Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [PH2]([O-])=O.[Na+].[OH2:5].[C:6]([C:8]1[CH:13]=[CH:12][C:11]([C@@:14]2([CH3:39])[C:18](=[O:19])[N:17]([CH2:20][C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:22])[C:16](=[O:31])[N:15]2[CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:10][CH:9]=1)#N>[Ni].N1C=CC=CC=1.C(O)(=O)C.O>[CH:6]([C:8]1[CH:13]=[CH:12][C:11]([C@@:14]2([CH3:39])[C:18](=[O:19])[N:17]([CH2:20][C:21]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[O:22])[C:16](=[O:31])[N:15]2[CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[CH:10][CH:9]=1)=[O:5]
Reactant: O
Reactant: C[C@]1(c2ccc(C#N)cc2)C(=O)N(CC(=O)OCc2ccccc2)C(=O)N1Cc1ccccc1
Agent: [Ni]
Agent: O=[PH2][O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CC(=O)O
Product: C[C@]1(c2ccc(C=O)cc2)C(=O)N(CC(=O)OCc2ccccc2)C(=O)N1Cc1ccccc1
Temperature: 60 °C
Yield: 79 %

Procedure:
24.3 g of sodium hypophosphite×H2O and 4.02 g of Raney nickel were added to a solution of 6.08 g (13.42 mmol) of 8.1 in 200 ml of pyridine/acetic acid/water (2:1:1) at 0° C. and the reaction mixture was heated at 60° C. for 8 h. After cooling to room temperature and filtration, the reaction mixture was concentrated in vacuo, the residue was taken up in ethyl acetate and the ethyl acetate phase was extracted 2× with water, 2× with 10% strength citric acid solution, 2× with saturated NaHCO3 solution and with saturated sodium chloride solution. The organic phase was dried over magnesium sulfate and, after filtration, the solvent was removed in vacuo. 4.82 g (79%) of 8.2 were obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]2([CH2:14][OH:15])[CH2:13][CH2:12][CH2:11]2)[CH:5]=[CH:4][N:3]=1.[C:16]1([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:16]1([N:22]2[CH2:27][CH2:26][N:25]([C:2]3[N:7]=[C:6]([O:8][CH2:9][C:10]4([CH2:14][OH:15])[CH2:13][CH2:12][CH2:11]4)[CH:5]=[CH:4][N:3]=3)[CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OCC1(COc2ccnc(Cl)n2)CCC1
Reactant: c1ccc(N2CCNCC2)cc1
Product: OCC1(COc2ccnc(N3CCN(c4ccccc4)CC3)n2)CCC1

Procedure:
The title compound was prepared from (1-{[(2-chloro-4-pyrimidinyl)oxy]methyl}cyclobutyl)methanol using the same experimental procedure as in example 21a using 1-phenylpiperazine. 1H NMR (300 MHz, CDCl3) δ 8.01 (d, J=6 Hz, 1H), 7.21 (m, 2H), 6.92-6.82 (m, 3H), 5.93 (d, J=6 Hz, 1H), 4.37 (s, 2H), 3.90 (m, 4H), 3.58 (s, 2H), 3.18 (m, 4H), 2.54 (br s, 1H).
Reaction SMILES: CNC(C1C2C=C(C3C(Cl)=CN=C(NCCCN4CCNC[C@H]4C)N=3)SC=2C=CC=1)=O.[CH:32]1([NH:35][C:36]([C:38]2[C:46]3[CH:45]=[C:44]([C:47]4[C:52]([Cl:53])=[CH:51][N:50]=[C:49](Cl)[N:48]=4)[S:43][C:42]=3[CH:41]=[CH:40][CH:39]=2)=[O:37])[CH2:34][CH2:33]1.C(OC([N:62]1[CH2:67][CH2:66][N:65]([CH2:68][CH2:69][NH2:70])[C@H:64]([CH3:71])[CH2:63]1)=O)(C)(C)C>>[CH:32]1([NH:35][C:36]([C:38]2[C:46]3[CH:45]=[C:44]([C:47]4[C:52]([Cl:53])=[CH:51][N:50]=[C:49]([NH:70][CH2:69][CH2:68][N:65]5[CH2:66][CH2:67][NH:62][CH2:63][C@H:64]5[CH3:71])[N:48]=4)[S:43][C:42]=3[CH:41]=[CH:40][CH:39]=2)=[O:37])[CH2:34][CH2:33]1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1CCN
Reactant: O=C(NC1CC1)c1cccc2sc(-c3nc(Cl)ncc3Cl)cc12
Agent: CNC(=O)c1cccc2sc(-c3nc(NCCCN4CCNC[C@H]4C)ncc3Cl)cc12
Product: C[C@@H]1CNCCN1CCNc1ncc(Cl)c(-c2cc3c(C(=O)NC4CC4)cccc3s2)n1

Procedure:
Using the method of (R)-2-{5-chloro-2-[3-(2-methylpiperazin-1-yl)-propylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid methylamide, the title compound is synthesized from 2-(2,5-dichloropyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid cyclopropylamide and (R)-4-(2-aminoethyl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester and isolated as a yellow solid. ES+(m/z) 471 (35Cl) and 473 (37Cl) [M+H].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]=O)=[CH:4][C:3]=1[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15].CO.C(O)(=O)C>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH3:9])=[CH:4][C:3]=1[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:16])([CH3:15])[CH3:17]
Reactant: CC(C)(C)OC(=O)Nc1cc(NC=O)ccc1F
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: CNc1ccc(F)c(NC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 73 %

Procedure:
To a solution of the above-mentioned crude product of tert-butyl [2-fluoro-5-(formylamino)phenyl]carbamate in tetrahydrofuran (100 mL) was added borane dimethylsulfide complex (11.7 mL, 111 mmol), and the mixture was stirred at room temperature for 1.5 hr. To the reaction mixture were successively added methanol (20 mL) and acetic acid (10 mL), and the mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure. To the obtained residue was added saturated aqueous sodium hydrogen carbonate solution (100 mL), and the mixture was extracted with ethyl acetate (100 mL, 30 mL). The combined organic layer was washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0→90/10), and the fractions containing the object product were concentrated under reduced pressure to give the title compound (7.80 g, 73%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH:11]([CH3:25])[C:12]([C:18]1[CH:23]=[CH:22][N:21]=[C:20]([Cl:24])[CH:19]=1)([OH:17])[C:13]([F:16])([F:15])[F:14])[C:5]([OH:7])=O.Cl.[CH3:27][O:28][C:29](=[O:33])[CH2:30][CH2:31][NH2:32].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[CH3:27][O:28][C:29](=[O:33])[CH2:30][CH2:31][NH:32][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([CH:11]([CH3:25])[C:12]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([Cl:24])[CH:19]=2)([OH:17])[C:13]([F:15])([F:16])[F:14])=[C:2]([Cl:1])[CH:3]=1
Reactant: COC(=O)CCN
Reactant: CC(c1ccc(C(=O)O)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Product: COC(=O)CCNC(=O)c1ccc(C(C)C(O)(c2ccnc(Cl)c2)C(F)(F)F)c(Cl)c1

Procedure:
In analogy to Example 26, step 4, 3-chloro-4-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-benzoic acid (Example 26, step 3) was reacted with beta-alanin-methyl ester hydrochloride and HBTU at 80° C. 2 h to give the title compound as a colorless viscous oil. MS (m/e, ISP neg. ion)=477.0 [M−H+].
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([N:13]2[C:17]3=[N:18][CH:19]=[N:20][C:21](Cl)=[C:16]3[CH:15]=[N:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([OH:38])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].[H-].[Na+]>C1COCC1>[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([O:38][C:21]2[N:20]=[CH:19][N:18]=[C:17]3[N:13]([C:5]4[CH:4]=[C:3]([C:2]([F:24])([F:23])[F:1])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=4)[N:14]=[CH:15][C:16]=23)[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: FC(F)(F)c1cc(-n2ncc3c(Cl)ncnc32)cc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ncnc3c2cnn3-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(3,5-Bis-trifluoromethyl-phenyl)-4-chloro-1H-pyrazolo[3,4-d]pyrimidine (73 mg, 0.2 mmole), 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.3 mmole, 1.5 eq) and NaH (1.2 mmol, 6 eq) were dissolved in THF (3 mL) and then stirred at room temperature overnight. THF solvent was removed in vacuo and the oily solid residue was re-dissolved in water and extracted with ethyl acetate provided compound A46 as greenish yellow oil (111 mg, 90%). 1H NMR (CDCl3, 400 MHz) δ 1.48 (s, 9H), 1.88-1.84 (m, 2H), 2.09 (m, 2H), 3.35-3.29 (m, 2H), 3.87-3.80 (m, 2H), 5.62-5.59 (m, 1H), 7.81 (s, 1H), 8.26 (s, 1H), 8.69 (s, 1H), 8.96 (s, 2H). Exact mass calculated for C23H23F6N5O3 531.17, found 532.2 (MH+).
Reaction SMILES: NC1C=CC(S(NC2C=CC=CC=2C)(=O)=O)=CC=1.[CH3:19][O:20][C:21]1[CH:26]=[C:25]([N+:27]([O-])=O)[CH:24]=[CH:23][C:22]=1[S:30]([NH:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1)(=[O:32])=[O:31]>>[NH2:27][C:25]1[CH:24]=[CH:23][C:22]([S:30]([NH:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)(=[O:32])=[O:31])=[C:21]([O:20][CH3:19])[CH:26]=1
Reactant: COc1ccc(NS(=O)(=O)c2ccc([N+](=O)[O-])cc2OC)cc1
Agent: Cc1ccccc1NS(=O)(=O)c1ccc(N)cc1
Product: COc1ccc(NS(=O)(=O)c2ccc(N)cc2OC)cc1
Yield: 77 %

Procedure:
(RK1-1-45) I This compound was prepared according to the procedure described for compound 12a except using 11k to obtain the required product as a yellow solid (141 mg, 77%). Mp=51-54° C.; 1H NMR (400 MHz, CDCl3) δ 7.44 (d, J=8.4 Hz, 1H), 6.97 (d, J=8.8 Hz, 2H), 6.72 (d, J=8.8 Hz, 2H), 6.61 (br s, 1H), 6.19 (d, J=2.0 Hz, 1H), 6.14 (dd, J=8.6, 2.2 Hz, 1H), 4.06 (br s, 2H), 3.98 (s, 3H), 3.72 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25](C)([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)=[CH:11][C:10]2=[O:29])=[C:5]([F:30])[CH:4]=1)#[N:2].N1(C([O-])=O)CCCCC1.ClC1N=CC(CCC)=CN=1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][CH:25]([CH3:26])[CH3:27])=[O:23])[CH2:18][CH2:17]3)=[CH:11][C:10]2=[O:29])=[C:5]([F:30])[CH:4]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccn(-c3ccc(C#N)cc3F)c(=O)c2)CC1
Agent: CCCc1cnc(Cl)nc1
Agent: O=C([O-])N1CCCCC1
Agent: O=C([O-])[O-]
Product: CC(C)OC(=O)N1CCC(Oc2ccn(-c3ccc(C#N)cc3F)c(=O)c2)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Example 188 was prepared according to procedures described in Example 132 substituting tert-butyl 4-(1-(4-cyano-2-fluorophenyl)-2-oxo-1,2-dihydropyridin-4-yloxy)piperidine-1-carboxylate (Example 176) for tert-butyl 4-(2-oxo-1-pyridin-3-yl)-1,2-dihydropyridin-4-yloxy)piperidine-1-carboxylate in Step C and substituting isopropyl carbonochloridate (1 Molar in Toluene, Aldrich) for 2-chloro-5-propylpyrimidine and substituting triethyl amine for cesium carbonate in Step D except that reaction was stirred at room temperature for 20 min and then washed with HCl solution (1 Molar in H2O). The crude solid was purified by flash chromatography (SiO2, 0 to 100% EtOAc in CH2Cl2). 1H NMR (500 MHz, CDCl3) δ ppm 7.49-7.58 (m, 3H), 7.08 (d, J=7.70 Hz, 1H), 6.02 (dd, J=7.70, 2.20 Hz, 1H), 5.93 (d, J=2.20 Hz, 1H), 4.87-4.95 (m, 1H), 4.45-4.49 (m, 1H), 3.69-3.77 (m, 2H), 3.32-3.39 (m, 2H), 1.92-2.00 (m, 2H), 1.72-1.81 (m, 2H), 1.24 (d, J=6.60 Hz, 6H). MS (ESI) 400 (M+H).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](OCC)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]1=[O:26])(=O)C.[CH3:27][N:28]([CH2:30][C:31]([NH:33][CH2:34][C:35]1[CH:36]=[C:37]([CH:39]=[CH:40][CH:41]=1)[NH2:38])=[O:32])[CH3:29].[OH-].[Na+]>CN(C=O)C.CO>[CH3:29][N:28]([CH2:30][C:31]([NH:33][CH2:34][C:35]1[CH:36]=[C:37]([NH:38]/[C:16](=[C:6]2\[C:5](=[O:26])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=3)/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:39]=[CH:40][CH:41]=1)=[O:32])[CH3:27]
Reactant: CN(C)CC(=O)NCc1cccc(N)c1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccc([N+](=O)[O-])cc21)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: CN(C)CC(=O)NCc1cccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)c1

Procedure:
Prepared analogously to Example 82 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 3-dimethylaminomethylcarbonylaminomethyl-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][C:8]([O:10]C(C)C)=[O:9])=[C:4]([CH3:16])[C:3]=1[NH:17][CH2:18][C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=2)[C:20]=1[F:33].[OH-].[Na+].Cl>C1COCC1.O>[F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][C:8]([OH:10])=[O:9])=[C:4]([CH3:16])[C:3]=1[NH:17][CH2:18][C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=2)[C:20]=1[F:33]
Reactant: Cc1cc(CNc2c(F)ccc(OCC(=O)OC(C)C)c2C)c(F)c(-c2cccc(F)c2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(CNc2c(F)ccc(OCC(=O)O)c2C)c(F)c(-c2cccc(F)c2)c1
Reaction time: 2 h
Yield: 9.8 %

Procedure:
To a stirred solution of isopropyl 2-[4-fluoro-3-[[2-fluoro-3-(3-fluorophenyl)-5-methyl-phenyl]methylamino]-2-methyl-phenoxy]acetate (100 mg, 0.22 mmol, 1.0 eq) in a mixture of THF (10 mL) and H2O (10 mL) was added NaOH (17 mg, 0.44 mmol, 2.0 eq). The reaction was stirred for 2 h then acidified to pH 4 by addition of 1M HCl. The aqueous layer was extracted with EtOAc and the combined organic extracts were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was purified by column chromatography (CH2Cl2:MeOH, 20:1) to give a partially purified material. Further purification by preparative HPLC provided the title compound as yellow solid (9 mg, 10%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH3:25])=[CH:21][CH:22]=3)[C:11]3([CH2:15][C:14](=O)[NH:13][C:12]3=O)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH3:25])=[CH:21][CH:22]=3)[C:11]3([CH2:15][CH2:14][NH:13][CH2:12]3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1ccc2c(c1)C1(CC(=O)NC1=O)CC2c1ccc(Cl)c(Cl)c1
Agent: Cl
Product: COc1ccc2c(c1)C1(CCNC1)CC2c1ccc(Cl)c(Cl)c1

Procedure:
Using a procedure similar to that described in Example 3, except replacing the 1a used therein with the 1c, the title compound was prepared; 1H NMR (free base) (CDCl3): δ 1.40-2.05 (m, 4H, CH2), 2.45 (m, 2H, CH2), 2.98-3.65 (m, 3H, CH2 and NH), 3.80 (s, 3H, OCH3),4.28 (t, 1H, CH), 6.71-6.81 (m, 3H, Ar--H), 7.0 (d, 1H, Ar--H), 7.21-7.38 (m, 2H, Ar--H). Elemental analysis calcd. for Cl19H19Cl2NO.HCl: C, 59.52; H, 5.26; N, 3.66. Found: C, 59.61; H, 5.57; 2.95.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:28]2[C:29]([C:34]#[N:35])=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:10](=[O:27])[N:11]([C@H:22]2[CH2:25][C@@H:24]([OH:26])[CH2:23]2)[C:12]2[N:13]([N:18]=[C:19]([CH3:21])[N:20]=2)[C:14]=1[CH2:15][CH2:16][CH3:17].[N+](=[CH:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[N-]>C([O-])(=O)C.[Rh+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[C:34]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[C:4]1[CH:5]=[CH:6][C:7]([CH2:8][C:9]2[C:10](=[O:27])[N:11]([C@@H:22]3[CH2:25][C@H:24]([O:26][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:23]3)[C:12]3[N:13]([N:18]=[C:19]([CH3:21])[N:20]=3)[C:14]=2[CH2:15][CH2:16][CH3:17])=[C:2]([F:1])[CH:3]=1)#[N:35]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2C[C@@H](O)C2)c2nc(C)nn12
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2C[C@@H](OCC(=O)OCC)C2)c2nc(C)nn12
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a mixture of 3′-fluoro-4′-{[4-(cis-3-hydroxycyclobutyl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (1.70 g), rhodium(II) acetate (dimer) (80 mg) and toluene (40 mL) was added dropwise ethyl diazoacetate (0.88 mL) under an argon atmosphere at 70° C., and the mixture was stirred at 70° C. for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography [eluent: hexane/ethyl acetate=70/30→55/45 (volume ratio)] to give the title compound as a colorless amorphous compound (895 mg, 45%).
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]([CH2:14][CH3:15])[C:4]=1[C:16]1[CH:21]=[CH:20][C:19]([NH:22][S:23]([CH:26]=[CH2:27])(=[O:25])=[O:24])=[CH:18][CH:17]=1)#[N:2].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>CC#N>[C:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]([CH2:14][CH3:15])[C:4]=1[C:16]1[CH:21]=[CH:20][C:19]([NH:22][S:23]([CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)(=[O:24])=[O:25])=[CH:18][CH:17]=1)#[N:2]
Reactant: C=CS(=O)(=O)Nc1ccc(-c2c(C#N)c3ccc(OC)cc3n2CC)cc1
Reactant: C1COCCN1
Solvent: CC#N
Product: CCn1c(-c2ccc(NS(=O)(=O)CCN3CCOCC3)cc2)c(C#N)c2ccc(OC)cc21
Temperature: 25 °C
Yield: 100 %

Procedure:
A suspension of ethenesulfonic acid [4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]amide, prepared above, (70 mg, 0.18 mmol), morpholine (0.05 mL, 0.55 mmol) in CH3CN (1.5 mL) is heated at reflux for 1.5 h. After cooling to room temperature, the reaction is concentrated and the residue is purified by flash chromatography (acetone/EtOAc, 2/98) over silica gel to afford 89 mg (100%) of 2-morpholin-4-yl-ethanesulfonic acid [4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]amide as a tan foam.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[C:15]([O:19][CH3:20])(=[O:18])[CH:16]=[CH2:17]>>[CH:4]1[C:5]2[CH:6]3[CH2:17][CH:16]([C:15]([O:19][CH3:20])=[O:18])[CH:13]([C:12]4[C:7]3=[CH:8][CH:9]=[CH:10][CH:11]=4)[C:14]=2[CH:1]=[CH:2][CH:3]=1
Reactant: C=CC(=O)OC
Reactant: c1ccc2cc3ccccc3cc2c1
Product: COC(=O)C1CC2c3ccccc3C1c1ccccc12
Temperature: 210 °C

Procedure:
Anthracene (89.0 gm) was combined with methyl acrylate (51.5 gm) and xylenes (500 ml) in a Parr bomb and heated to 210° C. for 12 hours. The solvent was removed on a rotary evaporator and the residue was recrystallized from methanol to provide the product as a white solid (mp=113°-114° C.).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=O)[NH:12][N:11]=2)[CH:2]=1.P(Cl)(Cl)([Cl:23])=O.Cl.C([O-])([O-])=O.[Na+].[Na+]>C(#N)C.O1CCOCC1.O>[Cl:23][C:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]([CH2:9][CH2:8][CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[N:11][N:12]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]nc(CCCc2cccnc2)c2ccccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CC#N
Product: Clc1nnc(CCCc2cccnc2)c2ccccc12
Temperature: 45 °C
Reaction time: 36 h

Procedure:
Under exclusion of air, 771 mg (2.9 mmol) 4-[3-(pyridin-3-yl)propyl]phthalazin-1(2H)-one in 14 ml acetonitrile is mixed with 1.11 g (7.25 mmol) phosphoryl chloride and 1.45 ml 4 N HCl in dioxane and stirred for 36 h at 45° C. Then 50 ml water is added, the reaction mixture adjusted to alkaline pH with sat. Na2CO3 solution and immediately extracted 3 times with EtOAc. Drying (Na2SO4) of the organic phases and evaporation yield the title compound; FAB-MS (M+H)+=284.
Reaction SMILES: CS[C:3](SC)=[C:4]1[C:13](=[O:14])[C:12]([CH2:16][CH2:17][CH2:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)([CH3:15])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:25].[NH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[S:35]([NH2:38])(=[O:37])=[O:36]>C1(C)C=CC=CC=1>[CH:19]1([CH2:18][CH2:17][CH2:16][C:12]2([CH3:15])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([OH:25])=[C:4]([C:3]3[NH:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[S:35](=[O:36])(=[O:37])[N:38]=3)[C:13]2=[O:14])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CSC(SC)=C1C(=O)c2ccccc2C(C)(CCCC2CCCCC2)C1=O
Reactant: Nc1ccccc1S(N)(=O)=O
Solvent: Cc1ccccc1
Product: CC1(CCCC2CCCCC2)C(=O)C(C2=NS(=O)(=O)c3ccccc3N2)=C(O)c2ccccc21
Temperature: 25 °C
Yield: 865 %

Procedure:
A solution of Example 36H (0.075 g, 0.186 mmol) and 2-amino-benzenesulfonamide (0.034 g, 0.195 mmol) in toluene (7 mL) was refluxed for 6 hours. The solution was cooled to 25° C. and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexane followed by 20% and 30% ethyl acetate in hexane to give the desired product (0.77 g, 87%).
Reaction SMILES: C[O:2][C:3](=[O:36])[CH:4]([O:33][CH2:34][CH3:35])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][N:14]([C:22](=[O:32])[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[F:31])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:8][CH:7]=1.[Li+].[OH-]>O1CCCC1>[F:31][C:25]1[CH:26]=[C:27]([F:30])[CH:28]=[CH:29][C:24]=1[CH2:23][C:22]([N:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:13][CH2:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH:4]([O:33][CH2:34][CH3:35])[C:3]([OH:36])=[O:2])=[CH:7][CH:8]=1)=[O:32]
Reactant: CCCCCCCN(CCc1ccc(CC(OCC)C(=O)OC)cc1)C(=O)Cc1ccc(F)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCCCCN(CCc1ccc(CC(OCC)C(=O)O)cc1)C(=O)Cc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 78 h
Yield: 83.5 %

Procedure:
A solution of 3-[4-(2-{[(2,4-difluoro-phenyl)-acetyl]-heptyl-amino}-ethyl)-phenyl]-2-ethoxy-propionic acid methyl ester (35 mg, 0.07 mmol) and 1 M LiOH (0.208 mmol, 0.208 mL) in tetrahydrofuran (1 mL) was allowed to stir at room temperature for 78 hours. 2 N HCL was added until the solution had a pH<2. After dilution with twice its volume in water, the aqueous layer was extracted with diethyl ether (2×). The organic layers were combined, washed with 2M HCl (2×), dried over anhydrous sodium sulfate, and concentrated to give 3-[4-(2-{[(2,4-difluoro-phenyl)-acetyl]-heptyl-amino}-ethyl)-phenyl]-2-ethoxy-propionic acid as a clear oil (28.6 mg, 84%).
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[OH:27][C:28]([CH3:33])([CH3:32])[C:29](O)=[O:30]>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:29](=[O:30])[C:28]([OH:27])([CH3:33])[CH3:32])[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: CC(C)(O)C(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Agent: Cl
Product: CC(C)(O)C(=O)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1

Procedure:
The title compound, off-white solid (85 mg, 83%), MS (ISP) m/z=415.5 [(M+H)+], mp 163° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and 2-hydroxy-2-methyl-propionic acid.
Reaction SMILES: O=C1C2C(=CC=CC=2)N=C(C(OCC)=O)N1.[C:17]([CH2:19][C:20]1[C:28]2[C:27](=[O:29])[NH:26][C:25]([C:30]([O:32]CC)=O)=[N:24][C:23]=2[S:22][CH:21]=1)#[N:18].C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)N2C=NC(CCCOC3C=C(CN)C=CN=3)=N2)C=CC=CC=1.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:78]2[CH:82]=[N:81][C:80]([O:83][CH2:84][CH2:85][O:86][C:87]3[CH:88]=[C:89]([CH2:93][NH2:94])[CH:90]=[CH:91][CH:92]=3)=[N:79]2)C=CC=CC=1>>[C:17]([CH2:19][C:20]1[C:28]2[C:27](=[O:29])[NH:26][C:25]([C:30]([NH:94][CH2:93][C:89]3[CH:90]=[CH:91][CH:92]=[C:87]([O:86][CH2:85][CH2:84][O:83][C:80]4[N:81]=[CH:82][NH:78][N:79]=4)[CH:88]=3)=[O:32])=[N:24][C:23]=2[S:22][CH:21]=1)#[N:18]
Reactant: CCOC(=O)c1nc2scc(CC#N)c2c(=O)[nH]1
Reactant: NCc1cccc(OCCOc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Agent: CCOC(=O)c1nc2ccccc2c(=O)[nH]1
Agent: NCc1ccnc(OCCCc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Product: N#CCc1csc2nc(C(=O)NCc3cccc(OCCOc4nc[nH]n4)c3)[nH]c(=O)c12

Procedure:
By a method similar to that in Example 22, and using, instead of ethyl 4-oxo-3,4-dihydro-2-quinazolinecarboxylate, ethyl 5-cyanomethyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-2-carboxylate obtained in Reference Example 61 and using, instead of 1-[2-({3-[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]propyl}oxy)pyridin-4-yl]methaneamine, 1-{3-[(2-{[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]oxy}ethyl)oxy]phenyl}methanamine obtained in Reference Example 32, the title compound was obtained as a white powder (85.4 mg, 38%).