Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12].COC1C=C(OC)C=CC=1C1C=CC(C(O)=O)=CC=1C.[CH3:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][C:36]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CCOC(C)=O.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.O>[CH3:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][C:36]=1[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12]
Reactant: COc1ccc(OC)c(B(O)O)c1
Reactant: COC(=O)c1ccc(Br)c(C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: COc1ccc(-c2ccc(C(=O)O)cc2C)c(OC)c1
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2cc(OC)ccc2OC)c(C)c1
Temperature: 25 °C
Yield: 102 %

Procedure:
Methyl 4-bromo-3-methylbenzoate (Intermediate 17, step 1) (4 g; 17.46 mmol; 1 eq.), 2,5-dimethoxyphenylboronic acid (3.50 g; 19.21 mmol; 1.10 eq.), potassium carbonate (12.07 g; 87.31 mmol; 5 eq.), tetrakis(triphenylphosphine)palladium(0) (2.02 g; 1.75 mmol; 0.10 eq.) were taken in Toluene (20 mL) and water (20 mL) under N2 atmosphere. The reaction mixture was degassed with N2 and then refluxed for 24 hours. The reaction mixture was cooled to RT, filtered over a pad of celite and washed with toluene (200 mL). The filtrate was concentrated to afford a brown oil which was taken up in EtOAc (300 mL). The organic layer was washed with a saturated aqueous solution of NaHCO3 solution (100 mL), water (100 mL) and brine (1000 mL), dried over MgSO4 and concentrated affording methyl 2′,5′-dimethoxy-2-methylbiphenyl-4-carboxylate as a brown oil (5.1 g) used without further purification (HPLC (Method A) Rt 4.73 min (Purity: 59.7%)). A solution of methyl 2′,5′-dimethoxy-2-methylbiphenyl-4-carboxylate (4.50 g; 15.72 mmol; 1 eq.) in EtOH (135 mL) at RT was treated with sodium hydroxide (9.43 mL; 5 M; 47.15 mmol; 3 eq.). The reaction mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated to give a beige solid which was taken up in water (100 mL) and the aqueous phase was washed twice with EtOAc. The aqueous phase was acidified with HCl cc to pH 2. Then it was concentrated until precipitation (volume divided by 2). The suspension was filtered affording the title compound as a beige solid (3.43 g, 80%). 1H NMR (DMSO-d6, 300 MHz) δ 12.91 (br s, 1H), 7.85-7.78 (m, 2H), 7.27-7.24 (d, J=7.17 Hz, 1H), 7.08-6.96 (m, 2H), 6.72-6.71 (d, J=3.01 Hz, 1H), 3.76 (s, 3H), 3.68 (s, 3H), 2.14 (s, 3H). LC/MS (Method A): 270.9 (M−H)−. HPLC (Method A) Rt 3.84 min (Purity: 97.8%).
Reaction SMILES: C(O)(=O)C.[C:5]([CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]1[OH:21])(=[NH:7])[NH2:6].C[O-].[Na+].[CH2:25]([O:32][C:33](=[CH:36]N(C)C)[CH:34]=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CO>[CH2:25]([O:32][C:33]1[CH:34]=[N:7][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:10][CH:9]2[OH:21])=[N:6][CH:36]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CN(C)C=C(C=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=N)N)C(O)C1
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2ncc(OCc3ccccc3)cn2)C(O)C1
Temperature: 25 °C
Yield: 27.5 %

Procedure:
A solution of 372 mg (1 mmol) of tert-butyl (3RS,4RS)-4-carbamimidoyl-3-hydroxy-piperidine-1-carboxylate acetate in 10 ml of methanol was treated with 1 ml of 1N sodium methylate solution and stirred at room temperature. Subsequently, 205 mg (1 mmol) of 2-benzyloxy-3-dimethylamino-acrolein (EPA 0 477 901) were added thereto and the solution was heated to reflux for 18 hours. For the working-up, the reaction mixture was evaporated under reduced pressure and the residue was taken up in 20 ml of methylene chloride and washed with 5 ml of water. The organic phase was separated, dried over sodium sulphate and finally evaporated under reduced pressure. For purification, the residue was chromatographed on silica gel using a 1:4 mixture of methylene chloride and ethyl acetate as the eluent. There were obtained 106 mg (27% of theory) of tert-butyl (3RS,4RS)-4-(5-benzyloxy-pyrimidin-2-yl)-3-hydroxy-piperidine-1-carboxylate as a colourless oil; MS: 386 (M+H)+.
Reaction SMILES: [O:1]=[S:2]1(=[O:23])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:16]=[CH:15][C:10]([C:11](OC)=[O:12])=[C:9]([N:17]2[CH2:21][CH2:20][CH2:19][C:18]2=[O:22])[CH:8]=1.[CH3:24][C:25]1[C:26]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[N:27][CH:28]=[C:29]([CH3:31])[CH:30]=1>>[CH3:24][C:25]1[C:26]([N:32]2[CH2:33][CH2:34][N:35]([C:11]([C:10]3[CH:15]=[CH:16][C:7]([N:3]4[CH2:4][CH2:5][CH2:6][S:2]4(=[O:1])=[O:23])=[CH:8][C:9]=3[N:17]3[CH2:21][CH2:20][CH2:19][C:18]3=[O:22])=[O:12])[CH2:36][CH2:37]2)=[N:27][CH:28]=[C:29]([CH3:31])[CH:30]=1
Reactant: COC(=O)c1ccc(N2CCCS2(=O)=O)cc1N1CCCC1=O
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3N3CCCC3=O)CC2)c(C)c1
Yield: 2.3 %

Procedure:
Using methyl 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-2-(2-oxopyrrolidin-1-yl)benzoate (148 mg) described in Preparation Example 33 and 1-(3,5-dimethylpyridin-2-yl)piperazine (84 mg) described in Preparation Example 79 and by the reaction and treatment in the same manner as in Example 109, the title compound (5 mg) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:15](OS(C(F)(F)F)(=O)=O)=[C:10]3[CH:9]=[CH:8]2)=[CH:4][CH:3]=1.[CH2:31]([O:33][CH:34]=[CH:35][Sn](CCCC)(CCCC)CCCC)[CH3:32].C(N(CC)CC)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:34]([O:33]/[CH:31]=[CH:32]/[C:15]1[C:14]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[N:13][CH:12]=[C:11]2[N:7]([CH2:6][C:5]3[CH:29]=[CH:30][C:2]([F:1])=[CH:3][CH:4]=3)[CH:8]=[CH:9][C:10]=12)[CH3:35]
Reactant: CCCC[Sn](C=COCC)(CCCC)CCCC
Reactant: CCOC(=O)c1ncc2c(ccn2Cc2ccc(F)cc2)c1OS(=O)(=O)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCO/C=C/c1c(C(=O)OCC)ncc2c1ccn2Cc1ccc(F)cc1
Temperature: 140 °C

Procedure:
To a stirred solution of ethyl 1-(4-fluorobenzyl)-4-{[(trifluoromethyl)sulfonyl]oxy}-1H-pyrrolo[2,3-c]pyridine-5-carboxylate (10.09, 22.4 mmol) and ethoxyvinyl tributyltin [prepared according to A. Leusik, H. A. Budding, J. W. Marsman, J. Organomet. Chem., 1967, 9, 285-294] (9.7 g, 26.9 mmol, mixture of E-1,2: Z-1,2:1:1, ratio=1:0.3:0.1) in DMF (30 mL) under a nitrogen atmosphere were added triethylamine (3.2 mL, 22.4 mmol) and dichlorobis(triphenylphosphine)palladium(II) (1.0 g, 1.4 mmol). The resulting mixture was heated to 140° C. for 10 minutes. It was quenched with aq NaHCO3 solution, and extracted with ethyl acetate. The organic layer was washed with brine (2×), dried over sodium sulfate, concentrated in vacuo and purified by Biotage flash chromatography. Elution with hexane:ethyl acetate (3:2) provided the title compound as a brown glue (2.1 g) pure E-isomer together with 5.6 g of a mixture of E-1,2 and Z-1,2 and 1,1 isomers). 1H NMR (DMSO-d6) δ; 8.69 (s, 1H), 7.85 (d, J=3.3 Hz, 1H), 7.33 (t, J=6.8 Hz, 2H), 7.13-7.20 (m, 3H), 6.86 (d, J=3.3 Hz, 1 H), 6.43 (d, J=13 Hz, 1H), 5.55 (s, 2H), 4.27 (q, J=7.2 Hz, 2 H), 3.98 (q, J=7.0 Hz, 2 H), 1.29 (t, J=7.1 Hz, 6 H). LCMS (APCl, M+H+): 369.1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:34][CH2:33][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14][N:13]([CH2:22][C:23]3[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=3)[C:26]([OH:28])=[O:27])[C:12]2=[O:32])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1.[CH3:50][N:51]([CH3:55])[CH2:52][CH2:53]O>CN(C)C1C=CN=CC=1.ClCCl>[CH3:50][N:51]([CH3:55])[CH2:52][CH2:53][O:27][C:26]([C:25]1[CH:24]=[C:23]([CH:31]=[CH:30][CH:29]=1)[CH2:22][N:13]1[C:12](=[O:32])[C:11]2([CH2:33][CH2:34][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]2)[N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:14]1)=[O:28]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)N(Cc1cccc(C(=O)O)c1)CN2c1ccccc1
Reactant: CN(C)CCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CN(C)CCOC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCN(C(=O)OC(C)(C)C)CC3)C2=O)c1
Temperature: 25 °C
Reaction time: 60 h
Yield: 43.4 %

Procedure:
To a solution of 3-((8-(tert-butoxycarbonyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoic acid (0.34 g, 0.73 mmol), dicyclohexylcarbodiimide (0.18 g, 0.88 mmol) and 4-(dimethylamino)pyridine (0.011 g, 0.088 mmol) in dichloromethane (10 mL), was added N,N-dimethylethanolamine (0.065 mg, 0.73 mmol). After stirring at room temperature for 60 hours, the reaction mixture was filtered, concentrated in vacuo and isolated by preparatory TLC (10% methanol/dichloromethane) to obtain tert-butyl 3-(3-((2-(dimethylamino)ethoxy)carbonyl)benzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (0.17 g, 43%); MS for C30H40N4O5 m/z 537 (M+H)+.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[OH-].[K+].O.Cl.[C:10]([NH2:16])(=[NH:15])[CH2:11][CH:12]([CH3:14])[CH3:13]>C(Cl)Cl>[CH3:5][O:4][C:2]([NH:16][C:10](=[NH:15])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:3]
Reactant: CC(C)CC(=N)N
Reactant: COC(=O)Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: COC(=O)NC(=N)CC(C)C
Yield: 93.3 %

Procedure:
78.8 parts of methyl chloroformate and a mixture of 46.8 parts of potassium hydroxide in 215 parts of water are added via two inlets to a mixture of 113.8 parts of isovaleramidine hydrochloride in 530 parts of methylene chloride, at from 0° to 10° C., in the course of 25 minutes, while stirring. The mixture is stirred at 25° C. for 30 minutes, the phases are separated and the aqueous phase is extracted once with methylene chloride. The solvent is removed from the organic extract to give 123 parts (93.3% of theory) of N-methoxycarbonylisovaleramidine of melting point 82°-86° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=1)[C:9]([CH3:25])([CH3:24])[CH:8]2O)(=[O:4])=[O:3].C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=1)[C:9]([CH3:25])([CH3:24])[CH2:8]2)(=[O:3])=[O:4]
Reactant: CC1(C)C(O)c2cc(S(C)(=O)=O)ccc2NC1c1cccc([N+](=O)[O-])c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)Cc2cc(S(C)(=O)=O)ccc2NC1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.8 %

Procedure:
To a mixture of 6-methanesulfonyl-3,3-dimethyl-2-(3-nitro-phenyl)-1,2,3,4-tetrahydro-quinolin-4-ol (10 g, 27 mmol) and triethylsilane (20 mL) at 25° C. was added trifluoroacetic acid (10 mL) dropwise. The resulting mixture was stirred at 25° C. for 1 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×200 mL), washed with saturated aqueous sodium bicarbonate solution (2×100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. Purification on flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company) (50% ethyl acetate/hexanes) to afford 6-methanesulfonyl-3,3-dimethyl-2-(3-nitro-phenyl)-1,2,3,4-tetrahydro-quinoline (6.5 g, 16%) as a yellow solid: LC/MS m/e calcd for C18H20N2O4S (M+H)+: 361.44, observed: 360.8.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11]([C:12]2[N:20]=[C:19]3[C:15]([N:16]=[CH:17][N:18]3COCC[Si](C)(C)C)=[C:14]([NH:29][C:30]3[CH:35]=[CH:34][C:33]([N:36]4[CH2:41][CH2:40][N:39]([CH:42]5[CH2:45][O:44][CH2:43]5)[CH2:38][CH2:37]4)=[CH:32][CH:31]=3)[N:13]=2)=[CH:10][C:9]([F:46])=[CH:8][C:7]=1[N:47]1[CH2:58][CH2:57][N:56]2[C:49](=[CH:50][C:51]3[CH2:52][C:53]([CH3:60])([CH3:59])[CH2:54][C:55]=32)[C:48]1=[O:61])(=[O:3])[CH3:2].C(O)(C(F)(F)F)=O>>[C:1]([O:4][CH2:5][C:6]1[C:11]([C:12]2[N:20]=[C:19]3[C:15]([N:16]=[CH:17][NH:18]3)=[C:14]([NH:29][C:30]3[CH:35]=[CH:34][C:33]([N:36]4[CH2:37][CH2:38][N:39]([CH:42]5[CH2:43][O:44][CH2:45]5)[CH2:40][CH2:41]4)=[CH:32][CH:31]=3)[N:13]=2)=[CH:10][C:9]([F:46])=[CH:8][C:7]=1[N:47]1[CH2:58][CH2:57][N:56]2[C:49](=[CH:50][C:51]3[CH2:52][C:53]([CH3:60])([CH3:59])[CH2:54][C:55]=32)[C:48]1=[O:61])(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1c(-c2nc(Nc3ccc(N4CCN(C5COC5)CC4)cc3)c3ncn(COCC[Si](C)(C)C)c3n2)cc(F)cc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)OCc1c(-c2nc(Nc3ccc(N4CCN(C5COC5)CC4)cc3)c3nc[nH]c3n2)cc(F)cc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.9 %

Procedure:
A mixture of 123a (200 mg, 0.25 mmol) and CF3COOH (4 mL) was stirred at room temperature for 2 h. The mixture was then concentrated under reduced pressure to afford crude 123b as a yellow solid (160 mg, 90%), which was used for the next step without further purification. MS-ESI: [M+H]+ 720.4
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:18]([CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:17]3[C:12]([C:13]4[CH:27]=[CH:26][C:25]([C:28]([OH:30])=[O:29])=[CH:24][C:14]=4[CH2:15][CH2:16]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH3:31][Si:32]([CH3:37])([CH3:36])[CH2:33][CH2:34]O>>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:18]([CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23]3)[CH:17]3[C:12]([C:13]4[CH:27]=[CH:26][C:25]([C:28]([O:30][CH2:34][CH2:33][Si:32]([CH3:37])([CH3:36])[CH3:31])=[O:29])=[CH:24][C:14]=4[CH2:15][CH2:16]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: C[Si](C)(C)CCO
Reactant: N#Cc1ccc(N2N=C3c4ccc(C(=O)O)cc4CCC3C2C2CCCC2)cc1Cl
Product: C[Si](C)(C)CCOC(=O)c1ccc2c(c1)CCC1C2=NN(c2ccc(C#N)c(Cl)c2)C1C1CCCC1

Procedure:
The title compound was prepared according to Method E from (±)-(3SR,3aRS)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid, Example 15 and 2-(trimethylsilyl)ethanol. Yellow solid, 192 mg. ES-MS m/z 520 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([OH:12])[CH:7]=1)[CH3:2].F[C:15]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:16]=1[CH:17]=[O:18].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:15]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:16]=2[CH:17]=[O:18])[CH:7]=1)[CH3:2]
Reactant: Cc1ccc(F)c(C=O)c1
Reactant: CCOC(=O)Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)Cc1cccc(Oc2ccc(C)cc2C=O)c1
Temperature: 120 °C
Yield: 12.9 %

Procedure:
(3-Hydroxy phenyl)-acetic acid ethyl ester (1.0 g, 5.2 mmol), 2-fluoro-5-methylbenzaldehyde (0.72 g, 5.2 mmol), and potassium carbonate (1.44 g, 10.4 mmol) were combined in 1,4-dioxane (30 mL) and heated to 120° C. for 3 days. After work-up, the crude material was purified by silica gel chromatography (0-20% EtOAc in hexanes) to give the desired product (0.20 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:16]=[C:17]([O:19][CH3:20])[CH:18]=1)[CH2:6][N:7]1[C:11](=[O:12])[CH2:10][CH2:9][C@@H:8]1[C:13]([OH:15])=O.[NH2:21][CH:22]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH:23]([OH:27])[C:24]([NH2:26])=[O:25].O[NH-].O=[N-]>>[NH2:26][C:24](=[O:25])[C:23](=[O:27])[CH:22]([NH:21][C:13]([C@H:8]1[CH2:9][CH2:10][C:11](=[O:12])[N:7]1[CH2:6][C:5]1[CH:16]=[C:17]([O:19][CH3:20])[CH:18]=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:15])[CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: NC(=O)C(O)C(N)Cc1ccccc1
Reactant: COc1cc(CN2C(=O)CC[C@@H]2C(=O)O)cc(OC)c1
Agent: [N-]=O
Agent: [NH-]O
Product: COc1cc(CN2C(=O)CC[C@@H]2C(=O)NC(Cc2ccccc2)C(=O)C(N)=O)cc(OC)c1

Procedure:
Coupling of (R)-1-(3,5-dimethoxy-benzyl)-5-oxo-pyrrolidine-2-carboxylic acid with 3-amino-2-hydroxy-4-phenylbutanamide and oxidation of the resulting hydroxyamide intermediate to the corresponding ketoamide.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C@H:7]2[CH2:12][CH2:11][C@@H:10]([NH:13][CH3:14])[CH2:9][C@H:8]2[NH:15][C:16](=[O:18])[CH3:17])[C:3]1=[O:19].C(N(CC)CC)C.Cl[C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[C:35]([C:38]([F:41])([F:40])[F:39])[CH:36]=2)[N:31]=[CH:30][N:29]=1>ClCCl>[CH3:14][NH:13][C@H:10]1[CH2:9][C@@H:8]([NH:15][C:16](=[O:18])[CH3:17])[C@@H:7]([N:4]2[CH2:5][CH2:6][C@H:2]([NH:1][C:28]3[C:37]4[C:32](=[CH:33][CH:34]=[C:35]([C:38]([F:40])([F:41])[F:39])[CH:36]=4)[N:31]=[CH:30][N:29]=3)[C:3]2=[O:19])[CH2:12][CH2:11]1
Reactant: CN[C@@H]1CC[C@H](N2CC[C@H](N)C2=O)[C@H](NC(C)=O)C1
Reactant: FC(F)(F)c1ccc2ncnc(Cl)c2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN[C@@H]1CC[C@H](N2CC[C@H](Nc3ncnc4ccc(C(F)(F)F)cc34)C2=O)[C@H](NC(C)=O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.6 %

Procedure:
To a solution of N-((1R,2S,5R)-2-((S)-3-amino-2-oxopyrrolidin-1-yl)-5-(methylamino)cyclohexyl)acetamide (12.5 g, 46.6 mmol) in dichloromethane was added triethylamine (12.98 mL, 93 mmol) and 4-chloro-6-(trifluoromethyl)quinazoline (10.83 g, 46.6 mmol). The mixture was stirred at room temperature overnight and then concentrated under reduced pressure to dryness. The residue was dissolved in dichloromethane (350 mL) and extracted with a solution of aqueous acetic acid (1×200 mL, 1×100 mL; made from 300 mL of H2O and 16 mL of acetic acid. The acidic aqueous layer (pH 4-5) was extracted with dichloromethane (2×300 mL), basified with Na2CO3 to pH 10-11, and then extracted with dichloromethane (2×350 mL; maintained pH of aqueous layer at 10-11 with Na2CO3 as necessary). The organic phase was washed with saturated NaCl solution (1×200 mL); the NaCl layer was back-extracted with dichloromethane (1×100 mL). The organic extracts were combined, dried (Na2SO4), filtered, and concentrated in vacuo to give the title compound (19.4 g, 90%). LC/MS found [M+H]+=465. HPLC shows the purity as 99.4%, with the largest single impurity as 0.5%. 1H-NMR (500 MHz, CD3OD), δ ppm: 8.77 (1H, s), 8.56 (1H, s), 8.02 (1H, dd, J=8.80, 1.37 Hz), 7.87 (1H, d, J=8.52 Hz), 5.25 (1H, t, J=8.52 Hz), 4.53 (1H, q, J=3.94 Hz), 4.01 (1H, dt, J=11.96, 3.85, 3.71 Hz), 3.46-3.64 (2H, m), 2.77-2.86 (1H, m), 2.47-2.57 (1H, m), 2.41 (3H, s), 2.22 (1H, dq, J=12.51, 12.44, 3.57 Hz), 1.98 (3H, s), 1.95-1.98 (1H, m), 1.92-1.98 (1H, m), 1.84-1.91 (1H, m), 1.78 (1H, t, J=3.44 Hz), 1.71-1.76 (1H, m), 1.62-1.69 (1H, m).
Reaction SMILES: [CH3:1][C:2]1[C:39]([CH3:40])=[CH:38][CH:37]=[CH:36][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([N:10]1[C:19]2[C:14](=[C:15]([C:20]3[CH:21]=[N:22][N:23]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH2:33][CH2:34]O)[CH:27]=4)[CH:24]=3)[CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1)=[O:9].[C:41]([O:45][C:46]([NH:48][C:49]([NH:51][C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])=[NH:50])=[O:47])([CH3:44])([CH3:43])[CH3:42].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C(Cl)Cl>[C:55]([O:54][C:52]([NH:51][C:49](=[N:48][C:46](=[O:47])[O:45][C:41]([CH3:44])([CH3:43])[CH3:42])[NH:50][CH2:34][CH2:33][O:32][C:28]1[CH:29]=[CH:30][CH:31]=[C:26]([CH2:25][N:23]2[CH:24]=[C:20]([C:15]3[CH:16]=[CH:17][CH:18]=[C:19]4[C:14]=3[CH2:13][CH2:12][CH2:11][N:10]4[C:8](=[O:9])[CH2:7][CH2:6][CH2:5][O:4][C:3]3[CH:36]=[CH:37][CH:38]=[C:39]([CH3:40])[C:2]=3[CH3:1])[CH:21]=[N:22]2)[CH:27]=1)=[O:53])([CH3:58])([CH3:57])[CH3:56]
Reactant: Cc1cccc(OCCCC(=O)N2CCCc3c(-c4cnn(Cc5cccc(OCCO)c5)c4)cccc32)c1C
Reactant: CC(C)(C)OC(=O)NC(=N)NC(=O)OC(C)(C)C
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cccc(OCCCC(=O)N2CCCc3c(-c4cnn(Cc5cccc(OCCNC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c5)c4)cccc32)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a solution of 4-(2,3-dimethylphenoxy)-1-(5-(1-(3-(2-hydroxyethoxy)benzyl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)butan-1-one (0.02 g, 0.037 mmol), 1,3-bis(tert-butoxycarbonyl)-guanidine (0.024 g, 0.093 mmol), triphenylphosphine (0.024 g, 0.093 mmol) in DCM (0.1 mL) was added DEAD (0.040 g, 0.093 mmol, 40% wt in toluene). The reaction mixture was stirred at room temperature for 1 h and then concentrated. The resulting residue was purified by flash chromatography (0-100% ethyl acetate:hexanes) to afford the title compound (0.026 g, 90% yield) as a white powder. LCMS, [M+H]+=781.3.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:4]([NH2:12])=[CH:5][C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1.[C:13]([N:17]=[C:18]=S)([CH3:16])([CH3:15])[CH3:14]>>[C:13]([NH:17][C:18]1[N:2]([CH3:1])[C:3]2[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=2[N:12]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CNc1ccc([N+](=O)[O-])cc1N
Reactant: CC(C)(C)N=C=S
Product: Cn1c(NC(C)(C)C)nc2cc([N+](=O)[O-])ccc21

Procedure:
N1-methyl-4-nitro-benzene-1,2-diamine (2.0 g, 12.0 mmol) and tert-butyl isothiocyanate (1.67 ml, 13.2 mmol) were coupled using the procedure of intermediate example one part B to give the title compound as a yellow solid. 1H NMR (300 MHz, d6-DMSO) d 8.01 (d, J=2.1 Hz, 1H), 7.90 (dd, J=8.7 and 2.1 Hz, 1H), 7.32 (d, J=8.7 Hz, 1H), 6.41 (s, 1H), 3.58 (s, 3H), 1.48 (s, 9H) ppm.
Reaction SMILES: [C:1]1([CH:7]2[C:12](=[O:13])[CH2:11][CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([BH-](C(CC)C)C(CC)C)(CC)C.[Li+].[OH-].[Na+].OO>C1COCC1.CCOCC>[C:1]1([C@H:7]2[C@@H:12]([OH:13])[CH2:11][CH2:10][NH:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCNCC1c1ccccc1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: OO
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O[C@H]1CCNC[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 1.75 g of the free base 3-phenyl-4-piperidone of Example 50c, above, in 10 ml of dry THF is cooled to 5° C. and treated dropwise with 15 ml of lithium tri-secondarybutylborohydride in THF over a ten minute period under nitrogen. After the addition the mixture is stirred 18 hours at room temperature, then cooled to 0°-10° C. during dropwise addition of 10 ml of 10% aqueous NaOH solution. This is followed by addition of 7 ml of 30% aqueous hydrogen peroxide solution added at a rate sufficient to keep the pot temperature between 30°-40° C. The mixture is then stirred 18 hours at room temperature, followed by 1 hour of refluxing. The mixture is cooled and the phases are separated. The aqueous phase is extracted with chloroform. The combined organic phases are concentrated in vacuo to oil which is treated with 50 ml of cyclohexane and reconcentrated to an oil. This material is taken up in chloroform, and the solution is washed with saturated aqueous NaCl solution, and dried over anhydrous Na2SO4. Concentration in vacuo affords an oil which solidifies upon trituration with ether. A solid is then obtained, mp s 111°, 114°-117° C. Recrystallization from benzene affords cis-3-phenyl-4-piperidinol, mp s 115°, 117°-119° C.