Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5](=[O:14])[C:6]1[CH:11]=[C:10]([CH3:12])[C:9](Cl)=[N:8][CH:7]=1)([CH3:3])[CH3:2].[CH:15]([NH2:18])([CH3:17])[CH3:16]>O1CCOCC1>[CH:1]([O:4][C:5](=[O:14])[C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([NH:18][CH:15]([CH3:17])[CH3:16])=[N:8][CH:7]=1)([CH3:3])[CH3:2]
Reactant: Cc1cc(C(=O)OC(C)C)cnc1Cl
Reactant: CC(C)N
Solvent: C1COCCO1
Product: Cc1cc(C(=O)OC(C)C)cnc1NC(C)C

Procedure:
A solution of 6-chloro-5-methyl-nicotinic acid isopropyl ester (200 mg, 0.936 mmol) in dioxane (5 mL) and isopropylamine (3 mL) is stirred in a sealed vial at 100° C. for 1 week. The solvent is evaporated and the residue dissolved in DCM (50 mL) and washed with sat. aq. NaHCO3 solution (20 mL). The org. extract is dried over MgSO4, filtered and concentrated. The crude product is purified on prep. TLC plates with heptane:EA 1:1 to give 6-isopropylamino-5-methyl-nicotinic acid isopropyl ester (137 mg) as a yellow oil; LC-MS: tR=0.68 min, [M+1]+=237.02.
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[F:6][C:7]([F:17])([F:16])[S:8](N1C=CN=C1)(=[O:10])=[O:9].[Cl-].[CH2:19]([NH+:21]1[CH:25]=[CH:24][N:23]([CH3:26])[CH2:22]1)[CH3:20].O>C1COCC1>[CH2:19]([NH+:21]1[CH:25]=[CH:24][N:23]([CH3:26])[CH2:22]1)[CH3:20].[F:6][C:7]([F:17])([F:16])[S:8]([CH:2]([C:1]#[N:5])[C:3]#[N:4])(=[O:10])=[O:9]
Reactant: O=S(=O)(n1ccnc1)C(F)(F)F
Reactant: N#CCC#N
Agent: CC[NH+]1C=CN(C)C1
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: N#CC(C#N)S(=O)(=O)C(F)(F)F
Reaction time: 2 h

Procedure:
To 6.61 g of malononitrile (100 mmoles) in solution in 50 ml of THF at −20° C., there is added, in portions, 795 mg of lithium hydride LiH. After 2 hours at −20° C., there is added 20.14 g (100 mmoles) of 1-(trifluoromethanesulfonyl)imidazole) (commercially available from Fluka). The reaction was continued during 4 hours at −20° C., and during 48 hours at room temperature. The solvent was then evaporated and the residue was reclaimed in 60 ml of water. There is then added 14.66 g (100 mmoles) of 1-ethyl-3-methyl-1H-imidazolium chloride (commercially available from Aldrich) to the aqueous solution. A dense phase which is denser than water was immediately formed. This phase was recovered by extraction with dichloromethane. After evaporation of dichloromethane and drying under vacuum at 40° C. of the liquid obtained, a molten salt of 1-ethyl-3-methyl-1H-imidazolium of trifluoromethanesulfonylmalononitrile was obtained, with a purity characterized by a proton, carbon and fluorine RMN higher than 98%.
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:23])[NH:5][C:6]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=2[O:19][CH2:20][CH2:21][CH3:22])[C:12]([O:14]C)=O)=[CH:7][CH:8]=1)#[N:2].[CH3:24][NH:25][CH3:26]>>[CH3:24][N:25]([CH3:26])[C:12](=[O:14])[C:11]1[CH:16]=[CH:17][C:18]([O:19][CH2:20][CH2:21][CH3:22])=[C:9]([C:6]2[NH:5][C:4](=[O:23])[C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)[CH:10]=1
Reactant: CNC
Reactant: CCCOc1ccc(C(=O)OC)cc1-c1ccc(C#N)c(=O)[nH]1
Product: CCCOc1ccc(C(=O)N(C)C)cc1-c1ccc(C#N)c(=O)[nH]1

Procedure:
In a similar method to that of Example 16, methyl 3-(3-cyano-1,2-dihydro-2-oxo-6-pyridinyl)-4-propoxybenzoate (2.14 g) was saponified, converted into the acid chloride and treated with dimethylamine to give 2.0 g of a solid. This was combined with a further 0.2 g obtained in a similar manner, and purified by flash chromatography to give 1.9 g of solid m.p. 201-202° C. Recrystallization of part of this gave the title compound, m.p. 214-215° C.
Reaction SMILES: [OH2:1].[OH-].[K+].Cl[C:5]1[N:9]([CH3:10])[N:8]=[C:7]([CH3:11])[C:6]=1[C:12](=[O:21])[C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:20]>C(O)C>[CH3:10][N:9]1[C:5]([OH:1])=[C:6]([C:12](=[O:21])[C:13]2[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:20])[C:7]([CH3:11])=[N:8]1
Reactant: O
Reactant: Cc1nn(C)c(Cl)c1C(=O)c1c(Cl)cccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nn(C)c(O)c1C(=O)c1c(Cl)cccc1Cl
Yield: 48 %

Procedure:
In 5 ml. of water is dissolved 0.56 g. of potassium hydroxide and a solution of 1.52 g. of 5-chloro-4-(2,6-dichlorobenzoyl)-1,3-dimethylpyrazole in 10 ml. of ethanol is added thereto. The mixture is heated under reflux for 12 hours. After completion of the reaction, the reaction mixture is allowed to cool and extracted with benzene. An aqueous layer is separated and 2N HCl solution is added to adjust the pH to 3-4, whereby crystalline substance is separated out. The resulting crystalline substance is recovered by filtration and recrystallized from ethanol to give 0.68 g. of the desired product as colorless needles melting 249.5°-250.5° C. Yield 48.0%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([O:18][CH:19]3[CH2:37][CH:36]4[N:21]([C:22](=[O:57])[N:23](CC5C=CC(OC)=CC=5)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH:30][CH:31]5[C:33]([C:39]([NH:41][S:42]([CH:45]6[CH2:47][CH2:46]6)(=[O:44])=[O:43])=[O:40])([NH:34][C:35]4=[O:38])[CH2:32]5)[CH2:20]3)[C:15]3[C:10](=[C:11]([CH3:60])[C:12]([O:58][CH3:59])=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1>ClCCl.FC(F)(F)C(O)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:17]=[C:16]([O:18][CH:19]3[CH2:37][CH:36]4[N:21]([C:22](=[O:57])[NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH:30][CH:31]5[C:33]([C:39]([NH:41][S:42]([CH:45]6[CH2:47][CH2:46]6)(=[O:44])=[O:43])=[O:40])([NH:34][C:35]4=[O:38])[CH2:32]5)[CH2:20]3)[C:15]3[C:10](=[C:11]([CH3:60])[C:12]([O:58][CH3:59])=[CH:13][CH:14]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(CN2CCCCCC=CC3CC3(C(=O)NS(=O)(=O)C3CC3)NC(=O)C3CC(Oc4nc(-c5ccc(F)cc5)nc5c(C)c(OC)ccc45)CN3C2=O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCCNC(=O)N4C3)nc(-c3ccc(F)cc3)nc2c1C
Yield: 38.5 %

Procedure:
Compound 103 (75 mg, 0.09 mmol) was stirred for 2 h in a mixture of dichloro-methane-trifluoroacetic acid; 2:1. Evaporation and purification by HPLC gave pure title compound (25 mg, 38%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[N:13][C:14]([NH:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)=[N:15]3)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[CH3:29][C:30]([CH3:32])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(O)(=O)C>[CH:30]([N:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[N:13][C:14]([NH:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)=[N:15]3)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1)([CH3:32])[CH3:29]
Reactant: FC(F)(F)c1cccc(Nc2ncc3ccc(OC4CCNCC4)cc3n2)c1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)N1CCC(Oc2ccc3cnc(Nc4cccc(C(F)(F)F)c4)nc3c2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 7-(piperidin-4-yloxy)-N-(3-(trifluoromethyl)phenyl)quinazolin-2-amine in DCM was added acetone (10 eq), a few drops of acetic acid and sodium triacetoxy borohydride (4 eq). The reaction mixture was stirred for 16 h at ambient temperature. The reductive amination went to completion to give 7-(1-isopropylpiperidin-4-yloxy)-N-(3-(trifluoromethyl)phenyl)quinazolin-2-amine. The mixture was then purified on prep HPLC to give 7-(1-isopropylpiperidin-4-yloxy)-N-(3-(trifluoromethyl)phenyl)quinazolin-2-amine. ES/MS m/z 431 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@:9]1([C:14]([OH:16])=O)[CH2:11][C@H:10]1[CH:12]=[CH2:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:29]1([S:32]([NH2:35])(=[O:34])=[O:33])[CH2:31][CH2:30]1.C1CCN2C(=NCCC2)CC1>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@:9]1([C:14]([NH:35][S:32]([CH:29]2[CH2:31][CH2:30]2)(=[O:34])=[O:33])=[O:16])[CH2:11][C@H:10]1[CH:12]=[CH2:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: NS(=O)(=O)C1CC1
Reactant: C=C[C@@H]1C[C@]1(NC(=O)OC(C)(C)C)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: C=C[C@@H]1C[C@]1(NC(=O)OC(C)(C)C)C(=O)NS(=O)(=O)C1CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 63.2 %

Procedure:
A solution of the product of Step 1 (2.62 g, 11.5 mmol) and CDI (2.43 g, 15.0 mmol) in THF (40 mL) was heated at reflux for 50 minutes under nitrogen. The solution was cooled to room temperature and transferred by cannula to a solution of cyclopropylsulfonamide (1.82 g, 15.0 mmol) in THF (10 mL). To the resulting solution was added DBU (2.40 mL, 16.1 mmol) and stirring was continued for 20 hours. The mixture was quenched with 1N HCl to pH 1 and THF was concentrated in vacuo. The suspension was extracted with ethyl acetate (2×50 mL) and the combined organic extracts were dried (Na2SO4), filtered, and concentrated. Purification by recrystallization from hexanes-ethyl acetate (1:1) afforded the title compound (2.4 g) as a white solid. The mother liquor was purified by a Biotage 40S column (eluted 9% acetone in dichloromethane) to give a second batch of the title compound (1.1 g). Both batches were combined (total yield 92%). 1H NMR (DMSO-d6) δ 0.96-1.10 (m, 4H), 1.22 (dd, J=5.5, 9.5 Hz, 1H), 1.39 (s, 9H), 1.70 (t, J=5.5 Hz, 1H), 2.19-2.24 (m, 1H), 2.90 (m, 1H), 5.08 (d, J=10 Hz, 1H), 5.23 (d, J=17 Hz, 1H), 5.45 (m, 1H), 6.85, 7.22 (s, NH (rotamers); MS m/z 331 (M++H).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[C:9]([O:14][CH3:15])[CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)[CH:2]1[O:4][CH2:3]1.[NH:16]1[CH:21]=[CH:20][CH:19]([C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[NH:24][CH:23]=2)[CH2:18][CH2:17]1>>[NH:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22]([C:19]2[CH2:20][CH2:21][N:16]([CH2:3][CH:2]([OH:4])[CH2:1][N:5]3[C:13]4[C:8](=[C:9]([O:14][CH3:15])[CH:10]=[CH:11][CH:12]=4)[CH:7]=[CH:6]3)[CH2:17][CH:18]=2)=[CH:23]1
Reactant: C1=CC(c2c[nH]c3ccccc23)CCN1
Reactant: COc1cccc2c1ccn2CC1CO1
Product: COc1cccc2c1ccn2CC(O)CN1CC=C(c2c[nH]c3ccccc23)CC1
Yield: 60.6 %

Procedure:
A methanolic solution of 1-N-glycidyl-4-methoxyindole (0.6 g, 3.0 mmole) from example 2 and 3-(4-tetrahydropyridinyl)indole (0.59 g, 3.0 mmole) was refluxed under nitrogen for 15 hours. The reaction mixture was concentrated in vacuo and the product purified by flash silica gel chromatography (ethyl acetate) to afford the titled compound as a yellow colored solid (0.73 g, 60% yield). Treatment with a 0.25M ethanolic solution of fumaric acid (0.5 equivalents) gave the required product as a yellow colored solid. The product was recrystallized from ethanol.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][CH:15]([C:21]2[N:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:24]=[CH:23][CH:22]=2)[CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])(=[O:13])=[O:12])=[CH:7][CH:6]=1)#[N:4].I[CH3:33]>C1COCC1>[C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH:15]([C:21]2[N:25]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:24]=[CH:23][CH:22]=2)[CH:16]([CH2:17][CH3:18])[CH2:19][CH3:20])[CH3:33])(=[O:13])=[O:12])=[CH:7][CH:6]=1)#[N:4]
Reactant: CCC(CC)C(NS(=O)(=O)c1ccc(C#N)cc1)c1ccnn1-c1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(CC)C(c1ccnn1-c1ccccc1)N(C)S(=O)(=O)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.9 %

Procedure:
To a suspension of NaH (16.3 nmg, 410 μmol, 60% dispersion in mineral oil) in THF (300 μL) at 0° C. was added a solution of 4-cyano-N-[2-ethyl-1-(1-phenyl-1H-pyrazol-5-yl)butyl]benzenesulfonamide (example 37, 140 mg, 340 μmol) in THF (600 μL). The reaction mixture was warmed to room temperature, and after 20 min iodomethane (45 μL, 714 μmol) was added. The mixture was allowed to stir overnight. TLC indicated that the reaction was not complete. Additional aliquots of NaH and iodomethane were added until the reaction was driven to completion. The mixture was then quenched with H2O and extracted with EtOAc twice. The organic extracts were dried (MgSO4) and concentrated. Column chromatography (EtOAc/hexanes, 1:1) provided 89 mg (57% yield) of the title compound as a glassy yellow solid. mp 37.8-54° C.; Mass Spectrum (ES): 481.1;
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[N:9][C:4]=2[CH2:3][C:2]1=O.P(Cl)(Cl)([Cl:13])=O>>[Cl:13][C:4]1[N:9]=[CH:8][CH:7]=[C:6]2[CH:3]=[CH:2][O:1][C:5]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C1Cc2ncccc2O1
Product: Clc1nccc2ccoc12

Procedure:
For example, furan-3-acrylic acid is converted to the acid azide by first reacting the acid with ethoxycarbonyl chloride and triethylamine to form the acid chloride and then reacting the mixed anhydride with sodium azide in water. The furan-3-acrylic acid azide is then heated in diphenylmethane with tributylamine to a temperature of about 190° C. to about 210° C. to form the furopyridone represented by the formula ##STR12## The furopyridone is allowed to react with phosphorus oxychloride to form 7-chlorofuro[2,3-c]pyridine and the latter is reductively dechlorinated with zinc in acetic acid to provide furo[2,3-c]pyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]([C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[N:19]=[C:20]=S.[NH2:22][C:23]1[C:24]([NH:34][CH3:35])=[CH:25][C:26]([O:32][CH3:33])=[C:27]([CH:31]=1)[C:28]([OH:30])=[O:29].FC(F)(F)C(=N[Si](C)(C)C)O[Si](C)(C)C.CC(C)N=C=NC(C)C>CN(C=O)C.C(O)(=O)C>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]([C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[NH:19][C:20]1[N:34]([CH3:35])[C:24]2[CH:25]=[C:26]([O:32][CH3:33])[C:27]([C:28]([OH:30])=[O:29])=[CH:31][C:23]=2[N:22]=1
Reactant: O=C(NCc1ccc(Cl)c(N=C=S)c1)C1(C(F)(F)F)CC1
Reactant: CNc1cc(OC)c(C(=O)O)cc1N
Agent: CC(C)N=C=NC(C)C
Agent: C[Si](C)(C)N=C(O[Si](C)(C)C)C(F)(F)F
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COc1cc2c(cc1C(=O)O)nc(Nc1cc(CNC(=O)C3(C(F)(F)F)CC3)ccc1Cl)n2C
Temperature: 25 °C

Procedure:
A mixture of N-(4-chloro-3-isothiocyanatobenzyl)-1-(trifluoromethyl)cyclopropane carboxamide (1.71 g; 5.10 mmol) and 5-amino-2-methoxy-4-(methylamino)benzoic acid (1.00 g; 1.00 mmol) in DMF (20 mL) was stirred over night at rt. The mixture was thereafter heated to 60° C. and BSTFA (1.44 g; 5.61 mmol) was added and stirred for 1 h before the addition of DIC (0.772 g; 6.12 mmol). The resulting mixture was stirred at 80° C. for 3 h. Acetic acid (2 mL) was added and the mixture was concentrated and the residue poured in aqueous NaOH (2 M) and pH adjusted to −3-4. The mixture was extracted with EtOAc and the organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was recrystallized from EtOAc/petroleum ether to give the sub-title compound. Yield: 0.570 g (22%).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([S:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[C:14]([C:16]#[N:17])[CH:13]=[CH:12][N:11]=2)=[N:2]1.[C:18](Cl)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C>C1COCC1>[C:19]1([C:18]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:1]2[CH:5]=[N:4][C:3]([S:6][CH2:7][CH2:8][O:9][C:10]3[CH:15]=[C:14]([C:16]#[N:17])[CH:13]=[CH:12][N:11]=3)=[N:2]2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N#Cc1ccnc(OCCSc2nc[nH]n2)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#Cc1ccnc(OCCSc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 80 %

Procedure:
A solution of 2-{[2-(1H-1,2,4-triazol-3-ylthio)ethyl]oxy}pyridine-4-carbonitrile obtained in Reference Example 17 (3.40 g, 13.7 mmol), trityl chloride (5.73 g, 20.6 mmol) and triethylamine (2.87 mL, 20.6 mmol) in THF (30 mL) was stirred at room temperature for 15 hr. The mixture was concentrated under reduced pressure, and the residue was extracted with ethyl acetate and water. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated. The obtained oil was purified by silica gel column chromatography (20%-40% ethyl acetate/hexane) to give the title compound as a white powder (5.37 g, 80%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[Cl:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH:16]=O.C(O)(C(F)(F)F)=O>>[Cl:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH:16]1[C:5]2[NH:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:4]=2[CH2:3][CH2:2][NH:1]1
Reactant: NCCc1c[nH]c2ccccc12
Reactant: O=Cc1ccccc1Cl
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccccc1C1NCCc2c1[nH]c1ccccc21
Yield: 69 %

Procedure:
This product was prepared using the same procedure as for Intermediate 1 with tryptamine (1.0 g, 6.2 mmol), 2-chlorobenzaldehyde (0.7 mL, 1.0 equiv.) and TFA (1.0 mL, 2 equiv.) to give the title compound (1.2 g, 69%).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:7][CH2:6][C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=2)([N+:8]([O-])=O)[CH2:4][O:3]1.O>C(O)C.[Ni]>[CH3:1][C:2]1([CH3:18])[O:3][CH2:4][C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=2)([NH2:8])[CH2:6][O:7]1
Reactant: Cc1cccc(C2([N+](=O)[O-])COC(C)(C)OC2)c1
Agent: [Ni]
Solvent: CCO
Solvent: O
Product: Cc1cccc(C2(N)COC(C)(C)OC2)c1
Reaction time: 22 h
Yield: 110 %

Procedure:
To a mixture of 1.6 g of 2,2-dimethyl-5-(3-methylphenyl)-5-nitro-1,3-dioxane in 24 ml of ethanol was added a suspension of a Raney nickel (manufactured by Aldrich, product obtained by washing 1 ml of an aqueous suspension with water and ethanol) in 9 ml of ethanol, followed by stirring for 22 hours under a hydrogen atmosphere at 4 atm. The reaction mixture was filtered over Celite and the solvent was then evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 1.55 g of 2,2-dimethyl-5-(3-methylphenyl)-1,3-dioxan-5-amine.
Reaction SMILES: CN(C)[C:3]1[S:4][C:5]2[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:6]=2[C:7]=1[C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:12][CH:11]=1)=[O:9].[S:32]1[CH:36]=[CH:35][CH:34]=[C:33]1[Mg]Br>C1COCC1>[S:32]1[CH:36]=[CH:35][CH:34]=[C:33]1[C:3]1[S:4][C:5]2[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:6]=2[C:7]=1[C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:12][CH:11]=1)=[O:9]
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(N(C)C)sc2c1
Reactant: Br[Mg]c1cccs1
Solvent: C1CCOC1
Product: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(-c3cccs3)sc2c1
Yield: 72.1 %

Procedure:
By the method described in Example 1, [2-dimethylamino-6-methoxybenzothien-3-yl][4-[2-(1-piperdinyl)ethoxy]phenyl]methanone (1.97 g, 4.5 mmol) in THF (15 mL) was reacted with a 0.60M THF solution of 2-thienylmagnesium bromide (31.8 mL, 13.5 mmol) (prepared from 2-bromothiophene, n-butyllithium, and magnesium bromide in ether) at ambient temperature. Purification by chromatography (silica gel, 1:1 hexane:ethyl acetate, 10% methanol, 0.1% ammonium hydroxide) gave 1.55 g (72%) of the title compound as a yellow foam: 1H NMR (300 MHz) δ1.3-1.4 (m, 2H), 1.4-1.6 (m, 4H), 2.42 (m, 4H), 2.66 (t, J=5.8 Hz, 2H), 3.88 (s, 3H), 4.12 (t, J=5.9 Hz, 2H), 6.96 (m, 4H), 7.16 (d, J=2.5 Hz, 1H), 7.35 (d, J=8.9 Hz, 1H), 7.43 (d, J=5.0 Hz, 1H), 7.55 (d, J=2.2 Hz, 1H), 7.77 (d, J=8.8 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ24.1, 25.9, 55.1, 55.6, 57.7, 66.3, 104.4, 114.4, 115.0, 124.2, 127.1, 127.7, 127.7, 130.3, 131.5, 132.3, 133.6, 134.2, 135.0, 140.0, 158.0, 163.4, 192.8; IR (CHCl3) 1649, 1599 cm-1 ; MS (FD+) m/e 477 (M+); Anal. calc'd. for C27H27NO3S2 : C, 67.89; H, 5.70; N, 2.93. Found: C, 68.13; H, 5.89; N, 2.78.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)=[CH:10][C:9]=2[CH2:25][CH2:26][C:27]2[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=2)[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.[NH:45]1[C:49]([NH2:50])=[N:48][N:47]=[N:46]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)=[CH:10][C:9]=2[CH2:25][CH2:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([NH:50][C:49]3[NH:48][N:47]=[N:46][N:45]=3)=[O:32])=[CH:29][CH:28]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(CCc2cc(-c3ccc(OC(F)(F)F)cc3)ccc2-c2cccc(Cl)c2)cc1
Reactant: Nc1nnn[nH]1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1nnn[nH]1)c1ccc(CCc2cc(-c3ccc(OC(F)(F)F)cc3)ccc2-c2cccc(Cl)c2)cc1
Temperature: 50 °C

Procedure:
A DMF solution (1 mL) containing 4-{2-[3-chloro-4″-(trifluoromethoxy)-1,1′:4′,1″-terphenyl-2′-yl]ethyl}benzoic acid (12 mg, 0.024 mmol), prepared using the procedures described in EXAMPLE 1, DIEA (21 μg, 0.12 mmol), 1H-tetrazol-5-amine (3 mg, 0.036 mmol), and BOP (21 mg, 0.048 mmol) was heated at 50° C. for 30 minutes. The solution was then purified directly by RP-HPLC to give the title compound. LCMS1 4.36 min (N+H)=564
Reaction SMILES: C[O:2][C:3]([CH:5]1[O:9][C:8](=[O:10])[NH:7][CH:6]1[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O.[BH4-].[Na+].O.Cl>C(O)C>[CH2:11]([C@H:6]1[C@@H:5]([CH2:3][OH:2])[O:9][C:8](=[O:10])[NH:7]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COC(=O)C1OC(=O)NC1Cc1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C1N[C@@H](Cc2ccccc2)[C@@H](CO)O1
Reaction time: 2 h

Procedure:
150 g of the 98:2 mixture of the (4S,5S) and (4S,5R) isomers of 4-benzyl-2-oxo-oxazolidine-5-carboxylic acid methyl ester were added at 15°-20° over a period of 1.5 hours to a stirred solution of 20.8 g of sodium borohydride in 360 ml of ethanol and then stirred for a further 2 hours. The suspension was combined at 20° with 540 ml of water and the pH value adjusted to 7 with 165 ml of 3N hydrochloric acid. The suspension was stirred at room temperature for 2.5 hours, left to stand for 18 hours at 4° and then filtered. The residue was washed with water and dried and yielded 111.6 g (84%) of 99% (4S,5S)-4-benzyl-5-hydroxymethyl-oxazolidin-2-one, melting point 167.3°-168.9°, [α]D20 : -79.4° (1% in methanol).
Reaction SMILES: C[C:2](C)([O-:4])C.[K+].[Cl:7][CH2:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].C(OCC)=O>CCOCC>[Cl:7][CH:8]([CH:2]=[O:4])[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10]
Reactant: CC(C)(C)[O-]
Reactant: O=C(CCl)OCc1ccccc1
Agent: [K+]
Solvent: CCOCC
Solvent: CCOC=O
Product: O=CC(Cl)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To potassium tert-butoxide (141 mL, 141 mmol) at 0° C. was added dropwise a solution of benzyl 2-chloroacetate (26.8 g, 141 mmol) and ethyl formate (11.6 mL, 141 mmol) in Et2O (45 mL). The reaction was warmed to ambient temperature and stirred for 16 hours. The reaction mixture was filtered and washed with cold ether (100 mL). The potassium salt was dissolved in H2O (50 mL) and the solution was acidified with concentrated HCl to pH=4 in a cold bath. The solution was extracted with ether and the organic phase was dried (MgSO4) and concentrated to give the crude product. A lower boiling point impurity was removed by vacuum distillation (90° C., 5 mm Hg) and the residue was taken directly to the next step.
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][C:7]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[O:9])=[CH:6][CH:5]=1)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:8]([N:10]2[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:14][CH2:15]2)=[O:9])=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc([N+](=O)[O-])cc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(N)cc2)CC1
Yield: 93 %

Procedure:
A solution of tert-butyl 4-(4-nitrobenzoyl)piperazine-1-carboxylate (1.00 g, 3.00 mmol) in MeOH (60 ml) was hydrogenated at 20° C. at atmospheric pressure using an H-Cube (flow rate at 1 ml/min and full hydrogen mode) using a Pd/C cartridge. The solvent was removed in vacuo to afford tert-butyl 4-(4-aminobenzoyl)piperazine-1-carboxylate (0.85 g, 2.79 mmol, 93%) as a white solid. 1H NMR (CDCl3) δ 1.41 (9H, s), 3.38 (4H, m), 3.53 (4H, m), 4.07 (2H, br. s), 6.55 (2H, d), 7.17 (2H, d). LCMS (2) Rt: 2.14 min; m/z (ES+) 306.