Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[C:32]([CH3:33])=[C:31]([CH:34]=O)[NH:30][C:29]=2[CH3:36])=[O:27])[CH:22]=[CH:21][N:20]=[N:19]1>C(O)C.N1CCCCC1>[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[C:32]([CH3:33])=[C:31]([CH:34]=[C:10]3[C:9]4[C:13](=[CH:14][CH:15]=[CH:16][C:8]=4[C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=4)[NH:12][C:11]3=[O:17])[NH:30][C:29]=2[CH3:36])=[O:27])[CH:22]=[CH:21][N:20]=[N:19]1
Reactant: O=C1Cc2c(cccc2-c2cccc(F)c2)N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCn1ccnn1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4cccc(F)c4)c32)c(C)c1C(=O)NCCn1ccnn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 42.4 %

Procedure:
To a solution of 4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide (67.9 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-[4-(3-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide as a yellow solid (49.9 mg, 42%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C@H:8]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([O:5][C:6]([NH:7][C@@H:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:15]1[CH:16]=[C:17]([CH:18]=[CH:19][CH:20]=1)[O:21][CH2:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1)=[O:22])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](c1ccccc1)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(COc2cccc([C@@H](NC(=O)OC(C)(C)C)c3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.9 %

Procedure:
A mixture of (S)-tert-butyl((3-hydroxyphenyl)(phenyl)methyl)carbamate (3.20 g, 10.7 mmol), methyl 4-(bromomethyl)benzoate (2.70 g, 11.8 mmol) and potassium carbonate (2.20 g, 16.1 mmol) in acetonitrile (54 mL) was stirred at RT for 16 hours. The reaction mixture was concentrated at reduced pressure and the residue partitioned between ethyl acetate and water. The aqueous phase was extracted with further ethyl acetate and the combined organic extracts combined, dried with anhydrous magnesium sulfate, filtered and the solvent evaporated at reduced pressure. The residue was recrystallised from ethyl acetate and iso-hexane to afford the title compound as a white solid (3.25 g, 68%).
Reaction SMILES: [F:1][C:2]1[C:3](C(O)=O)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[Br:15]Br>C(Cl)(Cl)(Cl)Cl>[Br:15][C:3]1[C:2]([F:1])=[CH:7][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:5][N:4]=1
Reactant: BrBr
Reactant: O=C(O)c1ncc(C(F)(F)F)cc1F
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1cc(C(F)(F)F)cnc1Br
Reaction time: 16 h
Yield: 28.7 %

Procedure:
The 3-fluoro-5-(trifluoromethyl)-picolinic acid (7.35 g, 0.035 mole) starting material was put into 150 ml of dry carbon tetrachloride and then red mercuric oxide (9.1 g, 0.042 mole) was added and the mixture was stirred and refluxed 1 hour and 25 minutes. A solution of bromine (6.7 g, 0.042 mole) in 20 ml of dry carbon tetrachloride was added slowly with the mixture at reflux over the next 21/3 hours. Light from a UV lamp was directed on the reaction mixture during the addition and the reaction mixture was refluxed for another hour. 25 Ml more of dry carbon tetrachloride was added and the refluxing was continued for about 16 hours more while UV radiation was applied. The reaction was then filtered through CELITE diatomaceous earth to remove the mercury salt. The carbon tetrachloride was removed on a still and the product was distilled over to yield 2.45 g of yellow oil with an analysis of, in percent by weight:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH3:9])[C:3]=1[N+:10]([O-])=O.C(N(CC)CC)C.[O:20]=[C:21]1[N:25]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[C:24]2[CH:32]=[CH:33][CH:34]=[CH:35][C:23]=2[NH:22]1>CO.[Pd]>[NH2:10][C:3]1[C:2]([N:29]2[CH2:28][CH2:27][CH:26]([N:25]3[C:24]4[CH:32]=[CH:33][CH:34]=[CH:35][C:23]=4[NH:22][C:21]3=[O:20])[CH2:31][CH2:30]2)=[N:7][CH:6]=[N:5][C:4]=1[NH:8][CH3:9]
Reactant: CNc1ncnc(Cl)c1[N+](=O)[O-]
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: CNc1ncnc(N2CCC(n3c(=O)[nH]c4ccccc43)CC2)c1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.9 %

Procedure:
To a suspension of 6-chloro-N-methyl-5-nitropyrimidin-4-amine (550 mg, 2.92 mmol) in methanol (11 mL) was added triethylamine (0.55 mL, 3.94 mmol) and 4-(2-keto-1-benzimidazolinyl)piperidine (638 mg, 2.94 mmol). The mixture was stirred at ambient temperature for 1 h and then 10 wt % Pd on C (wet) was added and the mixture was stirred under hydrogen for 1 h. The mixture was diluted with methanol and was filtered through Celite. The filtrate was concentrated and the resulting solid was triturated with a solution of 50% aqueous methanol. The methanol was removed in vacuo and the aqueous slurry was filtered and dried to afford 1-{1-[5-amino-6-(methylamino)pyrimidin-4-yl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one (842 mg, 2.48 mmol, 85% yield) as a peach colored solid. 1H NMR (400 MHz, DMSO-d6): δ 10.86 (s, 1H), 7.82 (s, 1H), 7.43-7.36 (m, 1H), 7.01-6.94 (m, 3H), 6.29 (q, 1H), 4.31 (tt, 1H), 4.20 (s, 2H), 3.50 (br d, 2H), 2.85 (d, 3H), 2.74 (t, 2H), 2.54 (qd, 2H), 1.68 (dd, 2H). MS (EI) for C17H21N7O: 340 (MH+).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[CH2:8][CH:7]([N:9]2[C:13]3[N:14]=[CH:15][N:16]=[C:17]([NH2:18])[C:12]=3[C:11](I)=[CH:10]2)[CH2:6]1)[CH3:3].[C:20]1([C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][C:30](B4OC(C)(C)C(C)(C)O4)=[CH:31][CH:32]=3)[N:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C=O)C.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>[CH3:1][N:2]([CH2:4][C@@H:5]1[CH2:8][C@H:7]([N:9]2[C:13]3[N:14]=[CH:15][N:16]=[C:17]([NH2:18])[C:12]=3[C:11]([C:30]3[CH:29]=[C:28]4[C:33]([CH:34]=[CH:35][C:26]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)=[N:27]4)=[CH:32][CH:31]=3)=[CH:10]2)[CH2:6]1)[CH3:3]
Reactant: CC1(C)OB(c2ccc3ccc(-c4ccccc4)nc3c2)OC1(C)C
Reactant: CN(C)CC1CC(n2cc(I)c3c(N)ncnc32)C1
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: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C[C@H]1C[C@@H](n2cc(-c3ccc4ccc(-c5ccccc5)nc4c3)c3c(N)ncnc32)C1
Temperature: 80 °C

Procedure:
Nitrogen was bubbled into a mixture of 7-(3-dimethylaminomethylcyclobutyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (891.5 mg, 2.401 mmol), 2-phenyl-7-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-quinoline (795 mg, 2.40 mmol), Na2CO3 (634 mg, 5.98 mmol), and Pd(PPh3)4 (171 mg, 0.148 mmol; 6 mol %) in DMF (40 mL)/water (8 mL) for 5 min at ambient temperature, then the mixture was heated to 80° C. (bath temp.) for 4.5 h. The solvents were evaporated, water was added, the mixture was extracted with CH2Cl2 (4×30 mL), and the combined extracts were washed with brine and dried over MgSO4. The crude material (yellow oil) was chromatographed on silica gel [Jones Flashmaster, 50 g/150 mL cartridge, eluting with CH2Cl2 (1-28)→5% MeOH in CH2Cl2 (29-56)->10% MeOH in CH2Cl2 (57-80)→10% MeOH in CH2Cl2 with 0.07M NH3 (81-130)]. Mixed fractions were chromatographed again [5 g/25 mL cartridge, eluting with CH2Cl2 (1-5)→5% MeOH in CH2Cl2 (6-24)→10% MeOH in CH2Cl2 with 0.07M NH3 (25-40)]. One obtained the target compound as beige solid. 1H NMR (CDCl3, 400 MHz): δ=2.10-2.23 (mc, 2H), 2.27 (s, 6H), 2.35-2.46 (mc, 1H), 2.49 (d, J=6.8 Hz, 2H), 2.77-2.86 (mc, 2H), 5.17 (brs, 2H), 5.20-5.30 (mc, 1H), 7.31 (s, 1H), 7.46-7.52 (m, 1H), 7.52-7.58 (m, 2H), 7.70 (dd, J=1.6, 8.4 Hz, 1H), 7.92 (d, J=8.7 Hz, 1H), 7.94 (d, J=8.1 Hz, 1H), 8.17-8.22 (m, 2H), 8.27 (d, J=8.5 Hz, 1H), 8.30 (brs, 1H), 8.36 (s, 1H). 13C NMR (CDCl3, 100.6 MHz, DEPT135): δ=27.13 (+), 36.50 (2C, −), 45.26 (+), 45.73 (2C, +), 66.10 (−), 101.20 (Cquart), 116.07 (Cquart), 119.00 (+), 120.74 (+), 125.98 (Cquart), 127.38 (+), 127.55 (2C, +), 128.28 (+), 128.47 (+), 128.86 (2C, +), 129.52 (+), 136.45 (Cquart), 136.55 (+), 139.41 (Cquart), 148.51 (Cquart), 150.92 (Cquart), 152.04 (+), 156.99 (Cquart), 158.13 (Cquart). MS (ES+): m/z 449.2 (23) [MH+], 404.1 (4) [MH+—HN(CH3)2], 338.2 (4) [MH+—C4H5CH2N(CH3)2]. HPLC: tR=2.0 min (OpenLynx, polar—5 min).
Reaction SMILES: Br[CH2:2][CH:3]=[C:4]1[CH2:7][CH2:6][CH2:5]1.[C:8]1([S:14]([O-:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Na+]>>[C:4]1(=[CH:3][CH2:2][S:14]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)(=[O:16])=[O:15])[CH2:7][CH2:6][CH2:5]1
Reactant: O=S([O-])c1ccccc1
Reactant: BrCC=C1CCC1
Agent: [Na+]
Product: O=S(=O)(CC=C1CCC1)c1ccccc1

Procedure:
Using the procedure of Example I, 1-bromo-2-cyclobutylidene-ethane was reacted with sodium phenyl sulfinate to form (2-cyclobutylidene-ethyl)-phenyl sulfone having a melting point of 76° to 78° C. which was then reacted with ethyl β,β-dimethylacrylate to form ethyl dl-trans 3,3-dimethyl-2-cyclobutylidenemethyl-cyclopropanecarboxylate. The said ethyl ester was hydrolyzed under alkaline conditions to form dl-trans 3,3-dimethyl-2-cyclobutylidenemethyl-cyclopropanecarboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:11]([C:13]1[CH:24]=[CH:23][C:16]([CH2:17][C@@H:18]([C:20]([OH:22])=[O:21])[NH2:19])=[CH:15][CH:14]=1)#[N:12].C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CS(C)=O>[Cl:1][C:2]1[CH:9]=[C:8]([NH:19][C@H:18]([C:20]([OH:22])=[O:21])[CH2:17][C:16]2[CH:15]=[CH:14][C:13]([C:11]#[N:12])=[CH:24][CH:23]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(F)cc1Cl
Reactant: N#Cc1ccc(C[C@H](N)C(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#Cc1ccc(C[C@H](Nc2ccc(C#N)c(Cl)c2)C(=O)O)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 91.7 %

Procedure:
To a solution of 2-chloro-4-fluorobenzonitrile (0.90 g) in dimethyl sulfoxide (20 mL) were added 4-cyanophenylalanine (1.00 g) and cesium carbonate (2.23 g), and the mixture was stirred at 90° C. overnight. After warming to room temperature, ethyl acetate was added, and the mixture was extracted twice with saturated aqueous sodium hydrogen carbonate solution. The aqueous layers were combined, and acidified with citric acid, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound as a brown oil (yield: 1.57 g, 92%).
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH2:13][CH2:14][CH2:15]/[CH:16]=[CH:17]/[C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([F:27])[CH:25]=2)[N:20]([CH2:28][CH2:29][CH2:30][O:31][C:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=[CH:34][CH:33]=2)[C:19]=1[C:42]([O:44]CC)=[O:43].NN>O1CCCC1.C(O)C>[NH2:3][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([F:27])[CH:25]=2)[N:20]([CH2:28][CH2:29][CH2:30][O:31][C:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=[CH:34][CH:33]=2)[C:19]=1[C:42]([OH:44])=[O:43]
Reactant: CCOC(=O)c1c(/C=C/CCCCN2C(=O)c3ccccc3C2=O)c2cc(F)ccc2n1CCCOc1cccc2ccccc12
Agent: NN
Solvent: CCO
Solvent: C1CCOC1
Product: NCCCCCCc1c(C(=O)O)n(CCCOc2cccc3ccccc23)c2ccc(F)cc12
Temperature: 50 °C

Procedure:
A mixture of (E)-ethyl 3-(6-(1,3-dioxoisoindolin-2-yl)hex-1-enyl)-5-fluoro-1-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylate (The synthesis of this compound was described in EXAMPLE 160B as an intermediate.) (270 mg) and hydrazine (0.030 ml) in tetrahydrofuran (1.00 ml) and ethanol (3 ml) was heated at 50° C. overnight and concentrated. The residue was dissolved in tetrahydrofuran and methanol and then aqueous 10% NaOH was added. The resulting was heated at 50° C. overnight and concentrated. The residue was purified by RPHPLC to provide the title compound. 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 8.17 (dd, J=8.44, 1.07 Hz, 1H), 7.84-7.89 (m, 1H), 7.60 (dd, J=9.21, 4.30 Hz, 1H), 7.41-7.56 (m, 4H), 7.32-7.40 (m, 1H), 7.01-7.11 (m, 1H), 6.84 (d, J=7.06 Hz, 1H), 4.80 (t, J=7.21 Hz, 2H), 4.12 (t, J=5.83 Hz, 2H), 2.94-3.06 (m, 2H), 2.75 (t, J=8.29 Hz, 2H), 2.20-2.35 (m, 2H), 1.43-1.63 (m, 4H), 1.27-1.36 (m, 4H).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:3]=1[C:4]([CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])=[O:5].[CH2:18]([CH:20]1[O:22][CH2:21]1)Br>>[O:22]1[CH2:21][CH:20]1[CH2:18][O:1][C:2]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:3]=1[C:4]([CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])=[O:5]
Reactant: BrCC1CO1
Reactant: COC(=O)CCC(=O)c1cc(OC)ccc1O
Product: COC(=O)CCC(=O)c1cc(OC)ccc1OCC1CO1

Procedure:
Methyl 3-(2-hydroxy-5-methoxybenzoyl)propionate was reacted with epibromohydrin in a similar manner to that described in Example 1 (ii) to give methyl 3-[2-(2,3-epoxypropoxy)-5-methoxybenzoyl]propionate which, recrystallised from ether-petroleum ether (b.p. 60°-80°), had m.p. 50° - 51.5° C). (Found: C, 60.91; H, 6.07; C15H18O6 requires: C, 61.21; H, 6.17%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7](=O)[CH:8]2[CH2:13][C:14]([O:16]CC)=O.[C:20]1([CH2:26][CH2:27][CH2:28][CH2:29][NH2:30])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>C1(C)C=CC=CC=1>[CH:20]1([CH2:26][CH2:27][CH2:28][CH2:29][N:30]2[C@@H:7]3[C@@H:8]([C:9]4[CH:10]=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[C:4]=4[CH2:5][CH2:6]3)[CH2:13][C:14]2=[O:16])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CCOC(=O)CC1C(=O)CCc2c(OC)cccc21
Reactant: NCCCCc1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cccc2c1CC[C@H]1[C@@H]2CC(=O)N1CCCCC1CCCCC1
Reaction time: 10 h
Yield: 82.5 %

Procedure:
5.0 g (0.0191 mol) of ethyl 1,2,3,4-tetrahydro-5-methoxy-2-oxo-1-naphthylacetate were dissolved in 100 ml of toluene, 3.0 ml (0.0191 mol) of 4-phenyl-butylamine were added thereto and the mixture was boiled for 16 hours on a water separator. After concentration the residue was hydrogenated with 2.0 g of Raney-nickel in 200 ml of ethanol at 120° and 140 bar for 10 hours. The product was chromatographed over silica gel with n-hexane/ethyl acetate 3:1. There were obtained 5.60 g (82.5%) of oily rac-cis-3-(4-cyclohexyl-butyl)-1,3,3a,4,5,9b-hexahydro-6-methoxy-2H-benzo[e]indol-2-one.
Reaction SMILES: [Cl:1][C:2]1[N:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][C:3]=1[CH:4]=[O:5].C1N2CCN(CC2)C1.[C:24](#[N:27])[CH:25]=[CH2:26]>C(OCC)C>[Cl:1][C:2]1[C:3]([CH:4]([OH:5])[C:25](=[CH2:26])[C:24]#[N:27])=[CH:6][C:7]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:8][N:9]=1
Reactant: C=CC#N
Reactant: O=Cc1cc(-c2ccccc2)cnc1Cl
Agent: C1CN2CCN1CC2
Solvent: CCOCC
Product: C=C(C#N)C(O)c1cc(-c2ccccc2)cnc1Cl

Procedure:
To a mixture of 2-Chloro-5-phenylnicotinaldehyde (10 mmol, 2.17 g) and DABCO (10 mmol. 1.12 g) was added an acrylonitrile (60 mmol.) under neat conditions [solvent free conditions] at room temperature and the reaction progress was monitored by TLC. Upon completion of the reaction mixture (˜4-5 min.) was diluted with diethyl ether (300 ml.) and washed with water 3×50 ml. The organic layer was dried over Na2SO4 and concentrated, the residue was subjected to column chromatography over silica gel, eluting with ethyl acetate and hexane (2:8, v/v) to give the desired product in almost quantitative (2.68 g.).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([CH3:14])(O)[CH2:5][CH2:6][O:7]2.FC(F)(F)C(O)=O.[CH3:22][S:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]2[C:33]=1[NH:32][CH:31]=[CH:30]2>ClCCl>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([C:30]1[C:29]3[C:33](=[C:25]([CH2:24][S:23][CH3:22])[CH:26]=[CH:27][CH:28]=3)[NH:32][CH:31]=1)([CH3:14])[CH2:5][CH2:6][O:7]2
Reactant: CC1(O)CCOc2cc(F)cc(F)c21
Reactant: CSCc1cccc2cc[nH]c12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CSCc1cccc2c(C3(C)CCOc4cc(F)cc(F)c43)c[nH]c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
565 mg (2.82 mmol) of the compound from Example 171A and 0.26 ml (3.39 mmol) of trifluoroacetic acid were added to 500 mg (2.82 mmol) of the compound from Example 8A in 20 ml of dichloromethane. The reaction mixture was stirred at RT for 30 min, the solvent was removed in vacuo, and the crude product was then purified by preparative HPLC (mobile phase: acetonitrile/water gradient) and subsequent flash chromatography on silica gel (mobile phase: dichloromethane). 632 mg (62% of theory) of the title compound were obtained.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[O:11][CH3:12].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:25]1([CH2:28][NH:29][CH2:30][CH2:31][N:32]2[CH2:37][CH2:36][CH:35]([O:38][C:39]3[CH:44]=[CH:43][C:42]([F:45])=[C:41]([F:46])[CH:40]=3)[CH2:34][CH2:33]2)[CH2:27][CH2:26]1>C1COCC1>[CH:25]1([CH2:28][N:29]([CH2:30][CH2:31][N:32]2[CH2:33][CH2:34][CH:35]([O:38][C:39]3[CH:44]=[CH:43][C:42]([F:45])=[C:41]([F:46])[CH:40]=3)[CH2:36][CH2:37]2)[C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:2]([F:1])=[C:3]([O:11][CH3:12])[CH:4]=2)[CH2:27][CH2:26]1
Reactant: COc1cc(C(=O)O)ccc1F
Reactant: Fc1ccc(OC2CCN(CCNCC3CC3)CC2)cc1F
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COc1cc(C(=O)N(CCN2CCC(Oc3ccc(F)c(F)c3)CC2)CC2CC2)ccc1F
Reaction time: 2 h
Yield: 4.9 %

Procedure:
To a solution of 4-fluoro-3-methoxybenzoic acid (0.082 g) in THF (1 ml) was added carbonyldiimidazole (0.078 g) and the resulting solution stirred at room temperature for 10 minutes before addition of the product of Step e (0.15 g) in THF (1.5 ml). The mixture was stirred for 2 hours and the solvent removed by evaporation to yield a colourless gum. Purification by reverse phase HPLC (with a gradient eluent system 25% MeCN/NH4OAc(aq) (0.1%) to 95% MeCN//NH4OAc(aq) (0.1%)) gave the title compound (0.011 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[OH:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.Cl[C:32](Cl)([O:34]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][C:32]2=[O:34])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccccc2O)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(n2c(=O)oc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred 0° C. solution of 1-t-Butyloxycarbonyl-4-(2-hydroxyphenylamino)piperidine (3.0 g, 10 mmol) from Step 1 of Example 41 in dry THF (40 mL) was added DIEA (5.2 mL, 30 mmol), followed by triphosgene (1.08 g, 3.60 mmol). After 30 min, the reaction was warmed to ambient temperature and stirred for 24 h. The precipitated hydrochloride salt of DIEA was removed by filtration and the solvent was removed under reduced pressure. The residue was dissolved in EtOAc (200 mL) and washed with saturated aqueous NaHCO3 (2×100 mL), water (100 mL), 5% aqueous citric acid (100 mL), and brine (100 mL). The EtOAc layer was dried (MgSO4), filtered, and the solvent was removed under reduced pressure. 3-(1-t-Butyloxycarbonyl-4-piperidinyl)benzoxazolidin-2-one was obtained as a solid (82% yield).
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][CH2:6][NH:7][C:8](=[O:35])[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH:29]2[CH2:32][C:31]([CH3:34])([CH3:33])[CH2:30]2)[NH:16][C:17]2[C:26]([CH3:27])=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([F:28])[CH:23]=3)[N:18]=2)=[CH:11][CH:10]=1)C.[OH-].[Na+].Cl>O1CCCC1.CO>[CH3:33][C:31]1([CH3:34])[CH2:32][CH:29]([CH:15]([NH:16][C:17]2[C:26]([CH3:27])=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([F:28])[CH:23]=3)[N:18]=2)[C:12]2[CH:11]=[CH:10][C:9]([C:8]([NH:7][CH2:6][CH2:5][C:4]([OH:36])=[O:3])=[O:35])=[CH:14][CH:13]=2)[CH2:30]1
Reactant: CCOC(=O)CCNC(=O)c1ccc(C(Nc2nc3ccc(F)cc3cc2C)C2CC(C)(C)C2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc2cc(F)ccc2nc1NC(c1ccc(C(=O)NCCC(=O)O)cc1)C1CC(C)(C)C1
Yield: 74.4 %

Procedure:
(+/−)-3-{4-[(3,3-Dimethyl-cyclobutyl)-(6-fluoro-3-methyl-quinolin-2-ylamino)-methyl]-benzoylamino}-propionic acid ethyl ester (14.3 mg, 0.029 mmol), made in a similar manner as Intermediate 27 from Intermediate 29, was dissolved in tetrahydrofuran (1.5 mL) and methanol (0.5 mL), and 1.0 M sodium hydroxide (1 mL) was added. This was stirred as a solution at room temperature for 20 min before 1 N HCl was added to bring to pH 5. This was extracted twice with ethyl acetate and the combined organics dried over MgSO4, and concentrated in vacuo. Purification by reversed-phase HPLC gave (+/−)-3-{4-[(3,3-dimethyl-cyclobutyl)-(6-fluoro-3-methyl-quinolin-2-ylamino)-methyl]-benzoylamino}-propionic acid (10 mg). Analytical LCMS: retention time 2.3998 minutes (Waters Atlantic dC18 4.6×50 mm, 5 μm column; 5% acetonitrile/water (0.05% trifluoroacetic acid modifier) linear gradient to 95% acetonitrile/water over 4.0 minutes, hold at 95% acetonitrile/water for 1.0 minute; flow rate 2.0 mL/minute); MS (M+1): 464.0.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[O:16][C:15](=O)[NH:14][C:13]=2[CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:28])=O>N1C=CC=CC=1>[Cl:28][C:15]1[O:16][C:12]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]([F:1])=[CH:3][CH:4]=2)=[C:13]([CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:14]=1
Reactant: CCOC(=O)CCCc1[nH]c(=O)oc1-c1ccc(F)c2ccccc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CCOC(=O)CCCc1nc(Cl)oc1-c1ccc(F)c2ccccc12
Temperature: 125 °C
Reaction time: 0.75 h

Procedure:
A mixture of ethyl 4-[5-(4-fluoro-1-naphthyl)-2-oxo-4-oxazolin-4-yl]butanoate (3.09 g), phosphorus oxychloride (6.00 g) and pyridine (0.80 g) was heated to 120-130° C. and stirred for 45 minutes. The reaction mixture was poured into 100 ml of ice water and extracted with ethyl acetate (100 ml×2). The organic layer was washed in sequence with a 10% aqueous solution of sodium hydrogen carbonate (50 ml) and a saturated aqueous solution of sodium chloride (50 ml), and dried over anhydrous magnesium sulfate. The organic layer was concentrated, the residue was subjected to silica gel column chromatography, and ethyl 2-chloro-5-(4-fluoro-1-naphthyl)-4-oxazolebutanoate was obtained as a yellow oil (903 mg, 28%) from an ethyl acetate-hexane (1:4, v/v)-eluted fraction.