, 9.42 mL, 18.9 mmol) at room temperature and stir for one hour. Cool in an ice bath for 10 min and carefully add water dropwise, followed by addition of saturated sodium bicarbonate solution (50 mL). Dilute the resulting suspension with ethyl acetate (150 mL). Wash the organic portion with brine, dry over sodium sulfate, and concentrate in vacuo. Purify the crude product by flash chromatography (120 g silica, 40 to 50% ethyl acetate/hexanes) to obtain the title compound (6.8 g, 79%). LC-ES/MS m/z 456 [M+H]+.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=O)[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[CH3:32][NH:33][CH3:34].C1COCC1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CS(C)=O>[CH3:32][N:33]([CH2:27][C:23]1[CH:22]=[C:21]([C:18]2[CH:19]=[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=2)[NH:14][CH:13]=[C:12]3[CH:9]2[CH2:10][CH2:11][N:6]([S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])[CH2:7][CH2:8]2)[CH:26]=[CH:25][CH:24]=1)[CH3:34]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(C=O)c4)cc23)CC1
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CN(C)C)c4)cc23)CC1
Reaction time: 8 h
Yield: 19.2 %

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1H-indole-7-carboxamide (45 mg, 0.10 mmol) in DMSO (2 mL) was added 2 M dimethylamine in THF (500 μL, 1.0 mmol). The reaction mixture was stirred at room temperature for h before addition of sodium triacetoxyborohydride (220 mg, 1.04 mmol). The reaction was then stirred overnight. Compound was purified by Gilson Preparatory HPLC to give 9.0 mg of the title compound (19.2%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:12]=[O:13])=[CH:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:17][C:16]=1O.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>C(O)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[O:13][C:16]4[CH:17]=[C:18]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH:19]=[CH:20][C:15]=4[N:14]=3)=[CH:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: Cn1cc(C=O)c2ccc(F)cc21
Reactant: COC(=O)Cc1ccc(N)c(O)c1
Solvent: CC(=O)O
Solvent: Ic1ccccc1
Solvent: CCO
Product: COC(=O)Cc1ccc2nc(-c3cn(C)c4cc(F)ccc34)oc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.2 %

Procedure:
In ethanol (15 ml), 6-fluoro-1-methylindole-3-carbaldehyde (500 mg, 2.82 mmol) and methyl 4-amino-3-hydroxyphenylacetate (767 mg, 4.23 mmol) were stirred at room temperature for 2 hours. Iodobenzene diacetate (1.09 g, 3.38 mmol) was added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was then distilled under reduced pressure to remove the solvent. The residue was purified chromatography on a silica gel column, whereby from n-hexane-ethyl acetate (1:1, v/v) eluate fractions, methyl (2-(6-fluoro-1-methyl-3-indolyl)-6-benzoxazolyl)acetate (889 mg, 93%) was obtained as a brown solid.
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.[O:8]=[C:9]1[NH:16][CH2:15][CH:14]2[CH:10]1[CH2:11][CH2:12][CH2:13]2.[OH-].[Na+]>C1C=CC=CC=1>[CH3:5][O:8][C:9]1[CH:10]2[CH:14]([CH2:15][N:16]=1)[CH2:13][CH2:12][CH2:11]2
Reactant: O=C1NCC2CCCC12
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: COC1=NCC2CCCC12
Reaction time: 1 h

Procedure:
Over a period of 1 hour, 94.7 ml of dimethyl sulfate are added dropwise to a solution, maintained at reflux, of 125.2 g of 2-oxo-3-azabicyclo(3,3,0)octane in 350 ml of anhydrous benzene. Reflux is then maintained for 4 hours. After cooling, the reaction mixture is poured onto 100 ml of concentrated sodium hydroxide solution. The organic layer is decanted, and the aqueous layer is extracted twice with 200 ml of benzene each time. The benzene extracts are combined, dried over magnesium sulfate and concentrated in vacuo and the residue is distilled. In this manner 79.5 g of 2-methoxy-3-azabicyclo(3,3,0)oct-2-ene are obtained, b.p.: 64°-68° C., nD23 =1.4718.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([NH:15][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)=O.OS([O-])=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1.[NH2:40][C:41]1[CH:49]=[C:48]([O:50][CH3:51])[CH:47]=[C:46]([O:52][CH3:53])[C:42]=1[C:43]([NH2:45])=[O:44]>CC(N(C)C)=O>[CH3:53][O:52][C:46]1[CH:47]=[C:48]([O:50][CH3:51])[CH:49]=[C:41]2[C:42]=1[C:43](=[O:44])[NH:45][C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]3[CH2:10][CH2:11][CH:12]([NH:15][C:16](=[O:23])[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:13][CH2:14]3)=[CH:7][CH:8]=1)=[N:40]2
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Reactant: O=Cc1ccc(N2CCC(NC(=O)c3ccccc3)CC2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCC(NC(=O)c5ccccc5)CC4)cc3)nc2c1
Temperature: 150 °C
Yield: 9.4 %

Procedure:
A mixture of N-(1-(4-formylphenyl)piperidin-4-yl)benzamide (0.350 g, 1.10 mmol), NaHSO3 (0.180 g, 1.70 mmol) and p-TsOH (0.022 g, 0.11 mmol) and 2-amino-4,6-dimethoxybenzamide (0.223 g, 1.10 mmol) in DMA (10 mL) was heated at 150° C. overnight. The mixture was concentrated in vacuo, and the residue was dissolved in EtOAc and washed with H2O and brine, dried (Na2SO4), filtered and concentrated in vacuo. The resulting solid was purified by silica gel chromatography eluting with 10% to 50% CHCl3/MeOH/concentrated NH4OH in CH2Cl2 to afford the title compound (0.050 g, 10%): 1H NMR (300 MHz, DMSO-d6): δ 11.75 (s, 1H), 8.26 (d, J=7.4 Hz, 1H), 8.10 (d, J=9.0 Hz, 2H), 7.83 (d, J=6.9 Hz, 2H), 7.44-7.49 (m, 3H), 7.05 (d, J=8.8 Hz, 2H), 6.68 (s, 1H), 6.46 (s, 1H), 3.93-4.17 (m, 3H), 3.88 (s, 3H), 3.83 (s, 3H), 2.91-3.08 (m, 2H), 1.82-1.93 (m, 2H), 1.52-1.72 (m, 2H); APCI MS m/z 485 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@:6]12[CH2:24][C@H:23]1[CH:22]=[CH:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][C@H:15]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:14](=[O:33])[N:13]1[C@@H:9]([CH2:10][C@@H:11]([OH:34])[CH2:12]1)[C:8](=[O:35])[NH:7]2)=[O:5])[CH3:2].C1N=CN([C:41]([N:43]2[CH:47]=N[CH:45]=[CH:44]2)=[O:42])C=1.C(Cl)Cl.CO.C1[C:61]2[C:56](=[CH:57][CH:58]=C[CH:60]=2)CN1>C(Cl)Cl>[CH2:1]([O:3][C:4]([C@@:6]12[CH2:24][C@H:23]1[CH:22]=[CH:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][C@H:15]([NH:25][C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[C:14](=[O:33])[N:13]1[C@@H:9]([CH2:10][C@@H:11]([O:34][C:41]([N:43]3[CH2:44][C:45]4[C:58](=[CH:57][CH:56]=[CH:61][CH:60]=4)[CH2:47]3)=[O:42])[CH2:12]1)[C:8](=[O:35])[NH:7]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@]12C[C@H]1C=CCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)N2
Reactant: c1ccc2c(c1)CNC2
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)[C@@]12C[C@H]1C=CCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](OC(=O)N3Cc4ccccc4C3)C[C@H]1C(=O)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.2 %

Procedure:
The macrocyclic intermediate 10 (110 mg, 0.22 mmol) was dissolved in DCM (2.2 mL), followed by addition of CDI (45 mg, 0.27 mmol) in one portion. The reaction was stirred at rt overnight. After 15 h, the reaction was complete as monitored by TLC (DCM/MeOH 9:1). 2,3-Dihydro-1H-isoindole (0.14 mL, 1.1 mmol) was added to the reaction drop-wise, and the reaction was stirred at rt overnight. After 22 h, TLC showed reaction complete. The reaction was diluted with DCM (6 mL) and washed with 1N aq. HCl (2×2 mL), sat. sodium bicarbonate (2 mL), brine (2 mL), dried (Na2SO4), and concentrated down. The crude was purified on silica gel (Biotage 40S, eluent: 2 to 4% MeOH in DCM), giving 11 as a pale yellowish foamy powder (131 mg, 90%).
Reaction SMILES: C1C2C(COC([NH:18][C:19]3[CH:24]=[CH:23][C:22]([S:25][C:26]4[S:30][C:29]([C:31]([O:33]CC)=[O:32])=[CH:28][C:27]=4[NH:36][C:37]4[C:38]5[CH:46]=[CH:45][C:44]([CH:47]([CH3:49])[CH3:48])=[N:43][C:39]=5[N:40]=[CH:41][N:42]=4)=[CH:21][CH:20]=3)=O)C3C(=CC=CC=3)C=2C=CC=1.O.[OH-].[Li+].Cl>O1CCOCC1.O>[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25][C:26]2[S:30][C:29]([C:31]([OH:33])=[O:32])=[CH:28][C:27]=2[NH:36][C:37]2[C:38]3[CH:46]=[CH:45][C:44]([CH:47]([CH3:49])[CH3:48])=[N:43][C:39]=3[N:40]=[CH:41][N:42]=2)=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1cc(Nc2ncnc3nc(C(C)C)ccc23)c(Sc2ccc(NC(=O)OCC3c4ccccc4-c4ccccc43)cc2)s1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)c1ccc2c(Nc3cc(C(=O)O)sc3Sc3ccc(N)cc3)ncnc2n1
Yield: 72.5 %

Procedure:
The product of Example 430E (0.245 g, 0.356 mmol) in 1,4-dioxane (3 mL), was treated with a solution of lithium hydroxide monohydrate (0.0747 g, 1.78 mmol) in water (1.5 mL) at room temperature, the resulting mixture was heated at 60° for 25 minutes. The reaction mixture was cooled, diluted with water (10 mL), adjusted the pH to 3 with 1N aqueous HCl, and the resulting precipitate was collected by vacuum filtration. Washing of the crude product with small volumes of 1,4-dioxane afforded the title compound (0.113 g, 0.258 mmol, 72%). MS (ESI+) m/z 438 (M+H)+, MS (ESI−) m/z 436 (M−H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=2)[N:3]=1.[CH3:17][N:18]([CH3:22])[CH2:19][CH2:20][NH2:21]>O>[Cl:8][C:6]1[CH:7]=[C:2]([NH:21][CH2:20][CH2:19][N:18]([CH3:22])[CH3:17])[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=2)[N:5]=1
Reactant: Clc1cc(Cl)nc(-c2ccc(Cl)c(Cl)c2)n1
Reactant: CN(C)CCN
Solvent: O
Product: CN(C)CCNc1cc(Cl)nc(-c2ccc(Cl)c(Cl)c2)n1

Procedure:
Seven grams of 4,6-dichloro-2-(3,4-dichlorophenyl)pyrimidine is added in small portions to 25 ml. of N,N-dimethylethylenediamine with slight warming and stirring. The resulting mixture is heated on a steam bath for several minutes then poured into 500 ml. of water. The product thus obtained is recrystallized from n-heptane to afford 4-chloro-2-(3,4-dichlorophenyl)-6-[2-(dimethylamino)ethylamino]-pyrimidine, m.p. 99.5°-102°C.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH2:7][CH:6]([CH2:8][CH:9]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11](OC)=[N:10]2)[O:5][N:4]=1.[Cl-:20].[NH4+:21]>>[ClH:20].[F:1][C:2]([F:19])([F:18])[C:3]1[CH2:7][CH:6]([CH2:8][CH:9]2[NH:10][C:11](=[NH:21])[CH2:12][CH2:13][CH2:14][CH2:15]2)[O:5][N:4]=1
Reactant: COC1=NC(CC2CC(C(F)(F)F)=NO2)CCCC1
Reactant: [NH4+]
Reactant: [Cl-]
Product: Cl
Product: N=C1CCCCC(CC2CC(C(F)(F)F)=NO2)N1

Procedure:
The product of Example 115 is reacted with ammonium chloride by the method of Example 5 to generate the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([P:9]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[CH3:26][I:27]>>[I-:27].[CH3:26][P+:9]([C:18]1[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1)([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1
Reactant: CI
Reactant: COc1ccc(P(c2ccc(OC)cc2)c2ccc(OC)cc2)cc1
Product: COc1ccc([P+](C)(c2ccc(OC)cc2)c2ccc(OC)cc2)cc1
Product: [I-]
Yield: 93.2 %

Procedure:
Starting from 10.4 g (29.5 mmol) of tris(4-methoxyphenyl)phosphine and 6.7 g (48 mmol, 1.6 eq) of methyl iodide, 13.6 g (27.5 mmol, 93.3%) of methyltris(4-methoxyphenyl)phosphonium iodide was obtained: mp 220.1°-221.9° C.;
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Br:24]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([Br:24])[N:6]2[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: BrBr
Reactant: CCCCCOc1nc(N)c2ncn(Cc3ccccc3)c2n1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCOc1nc(N)c2nc(Br)n(Cc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
6-Amino-9-benzyl-2-pentoxypurine (95 mg, 0.305 mmol) and bromine (0.5 ml) were dissolved in 100 ml of methylene chloride and the solution was stirred at room temperature for 1 hour. Aqueous sodium thiosulfate was added to the reaction mixture. The organic layer was separated and dried on sodium sulfate and evaporated in vacuo to dryness. The residue was purified with silica gel chromatography (1% methanol/chloroform) to give the subject compound (78 mg, yield 82%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:18][CH:19]1[CH2:21][CH2:20]1)[CH:13]([OH:17])[C:14](O)=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[N:23]1C(=O)CC[C:24]1=O.C(Cl)CCl.CN>C(Cl)Cl.C1COCC1>[CH:19]1([CH2:18][C@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:13]([OH:17])[C:14]([NH:23][CH3:24])=[O:15])[CH2:21][CH2:20]1
Reactant: O=C(N[C@@H](CC1CC1)C(O)C(=O)O)OCc1ccccc1
Reactant: O=C1CCC(=O)N1O
Agent: CN
Solvent: ClCCCl
Solvent: C1CCOC1
Solvent: ClCCl
Product: CNC(=O)C(O)[C@H](CC1CC1)NC(=O)OCc1ccccc1
Reaction time: 0.5 h
Yield: 62.8 %

Procedure:
To a solution of (3S)-3-(benzyloxycarbonylamino)-4-cyclopropyl-2-hydroxybutanoic acid (180 mg, 0.26 mmol) in DCM (20 mL) was added HOSu (105 mg, 0.92 mmol), EDC (175 mg, 0.92 mmol). After stirred for 30 minutes, methylamine in THF (2 N, 0.92 mL) was added to above mixture. The reaction mixture was stirred for 18 hours and then concentrated in vacuo. The residue was purified by Gilson Prep to afford title compound (50 mg). 1H-NMR (CDCl3): δ 7.53-7.26 (m, 5H), 6.83 (NH, 1H), 5.25 (NH, 1H), 5.05 (m, 2H), 4.25-3.89 (m, 3H), 2.70 (m, 3H), 1.4 (m, 1H), 0.86 (m, 1H), 0.61 (m, 1H), 0.38 (m, 2H), 0.33 (m, 2H). (M+1) 307.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].Cl[CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=1>CN(C)C=O>[N+:18]([C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[O:11][CH2:10][CH2:9][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)([O-:20])=[O:19]
Reactant: c1c[nH]cn1
Reactant: O=[N+]([O-])c1cccc(OCCCl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc(OCCn2ccnc2)c1
Reaction time: 8 h

Procedure:
After dissolving 3.74 g. of imidazole in 60 ml. of dry N,N-dimethylformamide, 1.78 g. of 50% sodium hydride in oil was added. When the effervescence had stopped (circa 1 hr.), 7.35 g. of 1-(2-chloroethoxy)-3-nitrobenzene was added. After stirring overnight, the reaction was concentrated under vacuum. Water was added to the residue and the product was extracted into chloroform. The product was extracted out of the chloroform layer with dilute hydrochloric acid. Next, the aqueous acid layer was neutralized with potassium carbonate and the oily product extracted into chloroform. Upon drying the chloroform extract with sodium sulfate, it was concentrated under vacuum to an oil which crystallized on standing. Recrystallization from isopropyl acetate gave 6.12 g. of product as the monohydrate, m.p. 52.5°-55.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:9](=[O:17])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.CN(C)CC.I[CH2:30][CH2:31][CH3:32]>C1C=CC=CC=1>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH:18]2[CH2:23][CH2:22][N:21]([CH2:30][CH2:31][CH3:32])[CH2:20][CH2:19]2)[C:9](=[O:17])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:6][CH:7]=1
Reactant: O=C(Cc1ccccc1)N(c1ccc(Cl)cc1)C1CCNCC1
Reactant: CCCI
Agent: CCN(C)C
Solvent: c1ccccc1
Product: CCCN1CCC(N(C(=O)Cc2ccccc2)c2ccc(Cl)cc2)CC1
Product: Cl

Procedure:
To a stirred solution of 4 parts of N-(4-chlorophenyl)-N-(4-piperidinyl)benzeneacetamide and 3 parts of N,N-dimethylethanamine in 200 parts of benzene are added portionwise 4 parts of 1-iodopropane and the whole is stirred and refluxed for 47 hours. Then the second portion of 4 parts of 1-iodopropane is added and stirring and refluxing is continued for another 20h.20. The reaction mixture is cooled and filtered. The filtrate is washed with water, dried and evaporated in vacuo. From the oily free base, the hydrochloride salt is prepared in the conventional manner in 1,1'-oxybisethane. The precipitated solid salt is filtered off and dried, yielding 3.5 parts of N-(4-chlorophenyl)-N-(1-propyl-4-piperidinyl)benzeneacetamide hydrochloride; mp. 235.5° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11]([OH:13])=O.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[NH2:27][CH2:28][C:29]1[CH:37]=[CH:36][CH:35]=[C:34]2[C:30]=1[C:31](=[O:47])[N:32]([CH:39]1[CH2:44][CH2:43][C:42](=[O:45])[NH:41][C:40]1=[O:46])[C:33]2=[O:38].C(N(CC)CC)C>CN(C=O)C.O>[O:46]=[C:40]1[CH:39]([N:32]2[C:31](=[O:47])[C:30]3[C:34](=[CH:35][CH:36]=[CH:37][C:29]=3[CH2:28][NH:27][C:11]([C:2]3[CH:3]=[N:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:1]=3)=[O:13])[C:33]2=[O:38])[CH2:44][CH2:43][C:42](=[O:45])[NH:41]1
Reactant: O=C(O)c1cnc2ccccc2n1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)c4cnc5ccccc5n4)c3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 69 %

Procedure:
A mixture of 2-quinoxalinecarboxylic acid (0.35 g, 2.0 mmol) and CDI (0.39 g, 2.4 mmol) in DMF (25 mL) was stirred at ambient temperature under nitrogen for 90 minutes. 4-Aminomethyl-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione hydrochloride (0.65 g, 2.0 mmol) and triethylamine (0.61 g, 6.0 mmol) were added, and the mixture was allowed to stir for 16 hours. The mixture was poured into water, resulting in precipitation of the product, which was filtered, washed with additional water (40 mL) and dried, providing 0.61 g, in 69% yield: mp>260° C.; 1H NMR (DMSO-d6) δ 2.07-2.12 (m, 1H), 2.56-2.65 (m, 2H), 2.85-2.98 (m, 1H), 5.05 (d, J=6.3 Hz, 2H), 5.19 (dd, J=12.6 Hz, d=5.4 Hz, 1H), 7.78-7.83 (m, 3H), 7.98-8.04 (m, 2H), 8.19-8.24 (m, 2H), 9.50 (s, 1H), 9.76 (t, J=6.3 Hz, 1H), 11.16 (s, 1H); 13C NMR (DMSO-d6) δ 22.0, 30.9, 38.4, 48.9, 121.9, 127.2, 129.1, 129.4, 131.3, 131.6, 132.0, 133.1, 134.8, 138.7, 139.8, 143.0, 143.8, 144.1, 163.7, 167.0, 167.6, 169.8, 172.8; Anal. calcd for C23H17N5O5.0.5H2O: C, 61.06; H, 4.01; N, 15.47. Found: C, 61.19; H, 3.95; N, 15.37.
Reaction SMILES: [N:1]1([C:15]([O:17][CH2:18][CH:19]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]3[C:20]2=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:16])CC[CH:6]([C:9]2[CH:14]=[CH:13]C=CC=2)[C@H:2]1C(O)=O.C1C=CC(C(Cl)(C2C(Cl)=CC=CC=2)C2C=CC=CC=2)=CC=1.CCN(C(C)C)C(C)C.CO>C(Cl)Cl>[C:15]([N:1]1[CH2:13][CH2:14][CH2:9][CH2:6][CH2:2]1)([O:17][CH2:18][CH:19]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16]
Reactant: O=C(O)[C@@H]1C(c2ccccc2)CCN1C(=O)OCC1c2ccccc2-c2ccccc21
Agent: Clc1ccccc1C(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: ClCCl
Product: O=C(OCC1c2ccccc2-c2ccccc21)N1CCCCC1
Reaction time: 0.17 h

Procedure:
A solution of 7.4 g Fmoc-βPhPro-OH in 120 ml dry DCM was added to 12.0 g 2-chlorotrityl chloride resin (0.83 mmol/g, Novabiochem). DIPEA (3.0 ml) was added and the mixture was shaken for 10 min. Additional 4.5 ml DIPEA were added and shaking was continued for 145 min. Methanol (10 ml) was added the mixture was shaken for another 25 min. The resin was filtered off, washed with DCM (5×100 ml), methanol (2×100 ml) and DCM (4×100 ml). A small sample was dried carefully and deprotected with DCM/piperidine (1:1) for 30 min. Photometric determination of the resulting Fmoc-piperidine adduct (absorption at 301 nm) gave a resin loading of 0.54 mmol/g. The remaining resin was treated with 100 ml DCM and 80 ml piperidine at r.t. for 160 min, washed with DCM (10×100 ml) and diethyl ether (4×80 ml) and dried in vacuo to give 14.37 g HβPhPro-2-chlorotrityl resin.
Reaction SMILES: [S:1]([O-:5])([O-:4])(=[O:3])=[O:2].[Ti:6].[S:7](=[O:11])(=[O:10])([OH:9])[OH:8]>>[S:1]([O-:5])([O-:4])(=[O:3])=[O:2].[Ti+4:6].[S:7]([O-:11])([O-:10])(=[O:9])=[O:8]
Reactant: O=S(=O)(O)O
Reactant: [Ti]
Agent: O=S(=O)([O-])[O-]
Product: [Ti+4]

Procedure:
The sulfate process generally comprises the steps of (1) dissolving a titanium slag or raw ilmenite ore into sulfuric acid to obtain a titanium sulfate solution, (2) adding waste iron or waste aluminum to the titanium sulfate solution to chemically reduce ferric ion contained as an impurity in the solution to the divalent (ferrous) state in order to prevent precipitation of iron and to increase the degree of whiteness of the titanium oxide product, followed by cooling the solution to precipitate and remove ferrous sulfate, (3) heat-hydrolyzing the titanium sulfate solution from which ferrous sulfate had been removed, followed by precipitating hydrous titanium oxide, which is then filtered and washed, and (4) then calcining the washed hydrous titanium oxide at 800 to 1,100° C. to obtain anhydrous titanium oxide.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:8]([NH2:17])[CH2:9][NH:10][CH2:11][CH2:12][NH:13][CH2:14][CH2:15][NH2:16].[H][H]>[Pt]>[CH:1]1([NH:17][CH2:8][CH2:9][NH:10][CH2:11][CH2:12][NH:13][CH2:14][CH2:15][NH2:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: O=C1CCCCC1
Reactant: NCCNCCNCCN
Agent: [Pt]
Product: NCCNCCNCCNC1CCCCC1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
2.1 moles of cyclohexanone was reacted with 1 mole of TETA in the presence of hydrogen and 3.5% wt of Pt/C. A 1 L Parr pressure reactor was charged with 292.5 g of TETA, 10 g of Pt/C, and 412.2 g of cyclohexanone. The reactor was sealed and pressure cycled 3× each with nitrogen to remove air and hydrogen to remove the nitrogen. The vessel was then heated to 80° C. and pressurized to 100 psig (7.8 atm) with hydrogen and stirring at 750-1000 rpm. The temperature was held at 80° C. for 90 minutes and then raised to 100° C. and 800 psig (55.4 atm) with hydrogen for 40 minutes to complete the reaction. The reactor was cooled down to 40° C. and then down loaded.