Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([C:18]([OH:21])([CH3:20])[CH3:19])[CH2:14][CH2:13]2)=[N:9][C:8]2[C:3]1=[N:4][C:5]([Sn](CCCC)(CCCC)CCCC)=[N:6][C:7]=2[N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.Br[C:42]1[CH:50]=[N:49][CH:48]=[C:47]2[C:43]=1[CH:44]=[CH:45][NH:46]2>>[CH3:1][N:2]1[C:10]([CH2:11][N:12]2[CH2:13][CH2:14][CH:15]([C:18]([OH:21])([CH3:20])[CH3:19])[CH2:16][CH2:17]2)=[N:9][C:8]2[C:3]1=[N:4][C:5]([C:42]1[CH:50]=[N:49][CH:48]=[C:47]3[NH:46][CH:45]=[CH:44][C:43]=13)=[N:6][C:7]=2[N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1
Reactant: Brc1cncc2[nH]ccc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)O)CC3)n(C)c2n1
Product: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(-c3cncc4[nH]ccc34)nc21

Procedure:
2-(1-((9-methyl-6-morpholino-2-(tributylstannyl)-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol (150 mg) was reacted with 4-bromo-6-azaindole via General Procedure G to afford 118 (31.8 mg) following reverse phase purification. MS (Q1) 491.2 (M)+. 1H NMR (400 MHz, DMSO) δ 11.70 (s, 1H), 9.14 (s, 1H), 8.79 (s, 1H), 7.70 (t, 1H), 7.43 (s, 1H), 4.30 (s, 4H), 4.02 (s, 1H), 3.89 (s, 3H), 3.83-3.76 (m, 4H), 3.73 (s, 2H), 2.92 (t, 2H), 1.97 (dd, 16.9, 2H), 1.69 (t, 2H), 1.40-1.09 (m, 3H), 1.02 (s, 6H)
Reaction SMILES: [C:1]1([CH2:7][CH2:8][S:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.[Ni]>[C:1]1([CH2:7][CH2:8][S:9][C:10]2[CH:11]=[CH:12][C:13]([NH2:16])=[CH:14][CH:15]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(SCCc2ccccc2)cc1
Agent: [Ni]
Solvent: CO
Product: Nc1ccc(SCCc2ccccc2)cc1

Procedure:
86 g of 4-(2'-phenyl-ethylthio)-nitrobenzene is dissolved in 900 ml of methanol and catalytically hydrogenated with Raney nickel. After completion of the absorption of hydrogen, the catalyst is filtered off and the filtrate is concentrated by evaporation. There is obtained 4-(2'-phenyl-ethylthio)-aniline as oily residue, which is used without purification in the next reaction stage.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][CH:3]=1.[C:11]([OH:14])(=S)[CH3:12]>C([O-])([O-])=O.[K+].[K+]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:11](=[O:14])[CH3:12])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: CC(O)=S
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(=O)Nc1ccc(Cl)cc1
Temperature: 150 °C
Yield: 90.5 %

Procedure:
In one example, under nitrogen gas, a stirred mixture of 4-Chloro-1-nitrobenzene (e.g., about 1 g, 6.35 mmol), thioacetic acid (e.g., about 1.93 g, 25.39 mmol), K2CO3 (e.g., about 0.050 g, 0.36 mmol), and dry Triton-X 405 (e.g., about 0.010 g) were heated at about 150° C. The progress of the reaction was monitored by HPLC and GC. After four hours the reaction was cooled to room temperature, and acetone (e.g., about 8 mL) was added and filtered through a sintered glass funnel. Evaporation of the acetone produced about 0.975 g of N-(4-Chloro-phenyl)-acetamide (e.g., about 91%).
Reaction SMILES: [NH2:1][C:2]1[NH:21][C:5]2=[CH:6][C:7]3[C:8]([CH3:20])([CH3:19])[C:9](=[O:18])[N:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:11]=3[CH:12]=[C:4]2[N:3]=1.[Br:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26]>>[Br:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25]([NH:1][C:2]1[NH:21][C:5]2=[CH:6][C:7]3[C:8]([CH3:20])([CH3:19])[C:9](=[O:18])[N:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:11]=3[CH:12]=[C:4]2[N:3]=1)=[O:26]
Reactant: O=C(Cl)c1ccccc1Br
Reactant: CCCCCN1C(=O)C(C)(C)c2cc3[nH]c(N)nc3cc21
Product: CCCCCN1C(=O)C(C)(C)c2cc3[nH]c(NC(=O)c4ccccc4Br)nc3cc21
Yield: 39.3 %

Procedure:
2-Bromo-N-(7,7-dimethyl-6-oxo-5-pentyl-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-benzamide (136 mg) is prepared from D5 (211 mg) and 2-bromobenzoyl chloride (342 mg; 1.51 mmol) as described in Example 170.
Reaction SMILES: CN(C=O)C.[C:6]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1I)(=[O:8])[CH3:7].[C:18]([OH:22])(=[O:21])[CH:19]=[CH2:20].C([O-])(=O)C.[Na+]>[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[C:6]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[CH:20]=[CH:19][C:18]([OH:22])=[O:21])(=[O:8])[CH3:7]
Reactant: CC(=O)Nc1ccc(Cl)cc1I
Reactant: C=CC(=O)O
Agent: Cl[Pd]Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(Cl)cc1C=CC(=O)O
Temperature: 115 °C
Reaction time: 5 h
Yield: 85.7 %

Procedure:
To a 200-ml flask were added 40 ml of DMF, 20 g (0.0677 mole) of 2-acetylamino-5-chloroiodobenzene, 5.85 g (0.0812 mole) of acrylic acid, 7.77 g (0.0947 mole) of anhydrous sodium acetate, 10 mg of palladium chloride and 30 mg of triphenylphosphine. This mixture was stirred at 115° C. for 5 hours and poured into 200 ml of water, and then a large amount of crystal precipitated. Sodium hydroxide was added to this aqueous solution containing the crystal while stirring the solution as it was, until the pH of the solution became 9.0. Then, the crystal dissolved in the solution to obtain a uniform solution. Thereafter, 2 g of activated carbon was added to the solution, and after stirring at room temperature for 15 minutes, the insoluble matter was filtered off. The filtrate was acidified to a pH of 1.5 with conc. hydrochloric acid, and then white crystal precipitated. This crystal was filtered off and vacuum-dried to obtain 13.9 g of 2-acetylamino-5-chlorocinnamic acid. The yield was 85.2% of the theoretical value, and the melting point was 243° to 245° C. The 1H-NMR and IR of this compound were as follows:
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6](=[C:17](OCC)[CH2:18][CH3:19])[C:5]1=[O:23])(=O)C.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[NH:24](/[C:17](=[C:6]1\[C:5](=[O:23])[NH:4][C:12]2[C:7]\1=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)/[CH2:18][CH3:19])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCOC(CC)=C1C(=O)N(C(C)=O)c2cc(OC)c(OC)cc21
Reactant: Nc1ccccc1
Product: CC/C(Nc1ccccc1)=C1/C(=O)Nc2cc(OC)c(OC)cc21

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone and aniline
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.[H-].[Na+].[Cl:15][C:16]1[CH:21]=[C:20]([O:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][OH:30])=[CH:25][C:24]=2[F:31])[CH:19]=[CH:18][N:17]=1>CN(C=O)C>[Cl:15][C:16]1[CH:21]=[C:20]([O:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][O:30][C:2]3[CH:3]=[C:4]4[N:11]([CH3:12])[CH2:10][CH2:9][N:5]4[C:6](=[O:8])[N:7]=3)=[CH:25][C:24]=2[F:31])[CH:19]=[CH:18][N:17]=1
Reactant: OCc1ccc(Oc2ccnc(Cl)c2)c(F)c1
Reactant: CN1CCn2c1cc(Cl)nc2=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCn2c1cc(OCc1ccc(Oc3ccnc(Cl)c3)c(F)c1)nc2=O

Procedure:
Prepared in a manner similar to that described for E1 using 7-chloro-1-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one (50 mg, 0.269 mmol), sodium hydride (21.55 mg, 0.539 mmol) and (4-((2-chloropyridin-4-yl)oxy)-3-fluorophenyl)methanol (68.3 mg, 0.269 mmol) in DMF (2 mL).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11]([CH:12]([CH3:26])[N:13]([C:16](=[O:25])[C:17]4[CH:22]=[CH:21][C:20]([O:23]C)=[CH:19][CH:18]=4)[C:14]=2[CH:15]=1)=[CH:10][CH:9]=[CH:8][CH:7]=3.ClC1C=CC(C2C=CC=CC=2C(NC(=O)C2C=CC(OC)=CC=2)C)=C(F)C=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11]([CH:12]([CH3:26])[N:13]([C:16]([C:17]4[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=4)=[O:25])[C:14]=2[CH:15]=1)=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: COc1ccc(C(=O)N2c3cc(Cl)ccc3-c3ccccc3C2C)cc1
Agent: COc1ccc(C(=O)NC(C)c2ccccc2-c2ccc(Cl)cc2F)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1c2ccccc2-c2ccc(Cl)cc2N1C(=O)c1ccc(O)cc1
Yield: 75 %

Procedure:
3-chloro-5-(4-methoxybenzoyl)-6-methyl-5,6-dihydrophenanthridine—The title compound was prepared from N-[1-(4′-chloro-2′-fluoro-biphenyl-2-yl)-ethyl]-4-methoxy-benzamide (1.04 g, 2.7 mmol), anhydrous THF (10 mL), and lithium bis(trimethylsilyl)amide (4.1 mL, 1M in THF) according to the procedure and in the same manner as described in Example 24, step d. The THF was removed and the resulting residue was purified by flash column chromatography (Biotage® 40 Mi, 30-50% methyl tert-butylether in hexane) affording 738 mg (75%) of the desired product. MS [(ES+), m/z]: 364/366 [M+H]+, 1 Cl pattern;
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:16])[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][C:9](=O)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1.B(F)(F)F>O1CCCC1>[C:1]([C:5]1[C:6](=[O:16])[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][C:9](=[N:17][C:18]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C1=CC(=O)C=C(C(C)(C)C)C1=O
Reactant: Nc1ccc(C(=O)O)cc1
Agent: FB(F)F
Solvent: C1CCOC1
Product: CC(C)(C)C1=CC(=Nc2ccc(C(=O)O)cc2)C=C(C(C)(C)C)C1=O
Temperature: 20 °C

Procedure:
A mixture of 22 g (0.10 mole) of 2,6-di(tertiary-butyl)-p-benzoquinone, 13.7 g (0.10 mole) of 4-aminobenzoic acid, 175 ml of tetrahydrofuran and 1 ml of boron trifluoride: diethyl ether complex was heated on a steam bath for 1.25 hours. The mixture was allowed to cool to about 20° C. over 16 hours under a nitrogen atmosphere. Evaporation provided a solid which was washed with hexane and recrystallized from ethanol to provide orange solid 2,6-di(tertiary-butyl)-4-(4'-carboxyphenylimino)-2,5-cyclohexadien-1-one, m.p. 305°-309° C. Analysis: Calculated for C21H25NO3 : % C, 74.3; % H, 7.4; % N, 4.1; Found: % C, 74.2; % H, 7.4; % N, 4.1.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=O.[BH3-][C:16]#N.[Na+].CC(O)=O>CC#N.O.C(Cl)Cl>[CH3:16][N:10]1[CH2:9][CH2:8][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12][CH2:11]1
Reactant: [BH3-]C#N
Reactant: c1ccc(C2CCNCC2)cc1
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Solvent: CC(=O)O
Product: CN1CCC(c2ccccc2)CC1

Procedure:
To a stirring mixture at RT of 4-phenylpiperidine (5.24 g, 32.48 mmol) in CH3CN (95 ml) was added a 37% solution of HCHO in H2O (13 ml). To this mixture was added NaCNBH3 (3.27 g, 51.97 mmol). AcOH was added dropwise every 10 min over the next h to maintain the reaction pH near 7. The reaction volume was then reduced in vacuo. The reaction mix was diluted with CH2Cl2 and washed with 2N NaOH and then brine. The crude was concentrated in vacuo and eluted through a silica gel column with 10% MeOH/CH2Cl2. The 1-methyl-4-phenylpiperidine was concentrated in vacuo, yielding a clear oil.
Reaction SMILES: [CH2:1]([O:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(OC1C=CC(C(O)=O)=CC=1)CCCCCCCCCCCCCCCCC>>[CH2:1]([O:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([OH:20])=[O:19])=[CH:22][CH:23]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCOc1ccc(C(=O)OC)cc1
Agent: CCCCCCCCCCCCCCCCCCOc1ccc(C(=O)O)cc1
Product: CCCCCCCCCCCCOc1ccc(C(=O)O)cc1

Procedure:
This compound was prepared by hydrolysis of methyl 4-dodecyloxybenzoate in a manner analogous to that described above for 4-octadecyloxybenzoic acid.
Reaction SMILES: C(OC([NH:8][C:9]1[C:14]([C:15](O)=[O:16])=[CH:13][C:12]([Cl:18])=[N:11][CH:10]=1)=O)(C)(C)C.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26](=O)[CH3:27].[OH-].[Na+]>O>[Cl:18][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][N:11]=1)[NH:8][C:26]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[Cl:19])=[CH:27][C:15]2=[O:16]
Reactant: CC(=O)c1ccccc1Cl
Reactant: CC(C)(C)OC(=O)Nc1cnc(Cl)cc1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=c1cc(-c2ccccc2Cl)[nH]c2cnc(Cl)cc12
Temperature: 150 °C
Reaction time: 0.17 h
Yield: 5.5 %

Procedure:
5-(tert-Butoxycarbonylamino)-2-chloroisonicotinic acid (502 mg, 1.84 mmol) was suspended in polyphosphoric acid (9.5 g, 102 mmol) at ambient temperature and stirred for 10 mins causing a bright yellow coloration and visible evolution of gas. 2′-Chloroacetophenone (570 mg, 3.69 mmol) was added and the mixture heated to 150° C. for 2.5 h. The mixture was diluted with cold water (50 mL), and then cooled in ice and treated with solid sodium hydroxide (6.0 g, 150 mmol) to pH ˜7. The mixture was filtered and the recovered oily solids washed with water, dissolved in methanol and reconcentrated in vacuo. The residue was purified by flash chromatography (silica, ISCO, 0.5-20% methanol in DCM) to afford the title compound as a cream solid (29.2 mg, 5.5%). 1H NMR (400 MHz, MeOD) δ 8.87 (s, 1H), 8.12 (s, 1H), 7.64-7.58 (m, 2H), 7.58-7.46 (m, 2H), 6.47 (s, 1H); NH absent. LCMS: M+H+=291 & 293.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[C:7]([NH2:10])[CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.CO.[CH:13](I)([CH3:15])[CH3:14]>C(N(CC)CC)C>[CH:13]([NH:10][C:7]1[CH:8]=[CH:9][C:4]2[CH2:3][CH2:2][O:1][C:5]=2[CH:6]=1)([CH3:15])[CH3:14]
Reactant: Nc1ccc2c(c1)OCC2
Reactant: CC(C)I
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)Nc1ccc2c(c1)OCC2

Procedure:
To a solution of 2.8 g. of 2,3-dihydro-6-benzofuranamine in 150 ml. of methanol is added 18 ml. of isopropyl iodide and 26.5 ml. of triethylamine. The solution is refluxed for 60 hours and then concentrated in vacuo. The resultant oil is extracted repeatedly with diethyl ether. The extracts are combined, filtered through Celite, and the ether removed in vacuo to give an oil of N-isopropyl-2,3-dihydro-6-benzofuranamine.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]([CH3:20])[C:7]3[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=3[C@@H:9]3[C@H:14]([NH2:15])[CH2:13][CH2:12][CH2:11][N:10]3[C:4]=2[CH:3]=1.Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].C(N(CC)CC)C.O>CN(C=O)C>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]([CH3:20])[C:7]3[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=3[C@@H:9]3[C@H:14]([NH:15][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:13][CH2:12][CH2:11][N:10]3[C:4]=2[CH:3]=1
Reactant: CN1c2ccccc2[C@@H]2[C@H](N)CCCN2c2cc(Cl)ccc21
Reactant: CCOC(=O)CBr
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)CN[C@@H]1CCCN2c3cc(Cl)ccc3N(C)c3ccccc3[C@H]12
Temperature: 60 °C
Reaction time: 5 h
Yield: 80 %

Procedure:
To a suspension of trans-7-chloro-1,2,3,4,10,14b-hexahydro-10-methyldibenzo[b,f]pyrido[1,2-d][1,4]-diazepin-1-ylamine (100 mg, 0.25 mmol) in DMF (2 mL) was added ethyl bromoacetate (56 μl, 0.51 mmol) and triethylamine (107 ul, 0.76 mmol). The resulting reaction mixture was heated to 60° C. and stirred for 5 h. The mixture was poured into water and extracted with ethyl acetate (3×). The organic layers were washed with sat (aq) NaHCO3 and brine. After drying (MgSO4), the solvents were removed under reduced pressure. The crude product was purified on silica with heptane/ethyl acetate 8:2 to afford 80 mg (80%) of the title compound.
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[C:23]1([C@H:33]([N:35]([CH2:43][C@@H:44]2[C@@H:48]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[CH2:47][NH:46][CH2:45]2)[C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH3:34])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1.[C:55]([O:66][CH3:67])(=[O:65])[C:56]1[CH:64]=[CH:63][C:59]([C:60]([O-])=[O:61])=[CH:58][CH:57]=1>ClCCl.C(N(CC)CC)C>[C:38]([O:37][C:36]([N:35]([CH2:43][C@@H:44]1[C@@H:48]([C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[CH2:47][N:46]([C:60]([C:59]2[CH:63]=[CH:64][C:56]([C:55]([O:66][CH3:67])=[O:65])=[CH:57][CH:58]=2)=[O:61])[CH2:45]1)[C@@H:33]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:34])=[O:42])([CH3:40])([CH3:41])[CH3:39]
Reactant: COC(=O)c1ccc(C(=O)[O-])cc1
Reactant: C[C@H](c1cccc2ccccc12)N(C[C@H]1CNC[C@@H]1c1ccccc1)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C(=O)N2C[C@H](CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc4ccccc34)[C@@H](c3ccccc3)C2)cc1

Procedure:
At room temperature, WSC hydrochloride, HOBt, tert-butyl [(1R)-1-(1-naphthyl)ethyl]{[(3R,4S)-4-phenylpyrrolidin-3-yl]methyl}carbamate and triethylamine were added in that order to a mixture of monomethyl terephthalate and dichloromethane and stirred for 7.5Hours. Monomethyl terephthalate was further added thereto and stirred for 16Hours, and then work-up and purification were carried out in the standard method to obtain methyl 4-{[(3R,4S)-3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]carbonyl}benzoate. FP: 593.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3=[CH:12][S:13][CH:14]=[C:9]3[C:8](=O)[NH:7][C:6]=2[CH:16]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:18]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3=[CH:12][S:13][CH:14]=[C:9]3[C:8](=[S:18])[NH:7][C:6]=2[CH:16]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=C1Nc2cc(Cl)ccc2Nc2cscc21
Solvent: c1ccncc1
Product: S=C1Nc2cc(Cl)ccc2Nc2cscc21
Reaction time: 18 h

Procedure:
A mixture of 0.88 g. of 7-chloro-4,9-dihydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and 1.0 g. of phosphorus pentasulfide in 10 ml. of dry pyridine is stirred and heated under reflux for 4 hours. The mixture is concentrated to dryness and the residue is stirred in 20 ml. of 1 N sodium carbonate solution (pH 7-7.2) for 18 hours. The precipitate is collected, washed with water and recrystallized from methanol-water to give a deep yellow solid, m.p. 197°-198.5° C. (dec.).
Reaction SMILES: [NH2:1][C:2]([CH3:7])([CH3:6])[C:3]([OH:5])=[O:4].N1C=CC=CC=1.[C:14](OC(=O)C)(=[O:16])[CH3:15]>O>[C:14]([NH:1][C:2]([CH3:7])([CH3:6])[C:3]([OH:5])=[O:4])(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(N)C(=O)O
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)NC(C)(C)C(=O)O
Reaction time: 1 h
Yield: 63724.3 %

Procedure:
A suspension of 41.2 g (0.4 mmol) of alpha -aminoisobutyric acid, 100 ml pyridine, and 100 ml water is stirred at 0°-5° C. and 45.0 ml (0.45 mmol) of acetic anhydride is added over a period of 30 min. Solution is observed after 1 hr and the mixture is allowed to stand at room temperature for 10 hrs. The reaction mixture is diluted with 500 ml water and evaporated in vacuo. The residue is then recrystallized from water, dried in vacuo affording 37.0 g alpha-acetamidoisobutyric acid.
Reaction SMILES: [CH:1]1(N)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:8]([C:11]1[C:24]2[C:23](=[O:25])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][C:21]=3[N+:26]([O-:28])=[O:27])[C:16](=[O:29])[C:15]=2[CH:14]=[CH:13][CH:12]=1)([O-])=O>[N+](C1C=CC=CC=1)([O-])=O>[N+:26]([C:21]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:22]=1[C:23](=[O:25])[C:24]1[C:11]([NH:8][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:12][CH:13]=[CH:14][C:15]=1[C:16]2=[O:29])([O-:28])=[O:27]
Reactant: NC1CCCCC1
Reactant: O=C1c2cccc([N+](=O)[O-])c2C(=O)c2c1cccc2[N+](=O)[O-]
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C1c2cccc(NC3CCCCC3)c2C(=O)c2c1cccc2[N+](=O)[O-]
Reaction time: 0.25 h

Procedure:
175 ml of cyclohexylamine are added over the course of one hour to 300 g of 67% strength 1,8-dinitroanthraquinone in 1,200 ml of nitrobenzene at 175°-180°, the mixture is stirred for a further 15 minutes at the same temperature and then overnight until cold and the product is filtered off and washed with 200 ml of nitrobenzene and finally with a large amount of methanol until free of nitrobenzene. 187 g of 8-nitro-1-cyclohexylamino-anthraquinone of very good quality are obtained.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:15]=[N:16][C:17](F)=[CH:18][CH:19]=2)[C:3]=1[CH3:21].Cl.[F:23][C:24]1([F:30])[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:15]=[N:16][C:17]([N:27]3[CH2:28][CH2:29][C:24]([F:30])([F:23])[CH2:25][CH2:26]3)=[CH:18][CH:19]=2)[C:3]=1[CH3:21]
Reactant: FC1(F)CCNCC1
Reactant: Cc1c(-c2ccc(F)nc2)nc2cc(F)cc(F)c2c1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(-c2ccc(N3CCC(F)(F)CC3)nc2)nc2cc(F)cc(F)c2c1Cl
Temperature: 100 °C
Reaction time: 66.5 h

Procedure:
To a stirred solution of 4-chloro-5,7-difluoro-2-(6-fluoropyridin-3-yl)-3-methylquinoline (0.10 g, 0.32 mmol) in DMF (2 mL) was added 4,4-difluoropiperidine hydrochloride (0.056 g, 0.36 mmol) followed by potassium carbonate (0.090 g, 0.65 mmol). The reaction was stirred at 100° C. and stirring continued for 66.5 h. After which, the reaction mixture was cooled to rt and water was added. The crude reaction mixture was extracted with EtOAc and dried over magnesium sulfate and concd in vacuo. The crude material was purified on silica gel, eluting with 0-30% EtOAc in hexanes to provide 4-chloro-2-(6-(4,4-difluoropiperidin-1-yl)pyridin-3-yl)-5,7-difluoro-3-methylquinoline as a brown solid. Mass Spectrum (ESI) m/e=410.0 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]=[CH:10][CH2:11][N:12]1[CH2:17][CH2:16][O:15][C:14]([CH2:22][CH2:23][CH2:24][C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[C:32]([O:35][CH3:36])[CH:33]=3)[N:28]=[CH:27][C:26]=2[F:37])([C:18]([O:20]C)=[O:19])[CH2:13]1.CO.[OH-].[Na+].Cl>O1CCOCC1.ClCCl.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]=[CH:10][CH2:11][N:12]1[CH2:17][CH2:16][O:15][C:14]([CH2:22][CH2:23][CH2:24][C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[C:32]([O:35][CH3:36])[CH:33]=3)[N:28]=[CH:27][C:26]=2[F:37])([C:18]([OH:20])=[O:19])[CH2:13]1
Reactant: COC(=O)C1(CCCc2c(F)cnc3ccc(OC)cc23)CN(CC=Cc2cc(F)ccc2F)CCO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: COc1ccc2ncc(F)c(CCCC3(C(=O)O)CN(CC=Cc4cc(F)ccc4F)CCO3)c2c1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
A solution of 0.21 g of the enantiomer A of methyl 4-[3-(2,5-difluorophenyl)-2-propenyl]-2-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-2-morpholinecarboxylate in a mixture of 10 cm3 of 1,4-dioxane, 10 cm3 of methanol and 1.22 cm3 of 5 N sodium hydroxide is heated at a temperature in the region of 80° C. with stirring and under an inert atmosphere for 12 hours. After cooling to about 20° C., the reaction medium is evaporated under reduced pressure (2 kPa; 45° C.) to give a whitish crust. The residue is taken up in 25 cm3 of dichloromethane and then 10 cm3 of distilled water and then neutralized with 1.23 cm3 of 5 N hydrochloric acid. The organic phase is dried over magnesium sulfate, filtered and then evaporated to dryness under reduced pressure (2 kPa) at a temperature in the region of 30° C. The residue obtained is purified by chromatography on a silica gel column (particle size 70–200 μm; diameter 2 cm), eluting with a mixture of chloroform-methanol-aqueous ammonia (28%) (12/3/0.5 by volume) and collecting 10 cm3 fractions. The fractions containing the expected product are combined and then evaporated according to the conditions described above. 0.13 g of the enantiomer A of 4-[3-(2,5-difluorophenyl)-2-propenyl]-2-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-2-morpholinecarboxylic acid is obtained in the form of a yellow glaze.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([OH:12])=[O:11].[C:13]1(Br)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O.CCCCCC.CCOC(C)=O>[C:13]1([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][CH2:9][C:10]([O:12][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:11])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Brc1ccccc1
Reactant: O=C(O)CCc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CC(C)=O
Product: O=C(CCc1ccccc1Oc1ccccc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 76.5 %

Procedure:
A mixture of 3-(2-hydroxyphenyl)propionic acid (0.57 g, 3.4 mmol), phenylbromide (0.4 ml, 3.37 mmol), and K2CO3 (2.5 g) in acetone (10 ml) was stirred at room temperature for 2 days. The mixture was diluted with 1:1 hexane/EtOAc (100 ml), washed with water and brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography (5:1 then 4:1 hexane/EtOAc) to yield phenyl 3-(2-phenyloxyphenyl)propionate (0.45 g, 1.30 mmol, 77%).