Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8](=[O:15])[C:9]([N:12]=[N+]=[N-])([CH3:11])[CH3:10])[CH2:4][CH2:3]1.[H][H].[C:18]([O-:23])(=[O:22])[C:19]([O-:21])=[O:20]>[Ni].CO>[C:18]([OH:23])(=[O:22])[C:19]([OH:21])=[O:20].[OH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8](=[O:15])[C:9]([NH2:12])([CH3:10])[CH3:11])[CH2:6][CH2:7]1
Reactant: [H][H]
Reactant: O=C([O-])C(=O)[O-]
Reactant: CC(C)(N=[N+]=[N-])C(=O)N1CCC(O)CC1
Agent: [Ni]
Solvent: CO
Product: CC(C)(N)C(=O)N1CCC(O)CC1
Product: O=C(O)C(=O)O
Yield: 74 %

Procedure:
3.8 g. (18 mmole) 2-Azido-2-methylpropionic acid 4-hydroxypiperidide are dissolved in 10 ml. methanol and hydrogenated over Raney nickel at ambient temperature and 1 bar hydrogen pressure. After filtering off with suction and evaporation of the filtrate, the residue is reacted in ethanol with oxalic acid. There are obtained 3.0 g. of the oxalate of the title compound; m.p. 197° C. Yield 74% of theory.
Reaction SMILES: [N:1]1([CH:7]2[CH2:16][CH2:15][C:14]3[CH:13]=[C:12]([C:17]#[N:18])[CH:11]=[CH:10][C:9]=3[CH2:8]2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1.CCN(C(C)C)C(C)C.[OH-].[Na+]>CN(C=O)C.C(Cl)Cl>[N+:28]([C:25]1[CH:26]=[CH:27][C:22]([CH2:21][CH2:20][N:4]2[CH2:3][CH2:2][N:1]([CH:7]3[CH2:16][CH2:15][C:14]4[CH:13]=[C:12]([C:17]#[N:18])[CH:11]=[CH:10][C:9]=4[CH2:8]3)[CH2:6][CH2:5]2)=[CH:23][CH:24]=1)([O-:30])=[O:29]
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Reactant: N#Cc1ccc2c(c1)CCC(N1CCNCC1)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: N#Cc1ccc2c(c1)CCC(N1CCN(CCc3ccc([N+](=O)[O-])cc3)CC1)C2
Temperature: 60 °C
Reaction time: 21 h

Procedure:
A mixture of 6-piperazin-1-yl-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (generated from treateding tert-Butyl 4-(6-cyano-1,2,3,4-tetrahydronaphthalen-2-yl) piperazine-1-carboxylate (110 mg, 0.32 mmol) with trifluoroacetic acid (2 ml, 26 mmol) at RT), 1-(2-bromoethyl)-4-nitrobenzene (47 mg, 0.21 mmol), and Hunig's Base (0.054 ml, 0.31 mmol in 1 ml DMF was stirred at 60° C. for 21 hours. The reaction was shaken with 1 ml 1 N NaOH and 1 mL DCM. The organic layer was separated and evaporated to dryness. The residue was purified by mass directed HPLC to yield 6-{4-[2-(4-nitrophenyl)ethyl]piperazin-1yl}-5,6,7,8-tetrahydronaphthalene-2-carbonitrile. LC-MS (IE, m/z): 391 [M+1]+. (0.050 μM)
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([F:12])[C:9]([N+:13]([O-])=O)=[CH:8][C:3]=1[NH:4][C:5](=[O:7])[CH3:6]>[Pt].O1CCCC1.C(OCC)(=O)C.C(O)C>[NH2:13][C:9]1[C:10]([F:12])=[CH:11][C:2]([Cl:1])=[C:3]([CH:8]=1)[NH:4][C:5](=[O:7])[CH3:6]
Reactant: CC(=O)Nc1cc([N+](=O)[O-])c(F)cc1Cl
Agent: [Pt]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCO
Product: CC(=O)Nc1cc(N)c(F)cc1Cl
Reaction time: 22 h

Procedure:
A mixture of 2′-chloro-4′-fluoro-5′-nitroacetanilide (26.1 g, 112 mmol) and 5% platinum on carbon (7.8 g, 30 wt %) in a tetrahydrofuran/ethyl acetate/ethanol solution (1:1:1) is hydrogenated at 50 psi for 22 hours and filtered. The resultant filtrate is concentrated in vacuo to obtain a solid which is recrystallized from an ethanol/water solution to give the title product as off-white plates (14.5 g, mp 176-178° C.).
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][N:6]([CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:7](=[O:19])[CH2:8][CH2:9][O:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)C.Cl.ClCCl>O1CCOCC1>[O:3]=[CH:4][CH2:5][N:6]([CH2:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:7](=[O:19])[CH2:8][CH2:9][O:10][CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(CN(CCc1ccccc1)C(=O)CCOCCc1ccccc1)OCC
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=CCN(CCc1ccccc1)C(=O)CCOCCc1ccccc1

Procedure:
N-(2,2-Diethyloxyethyl)-N-phenethyl-3-phenethyloxy-propanamide (Example 3a), 0.23 g) was dissolved in dioxane (5 mL) and treated with concentrated hydrochloric acid (1.5 mL) at ambient temperature. The resultant solution was stirred at ambient temperature for 2.5 hours. The reaction mixture was then poured into dichloromethane (20 mL) and washed with water (2×20 mL) and brine (20 mL). The organic layer was isolated, dried over anhydrous magnesium sulphate, filtered and concentrated to give the sub-titled compound (0.13 g) as a viscous oil.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20](F)=[CH:19][C:18]=3[C:24]([F:27])([F:26])[F:25])(=[O:16])=[O:15])[CH2:11][N:10]2[C:28]2[N:29]([CH:34]3[CH2:37][CH2:36][CH2:35]3)[N:30]=[C:31]([CH3:33])[CH:32]=2)=[O:8])[CH2:5][CH2:4]1)#[N:2].Cl.[F:39][C:40]1([F:44])[CH2:43][NH:42][CH2:41]1>C(#N)C>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([N:42]4[CH2:43][C:40]([F:44])([F:39])[CH2:41]4)=[CH:19][C:18]=3[C:24]([F:25])([F:27])[F:26])(=[O:16])=[O:15])[CH2:11][N:10]2[C:28]2[N:29]([CH:34]3[CH2:35][CH2:36][CH2:37]3)[N:30]=[C:31]([CH3:33])[CH:32]=2)=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: Cc1cc(N2C[C@H](S(=O)(=O)c3ccc(F)cc3C(F)(F)F)C[C@H]2C(=O)NC2(C#N)CC2)n(C2CCC2)n1
Reactant: FC1(F)CNC1
Agent: Cl
Solvent: CC#N
Product: Cc1cc(N2C[C@H](S(=O)(=O)c3ccc(N4CC(F)(F)C4)cc3C(F)(F)F)C[C@H]2C(=O)NC2(C#N)CC2)n(C2CCC2)n1

Procedure:
In analogy to the procedure described in example 389, (2S,4R)-1-(2-cyclobutyl-5-methyl-2H-pyrazol-3-yl)-4-(4-fluoro-2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide (example 388 g) was reacted with 3,3-difluoroazetidine hydrochloride (CAS Reg. No. 288315-03-7) in acetonitrile at 90° C. for 48 h to give the title compound as colorless oil. MS (ESI): m/z=613.1 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1.[H-].[Na+].I[CH3:12].O>O1CCCC1>[CH3:12][O:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: CI
Reactant: OCc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCc1cccnc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3-hydroxymethylpyridine (10 g, 92 mmol) in anhydrous tetrahydrofuran (200 ml), under an atmosphere of nitrogen, was treated with sodium hydride (4 g of a 55% oil dispersion, 92 mmol) in portions. After stirring for 15 minutes iodomethane (5.7 ml, 92 mmol) was added dropwise and the reaction mixture was stirred at ambient temperature for 2 hours. Water (20 ml) was added and the tetrahydrofuran evaporated. The residue was partitioned between water (50 ml) and dichloromethane (70 ml). The organic layer was separated, dried (sodium sulphate) then evaporated. The crude product was purified by column chromatography on silica using ethyl acetate. The title compound was obtained (11 g, 93%) as an oil, δH (250 MHz, CDCl3) 3.42 (3H, s), 4.48 (2H, s), 7.27-7.32 (1H, m), 7.66-7.71 (1H, m), 8.53-8.60 (2H, m).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][C:11]2=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].[BH4-].[Na+].C[OH:18]>>[N+:1]([CH:4]1[CH2:5][CH2:6][C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:13]1=[O:18])([O-:3])=[O:2].[C:11]1(=[O:14])[C:12]2[C:7](=[CH:6][CH:5]=[CH:4][CH:13]=2)[CH2:8][CH2:9][CH2:10]1
Reactant: O=C1CCCc2ccc([N+](=O)[O-])cc21
Reactant: CO
Agent: [BH4-]
Agent: [Na+]
Product: O=C1CCCc2ccccc21
Product: O=C1c2ccccc2CCC1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
A suspension of 7-nitro-1-tetralone (10.14 g, 0.053 mol) in MeOH (600 ml) was cooled to 0° C. and treated with NaBH4 (4.25 g, 0.11 mol. 2.1 equiv.). A nitrotetralone can be obtained by nitration of a 1-tetralone, the desired product being separated from minor component byproducts. The reaction mixture became homogeneous almost immediately. After stirring at 0° C. for 30 min. 2N HCl (100 ml) was added and stirring was continued for an additional 30 min. The reaction mixture was concentrated under reduced pressure (approx. 150 ml) and diluted with CH2Cl2 (200 ml) and H2O (100 ml). The aqueous layer was separated and extracted with additional CH2Cl2 (2×100 ml). The combined organic layers were washed with brine (100 ml), dried (Na2SO4), filtered and concentrated under reduced pressure to 7-nitro-1,2,3,4-tetrahydo-2-naphthalenol as a white solid (10.13 g, 99%) which was used in the next step without further purification. Rf (silica gel): 0.50 (40% hexane: 40% CH2Cl2: 20% EtOAc); 1H NMR (300 MHZ, CDCl3) 8.29 (d,J=2.1 Hz, 1H), 7.97(dd,J=2.1 and 8.1 Hz, 1H), 7.21 (d, J=8.1 Hz, 1H), 4.80-4.77 (m, 1H), 2.94-2.73 (m, 2H), 2.47 (d, J=6.0 Hz, 1H), 2.12-1.93 (m, 2H), 1.90-1.74 (m, 2H); 13C NMR (75 MHZ, CDCl3) 146.5, 145.1, 140.6, 129.9, 123.6, 122.2, 67.8, 31.9, 29.3, 18.6.
Reaction SMILES: [CH2:1]([CH:4]([C:10]([CH3:12])=O)[C:5]([O:7]CC)=O)[CH2:2][CH3:3].[F:13][C:14]([F:19])([F:18])[C:15]([NH2:17])=[NH:16].[O-][CH2:21]C.[Na+]>C(O)C>[OH:7][C:5]1[C:4]([CH2:10][CH2:12][CH3:21])=[C:1]([CH2:2][CH3:3])[N:17]=[C:15]([C:14]([F:19])([F:18])[F:13])[N:16]=1
Reactant: CCCC(C(C)=O)C(=O)OCC
Reactant: N=C(N)C(F)(F)F
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCc1c(O)nc(C(F)(F)F)nc1CC

Procedure:
A mixture of ethyl 2-n-propylacetoacetate (0.5 mole), trifluoroacetamidine (0.67 mole) and sodium ethoxide (1 mole) in ethanol was heated at reflux temperature overnight and then evaporated to dryness. The residue was triturated in water and acidified with glacial acetic acid to yield the title compound. TLC, Silica gel (cyclohexane-ethyl acetate, 1:1) Rf 0.80 1H NMR (CDCl3): δ 0.95 (t,3H) 1.25 (t,3H) 1.57 (m,2H) 2.58 (q,2H) 2.70 (q,2H).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]3[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=3[N:9]=[CH:10][N:11]=2)[CH:3]=[N:2]1.C(#N)C.C1CCN2C(=NCCC2)CC1.[C:37]([O:46][CH3:47])(=[O:45])/[CH:38]=[CH:39]/[CH2:40][C:41]([O:43][CH3:44])=[O:42]>C(OCC)(=O)C>[CH3:20][Si:19]([CH3:22])([CH3:21])[CH2:18][CH2:17][O:16][CH2:15][N:12]1[C:8]2[N:9]=[CH:10][N:11]=[C:6]([C:4]3[CH:5]=[N:1][N:2]([CH:39]([CH2:40][C:41]([O:43][CH3:44])=[O:42])[CH2:38][C:37]([O:46][CH3:47])=[O:45])[CH:3]=3)[C:7]=2[CH:14]=[CH:13]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Reactant: COC(=O)/C=C/CC(=O)OC
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)CC(CC(=O)OC)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Temperature: 65 °C
Reaction time: 8 h
Yield: 63.4 %

Procedure:
4-(1H-Pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (31.0 g, 0.0983 mol) was suspended in ACN (620 mL, 12 mol), and DBU (9.3 mL, 0.062 mol) was added under nitrogen. The reaction was heated to 65° C. and dimethyl (2E)-pent-2-enedioate (16 mL, 0.12 mol) was added in 5 mL portions over 2 h. After stirring overnight, the reaction was complete. The reaction was allowed to cool to room temperature and was concentrated in vacuo to give a dark oil. The oil was partitioned between ethyl acetate and water. The organic layer was washed with 1.0 N HCl, brine, dried over magnesium sulfate, and then concentrated to give a dark oil. The viscous oil was triturated with ethyl ether 3×500 mL to give a dark precipitate. The oil was taken up in ethyl acetate to form a solid. The solids were collected, washed with ethyl ether and dried to give dimethyl 3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentanedioate as a white powder (29.5 gm, 64%), LC/MS (M+H)+: 474, 1H NMR (DMSO-d6) δ 9.1 (s, 1H), 9.02 (s, 1H), 8.65 (s, 1H), 8.11 (d, 1H), 7.42 (d, 1H), 5.78 (s, 2H), 5.27 (m, 1H), 3.65 (m, 8H), 3.15 (m, 4H), 0.95 (t, 2H), 0.1 (s, 9H).
Reaction SMILES: [CH3:1][SH:2].Cl[C:4]1[S:5][C:6]([C:12](=[O:14])[CH3:13])=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].O>C(O)C>[CH3:1][S:2][C:4]1[S:5][C:6]([C:12](=[O:14])[CH3:13])=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: CS
Reactant: CC(=O)c1cc([N+](=O)[O-])c(Cl)s1
Solvent: CCO
Solvent: O
Product: CSc1sc(C(C)=O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Liquid methylmercaptan (4 ml) was added to a solution of 0.82 g of Na in 50 ml of absolute ethanol. The resulting solution was added to a solution of 7.2 g of 2-chloro-3-nitro-5-acetylthiophene in 200 ml of absolute ethanol in 15 minutes at 5° C. After stirring at room temperature for 30 minutes, 100 ml of water was added, after which the precipitate was sucked off and washed successively with water and isopropanol. The precipitate was boiled a moment with 300 ml of carbontetrachloride, cooled down, and sucked off. After drying the title compound was obtained in a yield of 6.4 g; m.p. 191°-193° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4]([C:6](=[O:17])[CH:7]([O:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)[CH3:8])[OH:5].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[O:27][C:28]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:29]=2[N:30]=1>C(#N)C>[CH3:1][O:2][C:3](=[O:18])[CH:4]([C:6](=[O:17])[CH:7]([O:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][C:26]2[O:27][C:28]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:29]=3[N:30]=2)=[CH:14][CH:15]=1)[CH3:8])[OH:5]
Reactant: COC(=O)C(O)C(=O)C(C)Oc1ccc(O)cc1
Reactant: Clc1ccc2oc(Cl)nc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)C(O)C(=O)C(C)Oc1ccc(Oc2nc3cc(Cl)ccc3o2)cc1
Yield: 83.9 %

Procedure:
25.4 g of 2-(4-hydroxyphenoxy)-propionyl-glycolic acid methyl ester and 16.6 g of potassium carbonate in 180 cc of acetonitrile are refluxed for 1 hour to form a salt. After addition of 20 g of 2,5-dichlorobenzoxazole, the mixture is refluxed for 10 hours. The salt is filtered off at 60° C. and the acetonitrile is distilled off. The residue is freed in vacuo from volatile residues. 34 g (84.8% of theory) of 2-[4-(5-chloro-2-benzoxazolyloxy)-phenoxy]-propionyl-glycolic acid methyl ester are obtained as a brownish viscous oil, nD23 =1.5587. ##STR12##
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2=[N:7][CH2:8][CH2:9][N:4]2[C:3]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+].C(Cl)(Cl)Cl.[CH2:26]([Br:42])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>C(#N)C>[Br-:42].[CH2:41]([N:7]1[C:5]2[S:6][C:2]([CH3:1])=[C:3]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[N+:4]=2[CH2:9][CH2:8]1)[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH3:26]
Reactant: CCCCCCCCCCCCCCCCBr
Reactant: CC1=C(c2ccccc2)N2CCN=C2S1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCN1CC[n+]2c1sc(C)c2-c1ccccc1
Product: [Br-]
Yield: 86.6 %

Procedure:
2-Methyl-3-phenyl-5,6-dihydro-imidazo[2,1-b]thiazole (6.0 g., 0.027 mole) (prepared by basification of the hydrobromide salt with sodium carbonate solution and extraction into chloroform) and cetyl bromide (9.15 g., 0.03 mole) were refluxed in acetonitrile (50 ml.) for 12 hours. A crystalline solid separated on cooling which was collected and recrystallized from acetonitrile to yield 7-cetyl-2-methyl-3-phenyl--5,6-dihydro-imidazo[2,1-b]thiazolium bromide (12.2 g., 87%), m.p. 111°-113° C. (Found: C, 64.8; H, 8.6; N, 4.9. C28H45N2SBr requires C, 64.5; H, 8.6; N, 5.4%).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([F:38])=[C:11]([CH:15]2[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[CH:18]([CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[NH:17][CH:16]2[C:35](O)=[O:36])[CH:12]=[CH:13][CH:14]=1.[CH3:39][O:40][C:41](=[O:49])[C:42]1[CH:47]=[CH:46][C:45]([NH2:48])=[N:44][CH:43]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:39][O:40][C:41](=[O:49])[C:42]1[CH:47]=[CH:46][C:45]([NH:48][C:35]([C@H:16]2[C@H:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[C:10]=3[F:38])[C@:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[C@H:18]([CH2:30][C:31]([CH3:33])([CH3:32])[CH3:34])[NH:17]2)=[O:36])=[N:44][CH:43]=1
Reactant: COC(=O)c1ccc(N)nc1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)nc1
Yield: 58 %

Procedure:
In a manner similar to the method described in Examples 1e, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 52c (0.5 g, 0.86 mmol) was reacted with 6-amino-nicotinic acid methyl ester (Aldrich) (0.3 g, 2 mmol), HATU (0.38 g, 1 mmol) and iPr2NEt (0.6 g, 4.6 mmol) in CH2Cl2 at room temperature for 20 h to give rac-6-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-nicotinic acid methyl ester as a white solid (0.3 g, 58%).
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:12]#[N:13])=[CH:9][NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-].C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:21][C:22]1[CH:27]=[C:26](I)[CH:25]=[CH:24][N:23]=1>CS(C)=O.ClCCl.O>[Cl:21][C:22]1[CH:27]=[C:26]([N:10]2[CH:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:8]([C:12]#[N:13])=[CH:9]2)[CH:25]=[CH:24][N:23]=1
Reactant: Clc1cc(I)ccn1
Reactant: N#Cc1c[nH]cc1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: O
Product: N#Cc1cn(-c2ccnc(Cl)c2)cc1-c1ccccc1
Temperature: 25 °C
Yield: 57.3 %

Procedure:
To a solution of 4-phenyl-1H-pyrrole-3-carbonitrile (0.168 g), cupper (I) iodide (0.019 g), N,N-dimethyl grycine (0.021 g) and cesium carbonate (0.325 g) in dimethylsulfoxide (10 mL) was added 2-chloro-4-iodopyridine (0.287 g) at room temperature, and this mixture was at 180° C. in a sealed tube under microwave irradiation for 5 minutes. After cooling to ambient temperature, this reaction mixture was diluted with dichloromethane and water, and the insoluble material was removed by filtered though a Celite pad. This organic layer was separated and this organic solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/hexane=80/20) to give the title compound (0.16 g).
Reaction SMILES: [CH3:1][N:2]([CH3:22])[CH2:3][C:4]#[C:5][C:6]1[N:11]=[CH:10][C:9]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[O:13])=[CH:8][CH:7]=1>[Ni].CO>[CH3:22][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][C:6]1[N:11]=[CH:10][C:9]([C:12]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)=[O:13])=[CH:8][CH:7]=1
Reactant: COc1ccc(C(=O)c2ccc(C#CCN(C)C)nc2)cc1
Agent: [Ni]
Solvent: CO
Product: COc1ccc(C(=O)c2ccc(CCCN(C)C)nc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.2 %

Procedure:
A flask was charged with (6-(3-(dimethylamino)prop-1-ynyl)pyridin-3-yl)-(4-methoxyphenyl)methanone (294 mg, 1 mmol) and Riney Ni (0.2 eq), and 20 mL methanol. The mixture was stirred under hydrogen at room temperature and atmospheric pressure for 2 h. The catalyst was filtered off through a pad of celite, washed with EtOAc. The filtrate was concentrated under reduced pressure to give the product (284 mg, 95% yield).
Reaction SMILES: [CH2:1]([C:3]1[CH2:4][CH:5]([OH:9])[CH2:6][C:7]=1[CH3:8])[CH3:2].N1C=CC=CC=1.[Cl:16]/[C:17](/[C:27]([F:30])([F:29])[F:28])=[CH:18]\[C@@H:19]1[C@H:21]([C:22](Cl)=[O:23])[C:20]1([CH3:26])[CH3:25].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.C1(C)C=CC=CC=1>[Cl:16]/[C:17](/[C:27]([F:28])([F:29])[F:30])=[CH:18]\[C@@H:19]1[C@H:21]([C:22]([O:9][CH:5]2[CH2:6][C:7]([CH3:8])=[C:3]([CH2:1][CH3:2])[CH2:4]2)=[O:23])[C:20]1([CH3:26])[CH3:25]
Reactant: CC1(C)[C@H](/C=C(\Cl)C(F)(F)F)[C@@H]1C(=O)Cl
Reactant: CCC1=C(C)CC(O)C1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCC1=C(C)CC(OC(=O)[C@H]2[C@@H](/C=C(\Cl)C(F)(F)F)C2(C)C)C1
Yield: 82.9 %

Procedure:
To a mixture of (RS)-3-ethyl-4-methyl-3-cyclopenten-1-ol (115 mg), 2,6-di-tert-butyl-4-methylphenol (5 mg), pyridine (92 mg) and toluene (10 ml), (1RS)-cis-3-(Z-2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarbonyl chloride (238 mg) was added under ice-cooling. The resulting reaction mixture was further allowed to react for 8 hours at room temperature. Then the reaction mixture was poured into ice-cooled 5% aqueous solution of citric acid and extracted three times with diethyl ether. After the combined ether layer was washed successively with saturated sodium bicarbonate solution and saturated sodium chloride solution and dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (eluent; n-hexane/ethyl acetate=30/1) to afford 265 mg of (RS)-3-ethyl-4-methyl-3-cyclopenten-1-yl (1RS)-cis-3-(Z-2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarboxylate (Compound No. 11). Yield 83% nD27 1.4645
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]#N)[CH:5]=[CH:4][CH:3]=1.[OH-:11].[Na+].C[OH:14]>C(OCC)(=O)C.O>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([OH:14])=[O:11])[CH:5]=[CH:4][CH:3]=1
Reactant: CO
Reactant: N#CCc1cccc(Br)n1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)Cc1cccc(Br)n1
Temperature: 80 °C

Procedure:
(6-Bromopyridin-2-yl)acetonitrile (50 mg, 0.25 mmol) was taken up in methanol (2 mL) and 1 N aqueous sodium hydroxide (2 ml, 2 mmol) was added. The reaction was heated to 80° C. overnight. Upon completion, the reaction was cooled to ambient temperature, diluted with ethyl acetate (15 mL) and water (15 mL), and the layers were separated. The aqueous layer was acidified with 2N aqueous hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the title compound which was used without further purification.
Reaction SMILES: [NH:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1.[NH:14]1[C:26]2[C:25]3[N:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:19]=[CH:18][C:17]=2[N:16]=[CH:15]1>>[NH:1]1[C:13]2[C:12]3[C:7](=[C:8]([NH2:14])[CH:9]=[CH:10][CH:11]=3)[N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1.[NH:14]1[C:26]2[C:25]3[C:20](=[C:21]([NH2:1])[CH:22]=[CH:23][N:24]=3)[N:19]=[CH:18][C:17]=2[N:16]=[CH:15]1
Reactant: c1ccc2c(c1)ncc1nc[nH]c12
Reactant: c1cnc2c(c1)ncc1nc[nH]c12
Product: Nc1cccc2c1ncc1nc[nH]c12
Product: Nc1ccnc2c1ncc1nc[nH]c12

Procedure:
In steps (6) and (7) of Reaction Scheme VI, a 1H-imidazo[4,5-c]quinoline or 1H-imidazo[4,5-c][1,5]naphthyridine of Formula LVI is oxidized and then aminated to provide a 1H-imidazo[4,5-c]quinolin-6-amine or 1H-imidazo[4,5-c][1,5]naphthyridin-6-amine of Formula LVIII, a subgenus of Formulas I, II, III, and IV. Steps (6) and (7) of Reaction Scheme VI can be carried out as described in steps (5) and (6) of Reaction Scheme I.
Reaction SMILES: [CH:1](=[N:8]/[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)\[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1C=CC(S([CH2:25][N+:26]#[C-:27])(=O)=O)=CC=1.C(O[Na])(C)(C)C>C1COCC1>[C:9]1([N:8]2[C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:27][N:26]=[CH:25]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C(=N/c1ccccc1)\c1ccccc1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)O[Na]
Solvent: C1CCOC1
Product: c1ccc(-c2cncn2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 18 %

Procedure:
To a stirred solution of (E)-N-benzylideneaniline (1.0 mmol) in THF (5 mL) was added TOSMIC (1.1 mmol) and t-BuONa (2.2 mmol). The solution was allowed to stir at room temperature for 5 days. The solvent was evaporated under reduced pressure and the crude product was absorbed on silica gel. After purification by flash column chromatography on silica gel the desired product was obtained in 18% yield. 1H NMR: 7.10-7.16 (m, 2H), 7.16-7.23 (m, 2H), 7.23-7.31 (m, 4H), 7.36-7.42 (m, 3H), 7.73 (s, 1H)