Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:4]([N:12]=[CH:13][N:14](C)C)=[N:5][C:6]([CH2:9][CH2:10][CH3:11])=[CH:7][N:8]=1)#[N:2].[CH3:17][C:18]1[CH:19]=[CH:20][C:21]([S:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:22](N)[CH:23]=1>C(O)(=O)C>[CH3:17][C:18]1[CH:19]=[CH:20][C:21]([S:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[C:22]([NH:2][C:1]2[C:3]3[C:4](=[N:5][C:6]([CH2:9][CH2:10][CH3:11])=[CH:7][N:8]=3)[N:12]=[CH:13][N:14]=2)[CH:23]=1
Reactant: Cc1ccc(Sc2ccccc2)c(N)c1
Reactant: CCCc1cnc(C#N)c(N=CN(C)C)n1
Solvent: CC(=O)O
Product: CCCc1cnc2c(Nc3cc(C)ccc3Sc3ccccc3)ncnc2n1
Temperature: 25 °C
Yield: 27.9 %

Procedure:
A mixture of the product from Example 243A (38.2 mg, 0.176 mmol) and the product of Example 5I (41.6 mg, 0.193 mmol, 1.1 eq) in acetic acid (1 mL) was heated under reflux for 1.5 h. The reaction mixture was cooled to room temperature and the solvent evaporated under reduced pressure. The resulting residue was triturated with methanol to provide the title compound (19 mg, 28% yield) as a beige solid. 1H NMR (300 MHz, DMSO-D6) δ ppm: 0.97 (t, J=7.35 Hz, 3H), 1.76-1.90 (m, 2H), 2.42 (s, 3H), 2.94-3.05 (m, 2H), 7.08-7.28 (m, 6H), 7.55 (d, J=8.09 Hz, 1H), 8.45 (s, 1H), 8.81 (s, 1H), 8.89 (s, 1H), 10.32 (s, 1H). MS (ESI+) m/z 388.1 (M+H)+ (ESI−) m/z 386.1 (M−H)−.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:8][CH2:7][C:6]=2[CH:5]=1)([O-])=O.C(O)C.O.NN>[C].[Pd].O>[NH2:1][C:4]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:8][CH2:7][C:6]=2[CH:5]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)CCc1ccccc1-2
Agent: [Pd]
Agent: NN
Solvent: CCO
Solvent: O
Product: Nc1ccc2c(c1)CCc1ccccc1-2
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.6 %

Procedure:
First, 280 g of 2-nitro-9,10-dihydrophenanthrene, 2.0 g of palladium carbon, and 2.5 L of ethanol were loaded, and then 140 mL of hydrazine monohydrate were added to the mixture. The reaction solution was stirred for 4 hours under heating reflux. After having been cooled to room temperature, the reaction solution was poured into 5 L of water. Then, the mixture was extracted with 3 L of toluene. After the water layer had been removed, the organic layer was dried with magnesium sulfate. After magnesium sulfate had been separated by filtration, the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 220 g of a pale yellow solid were obtained (in 89% yield).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([O:16][CH3:17])[CH:10]=1>>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:11]([O:16][CH3:17])[CH:10]=1
Reactant: COc1cc(Cl)ccc1O
Reactant: CCOC(=O)CBr
Product: CCOC(=O)COc1ccc(Cl)cc1OC

Procedure:
The subtitle compound was prepared by the method of example 1 step (iv) using ethyl bromoacetate and 4-chloro-2-methoxyphenol Yield 2.7 g
Reaction SMILES: Cl[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4](=[O:12])(=[O:11])[N:3]=1.Cl.Cl.[NH2:15][CH:16]([CH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)[C:17]([NH:19][C:20]1([C:30]#[N:31])[CH2:24][CH2:23][N:22]([CH:25]([CH2:28][CH3:29])[CH2:26][CH3:27])[CH2:21]1)=[O:18]>>[C:30]([C:20]1([NH:19][C:17](=[O:18])[CH:16]([NH:15][C:2]2[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[S:4](=[O:12])(=[O:11])[N:3]=2)[CH2:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)[CH2:24][CH2:23][N:22]([CH:25]([CH2:26][CH3:27])[CH2:28][CH3:29])[CH2:21]1)#[N:31]
Reactant: O=S1(=O)N=C(Cl)c2ccccc21
Reactant: CCC(CC)N1CCC(C#N)(NC(=O)C(N)CC2CCCCC2)C1
Agent: Cl
Product: CCC(CC)N1CCC(C#N)(NC(=O)C(CC2CCCCC2)NC2=NS(=O)(=O)c3ccccc32)C1

Procedure:
The title compound was prepared starting from 3-chloro benzo [d] isothiazole 1,1-dioxide and 2-amino-N-[3-cyano-1-(1-ethyl-propyl)-pyrrolidin-3-yl]-3-cyclohexyl-propionamide bis hydrochloride salt according to the procedure from Example 81, except that the compound was further purified by HPLC using a 20×250 mm C18 reverse phase column with the method being 40% acetonitrile in water to acetonitrile. MS, m/z 500=M+1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12](=[O:14])[CH2:11][C:10](=[O:15])[CH2:9]1.[O-]CC.[Na+].Br[CH2:21][C:22](=O)[C:23]([O:25][CH2:26][CH3:27])=[O:24]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12](=[O:14])[C:11]2[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][O:15][C:10]=2[CH2:9]1
Reactant: CCOC(=O)C(=O)CBr
Reactant: O=C1CC(=O)CC(c2ccccc2Cl)C1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1coc2c1C(=O)CC(c1ccccc1Cl)C2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 5-(2-chlorophenyl)cyclohexane-1,3-dione (2.23 g) in ethanol (30 ml) was added sodium ethoxide (0.75 g), and the mixture was stirred, under argon atmosphere, at room temperature for 15 minutes. To the mixture was added ethyl bromopyruvate (1.66 ml), and the mixture was stirred, under argon atmosphere, at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and to the residue were added DMF (30 ml) and potassium carbonate (1.38 g). The mixture was stirred, under argon atmosphere, at 150° C. overnight (14 hours). The reaction solution was cooled, and to the mixture was added ice-water. The mixture was extracted with ethyl acetate. The upper layer was washed with saturated brine, dried (anhydrous magnesium sulfate), and concentrated under reduced pressure, and the residue was subjected to silica gel chromatography and eluted with ethyl acetate/hexane to give 6-(2-chlorophenyl)-3-ethoxycarbonyl-4,5,6,7-tetrahydrobenzofuran-4-one (0.14 g).
Reaction SMILES: F[C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH2:29].C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1(C)C=CC=CC=1>>[CH3:22][C:3]1[C:2]([NH:29][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=2)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:12]2[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=2)[N:4]=1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Reactant: Nc1ccccn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1Nc1ccccn1
Temperature: 22 °C
Reaction time: 1 h
Yield: 9 %

Procedure:
Prepared similarly to that described in Example 131 using 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 61 mg, 0.206 mmol), pyridin-2-amine (97 mg, 1.029 mmol, Aldrich), and KHMDS in toluene (2059 μl, 1.029 mmol) stirring at 22° C. for 1 h. Purification by silica gel (100% DCM to 8% MeOH/DCM) provided 2-(2-methyl-3-(pyridin-2-ylamino)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (9% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.80 (s, 3H) 2.85 (t, J=6.75 Hz, 2H) 3.44 (dt, J=6.85, 3.42 Hz, 2H) 5.86 (br. s., 1H) 6.99 (br. s., 1H) 7.06 (s, 1H) 7.15 (t, J=5.97 Hz, 1H) 7.53 (t, J=7.82 Hz, 1H) 7.70 (d, J=8.22 Hz, 1H) 7.78-7.83 (m, 1H) 7.86 (dd, J=7.04, 1.76 Hz, 1H) 8.02 (d, J=7.24 Hz, 1H) 8.52 (d, J=3.52 Hz, 1H) 9.32 (s, 1H). MS (ESI, pos. ion) m/z: 371.1 (M+1).
Reaction SMILES: CC1C=CC=CC=1N.[CH2:9]([O:11][C:12]1[CH:21]=[C:20]([O:22][CH:23]2[CH2:40][CH:39]3[CH:25]([C:26](=[O:46])[N:27]([CH3:45])[CH2:28][CH2:29][CH2:30][CH2:31][CH:32]=[CH:33][CH:34]4[C:36]([C:42]([OH:44])=[O:43])([NH:37][C:38]3=[O:41])[CH2:35]4)[CH2:24]2)[C:19]2[C:14](=[C:15]([CH3:49])[C:16](OC)=[CH:17][CH:18]=2)[N:13]=1)[CH3:10]>>[CH2:9]([O:11][C:12]1[CH:21]=[C:20]([O:22][CH:23]2[CH2:40][CH:39]3[CH:25]([C:26](=[O:46])[N:27]([CH3:45])[CH2:28][CH2:29][CH2:30][CH2:31][CH:32]=[CH:33][CH:34]4[C:36]([C:42]([OH:44])=[O:43])([NH:37][C:38]3=[O:41])[CH2:35]4)[CH2:24]2)[C:19]2[C:14](=[C:15]([CH3:49])[CH:16]=[CH:17][CH:18]=2)[N:13]=1)[CH3:10]
Reactant: CCOc1cc(OC2CC3C(=O)NC4(C(=O)O)CC4C=CCCCCN(C)C(=O)C3C2)c2ccc(OC)c(C)c2n1
Solvent: Cc1ccccc1N
Product: CCOc1cc(OC2CC3C(=O)NC4(C(=O)O)CC4C=CCCCCN(C)C(=O)C3C2)c2cccc(C)c2n1

Procedure:
The title compound (12) was prepared from 2-methylaniline following the procedure (Steps A-J) reported for synthesis of 17-[2-ethoxy-7-methoxy-8-methylquinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (2): m/z=536 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][O:17][CH3:18])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH2:23])([CH3:4])([CH3:3])[CH3:2].C([O:29][C:30](=O)[CH2:31][C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]2[CH:45]=[CH:44][N:43]=[C:42]([C:46]#[N:47])[CH:41]=2)[CH:35]=1)=[O:33])(C)(C)C>>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][O:17][CH3:18])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH:23][C:30](=[O:29])[CH2:31][C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]2[CH:45]=[CH:44][N:43]=[C:42]([C:46]#[N:47])[CH:41]=2)[CH:35]=1)=[O:33])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccnc(C#N)c2)c1
Reactant: COCCOc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: COCCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(C#N)c3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from [2-amino-5-(2-methoxy-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J32) (263 mg, 0.75 mmol) and 3-[3-(2-cyano-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K24) (242 mg, 0.75 mmol) according to the general procedure M. Obtained as a light yellow solid (278 mg, 61%).
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]([CH2:18][CH3:19])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1>>[CH2:18]([N:13]1[C:12]([C:33]2[CH:34]=[CH:35][C:30]([O:29][CH3:28])=[CH:31][CH:32]=2)=[C:11]2[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]2)=[N:14]1)[CH3:19]
Reactant: COc1ccc(B(O)O)cc1
Reactant: CCn1nc2c(c1OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)CC2
Product: CCn1nc2c(c1-c1ccc(OC)cc1)CCNCC2
Yield: 93.2 %

Procedure:
The title compound (134 mg) was prepared according to Example 193 using 219 mg of 2-ethyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 193, Step A) and 241 mg of 4-methoxyphenylboronic acid. MS (ESI): exact mass calculated for C16H21N3O, 271.17. found, m/z 272.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.36-7.33 (m, 2H), 7.15-7.12 (m, 2H), 4.12 (q, J=7.3 Hz, 2H), 3.88 (s, 3H), 3.49-3.47 (m, 2H), 3.36-3.34 (m, 2H), 3.28-3.25 (m, 2H), 2.88-2.85 (m, 2H), 1.35 (t, J=7.3 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[CH:15][C:14]([O:17][CH:18]3[CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19]3)=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[ClH:29].O1CCOCC1>CO>[ClH:29].[NH:20]1[CH2:21][CH:18]([O:17][C:14]2[CH:13]=[CH:12][C:11]([NH:10][C:4]3[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=[C:2]([Br:1])[CH:3]=3)=[N:16][CH:15]=2)[CH2:19]1
Reactant: Cn1cc(Br)cc(Nc2ccc(OC3CN(C(=O)OC(C)(C)C)C3)cn2)c1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cn1cc(Br)cc(Nc2ccc(OC3CNC3)cn2)c1=O
Temperature: 80 °C
Yield: 100 %

Procedure:
A mixture of 199d (1.46 g, 3.2 mmol) and HCl/1,4-dioxane (3.2 mL, 12.8 mmol, 4 M) in methanol (20 mL) was heated at 80° C. for 1 h. The mixture was concentrated under reduced pressure to give 199e (1.24 g, 99%). MS: [M+H]+ 351.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.[CH:10]([O:13][C:14]1[NH:18][N:17]=[C:16]([NH2:19])[CH:15]=1)([CH3:12])[CH3:11].C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:19][C:16]2[CH:15]=[C:14]([O:13][CH:10]([CH3:12])[CH3:11])[NH:18][N:17]=2)[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: CC(C)Oc1cc(N)n[nH]1
Reactant: Clc1ncc(Cl)c(Cl)n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)Oc1cc(Nc2nc(Cl)ncc2Cl)n[nH]1
Yield: 68.9 %

Procedure:
A solution of 2,4,5-trichloropyrimidine (533 mg, 2.93 mmol), 5-isopropoxy-1H-pyrazol-3-amine (413 mg, 2.93 mmol) and triethylamine (0.49 ml) in THF (5 ml) was stirred at room temperature for 10 hours. Solvent was removed and EtOAc was added. The solution was washed with water and dried over anhydrous sodium sulfate and was concentrated to give title compound as a white solid (582 mg, 69%). LC-MS, 246 (M-42); 1H NMR (CDCl3) δ 8.19 (s, 1H), 7.80 (s, 1H), 5.79 (s, 1H), 4.65 (m, 1H), 1.30 (d, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[C:12]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=3[F:28])[C:13]([NH2:19])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH:10]=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:29]1([S:32](Cl)(=[O:34])=[O:33])[CH2:31][CH2:30]1.O.C(OCC)(=O)C>N1C=CC=CC=1.C1CCCCC1>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[C:12]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=3[F:28])[C:13]([NH:19][S:32]([CH:29]3[CH2:31][CH2:30]3)(=[O:34])=[O:33])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH:10]=[N:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)C1CC1
Reactant: COc1cc2c(cnn2C(=O)OC(C)(C)C)c(Nc2ccc(I)cc2F)c1N
Solvent: c1ccncc1
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: COc1cc2c(cnn2C(=O)OC(C)(C)C)c(Nc2ccc(I)cc2F)c1NS(=O)(=O)C1CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.8 %

Procedure:
To a solution of 5-amino-4-(2-fluoro-4-iodo-phenylamino)-6-methoxy-indazole-1-carboxylic acid tert-butyl ester (200 mg, 0.401 mmol) in pyridine (2 mL) was added cyclopropyl sulfonyl chloride (281 mg, 2.0 mmol) and the reaction mixture stirred at room temperature for 18 hours. The reaction mixture was treated with water and extracted twice with ethyl acetate. The combined organic extracts were washed with water, dried (Na2SO4), filtered and concentrated in vacuo to give an oily residue. The residue was subjected to flash chromatography (Si—PPC, gradient 0 to 25% ethyl acetate in cyclohexane) to give the title compound as an off-white foam (217 mg, 89%). LCMS (Method B) RT=4.16 min, [M+H]+=603.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[CH:5][S:4][C:3]=1[CH:8]([OH:14])[CH2:9][NH:10][CH:11]([CH3:13])[CH3:12].[C:15](O)(=[O:19])[CH:16]([CH3:18])[OH:17]>O>[C:15]([O:14][CH:8]([C:3]1[S:4][CH:5]=[C:6]([CH3:7])[C:2]=1[CH3:1])[CH2:9][NH:10][CH:11]([CH3:12])[CH3:13])(=[O:19])[CH:16]([CH3:18])[OH:17]
Reactant: Cc1csc(C(O)CNC(C)C)c1C
Reactant: CC(O)C(=O)O
Solvent: O
Product: Cc1csc(C(CNC(C)C)OC(=O)C(C)O)c1C

Procedure:
To 1.2 g of 1-(3-methyl-4-methylthiophenyl)-2-isopropylaminoethanol in 32 ml of water, 0.53 g of a 85% aqueous lactic acid solution are added. The product is heated in a water-bath for 2 hours at 50°, then the solution is lyophilised. (1.55g of the salt obtained are soluble in 5 ml of water).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][CH2:11][CH2:12][CH2:13][C:14]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([OH:19])[CH2:15][C:16]([CH3:18])=[CH2:17])[CH3:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:33](Cl)(Cl)=[O:34].C1(C)C=CC=CC=1.[H-].[Na+]>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([N:10]2[CH2:11][CH2:12][CH2:13][C:14]([CH2:15][C:16]([CH3:18])=[CH2:17])([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[O:19][C:33]2=[O:34])[CH3:9])=[CH:6][CH:7]=1
Reactant: C=C(C)CC(O)(CCCN[C@@H](C)c1ccc(Br)cc1)c1ccccc1
Reactant: O=C(Cl)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: CC#N
Product: C=C(C)CC1(c2ccccc2)CCCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Temperature: 0 °C
Reaction time: 2 h
Yield: 42 %

Procedure:
A solution of 7-((1S)-1-(4-bromophenyl)ethylamino)-2-methyl-4-phenylhept-1-en-4-ol (111.7 mg, 0.279 mmol) in anhydrous acetonitrile (7 mL) was cooled to 0° C. Triethylamine (78 μL, 2 equiv) and 20% phosgene in toluene solution (161 μL, 1.1 equiv) were added sequentially and slowly. After stirring 2 h at 0° C., NaH (60% in mineral oil, 22 mg, 2 equiv) was added. The mixture was stirred overnight and the ice bath was allowed to melt. LC-MS showed the reaction was complete. The mixture was cooled to 0° C. again, quenched by addition of satd aq NH4Cl (2 mL), concentrated to remove the organic solvents, diluted with ether (10 mL), washed with 1% HCl (3 mL), satd aq NaHCO3 (2 mL) and brine (2 mL), and dried over Na2SO4. After filtration and concentration, the residue was purified by chromatography on a 12-g silica cartridge, eluted with a 15˜40% EtOAc in hexanes gradient, to afford 3-((1S)-1-(4-bromophenyl)ethyl)-7-(2-methylallyl)-7-phenyl-1,3-oxazepan-2-one (49.6 mg, 42%) as a mixture of two diastereomers.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1([CH3:26])[CH:10]([CH3:11])[C:9](=[N:12][OH:13])[CH2:8][C:7]([CH2:15][CH3:16])([CH3:14])[N:6]1[O:17][CH:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:19])[CH3:4].[CH3:27][N:28]([CH3:33])[CH2:29][CH2:30][CH2:31]Cl>CN(C=O)C>[CH3:27][N:28]([CH3:33])[CH2:29][CH2:30][CH2:31][O:13][N:12]=[C:9]1[CH2:8][C:7]([CH2:15][CH3:16])([CH3:14])[N:6]([O:17][CH:18]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH3:19])[C:5]([CH2:3][CH3:4])([CH3:26])[CH:10]1[CH3:11]
Reactant: CCC1(C)CC(=NO)C(C)C(C)(CC)N1OC(C)c1ccccc1
Reactant: CN(C)CCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC1(C)CC(=NOCCCN(C)C)C(C)C(C)(CC)N1OC(C)c1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 60.1 %

Procedure:
To a slurry of sodium hydride (4.36 g, 0.1 mol, 55% in mineral oil) in DMF (30 ml) is added dropwise the solution of 2,6-diethyl-2,3,6-trimethyl-1-(1-phenyl-ethoxy)-piperidine-4-one oxime (16.6 g, 0.05 mol, prepared as described in WO 02/100831 A1). The mixture is stirred 150 min at 25° C. and then 3-dimethylaminopropylchloride (9.48 g, 0.06 mol) is added during 1 h. The mixture is stirred at room temperature for 18 h, the DMF is then evaporated in vacuo. The residue is dissolved in ethyl acetate (100 ml), washed with water (2×25 ml), dried over MgSO4 and evaporated. Chromatography on silica gel column (hexane-ethylacetate 1:1) affords 12.55 g of the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([N:22]2[CH2:27][CH2:26][CH:25]([OH:28])[CH2:24][CH2:23]2)[N:9]([CH3:21])[C:10](=[O:20])[C:11]=1[O:12]CC1C=CC=CC=1)=[O:5])[CH3:2].[F:29][C:30]([F:35])([F:34])[C:31](O)=[O:32]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([N:22]2[CH2:27][CH2:26][CH:25]([O:28][C:31](=[O:32])[C:30]([F:35])([F:34])[F:29])[CH2:24][CH2:23]2)[N:9]([CH3:21])[C:10](=[O:20])[C:11]=1[OH:12])=[O:5])[CH3:2]
Reactant: O=C(O)C(F)(F)F
Reactant: CCOC(=O)c1nc(N2CCC(O)CC2)n(C)c(=O)c1OCc1ccccc1
Product: CCOC(=O)c1nc(N2CCC(OC(=O)C(F)(F)F)CC2)n(C)c(=O)c1O
Reaction time: 10 h

Procedure:
5-Benzyloxy-2-(4-hydroxypiperidin-1-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylic acid ethyl ester (0.760 g, 1.96 mmol) was treated with trifluroacetic acid (20 mL) at ambient temperature. After 10 h, the reaction mixture was concentrated and purified on silica gel column using 2–5% MeOH/CH2Cl2 to afford desired product as a brown paste (0.650 g, 84%). 1H NMR (500 MHz, CDCl3) δ: 10.02 (br s, 1H), 5.23–5.19 (m, 1H), 4.44 (q, J=7.0 Hz, 2H), 3.57 (s, 3H), 3.36–3.31 (m, 2H), 3.15–3.10 (m, 2H), 2.17–2.11 (m, 2H), 2.02–1.95 (m, 2H), 1.42 (t, J=7.0 Hz, 3H). LRMS (M+H) calcd for C15H19F3N3O6: 394.32. found: 394.09
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[C:4]([F:10])[CH:3]=1.[NH:11]1[CH:15]=[CH:14][CH:13]=[N:12]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:11]2[CH:15]=[CH:14][CH:13]=[N:12]2)=[C:4]([F:10])[CH:3]=1
Reactant: Fc1cc(Br)ccc1CBr
Reactant: c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Fc1cc(Br)ccc1Cn1cccn1
Temperature: 90 °C

Procedure:
A mixture of 4-bromo-1-(bromomethyl)-2-fluorobenzene (0.268 g, 1.0 mmol), 1H-pyrazole (0.0681 g, 1.0 mmol) and cesium carbonate (0.489 g, 1.5 mmol) in N,N-dimethylformamide (1.0 mL) was heated at 90° C. for 3 h. After cooling to RT, the mixture was diluted with EtOAc, and filtered. The filtrate was washed with water and brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue (210 mg, 82.3%) was directly used in next step without further purification. LCMS: (M+H)=256.9/254.9.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[C:28]([O:32][C:33](=[O:60])[CH:34]([NH:44][C:45]([C:47]1[CH:52]=[CH:51][C:50]([C:53]2[CH:58]=[CH:57][C:56]([NH2:59])=[CH:55][CH:54]=2)=[CH:49][CH:48]=1)=[O:46])[CH2:35][CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])([CH3:31])([CH3:30])[CH3:29].[O:61]1[C:65]2[CH:66]=[CH:67][CH:68]=[CH:69][C:64]=2[CH:63]=[C:62]1[C:70](O)=[O:71]>>[C:28]([O:32][C:33](=[O:60])[CH:34]([NH:44][C:45]([C:47]1[CH:48]=[CH:49][C:50]([C:53]2[CH:54]=[CH:55][C:56]([NH:59][C:70]([C:62]3[O:61][C:65]4[CH:66]=[CH:67][CH:68]=[CH:69][C:64]=4[CH:63]=3)=[O:71])=[CH:57][CH:58]=2)=[CH:51][CH:52]=1)=[O:46])[CH2:35][CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])([CH3:29])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)CCC(NC(=O)c1ccc(-c2ccc(N)cc2)cc1)C(=O)OC(C)(C)C
Reactant: O=C(O)c1cc2ccccc2o1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CC(C)(C)OC(=O)CCC(NC(=O)c1ccc(-c2ccc(NC(=O)c3cc4ccccc4o3)cc2)cc1)C(=O)OC(C)(C)C
Yield: 40.1 %

Procedure:
BOP coupling of 2-[(4′-Amino-biphenyl-4-carbonyl)-amino]-pentanedioic acid di-tert-butyl ester (349 mg, 0.77 mmol) with 2-Benzofuran carboxylic acid (124 mg, 0.77 mmol, 1 equiv.) was carried out according to procedures in step A of Example 6B to give 185 mg of 2-({4′-[(Benzofuran-2-carbonyl)-amino]-biphenyl-4-carbonyl}-amino)-pentanedioic acid di-tert-butyl ester in 40% yield. MS (ESI) m/z 597.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][OH:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.N1CCNCC1.C(=O)([O-])[O-].[K+].[K+].Br[CH:29]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O.CN(C=O)C>[CH:29]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][OH:15])=[CH:11][CH:12]=2)[CH2:2][CH2:3]1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: OCCc1ccc(N2CCNCC2)cc1
Reactant: BrC(c1ccccc1)c1ccccc1
Agent: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: OCCc1ccc(N2CCN(C(c3ccccc3)c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57 %

Procedure:
The product of (1) (the piperazine compound) (5.996 g, 29.1 mmol) was put in a 100 ml-three-necked flask, which was equipped with a Dimroth condenser on the central mouth and septum rubbers on the side mouths. In the flask, DMF (33 ml) was added to dissolve the content, and potassium carbonate (8.034 g, 58.1 mmol) and bromodiphenylmethane (7.543 g, 30.5 mmol) were added. The mixture was stirred at room temperature for 2 hours. The reaction mixture was added to water (80 ml) in a 200 ml-conical flask, and the mixture was extracted with diethyl ether (four times, 100 ml each time). The ether layer was washed with brine (twice, 40 ml each time), dried and distilled off under reduced pressure. The residue (10.616 g) was subjected to column chromatography [silica gel, ethyl acetate-n-hexane (1:1)] for separation and purification to give 6.188 g of the above-captioned benzhydrylpiperazine compound (Yield: 57%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([OH:19])([CH:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[OH:11])[CH:8]=[CH2:9])[CH:2]=1.OS(O)(=O)=O>COC(OC)C1C=CC=CC=1>[C:12]1([CH:10]2[O:19][C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)([CH:8]=[CH2:9])[CH:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[O:11]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C=CC(O)(c1cccnc1)C(O)c1ccccc1Cl
Agent: COC(OC)c1ccccc1
Agent: O=S(=O)(O)O
Product: C=CC1(c2cccnc2)OC(c2ccccc2)OC1c1ccccc1Cl

Procedure:
3 g (0.018 mol) of 3-(pyrid-3-yl)-4-(2-chlorophenyl)but-1-ene-3,4-diol were dissolved in 50 ml of benzaldehyde dimethyl acetal. 1 ml of concentrated H2SO4 was then added and the mixture was heated to 80°-90° C. The excess benzaldehyde dimethyl acetal was distilled off under reduced pressure, together with the resulting methanol. The crude product was dissolved in methylene chloride and the solution was neutralized with NaHCO3 solution. After the solvent had been separated off, the product was purified by chromatography.