Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([B:9]([OH:11])[OH:10])=[C:4]([O:12]C)[CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([B:9]([OH:10])[OH:11])=[C:4]([OH:12])[CH:3]=1
Reactant: COc1cc(Cl)c(C)cc1B(O)O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc(B(O)O)c(O)cc1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
A mixture of (4-chloro-2-methoxy-5-methylphenyl)boronic acid (100 mg, 0.499 mmol) in DCM (2 mL) was cooled to 0° C. and BBr3 (0.142 mL, 1.497 mmol) was added. The mixture was then stirred at rt for 2 h. It was then poured into ice and extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated to obtain 150 mg (97% yield, 60% pure) of the desired product as a brown solid. 1H NMR (400 MHz, CDCl3) δ 7.59 (br. s., 1H), 7.11 (br. s., 1H), 4.30-4.11 (m, 1H), 4.01 (br. s., 1H), 2.37 (s, 3H).
Reaction SMILES: O[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]([CH3:13])[CH:4]=1.S(Cl)([Cl:16])=O>C(Cl)(Cl)Cl>[Cl:16][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]([CH3:13])[CH:4]=1
Reactant: Cc1cc(CO)c2ccccc2n1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cc1cc(CCl)c2ccccc2n1
Temperature: 0 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
4-hydroxymethyl-2-methyl quinoline (7.0 g, 40 mmol) was dissolved in chloroform (150 mL) and cooled to 0° C., thionyl chloride (15.0 mL) was added slowly at this temperature and then the reaction mixture was allowed to warm up to room temperature and stirred overnight. The solvent was removed in-vacuo and the residue was titureted with ethyl acetate/ethyl ether to provide 9.0 g (100%) of 4-chloromethyl-2-methyl quinoline as an HCl salt. MS (ESI): 191.9 (M+H+).
Reaction SMILES: O[C@H:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[O:8])[C@H:4]([C:20]2[N:21]([C:25]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=3)=[O:26])[CH2:22][CH2:23][N:24]=2)[CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[C:69]([SH:72])(=[O:71])[CH3:70]>O1CCCC1.C(OCC)(=O)C>[C:69]([S:72][C@@H:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[O:8])[C@H:4]([C:20]2[N:21]([C:25]([O:27][CH2:28][C:29]3[CH:30]=[CH:31][C:32]([N+:35]([O-:37])=[O:36])=[CH:33][CH:34]=3)=[O:26])[CH2:22][CH2:23][N:24]=2)[CH2:3]1)(=[O:71])[CH3:70]
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)N1CCN=C1[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)S
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)S[C@H]1C[C@@H](C2=NCCN2C(=O)OCc2ccc([N+](=O)[O-])cc2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 0.5 h

Procedure:
(2S,4R)-4-Hydroxy-1-(4-nitrobenzyloxycarbonyl)-2-[1-(4-nitrobenzyloxycarbonyl)-2-imidazolin-2-yl]pyrrolidine (655 mg) and triphenylphosphine (0.51 g) were dissolved in tetrahydrofuran (20 ml) at 0° C. To this solution was added dropwise a solution of diethyl azodicarboxylate (0.30 ml) in tetrahydrofuran (5 ml) with stirring for 30 minutes, followed by addition of a solution of thioacetic S-acid (0.14 ml). Stirring was continued at ambient temperature for 2 hours. The reaction mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate and brine, dried over magnesium sulfate and evaporated. The obtained oily residue was subjected to a column chromatography on silica gel and eluted with a mixture of dichloromethane and acetone (20:1, V/V) to give (2S,4S)-4-acetylthio-1-(4-nitrobenzyloxycarbonyl)-2-[1-(4-nitrobenzyloxycarbonyl)-2-imidazolin-2-yl]pyrrolidine (1.2 g).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]([O:15][C:16]([N:18]1[C@@H:22]([CH2:23][C:24]2([CH2:27][OH:28])[CH2:26][CH2:25]2)[CH2:21][O:20][C:19]1([CH3:30])[CH3:29])=[O:17])([CH3:14])([CH3:13])[CH3:12].S([O-])(O)(=O)=O.[K+]>C(Cl)Cl.C(N(CC)CC)C>[C:11]([O:15][C:16]([N:18]1[C@@H:22]([CH2:23][C:24]2([CH:27]=[O:28])[CH2:26][CH2:25]2)[CH2:21][O:20][C:19]1([CH3:30])[CH3:29])=[O:17])([CH3:13])([CH3:14])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1[C@@H](CC2(CO)CC2)COC1(C)C
Agent: O=C(Cl)C(=O)Cl
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1[C@@H](CC2(C=O)CC2)COC1(C)C
Reaction time: 0.17 h

Procedure:
11.1 ml of dimethylsulfoxide in 150 ml of methylene chloride are added dropwise to a solution of 10.1 ml of oxalyl chloride in 130 ml of methylene chloride at -60° C. When the addition has ended, the mixture is subsequently stirred for a further 10 min, a solution of 22.3 g of 3-tert-butoxycarbonyl-2,2-dimethyl-4(S)-[(1-hydroxymethylcyclopropyl)methyl]-1,3-oxazolidine in 270 ml of methylene chloride is then added at -60° C. in the course of 20 min and the mixture is stirred for a further 30 min. 43.6 ml of triethylamine are then added at the same temperature and finally, after 30 min, 140 ml of a 20% potassium hydrogen sulfate solution are added to the reaction mixture. Customary working up gives the title compound as a crude product: Rf (A)=0.73.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([O:17][CH3:18])[C:14]([OH:16])=[O:15])=[CH:8][CH:7]=1.[CH3:19][CH2:20][CH2:21][CH2:22][C:23]1[CH:24]=[CH:25][C:26](O)=[CH:27][CH:28]=1>>[CH2:22]([C:23]1[CH:24]=[CH:25][C:26]([O:1][CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([O:17][CH3:18])[C:14]([OH:16])=[O:15])=[CH:8][CH:7]=2)=[CH:27][CH:28]=1)[CH2:21][CH2:20][CH3:19]
Reactant: CO[C@@H](Cc1ccc(OCCCO)cc1)C(=O)O
Reactant: CCCCc1ccc(O)cc1
Product: CCCCc1ccc(OCCCOc2ccc(C[C@H](OC)C(=O)O)cc2)cc1

Procedure:
The title compound was prepared from (2S)-3-[4-(3-hydroxy-propoxy)-phenyl]-2-methoxy-propionic acid linked to Wang's Resin (Example 94, Step D) via Mitsunobu coupling with 4-n-butylphenol and cleavage from the resin (Standard Procedure G) gave an oily solid (7%). 1H-NMR (200.15 MHz, CDCl3): δ 7.11 (dd, 4H, J=12.7, 8.6), 6.82 (dd, 4H, J=8.6, 3.2), 4.12 (t, 4H, J=6.2), 3.97 (dd, 1H, J=7.7, 4.4), 3.38 (s, 3H), 3.30 (dd, 1H, J=14.5, 4.4), 2.94 (dd, 1H, J=14.5, 7.7), 2.54 (t, 2H, J=7.7), 2.23 (qn, 2H, J=6.2), 1.63–1.48 (m, 2H), 1.42–1.24 (m, 2H), 0.91 (t, 3H, J=7.2).
Reaction SMILES: C(OC(=O)[NH:10][C:11]1([C:14]2[S:15][CH:16]=[N:17][N:18]=2)[CH2:13][CH2:12]1)C1C=CC=CC=1.CCOCC.[BrH:25]>C(O)(=O)C>[BrH:25].[S:15]1[CH:16]=[N:17][N:18]=[C:14]1[C:11]1([NH2:10])[CH2:13][CH2:12]1
Reactant: O=C(NC1(c2nncs2)CC1)OCc1ccccc1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: NC1(c2nncs2)CC1
Reaction time: 0.5 h

Procedure:
(1-1,3,4-Thiadiazol-2-yl-cyclopropyl)-carbamic acid benzyl ester (0.2 g, 0.73 mmol) was dissolved in 48% HBr in acetic acid (5 mL) and allowed to stir for 30 min. Et2O was then added and the majority of the liquid decanted off. The remaining residue was concentrated under reduced pressure to give 1-1,3,4-thiadiazol-2-yl-cyclopropylamine hydrobromide (0.12 g, 0.54 mmol) as an orange gum, m/z 142.4 [M+H]+.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[C:11]([CH3:17])[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:18][Mg+].[Br-].CO.[BH4-].[Na+]>C1COCC1>[NH2:16][CH:15]([C:12]1[CH:13]=[CH:14][C:9]([S:6]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:8])=[O:7])=[CH:10][C:11]=1[CH3:17])[CH3:18]
Reactant: Cc1cc(S(=O)(=O)NC(C)(C)C)ccc1C#N
Reactant: C[Mg+]
Agent: [BH4-]
Agent: [Br-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(S(=O)(=O)NC(C)(C)C)ccc1C(C)N
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of N-tert-butyl-4-cyano-3-methylbenzenesulfonamide (0.4861 g) in THF (19 ml) at 0° C. was treated with MeMgBr (1.4 M in THF, 4.13 ml). The reaction mixture was heated at reflux overnight. After cooling, the reaction was quenched with MeOH and sodium borohydride (3 eq) was added. The mixture was stirred at 0° C. for 1 h, warmed to room temperature and stirred for 4 hours. The reaction mixture was then quenched with H2O, stirred overnight and concentrated to give a yellow solid. The solid was partitioned between EtOAc/H2O and the organic layer was separated, dried (MgSO4) and concentrated to give a yellow oil. The oil was purified by reverse phase HPLC (5-100% ACN/H2O+0.1% TFA) to give 0.3403 g 4-(1-aminoethyl)-N-tert-butyl-3-methylbenzenesulfonamide as white powder after lyophilization.
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]([OH:11])[CH2:9][CH3:10])=[CH:6][CH:5]=[CH:4][N:3]=1.S(=O)(=O)(O)O.[OH-].[Na+].[C:19](O)(=[O:21])[CH3:20]>>[C:19]([O:11][CH:8]([C:7]1[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=1)[CH2:9][CH3:10])(=[O:21])[CH3:20]
Reactant: CCC(O)c1cccnc1F
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CCC(OC(C)=O)c1cccnc1F
Temperature: 130 °C

Procedure:
2.75 g (17.7 mmol) of the product from example 48A are dissolved in 12 ml of glacial acetic acid and admixed with 4 ml of concentrated sulfuric acid. The mixture is heated to 130° C. for 30 min and, after cooling, stirred into ice-water. A pH of 8 is established with sodium hydroxide solution, and then extraction is effected with dichloromethane. The combined organic phases are dried over sodium sulfate and concentrated cautiously. This affords 3.30 g (94% of theory) of the title compound, which is converted further without purification.
Reaction SMILES: CS(CC1C(C2C=CC=CC=2)=NC2C(C=1C(N[C@H](C1C=CC=CC=1)CC)=O)=CC=CC=2)=[O:3].[CH:33]([S:36][CH2:37][C:38]1[C:39]([C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)=[N:40][C:41]2[C:46]([C:47]=1[C:48]([NH:50][C@H:51]([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[CH2:52][CH3:53])=[O:49])=[CH:45][CH:44]=[CH:43][CH:42]=2)([CH3:35])[CH3:34]>>[CH:33]([S:36]([CH2:37][C:38]1[C:39]([C:60]2[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=2)=[N:40][C:41]2[C:46]([C:47]=1[C:48]([NH:50][C@H:51]([C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1)[CH2:52][CH3:53])=[O:49])=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:3])([CH3:34])[CH3:35]
Reactant: CC[C@H](NC(=O)c1c(CS(C)=O)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Reactant: CC[C@H](NC(=O)c1c(CSC(C)C)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Product: CC[C@H](NC(=O)c1c(CS(=O)C(C)C)c(-c2ccccc2)nc2ccccc12)c1ccccc1

Procedure:
This compound [two diastereomers] was prepared similarly to 3-[(methylsulfinyl)methyl]-2-phenyl-N-[(1S)-1-phenylpropyl]quinoline-4-carboxamide (2, scheme 1) except 3-[(isopropylthio)methyl]-2-phenyl-N-[(1S)-1-phenylpropyl]quinoline-4-carboxamide (Example 13) was used instead of 3-[(methylthio)methyl]-2-phenyl-N-[(1S)-1-phenylpropyl]quinoline-4-carboxamide (1). 1H NMR (300 MHz, CDCl3) δ 8.90-8.68 (m, 1H), 8.16-8.03 (m, 2H), 7.80-7.27 (m, 12H), 5.35-5.12 (m, 1H), 4.30-3.67 (m, 2H), 2.86-1.83 (m, 3H), 1.19-0.55 (m, 9H); HRMS m/z 471.2077, calcd 471.2106.
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:12][C:11]2[N:10]=[CH:9][C:8](/[CH:13]=[CH:14]/[C:15]([OH:17])=O)=[CH:7][C:6]=2[CH2:5][CH2:4]1.Cl.[O:19]([CH:26]1[CH2:29][NH:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[O:17]=[C:15]([N:28]1[CH2:27][CH:26]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:29]1)/[CH:14]=[CH:13]/[C:8]1[CH:7]=[C:6]2[C:11](=[N:10][CH:9]=1)[NH:12][C:3](=[O:2])[CH2:4][CH2:5]2
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Reactant: c1ccc(OC2CNC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCc2cc(/C=C/C(=O)N3CC(Oc4ccccc4)C3)cnc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.8 %

Procedure:
A 16 mL vial flask was successively charged with (2E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid hydrochloride (30 mg, 0.12 mmol), DMF (3 mL), 3-phenoxyazetidine hydrochloride (26 mg, 0.14 mmol; which may be prepared as described in Step 3), DIPEA (48 μL, 0.28 mmol) and EDAC (27 mg, 0.14 mmol). The reaction mixture was stirred at room temperature overnight and concentrated to dryness. The residue was purified on preparative TLC (eluent: dichloromethane/NH3 7N in MeOH, 2.5%) to give a pale yellow solid. This solid was triturated in acetone, filtered, washed with acetone and diethyl ether then dried to give the title compound (15 mg, 36%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2(CCO)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[C:31]([O:34][C:35](=O)[CH3:36])(=[O:33])[CH3:32]>ClCCl.N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH2:35]([O:34][C:31](=[O:33])[CH2:32][C:9]1([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]2[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=2)[CH2:10]1)[CH3:36]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(C(=O)N2CCC(CCO)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)CC1(c2ccc(Cl)c(Cl)c2)CCN(C(=O)c2cc(OC)c(OC)c(OC)c2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-[3-(3,4-Dichloro-phenyl)-1-(3,4,5-trimethoxybenzoyl)-pyrrolidin-3-yl]-ethanol (4.5 g, 9.9 mmol) was dissolved in dichloromethane/pyridine (70 mL, 6/1). The solution was treated with acetic anhydride (1.04 mL, 11.02 mmol, 1.1 eq.) and 4-dimethylaminopyridine (50 mg, 0.41 mmol, 0.04 eq.). The solution was allowed to stir for 2 h at ambient temperature. The organics were concentrated in vacuo and the residue was dissolved in ethyl acetate and washed with 1N HCl (2×200 mL), 5% NaHCO3 (100 mL), brine (100 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel (300 g) with ethyl acetate to afford the title compound:
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.O1CCCC1.C(N(C(C)C)C(C)C)C.F[C:29]1[CH:34]=[CH:33][C:32]([S:35]([NH2:38])(=[O:37])=[O:36])=[CH:31][C:30]=1[N+:39]([O-:41])=[O:40]>CN(C)C=O>[N+:39]([C:30]1[CH:31]=[C:32]([S:35](=[O:37])(=[O:36])[NH2:38])[CH:33]=[CH:34][C:29]=1[NH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1)([O-:41])=[O:40]
Reactant: NS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC[C@@H](Nc2ccc(S(N)(=O)=O)cc2[N+](=O)[O-])C1
Reaction time: 18 h

Procedure:
To a solution of (R)-tert-butyl 3-aminopyrrolidine-1-carboxylate (1.0 g), tetrahydrofuran (50 ml), N-ethyl-N-isopropylpropan-2-amine (5.61 mL) and N,N-dimethylformamide (10 mL) was added 4-fluoro-3-nitrobenzenesulfonamide (1.212 g) and the mixture was stirred for 18 hours. The crude product was isolated by concentration and was the material was purified on silica gel, and was eluted with a 30, 50, and 75% ethyl acetate in hexane step gradient to provide the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:18]#[N:19])=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[NH:5][C:6]=1[C:7]([F:10])([F:9])[F:8].[CH2:20]([O:24][CH2:25]OCCCC)[CH2:21][CH2:22][CH3:23].CN(C)C=O.P(Cl)(Cl)(Cl)=O.C(N(CC)CC)C>O>[Br:1][C:2]1[C:3]([C:18]#[N:19])=[C:4]([C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)[N:5]([CH2:25][O:24][CH2:20][CH2:21][CH2:22][CH3:23])[C:6]=1[C:7]([F:10])([F:9])[F:8]
Reactant: CCCCOCOCCCC
Reactant: N#Cc1c(-c2ccc(Cl)cc2)[nH]c(C(F)(F)F)c1Br
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCOCn1c(-c2ccc(Cl)cc2)c(C#N)c(Br)c1C(F)(F)F
Temperature: 35 °C
Reaction time: 0.5 h
Yield: 94.6 %

Procedure:
A stirred mixture of 4-bromo-2- (p-chlorophenyl)-5-(trifluoromethyl)pyrrole-3-carbonitrile (17.4 g, 0.05 mole), di-(n-butoxy)methane (12.0 g, 0.075 mole and dimethylformamide (DMF) (4.6 g, 0.063 mole) in xylenes, under N2, is treated with phosphorous oxychloride (9.6 g, 0.063 mole) portion-wise at 30°-37° C. over a 10 minute period, heated at 45°-50° C. for 0.75 hour, cooled to 35° C., treated dropwise with triethylamine (8.1 g, 0.08 mole) over a 0.25 hour period and heated at 45°-50° C. for an additional 0.75 hour. The reaction mixture is then cooled to 25° C., treated with water and additional xylenes and stirred for 0.5 hour. The phases are separated and the organic phase is concentrated in vacuo to give the title product as a light brown solid, mp 52.0°-53.5° C., 20.6 g, 94.6% yield identified by H1NMR and mass spectral analyses.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH:15]1([NH2:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>O1CCOCC1.C(OCC)(=O)C>[CH:15]1([NH:21][C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=2[N+:12]([O-:14])=[O:13])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: NC1CCCCC1
Reactant: NS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: NS(=O)(=O)c1ccc(NC2CCCCC2)c([N+](=O)[O-])c1

Procedure:
A room temperature solution of Example 1C (2.36 g, 10.0 mmol) and cyclohexylamine (2.0 mL) in dioxane (5 mL) was stirred for 16 hours, diluted with ethyl acetate (100 mL), washed sequentially with 3M HCl (20 mL), water (20 mL) and brine (10 mL), dried (MgSO4), filtered, and concentrated to provide the desired product of sufficient purity for subsequent use.
Reaction SMILES: Cl.[CH:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH:3]1[NH2:12])[CH2:9]2.[C:13](N1C=CN=C1)([N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1)=[O:14].C(N(CC)CC)C.O>C(Cl)Cl>[CH:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH:3]1[NH:12][C:13]([N:15]1[CH2:19][CH2:18][N:17]=[CH:16]1)=[O:14])[CH2:9]2
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NC1C2CC3CC(C2)CC1C3
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(NC1C2CC3CC(C2)CC1C3)N1C=NCC1
Yield: 93.4 %

Procedure:
A solution of 2-adamantylamine hydrochloride 3 g (15.98 mmol), carbonyldiimidazole 2.59 g (15.98 mmol), triethylamine 2.215 ml (15.98 mmol) in CH2Cl2 100 ml was stirred overnight at room temperature. Water was added, the organic phase separated, dried and concentrated to dryness yielding the title crude product 3.69 g (94%) as white solid.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[C:7]([C:8]([OH:10])=O)[C:6]([OH:12])=[CH:5][CH:4]=1)#[N:2].[F:13][C:14]([F:27])([F:26])[C:15]1[CH:16]=[C:17]([CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=1)[NH2:18]>>[F:13][C:14]([F:26])([F:27])[C:15]1[CH:16]=[C:17]([NH:18][C:8](=[O:10])[C:7]2[CH:11]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=2[OH:12])[CH:19]=[C:20]([C:22]([F:23])([F:25])[F:24])[CH:21]=1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: N#Cc1ccc(O)c(C(=O)O)c1
Product: N#Cc1ccc(O)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Yield: 16.6 %

Procedure:
Using 5-cyanosalicylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH:9]1[CH2:21]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][NH:24][CH3:25]>C(O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH:9]1[CH2:21][N:24]([CH3:25])[CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNC
Reactant: ClCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Solvent: CCO
Product: CN(C)CC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Temperature: 150 °C

Procedure:
A mixture of 1,4-bisbenzyl-2-(chloromethyl)piperazine (1 equivalent) and dimethylamine (5 equivalents) in ethanol, was heated at 150° C. for 36 hours in a sealed high pressure vessel. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was taken up in 1 N HCl, and the solution was washed with CH2Cl2. The water phase was made basic with a 30% aqueous NaOH solution (pH=12) and extracted with CH2Cl2. The organic extracts were collected and dried over Na2SO4. Evaporation of the solvent under reduced pressure afforded {[1,4-bisbenzylpiperazin-2-yl]methyl}dimethylamine. LC/MS (m/z): 324.3 (MH+), Rt 1.76 minutes.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19](Cl)=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([C:26]3[CH:27]=[C:22]([CH3:21])[CH:23]=[CH:24][CH:25]=3)=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cccc(B(O)O)c1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2Cl)CC1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: Cc1cccc(-c2nccnc2N2CCN(C(=O)OC(C)(C)C)CC2)c1
Yield: 46.1 %

Procedure:
Dissolve 3′-chloro-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid t-butyl ester (6.0 g, 20.2 mmol) and 3-methylbenzeneboronic acid (3.3 g, 24.0 mmol) in dimethoxyethane (20 mL) and water (10 mL). Add tetrakis(triphenylphosphine) palladium(0) (2.3 g, 2.0 mmol) and potassium carbonate (7.5 g, 54 mmol). Heat for 17 hr. at 102° C. and allow to cool about 1.5 hr. to room temperature. Partition reaction mixture between ethyl acetate and water. Separate layers. Wash organic layer with brine, dry (sodium sulfate), filter, concentrate and purify (silica gel chromatography eluting with 10:90 to 20:80 ethyl acetate:hexanes), to give 3′-m-tolyl-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid t-butyl ester (3.3 g, 47%). MS (ES): m/z=355 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([O:11][CH2:12][C@@H:13]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH3:14])[CH:3]=1.C([O-])(=[O:25])C.[Cs+]>CN(C=O)C>[OH:25][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([O:11][CH2:12][C@@H:13]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH3:14])[CH:3]=1
Reactant: CC(=O)[O-]
Reactant: C[C@@H](COc1cc(Cl)c([N+](=O)[O-])cn1)NC(=O)OC(C)(C)C
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C[C@@H](COc1cc(O)c([N+](=O)[O-])cn1)NC(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 1 h
Yield: 84.2 %

Procedure:
A mixture of tert-butyl ((2S)-1-((4-chloro-5-nitropyridin-2-yl)oxy)propan-2-yl)carbamate (4.83 g), cesium acetate (6.99 g) and DMF (40 mL) was stirred at 80° C. for 1 hr. The mixture was allowed to cool to room temperature, and concentrated under reduced pressure. The residue was diluted with ethyl acetate and water, and the organic layer was separated. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (3.84 g).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[C:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]=1)=[O:4].[OH-].[Li+].Cl>O1CCCC1.O>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([C:7]2[N:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:10]=[CH:9][C:8]=2[O:11][CH2:12][C:13]([F:16])([F:14])[F:15])=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
To a solution of 3.0 g 6-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid methyl ester in 30 mL tetrahydrofuran was added 14 mL of a 1M solution of lithium hydroxide in water and the mixture was stirred at room temperature for 1 h. The reaction mixture was acidified by addition of 1M hydrochloric acid. The precipitate was collected by filtration washed with water and dried to constant weight under high vacuum to yield 2.36 g of the title compound as white solid, MS 330.3 (M−H)−.