Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C@:8]2([CH3:19])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.[Cl:21][C:22]1[C:23]([C:30](O)=[O:31])=[N:24][N:25]([CH:27]([F:29])[F:28])[CH:26]=1>>[NH2:18][C:10]1[O:11][C@H:12]([C:14]([F:16])([F:17])[F:15])[CH2:13][C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:30]([C:23]3[C:22]([Cl:21])=[CH:26][N:25]([CH:27]([F:29])[F:28])[N:24]=3)=[O:31])[CH:3]=[CH:4][C:5]=2[F:20])([CH3:19])[N:9]=1
Reactant: O=C(O)c1nn(C(F)F)cc1Cl
Reactant: C[C@@]1(c2cc(N)ccc2F)C[C@@H](C(F)(F)F)OC(N)=N1
Product: C[C@@]1(c2cc(NC(=O)c3nn(C(F)F)cc3Cl)ccc2F)C[C@@H](C(F)(F)F)OC(N)=N1

Procedure:
The coupling of (4S,6S)-4-(5-amino-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (XI-1) and 4-chloro-1-(difluoromethyl)-1H-pyrazole-3-carboxylic acid [D. Banner et al. WO2011069934 (2011)] following General Procedure F yielded the title compound as an off-white solid. MS: m/z=470.4 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH2:21]([N:23]1[CH:27]=[C:26]([NH2:28])[N:25]=[N:24]1)[CH3:22]>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:28][C:26]2[N:25]=[N:24][N:23]([CH2:21][CH3:22])[CH:27]=2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: CCn1cc(N)nn1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: CCn1cc(NC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)nn1

Procedure:
Prepared according to the procedure described for example 44 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (35 mg, 0.1 mmol) and 1-ethyltriazol-4-amine (11.0 mg, 0.12 mmol). The title compound was obtained as a solid (7.1 mg, 16% yield). MS m/z: 458.00, 460.00 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][CH2:4][O:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][O:14][CH2:15][CH3:16])[CH:9]=[CH:8][C:7]=1[O:17][CH:18]([CH3:20])[CH3:19])[CH3:2].[Li][CH2:22]CCC.CI>C1COCC1>[CH2:15]([O:14][CH2:13][O:12][C:10]1[CH:9]=[CH:8][C:7]([O:17][CH:18]([CH3:20])[CH3:19])=[C:6]([O:5][CH2:4][O:3][CH2:1][CH3:2])[C:11]=1[CH3:22])[CH3:16]
Reactant: CCOCOc1ccc(OC(C)C)c(OCOCC)c1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: CCOCOc1ccc(OC(C)C)c(OCOCC)c1C
Temperature: -78 °C
Reaction time: 1 h
Yield: 78.5 %

Procedure:
A solution of 4c (190 mg, 0.67 mmol) in anhydrous THF (530 μL) was added dropwise to a solution of nBuLi (2.5 M in hexanes, 410 μL, 1.00 mmol) in anhydrous THF (440 μL) at room temperature. After one hour, the solution was cooled to −78° C. and methyl iodide (170 μL, 2.67 mmol) was added. The resulting solution was warmed to room temperature over 12 hours, and the reaction was quenched by the addition of saturated aqueous NH4Cl. Water (5 mL) was added and the solution was extracted with CH2Cl2 (3×10 mL). Combined organic fractions were dried (Na2SO4), filtered, and concentrated. The residue was purified via column chromatography (SiO2, 6:1 Hexane:EtOAc) to afford 5c as a yellow oil (157 mg, 79%): 1H NMR (CDCl3, 500 MHz) 6.70 (d, J=9.0 Hz, 1H), 6.61 (d, J=9.0 Hz, 1H), 5.10 (s, 2H), 5.08 (s, 2H), 4.34 (quintet, J=6.1 Hz, 1H), 3.78 (q, J=7.1 Hz, 2H), 3.67 (q, J=7.1 Hz, 2H), 2.13 (s, 3H), 1.23 (d, J=6.1 Hz, 6H), 1.24-1.15 (m, 6H); 13C NMR (CDCl3, 125 MHz) δ 150.3, 146.6, 145.3, 122.7, 113.7, 110.1, 97.3, 94.0, 71.5, 65.4, 64.2, 29.4, 22.2, 15.2, 15.2, 9.9; IR (film) νmax 2924, 2853, 2359, 2339, 1591, 1483, 1113, 1057, 974 cm−1; HRMS (ESI+) m/z: [M+H]+ calcd for C16H26O5, 299.1858; found, 299.1909.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.[N:8]12[CH2:15][CH2:14][CH:11]([CH2:12][CH2:13]1)[C@@H:10]([C:16]([Cl:18])=[O:17])[CH2:9]2.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:37])[C:34]([OH:36])=[O:35])=[CH:28][CH:27]=2)=[CH:22][CH:21]=1.O1CCOCC1>CN(C=O)C>[ClH:18].[N:8]12[CH2:15][CH2:14][CH:11]([CH2:12][CH2:13]1)[C@@H:10]([C:16]([NH:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:37])[C:34]([OH:36])=[O:35])=[CH:28][CH:27]=3)=[CH:24][CH:25]=1)=[O:17])[CH2:9]2
Reactant: O=C(Cl)[C@H]1CN2CCC1CC2
Reactant: Nc1ccc(-c2ccc(NC(=O)C(=O)O)cc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: O=C(O)C(=O)Nc1ccc(-c2ccc(NC(=O)[C@H]3CN4CCC3CC4)cc2)cc1
Reaction time: 18 h

Procedure:
300 mg (2.14 mmol) of potassium carbonate are added to a mixture, prepared under argon, of 300 mg (1.43 mmol) of (3R)-quinuclidine-3-carbonyl chloride hydrochloride (Example 5A) and 180 mg (0.71 mmol) of [(4′-aminobiphenyl-4-yl)amino](oxo)acetic acid [CAS Registry No. 100872-66-0] in 11 ml of a 10:1 mixture of dioxane and DMF. After 18 h at 100° C., the reaction mixture is concentrated in vacuo, and the residue is dissolved in water and acetonitrile and purified by preparative HPLC. The concentrated product fractions are mixed with 5 ml of a 2:1 mixture of acetonitrile and 1 N hydrochloric acid and again concentrated. Drying under high vacuum results in 64 mg (20.3% of theory) of the title compound.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:18])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.[CH3:19][NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](O)=[O:27])[N:25]=1>>[Cl:17][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:26]([C:24]3[N:25]=[C:21]([NH:20][CH3:19])[S:22][CH:23]=3)=[O:27])[CH3:18])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: CNc1nc(C(=O)O)cs1
Product: CNc1nc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)cs1
Yield: 8.28 %

Procedure:
(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(methylamino)thiazole-4-carboxamide was prepared using the method of Example 34(d) starting from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.389 g, 1.343 mmol) and 2-(methylamino)thiazole-4-carboxylic acid (255 mg, 1.612 mmol). The product was purified by Flash-chromatography and triturated using diethyl ether. Yield 8.28%. 1H-NMR (400 MHz; DMSO-d6): δ 1.21 (d, 3H), 2.85 (d, 3H), 4.28-4.43 (m, 3H), 6.96 (d, 1H), 7.18 (s, 1H), 7.59 (q, 1H), 7.84 (d, 1H), 7.91 (d, 1H), 7.95-7.96 (m, 2H), 8.08 (dd, 1H).
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[O:16][C@:17]4([CH2:25][N:26]=3)[CH:22]3[CH2:23][CH2:24][N:19]([CH2:20][CH2:21]3)[CH2:18]4)[CH:9]=2)=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:35])C=1>C1COCC1>[F:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[O:16][C@:17]4([CH2:25][N:26]=3)[CH:22]3[CH2:23][CH2:24][N+:19]([O-:35])([CH2:20][CH2:21]3)[CH2:18]4)[CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Fc1ccc(-c2ccnc(NC3=NC[C@@]4(CN5CCC4CC5)O3)c2)cn1
Solvent: C1CCOC1
Product: [O-][N+]12CCC(CC1)[C@]1(CN=C(Nc3cc(-c4ccc(F)nc4)ccn3)O1)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.1 %

Procedure:
(R)—N-(6-Fluoro-3,4′-bipyridin-2′-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (0.11 g, 0.311 mmol) in THF (10 mL) was treated with m-CPBA (0.059 g, 0.342 mmol) and stirred at room temperature for 2 hours. Reaction was complete by TLC and the product was purified by chromatography (Biotage: 5-20% of 8:2 MeOH:NH4OH in CHCl3) and the pure fractions were combined to yield (S)-2-(6-fluoro-3,4′-bipyridin-2′-ylamino)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octane]1′-oxide (0.05 g, 0.134 mmol, 43.1% yield) as a yellow powder. 1H NMR (500 MHz, DMSO-d6) δ ppm 9.11 (br. s., 1H), 8.64 (br. s., 1H), 8.21-8.43 (m, 2H), 7.04-7.44 (m, 3H), 3.77 (d, J=10.1 Hz, 2H), 2.98-3.65 (m, 6H), 2.18 (br. s., 2H), 1.74-2.01 (m, 3H). LC/MS: retention time 0.78 (M+1=370.2).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:26]#[C:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:8][C:9]=1[N:10]1[C@H:15]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:14][O:13][C@H:12]([CH2:22][CH:23]=C)[C:11]1=[O:25])=[O:4].C[N+]1([O-])CC[O:36]CC1.O.I([O-])(=O)(=O)=O.[Na+]>CC(C)=O.[Os](=O)(=O)(=O)=O>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:26]#[C:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[CH:8][C:9]=1[N:10]1[C@H:15]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:14][O:13][C@H:12]([CH2:22][CH:23]=[O:36])[C:11]1=[O:25])=[O:4]
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=CC[C@H]1OC[C@@H](C2CCCCC2)N(c2cc(C#CC(C)(C)C)sc2C(=O)OC)C1=O
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N1C(=O)[C@@H](CC=O)OC[C@H]1C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.4 %

Procedure:
To a solution of 3-((2R,5R)-2-allyl-5-cyclohexyl-3-oxo-morpholin-4-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester (3.15 g, 7.10 mmol, 1.0 equiv) in acetone (40 mL) at 0° C. was added N-methylmorpholine oxide (2.51 g, 21.30 mmol, 3.0 equiv), water (14 mL) and osmium tetroxide (3.60 g, 2.5% wt in THF, 0.36 mmol, 0.05 equiv). The mixture was stirred at room temperature for 60 minutes. Acetone was removed under vacuum and the residue was partitioned between EtOAc (80 mL) and brine (15 mL). The phases were separated and the organic layer was dried (over Na2SO4) and concentrated. To the residue was added THF (40 mL) and water (14 mL). At 0° C., sodium periodate (2.28 g, 10.65 mmol, 1.5 equiv) was added to the mixture and the mixture was stirred at room temperature for 30 minutes. After cooled at 0° C., another portion of sodium periodate (0.76 g, 3.55 mmol, 0.5 equiv) was added. The mixture was stirred at room temperature for another 30 minutes. Volatile solvent was removed under vacuum and the residue was partitioned between EtOAc (100 mL) and brine (10 mL). The organic layer was separated, dried (over Na2SO4) and concentrated. The residue was purified by silica gel column chromatography (EtOAc/Heptane, 25% to 50%) to give product (2.1 g, 66%). MS: 446.3 [M−H+].
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C@H:12]2[O:16][C@@H:15]([N:17]3[CH:25]=[C:23]([CH3:24])[C:21](=[O:22])[NH:20][C:18]3=[O:19])[CH2:14][C@@H:13]2[OH:26])(=O)=O)=CC=1.[CH3:28][NH2:29].[K+].[Br-]>O>[CH3:28][NH:29][CH2:11][C@H:12]1[O:16][C@@H:15]([N:17]2[CH:25]=[C:23]([CH3:24])[C:21](=[O:22])[NH:20][C:18]2=[O:19])[CH2:14][C@@H:13]1[OH:26]
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@H]2O)cc1
Agent: [Br-]
Agent: [K+]
Solvent: O
Product: CNC[C@H]1O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@@H]1O
Reaction time: 72 h

Procedure:
5'-O-(p-toluenesulfonyl)thymidine (19.8 g, 50 mmol) was placed in a pressure vessel into which monomethylamine (250 g) was condensed. The vessel was sealed and allowed to stand at room temperature for 3 days. The vessel was cooled, opened, and the monomethylamine allowed to evaporate. The remaining contents of the vessel were removed by rinsing with water. The aqueous solution was passed through a column (6.5×20 cm) of AG50Wx8 ion-exchange resin (H+ form). The column was washed with water until the washings were neutral. The product was then eluted with 1N aqueous ammonium hydroxide. The eluent was stripped down and the resulting solid chromatographed on a column (6.5×20 cm) of silica gel with methylene chloride/methanol/concentrated aqueous ammonium hydroxide (85:13:2) as the eluting solvent. The product containing fractions were stripped down, then taken up in water and lyophilized. The product was a pale-yellow, amorphous solid (8.81 g, 69%). A satisfactory combustion analysis could not be obtained for this material.) [α]D25 (c=1.0 in water): +25.9 deg. ir (KBr): cm-1 1693, 1472, 1273, 1076. NMR (DMSO-d6): δ 1.790 (d, 3H), 2.051 (ddd, 13.4, 6.3, 3.5 hz, 1H), 2.142 (dt, 13.4, 6.9 hz, 1H), 2.314 (s, 3H), 2.658 (d, 5.5 hz, 2H), 3.775 (td, 5.3, 3.2 hz, 1H), 4.171 (dt, 6.3, 3.2 hz, 1H), 6.134 (t, 6.9 hz, 1H) and d7.639 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][CH:13]=[CH:12]3)[CH:5]=[N:4][CH:3]=1.[F:18][C:19]1[CH:24]=[C:23](B(O)O)[CH:22]=[CH:21][N:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[F:18][C:19]1[CH:24]=[C:23]([C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:10]=[C:11]4[C:15](=[CH:16][CH:17]=3)[NH:14][CH:13]=[CH:12]4)[CH:5]=[N:4][CH:3]=2)[CH:22]=[CH:21][N:20]=1
Reactant: Clc1cncc(Nc2ccc3[nH]ccc3c2)n1
Reactant: OB(O)c1ccnc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Fc1cc(-c2cncc(Nc3ccc4[nH]ccc4c3)n2)ccn1
Yield: 24 %

Procedure:
A mixture of N-(6-chloro-pyrazin-2-yl)-1H-indol-5-amine (0.05 g, 0.205 mmol), 2-fluoropyridine-4-boronic acid (0.057 g, 0.4 mmol), sodium carbonate (0.112 g, 1.025 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.012 g, 0.01 mmol) in DME:water (3:2, 3 mL) was heated at reflux for 20 h. The reaction mixture was concentrated under reduced pressure and the residue obtained was extracted with dichloromethane. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography (5% methanol in CH2Cl2 as eluent) to yield the title compound (0.015 g, 24%) as a yellow solid. 1H NMR (CD3OD) δ 8.47 (s, 1H), 8.35-8.33 (d, J=5.29 Hz, 1H), 8.16 (s, 1H), 8.01-8.00 (d, J=5.13 Hz, 1H), 7.94 (s, 1H), 7.78 (s, 1H), 7.45-7.43 (d, J=8.64 Hz, 1H), 7.35-7.33 (dd, J=10.33, 1.72 Hz, 1H), 7.29 (d, J=2.95 Hz, 1H), 6.48-6.47 (d, J=2.58 Hz, 1H); MS (API-ES/Positive); m/z: 306 (M+H)+.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=1>>[F:33][C:29]1[CH:28]=[C:27]([C:4]([C:6]2[N:7]=[CH:8][N:9]([C:11]3[CH:12]=[C:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[O:23][CH3:24])[CH:14]=[CH:15][CH:16]=3)[CH:10]=2)=[O:5])[CH:32]=[CH:31][CH:30]=1
Reactant: COc1ccccc1-c1cccc(-n2cnc(C(=O)N(C)OC)c2)c1
Reactant: Fc1cccc(Br)c1
Product: COc1ccccc1-c1cccc(-n2cnc(C(=O)c3cccc(F)c3)c2)c1

Procedure:
This compound is prepared by method C using compound 12c and 1-bromo-3-fluorobenzene
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6]2)#[N:2]>[Pd].C(O)(=O)C>[NH2:2][CH2:1][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6]2
Reactant: N#Cc1ccc2c(c1)CC(=O)N2
Agent: [Pd]
Solvent: CC(=O)O
Product: NCc1ccc2c(c1)CC(=O)N2

Procedure:
A slurry of 5-cyanooxindole (1.0 g, 6.3 mmol) and 10 palladium on carbon (0.05 g) in glacial acetic acid (50 mL) at room temperature was hydrogenated under 40 psi pressure for 24 hours. The catalyst was removed by filtration through a pad of diatomaceous earth and the solvent evaporated from the filtrate to leave an orange oil of 5-aminomethyloxindole as an acetate salt (1.16 g). 1H NMR (DMSO-d6) δ7.21 (s, 1H), 7.14 (d, 1H, J=7.6 Hz), 6.75 (d, 1H, J=7.6 Hz), 3.74 (s, 2H), 3.44 (s, 2H). MS (+ve ES) 146 (100), (M−NH2).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C@H:13]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14]1)[CH:6]=[CH:5]2.[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[C@H:13]1([NH:12][C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([N:26]4[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]4)[CH:3]=3)[N:8]=2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14]1
Reactant: CN1CCNCC1
Reactant: Brc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Product: CN1CCN(c2ccc3nc(N[C@@H]4CCc5ccccc54)ccc3c2)CC1

Procedure:
The title compound, brown oil, MS (ISP): m/e=359.3 (M+H+), was prepared in accordance with the general method of example 163, step B from (6-bromo-quinolin-2-yl)-(R)-indan-1-yl-amine (see example 163, step A) and commercially available 1-methyl-piperazine.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:3]([OH:5])=[S:4].Cl[CH2:23]CCl.S(=O)(=O)(O)O>CO>[CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:3]([O:5][CH3:23])=[S:4]
Reactant: CCCCCCCCCCCCCCCCC(C)C(O)=S
Reactant: ClCCCl
Agent: O=S(=O)(O)O
Solvent: CO
Product: CCCCCCCCCCCCCCCCC(C)C(=S)OC
Yield: 97 %

Procedure:
A 250 ml round bottom flask equipped with a magnetic stirrer and reflux condenser was charged with 50 g (0.15 mole) of alpha-methylthiostearic acid, 60 ml of 1,2-dichloroethane, and 25 ml of methanol. The resulting mixture was stirred and warmed with a heating mantle while 0.6 ml of concentrated sulfuric acid was added. It was then heated to reflux overnight. The reaction mixture was cooled, placed in a separatory funnel and washed three times with 10% aqueous sodium chloride solutions. The organic solution was dried over anhydrous magnesium sulfate and evaporated to dryness. The product was further dried under high vacuum and consisted of 50.5 g (97% yield) of methyl alpha-methylthiostearate.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:15]#[N:16])[CH:11]=2)[CH:6]=1)=[O:4].[N+:17]([O-])([O-:19])=[O:18].[K+]>S(=O)(=O)(O)O>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:15]#[N:16])[CH:11]=2)[CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2cc(C#N)ccc2c1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COC(=O)c1cc([N+](=O)[O-])c2cc(C#N)ccc2c1

Procedure:
Nitration of 6-cyano-naphthalene-2-carboxylic acid methyl ester, prepared as described in U.S. Pat. No. 6,284,796, is carried out with KNO3 in sulfuric acid at 0° C. for 30 min. The reaction mixture is poured into ice and filtered, and the compound is washed with water and dried. The product, 6-cyano-4-nitro-naphthalene-2-carboxylic acid methyl ester is obtained and used without further purification.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16]([NH:20][CH2:21][CH3:22])([C:18]#[N:19])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:23]S(O)(=O)=O>C(Cl)Cl.C(OCC)(=O)C>[CH:1]([N:14]1[CH2:17][C:16]([NH:20][CH2:21][CH3:22])([C:18]([NH2:19])=[O:23])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(O)O
Reactant: CCNC1(C#N)CN(C(c2ccccc2)c2ccccc2)C1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCNC1(C(N)=O)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A vigorously stirred solution of 1-benzhydryl-3-ethylaminoazetidine-3-carbonitrile (I-(13A-9)d; 11.7 g, 40 mmol) in methylene chloride (150 ml) cooled in an ice bath was treated with H2SO4 (22 ml, 0.4 mol), dropwise. After the reaction mixture was allowed to warm to room temperature and stir overnight, it was cooled in an ice bath and then carefully quenched with concentrated NH4OH to pH 11. The off-white solids that formed during the quench were collected by vacuum filtration. The aqueous mixture was then extracted with methylene chloride, the combined organic layers were washed with brine, dried (Na2SO4) and then concentrated, in vacuo, to afford additional solids. The combined solids were stirred for 1 hour in ethyl acetate (150 mL) and then collected by vacuum filtration to give I-(13A-9)e (9.2 g, 74%) as a solid: +ES MS (M+1) 310.2; 1H NMR (400 MHz, CD3OD) δ 7.41 (d, J=7.1 Hz, 4H), 7.25 (t, J=7.5 Hz, 4H), 7.16 (t, J=7.5 Hz, 2H), 4.49 (s, 1H), 3.44 (d, J=8.3 Hz, 2H), 3.11 (d, J=8.3 Hz, 2H), 2.47 (q, J=7.1 Hz, 2H), 1.10 (t, J=7.3 Hz, 3H).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[F:13][C:14]([F:22])([F:21])[C:15]1([C:18](O)=[O:19])[CH2:17][CH2:16]1.[CH2:23]([O:25][C:26]([CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)=[O:27])[CH3:24]>O1CCCC1>[CH2:23]([O:25][C:26]([CH:28]1[CH2:33][CH2:32][N:31]([C:18]([C:15]2([C:14]([F:22])([F:21])[F:13])[CH2:17][CH2:16]2)=[O:19])[CH2:30][CH2:29]1)=[O:27])[CH3:24]
Reactant: CCOC(=O)C1CCNCC1
Reactant: O=C(O)C1(C(F)(F)F)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCOC(=O)C1CCN(C(=O)C2(C(F)(F)F)CC2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 102.2 %

Procedure:
1,1′-Carbonyldiimidazole (77.36 g; 467.52 mmol) is added to a solution of 1-(trifluoromethyl)cyclopropanecarboxylic acid (72.04 g; 467.52 mmol) in tetrahydrofuran (600 mL) while keeping the internal temperature below 30° C. Piperidine-4-carboxylic acid ethyl ester (50 g; 311.68 mmol) is added after 10 min and the reaction is stirred under nitrogen atmosphere at room temperature for 16 h. The solvent is removed under controlled vacuum and the residue is partitioned between 2 M aqueous solution of sodium hydroxide (200 mL) and dichloromethane (300 mL). The organic layer is washed with brine (100 mL), dried over magnesium sulphate, filtered and concentrated to obtain 93.45 g of the title compound. MS (m/z) 294 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][C@@H:15]([C:29]([O:31]C)=[O:30])[NH:16][C:17]([C:19]1[N:20]([CH3:28])[C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.[OH-].[Na+].Cl>CO>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][C@@H:15]([C:29]([OH:31])=[O:30])[NH:16][C:17]([C:19]1[N:20]([CH3:28])[C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@H](CCCNC(=O)OCc1ccccc1)NC(=O)c1cc2ccccc2n1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cn1c(C(=O)N[C@@H](CCCNC(=O)OCc2ccccc2)C(=O)O)cc2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.8 %

Procedure:
To a mixture of methyl N5-[(benzyloxy)carbonyl]-N2-[(1-methyl-1H-indol-2-yl)carbonyl]-L-ornithinate (13.2 g), THF (65 ml), and methanol (65 ml) was added a 1 M aqueous sodium hydroxide solution (60 ml) under ice-cooling, followed by stirring at room temperature for 3 hours. To the reaction mixture was added 1 M hydrochloric acid (60 ml) under ice-cooling, and the solvent was removed by evaporation under reduced pressure. The residue was stirred at room temperature for 14 hours, and the solid precipitated was collected by filtration and washed with water to obtain N5-[(benzyloxy)carbonyl]-N2-[(1-methyl -1H-indol-2-yl)carbonyl]-L-ornithine (11.6 g).