Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8](/[N:10]=[C:11](/[NH2:46])\[C:12]1[CH:17]=[CH:16][C:15]([NH:18][CH2:19][C:20]2[N:24]([CH3:25])[C:23]3[CH:26]=[CH:27][C:28]([C:30]([N:32]([C:40]4[N:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[O:31])=[CH:29][C:22]=3[N:21]=2)=[CH:14][CH:13]=1)=[O:9].CS(O)(=O)=O>C(O)(C)C>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8](/[N:10]=[C:11](\[NH2:46])/[C:12]1[CH:13]=[CH:14][C:15]([NH:18][CH2:19][C:20]2[N:24]([CH3:25])[C:23]3[CH:26]=[CH:27][C:28]([C:30]([N:32]([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][N:45]=4)[CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[O:31])=[CH:29][C:22]=3[N:21]=2)=[CH:16][CH:17]=1)=[O:9]
Reactant: CCCCCCOC(=O)/N=C(/N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OCC)c4ccccn4)ccc3n2C)cc1
Agent: CS(=O)(=O)O
Solvent: CC(C)O
Product: CCCCCCOC(=O)/N=C(\N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OCC)c4ccccn4)ccc3n2C)cc1

Procedure:
26.5 kg of hydroxypropylcellulose are added to 720 kg of isopropanol in a 1200 L mixing container fitted with a propeller stirrer and the mixture is stirred until fully dissolved (about 12 to 60 hours; roughly 500 rpm). Once the solution is clear, 132.3 kg of dabigatran etexilate methanesulfonate (polymorph I) is added with stirring (400 rpm) and the mixture is stirred for about another 20 to 30 minutes. Then 21.15 kg of talc is added at a constant stirring rate and stirring is continued at the same speed for about another 10 to 15 minutes. The steps described above are preferably carried out under a nitrogen atmosphere.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1.[F:14][C:15]([F:26])([F:25])[C:16]1[CH:17]=[C:18]([CH2:22][CH2:23][NH2:24])[CH:19]=[CH:20][CH:21]=1>>[F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][NH:24][CH2:23][CH2:22][C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([C:15]([F:14])([F:25])[F:26])[CH:17]=2)=[CH:6][CH:5]=1
Reactant: NCCc1cccc(C(F)(F)F)c1
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Product: FC(F)(F)Oc1ccc(CNCCc2cccc(C(F)(F)F)c2)cc1

Procedure:
(4-trifluoromethoxy-benzyl)-[2-(3-trifluoromethyl-phenyl)-ethyl]-amine was synthesized in analogy to the above procedure using 1.232 g 4-(trifluoromethoxy)benzaldehyde (6.48 mmol) and 0.817 g 2-(3-trifluoromethyl-phenyl)-ethylamine (4.32 mmol), 1.31 g (83%) of a light yellow liquid were obtained. MS: 364 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][O:8][C:9]([CH3:27])([CH3:26])[CH2:10][O:11][C:12]2[N:13]=[CH:14][C:15]([NH:18]C(=O)OC(C)(C)C)=[N:16][CH:17]=2)=[CH:5][CH:4]=1.O.NN.[OH-].[K+].C(O)CO>O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9]([CH3:27])([CH3:26])[CH2:10][O:11][C:12]2[N:13]=[CH:14][C:15]([NH2:18])=[N:16][CH:17]=2)=[CH:28][CH:29]=1
Reactant: COc1ccc(COC(C)(C)COc2cnc(NC(=O)OC(C)(C)C)cn2)cc1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: COc1ccc(COC(C)(C)COc2cnc(N)cn2)cc1
Temperature: 120 °C
Reaction time: 3 h
Yield: 88.7 %

Procedure:
A mixture of tert-butyl (5-{2-[(4-methoxybenzyl)oxy]-2-methylpropoxy}pyrazin-2-yl)carbamate (330 mg), hydrazine monohydrate (198 μL), potassium hydroxide (1.15 g), and ethylene glycol (9.9 mL) was stirred at 120° C. for 3 hours. To the reaction mixture was added water, followed by extraction with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=50:50) to obtain 5-{2-[(4-methoxybenzyl)oxy]-2-methylpropoxy}pyrazin-2-amine (220 mg) as a yellow oily substance.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[N+:8]([C:11]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[C:16]([N+:24]([O-:26])=[O:25])[C:12]=1[NH:13][O:14][CH3:15])([O-:10])=[O:9].[CH2:27](I)[CH3:28]>CCOCC>[N+:8]([C:11]1[CH:19]=[C:18]([C:20]([F:21])([F:22])[F:23])[CH:17]=[C:16]([N+:24]([O-:26])=[O:25])[C:12]=1[N:13]([CH2:27][CH3:28])[O:14][CH3:15])([O-:10])=[O:9]
Reactant: CCI
Reactant: CONc1c([N+](=O)[O-])cc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCN(OC)c1c([N+](=O)[O-])cc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 0.017 mole of sodium hydride, obtained from 0.82 g. of a 50% dispersion of sodium hydride in mineral oil, was added 50 ml. of dimethylformamide. To the mixture there was added 5.0 g. (0.018 mole) of 2,6-dinitro-N-methoxy-α,α,α-trifluoro-p-toluidine (Example 5), and the mixture was heated for about 45 minutes at temperatures up to about 65° C. The reaction mixture was then cooled to room temperature and there was added thereto, dropwise, 5.3 g. (0.034 mole) of ethyl iodide. The mixture was allowed to stir at room temperature for about 30 minutes and was then heated for about 1 hour at about 80° C., and was checked by TLC. No starting material appeared on the thin layer chromatogram. The reaction product mixture was cooled and allowed to stand overnight at ambient room temperature. The reaction product mixture was worked up by diluting it with ether and washing several times with dilute aqueous hydrochloric acid, once with water, and drying the organic phase over anhydrous magnesium sulfate. The drying agent was filtered off and the solvent removed in vacuo. The residue was chromatographed on a Florisil column using benzene both as solvent and as eluent. The first fractions collected appeared to contain the desired product. The fractions were combined, the solvent was removed in vacuo, and the residue thus obtained was recrystallized from petroleum ether (b.p. 60°-71° C.). The product had a melting point of about 95°-97° C., weighed 1.0 g., and was identified by NMR spectrum and elemental analyses as 2,6-dinitro-N-ethyl-N-methoxy-α,α,α-trifluoro-p-toluidine.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[C@@:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)([CH3:15])[C@@:13]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)([CH3:23])[N:12]=[C:11]2[C:31]2[CH:32]=[N:33][C:34]([C:40]([CH3:43])([CH3:42])[CH3:41])=[CH:35][C:36]=2[O:37][CH2:38][CH3:39])=[O:9])[CH2:4][CH2:3]1.[CH3:44][N:45]=[C:46]=[O:47]>>[C:40]([C:34]1[N:33]=[CH:32][C:31]([C:11]2[N:10]([C:8]([N:5]3[CH2:4][CH2:3][CH:2]([NH:1][C:46]([NH:45][CH3:44])=[O:47])[CH2:7][CH2:6]3)=[O:9])[C@@:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)([CH3:15])[C@@:13]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)([CH3:23])[N:12]=2)=[C:36]([O:37][CH2:38][CH3:39])[CH:35]=1)([CH3:42])([CH3:41])[CH3:43]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(N)CC1
Reactant: CN=C=O
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(NC(=O)NC)CC1

Procedure:
In a manner similar to the method described in example 160, (4-amino-piperidin-1-yl)-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazol-1-yl]-methanone (example 204) was reacted with methyl isocyanate (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C36H45Cl2N6O3 [(M+H)+] 679.2925, observed 679.2929.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][CH2:7][C:8]2[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:19]([F:22])([F:21])[F:20].CCN=C=NCCCN(C)C.[CH3:34][N:35]([CH3:40])[S:36]([NH2:39])(=[O:38])=[O:37].OS([O-])(=O)=O.[K+]>ClCCl>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][CH2:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH:39][S:36]([N:35]([CH3:40])[CH3:34])(=[O:38])=[O:37])=[O:13])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:19]([F:22])([F:21])[F:20]
Reactant: O=C(O)c1ccc(COc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: CN(C)S(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: ClCCl
Product: CN(C)S(=O)(=O)NC(=O)c1ccc(COc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.6 %

Procedure:
To a solution of 4-{[4-chloro-3-(trifluoromethyl)phenoxy]methyl}benzoic acid (Preparation 16, 237 mg, 0.72 mmol) in dichloromethane (8 mL) was added EDCI (344 mg, 1.79 mmol) followed by addition of N,N-dimethylsulfamide (222 mg, 1.79 Calculation isn't correct mmol). The reaction was left to stir at room temperature for 3 hours. A solution of KHSO4 (10 mL) was added and the mixture separated using a phase separation cartridge. The organics were dried in vacuo to yield a white solid as the title compound (285 mg, 97%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([C:15]#[CH:16])[C:12]=1[O:13][CH3:14])[C:6]([O:8]C)=[O:7])#[N:2].O.[OH-].[Li+]>O1CCCC1.O>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([C:15]#[CH:16])[C:12]=1[O:13][CH3:14])[C:6]([OH:8])=[O:7])#[N:2]
Reactant: C#Cc1cc(C(=O)OC)cc(C#N)c1OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1cc(C(=O)O)cc(C#N)c1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 102 %

Procedure:
Methyl 3-cyano-5-ethynyl-4-methoxybenzoate (640 mg) was dissolved in tetrahydrofuran (6 mL) and water (3 mL), and lithium hydroxide monohydrate (495 mg) was added to the solution, and then the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure and 1N hydrochloric acid was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (610 mg) as a brown crystal.
Reaction SMILES: [CH3:1][C:2]1[C:7](/[CH:8]=[C:9](\[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])/[C:10]([OH:12])=[O:11])=[C:6]([O:22]C)[C:5]([O:24][CH3:25])=[C:4]([O:26][CH3:27])[C:3]=1[O:28]C>CCOCC>[CH3:27][O:26][C:4]1[C:3](=[O:28])[C:2]([CH3:1])=[C:7](/[CH:8]=[C:9](\[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])/[C:10]([OH:12])=[O:11])[C:6](=[O:22])[C:5]=1[O:24][CH3:25]
Reactant: CCCCCCCCC/C(=C\c1c(C)c(OC)c(OC)c(OC)c1OC)C(=O)O
Solvent: CCOCC
Product: CCCCCCCCC/C(=C\C1=C(C)C(=O)C(OC)=C(OC)C1=O)C(=O)O

Procedure:
Compound 1 was prepared from 9f (1.13 g, 2.77 mmol) as described above for 10a using Method A to give 0.443 g (1.17 mmol, 42%) of the product as a red solid following flash chromatography (2:3 Et2O:hexanes 0.5% AcOH) and recrystallization from Et2O/hexanes.
Reaction SMILES: [O:1]=[S:2]1(=[O:15])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH2:16]([CH:26]1[CH2:28][O:27]1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C>[O:15]=[S:2]1(=[O:1])[CH2:3][CH2:4][N:5]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:28][CH:26]([OH:27])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:12][CH:13]=2)[CH2:6][CH2:7]1
Reactant: CCCCCCCCCCC1CO1
Reactant: O=S1(=O)CCN(c2ccc(O)cc2)CC1
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: CCCCCCCCCCC(O)COc1ccc(N2CCS(=O)(=O)CC2)cc1
Yield: 38.9 %

Procedure:
4-(1,1-dioxo-thiomorpholin-4-yl)phenol (2.3 g, 10 mmol), 2-(decyl)-oxirane (1.9 g, 10 mmol) and ethyltriphenylphosphonium bromide (0.2 g) are reacted and purified as described for compound 102 to afford a light brown solid 1.6 g (38%), m.p. 84° C.
Reaction SMILES: C[O:2][C:3](=[O:22])[CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([C@@H:12]2[CH2:16][CH2:15][C:14](=O)[CH2:13]2)[CH:9]=[CH:8][C:7]=1[C:18]([F:21])([F:20])[F:19].[C:23]1([C@H:33]([NH2:35])[CH3:34])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1>>[C:23]1([C@H:33]([NH:35][CH:14]2[CH2:15][CH2:16][C@@H:12]([C:10]3[CH:9]=[CH:8][C:7]([C:18]([F:19])([F:21])[F:20])=[C:6]([CH2:5][CH2:4][C:3]([OH:2])=[O:22])[CH:11]=3)[CH2:13]2)[CH3:34])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: C[C@@H](N)c1cccc2ccccc12
Reactant: COC(=O)CCc1cc([C@@H]2CCC(=O)C2)ccc1C(F)(F)F
Product: C[C@@H](NC1CC[C@@H](c2ccc(C(F)(F)F)c(CCC(=O)O)c2)C1)c1cccc2ccccc12

Procedure:
General procedure A was followed using 3-[5-((1R)-3-oxo-cyclopentyl)-2-trifluoromethyl-phenyl]-propionic acid methyl ester (preparation 16) as the ketone and (R)-1-naphthalen-1-yl-ethylamine as the amine. The resulting mixture of isomeric esters was purified and separated by flash chromatography. The faster eluting peak was isolated and subjected to hydrolysis following general procedure B to afford the title compound. 1H NMR (600 MHz, DMSO) δ 8.30 (d, J=8.2 Hz, 1H), 7.93 (d, J=8.0 Hz, 1H), 7.84-7.75 (m, 2H), 7.59-7.48 (m, 4H), 7.41-7.17 (m, 2H), 4.78 (s, 1H), 3.35-3.06 (m, 2H), 2.99-2.88 (m, 2H), 2.55-2.42 (m, 2H), 2.24-1.67 (m, 4H), 1.63-1.39 (m, 5H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1.[F:14][C:15]1[CH:23]=[C:22]([F:24])[C:21]([N+:25]([O-:27])=[O:26])=[CH:20][C:16]=1[C:17](Cl)=[O:18]>C(Cl)Cl>[F:14][C:15]1[CH:23]=[C:22]([F:24])[C:21]([N+:25]([O-:27])=[O:26])=[CH:20][C:16]=1[C:17](=[O:18])[C:8]1[CH:7]=[C:6]([CH3:5])[CH:11]=[CH:10][C:9]=1[O:12][CH3:13]
Reactant: COc1ccc(C)cc1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(F)cc1F
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C)cc1C(=O)c1cc([N+](=O)[O-])c(F)cc1F
Temperature: 0 °C
Reaction time: 8 h
Yield: 57.1 %

Procedure:
A mixture of aluminum chloride (62.3 g, 0.467 mol) and methylene chloride is cooled to −20° C. to −10° C., treated with 4-methylanisole (60.1 g, 0.492 mol), treated dropwise with a mixture of 2,4-difluoro-5-nitrobenzoyl chloride (111 g, 0.468 mol) and methylene chloride over a 10 minute period, warmed to 0° C., stirred overnight at ambient temperature, slowly poured onto ice with stirring, and diluted with methylene chloride. The organic layer is washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to a solid. The solid is recrystallized from acetonitrile to afford the title compound as a yellow solid (82.1 g, 54.0%) which is identified by NMR spectral analysis.
Reaction SMILES: C[O:2][CH2:3][CH2:4][C:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([OH:7])[CH3:6].Br.C(O)(=O)C.[OH-].[K+]>C(Cl)(Cl)Cl.O>[C:9]1([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:5]([OH:7])([CH3:6])[CH2:4][CH2:3][OH:2]
Reactant: COCCC(C)(O)c1ccccc1-c1ccccc1
Agent: Br
Agent: [K+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CC(=O)O
Product: CC(O)(CCO)c1ccccc1-c1ccccc1
Reaction time: 2 h

Procedure:
2.56 g. of 1-methoxy-3-p-biphenylyl-3-butanol (obtainable from 3-methoxy-1-p-biphenylyl-1-propanone and CH3MgI) is boiled for 2 hours with a mixture of 5 ml. of 48% aqueous HBr and 5 ml. of acetic acid, 10 ml. of 10% methanolic KOH are added and boiling is continued for a further 2 hours and the mixture is worked up using water and chloroform to give 3-p-biphenylyl-1,3-butanediol m.p. 115°-117°.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[O:26])=[CH:20][CH:19]=1>ClCCl>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:1][CH:2]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:3]([OH:4])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:26])=[CH:20][CH:19]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: NC(c1ccccc1)C(O)c1ccccc1
Solvent: ClCCl
Product: O=C(Nc1ccc(Cl)cc1)NC(c1ccccc1)C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.2 %

Procedure:
To a solution of (-)-[R-(R*,S*)]-2-amino-1,2-diphenylethanol (1.0 g, 4.7 mmol) in dichloromethane (10 mL) is added dropwise a solution of 4-chlorophenyl isocyanate (0.72 g, 4.7 mmol) in dichloromethane (5 mL). The resulting mixture is stirred 1 hour at room temperature before filtering off the solid product and washing with CH2Cl2 (2X). The product is dried in vacuo at 114° C. to provide 1.4 g (81%) of desired product, mp 198° C. IR (KBr): 3327, 1665, 1549, 1234, 703 cm-1 ; NMR (DMSO-d6): 4.95 (m, 1H), 5.74 (m, 1H), 6.84-7.5 (m, 16H, 8.84 (S, 1H). Analysis calculated for C21H19ClN2O2.0.42H2O: C, 67.37; H, 5.34; N, 7.48. Found: C, 67.36; H, 5.16; N, 7.61.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)[CH:8]=[O:9].[CH3:11][N:12]1[C:29](=[O:30])[C:28](=[O:31])[N:15]2[C:16]3[CH:27]=[CH:26][CH:25]=[CH:24][C:17]=3[CH2:18][N:19]3[CH:23]=[CH:22][CH:21]=[C:20]3[CH:14]2[CH2:13]1.C([O-])(=O)C.[Na+]>C(Cl)Cl.O>[CH:8]([C:23]1[N:19]2[C:20]([CH:14]3[CH2:13][N:12]([CH3:11])[C:29](=[O:30])[C:28](=[O:31])[N:15]3[C:16]3[CH:27]=[CH:26][CH:25]=[CH:24][C:17]=3[CH2:18]2)=[CH:21][CH:22]=1)=[O:9]
Reactant: CN(C)C=O
Reactant: CN1CC2c3cccn3Cc3ccccc3N2C(=O)C1=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: CN1CC2c3ccc(C=O)n3Cc3ccccc3N2C(=O)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The starting material is prepared as follows: The mixture of 170 mg of phosphorous oxychloride and 100 ml of dimethylformamide is stirred at room temperature for 30 minutes, whereupon the solution of 281 mg of 2-methyl-3,4-dioxo-1,3,4,14b-tetrahydro-10H-pyrazino[1,2-a]pyrrolo[2,1-c][1,4]benzodiazepine in 5 ml of methylene chloride is added dropwise. After 30 minutes, the mixture is refluxed for another 30 minutes and cooled to room temperature. It is combined with 1.5 g of sodium acetate in 5 ml of water, stirred for 30 minutes and the organic layer separated. It is washed with water, 5% aqueous sodium bicarbonate, dried, evaporated and the residue triturated with diethyl ether, to yield the 12-formyl-2-methyl-3,4-dioxo-1,3,4,14b-tetrahydro-10H-pyrazino[1,2-a]pyrrolo[2,1-c][1,4]benzodiazepine melting at 300°-302°.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]([NH2:13])[CH:10]=[CH:11][CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[N:14]([O-])=O.[Na+].O.O.[Sn](Cl)Cl.[OH-].[Na+]>Cl>[N:1]1([C:7]2[CH:8]=[C:9]([NH:13][NH2:14])[CH:10]=[CH:11][CH:12]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: Nc1cccc(N2CCOCC2)c1
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: NNc1cccc(N2CCOCC2)c1
Temperature: 25 °C
Yield: 77.6 %

Procedure:
To a cooled (−5 ° C.) solution of 3-morpholin-4-yl-phenylamine (44)(0.18 g, 1.00 mmol) in 2M HCl(aq) was added sodium nitrite (69 mg, 1.00 mmol in 1 ml water) dropwise. The red solution was stirred at −5° C. for 10 minutes before the addition of tin (II) chloride dihydrate (1.13 g, 5.0 mmol). The mixture was stirred vigorously and allowed to warm to room temperature over the period of 1 hour. 2M NaOH(aq) was added until the solution was basic (pH=8), then extracted with EtOAc (2×20 ml). The combined organic extracts were dried using MgSO4, filtered and concentrated in vacuo to give the desired product (0.15 g, 79.0%) (3-Morpholin-4-yl-phenyl)-hydrazine. m/z (LC-MS, ESP): 194.4 [M+H]+, R/T=1.00 mins.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:11]2[CH:12]=[C:13]([C:17]([N:19]([CH:33]([CH3:35])[CH3:34])[C@@H:20]3[CH2:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21]3)=[O:18])[C:14]([CH3:16])=[CH:15][C:10]=2[O:9][C:8]([CH3:37])([CH3:36])[C:7]1=[O:38].[H-].[Na+].CN(C)C=O.Br[CH:47]1[CH2:49][CH2:48]1>O>[CH:47]1([O:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[C:11]3[CH:12]=[C:13]([C:17]([N:19]([CH:33]([CH3:34])[CH3:35])[C@@H:20]4[CH2:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])[CH2:21]4)=[O:18])[C:14]([CH3:16])=[CH:15][C:10]=3[O:9][C:8]([CH3:36])([CH3:37])[C:7]2=[O:38])[CH2:49][CH2:48]1
Reactant: Cc1cc2c(cc1C(=O)N(C(C)C)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1)N(CCCCO)C(=O)C(C)(C)O2
Reactant: BrC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc2c(cc1C(=O)N(C(C)C)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1)N(CCCCOC1CC1)C(=O)C(C)(C)O2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To tert-butyl (3R)-3-[{[4-(4-hydroxybutyl)-2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate (200 mg) were added sodium hydride (60 mg) and N,N-dimethylformamide (3 ml) under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. Then, to the mixture was added bromocyclopropane (0.30 ml), and the mixture was stirred at 150° C. for 6 hours. After the reaction was complete, water was added to the reaction solution, and the mixture was extracted with ethyl acetate solution. The obtained ethyl acetate solution was washed with water and an aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/2) to give the title compound (30 mg) as a colorless liquid.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]([CH2:14][C:15]([O:17]CC)=[O:16])[CH2:12][CH2:13][C:5]=3[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:27][C:28]1[CH:29]=[CH:30][C:31]([O:36][C:37]([F:40])([F:39])[F:38])=[C:32]([CH:35]=1)[C:33]#[N:34]>CN(C=O)C>[C:33]([C:32]1[CH:35]=[C:28]([CH:29]=[CH:30][C:31]=1[O:36][C:37]([F:38])([F:40])[F:39])[CH2:27][O:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]([CH2:14][C:15]([OH:17])=[O:16])[CH2:12][CH2:13][C:5]=3[C:4]=2[CH:3]=1)#[N:34]
Reactant: N#Cc1cc(CCl)ccc1OC(F)(F)F
Reactant: CCOC(=O)CC1CCc2c1[nH]c1ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#Cc1cc(COc2ccc3[nH]c4c(c3c2)CCC4CC(=O)O)ccc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 24.1 %

Procedure:
Ethyl 2-(7-hydroxy-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (0.100 g, 0.386 mmol) and cesium carbonate (0.138 g, 0.424 mmol) were dissolved in DMF (1.0 mL), stirred at room temperature for 10 min, followed by addition of 5-(chloromethyl)-2-(trifluoromethoxy)benzonitrile (0.100 g, 0.424 mmol) in DMF (0.300 mL) at 0° C. This mixture was stirred at room temperature for 3 h. The reaction mixture was quenched with water and extracted with ethylacetate (2×50 mL). The organic phase was washed with brine and concentrated. The residue was taken up in dioxane (4 mL) before aqueous 1 N LiOH (1.3 mL) was added. The mixture was stirred at room temperature for 2.5 h before it was quenched with water and acidified to pH 3 using aqueous 3 N HCl. The mixture was purified by HPLC to give the title compound (0.040 g). LCMS m/z=431.2 [M+H]+, 1H NMR (500 MHz, DMSO-d6) δ ppm 2.00-2.20 (m, 1H), 2.01-2.21 (m, 1H), 2.23-2.43 (m, 1H), 2.55-2.83 (m, 4H), 3.33-3.57 (m, 1H), 5.16 (s, 2H), 6.73 (dd, J=8.83, 2.52 Hz, 1H), 6.94 (s, 1H), 7.21 (d, J=8.83 Hz, 1H), 7.69 (dd, J=8.67, 1.42 Hz, 1H), 7.94 (dd, J=8.67, 2.05 Hz, 1H), 8.09 (s, 1H), 10.40 (s, 1H).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:11][CH3:12])[CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=[O:8].[OH-].[Na+]>CO>[CH3:12][O:11][CH:3]([O:2][CH3:1])[CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8]
Reactant: COC(=O)CCCC(OC)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(CCCC(=O)O)OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
12 mmoles methyl 5,5-dimethoxypentanoate (Stevens, R. V. et al., J Am Chem Soc (1979) 7054) were dissolved in 20 ml 50% aqueous methanol. 16 mmoles NaOH were added and the mixture was stirred for 2 hr at room temperature. The solvent was then evaporated, the residue layered with 30 ml EtOAc, and the sodium salt neutralized with ice-cold 1N HCl. The aqueous phase was extracted with an additional 20 ml EtOAc, the organic extracts combined and dried over K2CO3. The product was filtered and the solvent evaporated to provide 5,5-dimethoxypentanoic acid.