Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][C:6]=1[C:14]1[NH:15][C:16](=[O:24])[C:17]([CH2:22][CH3:23])=[C:18]([CH2:20][CH3:21])[N:19]=1)[CH2:2][CH3:3].S(Cl)(Cl)=O.[NH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32].C(N(CC)CC)C>ClCCl>[CH2:20]([C:18]1[N:19]=[C:14]([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][C:5]=2[O:4][CH2:1][CH2:2][CH3:3])[C:9]([NH:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:10])[NH:15][C:16](=[O:24])[C:17]=1[CH2:22][CH3:23])[CH3:21]
Reactant: CCCOc1ccc(C(=O)O)cc1-c1nc(CC)c(CC)c(=O)[nH]1
Reactant: CCOC(=O)CN
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCOc1ccc(C(=O)NCC(=O)OCC)cc1-c1nc(CC)c(CC)c(=O)[nH]1
Reaction time: 0.5 h
Yield: 33.1 %

Procedure:
The compound (250 mg, 0.76 mmol) of example 58 was suspended in dichloromethane (20 ml), and added with thionyl chloride (2 ml), followed by refluxing for 2 h to clear the reaction mixture. The reaction mixture was concentrated off thionyl chloride, and added with dichloromethane. Under ice-bath, the reaction mixture was added dropwise into a dichloromethane solution (20 ml) containing ethyl 2-aminoacetate (80 mg, 0.727 mmol) and triethylamine (0.2 ml, 1.454 mmol), followed by stirring for 0.5 h. The reaction mixture was then washed with water (20 ml) and saturated saline (20 ml) respectively. The organic layer was dried with anhydrous sodium sulfate, and concentrated. The residue was passed through a silica gel column to give the white title compound (100 mg, yield: 33%). 1H NMR (CDCl3) δ: 11.01 (1H, br), 8.87 (1H, d), 8.00 (1H, dd), 7.08 (1H, d), 6.87 (1H, br), 4.27 (2H, q), 4.25 (2H, t), 4.21 (2H, t), 2.69 (2H, q), 2.59 (2H, q), 2.00 (2H, m), 1.32 (3H, t), 1.30 (3H, t), 1.15 (6H, t).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:25]#[CH:26])[CH2:20][CH2:19][C:18]4([O:24][CH2:23][CH2:22][O:21]4)[CH2:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.I[C:28]1[CH:29]=[C:30]([CH:35]=[CH:36][CH:37]=1)[C:31]([O:33][CH3:34])=[O:32].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl>N1CCCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:25]#[C:26][C:28]4[CH:37]=[CH:36][CH:35]=[C:30]([C:31]([O:33][CH3:34])=[O:32])[CH:29]=4)[CH2:20][CH2:19][C:18]4([O:21][CH2:22][CH2:23][O:24]4)[CH2:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)c1cccc(I)c1
Reactant: C#CC1(c2ccc(OC)c(OC3CCCC3)c2)CCC2(CC1)OCCO2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: COC(=O)c1cccc(C#CC2(c3ccc(OC)c(OC4CCCC4)c3)CCC3(CC2)OCCO3)c1
Temperature: 80 °C

Procedure:
A mixture of 4-(3-cyclopentyloxy-4-methoxyphenyl)-1,1-(ethylenedioxy)-4-ethynylcyclohexane (0.150 g, 0.421 mmol) and methyl 3-iodobenzoate (0.110 g, 0.421 mmol) in piperidine (2.1 mL, dry) under an argon atmosphere was treated with a mixture of tetrakis(triphenylphosphine)palladium(0) (0.020 g, 0.017 mmol), cuprous iodide (0.010 g, 0.053 mmol) and triphenylphosphine (crystal) and the mixture was heated at 80° C. for 40 min. The reaction mixture was chilled to 0° C., was poured into ice-water, was acidified with 3N hydrochloric acid and was extracted five times with methylene chloride. The organic phase was washed with dilute hydrochloric acid, water, saturated brine, was dried over magnesium sulfate, was filtered and concentrated in vacuo. The residue was preadsorbed and chromatographed on silica gel, eluting the with 15 to 20% ethyl acetate in hexanes, to afford a light yellow oil. 1H-NMR (250 MHz, CDCl3) δ 8.11 (t, J=1.4 Hz, 1H), 7.97 (d-d, J=1.3 Hz;J=7.9 Hz, 1H), 7.63 (d-d, J=7.8 Hz;J=1.3 Hz, 1H), 7.39 (t, J=7.8 Hz, 1H), 7.23 (d, J=2.2, 1H), 7.15 (d-d, J=8.4 Hz;J=2.3 Hz, 1H), 6.89 (d, J=8.4 Hz, 1H), 4.80 (m, 1H), 4.00 (s, br, 4H), 3.92 (s, 3H), 3.84 (s, 3H), 2.4 to 1.75 (m, 18H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:12]=[N:13][C:14]([C:17]([F:20])([F:19])[F:18])=[N:15][CH:16]=1)[CH:5]=O.[H-].[Na+].[CH2:23]1COCC1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH2:23])[CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:12]=[N:13][C:14]([C:17]([F:20])([F:19])[F:18])=[N:15][CH:16]=1
Reactant: C1CCOC1
Reactant: O=Cc1ccc(Oc2cnc(C(F)(F)F)nc2)c(F)c1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [H-]
Product: C=Cc1ccc(Oc2cnc(C(F)(F)F)nc2)c(F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 27.2 %

Procedure:
To a stirred suspension of 3-fluoro-4-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)benzaldehyde (2 g, 6.99 mmol) and methyltriphenylphosphonium bromide (2.496 g, 6.99 mmol) in dry THF (40 mL) was added NaH (0.978 g, 24.46 mmol) under nitrogen at 0° C. The mixture was stirred at room temperature for 4 h. The organic layer was washed three times with brine, dried over Na2SO4, filtered, and concentrated. Purification via flash chromatography afforded the title compound (540 mg, 1.900 mmol, 27.2% yield). LCMS: rt=3.65 min, [M+H+]=285
Reaction SMILES: [FH:1].N[C:3]1[C:4]([O:10][C:11]2[CH:23]=[CH:22][C:14]([O:15][CH:16]([CH3:21])[C:17]([O:19][CH3:20])=[O:18])=[CH:13][CH:12]=2)=[N:5][CH:6]=[C:7]([Cl:9])[CH:8]=1.[N+]([O-])([O-])=O.[Na+]>>[Cl:9][C:7]1[CH:8]=[C:3]([F:1])[C:4]([O:10][C:11]2[CH:23]=[CH:22][C:14]([O:15][CH:16]([CH3:21])[C:17]([O:19][CH3:20])=[O:18])=[CH:13][CH:12]=2)=[N:5][CH:6]=1
Reactant: COC(=O)C(C)Oc1ccc(Oc2ncc(Cl)cc2N)cc1
Reactant: F
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Product: COC(=O)C(C)Oc1ccc(Oc2ncc(Cl)cc2F)cc1
Temperature: 55 °C
Reaction time: 2 h
Yield: 48 %

Procedure:
A vessel is charged with 400 g (20 moles) of hydrogen fluoride and 167.4 g (0.518 mole) of methyl 2-[4-(3-amino-5-chloropyridin-2-yloxy)phenoxy]propionate are added in portions at a temperature from -8° to 0° C. 37.3 g (0.540 mole) of sodium nitrate are added over one hour and the mixture is stirred for two hours before it is slowly heated in an autoclave to 55° C. Excess hydrogen fluoride is removed by distillation and the residue is taken up in a mixture of 200 ml of methylene chloride and ice-water and the solution is neutralised with concentrated ammonia. The neutralised solution is extracted three times with methylene chloride and the organic extracts are washed with water, dried and concentrated by evaporation, affording 81.0 g (48% of theory) of methyl 2-[4-(5-chloro-3-fluoropyridin-2-yloxy)phenoxy]propionate with a melting point of 63°-64°.
Reaction SMILES: [Cl:1][CH:2]=[CH:3][Cl:4].[CH:5]1[CH2:9][CH:8]=[CH:7][CH:6]=1>>[Cl:1][CH:2]1[CH:3]([Cl:4])[CH:7]2[CH2:8][CH:9]1[CH:5]=[CH:6]2
Reactant: C1=CCC=C1
Reactant: ClC=CCl
Product: ClC1C2C=CC(C2)C1Cl

Procedure:
1,2-Dichloroethylene was reacted with cyclopentadiene at 175° C. in the same manner as Examples 1-7 to produce 5,6-dichloronorbornene (called "DCN" hereinafter).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([C:15]2[C:16]3[N:17]([C:28]([CH2:31][CH3:32])=[CH:29][CH:30]=3)[N:18]=[C:19]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[C:20]=2[C:21]#[N:22])[CH:14]=1)[C:5]([O:7]C(C)(C)C)=[O:6]>FC(F)(F)C(O)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([C:15]2[C:16]3[N:17]([C:28]([CH2:31][CH3:32])=[CH:29][CH:30]=3)[N:18]=[C:19]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[C:20]=2[C:21]#[N:22])[CH:14]=1)[C:5]([OH:7])=[O:6]
Reactant: CCc1ccc2c(-c3cc(Br)cc(C(=O)OC(C)(C)C)c3)c(C#N)c(N3CCCC3)nn12
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccc2c(-c3cc(Br)cc(C(=O)O)c3)c(C#N)c(N3CCCC3)nn12
Yield: 76.1 %

Procedure:
A solution of tert-butyl 3-bromo-5-[3-cyano-7-ethyl-2-(1-pyrrolidinyl)pyrrolo[1,2-b]pyridazin-4-yl]benzoate (16.0 mg) in trifluoroacetic acid (0.5 mL) was stirred for 0.5 hour at room temperature. The reaction was quenched by adding water. The mixture was neutralized by adding NaOH (pH=3). The mixture was extracted with EtOAc. The extract was washed with brine, dried over MgSO4, and evaporated to give a greenish yellow solid. The solid was triturated in hexanes-CHCl3 (2-1) to afford 3-bromo-5-[3-cyano-7-ethyl-2-(1-pyrrolidinyl)pyrrolo[1,2-b]pyridazin-4-yl]benzoic acid as an yellow powder (10.8 mg).
Reaction SMILES: [Cl:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]3([CH2:16][CH3:17])OCC[O:12]3)=[CH:7][C:5]=2[CH:6]=1.Cl>CO>[Cl:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([C:11](=[O:12])[CH2:16][CH3:17])=[CH:7][C:5]=2[CH:6]=1
Reactant: CCC1(c2ccc3oc(Cl)cc3c2)OCCO1
Agent: Cl
Solvent: CO
Product: CCC(=O)c1ccc2oc(Cl)cc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.8 %

Procedure:
To a stirred solution of 2-chloro-5-(2-ethyl-1,3-dioxolan-2-yl)benzofuran (250 mg, 1.0 eq) in 15 mL MeOH was added 3 mL 3N HCl (aq) at rt. The reaction was stirred for 30 min at rt, quenched with sat NaHCO3 (aq), and extracted with EtOAc. The extract was washed with brine, dried, concentrated, and purified by column chromatography to give the desired product (140 mg, 68%). 1H NMR (400 MHz, CDCl3) δ 8.15 (d, J=1.6 Hz, 1H), 7.95 (dd, J=8.4 Hz, 1.6 Hz, 1H), 7.48 (d, J=8.8 Hz, 1H), 6.68 (s, 1H), 3.06 (q, J=6.8 Hz, 2H), 1.25 (t, J=6.8 Hz, 3H).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:12]=2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[NH2:28][C:29]1[S:30][CH:31]=[CH:32][N:33]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl.CN(C)C=O>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([C:18]([F:19])([F:21])[F:20])[CH:12]=2)[C:8]([NH:28][C:29]2[S:30][CH:31]=[CH:32][N:33]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1nccs1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(F)c(C(F)(F)F)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Nc1nccs1)C(CC1CCCC1)c1ccc(F)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 84.4 %

Procedure:
A solution of 3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-propionic acid (304 mg, 1.0 mmol) in methylene chloride (10 mL) was cooled to 0° C. and then treated with a 2.0M solution of oxalyl chloride in methylene chloride (0.6 mL, 1.2 mmol) and a few drops of N,N-dimethylformamide. The reaction mixture was stirred at 0° C. for 15 min and at 25° C. for 24 h. The reaction mixture was then treated with 2-amino-thiazole (175 mg, 1.75 mmol) and N,N-diisopropylethylamine (0.4 mL, 2.41 mmol). This solution was stirred at 25° C. for 48 h. At this time, the reaction was concentrated in vacuo. High pressure liquid chromatography (Chromegasphere SI-60, 10 μM, 60 Å, 25 cm×23 cm ID, 60/40 heptane/ethyl acetate) afforded 3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-N-thiazol-2-yl-propionamide (326 mg, 84.5%) as a light yellow solid: mp 125-127° C.; EI-HRMS m/e calcd for C18H18F4N2OS (M+) 386.1076, found 386.1086.
Reaction SMILES: [CH:1]1[CH:10]=[C:9]2[C:11]([O:13][C:14](=O)[C:7]3=[C:8]2[C:3](=[C:4]([S:16]([O-:19])(=[O:18])=[O:17])[CH:5]=[CH:6]3)[CH:2]=1)=[O:12].[K+:20].Cl.[NH2:22][OH:23]>N1C=CC=CC=1>[OH:23][N:22]1[C:14](=[O:13])[C:7]2[CH:6]=[CH:5][C:4]([S:16]([O-:19])(=[O:18])=[O:17])=[C:3]3[C:8]=2[C:9](=[CH:10][CH:1]=[CH:2]3)[C:11]1=[O:12].[K+:20]
Reactant: NO
Reactant: O=C1OC(=O)c2ccc(S(=O)(=O)[O-])c3cccc1c23
Agent: Cl
Agent: [K+]
Solvent: c1ccncc1
Product: O=C1c2cccc3c(S(=O)(=O)[O-])ccc(c23)C(=O)N1O
Yield: 102.2 %

Procedure:
4-Sulfo-1,8-naphthalic anhydride potassium salt (2.0 g, 6.2 mmol) and hydroxylamine hydrochloride (0.9 g, 12.4 mmol) were reacted in pyridine (50 mL) following the procedure of Example 1. The solids formed were filtered, washed with ethanol, and dried to give 2.1 g of the title compound, mp>380° C.;
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=[C:10]([CH2:19][CH2:20][CH:21]=O)[CH:9]=2)=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:25]=[C:26]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:27]=[CH:28][C:29]=1[Cl:30].CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[Cl:23][C:24]1[CH:25]=[C:26]([N:31]2[CH2:36][CH2:35][N:34]([CH2:21][CH2:20][CH2:19][C:10]3[CH:9]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[N:12]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:11]=3)[CH2:33][CH2:32]2)[CH:27]=[CH:28][C:29]=1[Cl:30]
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Reactant: O=CCCc1cc(-c2ccc(F)cc2)n(-c2ccccc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc(-c2cc(CCCN3CCN(c4ccc(Cl)c(Cl)c4)CC3)nn2-c2ccccc2)cc1

Procedure:
90 mg (61%) of target compound was obtained by using a method same as in Example 1 by using 3-(5-(4-fluorophenyl)-1-phenyl-1H-pyrazol-3-yl)-propanal (80 mg, 0.272 mmol), 1-(3,4-dichlorophenyl)piperazine (63 mg, 0.272 mmol), DIPEA (0.071 mL, 0.408 mmol) and NaBH(OAc)3 (173 mg, 0.816 mmol).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]3[O:17][C:16]([CH:18]([NH:20][C:21](=[O:23])[CH3:22])[CH3:19])=[CH:15][C:14]=3[CH:24]=2)=[CH:4][CH:3]=1.Br[CH2:26][CH2:27][CH2:28][CH3:29]>>[CH2:26]([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]3[O:17][C:16]([CH:18]([NH:20][C:21](=[O:23])[CH3:22])[CH3:19])=[CH:15][C:14]=3[CH:24]=2)=[CH:4][CH:3]=1)[CH2:27][CH2:28][CH3:29]
Reactant: CCCCBr
Reactant: CC(=O)NC(C)c1cc2cc(CCc3ccc(O)cc3)ccc2o1
Product: CCCCOc1ccc(CCc2ccc3oc(C(C)NC(C)=O)cc3c2)cc1
Yield: 66 %

Procedure:
Using N-(1-{5-[2-(4-hydroxyphenyl)ethyl]-1-benzofuran-2-yl}ethyl)acetamide (124 mg, 0.348 mmol) obtained in Example 157 and bromobutane (263 mg, 1.92 mmol) and in the same manner as in Example 158, the title compound was obtained (96.3 mg, yield 66%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16](O)[CH2:17][CH2:18][Cl:19])=[CH:12][CH:11]=1>>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([CH:16]([O:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH2:17][CH2:18][Cl:19])=[CH:14][CH:15]=1
Reactant: OC(CCCl)c1ccc(Br)cc1
Reactant: Oc1cccc(Cl)c1
Product: ClCCC(Oc1cccc(Cl)c1)c1ccc(Br)cc1

Procedure:
3-Chlorophenol was reacted with 1-(4-Bromo-phenyl)-3-chloro-propan-1-ol following the procedure set out in Example 48B to give the title compound, which was used in the next step without further purification.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][NH2:11].CO[CH:14]=[C:15]([C:18]#[N:19])[C:16]#[N:17].C[O-].[Na+]>C(O)C>[NH2:19][C:18]1[N:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[O:3][CH3:2])[N:11]=[CH:14][C:15]=1[C:16]#[N:17]
Reactant: COc1ccccc1NN
Reactant: COC=C(C#N)C#N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: COc1ccccc1-n1ncc(C#N)c1N
Yield: 53 %

Procedure:
To a solution of 1-(2-methoxyphenyl)hydrazine hydrogen chloride (3 g, 0.017 mol) in ethanol (50 mL) was added 2-(methoxymethylene)malononitrile (1.89 g, 0.9 eq.) and sodium methoxide (1.92 g, 2.1 eq). The reaction mixture was heated at reflux for 18 h and concentrated. The reaction mixture was partitioned between brine and ethyl acetate. The organic layer was separated, dried with magnesium sulfate, filtered and concentrated. MPLC Biotage chromatography eluting with 20-60% ethyl acetate/hexanes afforded the title compound in 53% yield (1.9 g). 400 MHz 1H NMR (CDCl3) δ 7.64 (m, 1 H), 7.40 (m, 2H), 7.08 (m,2H), 4.51 (bs, 2H), 3.87 (s, 3 H); MS: (M+H m/z=215.2).
Reaction SMILES: [CH3:1][C:2]([CH3:13])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].C(=O)=O.CC(C)=O.C([N-]C(C)C)(C)C.[Li+].CN1CCCN(C)C1=O.[CH3:38][S:39]SC>O1CCCC1>[CH3:1][C:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:13])[CH:3]([S:39][CH3:38])[C:4]([OH:6])=[O:5]
Reactant: CSSC
Reactant: CC(C)(CC(=O)O)c1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: O=C=O
Agent: [Li+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CSC(C(=O)O)C(C)(C)c1ccccc1
Temperature: 25 °C

Procedure:
In accordance with a modified literature procedure (Pfeffer, P. E.; Silbert, L. S.; Chirinko, J. M. J. Org. Chem. 37(3), 1972, 451-458), a solution of 3,3-dimethyl-3-phenyl propionic acid (0.50 g, 2.8 mmol, from Reference Example 22) in tetrahydrofuran (5 mL) is cooled to −40° C. (dry ice/acetone) while stirring under a nitrogen atmosphere. Lithium diisopropylamide (Aldrich, 2.0 M solution in tetrahydrofuran/ethylbenzene/heptane, 3.1 mL, 6.2 mmol) is added dropwise via syringe, followed by 1,3-dimethyl-3,4,5,6-tetrahydro-2(1 H)-pyrimidinone (DMPU, 0.37 mL, 3.1 mmol). The reaction mixture is then allowed to warm to room temperature and to stir for 30 minutes before being re-cooled to 0° C. (ice water bath). Dimethyl disulfide (0.38 mL, 4.2 mmol) is then added neat via syringe and the reaction mixture is allowed to stir for two days while warming to room temperature. The reaction is quenched by the addition of 10% aqueous hydrochloric acid solution and extracted thrice with ethyl acetate. The combined extracts are washed twice with 10% aqueous hydrochloric acid solution and once with saturated sodium chloride solution, dried over anhydrous sodium sulfite, and concentrated under reduced pressure. Flash chromatography (silica gel, hexanes/dichloromethane/methanol) is performed to give a clear light brown oil which solidified upon standing (0.54 g, 86%). TOF MS (ES−): (M−H)=222.9
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].[OH-].[Na+].Br[CH2:13][CH2:14][CH2:15][CH3:16]>O.CCCCCCC>[CH2:13]([O:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[F:1])[CH2:14][CH2:15][CH3:16]
Reactant: CCCCBr
Reactant: Oc1cccc(F)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCCCCCC
Product: CCCCOc1cccc(F)c1F
Temperature: 30 °C
Reaction time: 2 h
Yield: 79.9 %

Procedure:
2,3-Difluorophenol (21) (100.0 g) and sodium hydroxide (NaOH; 36.9 g) were added to water (300 ml) under a nitrogen atmosphere, and the stirring was continued at 70° C. 1-Bromobutane (158.0 g) was added thereto, and the stirring was continued at 70° C. for 2 hours. The reaction mixture obtained was cooled to 30° C., heptane (100 ml) and water (100 ml) were added, and mixed. The mixture was then allowed to separate into organic and aqueous phases. The extraction into an organic phase was carried out. The organic phase obtained was washed with brine and dried over anhydrous magnesium sulfate. Then, fractional distillation was carried out under reduced pressure, giving 114.4 g of 4-butoxy-2,3-difluorobenzene (22). The compound (22) obtained was a colorless oil having a boiling point of 109° C. to 110° C./20 mmHg. The yield based on the compound (21) was 80.0%.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[C:4](=[CH:5][S:6][CH:7]=2)[O:3][CH2:2]1.[Li]CCCC.[Sn:15](Cl)([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH3:19]>C1COCC1>[CH2:24]([Sn:15]([CH2:16][CH2:17][CH2:18][CH3:19])([CH2:20][CH2:21][CH2:22][CH3:23])[C:5]1[S:6][CH:7]=[C:8]2[O:9][CH2:1][CH2:2][O:3][C:4]=12)[CH2:25][CH2:26][CH3:27]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: c1scc2c1OCCO2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1scc2c1OCCO2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A structure of the product is depicted schematically in FIG. 13. To a cold (−15° C.) solution of 3,4-ethylenedioythiophene (EDOT) (20 ml, 188 mmol) in 350 mL of THF were slowly added 138 mL (207 mmol, 1.1 equiv) of nBuLi. The white slurry was allowed to stir at −15° C. for 3 h before the addition of 61.6 mL (227 mmol, 1.2 equiv) of Bu3SnCl. The beige slurry was allowed to stir while warming to room temperature for 18 h. The solvent was removed under vacuum and then stiffed in hexane for 30 min. The slurry was filtered through Celite and the amber filtrate was removed under vacuum to yield a yellow-orange oil which was purified by distillation (b.p. 120° C./30 mTorr) to yield 79.6 g (185, mmol 98%) of pale yellow oil. 1H NMR (CDCl3) δ6.57 (s, 1H), 4.20-4.10 (m, 4H), 1.62-1.50 (m, 6H), 1.40-1.25 (m, 6H), 1.12-1.06 (m, 6H), 0.89 (t, 3H). MS m/z 433 (M+H+); HRMS (FAB) m/z 433.1225 (M+H+); calcd for C18H32O2SSn m/z 433.1223 (M+H+).
Reaction SMILES: CS(Cl)(=O)=O.[C:6]([O:10][C:11]([NH:13][C:14]1[C:15]([NH:19][C:20](=[O:29])[C:21]2[CH:26]=[CH:25][C:24]([CH2:27]O)=[CH:23][CH:22]=2)=[CH:16][S:17][CH:18]=1)=[O:12])([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C.[NH2:37][CH2:38][CH2:39][CH2:40][N:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1>ClCCl.C(OCC)(=O)C.O.C(#N)C>[C:6]([O:10][C:11]([NH:13][C:14]1[C:15]([NH:19][C:20](=[O:29])[C:21]2[CH:26]=[CH:25][C:24]([CH2:27][NH:37][CH2:38][CH2:39][CH2:40][N:41]3[CH2:46][CH2:45][O:44][CH2:43][CH2:42]3)=[CH:23][CH:22]=2)=[CH:16][S:17][CH:18]=1)=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: NCCCN1CCOCC1
Reactant: CC(C)(C)OC(=O)Nc1cscc1NC(=O)c1ccc(CO)cc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cscc1NC(=O)c1ccc(CNCCCN2CCOCC2)cc1
Reaction time: 1.5 h
Yield: 39 %

Procedure:
Under ice cooling, methanesulfonyl chloride (0.37 mL, 4.8 mmol) was added to a solution of N-(4-t-butoxycarbonylaminothiophen-3-yl)-4-hydroxymethylbenzamide (Reference Compound No. 3-2, 1.51 g, 4.3 mmol) and triethylamine (1.5 mL, 11 mmol) in anhydrous dichloromethane (70 mL), and the reaction mixture was stirred for 1.5 hours. Acetonitrile (50 mL) and N-(3-aminopropyl)morpholin (3.1 mL, 21 mmol) were added to the reaction solution and the mixture was stirred at room temperature overnight. Water (0.20 L) and ethyl acetate (0.20 L) were added to the reaction solution, and then the mixture was partitioned. The organic layer was washed with brine (0.20 L), dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol) to give 0.81 g of the title reference compound as yellow oil. (Yield 39%)
Reaction SMILES: [F:1][C:2]1([C:6]2[C:7]([O:15][C@@H:16]([CH3:21])[C:17]([F:20])([F:19])[F:18])=[CH:8][C:9]([C:12](O)=[O:13])=[N:10][CH:11]=2)[CH2:5][O:4][CH2:3]1.[CH3:22][C:23]([CH3:33])([CH3:32])[CH:24]([C:26]1[O:27][C:28]([CH3:31])=[N:29][N:30]=1)[NH2:25]>>[CH3:22][C:23]([CH3:33])([CH3:32])[CH:24]([NH:25][C:12]([C:9]1[CH:8]=[C:7]([O:15][C@@H:16]([CH3:21])[C:17]([F:20])([F:19])[F:18])[C:6]([C:2]2([F:1])[CH2:3][O:4][CH2:5]2)=[CH:11][N:10]=1)=[O:13])[C:26]1[O:27][C:28]([CH3:31])=[N:29][N:30]=1
Reactant: C[C@H](Oc1cc(C(=O)O)ncc1C1(F)COC1)C(F)(F)F
Reactant: Cc1nnc(C(N)C(C)(C)C)o1
Product: Cc1nnc(C(NC(=O)c2cc(O[C@@H](C)C(F)(F)F)c(C3(F)COC3)cn2)C(C)(C)C)o1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-(3-fluorooxetan-3-yl)-4-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine-2-carboxylic acid (example 142b) and 2,2-dimethyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)propan-1-amine (example 174b) as starting materials and isolated (70 mg, 47%); MS (ESI, m/z): 461.5 (M+H+).
Reaction SMILES: Cl.[CH3:2][CH:3]1[NH:8][CH2:7][CH2:6][N:5]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[C:4]1=[O:20].[N+:21]([C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH:31]=O)=[CH:26][CH:25]=1)([O-:23])=[O:22].C(O)C.C([BH3-])#N.[Na+]>C(OCC)(=O)C>[CH3:2][CH:3]1[N:8]([CH2:31][CH2:30][C:27]2[CH:26]=[CH:25][C:24]([N+:21]([O-:23])=[O:22])=[CH:29][CH:28]=2)[CH2:7][CH2:6][N:5]([CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=2)[C:4]1=[O:20]
Reactant: CC1NCCN(CCc2ccc([N+](=O)[O-])cc2)C1=O
Reactant: O=CCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC1C(=O)N(CCc2ccc([N+](=O)[O-])cc2)CCN1CCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a mixture of 3-Methyl-1-[2-(4-nitrophenyl)ethyl]piperazin-2-one hydrochloride (38 mg, 0.13 mmol) and (4-Nitrophenyl)acetaldehyde (31 mg, 0.19 mmol) was added_titanium(IV) isopropoxide (0.37 mL, 1.3 mmol). After stirring the mixture at RT for 15 minutes, ethanol (2 mL) and sodium cyanoborohydride (80 mg, 1.3 mmol) were added to the reaction. The mixture was allowed to stir at RT for 16 hours. The reaction was diluted with ethyl acetate, washed with brine, dried over sodium sulfate, and concentrated to give the crude title product. The title product was purified by mass-directed reverse phase HPLC (AcCN-Water with 0.1% TFA). LC-MS (IE, m/z): 413 [M+1]+.