Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([N:17]([C:27]2[CH:31]=[C:30]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[S:29][C:28]=2[C:38]([O:40][CH3:41])=[O:39])[C:18]([CH:20]2[CH2:25][CH2:24][CH:23]([CH3:26])[CH2:22][CH2:21]2)=[O:19])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.C(OCC)(=O)C>[Pd].CO>[CH3:41][O:40][C:38]([C:28]1[S:29][C:30]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[CH:31][C:27]=1[N:17]([C:18]([CH:20]1[CH2:21][CH2:22][CH:23]([CH3:26])[CH2:24][CH2:25]1)=[O:19])[CH:14]1[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]1)=[O:39]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)C1CCC(C)CC1)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)C1CCC(C)CC1)C1CCNCC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 74 %

Procedure:
To a solution of 4-[(2-Methoxycarbonyl-5-phenyl-thiophen-3-yl)-(4-methyl-cyclohexanecarbonyl)-amino]-piperidine-1-carboxylic acid benzyl ester (506 mg, 0.88 mmol) in a 6:1 mixture of ethyl acetate and methanol (7 ml) was added the 10% palladium on charcoal (103 mg, 0.097 mmol). The resulting reaction mixture was placed under H2 atmosphere (25 psi), stirred at room temperature for 3 days, and then filtered on celite and evaporated to dryness. The crude product was purified by flash chromatography (100/90/16/1 CH2Cl2/CHCl3/MeOH/Et3N) to give 287 mg (74%) of 3-[(4-Methyl-cyclohexanecarbonyl)-piperidin-4-yl-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[C:11](#[N:13])[CH3:12]>>[Br:1][C:2]1[C:3]([F:10])=[C:4]([CH:5]([OH:6])[CH2:12][C:11]#[N:13])[CH:7]=[CH:8][CH:9]=1
Reactant: CC#N
Reactant: O=Cc1cccc(Br)c1F
Product: N#CCC(O)c1cccc(Br)c1F

Procedure:
Reaction of 3-bromo-2-fluorobenzaldehyde with acetonitrile gave 3-(3-bromo-2-fluorophenyl)-3-hydroxypropanenitrile as a light yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.54 (t, J=7.2 Hz, 2H), 7.11 (td, J=7.6, 0.4 Hz, 1H), 5.37 (dd, J=6.8, 4.4 Hz, 1H), 2.73-2.91 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24])[N:6]2[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1.[CH:25]([N:28]1[C:32]2([CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[C:31](=[O:38])[NH:30][CH2:29]1)([CH3:27])[CH3:26].C(N(CC)CC)C>C(O)C>[Cl:17][C:14]1[CH:13]=[CH:12][C:11]([N:6]2[C:5]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])=[N:4][C:3]3[C:7]2=[N:8][CH:9]=[N:10][C:2]=3[N:35]2[CH2:36][CH2:37][C:32]3([N:28]([CH:25]([CH3:26])[CH3:27])[CH2:29][NH:30][C:31]3=[O:38])[CH2:33][CH2:34]2)=[CH:16][CH:15]=1
Reactant: Clc1ccc(-n2c(-c3ccccc3Cl)nc3c(Cl)ncnc32)cc1
Reactant: CC(C)N1CNC(=O)C12CCNCC2
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)N1CNC(=O)C12CCN(c1ncnc3c1nc(-c1ccccc1Cl)n3-c1ccc(Cl)cc1)CC2

Procedure:
A mixture of 6-chloro-9-(4-chlorophenyl)-8-(2-chlorophenyl)-9H-purine I-(4A-7)c (19 mg, 0.052 mmol), 1-isopropyl-1,3,8-triazaspiro[4.5]decan-4-one (Janssen, P. A. J., U.S. Pat. No. 3,238,216; 20 mg, 0.10 mmol) and triethylamine (11 μl) in ethanol (1 ml) was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure and then purified on a Biotage™ Flash 12S column using 3% methanol in methylene chloride as eluant to afford title compound 13A-1 (25 mg): +ESI MS (M+1) 536.3; 1H NMR (400 MHz, CD3OD) δ 8.22 (s, 1H), 7.59 (d, J=7.5 Hz, 1H), 7.46–7.35 (m, 5H), 7.29 (d, J=8.7 Hz, 2H), 4.27 (s, 2H), 4.25 (v br s, 4H), 3.15 (septuplet, J=6.6 Hz, 1H), 2.00–1.83 (m, 4H), 1.07 (d, J=6.6 Hz, 6H). A solution of the material in methylene chloride/ methanol was treated with excess 1 N HCl in diethyl ether, stirred, evaporated to dryness, and then triturated in diethyl ether to afford the hydrochloride salt of compound 13A-1 (23 mg, 77%): 1H NMR (400 MHz, CD3OD) δ 8.43 (s, 1H), 7.61 (d, J=7.5 Hz, 1H), 7.53–7.40 (m, 5H), 7.35 (d, J=8.7 Hz, 2H), 4.20 (v br s), 3.94 (septuplet, J=6.6 Hz, 1H), 2.45 (m, 4H), 1.41 (d, J=6.6 Hz, 6H).
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][N:8]1[CH:17]=[C:16]([CH:18]=[O:19])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:20]3[CH:25]=[C:24]([C:26](=[O:31])[NH:27][CH:28]4[CH2:30][CH2:29]4)[CH:23]=[C:22]([F:32])[C:21]=3[CH3:33])[CH:14]=2)[C:9]1=[O:34])(=O)C.CO.C(=O)([O-])[O-].[K+].[K+]>O>[CH:28]1([NH:27][C:26](=[O:31])[C:24]2[CH:25]=[C:20]([C:13]3[CH:14]=[C:15]4[C:10](=[CH:11][CH:12]=3)[C:9](=[O:34])[N:8]([CH2:7][CH2:6][CH2:5][OH:4])[CH:17]=[C:16]4[CH:18]=[O:19])[C:21]([CH3:33])=[C:22]([F:32])[CH:23]=2)[CH2:30][CH2:29]1
Reactant: CC(=O)OCCCn1cc(C=O)c2cc(-c3cc(C(=O)NC4CC4)cc(F)c3C)ccc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CCCO)cc(C=O)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.2 %

Procedure:
3-(6-(5-(Cyclopropylcarbamoyl)-3-fluoro-2-methylphenyl)-4-formyl-1-oxoisoquinolin-2(1H)-yl)propyl acetate (Example 10d, 0.75 g) was treated with methanol (15 mL) and potassium carbonate (0.25 g) and the resulting mixture was stirred at room temperature for 30 min, diluted with water and extracted with ethyl acetate. The organic layer was dried (MgSO4), filtered and evaporated to afford the subtitle compound (0.67 g).
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[C:10]([Si:12]([CH3:15])([CH3:14])[CH3:13])[NH:9][N:8]2[C:16]([OH:18])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.O[N:21]1C2C=CC=CC=2N=N1.O.N>ClCCl>[C:1]1([N:7]2[CH:11]=[C:10]([Si:12]([CH3:15])([CH3:14])[CH3:13])[NH:9][N:8]2[C:16]([NH2:21])=[O:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[Si](C)(C)C1=CN(c2ccccc2)N(C(=O)O)N1
Reactant: On1nnc2ccccc21
Agent: N
Solvent: ClCCl
Solvent: O
Product: C[Si](C)(C)C1=CN(c2ccccc2)N(C(N)=O)N1
Temperature: -78 °C
Reaction time: 48 h
Yield: 87.6 %

Procedure:
In a nitrogen atmosphere, 630 mg of 3-phenyl-5-trimethylsilanyl-1H-[1,2,3]triazole-2-carboxylic acid which is the compound prepared in the above 2) was dissolved in 5 ml of dichloromethane, 671 mg of 1-hydroxybenzotriazole monohydrate and 907 mg of a water-soluble dichlorohexyl carbodiimide were added thereto, the reaction solution was cooled down to −78° C. and ammonia gas was introduced thereinto followed by stirring for 2 days. Water was added to the reaction solution, the mixture was extracted with ethyl acetate and the ethyl acetate layer washed with a saturated saline solution and dried over sodium sulfate. The solvent was evaporated in vacuo and the residue was separated and purified by a silica gel column chromatography (hexane/ethyl acetate=2/1) to give 550 mg of the title compound as a white solid.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH2:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[C:20](Cl)=[O:21]>C(OCC)C>[CH3:29][O:28][C:24]1[CH:23]=[C:19]([C:20]([NH:14][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:21])[CH:18]=[C:17]([O:16][CH3:15])[C:25]=1[O:26][CH3:27]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: Nc1ccccc1Nc1ccccc1
Solvent: CCOCC
Product: COc1cc(C(=O)Nc2ccccc2Nc2ccccc2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of N-phenyl-o-phenylenediamine (1.84 g, 10 mmol) in diethyl ether (90 ml) was stirred at room temperature as 3,4,5-trimethoxybenzoyl chloride (2.31 g, 10 mmol) in diethyl ether (40 ml) was added dropwise. The reaction mixture was then stirred overnight at room temperature. The solvents were then removed in vacuo leaving N-[(3,4,5-trimethoxyphenyl)carbonyl]-N'-phenylphenylenediamine.
Reaction SMILES: C[O:2][C:3](=[O:36])[C@@H:4]([NH:14][C:15]([C:17]1[S:18][C:19]([C:25](=[O:35])[NH:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([OH:34])[CH:29]=2)=[CH:20][C:21]=1[CH:22]([CH3:24])[CH3:23])=[O:16])[CH2:5][NH:6][C:7]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:8].O.[OH-].[Li+].Cl>C1COCC1.O>[OH:34][C:30]1[CH:29]=[C:28]([CH:33]=[CH:32][CH:31]=1)[CH2:27][NH:26][C:25]([C:19]1[S:18][C:17]([C:15]([NH:14][C@@H:4]([CH2:5][NH:6][C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[O:8])[C:3]([OH:36])=[O:2])=[O:16])=[C:21]([CH:22]([CH3:24])[CH3:23])[CH:20]=1)=[O:35]
Reactant: COC(=O)[C@H](CNC(=O)c1cccs1)NC(=O)c1sc(C(=O)NCc2cccc(O)c2)cc1C(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1cc(C(=O)NCc2cccc(O)c2)sc1C(=O)N[C@@H](CNC(=O)c1cccs1)C(=O)O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of (S)-2-{[5-(3-Hydroxy-benzylcarbamoyl)-3-isopropyl-thiophene-2-carbonyl]-amino}-3-[(thiophene-2-carbonyl)-amino]propionic acid methyl ester (40 mg, 0.076 mmol) in THF (2 mL) was added a solution of lithium hydroxide monohydrate (32 mg, 0.76 mmol) in water (3 mL). The mixture was then stirred at room temperature 15 h. The mixture was then acidified with 1N HCl and extracted with EtOAc (×3). The extracts were combined, washed with water and brine, dried over sodium sulfate, filtered, and evaporated to pure product, 29.4 mg (75%). MS m/e 516.0 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)[CH:6]=[CH:5][N:4]=1>CCOC(C)=O.[Ni]>[NH2:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][C:7]2[CH:6]=[CH:5][N:4]=[C:3]([O:2][CH3:1])[CH:8]=2)=[CH:11][CH:12]=1
Reactant: COc1cc(Oc2ccc([N+](=O)[O-])cc2)ccn1
Agent: [Ni]
Solvent: CCOC(C)=O
Product: COc1cc(Oc2ccc(N)cc2)ccn1

Procedure:
Hydrogenation of 2-methoxy-4-(4-nitro-phenoxy)pyridine (Stage 92.2; 0.12 g, 0.5 mmol) in AcOEt (10 ml) in the presence of Raney Nickel (20 mg) affords after filtration and concentration of the filtrate the title compound: 1H-NMR (CDCl3): 7.97 (d, 1H), 6.86 (d, 2H), 6.67 (d, 2H), 6.48 (d, 1H), 6.13 (s, 1H), 3.89 (s, H3CO), 3.70 (s, H2N).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[NH2:20][C@H:21]([CH2:26][OH:27])[CH2:22][CH:23]([CH3:25])[CH3:24]>>[O:1]1[C:5]2([CH2:6][CH2:7][N:8]([C:11]3[CH:12]=[CH:13][C:14]([C:15]([NH:20][C@H:21]([CH2:26][OH:27])[CH2:22][CH:23]([CH3:25])[CH3:24])=[O:16])=[CH:18][CH:19]=3)[CH2:9][CH2:10]2)[O:4][CH2:3][CH2:2]1
Reactant: CC(C)C[C@H](N)CO
Reactant: O=C(O)c1ccc(N2CCC3(CC2)OCCO3)cc1
Product: CC(C)C[C@@H](CO)NC(=O)c1ccc(N2CCC3(CC2)OCCO3)cc1

Procedure:
The title compound was prepared from 4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-benzoic acid (which was obtained in Example 150) (0.53 g, 2 mmol) and (S)-leucinol (0.30 g, 2.5 mmol) according to the procedure shown for Example 154 to give 0.53 g of a white solid; m.p. 90-91° C.; MS (ES) m/z: 363.3 (MH+); HRMS (ES) Calcd. for C20H31N2O4 (MH+): 363.2278, Found: 363.2275.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[N:5]=1.[O:16]=[C:17]1[NH:26][C:25]2[N:24]=[C:23]([O:27][CH2:28][CH2:29][CH2:30][CH:31]=O)[CH:22]=[CH:21][C:20]=2[CH:19]=[CH:18]1>>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([N:10]2[CH2:11][CH2:12][N:13]([CH2:31][CH2:30][CH2:29][CH2:28][O:27][C:23]3[N:24]=[C:25]4[C:20]([CH:19]=[CH:18][C:17](=[O:16])[NH:26]4)=[CH:21][CH:22]=3)[CH2:14][CH2:15]2)[N:5]=1
Reactant: COc1ccnc(N2CCNCC2)n1
Reactant: O=CCCCOc1ccc2ccc(=O)[nH]c2n1
Agent: Cl
Product: COc1ccnc(N2CCN(CCCCOc3ccc4ccc(=O)[nH]c4n3)CC2)n1

Procedure:
In a manner similar to that of other examples above, 4-methoxy-2-piperazin-1-yl-pyrimidine hydrochloride (U.S. Pat. No. 6,303,603) was coupled by reductive amination to 4-(7-oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde followed by typical workup and purification to give the title compound. MS: APCI: M+1: 411.2 (Exact Mass: 410.21).
Reaction SMILES: [CH2:1]([C:3]1([C:40]2[CH:45]=[CH:44][C:43]([OH:46])=[CH:42][CH:41]=2)[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]CCC(CCCCCCC(F)(F)C(F)(F)F)C(O)=O)[C:11]2[C:6](=[CH:7][C:8]([OH:39])=[CH:9][CH:10]=2)[O:5][CH2:4]1)[CH3:2].[F:47][C:48]([F:76])([C:66]([F:75])([F:74])[C:67]([F:73])([F:72])[C:68]([F:71])([F:70])[F:69])[CH2:49][CH2:50][CH2:51][CH:52]([CH2:58][CH2:59]CCCCC=C)[C:53]([O:55]CC)=[O:54]>>[CH2:1]([C:3]1([C:40]2[CH:41]=[CH:42][C:43]([OH:46])=[CH:44][CH:45]=2)[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:59][CH2:58][CH:52]([CH2:51][CH2:50][CH2:49][C:48]([F:47])([F:76])[C:66]([F:75])([F:74])[C:67]([F:73])([F:72])[C:68]([F:69])([F:70])[F:71])[C:53]([OH:55])=[O:54])[C:11]2[C:6](=[CH:7][C:8]([OH:39])=[CH:9][CH:10]=2)[O:5][CH2:4]1)[CH3:2]
Reactant: CCC1(c2ccc(O)cc2)COc2cc(O)ccc2C1CCCCCCCCCC(CCCCCCC(F)(F)C(F)(F)F)C(=O)O
Reactant: C=CCCCCCCC(CCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)OCC
Product: CCC1(c2ccc(O)cc2)COc2cc(O)ccc2C1CCCCCCCCCC(CCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)O

Procedure:
Starting with the allyl compound prepared in Example 21 and ethyl 2-(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)-9-decenoate prepared separately, the same procedure as shown in Example 21 was repeated to give 11-[(3RS,4RS)-3-ethyl-7-hydroxy-3-(4-hydroxyphenyl)chroman-4-yl]-2-(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)undecanoic acid.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>>[F:32][C:33]1[CH:38]=[CH:37][C:36]([C:12]2[N:13]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:14]=[C:15]3[C:11]=2[CH2:10][CH2:9][NH:8][CH2:17][CH2:16]3)=[CH:35][CH:34]=1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(-c3ccccc3)c(OS(=O)(=O)C(F)(F)F)c2CC1
Reactant: OB(O)c1ccc(F)cc1
Product: Fc1ccc(-c2c3c(nn2-c2ccccc2)CCNCC3)cc1
Yield: 50.8 %

Procedure:
The title compound (70.0 mg) was prepared from 207.0 mg of 2-phenyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 176, Step B) and 98.5 mg of 4-fluorophenylboronic acid as in Example 199. MS (ESI): exact mass calculated for C19H18FN3, 307.15; found, m/z 308.2 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.28-7.24 (m, 2H), 7.22-7.16 (m, 3H), 7.13-7.10 (m, 2H), 7.05-7.01 (m, 2H), 3.12-3.08 (m, 2H), 3.05-3.02 (m, 2H), 3.01-2.98 (m, 2H), 2.68-2.64 (m, 2H).
Reaction SMILES: [CH2:1]([C:8]1[C:13](=[O:14])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][C:11]2=[N:10][C:9]=1[CH:19](O)[CH:20]([CH3:22])[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]1(=[O:34])[NH:28][C:27](=[O:29])[C:26]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:25]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[CH2:1]([C:8]1[C:13](=[O:14])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][C:11]2=[N:10][C:9]=1[CH:19]([N:28]1[C:24](=[O:34])[C:25]2[C:26](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:27]1=[O:29])[CH:20]([CH3:22])[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C(O)c1nc2n(c(=O)c1Cc1ccccc1)CCCC2
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)C(c1nc2n(c(=O)c1Cc1ccccc1)CCCC2)N1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Yield: 44 %

Procedure:
A previous batch of the product from Step 8 (18) was combined with the above and 150 mg (0.48 mmol) of this crude material was dissolved in 3 ml of dry tetrahydrofuran then cooled to 0° C. Phthalimide 212 mg (1.4 mmol) was added to the cold solution followed by triphenylphosphine 189 mg (0.72 mmol) then DIAD 140 μl (0.72 mmol). The reaction mixture was stirred under nitrogen and allowed to warm to room temperature overnight. The solvent was evaporated and the solid redissolved in ethyl acetate then washed with saturated NaHCO3 and brine. The organic layer was then dried over MgSO4 and the solvent was removed in vacuo resulting in 700 mg of crude material that was purified by flash chromatography to give 95 mg (0.22 mmol, 44%) of 2-[1-(3-benzyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-2-yl)-2-methylpropyl]-1H-isoindole-1,3(2H)-dione (19) as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3]([C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][N:6]1C(OCC1C=CC=CC=1)=O)=[O:4].[ClH:22]>CO>[ClH:22].[CH3:1][N:2]([CH3:21])[C:3]([C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][NH:6]1)=[O:4]
Reactant: CN(C)C(=O)[C@@H]1CCCCN1C(=O)OCc1ccccc1
Agent: Cl
Solvent: CO
Product: CN(C)C(=O)[C@@H]1CCCCN1
Yield: 116.5 %

Procedure:
Phenylmethyl (2S)-2-[(dimethylamino)carbonyl]-1-piperidinecarboxylate (1.918 g, 6.609 mmol) was dissolved in a mixture of MeOH (40 mL) and 1N HCl (14.53 mL, 14.53 mmol), degassed and placed under argon. 10% Pd/C (575 mg) was added, and the contents were thoroughly degassed and placed under a hydrogen balloon for 2 h. The contents were then degassed, and the Pd/C was removed by filtration through a fiberglass filter, washing with MeOH. The filtrate was concentrated in vacuo to provide pure (2S)—N,N-dimethyl-2-piperidinecarboxamide hydrochloride (1.483 g, >99%). LCMS: (M+H)+: 157.2.
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)=[S:2].NC1[S:15][C:16]2C=C[CH:20]=[CH:19][C:17]=2N=1>C(#N)C>[S:15]1[C:16]2[CH:17]=[CH:19][CH:20]=[CH:12][C:11]=2[N:10]=[C:9]1[NH:8][C:1]([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)=[S:2]
Reactant: Nc1nc2ccccc2s1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: S=C(Nc1nc2ccccc2s1)n1ccnc1
Yield: 44.2 %

Procedure:
A solution of 1,1'-thiocarbonyldiimidazole (8.9 g, 50 mmol) and 2-aminobenzothiazole (7.5 g, 50 mmol) in acetonitrile (125 mL) was stirred at room temperature for 20 h. The resulting precipitate was collected by filtration to provide 5.75 g (44%) of the title product:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH2:11][N:12]([CH:34]1[CH2:36][CH:35]1[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:13]1[C:14]2[N:25]=[N:24][N:23]([CH:26]3[CH2:30][CH:29]([OH:31])[CH:28]([OH:32])[CH:27]3[OH:33])[C:15]=2[N:16]=[C:17]([S:19][CH2:20][CH2:21][CH3:22])[N:18]=1.[C:43]1(C)[CH:48]=CC(S(O)(=O)=O)=C[CH:44]=1>CC(C)=O.COC(OC)(C)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH2:11][N:12]([CH:34]1[CH2:36][CH:35]1[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:13]1[C:14]2[N:25]=[N:24][N:23]([CH:26]3[CH:27]4[O:33][C:43]([CH3:48])([CH3:44])[O:32][CH:28]4[CH:29]([OH:31])[CH2:30]3)[C:15]=2[N:16]=[C:17]([S:19][CH2:20][CH2:21][CH3:22])[N:18]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCCSc1nc(N(Cc2ccc(OC)cc2OC)C2CC2c2ccccc2)c2nnn(C3CC(O)C(O)C3O)c2n1
Solvent: COC(C)(C)OC
Solvent: CC(C)=O
Product: CCCSc1nc(N(Cc2ccc(OC)cc2OC)C2CC2c2ccccc2)c2nnn(C3CC(O)C4OC(C)(C)OC43)c2n1
Reaction time: 1 h
Yield: 90.3 %

Procedure:
To a solution of product of example 12, step (f) (4.50 g) in acetone (100 ml), 2,2-dimethoxypropane (12.60 ml) and p-toluenesulphonic acid (2.34 g) were added and the reaction mixture stirred for 1 hour. Purification (SiO2, ethyl acetate:isohexane 2:7 as eluant) afforded the subtitle compound (4.34 g).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([NH2:11])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10])[CH3:2].C([C:14]1C=C(CC(N)=O)C=C[C:19]=1[O:20]C)C>>[CH2:1]([C:3]1[CH:4]=[C:5]([NH:11][C:19](=[O:20])[CH3:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10])[CH3:2]
Reactant: CCc1cc(N)ccc1OC
Reactant: CCc1cc(CC(N)=O)ccc1OC
Product: CCc1cc(NC(C)=O)ccc1OC

Procedure:
By proceeding in a manner similar to Reference Example 33(a) but using 3-ethyl-4-methoxy-phenylamine [2.5 g, Reference Example 30(aa)] there was prepared N-(3-ethyl-4-methoxy-phenyl-acetamide (2.9 g) was prepared as a light brown solid. LC-MS (METHOD K): RT=3.92 minutes, 194.16 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:23])[C@@H:4]([N:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][C:18]=2[F:21])[C:13]1=[O:22])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.O.[OH-].[Li+].Cl>O1CCCC1.O>[CH:6]1([CH2:5][C@H:4]([N:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[F:21])[C:13]2=[O:22])[C:3]([OH:23])=[O:2])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)[C@H](CC1CCCCC1)N1Cc2c(F)cccc2C1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)[C@H](CC1CCCCC1)N1Cc2c(F)cccc2C1=O
Temperature: 25 °C
Yield: 77.7 %

Procedure:
A mixture of (S)-3-cyclohexyl-2-(4-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid methyl ester (311 mg, 0.97 mmol) in tetrahydrofuran (6 mL) at room temperature was treated with a mixture of lithium hydroxide monohydrate (82 mg, 1.95 mL) in water (6 mL). The reaction mixture was then stirred at room temperature until the reaction was complete by TLC (˜2 h). After this time, the reaction mixture was treated with 1N aqueous hydrochloric acid solution until the pH=2. The reaction mixture was then extracted with ethyl acetate (3×20 mL). The combined organic layers were then dried over magnesium sulfate, filtered to remove the drying agent and the filtrate was concentrated in vacuo to afford (S)-3-cyclohexyl-2-(4-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid (230 mg, 78%) as a white solid.
Reaction SMILES: [CH2:1]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]=1[C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([O:25][CH2:26][C:27]#[N:28])[CH:19]=[CH:18]2)[CH2:2][CH2:3][CH2:4][CH3:5].[CH3:29]I>>[CH3:29][N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[C:7]1[C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([O:25][CH2:26][C:27]#[N:28])[CH:19]=[CH:18]2
Reactant: CI
Reactant: CCCCCc1c(-c2ccc3cc(OCC#N)ccc3c2)[nH]c2ccccc12
Product: CCCCCc1c(-c2ccc3cc(OCC#N)ccc3c2)n(C)c2ccccc12

Procedure:
The title compound was prepared as a solid (0.412 g, 83%) from {[6-(3-pentyl-1H-indol-2-yl)-2-naphthyl]oxy}acetonitrile using MeI and the procedure from step 4 of Example 2; 1H NMR (DMSO-d6) δ 0.74 (t, J=7.5 Hz, 3H), 1.07-1.27 (m, 4H), 1.47-1.65 (m, 2H), 2.68 (t, J=8.3 Hz, 2H), 3.59 (s, 3H), 5.34 (s, 2H), 7.08 (t, J=8.3 Hz, 1H), 7.19 (t, J=8.3 Hz, 1H), 7.34 (dd, J=1.5, 9.0 Hz, 1H), 7.48 (d, J=9.0 Hz, 1H), 7.53-7.66 (m, 3H), 7.92-8.08 (m, 3H); mass spectrum [(+) ESI], m/z 383 (M+H)+.
Reaction SMILES: O[CH:2]([C:7]1[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=1)[CH2:3][N+:4]([O-:6])=[O:5].[CH2:14]1OCCOCCOCCOCCOCC[O:16][CH2:15]1.[F-].[K+].C(OC(=O)C)(=O)C>>[N+:4]([CH:3]=[CH:2][C:7]1[CH:8]=[C:9]([O:13][C:15](=[O:16])[CH3:14])[CH:10]=[CH:11][CH:12]=1)([O-:6])=[O:5]
Reactant: C1COCCOCCOCCOCCOCCO1
Reactant: O=[N+]([O-])CC(O)c1cccc(O)c1
Agent: [F-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Oc1cccc(C=C[N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 987 %

Procedure:
Add 3-(1-hydroxy-2-nitroethyl)-phenol (22.3 g, 121.8 mmol), 18-Crown-6 (3.3 g, 12.5 mmol), potassium fluoride (spray-dried) (7.1 g, 141 mmol) to acetic anhydride (115 mL, 1.218 mol). Stir for 1 hour. Cool in an ice bath and pour into ice water (400 mL) and stir for 15 minutes. Decant and extract the aqueous with ethyl acetate (twice). Combine extracts with the solid, wash with water (twice), saturated aqueous sodium chloride (twice), dry (magnesium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 25:75 hexanes:dichloromethane to 100% dichloromethane) to give the desired compound as an orange oil (25.56 g, 91%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.COC1C=C(CC)C=CC=1O.[CH2:23]([O:30][C:31]1[CH:36]=[C:35]([CH2:37][CH3:38])[CH:34]=[CH:33][C:32]=1[OH:39])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([O:30][C:31]1[CH:36]=[C:35]([CH2:37][CH3:38])[CH:34]=[CH:33][C:32]=1[O:39][C:7]1[CH:6]=[CH:5][C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]=1[F:1])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: CCc1ccc(O)c(OCc2ccccc2)c1
Agent: CCc1ccc(O)c(OC)c1
Product: CCc1ccc(Oc2ccc([N+](=O)[O-])cc2F)c(OCc2ccccc2)c1
Yield: 107.6 %

Procedure:
According to the procedure of example 20(a) except substituting 1-fluoro-4-nitro-2-(trifluoromethyl)benzene for 3,4-difluoronitrobenzene (30.5 g; 192 mmol), and 2-methoxy-4-ethylphenol for 2-(benzyloxy)-4-ethylphenol (33.6 g; 147 mmol) the title compound (58.1 g; 100%) was prepared as a brown oil, used without further purification.