Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.C1COCC1.[NH2:13][C:14]1[C:15]([S:23][CH3:24])=[N:16][C:17]([CH3:22])=[CH:18][C:19]=1[S:20][CH3:21].[Br:25][CH2:26][CH2:27][CH2:28][C:29](Cl)=[O:30]>O>[Br:25][CH2:26][CH2:27][CH2:28][C:29]([NH:13][C:14]1[C:15]([S:23][CH3:24])=[N:16][C:17]([CH3:22])=[CH:18][C:19]=1[S:20][CH3:21])=[O:30]
Reactant: O=C(Cl)CCCBr
Reactant: CSc1cc(C)nc(SC)c1N
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CSc1cc(C)nc(SC)c1NC(=O)CCCBr
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.7 %

Procedure:
Triethylamine (206 mg, 2.04 mmol) was added to a THF (6 ml) solution of 3-amino-2,4-bis(methylthio)-6-methylpyridine (341 mg, 1.70 mmol), and 4-bromobutanoyl chloride (379 mg, 2.04 mmol) was then slowly added thereto dropwise while being cooled with ice. The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water, and then extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Subsequently, the solvent was distilled off, and the resulting crude product was purified through silica gel chromatography (silica gel 75 g, eluent-hexane:acetone=5:1→3:1) to obtain 390 mg (yield 66%) of 4-bromo-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]butanamide as a colorless crystal (melting point: 139 to 140° C.).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([OH:16])[CH:13]=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].ClC(Cl)(O[C:21](=[O:27])[O:22][C:23](Cl)(Cl)Cl)Cl.N1C=CC=CC=1.[CH3:35][S:36]([C:39]1[CH:44]=[CH:43][C:42](/[C:45](=[C:48](\[C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)/[CH2:49][OH:50])/CO)=[CH:41][CH:40]=1)(=[O:38])=[O:37]>C(Cl)Cl>[C:21](=[O:27])([O:22][CH2:23]/[C:45](/[C:42]1[CH:41]=[CH:40][C:39]([S:36]([CH3:35])(=[O:38])=[O:37])=[CH:44][CH:43]=1)=[C:48](/[C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)\[CH2:49][OH:50])[O:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH:11]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(O)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CS(=O)(=O)c1ccc(/C(CO)=C(/CO)c2ccccc2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)OCc1cccc(OC(=O)OC/C(=C(\CO)c2ccccc2)c2ccc(S(C)(=O)=O)cc2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 42.8 %

Procedure:
To a solution of 3.06 g of 3-({[tert-butyl(dimethyl)silyl]oxy}methyl)phenol and 1.50 g of triphosgene in 20 mL of CH2Cl2 cooled at −78° C. was added 1.2 mL of pyridine. The reaction mixture was warmed to rt. After 15–30 min, the white suspension was transferred to a solution containing 5.95 g of (2Z)-2-[4-(methylsulfonyl)phenyl]-3-phenylbut-2-ene-1,4-diol and 1.5 mL of pyridine in 20 mL of CH2Cl2 at rt. The reaction was stirred at rt for 15 min. The reaction was quenched with aqueous 1N HCl, extracted with EtOAc and washed with brine, dried over sodium sulfate, evaporated, and purified by flash chromatography (50–70% EtOAc/hexane) to afford 1.26 g of the title compound as a yellow oil.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:12][CH:11]=2)[C:5]([C:20]#[N:21])=[C:4]([S:22][CH2:23][C:24]2[N:25]=[C:26]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[S:27][CH:28]=2)[N:3]=1.Cl.[F:37][CH2:38][CH2:39][NH2:40].C(N(CC)C(C)C)(C)C>O1CCCC1>[Cl:35][C:32]1[CH:33]=[CH:34][C:29]([C:26]2[S:27][CH:28]=[C:24]([CH2:23][S:22][C:4]3[C:5]([C:20]#[N:21])=[C:6]([C:10]4[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:14][CH:15]=4)[C:7]([C:8]#[N:9])=[C:2]([NH:40][CH2:39][CH2:38][F:37])[N:3]=3)[N:25]=2)=[CH:30][CH:31]=1
Reactant: N#Cc1c(Cl)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)cc1
Reactant: NCCF
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: N#Cc1c(NCCF)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
140 mg (0.260 mmol) of 2-chloro-6-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-4-(4-(2-hydroxyethoxy)phenyl)pyridine-3,5-dicarbonitrile (Example 2A), 52 mg (0.519 mmol) of 2-fluoroethylamine hydrochloride and 67 mg (0.519 mmol) of N,N-diisopropylethylamine were dissolved in 2 ml of tetrahydrofuran and stirred at room temperature overnight. Without further work-up, the reaction mixture was purified by preparative HPLC. 78 mg (yield: 53% of theory) of the target compound were obtained.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:8]1(=O)[CH2:11][CH2:10][CH2:9]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[CH:8]1([N:5]2[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]2)[CH2:11][CH2:10][CH2:9]1
Reactant: O=C1CCC1
Reactant: OC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: OC1CCN(C2CCC2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 66.9 %

Procedure:
4-Hydroxypiperidine (2.41 g, 23.8 mmol), cyclobutanone (5 g, 71.4 mmol) and acetic acid (1.36 ml, 23.8 mmol) were stirred in tetrahydrofuran (35 ml) at 0° C. for 1.5 hours. Sodium triacetoxyborohydride (10.1 g, 47.7 mmol) was then added at 0° C. and the reaction mixture stirred at 0° C. for 1 hour. The mixture was warmed to room temperature and stirred for 1 hour, then heated to 40° C. for 18 hours. The reaction was concentrated in vacuo. The residue was taken up in water (30 ml). The aqueous layer was basified to pH 9 with ammonia and extracted with diethyl ether (3×50 ml). The organics were combined, dried over magnesium sulphate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (100:0:0 to 93:7:0.7 by volume) to provide the title compound (2.47 g, 67%) as an oil. LRMS APCI+ m/z 156 [MH]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10](S(C)=O)[N:9]=2)=[CH:4][CH:3]=1.[NH2:17][CH:18]1[CH2:23][C:22]([CH3:25])([CH3:24])[NH:21][C:20]([CH3:27])([CH3:26])[CH2:19]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:17][CH:18]3[CH2:19][C:20]([CH3:27])([CH3:26])[NH:21][C:22]([CH3:25])([CH3:24])[CH2:23]3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: CS(=O)c1nccc(-c2ccc(Br)cc2)n1
Reactant: CC1(C)CC(N)CC(C)(C)N1
Product: CC1(C)CC(Nc2nccc(-c3ccc(Br)cc3)n2)CC(C)(C)N1

Procedure:
4-(4-Bromo-phenyl)-2-methanesulfinyl-pyrimidine (0.25 g, 0.84 mmol) and 4-amino-2,2,6,6,-tetramethylpiperidine (1 ml) were heated for 45 minutes at 130° C. Evaporation and chromatography on silicagel (EtOAc/MeOH/ammonia:95/4.5/0.5 to 90/9/1) gave the title compound as white crystals. Yield: 260 mg (78%).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[CH2:9][N:10]1[C:15](=[O:16])[C:14]([N:17]2[CH2:22][CH2:21][N:20]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-:32])=[O:31])[CH:25]=3)[C:19](=[O:33])[CH2:18]2)=[C:13]([CH3:34])[N:12]([CH2:35][C:36]2C(F)=[CH:40][CH:39]=[CH:38][C:37]=2[F:43])[C:11]1=[O:44])(C)(C)C.[F:52][C:53]([F:58])([F:57])[C:54](O)=O.C([O-])(O)=O.[Na+]>ClCCl>[NH2:7][C@H:8]([C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)[CH2:9][N:10]1[C:15](=[O:16])[C:14]([N:17]2[CH2:22][CH2:21][N:20]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-:32])=[O:31])[CH:25]=3)[C:19](=[O:33])[CH2:18]2)=[C:13]([CH3:34])[N:12]([CH2:35][C:36]2[C:54]([C:53]([F:58])([F:57])[F:52])=[CH:40][CH:39]=[CH:38][C:37]=2[F:43])[C:11]1=[O:44]
Reactant: Cc1c(N2CCN(Cc3cccc([N+](=O)[O-])c3)C(=O)C2)c(=O)n(C[C@H](NC(=O)OC(C)(C)C)c2ccccc2)c(=O)n1Cc1c(F)cccc1F
Reactant: O=C(O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1c(N2CCN(Cc3cccc([N+](=O)[O-])c3)C(=O)C2)c(=O)n(C[C@H](N)c2ccccc2)c(=O)n1Cc1c(F)cccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.3 %

Procedure:
To a solution of ((R)-2-{3-(2,6-difluoro-benzyl)-4-methyl-5-[4-(3-nitro-benzyl)-3-oxo-piperazin-1-yl]-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl}-1-phenyl-ethyl)-carbamic acid tert-butyl ester (28 mg, 0.0371 mmol) in 1 mL of dichloromethane was added trifluoroacetic acid (0.1 ml, 1.29 mmol) under ice cooling, followed by stirring at room temperature for 2 hrs. The solution was neutralized with sat. NaHCO3, extracted with dichloromethane and concentrated in a vacuum. The residue was purified by column chromatography eluting with a dichloromethane/methanol (20/1) eluent to afford 11 mg of compound 9-1 (45%). 1H NMR (300 MHz, CDCl3) δ 2.42 (3H, s), 2.81 (1H, m), 3.12 (1H, m), 3.30-3.49 (2H, m), 3.72 (1H, m), 4.02-4.22 (3H, m), 4.33 (1H, dd), 4.55 (1H, m), 4.91 (1H, m), 5.23 (2H, dd), 6.92 (2H, t), 7.20-7.37 (6H, m), 7.53 (1H, t), 7.65 (1H, d), 8.13 (1H, s), 8.15 (1H, m).
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[C:12](O)(=O)C.C=O.[H][H]>[Pd].C(OCC)(=O)C>[CH3:12][NH:4][C:3]1[C:2](=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:1]([O:10][CH3:11])=[O:9]
Reactant: [H][H]
Reactant: CC(=O)O
Reactant: COC(=O)c1ccccc1N
Agent: [Pd]
Agent: C=O
Solvent: CCOC(C)=O
Product: CNc1ccccc1C(=O)OC
Temperature: 5 °C

Procedure:
In a 2L Parr pressure reactor was placed methyl anthranilate (302 g, 2.0 mol), ethyl acetate (700 mL), glacial acetic acid (120 g, 2.0 mol), and 5% palladium on carbon catalyst (30 g). The mixture was cooled to 5° C. and 37% aqueous formaldehyde solution (160 mL, 2.12 mol) was added. The mixture was then hydrogenated at 25° C. at an initial hydrogen pressure of 50 psig with continuous stirring. After hydrogen uptake had ceased (12 h), the mixture was filtered through filter-aid. The filtrate was washed to neutrality with saturated NaHCO3 (3×300 mL) and the layers were separated. The organic layer was washed with saturated NaCl (400 mL), and dried. The solvent was evaporated at reduced pressure. The residue was distilled through a Vigreaux column (30×2 cm) to provide methyl N-methylanthranilate, b12.0 130°-132 ° C. as a colorless liquid. Yield: 300 g (91% of theor.). GLC purity: 97.3%.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]1=[O:11].[NH3:13]>CO>[OH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:2]([CH3:12])([CH3:1])[C:3]([NH2:13])=[O:11]
Reactant: N
Reactant: CC1(C)C(=O)Oc2ccccc21
Solvent: CO
Product: CC(C)(C(N)=O)c1ccccc1O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3,3-Dimethylbenzofuran-2(3H)-one (Example 198a, 19.7 g) was dissolved in 7N ammonia in methanol (50 mL) under nitrogen. The resulting solution was stirred at 25° C. for 16 h. The reaction mixture was evaporated to afford crude product. The solid was triturated with diethyl ether and filtered to give the subtitle compound (15.34 g).
Reaction SMILES: [CH:1]([NH:3][CH:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:2].[O-]CC.[Na+].C(O)C.Br[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:33]=1[N:32]=[CH:31][CH:30]=[CH:29]2>>[CH:1]([NH:3][C:4]([CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:33]=1[N:32]=[CH:31][CH:30]=[CH:29]2)([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:2]
Reactant: CCOC(=O)C(NC=O)C(=O)OCC
Reactant: BrCc1cccc2cccnc12
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(Cc1cccc2cccnc12)(NC=O)C(=O)OCC
Reaction time: 0.08 h
Yield: 57.8 %

Procedure:
Diethyl (formylamino)malonate (22.0 g, 0.108 mol) was added to a stirred solution of sodium ethoxide in ethanol (prepared from 2.4 g of sodium and 250 mL of ethanol, 0.10 mol). After 5 min, 8-(bromomethyl)quinoline (22.0 g, 0.10 mol) was added and the solution was stirred for an additional 15 minutes. The solvent was removed under reduced pressure and the product was partitioned between ethyl acetate and water. The ethyl acetate was removed and the residual oil was crystallized from ether to give 19.9 g (58%) of diethyl (formylamino)(8-quinolinylmethyl)propanedioate, mp 120°-122° C. Anal. Calcd. for C18H20N2O5 : C, 62.78; H, 5.85; N, 8.14. Found: C, 62.53; H, 6.03; N, 8.07.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:10][CH2:9][CH2:8][CH2:7][C:5]=2[N:6]=1.[Br:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>C(O)C.CCN(CC)CC>[BrH:11].[CH2:16]([O:15][C:13](=[O:14])[CH2:12][N:6]1[C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[S:3][C:2]1=[NH:1])[CH3:17]
Reactant: CCOC(=O)CBr
Reactant: Nc1nc2c(s1)CCCC2
Solvent: CCO
Solvent: CCN(CC)CC
Product: Br
Product: CCOC(=O)Cn1c2c(sc1=N)CCCC2
Yield: 79 %

Procedure:
A mixture of 2-amino-4,5,6,7-tetrahydrobenzothiazole (2.296 g, 14.9 mmol) and ethyl bromoacetate (2.747 g, 16.4 mmol) was refluxed in ethanol (50 mL) containing 3 drops of Et3N for 90 minutes. The reaction mixture was concentrated to half volume in vacuo and the resulting precipitate was filtered and rinsed with cold ethanol, then ether to give a white powder in 79% yield: mp 222-224° C.; 1H-NMR (DMSO-d6) 1.25 (t, 3H), 1.74 (d, 4H), 2.39 (s, 2H), 2.52 (m, 2H), 4.22 (q, 2H), 4.95 (s, 2H), 9.67 (s, 2H); Anal. C11H17Br1N2O2S (C, H, N); HR-MS (EI) m/z 240.0931 (M+).
Reaction SMILES: [Cl-:1].C([N:4]1[CH:8]=[C:7]2[S:9][C:10]([CH2:12][NH3+:13])=[CH:11][C:6]2=[N:5]1)C.[CH2:14](N1C2C=C(C(OC)=O)SC=2C=N1)[CH3:15].Cl.S1C2C=CN=CC=2C=C1CN>>[Cl-:1].[CH2:14]([N:5]1[C:6]2[CH:11]=[C:10]([CH2:12][NH2:13])[S:9][C:7]=2[CH:8]=[N:4]1)[CH3:15]
Reactant: CCn1ncc2sc(C(=O)OC)cc21
Reactant: CCn1cc2sc(C[NH3+])cc2n1
Agent: Cl
Agent: NCc1cc2cnccc2s1
Agent: [Cl-]
Product: CCn1ncc2sc(CN)cc21

Procedure:
Intermediate G′ was prepared from methyl 1-ethyl-1H-thieno[3,2-c]pyrazole-5-carboxylate (G′-3) following similar procedures for synthesizing intermediate D from D-2, as described above. MS (m/z): 182 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[C:3]2[O:21][CH2:20][CH2:19][C:18](=[CH:22][C:23]#[N:24])[C:4]=2[CH:5]=[C:6]2[C:10]=1[N:9]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[N:8]=[CH:7]2.[O:25]1CCOC[CH2:26]1.II.[CH3:33][OH:34]>[N+]([O-])([O-])=O.[Ag+]>[C:7](#[N:8])[CH3:6].[Br:1][C:2]1[C:3]2[O:21][CH2:20][CH2:19][C:18]([O:34][CH3:33])([O:25][CH3:26])[CH:22]([C:23]#[N:24])[C:4]=2[CH:5]=[C:6]2[C:10]=1[N:9]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[N:8]=[CH:7]2
Reactant: CO
Reactant: C1COCCO1
Reactant: N#CC=C1CCOc2c1cc1cnn(-c3ccc(F)cc3)c1c2Br
Agent: [Ag+]
Agent: II
Agent: O=[N+]([O-])[O-]
Product: CC#N
Product: COC1(OC)CCOc2c(cc3cnn(-c4ccc(F)cc4)c3c2Br)C1C#N
Temperature: 25 °C
Reaction time: 16 h
Yield: 74 %

Procedure:
Silver(I) nitrate (7.67 g, 45.1 mmol) was added to a solution of 2-(9-bromo-1-(4-fluorophenyl)-6,7-dihydropyrano[3,2-f]indazol-5 (1H)-ylidene)acetonitrile (100, R1=4-Fluorophenyl) (6.67 g, 17.4 mmol) and 1,4-dioxane (60.0 mL). MeOH (150 mL) was added. The mixture was warmed to reflux. A solution of iodine (5.74 g, 22.6 mmol) and MeOH (22.6 mL) was added over about 20 min. After about 16 h, the mixture was allowed to cool to rt. The volatiles were removed under reduced pressure. The residue was slurried in DCM (200 mL) then filtered rinsing with 10% EtOAc/DCM (6×50 mL). The volatiles were removed under reduced pressure. The residue was purified on silica gel (220 g) using a gradient of 0-50% EtOAc in DCM. The fractions containing the product and intermediate were combined and concentrated under reduced pressure. The material was dissolved in 1,4-dioxane (30 mL). Silver(I) nitrate (2.95 g, 17.4 mmol) was added. MeOH (75 mL) was added and the mixture was warmed to reflux for about 14 h. The mixture was allowed to cool to rt then the volatiles were removed under reduced pressure. The residue was slurried in DCM (100 mL) then filtered rinsing with 10% EtOAc/DCM (4×25 mL). The organics were concentrated under reduced pressure. The residue was dissolved in DCM (100 mL) then washed with water (2×100 mL). The aqueous layers were extracted with DCM (25 mL) then dried over Na2SO4, filtered and concentrated under reduced pressure to afford 10-bromo-1-(4-fluorophenyl)-6,6-dimethoxy-5,6,7,8-tetrahydro-1H-oxepino[3,2-f]indazole-5-carbonitrile acetonitrile (101, R1=4-Fluorophenyl) (5.75 g, 74% yield) as an orange solid. LC/MS, method 3, Rt=2.45 min, MS m/z 446 and 448 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.40 (s, 1H), 8.06 (s, 1H), 7.64-7.55 (m, 2H), 7.42-7.31 (m, 2H), 5.04 (d, J=1.8 Hz, 1H), 4.51-4.38 (m, 1H), 3.70-3.58 (m, 1H), 3.29 (s, 3H), 3.10 (s, 3H), 2.53-2.40 (m, 1H), 2.30-2.21 (m, 1H).
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].Cl.[CH3:13][NH:14][O:15][CH3:16].C(Cl)(=O)C(Cl)=O>N1C=CC=CC=1>[F:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:14]([O:15][CH3:16])[CH3:13])=[O:5]
Reactant: CNOC
Reactant: O=C(O)c1cccc(F)c1F
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Product: CON(C)C(=O)c1cccc(F)c1F
Yield: 93.5 %

Procedure:
Prepared according to Method A step A from 2,3-difluorobenzoic acid (4.0 g, 25 mmol), N,O-dimethylhydroxylamine hydrochloride (3.4 g, 35 mmol), oxalyl chloride (2.2 mL, 25 mmol) and 6 mL of pyridine to give the title compound (4.7 g) as an oil. Used as is in the next preparation.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([NH2:20])[CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:32]=[CH:31][C:30]=1[N+:39]([O-:41])=[O:40]>C(Cl)Cl>[CH2:1]([O:8][CH2:9][C@H:10]([NH:20][C:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:32]=[CH:31][C:30]=1[N+:39]([O-:41])=[O:40])[CH2:11][O:12][Si:13]([C:16]([CH3:17])([CH3:19])[CH3:18])([CH3:14])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H](N)COCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OC[C@H](COCc1ccccc1)Nc1c([N+](=O)[O-])cnc2ccccc12
Reaction time: 48 h
Yield: 73.7 %

Procedure:
(2S)-1-(Benzyloxy)-3-{[tert-butyl(dimethyl)silyl]oxy}propan-2-amine (1.55 g, 5.25 mmol) was dissolved in 60 mL of dry CH2Cl2. Triethylamine (1.46 mL, 10.5 mmol) and 4-chloro-3-nitroquinoline (1.09 g, 5.25 mmol) were then added and the reaction was stirred under N2 for 2 days. The reaction mixture was then concentrated and the resulting material was partitioned between 50 mL of CH2Cl2 and 50 mL of saturated NaHCO3 solution. The layers were separated and the organic portion was washed with H2O and brine. The organic portion was dried over Na2SO4, filtered and concentrated under reduced pressure. Chromatography (SiO2, 0-10% ethyl acetate/CH2Cl2) gave 1.81 g of N-[(1S)-2-(benzyloxy)-1-({[tert-butyl(dimethyl)silyl]oxy}methyl)ethyl]-3-nitroquinolin-4-amine as a yellow solid.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10]([O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH:24]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][N:37]3[CH2:41][CH2:40][CH2:39][CH2:38]3)=[CH:30][CH:29]=1)[NH:23][CH2:22][CH2:21]2)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CCN(CC)CC>C1COCC1>[CH2:10]([O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH:24]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][N:37]3[CH2:41][CH2:40][CH2:39][CH2:38]3)=[CH:30][CH:29]=1)[N:23]([C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:8])[CH2:22][CH2:21]2)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: c1ccc(COc2ccc3c(c2)CCNC3c2ccc(OCCN3CCCC3)cc2)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(c1ccccc1)N1CCc2cc(OCc3ccccc3)ccc2C1c1ccc(OCCN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 189.8 %

Procedure:
Benzoyl chloride (0.013 g, 0.09 mmol) was added to a solution of 6-benzyloxy-1-[4-(2-pyrrolidin-1-yl-ethoxy)phenyl]-1,2,3,4-tetrahydroisoquinoline (0.040 g, 0.09 mmol) and Et3N (0.026 ml, 0.19 mmol) in anhydrous THF (10 ml) at rt under N2. The resulting suspension was stirred at rt for 20 hr, then evaporated in vacuo to give 0.091 g of white solid. Purification by flash chromatography, eluting with EtOAc: MeOH (6:4) gave 0.049 g (98% yield) of white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.[C:10]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C:13]1=O)#[N:11].ClC1CCCCC1=O.[C-]#N.[K+]>C(O)(=O)C.C1(C)C=CC=CC=1.C(N(CC)CC)C>[NH2:11][C:10]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=[C:13]2[C:12]=1[CH2:17][CH2:16][CH2:15][CH2:14]2
Reactant: NNc1ccc(Cl)cc1
Reactant: N#CC1CCCCC1=O
Agent: O=C1CCCCC1Cl
Agent: [C-]#N
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: Nc1c2c(nn1-c1ccc(Cl)cc1)CCCC2
Temperature: 25 °C

Procedure:
A mixture of 3.6 parts of 4-chlorophenylhydrazine and 2.0 parts of triethylamine in 20.0 parts of toluene was stirred at room temperature for fifteen minutes. To the mixture was added 2.5 parts of 2-cyanocyclohexanone, prepared from commercial 2-chlorocyclohexanone and potassium cyanide [von R. E. Meyer, Helv. Chim. Acta., 16, 1291 (1933)], and a few drops of acetic acid. After refluxing for two hours, followed by stirring at room temperature overnight, the reaction mixture was evaporated to remove toluene and was treated with water, extracted with diethyl ether, dried over anhydrous magnesium sulfate and concentrated. Recrystallization from ethanol/water gave 2.6 parts of the compound, m.p. 140°-142°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH3:9])[CH:3]=1.C([Li])CCC.CN([CH:18]=[O:19])C>C1COCC1.C(OCC)C>[CH2:8]([C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[CH:18]=[O:19])[CH3:9]
Reactant: CN(C)C=O
Reactant: CCc1cccc(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCc1cccc(C=O)c1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 109.6 %

Procedure:
To a solution of 1-bromo-3-ethylbenzene (5 g, 27.2 mmol) in THF (135 mL) at −78° C. was added butyl lithium (1.6 M in hexanes, 18 mL, 28.8 mmol) dropwise. The mixture was stirred at −78° C. for 5 min. DMF (2.1 mL, 27.2 mmol) was added and the mixture was warmed to ambient temperature over 2 h. The mixture was diluted with diethyl ether (500 mL), washed with sat. NaHCO3 and brine, dried (Na2SO4) and concentrated to yield 4 g of Intermediate 370.1 as a clear oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.27 (t, J=7.58 Hz, 3H) 2.73 (q, J=7.58 Hz, 2H) 7.39-7.51 (m, 2H) 7.64-7.76 (m, 2H) 9.99 (s, 1H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]([F:33])([F:32])[C:8]1[CH:9]=[C:10]([CH:29]=[CH:30][CH:31]=1)[CH2:11][N:12]1[CH2:16][C@H:15]2[C@H:17]([NH:20][C:21](=[O:28])[C@H:22]([CH2:24][CH:25]([CH3:27])[CH3:26])[NH2:23])[CH2:18][CH2:19][C@H:14]2[CH2:13]1.CN[C@H:36]([C:41](N[C@@H]1[C@H]2[C@H](CN(CC3C=CC=C(C(F)(F)F)C=3)C2)CC1)=O)[CH2:37]C(C)C>>[CH2:1]([S:2]([NH:23][C@H:22]([C:21]([NH:20][C@H:17]1[C@H:15]2[C@H:14]([CH2:13][N:12]([CH2:11][C:10]3[CH:29]=[CH:30][CH:31]=[C:8]([C:7]([F:32])([F:6])[F:33])[CH:9]=3)[CH2:16]2)[CH2:19][CH2:18]1)=[O:28])[CH2:24][CH:25]([CH3:26])[CH3:27])(=[O:4])=[O:3])[CH:36]([CH3:41])[CH3:37]
Reactant: CC(C)C[C@H](N)C(=O)N[C@@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21
Reactant: CS(=O)(=O)Cl
Reactant: CN[C@@H](CC(C)C)C(=O)N[C@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21
Product: CC(C)C[C@H](NS(=O)(=O)CC(C)C)C(=O)N[C@@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21

Procedure:
The title compound was prepared by substituting 2-methylpropane-1-sulfonyl chloride for methanesulfonyl chloride and N1-{(3aS,4R,6aR)-2-[3-(trifluoromethyl)benzyl]octahydrocyclopenta[c]pyrrol-4-yl}-L-leucinamide from Example 170 Step B for N2-methyl-N1-{(3aS,4S,6aR)-2-[3-(trifluoromethyl)benzyl]octahydrocyclopenta[c]pyrrol-4-yl}-L-leucinamide in the procedure described in Example 167: 1H NMR (500 MHz, pyridine-d5) δ ppm 9.34 (d, J=9.3, 1H), 9.20 (d, J=7.4, 1H), 7.77 (s, 1H), 7.62 (d, J=7.6, 1H), 7.60-7.55 (m, 1H), 7.45 (t, J=7.7, 1H), 4.52-4.43 (m, 2H), 3.61 (d, J=13.5, 1H), 3.52 (d, J=13.6, 1H), 3.19-3.16 (m, 2H), 2.91 (dd, J=2.0, 9.0, 1H), 2.63-2.46 (m, 3H), 2.42 (dd, J=6.8, 8.9, 1H), 2.37 (dd, J=2.1, 9.0, 1H), 2.27 (dd, J=6.9, 8.8, 1H), 2.18 (td, J=5.8, 11.7, 1H), 2.01 (tt, J=6.7, 13.4, 1H), 1.96-1.85 (m, 2H), 1.73 (tdd, J=6.3, 10.3, 14.9, 2H), 1.45 (ddt, J=6.2, 9.0, 12.2, 1H), 1.08 (d, J=6.7, 3H), 1.04 (d, J=6.7, 3H), 0.81 (app t, J=7.0, 6H); MS (ESI+) m/z 518 (M+H)+.