Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:6](=[O:7])[O:5][CH2:4][C:2]1=[O:3].C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[CH:24]1([CH2:30][CH2:31][CH2:32][C:33](O)=[O:34])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.CN(C)CCCN=C=NCC>CN(C)C=O>[CH:24]1([CH2:30][CH2:31][CH2:32][C:33]([C:1]2[C:6](=[O:7])[O:5][CH2:4][C:2]=2[OH:3])=[O:34])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C1COC(=O)C1
Reactant: O=C(O)CCCC1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(CCCC1CCCCC1)C1=C(O)COC1=O
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of 1.0 g (10.0 mmol) of tetronic acid in 30 mL of dry N,N-dimethylformamide at 0° C. is added 1.5 mL (11 mmol) of triethylamine followed by 0.37 g (30 mmol) of 4 dimethylaminopyridine. After stirring at 0° C. for 5 minutes, 2.0 g (11.7 mmol) of 4-cyclohexyl butyric acid is added, followed by 2.25 g (11.7 mmol) of 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide. After 10 minutes, the ice bath is removed and the reaction mixture is allowed to stir overnight. The reaction mixture is quenched with 1N HCl and the solution is washed three times with hexanes. The combined organic layers are washed with water, dried over magnesium sulfate and evaporated. The residue is flash chromatographed on silica gel using 5% methanol/ethyl acetate with 2 mL of acetic acid/liter to give an orange solid: m.p. 38°-42° C.; IR (film) 2920, 2840, 1770, 1690, 1660, 1600 cm-1; NMR (CDCl3) δ5 0.9 (m, H), 1.2 (m, 6H), 1.7 (m, 6H), 2.9 (q, J=7 Hz, 2H), 4.6 and 4.7 (s, 2H), 12.1 (bs, H); MS (EI): M+252. Anal. Calc'd. for C14H20O4 : C, 66.64; H, 7.99 Found: C, 66.38; H, 7.90
Reaction SMILES: N12CCCN=C1CCCCC2.[NH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]2[S:27][CH:28]=[CH:29][C:30]=2[NH:31][S:32]([CH:35]([CH3:37])[CH3:36])(=[O:34])=[O:33])=[CH:22][CH:21]=1.[CH:38]([S:41](Cl)(=[O:43])=[O:42])([CH3:40])[CH3:39]>ClCCl>[CH3:39][CH:38]([S:41]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]2[S:27][CH:28]=[CH:29][C:30]=2[NH:31][S:32]([CH:35]([CH3:37])[CH3:36])(=[O:34])=[O:33])=[CH:22][CH:21]=1)(=[O:43])=[O:42])[CH3:40]
Reactant: CC(C)S(=O)(=O)Nc1ccsc1-c1ccc(-c2ccccc2CN)cc1
Reactant: CC(C)S(=O)(=O)Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CC(C)S(=O)(=O)NCc1ccccc1-c1ccc(-c2sccc2NS(=O)(=O)C(C)C)cc1

Procedure:
Add 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) drop wise (85 mg, 0.6 mmol) to a suspension of propane-2-sulfonic acid [2-(2′-aminomethyl-biphenyl-4-yl)-thiophen-3-yl]-amide (57 mg, 0.15 mmol) in dichloromethane (2 ml) at 0° C., followed by drop wise addition of isopropylsulfonyl chloride (42 mg, 0.3 mmol) and stir the reaction at room temperature overnight. Remove solvent under reduce pressure. Purify with flash chromatography (Silica gel-hexane/EtOAc). Concentrate the desired fractions to provide propane-2-sulfonic acid (2-{2′-[(propane-2-sulfonylamino)-methyl]-biphenyl-4-yl}-thiophen-3-yl)-amide. MS (m/e): 491.1(M−1), propane-2-sulfonic acid (2-{2′,2′-bis-[(propane-2-sulfonylamino)-methyl]-biphenyl-4-yl}-thiophen-3-yl)-amide. MS (m/e): 510.2(M−1).
Reaction SMILES: [N:1]1([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:20]I>O1CCCC1.O>[CH3:20][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:2][CH2:3]1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCNc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN1CCN(C(=O)OC(C)(C)C)c2ccccc21
Reaction time: 0.08 h

Procedure:
To a solution of tert-butyl 3,4-dihydroquinoxaline-1(2H)-carboxylate obtained in Reference Example 28 (1.06 g) in tetrahydrofuran (20 ml), sodium hydride (60% suspension in oil, 181 mg) was added and stirred for 5 minutes, followed by addition of methyl iodide (281 μl). After stirring at room temperature for 1 hour, sodium hydride (60% suspension in oil, 181 mg) was further added and stirred for 30 minutes, followed by addition of methyl iodide (281 μl). After stirring overnight at room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed sequentially with water and brine, and then dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure and the resulting residue was purified by silica gel column chromatography (eluting solvent: n-hexane:ethyl acetate=10:1 to 5:1) to give tert-butyl 4-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate (331 mg) as a brown powder. To a solution of tert-butyl 4-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate thus obtained (331 mg) in ethyl acetate (2 ml), 4N hydrochloric acid (in ethyl acetate, 1.1 ml) was added and stirred overnight at room temperature. The reaction mixture was diluted with 8M aqueous sodium hydroxide and then extracted with ethyl acetate. The organic layer was washed with brine and then dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure to give the titled compound, i.e., 1-methyl-1,2,3,4-tetrahydroquinoxaline (179 mg) as a brown oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([NH:18][C:19]([NH2:21])=[O:20])[CH2:14][CH2:13]2)=[CH:2]1.N1C=CC=CC=1.[CH:28]1([C:34](Cl)=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>C1C=CC=CC=1>[CH:28]1([C:34]([NH:21][C:19]([NH:18][CH:15]2[CH2:14][CH2:13][N:12]([CH2:11][CH2:10][C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][CH:2]=3)[CH2:17][CH2:16]2)=[O:20])=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: NC(=O)NC1CCN(CCc2c[nH]c3ccccc23)CC1
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: O=C(NC(=O)C1CCCCC1)NC1CCN(CCc2c[nH]c3ccccc23)CC1

Procedure:
To a suspension of 1-[1-(2-[3-indolyl]ethyl)piperid-4-yl]urea (0.35 g) in dry benzene (2 ml) was added anhydrous pyridine (0.12 g) and then cyclohexanoyl chloride (0.18 g). After refluxing the mixture for 2 for hours, the title compound was filtered off, washed, dried and converted in ethanolic hydrogen chloride to the hydrochloride (0.52 g) m.p. 236.3° C.
Reaction SMILES: Cl[C:2]([C:4]1[C:5]([O:26][C:27](=[O:29])[CH3:28])=[C:6]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[CH:9]=1)=[O:3].[Cl:30][C:31]1[CH:32]=[C:33]([C:38]2[CH:43]=[CH:42][C:41]([CH2:44][C@@H:45]([NH2:52])[C:46]3[O:50][N:49]=[C:48]([CH3:51])[N:47]=3)=[CH:40][CH:39]=2)[CH:34]=[CH:35][C:36]=1[F:37]>>[Cl:30][C:31]1[CH:32]=[C:33]([C:38]2[CH:43]=[CH:42][C:41]([CH2:44][C@@H:45]([NH:52][C:2]([C:4]3[C:5]([O:26][C:27](=[O:29])[CH3:28])=[C:6]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:7]=[C:8]([C:10]4[CH:11]=[CH:12][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:14][CH:15]=4)[CH:9]=3)=[O:3])[C:46]3[O:50][N:49]=[C:48]([CH3:51])[N:47]=3)=[CH:40][CH:39]=2)[CH:34]=[CH:35][C:36]=1[F:37]
Reactant: Cc1noc([C@H](N)Cc2ccc(-c3ccc(F)c(Cl)c3)cc2)n1
Reactant: CC(=O)Oc1c(C(=O)Cl)cc(-c2ccc(C(F)(F)F)cc2)cc1-c1ccccc1
Product: CC(=O)Oc1c(C(=O)N[C@H](Cc2ccc(-c3ccc(F)c(Cl)c3)cc2)c2nc(C)no2)cc(-c2ccc(C(F)(F)F)cc2)cc1-c1ccccc1
Yield: 40 %

Procedure:
Acetic acid 5′-[2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethylcarbamoyl]-4-trifluoromethyl-[1,1 ′;3′,1″]terphenyl-4′-yl ester (0.04 g ) was prepared from Acetic acid 5′-chlorocarbonyl-4-trifluoromethyl-[1,1′;3′,1″]terphenyl-4′-yl ester (0.06 g, 0.14 mmol) [prepared from 4′-Hydroxy-4-trifluoromethyl-[1,1′;3′,1″]terphenyl-5′-carboxylic acid following general procedures K & L.] and 2-(3′-Chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethylamine (0.047 g,0.14 mmol) following general procedure M.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][O:10][CH3:11])=[CH:4][CH:3]=1.[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[O:22][CH2:23][CH:24]1[CH2:26][O:25]1>>[OH:25][CH:24]([CH2:23][O:22][C:13]1[CH:14]=[CH:15][C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:12]=1)[CH2:26][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][O:10][CH3:11])=[CH:4][CH:3]=1
Reactant: COC=Cc1ccc(Br)cc1
Reactant: c1ccc2cc(OCC3CO3)ccc2c1
Product: COC=Cc1ccc(CC(O)COc2ccc3ccccc3c2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 57.8 %

Procedure:
By the method of example 48, 1-bromo-4-(2-methoxyethenyl)benzene (2.13 g) is lithiated and reacted with (2-naphthyloxymethyl)oxirane (2.0 g). The reaction mixture is allowed to warm to room temperature and stirred for 48 hr before quenching with saturated ammonium chloride. The product is extracted with ether, and the extract is dried and concentrated to leave 1-(2-hydroxy-3-(2-naphthyloxy)propyl)-4-(2-methoxyethenyl)benzene as a yellow oil (1.93 g). By the methods of example 1, this is converted into the title compound, which is obtained as a colorless solid, mp 175°-178° after recrystallization from hexane-ethyl acetate. This material is racemic at the propyl carbinol carbon, but substitution of a chiral form of the starting oxirane provides the title compound in chiral form.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:5]=[C:4](OS(C(F)(F)F)(=O)=O)[N:3]=1.[C:26]([NH:30][S:31]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([Sn](CCCC)(CCCC)CCCC)[N:41]=2)[CH:35]=1)(=[O:33])=[O:32])([CH3:29])([CH3:28])[CH3:27]>C1(C)C=CC=CC=1>[C:26]([NH:30][S:31]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([C:4]3[N:3]=[C:2]([CH3:1])[CH:7]=[C:6]([C:8]4[CH:9]=[CH:10][C:11]([C:14]([F:15])([F:16])[F:17])=[CH:12][CH:13]=4)[N:5]=3)[N:41]=2)[CH:35]=1)(=[O:33])=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(-c2cccc(S(=O)(=O)NC(C)(C)C)c2)n1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(OS(=O)(=O)C(F)(F)F)n1
Solvent: Cc1ccccc1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)n2)n1
Temperature: 25 °C

Procedure:
A stirred mixture of trifluoro-methanesulfonic acid 4-methyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl ester (Example A.62) (0.418 g, 1.08 mmol), N-tert-butyl-3-(6-tributylstannanyl-pyridin-2-yl)-benzenesulfonamide (Example F.6) (0.570 g, 0.98 mmol), tetrakis(triphenyl-phosphine)palladium (0.057 g, 5 mol %) in toluene (5 mL) was heated under reflux conditions for 18 h. Cooled to rt, extracted with ethyl acetate and water, dried the organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product which was purified by silica gel column chromatography with n-heptane/ethyl acetate to give the title compound after trituration with diethyl ether as a white solid (260 mg, 50%). MS (ISP) 527.3 [(M+H)+]; mp>250° C.
Reaction SMILES: [C:1]1([NH:7][CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O-:12][C:13]#[N:14].[K+].Cl>O.C(O)(=O)C>[C:1]1([N:7]2[CH2:8][C:9](=[O:11])[NH:14][C:13]2=[O:12])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#C[O-]
Reactant: O=C(O)CNc1ccccc1
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: O=C1CN(c2ccccc2)C(=O)N1
Temperature: 90 °C
Yield: 24.5 %

Procedure:
A solution of N-phenylglycine (Fluka) (30.2 g, 0.2 moles) in 900 ml of water and 1 ml of acetic acid was heated to 60° C. After thirty minutes potassium cyanate (16.2 g, 0.2 moles) in 100 ml of water was added. Heating was continued for 90', then 25 ml of 37% hydrochloric acid were added and the reaction mixture was heated for 15 h at 90° C. After cooling the precipitate was filtered and crystallized from 95% ethanol. 8.65 g of 1-phenylhydantoin were obtained, m.p. 197°-198°.
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:26]1[CH:27]=[CH:28][C:29]2[N:30]([C:32]([CH3:43])=[C:33]([C:35]([CH3:42])([CH3:41])[C:36]([O:38][CH2:39][CH3:40])=[O:37])[N:34]=2)[N:31]=1.O>CN1CCCC1=O>[C:19]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:26]3[CH:27]=[CH:28][C:29]4[N:30]([C:32]([CH3:43])=[C:33]([C:35]([CH3:42])([CH3:41])[C:36]([O:38][CH2:39][CH3:40])=[O:37])[N:34]=4)[N:31]=3)[CH2:11][CH2:10]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Reactant: CCOC(=O)C(C)(C)c1nc2ccc(Cl)nn2c1C
Solvent: CN1CCCC1=O
Solvent: O
Product: CCOC(=O)C(C)(C)c1nc2ccc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn2c1C
Temperature: 160 °C
Reaction time: 8.5 h
Yield: 69.6 %

Procedure:
In 25 mL of N-methyl-2-pyrrolidinone were dissolved 17.0 g of 4-(diphenylmethoxy)-1-piperidinepropaneamine and 7.39 g of ethyl 2-(6-chloro-3-methylimidazo[1,2-b]pyridazin-2-yl)-2-methylpropionate, and stirred at 160° C. for 8.5 hours. After cooling, a water was added and extracted with ethyl acetate. The extract was washed with a saturated brine solution and dried over magnesium sulfate. Following to concentration under reduced pressure. The residue was subjected to silica gel column chromatography to be eluted with ethyl acetate:methanol:triethylamine (50:5:1). The desired fraction was collected and concentrated to yield 10.4 g of ethyl 2-[6-[3-[4-(diphenylmethoxy)piperidino]propylamino]-3-methylimidazo[1,2-b]pyridazin-2-yl]-2-methylpropionate as an oily material. In 100 mL of ethanol was dissolved this oily material, and 18.3 mL of a 5N aqueous sodium hydroxide solution was added thereto and heated under reflux for 2 hours. After cooling, the mixture was concentrated under reduced pressure. The residue was diluted with water and washed with diisopropyl ether. The aqueous layer was adjusted to pH 5 by the addition of 5N hydrochloric acid. The crystals formed were collected by filtration, recrystallized from methanol-water (10:1), and dried to yield 4.09 g (of the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C@H:6]([C:7]([O:9][Si](C)(C)C)=[O:8])[N:5]2[C:14](=[O:21])[C@@H:15]([NH:16][Si](C)(C)C)[C@H:4]2[S:3]1.C1OC1C.ClC(Cl)C([O:31][N:32]=[C:33]([C:37]1[S:38][CH:39]=[CH:40][CH:41]=1)[C:34](Cl)=[O:35])=O.CS(C)=O>ClCCl>[CH3:1][C:2]1([CH3:22])[C@H:6]([C:7]([OH:9])=[O:8])[N:5]2[C:14](=[O:21])[C@@H:15]([NH:16][C:34](=[O:35])[C:33]([C:37]3[S:38][CH:39]=[CH:40][CH:41]=3)=[N:32][OH:31])[C@H:4]2[S:3]1
Reactant: CC1(C)S[C@@H]2[C@H](N[Si](C)(C)C)C(=O)N2[C@H]1C(=O)O[Si](C)(C)C
Reactant: O=C(Cl)C(=NOC(=O)C(Cl)Cl)c1cccs1
Agent: CC1CO1
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC1(C)S[C@@H]2[C@H](NC(=O)C(=NO)c3cccs3)C(=O)N2[C@H]1C(=O)O

Procedure:
A solution of trimethylsilyl 2,2-dimethyl-6β-trimethylsilylaminopenam-3α-carboxylate [prepared from the corresponding amino-acid (0.864 g.)] and propylene oxide (1 ml.) in dichloromethane (20 ml.) was cooled to 0° and treated dropwise with a solution of 2-dichloroacetoxyimino(thien-2-yl)acetyl chloride syn-isomer; [prepared from the corresponding acid (0.753 g.)] in dichloromethane (12 ml.). The resulting solution was maintained at 0° for 1 hour and was then evaporated to a small bulk and partitioned between ethylacetate and saturated sodium bicarbonate solution. The aqueous phase was washed with ethyl acetate, acidified with 2N-hydrochloric acid, and extracted with ethyl acetate. The dried organic solution was evaporated to a small bulk and added dropwise to stirred petroleum spirit (b.p. 40°-60°). The resulting precipitate was collected, washed, and dried to afford the title acid (0.337 g., 24% based on amine), [α]D + 224° (c 0.57, DMSO), λmax. (pH 6 buffer) 288 nm (ε 6,400), λ inf. 270 nm (ε 5,800), νmax. (Nujol), 2600 and 1730 (CO2H), 1776 (β-lactam), 1670 and 1526 cm.-1 (CONH), τ (d6 -DMSO) values include 0.44 (d, J 6 Hz; NH), 2.45 and 2.9 (multiplets, aromatic protons), 5.78 (s; C-3H), 8.46 and 8.55 (2 s; CH3 groups).
Reaction SMILES: NC1C=C(C=CC=1)O[C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]([NH2:14])=O)[CH:7]=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][C:20]=1[C:26]([F:29])([F:28])[F:27].ClC1C=CN=C(C#N)C=1>>[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:7]2[C:8]([C:12]#[N:14])=[N:9][CH:10]=[CH:11][CH:6]=2)=[CH:21][C:20]=1[C:26]([F:27])([F:28])[F:29]
Reactant: Nc1ccc(O)cc1C(F)(F)F
Reactant: NC(=O)c1cc(Oc2cccc(N)c2)ccn1
Agent: N#Cc1cc(Cl)ccn1
Product: N#Cc1ncccc1Oc1ccc(N)c(C(F)(F)F)c1

Procedure:
This material is prepared by a method analogous to that described for preparation of 2C, starting from 4-amino-3-(trifluoromethyl)phenol and 4-chloro-2-cyanopyridine.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]([C:8]([NH:10][CH2:11][CH2:12][CH3:13])=[O:9])=[CH:6][CH:5]=1)([O-])=O.CCO.[H][H]>CCOC(C)=O.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:10][CH2:11][CH2:12][CH3:13])=[O:9])=[CH:14][CH:15]=1
Reactant: [H][H]
Reactant: CCCNC(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCCNC(=O)c1ccc(N)cc1
Yield: 91 %

Procedure:
4-Nitro-N-propylbenzamide (3.31 g, 15.9 mmol) was dissolved in EtOAc (125 mL) and EtOH (125 mL) and passed through the H-Cube® at 1 mL/min equipped with a 10% Pd/C catcart (ThalesNano), at full hydrogen and temperature set to about 50° C. The solvent was stripped off and the solid was dried overnight in a vacuum oven set at about 50° C. to provide 4-amino-N-propylbenzamide (2.58 g, 91%): 1H NMR (DMSO-d6) δ 7.93 (t, J=5.48 Hz, 1H); 7.54 (d, J=8.57 Hz, 2H); 6.51 (d, J=8.67 Hz, 2H) 5.54 (br s, 2H) 3.13 (m, 2H) 1.47 (sextet, J=7.29 Hz, 2H) 0.85 (t, J=8.49 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]([C:14](O)=O)[CH2:12][N:11]2[CH2:17][CH2:18][CH2:19][C@@H:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)OCC(C)C.[NH2:28][C:29]1[CH:33]=[C:32]([Br:34])[S:31][C:30]=1[C:35]([NH2:37])=[O:36].C(=O)([O-])O.[Na+]>O1CCCC1.C(N(CC)CC)C>[Br:34][C:32]1[S:31][C:30]2[C:35](=[O:36])[NH:37][C:14]([CH:13]3[CH2:12][N:11]4[CH2:17][CH2:18][CH2:19][C@@H:10]4[CH2:9][N:8]3[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[N:28][C:29]=2[CH:33]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CCCN2CC1C(=O)O
Reactant: NC(=O)c1sc(Br)cc1N
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C[C@H]2CCCN2CC1c1nc2cc(Br)sc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 14.3 %

Procedure:
To a mixture of (8aR)-2-(tert-butoxycarbonyl)octahydropyrrolo[1,2-a]pyrazine-3-carboxylic acid (270 mg), triethylamine (0.18 mL) and tetrahydrofuran (10 mL) was added 2-methylpropyl chlorocarbonate (0.13 mL) with stirring at room temperature. After 2 hr, 3-amino-5-bromothiophene-2-carboxamide (221 mg) produced in Example 1, step D, was added and the mixture was stirred at 50° C. for 2 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethanol (10 mL), 2M aqueous sodium hydroxide solution (2 mL) was added, and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was allowed to cool to room temperature, and poured into saturated aqueous sodium hydrogen carbonate. The mixture was extracted with ethyl acetate/tetrahydrofuran mixture, and the extract was dried over anhydrous magnesium sulfate. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (methanol/ethyl acetate) to give the title compound (65 mg) as a yellow solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[N:9]1([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[NH:19][CH:18]=[CH:17]3)[CH2:13][CH2:12][CH2:11][CH2:10]1.[OH-].[K+]>CO>[CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:17]2[C:16]3[C:20](=[CH:21][CH:22]=[C:14]([N:9]4[CH2:13][CH2:12][CH2:11][CH2:10]4)[CH:15]=3)[NH:19][CH:18]=2)[CH2:4][CH2:3]1
Reactant: CN1CCC(=O)CC1
Reactant: c1cc2cc(N3CCCC3)ccc2[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CN1CC=C(c2c[nH]c3ccc(N4CCCC4)cc23)CC1
Yield: 39.5 %

Procedure:
1-methylpiperidin-4-one (1.2 g, 10.62 mmol) was added to a solution of 5-(pyrrolidin-1-yl)-1H-indole (200 mg, 1.08 mmol) in methanol (20 mL). KOH (600 mg, 10.71 mmol) was then added, and the resulting solution was stirred at reflux temperature overnight. The mixture was concentrated, quenched by the addition of water and filtered. The filter cake was washed with water and ether to afford 120 mg (37%) of 3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-(pyrro-lidin-1-yl)-1H-indole as a yellow solid. 1H NMR (CDCl3) δ 7.85 (s, 1H), 7.09 (d, 1H), 6.98 (s, 1H), 6.69 (d, 1H), 6.12 (s, 1H), 3.32 (t, 4H), 3.25 (s, 2H), 2.75 (t, 2H), 2.66 (t, 2H), 2.47 (s, 3H), 1.71 (t, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([S:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][C:11]=2[Cl:20])[CH:3]=1.C([O:25][C:26](=[O:31])[C:27](Br)([CH3:29])[CH3:28])(C)(C)C>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:27]([CH3:29])([CH3:28])[C:26]([OH:31])=[O:25])=[C:4]([S:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][C:11]=2[Cl:20])[CH:3]=1
Reactant: CS(=O)(=O)c1ccc(Sc2cc(Cl)ccc2O)c(Cl)c1
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Product: CC(C)(Oc1ccc(Cl)cc1Sc1ccc(S(C)(=O)=O)cc1Cl)C(=O)O

Procedure:
The title compound was prepared by the method of example 1 step (iv) using the product from example 7 step (iii) and tert-butyl-2-bromoisobutyrate, yield 0.028 g.
Reaction SMILES: [CH:1]([C:4]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[CH:12]=[C:11]([CH:18]([CH3:20])[CH3:19])[C:5]=1[CH2:6][S:7]([NH2:10])(=[O:9])=[O:8])([CH3:3])[CH3:2].[CH:21]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:32])[CH3:31])[C:25]=1[CH2:33][C:34](Cl)=[O:35])([CH3:23])[CH3:22].CCN(CC)CC>C1COCC1>[CH3:32][CH:30]([C:26]1[CH:27]=[CH:28][CH:29]=[C:24]([CH:21]([CH3:22])[CH3:23])[C:25]=1[CH2:33][C:34]([NH:10][S:7]([CH2:6][C:5]1[C:11]([CH:18]([CH3:20])[CH3:19])=[CH:12][C:13]([CH:15]([CH3:17])[CH3:16])=[CH:14][C:4]=1[CH:1]([CH3:3])[CH3:2])(=[O:9])=[O:8])=[O:35])[CH3:31]
Reactant: CC(C)c1cc(C(C)C)c(CS(N)(=O)=O)c(C(C)C)c1
Reactant: CC(C)c1cccc(C(C)C)c1CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)c1cc(C(C)C)c(CS(=O)(=O)NC(=O)Cc2c(C(C)C)cccc2C(C)C)c(C(C)C)c1
Yield: 12.1 %

Procedure:
A solution of 2,4,6 - triisopropylbenzylsulfonamide (100 mg, 0.33 mmol), 2,6-diisopropylphenylacetyl chloride (75 mg, 0.34 mmol), and Et3N (47 μL, 0.34 mmol) in 10 mL THF was stirred at room temperature overnight. The solvent was evaporated and the residue was distributed between ethyl acetate and 0.1N HCl, the organic layer was washed with brine, dried, and evaporated. The pure product (20 mg, 12%) was isolated by column chromatography (4:1 hexane:EtOAc), m/e=499; NMR (CDCl3):δ 7.05-7.4 (m, 5H), 4.25 (s, 2H), 3.95 (s, 2H), 3.45-3.6 (m, 1H), 3.0-3.15 (m, 2H), 2.85-3.0 (m, 2H), 1.05-1.4 (m, 30H) ppm.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH2:13]O)=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[N-:19]=[N+:20]=[N-:21].[Na+]>>[N:19]([CH2:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)=[N+:20]=[N-:21]
Reactant: [N-]=[N+]=[N-]
Reactant: OCc1ccccc1-c1ccncc1
Agent: [Na+]
Solvent: O=S(Cl)Cl
Product: [N-]=[N+]=NCc1ccccc1-c1ccncc1

Procedure:
The product of Example 120A, thionyl chloride and sodium azide were processed according to the method of Example 115A to provide the product. MS (ESI+) m/z 211 (M+H)+.