Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[N:8][NH:7][C:6]=2[CH:10]=1.[OH-].[Na+].[Cl:13][CH2:14][CH2:15][CH2:16][CH2:17]Br>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[N:8][N:7]([CH2:17][CH2:16][CH2:15][CH2:14][Cl:13])[C:6]=2[CH:10]=1
Reactant: Fc1ccc2nn[nH]c2c1
Reactant: ClCCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Product: Fc1ccc2nnn(CCCCCl)c2c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 74.7 %

Procedure:
6-fluoro-benzotriazole (15.3 g, 0.10 mol) is dissolved into 100 ml of 30% wt. sodium hydroxide, 4-chlorobromobutane (34.3 g, 0.20 mol), tetrabutyl ammonium bromide (0.8 g) are added, and mixed for 5 min. The reaction solution is gradually heated to 60° C., stirred for reaction for 2 hours. Then the reaction solution was cooled down to ambient temperature, 100 ml of dichloromethane was added for extraction and liquid separation. To the aqueous phase, 100 of dichloromethane was added for extraction. Organic phases were mixed, washed with 100 ml of saturated saline. Liquid was separated, and organic phase was evaporated to dryness to produce oily product. Oily products were separated and purified by chromatography with neutral Al2O3, and eluted with dichlormethane to produce 17.0 g of 6-fluoro-1-(4-chlorobutyl)-1H-benzotriazole, with a yield of 77.0%.
Reaction SMILES: [N:1](=[C:3]1[N:7]=[C:6]([CH3:8])[C:5]([CH3:10])([CH3:9])[S:4]1)[OH:2].[CH:11]1([N:14]=[C:15]=[O:16])[CH2:13][CH2:12]1>>[CH:11]1([NH:14][C:15]([O:2][N:1]=[C:3]2[N:7]=[C:6]([CH3:8])[C:5]([CH3:10])([CH3:9])[S:4]2)=[O:16])[CH2:13][CH2:12]1
Reactant: CC1=NC(=NO)SC1(C)C
Reactant: O=C=NC1CC1
Product: CC1=NC(=NOC(=O)NC2CC2)SC1(C)C

Procedure:
2-oxo-4,5,5-trimethyl-3-thiazoline-oxime was reacted with cyclopropyl isocyanate as described in Example 4 to yield 2-oxo-4,5,5-trimethyl-3-thiazoline-O-(cyclopropylcarbamoyl)-oxime, m.p. 86°-89° C.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.Br[CH2:11][CH2:12][CH2:13][OH:14]>ClCCl>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH2:11][CH2:12][CH2:13][OH:14])=[C:4]([CH3:9])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1N
Reactant: OCCCBr
Solvent: ClCCl
Product: Cc1cc(Cl)ccc1NCCCO
Temperature: 100 °C
Yield: 143.2 %

Procedure:
A mixture of 4-chloro-2-methylaniline (35.7 g) and 3-bromo-1-propanol (8.75 g) was heated at 100° C. under nitrogen for 1 hour. After cooling, a solid mass formed which was partitioned between dichloromethane and 1N sodium hydroxide. The organic layer was washed with brine, dried over anhydrous potassium carbonate and concentrated in vacuo to give a brown oil. The crude material was dissolved in dichloromethane and absorbed onto a column of Merck-60 flash silica gel. Elution with a solvent gradient (from 100% dichloromethane to 95:5 dichloromethane-methanol) provided the title product (18.0 g, 90%) as a brown oil, which was used as such in the next step.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH:3]=1.[NH:19]1[CH2:29][CH2:28][CH:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:21][CH2:20]1>O.C(O)C>[CH2:26]([O:25][C:23]([CH:22]1[CH2:28][CH2:29][N:19]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[CH:3]=2)[CH2:20][CH2:21]1)=[O:24])[CH3:27]
Reactant: CCOC(=O)C1CCNCC1
Reactant: Clc1ccc(-c2cc(Cl)c3ccccc3n2)cc1
Solvent: CCO
Solvent: O
Product: CCOC(=O)C1CCN(c2cc(-c3ccc(Cl)cc3)nc3ccccc23)CC1

Procedure:
A mixture of 10 g (36.4 mmol) of 4-chloro-2-(4-chlorophenyl)quinoline, and 20 ml of ethyl isonipecotate was stirred and heated at 160°-170° for 2 hr. It was then cooled and diluted with 200 ml of water and 5 ml of ethanol. The solid which formed was collected, and recrystallized from ethanol to give 5.5 g of product ester, mp 124°-126°.
Reaction SMILES: [CH:1]([OH:4])([CH3:3])[CH3:2].[H-].[Na+].[CH:7]([O:10][C:11](=[O:21])[C:12]1[C:17](Cl)=[CH:16][C:15]([Cl:19])=[N:14][C:13]=1[CH3:20])([CH3:9])[CH3:8]>C1COCC1.[Cu]I>[CH:7]([O:10][C:11](=[O:21])[C:12]1[C:17]([O:4][CH:1]([CH3:3])[CH3:2])=[CH:16][C:15]([Cl:19])=[N:14][C:13]=1[CH3:20])([CH3:9])[CH3:8]
Reactant: Cc1nc(Cl)cc(Cl)c1C(=O)OC(C)C
Reactant: CC(C)O
Agent: [Cu]I
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc(Cl)cc(OC(C)C)c1C(=O)OC(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Anhydrous isopropanol (1.5 mL, 20 mmol) is added to a suspension of NaH (1.5 g of 60% dispersion in mineral oil, 37 mmol) in THF (90 mL) at 0° C. and the mixture is stirred for 30 minutes at ambient temperature. To this is added a solution of 4,6-dichloro-2-methyl-nicotinic acid isopropyl ester (4.6 g, 19 mmol) in THF (10 mL) and CuI (178 mg, 0.94 mmol). The mixture is refluxed for 1 hour, cooled to room temperature, and poured into water-ice mixture. The layers are separated and the aqueous layer is extracted with EtOAc. The combined organic layers are dried (MgSO4) and concentrated in vacuo. The residue is purified by flash chromatography (elution with Hex/EtOAc 6:1) to yield 6-chloro-4-isopropoxy-2-methyl-nicotinic acid isopropyl ester as a pale yellow oil. 1H NMR (CDCl3) 6.65 (s, 1H), 5.24 (m, 1H), 4.60 (m, 1H), 2.41 (s, 3H), 1.28 (d, 12H).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[NH2:13][C:14]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:15]=1[O:16][C:17]1[CH:28]=[CH:27][C:20]([C:21]([NH:23][CH2:24][CH2:25][CH3:26])=[O:22])=[CH:19][CH:18]=1>>[Cl:33][C:31]1[CH:30]=[CH:29][C:15]([O:16][C:17]2[CH:28]=[CH:27][C:20]([C:21]([NH:23][CH2:24][CH2:25][CH3:26])=[O:22])=[CH:19][CH:18]=2)=[C:14]([NH:13][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:32]=1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Reactant: CCCNC(=O)c1ccc(Oc2ccc(Cl)cc2N)cc1
Product: CCCNC(=O)c1ccc(Oc2ccc(Cl)cc2Nc2ccnc3nc(C)ccc23)cc1

Procedure:
The product from Example 1d (111 mg, 0.62 mmol) was reacted with the product from Example 127b (190 mg, 0.62 mmol) for 18 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid (45.9 mg, 13%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 0.86 (t, J=7.54 Hz, 3 H) 1.39-1.60 (m, 2 H) 2.72 (s, 3 H) 3.08-3.26 (m, 2 H) 6.72 (d, J=6.99 Hz, 1 H) 6.96 (d, J=8.82 Hz, 2H) 7.29 (d, J=8.82 Hz, 1 H) 7.61 (dd, J=8.82, 2.57 Hz, 1 H) 7.69-7.80 (m, 4 H) 8.34 (t, J=5.52 Hz, 1H) 8.53 (d, J=6.99 Hz, 1 H) 8.82 (d, J=8.46 Hz, 1 H) 10.91 (s, 1 H) 14.55 (s, 1H); MS (ESI+) m/z 447 (M+H−TFA)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]=[C:3]([C:7]([O:9][CH3:10])=[O:8])[CH2:2]1.C(N(CC)CC)C.Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>C(Cl)Cl>[CH2:22]([O:21][C:19]([N:1]1[CH2:6][CH2:5][CH:4]=[C:3]([C:7]([O:9][CH3:10])=[O:8])[CH2:2]1)=[O:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)C1=CCCNC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1=CCCN(C(=O)OCc2ccccc2)C1
Temperature: -15 °C
Reaction time: 1.5 h
Yield: 93.1 %

Procedure:
Arecoline (39.5 g, 0.25 mol) was dissolved in dry toluene (20 ml). 1-Chloroethyl chloroformate (30.5 ml) was added slowly at 0-5° C. The mixture was heated at 80° C. for 2 h, cooled to room temperature, filtered and evaporated to dryness in vacuo. The residue was dissolved in methylene chloride (400 ml) and extracted with 10% aqueous sodium carbonate. The organic layer was dried over magnesium sulfate, filtered and evaporated to dryness to give methyl 1,2,5,6-tetrahydropyridine-3-carboxylate (Yield: 30.5 g, 85%). Methyl 1,2,5,6-tetrahydropyridine-3-carboxylate (1.1 g, 7.8 mmol) was dissolved in methylene chloride (20 ml) and cooled to -15° C. Triethyl amine (2.2 ml, 15,8 mmol) and a solution of benzyl chloroformate (1.2 ml, 8,4 mmol) in methylene chloride (10 ml) were added. Stirring at room temperature for 1.5 h followed by evaporation to dryness. The residue was dissolved in methylene chloride and extracted with water two times. The organic layer separated, dried and evaporated to dryness in vacuo to give methyl 1-benzyloxycarbonyl-1,2,5,6-tetrahydropyridine-3-carboxylate as an oil (Yield: 2.0 g, 92%).
Reaction SMILES: Br[CH2:2][CH2:3][O:4]/[N:5]=[C:6](/[C:12]1[N:13]=[C:14]([NH:17][C:18]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[S:15][CH:16]=1)\[C:7]([O:9][CH2:10][CH3:11])=[O:8].BrCCBr.[N-:41]=[N+:42]=[N-:43].[Na+]>CN(C=O)C>[N:41]([CH2:2][CH2:3][O:4]/[N:5]=[C:6](/[C:12]1[N:13]=[C:14]([NH:17][C:18]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[S:15][CH:16]=1)\[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N+:42]=[N-:43]
Reactant: CCOC(=O)/C(=N\OCCBr)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: BrCCBr
Solvent: CN(C)C=O
Product: CCOC(=O)/C(=N\OCCN=[N+]=[N-])c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1

Procedure:
The starting material was prepared as follows. Using the procedure of Footnote 15, ethyl 2-((Z)-2-bromoethoxyimino)-2-(2-tritylaminothiazol-4-yl)acetate was prepared from 1,2-dibromoethane, and reacted with sodium azide in DMF solution. Purification by chromatography gave ethyl 2-((Z)-2-azidoethoxyimino)-2-(2-tritylaminothiazol-4-yl)acetate, which was dissolved in 1,2-dimethyoxyethane and hydrogenated using 5% w/w palladium on charcoal as catalyst at ambient temperature and pressure for 16 hours. Catalyst was filtered off, and the solution was treated with bis(O-t-butyl)carbonic anhydride at ambient temperature. After 48 hours, the reaction was worked up conventionally, and the product isolated by chromatography on silica, eluting with 60:40 v/v hexane:EtOAc. The ethyl ester was saponified (see Footnote 15) to give 2-((Z)-2-t-butoxycarbonylaminoethoxyimino)-2-(2-tritylaminothiazol-4-yl)acetic acid, having the following n.m.r. in CDCl3 : 1.33(s, 9H); 3.37(m, 2H); 4.27(t, 2H); 5.38(br s, 1H); 6.59(s, 1H); s, 1H); 7.29(m, 16H).
Reaction SMILES: [Br:1][C:2]1[C:7]2=[N:8][O:9][N:10]=[C:6]2[C:5]([N+:11]([O-])=O)=[CH:4][CH:3]=1>CC(O)=O>[Br:1][C:2]1[C:7]2=[N:8][O:9][N:10]=[C:6]2[C:5]([NH2:11])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Br)c2nonc12
Solvent: CC(=O)O
Product: Nc1ccc(Br)c2nonc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 95.1 %

Procedure:
A solution of compound 422A (563 mg, 2.31 mmol) in AcOH (5 mL) was heated to 70° C. and Fe0 powder (258 mg, 4.62 mmol) was added in one portion. The resulting dark reaction mixture was stirred for 15 min, cooled to rt and concentrated under reduced pressure. The residue was taken up in EtOAc and the resulting solution was washed with sat. Na2CO3 solution. The organic layer was dried over Na2SO4, concentrated in vacuo and purified by flash chromatography on silica gel eluting with 10-60% EtOAc in hexanes to give 470 mg (95%) of compound 422B as a red solid.
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.Cl.[Cl:23][C:24]1[CH:25]=[C:26]([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:27]=[CH:28][CH:29]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:23][C:24]1[CH:25]=[C:26]([CH:30]2[CH2:35][CH2:34][N:33]([C:2]3[C:3]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:4][C:5]4[C:10]([N:11]=3)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=4)[CH2:32][CH2:31]2)[CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Reactant: Clc1cccc(C2CCNCC2)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCC(c4cccc(Cl)c4)CC3)nc2c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 71.2 %

Procedure:
A solution of methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (150 mg, 0.44 mmol, 1.00 equiv), 4-(3-chlorophenyl)piperidine hydrochloride (204.2 mg, 0.88 mmol, 2.00 equiv), and DIEA (194.8 mg, 1.51 mmol, 5.00 equiv) in DMF (4 mL) was placed in an 8-mL sealed tube and stirred overnight at 100° C. in an oil bath. The reaction was then quenched by the addition of water, then concentrated under vacuum. Purification via silica gel column (ethyl acetate/petroleum ether (1:100)) yielded 143.5 mg (64%) of methyl 3-(4-(3-chlorophenyl)piperidin-1-yl)-2-phenylquinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:29])[NH:6][CH:7]1[CH2:28][C:10]2[N:11]([CH2:20][C:21]3[C:26](Cl)=[N:25][CH:24]=[CH:23][N:22]=3)[C:12]3[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][C:17]=3[C:9]=2[CH2:8]1)([CH3:3])[CH3:2].[NH3:30]>CN1CCCC1=O>[CH:1]([O:4][C:5](=[O:29])[NH:6][CH:7]1[CH2:28][C:10]2[N:11]([CH2:20][C:21]3[C:26]([NH2:30])=[N:25][CH:24]=[CH:23][N:22]=3)[C:12]3[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][C:17]=3[C:9]=2[CH2:8]1)([CH3:3])[CH3:2]
Reactant: N
Reactant: CC(C)OC(=O)NC1Cc2c(n(Cc3nccnc3Cl)c3ccc(C#N)cc23)C1
Solvent: CN1CCCC1=O
Product: CC(C)OC(=O)NC1Cc2c(n(Cc3nccnc3N)c3ccc(C#N)cc23)C1
Temperature: -78 °C
Reaction time: 72 h
Yield: 28 %

Procedure:
In a screw-cap vial, dissolve (±)-[4-(3-chloro-pyrazin-2-ylmethyl)-7-cyano-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl]-carbamic acid isopropyl ester (30 mL, 0.073 mmol) in 1-methyl-2-pyrrolidinone (NMP) (0.5 mL) and cool to −78° C. Condense NH3 into the reaction mixture (1 mL), seal the reaction vessel, and warm to room temperature over 24 h. Heat the reaction up to 50° C. for 18 h, then at 80° C. for 72 h. Cool the reaction in a dry ice bath. Carefully open the reaction vessel and allow the liquid NH3 to evaporate. Dissolve the residue in EtOAc (50 mL) and wash the organics with water (3×20 mL). Dry the organics (MgSO4), filter, and concentrate to give 27 mg crude product as a colorless film. Purify on 4 g silica gel [50-100% EtOAc/(1:1 CH2Cl2/hexanes)] to give 8 mg (28%) of the title compound as a colorless film. LCMS 100% @ 4.23 min m/z 391 (M+H), 389 (M−H).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=3[O:24][CH3:25])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5])C.[OH-].[K+]>C(O)C>[F:23][C:21]1[CH:20]=[CH:19][C:18]([O:24][CH3:25])=[C:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=[CH:8]3)[CH:12]=2)[CH:22]=1
Reactant: CCOC(=O)c1cn(-c2cccc(-c3cc(F)ccc3OC)c2)cn1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(F)cc1-c1cccc(-n2cnc(C(=O)O)c2)c1

Procedure:
This compound was prepared by hydrolysis of 23b using a 1:1 mixture of aqueous potassium hydroxide (2M) and ethanol.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][OH:9].[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]Br.[OH-].[Na+]>O>[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:9][CH2:8][CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: OCCc1ccccn1
Reactant: BrCCCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: BrCCCCCCOCCc1ccccn1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 2-pyridineethanol (5 g), 1,6-dibromohexane (20 ml), 50% (w/v) sodium hydroxide (20 ml) and TAB (500 mg) was stirred at room temperature for 6 h. Water (100 ml) was added and the mixture was extracted with ether (2×100 ml). The organic extracts were washed with water and brine, dried and concentrated to an oil which was purified by FCC eluting with hexane→hexane-ether (1:1) to give the title compound as a colourless oil (6.6 g), t.l.c. (hexane-ether 1:1) Rf 0.19.
Reaction SMILES: [CH3:1][O:2][C:3]1([CH2:6][CH2:7][NH2:8])[CH2:5][CH2:4]1.[Cl:9][CH2:10][CH2:11][N:12]=[C:13]=[O:14]>C1COCC1>[Cl:9][CH2:10][CH2:11][NH:12][C:13]([NH:8][CH2:7][CH2:6][C:3]1([O:2][CH3:1])[CH2:5][CH2:4]1)=[O:14]
Reactant: O=C=NCCCl
Reactant: COC1(CCN)CC1
Solvent: C1CCOC1
Product: COC1(CCNC(=O)NCCCl)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.6 %

Procedure:
A 0° C. solution of 2-(1-methoxycyclopropyl)ethanamine (0.361 g, 2.413 mmol) in THF (15 mL) was treated drop-wise with 2-chloroethyl isocyanate (0.226 mL, 2.65 mmol), allowed to warm to RT, stirred overnight, then concentrated to dryness. The residue was treated with toluene and concentrated to dryness (twice) to afford 1-(2-chloroethyl)-3-(2-(1-methoxycyclopropyl)ethyl)urea (429 mg, 81%) as a yellow oil. MS (ESI) m/z: 221.1 (M+H+).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:10][CH2:11][CH3:12])[C:5]1[S:6][CH:7]=[CH:8][CH:9]=1)[CH3:2].C([Li])CCC.[CH2:18]([Sn:22](Cl)([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH3:21]>O1CCCC1>[CH2:11]([O:10][CH:4]([O:3][CH2:1][CH3:2])[C:5]1[S:6][C:7]([Sn:22]([CH2:23][CH2:24][CH2:25][CH3:26])([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:18][CH2:19][CH2:20][CH3:21])=[CH:8][CH:9]=1)[CH3:12]
Reactant: CCOC(OCC)c1cccs1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1ccc(C(OCC)OCC)s1
Temperature: -78 °C
Reaction time: 1 h
Yield: 77.4 %

Procedure:
18.6 g (100 mmol) of 2-(diethoxymethyl) thiophene in 100 ml of tetrahydrofuran ("THF") was placed in a 2-neck flask equipped with dropping funnel. The solution was cooled to -78° C. under nitrogen atmosphere and added 62.5 mL of 1.6 M n-butyl lithium (100 mmol) dropwise through dropping funnel in 1 hr. The reaction mixture was stirred at -78° C. for 1 hr and gradually warmed up to room temperature. After stirred for 30 minutes, the mixture was again cooled to -78° C. and added dropwise a THF (50 mL) solution of 32.5 g (100 mmol) of tributyl tin chloride with continual stirring. Gradually warmed up to room temperature, the mixture was stirred for another 10-12 hrs at room temperature and then concentrated. Reduced pressure distillation yielded 36.8 g (80%) of 2-(diethoxymethyl)-5-(tributylstannyl) thiophene (bp 195° C./1 torr).
Reaction SMILES: [N+:1]([C:4]1[C:5](=[O:15])[NH:6][C:7]([CH3:14])=[C:8]([CH2:10][CH2:11][CH2:12][CH3:13])[CH:9]=1)([O-])=O>CO.O1CCCC1.[Pd]>[NH2:1][C:4]1[C:5](=[O:15])[NH:6][C:7]([CH3:14])=[C:8]([CH2:10][CH2:11][CH2:12][CH3:13])[CH:9]=1
Reactant: CCCCc1cc([N+](=O)[O-])c(=O)[nH]c1C
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCc1cc(N)c(=O)[nH]c1C
Reaction time: 15 h
Yield: 88.8 %

Procedure:
A solution of 3-nitro-5-butyl-6-methylpyridin-2(1H)-one (293 mg, 1.40 mmol) in methanol (10 mL) and tetrahydrofuran (10 mL) containing 5% palladium/carbon (120 mg) was hydrogenated at atmosphere pressure for 10-20 hours. The catalyst was filtered off and the solvent evaporated. This residue was triturated with diethyl ether to give 224 mg (89%) of grayish product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([CH2:13][CH:14]([CH3:16])[CH3:15])[CH:11]=[N:10][C:9]=1[C:17]([OH:19])=O.C(Cl)(=O)C(Cl)=O.[NH3:26]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([CH2:13][CH:14]([CH3:15])[CH3:16])[CH:11]=[N:10][C:9]=1[C:17]([NH2:26])=[O:19]
Reactant: N
Reactant: CC(C)Cn1cnc(C(=O)O)c1-c1ccccc1Br
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: CC(C)Cn1cnc(C(N)=O)c1-c1ccccc1Br
Yield: 80.5 %

Procedure:
A 0.2 M solution of 5-(2-bromophenyl)-1-isobutyl-1H-imidazole-4-carboxylic acid (1.42 g; 4.4 mM) in anhydrous THF is added drop by drop, at 0° C., with oxalyl chloride (376 μl; 4.4 mM), then left to react at room temperature for about one hour, thus obtaining 5-(2-bromophenyl)-1-isobutyl-1H-imidazole-4-chlorocarbonyl. The mixture is then added drop by drop with 3 ml of conc. NH3 and reacted for one hour, then extracted with ethyl acetate, dried over Na2SO4, filtered and evaporated under reduced pressure, thereby obtaining 1.14 g of 5-(2-bromophenyl)-1-isobutyl-1H-imidazole-4-carboxamide which is used directly in the subsequent reaction. (Yield: 80.5%).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[CH:8][C:9]=1[N:10]([C:29]([CH:31]1[CH2:36][CH2:35][CH:34]([CH3:37])[CH2:33][CH2:32]1)=[O:30])[CH:11]1[CH2:16][CH2:15][CH:14]([O:17]C(=O)C2C=CC([N+]([O-])=O)=CC=2)[CH2:13][CH2:12]1)=[O:4].O.[Li+].[OH-]>O1CCOCC1>[OH:17][CH:14]1[CH2:15][CH2:16][CH:11]([N:10]([C:29]([CH:31]2[CH2:32][CH2:33][CH:34]([CH3:37])[CH2:35][CH2:36]2)=[O:30])[C:9]2[CH:8]=[C:7]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[S:6][C:5]=2[C:3]([OH:4])=[O:2])[CH2:12][CH2:13]1
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)C1CCC(C)CC1)C1CCC(OC(=O)c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC1CCC(C(=O)N(c2cc(-c3ccccc3)sc2C(=O)O)C2CCC(O)CC2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 46.5 %

Procedure:
3-{(4-Methyl-cyclohexanecarbonyl)-[4-(4-nitro-benzoyloxy)-cyclohexyl]-amino}-5-phenyl-thiophene-2-carboxylic acid methyl ester (44 mg, 0.073 mmol) was dissolved in a 4:1 mixture of dioxane:H2O (1 ml) and then LiOH 1N (365 ul, 0.365 mmol) was added. After 4 hours of stirring at room temperature, solvents were removed and then partitioned between 5 ml of H2O acidified to pH 4 and 5 ml of EtOAc. The organic layer was separated and the aqueous phase was washed twice with ethyl acetate (2×5 mL). The combined ethyl acetate layer was dried (Na2SO4) and concentrated. The residue was purified by preparative chromatography (10% MeOH/CH2Cl2) to obtain 15 mg (47%) of 3-[(4-Hydroxy-cyclohexyl)-(4-methyl-cyclohexanecarbonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.[F:9][C:10]([F:23])([O:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=O)[CH:11]([F:13])[F:12].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C>[F:9][C:10]([F:23])([O:14][C:15]1[CH:16]=[C:17]([CH2:18][NH:1][C:2]2[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=2)[CH:20]=[CH:21][CH:22]=1)[CH:11]([F:12])[F:13]
Reactant: O=Cc1cccc(OC(F)(F)C(F)F)c1
Reactant: Nc1cccc(S)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: FC(F)C(F)(F)Oc1cccc(CNc2cccc(S)c2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.9 %

Procedure:
EX-473A) 3-Aminobenzenethiol (2.4 mL, 22.5 mmol) and 3-(1,1,2,2-tetrafluoro-ethoxy)benzaldehyde (5 g, 22.5 mmol) were dissolved in 40 mL of dichloroethane and acetic acid (1.35 mL, 23.7 mmol), then solid NaBH(OAc)3 (6.2 g, 29.3 mmol) was added. The mixture was stirred at room temperature for 18 hours, then quenched with water and diluted with dichloromethane. The organic layer was washed with aqueous saturated sodium bicarbonate, then dried over MgSO4, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate:hexane 1:10 to give 5.36 g (72%) of the desired 3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]benzenethiol product as a brown oil. 1H NMR (CDCl3) δ3.4 (s, 1H), 4.4 (s, 2H), 5.9 (tt, 1H), 6.4 (dd, 1H), 6.55 (m, 1H), 6.65 (d, 1H), 7.05 (t, 1H), 7.2-7.4 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](Cl)[CH2:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[C:4]([CH3:16])[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[NH2:23][C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1.[I-].[Na+]>O.CC(N(C)C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:23][C:24]2[CH:25]=[CH:26][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:32][CH:33]=2)[CH2:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[C:4]([CH3:16])[CH:3]=1
Reactant: Cc1cc(Br)ccc1C(Cl)CCC(F)(F)F
Reactant: COC(=O)c1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COC(=O)c1ccc(NC(CCC(F)(F)F)c2ccc(Br)cc2C)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 231.4 %

Procedure:
A reaction mixture of 4-bromo-1-(1-chloro-4,4,4-trifluorobutyl)-2-methylbenzene (369 g), sodium carbonate (245% g), methyl 4-aminobenzoate (194 g), sodium iodide (347 g) and DMA (1.2 L) was stirred at 50° C. for 3 hr. The reaction mixture was added to water. This reaction was performed for 3 batches, the obtained respective reaction mixtures were combined, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting solid was collected by filtration and washed with petroleum ether to give the title compound (1164 g).