Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](Br)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH3:10].[Mg].[CH2:13]([CH:16]1[CH2:21][CH2:20][CH:19]([CH:22]2[CH2:27][CH2:26][CH:25]([CH2:28][CH:29]=[O:30])[CH2:24][CH2:23]2)[CH2:18][CH2:17]1)[CH2:14][CH3:15].[Cl-].[NH4+]>C1COCC1>[OH:30][CH:29]([C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][CH3:10])=[C:2]([F:1])[CH:3]=1)[CH2:28][CH:25]1[CH2:26][CH2:27][CH:22]([CH:19]2[CH2:20][CH2:21][CH:16]([CH2:13][CH2:14][CH3:15])[CH2:17][CH2:18]2)[CH2:23][CH2:24]1
Reactant: CCOc1ccc(Br)cc1F
Reactant: CCCC1CCC(C2CCC(CC=O)CC2)CC1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCC1CCC(C2CCC(CC(O)c3ccc(OCC)c(F)c3)CC2)CC1
Reaction time: 2 h
Yield: 96.8 %

Procedure:
30 ml of a THF solution of 15.0 g (68.5 mmol) of 3-fluoro-4-ethoxybromobenzene was dropped under stirring to 1.8 g (75.4 mmol) of dried turnings magnesium at 40 to 60° C. Then, 100 ml of a THF solution of 22.3 g (89.1 mmol) of (4-(4-propylcyclohexyl)cyclohexyl)acetoaldehyde was dropped to the solution and stirred for 2 hours. The reaction mixture was poured into 100 ml of an aqueous saturated ammonium chloride solution and extracted with 200 ml of toluene. The organic layer was washed with 100 ml of water and then with 100 ml of aqueous saturated sodium chloride solution successively and, after drying over anhydrous magnesium sulfate, concentrated under a reduced pressure to obtain 25.9 g of crude 1-hydroxy-1-(3-fluoro-4-ethoxyphenyl)-2-(4-(4-propylcyclohexyl)cyclohexyl)ethane.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.[CH3:30][O:31][C:32](=[O:43])[C:33]1[CH:38]=[CH:37][C:36]([CH2:39]Br)=[C:35]([O:41][CH3:42])[CH:34]=1>>[CH3:30][O:31][C:32](=[O:43])[C:33]1[CH:38]=[CH:37][C:36]([CH2:39][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[C:17]4[C:12](=[C:13]([C:18]([F:21])([F:19])[F:20])[CH:14]=[CH:15][CH:16]=4)[N:11]=[CH:10][C:9]=3[C:22](=[O:23])[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:3]=2)=[C:35]([O:41][CH3:42])[CH:34]=1
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(O)c1
Product: COC(=O)c1ccc(COc2cccc(-c3c(C(=O)c4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c(OC)c1

Procedure:
The title compound was prepared from [4-(3-hydroxyphenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and 4-Bromomethyl-3-methoxy-benzoic acid methyl ester following the procedure of Example 478: mp 60-63° C.; MS (ES) m/z 571.9; HRMS: calcd for C33H24F3NO5+H+, 572.16793; found (ESI, [M+H]+), 572.1708.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:14]3=[C:15]([C:17](=[O:20])[CH:18]=[CH:19][N:13]3[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]2=3)[CH:16]=1)(=[O:3])N.N([O-])=[O:22].[Na+].O>[N+]([O-])(O)=O>[C:1]([C:4]1[CH:5]=[C:6]2[C:14]3=[C:15]([C:17](=[O:20])[CH:18]=[CH:19][N:13]3[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]2=3)[CH:16]=1)([OH:22])=[O:3]
Reactant: O=N[O-]
Reactant: NC(=O)c1cc2c(=O)ccn3c4ccccc4c(c1)c23
Agent: [Na+]
Solvent: O=[N+]([O-])O
Solvent: O
Product: O=C(O)c1cc2c(=O)ccn3c4ccccc4c(c1)c23
Temperature: 25 °C
Reaction time: 12 h
Yield: 85.4 %

Procedure:
2-carbamoyl-4H-pyrido[3,2,1-jk]carbazole-4-one (350 mg) produced in Example 174 was suspended in conc. nitric acid (13 ml), and sodium nitrite (1.84 g) was added to the suspension in an ice bath. The mixture was stirred at room temperature for 12 hours, and water was added to the reaction mixture. The crystals precipitated were recovered by filtration, and washed with methanol and ether in succession to obtain the title compound (300 mg, 85%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]([C:33]([F:36])([F:35])[F:34])=[CH:11][C:12]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[C:19]2([CH2:25][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:23]2)[O:18][CH2:17]3)=[O:13])[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].[C:37](O)(=[S:39])[CH3:38]>ClCCl.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]([C:37](=[S:39])[CH3:38])([C:33]([F:35])([F:34])[F:36])[CH2:11][C:12]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[C:19]2([CH2:25][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:30])[CH3:31])=[O:27])[CH2:23]2)[O:18][CH2:17]3)=[O:13])[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8]
Reactant: CC(C)(C)OC(=O)N1CC2(C1)OCc1cc(C(=O)C=C(c3cc(Cl)c(F)c(Cl)c3)C(F)(F)F)ccc12
Reactant: CC(O)=S
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=S)C(CC(=O)c1ccc2c(c1)COC21CN(C(=O)OC(C)(C)C)C1)(c1cc(Cl)c(F)c(Cl)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 96 h

Procedure:
The starting material, tert-butyl 5′-[3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-2-enoyl]-3′H-spiro[azetidine-3,1′-isobenzofuran]-1-carboxylate (3.0 g, 6.0 mmoL), was dissolved in dichloromethane (14 mL) and to this solution were added thioacetic acid (2.6 mL, 6.0 eq) and 2 drops of triethylamine and the resulting mixture was stirred at room temperature for 96 h under argon. Solvents were removed under reduced pressure and the crude product was purified via flash silica gel chromatography to yield 1.3 g of tert-butyl 5′-[3-(3,5-dichloro-4-fluorophenyl)-3-thioacetyl-4,4,4-trifluorobutanoyl]-3′H-spiro[azetidine-3,1′-isobenzofuran]-1-carboxylate. HNMR (400 MHz, CDCl3) δ ppm 8.01 (d, 1H, J=8.0 Hz), 7.82 (s, 1H), 7.60 (d, 1H, J=8.0 Hz), 7.45 (d, 1H, J=5.8 Hz), 5.23 (d, 1H, J=18.5 Hz), 5.17 (s, 2H), 4.35 (d, 2H, J=9.7 Hz), 4.15 (d, 2H, J=9.7 Hz), 3.97 (d, 1H, J=18.5 Hz), 2.33 (s, 3H), 1.50 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:9]=1.[NH2:23][C:24]1[C:25]([C:32](O)=[O:33])=[N:26][C:27]([Br:31])=[C:28]([F:30])[CH:29]=1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C>[NH2:23][C:24]1[C:25]([C:32]([NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20])[CH:9]=2)=[O:33])=[N:26][C:27]([Br:31])=[C:28]([F:30])[CH:29]=1
Reactant: Nc1cc(F)c(Br)nc1C(=O)O
Reactant: Cc1nc(NC(=O)OC(C)(C)C)cc(-c2ccncc2N)n1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1nc(NC(=O)OC(C)(C)C)cc(-c2ccncc2NC(=O)c2nc(Br)c(F)cc2N)n1
Yield: 15 %

Procedure:
Method 27 was followed using tert-butyl 6-(3-aminopyridin-4-yl)-2-methylpyrimidin-4-ylcarbamate (1.0 equiv.), 3-amino-6-bromo-5-fluoropicolinic acid (1.0 equiv.), EDC (1.0 equiv.), and HOAt (1.0 equiv.) in DMF yielding tert-butyl 6-(3-(3-amino-6-bromo-5-fluoropicolinamido)pyridin-4-yl)-2-methylpyrimidin-4-ylcarbamate in 15% yield. LCMS (m/z): 520.1 (MH+); LC Rt=3.4 min.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9]O)=[C:4]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[N:3]=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]([OH:28])=[O:27])=[CH:21][CH:20]=1>Cl>[NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][C:24]2[CH:23]=[C:22]([CH2:25][C:26]([OH:28])=[O:27])[CH:21]=[CH:20][C:19]=2[O:18][CH3:17])=[C:4]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[N:3]=1
Reactant: COc1ccc(CC(=O)O)cc1
Reactant: CCCCCNc1nc(N)nc(C)c1CO
Agent: Cl
Product: CCCCCNc1nc(N)nc(C)c1Cc1cc(CC(=O)O)ccc1OC

Procedure:
To the product from step (iii) (0.8 g) in 1M aq HCl (20 ml), 4-methoxyphenylacetic acid (1.8 g) was added and heated under reflux for 48 h. The solvent was evaporated and the residue purified by SCX then by RPHPLC to give the subtitle compound, 164 mg.
Reaction SMILES: [C:1]([NH:4][C@@H:5]([C:9]([OH:11])=O)[CH2:6][O:7][CH3:8])(=[O:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(OCC)(=O)C>[CH3:2][C:1]([NH:4][C@@H:5]([C:9]([NH:34][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:11])[CH2:6][O:7][CH3:8])=[O:3]
Reactant: COC[C@@H](NC(C)=O)C(=O)O
Reactant: NCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: COC[C@@H](NC(C)=O)C(=O)NCc1ccccc1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
Into a 2 L, four-necked RB flask was charged 1250 ml of ethyl acetate and 25 g of N-acetyl-O-methyl-D-serine under nitrogen atmosphere. The reaction mass was cooled to −20° C. and added 16.5 g of N-methylmorpholine. Isobutyl chloroformate (22.3 g) was slowly added to the reaction mass. After stirring for 30 min benzylamine (17.5 g) was slowly added to the reaction mass and stirred for 30 min. Temperature of the reaction mass was raised to 25-30° C. and stirred for 1 h. Reaction mass was quenched with 100 ml of 1N HCl and transferred into a separating funnel. Organic layer was washed with brine and dried over sodium sulphate. Solvent was partially distilled of from the mass under vacuum. The residue was kept under stirring and filtered the solid. The wet solid was recrystallized from ethyl acetate to get 35 g of pharma grade lacosamide. Chiral HPLC purity is >99.9% and the related impurities are <0.5%.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[N:10]([O-])=[O:11].[Na+].Cl>C(O)(=O)C.O>[N:10]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1)=[O:11]
Reactant: O=N[O-]
Reactant: c1ccc2c(c1)CCN2
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=NN1CCc2ccccc21
Yield: 42.3 %

Procedure:
To a solution of 2,3-dihydro-1H-indole (10.0 g, 84 mmol) in acetic acid (100 ml) at 0° C. was added dropwise a solution of sodium nitrite (6.08 g, 88 mmol) in water (25 ml) so that the temperature was maintained below 5° C. After 1 hour water (500 ml) and 1 M hydrochloric acid (500 ml) were added to the precipitate that formed. The mixture was stirred for another hour before the product was filtered off, washed with water (3×100 ml) and dried under vacuum to give 1-nitroso-2,3-dihydro-1H-indole as a brown solid (5.27 g). 400 MHz 1H NMR (DMSO-d6) δ: 7.8 (d, J=7.6 Hz 1H), 7.45 (d, J=7.6 Hz, 1H), 7.37 (t, J=7.6 Hz 1H), 7.29 (t, J=7.6 Hz, 1H), 4.09 (m, 2H), 3.19 (t, J=7.6 Hz, 2H); LCMS: 149 [M+H]
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])=[CH:10][C:9]=1[NH2:22])([CH3:4])([CH3:3])[CH3:2].CC1(C)[O:30][C:29]([C:31]2[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=2)[C:34]#[N:35])=[CH:28][C:27](=O)[O:26]1>>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])=[CH:10][C:9]=1[NH:22][C:27](=[O:26])[CH2:28][C:29]([C:31]1[CH:38]=[CH:37][CH:36]=[C:33]([C:34]#[N:35])[CH:32]=1)=[O:30])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2F)cc1N
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2F)cc1NC(=O)CC(=O)c1cccc(C#N)c1

Procedure:
Prepared from (3-amino-2′,4′-difluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G43) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4) according to the general procedure K. Obtained as an orange oil (95 mg).
Reaction SMILES: [CH2:1]([N:3]([CH2:13][CH3:14])[C:4]1[N:9]=[C:8]([CH:10]=O)[CH:7]=[C:6]([CH3:12])[CH:5]=1)[CH3:2].Cl.NO.[N:18]1C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>CN1C(=O)CCC1.C(Cl)Cl>[CH2:1]([N:3]([CH2:13][CH3:14])[C:4]1[N:9]=[C:8]([C:10]#[N:18])[CH:7]=[C:6]([CH3:12])[CH:5]=1)[CH3:2]
Reactant: c1ccncc1
Reactant: CCN(CC)c1cc(C)cc(C=O)n1
Agent: Cl
Agent: NO
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: CCN(CC)c1cc(C)cc(C#N)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.3 %

Procedure:
A solution of 6-diethylamino-4-methyl-pyridine-2-carbaldehyde (427 mg, 2.22 mmol) and hydroxylamine hydrochloride (232 mg, 3.33 mmol) in NMP (10 mL) is stirred at 80° C. for 3 h, then at 90° C. for 10 h under microwave irradiation. The solution is cooled to 0° C. before pyridine (1.10 g, 11.3 mmol) and trifluoromethane sulfonic anhydride (3.15 g, 11.2 mmol) is added. The mixture is warmed to rt and stirred for 18 h before it is diluted with DCM (100 mL) and washed with 10% aq. citric acid solution (50 mL) followed by sat. aq. Na2CO3 solution. The org. extract is dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 7:3 to give 6-diethylamino-4-methyl-pyridine-2-carbonitrile (329 mg) as a pale yellow solid; LC-MS: tR=1.02 min, [M+1]+=190.02. 1H NMR (CDCl3): δ 1.19 (t, J=7.0 Hz, 6H), 2.28 (s, 3H), 3.52 (q, J=7.0 Hz, 4H), 6.44 (s, 1H), 6.74 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.[C:15]([CH:17]=[C:18]1[CH2:21][CH:20]([C:22]#[N:23])[CH2:19]1)#[N:16].N12CCCN=C1CCCCC2>C(#N)C>[C:15]([CH2:17][C:18]1([N:12]2[CH:13]=[C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]3)[CH:10]=[N:11]2)[CH2:21][CH:20]([C:22]#[N:23])[CH2:19]1)#[N:16]
Reactant: N#CC=C1CC(C#N)C1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC1(C)OB(c2cnn(C3(CC#N)CC(C#N)C3)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.73 g, 0.00890 mol) in acetonitrile (22.2 mL) was added 3-(cyanomethylene)cyclobutanecarbonitrile (1.05 g, 0.00889 mol), followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (0.666 mL, 0.00445 mol). The resulting mixture was stirred at room temperature overnight, then evaporated to dryness. The mixture was purified on silica gel, eluting with 0 to 80% EtOAc in hexanes, to give the desired product as racemic mixture (320 mg, 11.5%). LCMS (M+H) 313.4.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:13]=[C:12]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[CH:22][S:23][C:16]=34)[CH:11]=[CH:10][C:5]=2[C:6]=1[C:7](Cl)=[O:8].[NH2:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][CH:29]=[CH:28]2>>[NH:30]1[C:31]2[C:27](=[CH:26][C:25]([NH:24][C:7]([C:6]3[C:5]4[CH:10]=[CH:11][C:12]([O:14][C:15]5[CH:20]=[CH:19][N:18]=[C:17]6[CH:21]=[CH:22][S:23][C:16]=56)=[CH:13][C:4]=4[O:3][C:2]=3[CH3:1])=[O:8])=[CH:33][CH:32]=2)[CH:28]=[CH:29]1
Reactant: Cc1oc2cc(Oc3ccnc4ccsc34)ccc2c1C(=O)Cl
Reactant: Nc1ccc2[nH]ccc2c1
Product: Cc1oc2cc(Oc3ccnc4ccsc34)ccc2c1C(=O)Nc1ccc2[nH]ccc2c1

Procedure:
This material was prepared from 2-methyl-6-[thieno[3,2-b]pyridin-7-yloxy]benzofuran-3-carbonyl chloride 101 and 5-aminoindole in a similar manner as that described for example 108. 1H NMR (DMSO-d6) δ11.04 (1H, s), 9.96 (1H, s), 8.52 (1H, d, J=5.6 Hz), 8.15 (1H, d, J=5.3 Hz), 7.97 (1H, s), 7.83 (1H, d, J=8.3 Hz), 7.69 (1H, d, J=2.3 Hz), 7.60 (1H, d, J=5.6 Hz), 7.36 (2H, s), 7.33 (1H, t, J=2.8 Hz), 7.27 (1H, dd, J=8.6, 2.3 Hz), 6.64 (1H, d, J=5.3 Hz), 6.41 (1H, t, J=2.5 Hz), 2.69 (3H, s).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C@@H:13]1[O:15][CH2:14]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([NH:27][C:28]([CH:30]1[NH:34][CH:33]2[CH2:35][CH2:36][CH2:37][CH:32]2[CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>C(O)C>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C@H:13]([OH:15])[CH2:14][N:34]1[CH:30]([C:28]([NH:27][C:23]([CH3:25])([CH3:26])[CH3:24])=[O:29])[CH2:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH:33]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)[C@H]1CO1)OCc1ccccc1
Reactant: CC(C)(C)NC(=O)C1CC2CCCC2N1
Solvent: CCO
Product: CC(C)(C)NC(=O)C1CC2CCCC2N1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Yield: 92.7 %

Procedure:
A solution of 2.98 g of 3(S)-(benzyloxyformamido)-1,2(S)-epoxy-4-phenylbutane and 2.1 g of N-tert.butyl-octahydro-cyclopenta[b]pyrrole-2-carboxamide in 50 ml of ethanol was heated at reflux for 10 hours and the solvent was then removed by evaporation. Chromatography on silica gel using System H for the elution then gave 4.7 g of 1-[3(S)-(benzyloxyformamido)-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-octahydro-cyclopenta[b]pyrrole-2-carboxamide as a mixture of four diastereomers: MS: m/e 508 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([N+:14]([O-])=O)=[CH:9][C:8]=2[CH2:17][OH:18])([CH3:4])([CH3:3])[CH3:2]>[Ni].CO>[NH2:14][C:10]1[CH:11]=[C:12]2[C:7](=[C:8]([CH2:17][OH:18])[CH:9]=1)[NH:6][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:13]2
Reactant: CC(C)(C)c1cc2cc([N+](=O)[O-])cc(CO)c2[nH]1
Agent: [Ni]
Solvent: CO
Product: CC(C)(C)c1cc2cc(N)cc(CO)c2[nH]1
Temperature: 25 °C
Yield: 97.3 %

Procedure:
A mixture of (2-tert-butyl-5-nitro-1H-indol-7-yl)methanol (4.0 g, 16 mmol) and Raney Nickel (400 mg) in CH3OH (100 mL) was stirred for 5 g at room temperature under H2. The catalyst was filtered off through a celite pad and the filtrate was evaporated under vacuum to give (5-amino-2-tert-butyl-1H-indol-7-yl)methanol (3.4 g, 80%). 1H NMR (CDCl3, 400 MHz) δ 8.53 (br s, 1H), 6.80 (d, J=2.0 Hz, 1H), 6.38 (d, J=1.6 Hz, 1H), 4.89 (s, 2H), 1.37 (s, 9H).
Reaction SMILES: [N:1]1([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:4][CH:3]=[N:2]1.C([BH3-])#N.[Na+]>C(O)(=O)C.CCOC(C)=O.C([O-])([O-])=O.[Na+].[Na+]>[N:1]1([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:5]([C:6]([O:8][C:9]([CH3:11])([CH3:12])[CH3:10])=[O:7])[CH2:4][CH2:3][NH:2]1
Reactant: CC(C)(C)OC(=O)C1CC=NN1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C1CCNN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 100 %

Procedure:
Di-tert-butyl 4,5-dihydropyrazole-1,5-dicarboxylate (12.65 g, 46.8 mmol) was dissolved in acetic acid (69.2 ml), and the solution was cooled in a water bath. Sodium cyanoborohydride (5.88 g, 94 mmol) was added portionwise under N2. The reaction was stirred at 25° C. for 5 hrs. The solvent was then removed under reduced pressure to give a residue. The residue was diluted with EtOAc (150 mL), and Na2CO3 (sat.) (100 mL) was cautiously added to the solution. The layers were separated and the aq. solution was extracted with EtOAc (2×30 mL), and the organics were dried over Na2SO4. The solvent was removed under reduced pressure to give the crude product di-tert-butyl pyrazolidine-1,5-dicarboxylate (12.74 g) as light yellow oil, which was used directly in the next step.
Reaction SMILES: [Br:1][CH:2]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3](Cl)=[O:4].[CH3:10][O:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([O:19][CH3:20])[C:13]=1[OH:21].C(N(CC)CC)C>ClCCl>[Br:1][CH:2]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3]([O:21][C:13]1[C:14]([O:19][CH3:20])=[CH:15][C:16]([CH3:18])=[CH:17][C:12]=1[O:11][CH3:10])=[O:4]
Reactant: COc1cc(C)cc(OC)c1O
Reactant: CC(C)CC(Br)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C)cc(OC)c1OC(=O)C(Br)CC(C)C
Reaction time: 20 h
Yield: 76.1 %

Procedure:
A solution of sodium nitrite (31.55 g) in water (70 ml) was added dropwise to a stirred solution of D-leucine (20 g) in 47% aqueous hydrobromic acid (140 ml)/water (211 ml) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 20 hours, then diluted with diethyl ether (600 ml). The organic layer was separated and washed with aqueous sodium metabisulphite (200 ml), dried over sodium sulphate, filtered and the solvent removed under reduced pressure to give 2-bromo-4-methyl-pentanoic acid as a yellow oil (27.6 g) [1H NMR (CDCl3): δ0.93 (d, 3H), 0.98 (d, 3H), 1.75-1.85 (m, 1H), 1.91-1.95 (m, 2H), 4.30 (t, 1H)]. Oxalyl chloride (9.56 ml) was added dropwise to a stirred solution of the 2-bromo-4-methylpentanoic acid (10.7 g) and pyridine (0.1 ml) in dichloromethane (60 ml). The reaction mixture was stirred for 20 hours and the solvent was removed under reduced pressure to give 2-bromo-4-methylpentanoyl chloride (12 g) [1H NMR (CDCl3); δ0.95 (d, 3H), 1.01 (d, 3H), 1.80-2.07 (m, 3H), 4.52 (t, 1H)]. A solution of this 2-bromo-4-methylpentanoyl chloride (12 g) in dichloromethane (40 ml) was added dropwise to a stirred solution of 2,6-dimethoxy-4-methylphenol (9.41 g) and triethylamine (15.6 ml) in dichloromethane (20 ml). The reaction mixture was stirred for 20 hours and was then chromatographed on silica gel, eluting with dichloromethane, to give the title compound as a viscous yellow oil (14.7 g).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:3]=1[O:4][CH:5]1[CH2:8][N:7]([C:9](Cl)=[O:10])[CH2:6]1.[OH-].[NH4+:18]>O1CCCC1.O>[Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:3]=1[O:4][CH:5]1[CH2:8][N:7]([C:9]([NH2:18])=[O:10])[CH2:6]1
Reactant: [NH4+]
Reactant: Cc1cccc(Cl)c1OC1CN(C(=O)Cl)C1
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc(Cl)c1OC1CN(C(N)=O)C1
Reaction time: 72 h
Yield: 77.6 %

Procedure:
A stirred solution of 3.9 g (0.015 mole) of 3-(2-chloro-6-methylphenoxy)-1-azetidinecarbonyl chloride in 20 mL of tetrahydrofuran was treated all at once with 2.8 mL (0.045 mole) of 57% ammonium hydroxide. After stirring for 72 h the reaction mixture was diluted with 200 mL of water and the precipitated product collected by filtration (3.6 g of pale yellow product). Recrystallization from benzene yielded 2.8 g (69.2%) of fine white crystals, mp 256°-157° C.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH:6]1[O:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7]1)=[C:2]=[S:3].[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>>[C:11]1([C:8]2[CH2:7][CH:6]([CH2:5][CH2:4][NH:1][C:2]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[S:3])[O:10][N:9]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: S=C=NCCC1CC(c2ccccc2)=NO1
Reactant: C1COCCN1
Product: S=C(NCCC1CC(c2ccccc2)=NO1)N1CCOCC1

Procedure:
One hundred mg. of the product of Example 2 was reacted with excess morpholine to produce 100 mg. of product, m.p. 128°-130° C.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([F:15])=[CH:12][CH:13]=2)[C:8]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[S:23]([N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)(=[O:25])=[O:24])=[C:7]1[CH3:32])C.[OH-].[K+].Cl>C1COCC1.O>[F:15][C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][CH:12]=1)[N:6]([CH2:5][C:4]([OH:33])=[O:3])[C:7]([CH3:32])=[C:8]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([N:26]1[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1)(=[O:24])=[O:25]
Reactant: CCOC(=O)Cn1c(C)c(Cc2ccccc2S(=O)(=O)N2CCCCC2)c2cc(F)ccc21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(Cc2ccccc2S(=O)(=O)N2CCCCC2)c2cc(F)ccc2n1CC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
To a stirred solution of 2-(5-fluoro-2-methyl-3-(2-(piperidin-1-ylsulfonyl)benzyl)-1H-indol-1-yl)acetic acid ethyl ester (1.23 g, 2.60 mmol) in THF (50 mL), was added a solution of potassium hydroxide (0.73 g, 13.0 mmol) in water (50 mL), and the resulting solution stirred at room temperature for 2 hours. Aqueous HCl (2N, 15 mL) was then added and the aqueous layer extracted with ethyl acetate (100 mL). The organic layers were washed with brine (2×50 mL), dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The solid was triturated with diethyl ether and dried in vacuo to afford 2-(5-fluoro-2-methyl-3-(2-(piperidin-1-ylsulfonyl)benzyl)-1H-indol-1-yl)acetic acid (1.09 g, 2.45 mmol, 94%).