Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]=[C:15]([C:17]#[N:18])[C:14]([N+:19]([O-])=O)=[CH:13][CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[OH-].[NH4+]>CO.Cl.[Fe]>[NH2:19][C:14]1[C:15]([C:17]#[N:18])=[N:16][C:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:12][CH:13]=1
Reactant: COc1ccc(-c2ccc([N+](=O)[O-])c(C#N)n2)cc1OC
Agent: [Fe]
Agent: Cl
Agent: [NH4+]
Solvent: CO
Product: COc1ccc(-c2ccc(N)c(C#N)n2)cc1OC
Yield: 64.1 %

Procedure:
Iron (7.14 g, 128 mmol) was added portion wise to a stirred suspension of 6-(3,4-dimethoxyphenyl)-3-nitropyridine-2-carbonitrile (4.56 g; 16 mmol) in methanol (80 ml) and 37% HCl (25 ml). The mixture was refluxed for 5 hours and, after cooling, the pH was adjusted to 9-10 by means of concentrated ammonium hydroxide (30 ml). The mixture was filtered over Celite and washed with MeOH and EtOAc. The filtrate was evaporated to dryness and the residue was purified on silica gel column chromatography, using a mixture of CH2Cl2/EtOAc (in a ratio of 95:5) as eluent, to obtain the pure title compound (2.62 g, yield 64%) which was characterized by its mass spectrum as follows: MS (m/z): 256 ([M+H]+, 100).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[CH:16][N:15]=[C:14]2[CH3:24])=[CH:9][CH:8]=1.[OH-].[Na+].Cl>C(Cl)Cl>[CH3:24][C:14]1[N:13]([C:10]2[CH:11]=[CH:12][C:7]([OH:6])=[CH:8][CH:9]=2)[C:17]([C:18]2[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=2)=[CH:16][N:15]=1
Reactant: COc1ccc(-n2c(-c3ccncc3)cnc2C)cc1
Agent: BrB(Br)Br
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ncc(-c2ccncc2)n1-c1ccc(O)cc1
Temperature: 23 °C
Reaction time: 24 h
Yield: 72 %

Procedure:
A solution of boron tribromide (1 M in methylene chloride, 2.1 mL, 2.1 mmol) was added dropwise to a solution of Preparation 82 (4-(1-(4-methoxyphenyl)-2-methyl-1H-imidazol-5-yl)pyridine, 220 mg, 0.83 mmol) in methylene chloride (5 mL) at 0° C. After stirring at 23° C. for 24 h, aqueous sodium hydroxide solution (1 N, 15 mL) was added and the mixture was stirred at 23° C. for 1 h. The pH was adjusted to 7 by the addition of aqueous hydrochloric acid (1N), the mixture was extracted with methylene chloride/isopropanol (4:1, 3×30 mL), the combined organic layers were dried (MgSO4), were filtered, and were concentrated in vacuo. The residue was purified by silica gel chromatography using chloroform-methanol (20:1 to 10:1) to afford 150 mg (72% yield ) of the title compound; diagnostic 13C NMR signals (100 MHz, CDCl3) δ 159.337, 149.548, 149.302, 138.302, 131.131, 128.760, 128.170, 127.310, 121.163, 117.237, 13.881; MS (AP/Cl) 252.4 (M+H)+.
Reaction SMILES: [OH-].[K+].[CH2:3]([N:9]1[CH2:14][CH:13]2[CH:11]([C:12]2([C:16]2[CH:17]=[CH:18][C:19]([N+:26]([O-:28])=[O:27])=[C:20]([NH:22]C(=O)C)[CH:21]=2)[CH3:15])[CH2:10]1)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]>CO.O>[CH2:3]([N:9]1[CH2:14][CH:13]2[CH:11]([C:12]2([C:16]2[CH:17]=[CH:18][C:19]([N+:26]([O-:28])=[O:27])=[C:20]([NH2:22])[CH:21]=2)[CH3:15])[CH2:10]1)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCN1CC2C(C1)C2(C)c1ccc([N+](=O)[O-])c(NC(C)=O)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCCCN1CC2C(C1)C2(C)c1ccc([N+](=O)[O-])c(N)c1
Yield: 76.1 %

Procedure:
To a solution of potassium hydroxide (100 mg, 1.79 mmol) in methanol (5.0 ml) and water 2.0 ml) was added N-[5-(3-hexyl-6-methyl-3-azabicyclo[3.1.0]hex-6-yl)-2-nitrophenyl]acetamide (Preparation 46, 534 mg, 1.49 mmol) in methanol (5 ml). The mixture was heated under reflux for 30 minutes and then was allowed to cool. The solvent was removed in vacuo, water (5 ml) was added and the aqueous solution was extracted with ethyl acetate (3×5 ml). The combined extracts were dried (MgSO4), filtered and concentrated in vacuo to afford the title compound (360 mg, 76%) as a crude oil which was used without further purification.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C([C:27]1N=C(N2CCC(F)(F)C2)[C:30]2N=[N:34][NH:33][C:31]=2[N:32]=1)(C)(C)C.ClCC1N(C)C(C)=NN=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[N:32]([CH3:27])[C:31]([CH3:30])=[N:33][N:34]=3)[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Agent: Cc1nnc(CCl)n1C
Product: Cc1nnc(Cn2nc3nc(C(C)(C)C)nc(N4CCC(F)(F)C4)c3n2)n1C

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-(chloromethyl)-4,5-dimethyl-4H-1,2,4-triazole and isolated as light yellow solid. MS (m/e): 392.3 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH2:25][CH3:26])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.Cl[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=1)=[O:30]>>[CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][C:14]=2[CH2:23][N:24]([CH2:25][CH3:26])[C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)=[O:30])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: O=C(Cl)OCc1ccc(F)cc1
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC)C(=O)OCc1ccc(F)cc1

Procedure:
Prepared according to the procedure described in Example 56, Step 2, using the following starting materials: (2′-ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and 4-fluorobenzyl chloroformate.
Reaction SMILES: [CH2:1]([C:8]1[N:13]=[N:12][C:11]([N:14]2[CH2:19][CH2:18][C:17]([OH:38])([C:20]3[CH:25]=[CH:24][C:23]([C:26]([CH3:37])([O:28]COCC[Si](C)(C)C)[CH3:27])=[CH:22][N:21]=3)[CH2:16][CH2:15]2)=[C:10]([CH3:39])[C:9]=1[CH3:40])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([C:8]1[N:13]=[N:12][C:11]([N:14]2[CH2:15][CH2:16][C:17]([OH:38])([C:20]3[CH:25]=[CH:24][C:23]([C:26]([OH:28])([CH3:37])[CH3:27])=[CH:22][N:21]=3)[CH2:18][CH2:19]2)=[C:10]([CH3:39])[C:9]=1[CH3:40])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(Cc2ccccc2)nnc(N2CCC(O)(c3ccc(C(C)(C)OCOCC[Si](C)(C)C)cn3)CC2)c1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(Cc2ccccc2)nnc(N2CCC(O)(c3ccc(C(C)(C)O)cn3)CC2)c1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 0.1 %

Procedure:
To compound 35 (44 mg, 0.078 mol) in CH2Cl2 (1.5 mL) at 0° C. is added TFA (0.15 μL). The mixture is stirred at 0° C. for 2 h and is quenched with 25% ammonium acetate, extracted with ethyl acetate. The organic phase is washed with brine, dried and concentrated to give a yellow residue which is purified by silica gel chromatography (0-5% methanol in CH2Cl2) to give the desired product (17 mg, 50%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[C:12]([CH3:13])=[CH:11][C:10]([CH3:14])=[N:9]2)[N:5]=[C:4]([NH:15][CH:16]2[CH2:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17]2)[CH:3]=1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[CH3:14][C:10]1[CH:11]=[C:12]([CH3:13])[N:8]([C:6]2[N:5]=[C:4]([NH:15][CH:16]3[CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17]3)[CH:3]=[C:2]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[N:7]=2)[N:9]=1
Reactant: C1COCCN1
Reactant: Cc1cc(C)n(-c2nc(Cl)cc(NC3Cc4ccccc4C3)n2)n1
Product: Cc1cc(C)n(-c2nc(NC3Cc4ccccc4C3)cc(N3CCOCC3)n2)n1

Procedure:
Was prepared according to example 4 from [6-chloro-2-(3,5-dimethyl-pyrazol-1-yl)-pyrimidin-4-yl]-indan-2-yl-amine and morpholine. Mp. 66-70° C.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:3]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[F:21][C:22]([C:25]1[CH:26]=[CH:27][C:28]([O:33][C:34]([F:37])([F:36])[F:35])=[C:29]([CH:32]=1)[CH:30]=O)([F:24])[CH3:23].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[OH-].[Na+]>C(Cl)Cl>[C:11]([O:10][C:8]([N:4]1[CH2:5][CH2:6][CH2:7][C@H:2]([NH:1][CH2:30][C:29]2[CH:32]=[C:25]([C:22]([F:24])([F:21])[CH3:23])[CH:26]=[CH:27][C:28]=2[O:33][C:34]([F:35])([F:37])[F:36])[C@@H:3]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)[C@@H]1c1ccccc1
Reactant: CC(F)(F)c1ccc(OC(F)(F)F)c(C=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC[C@H](NCc2cc(C(C)(F)F)ccc2OC(F)(F)F)[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 66 h
Yield: 156.8 %

Procedure:
To a stirred solution of Compound 12 (500 mg, 1.81 mmol) and Compound 25 (552 mg, 2.17 mmol) in dry CH2Cl2 (10 ml) was added sodium triacetoxyborohydride (1.15 g, 5.43 mmol) portionwise at room temperature. Then to this was added acetic acid (109 mg, 1.81 mmol) at same temperature. The reaction mixture was stirred at room temperature for 66 h. The reaction mixture was basified to pH10-11 with 10% NaOH aq. with ice-cooling. The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined solution was washed with brine, dried (MgSO4), and concentrated in vacuo to give crude product (1.46 g) as a pale yellow oil. This was employed for the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[N:22]=[CH:23][NH:24][CH:25]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[H-].[Na+].I[CH2:29][CH3:30]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[N:22]=[CH:23][N:24]([CH2:29][CH3:30])[CH:25]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1c[nH]cn1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1cnc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(S)—N-{1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-1H-imidazole-4-carboxamide (250 mg, 0.705 mmol) in dry DMF (3 ml) was added slowly to the mixture of dry DMF (1 ml) and 55% NaH (61.4 mg, 1.41 mmol) at 0° C. under an nitrogen atmosphere. Thereafter the reaction mixture was stirred at RT for 30 min. The reaction mixture was recooled to 0° C. Iodoethane (0.057 ml, 0.712 mmol) was slowly added at 0° C. and then the reaction mixture was stirred at RT overnight. The reaction mixture was quenched with brine (20 ml), pH was adjusted over 9 with NaOH and the product was extracted into ethyl acetate (3×30 ml). The combined organic layers were washed with water, dried and concentrated. Flash chromatography on silica gel by using CH2Cl2-MeOH as a gradient eluent (100:0-99:1) afforded the title product. 1H NMR (400 MHz, DMSO-d6): 1.07 (3H, d), 1.34 (3H, t), 4.02 (2H, q), 4.20 (1H, distorted dd), 4.34 (2H, m), 6.95 (1H, d), 7.67 (1H, d), 7.76 (1H, d), 7.84 (1H, d), 8.00 (2H, m), 8.20 (1H, d), 8.27 (1H, d).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[CH2:5][CH:6]1[CH2:11][CH:10]([C:12]([O:14]C)=[O:13])[CH2:9][CH2:8][N:7]1[C:16]([O:18][CH3:19])=[O:17].[Br-].[Li+].C(N(CC)CC)C.CC(OC)(C)C>C(#N)C.O>[F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[CH2:5][CH:6]1[CH2:11][CH:10]([C:12]([OH:14])=[O:13])[CH2:9][CH2:8][N:7]1[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)C1CCN(C(=O)OC)C(Cc2cccc(F)c2)C1
Agent: [Br-]
Agent: [Li+]
Solvent: COC(C)(C)C
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)N1CCC(C(=O)O)CC1Cc1cccc(F)c1
Yield: 80.9 %

Procedure:
Dimethyl 2-(3-fluorobenzyl)piperidine-1,4-dicarboxylate (9.153 g, 29.59 mmol) was dissolved in acetonitrile (100 mL) and water (2 mL), then lithium bromide (20.56 g, 236.72 mmol) was added. Triethylamine (16.41 mL, 118.36 mmol) was added and the resulting brown suspension was heated at reflux for 2 h. Water (100 mL) and MTBE (300 mL) were added. The organic phase was extracted with water (×2). The pooled aqueous layer was acidified to pH 1 with 3.8 M HCl and then extracted with MTBE (×2). The combined organic layer was washed with water, dried over Na2SO4, filtered through a Celite containing filter and evaporated. 2-(3-Fluorobenzyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (7.07 g, 81%) was isolated as a yellow solid. MS m/z 296 (M+H)+
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1.[Li]CCCC.CON(C)[C:17]([C:19]1[CH:20]=[N:21][C:22]2[C:27]([C:28]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[CH:26][CH:25]=[CH:24][C:23]=2[C:35]([F:38])([F:37])[F:36])=[O:18].Cl>C1COCC1.CO>[CH3:8][C:4]1[CH:3]=[C:2]([C:17]([C:19]2[CH:20]=[N:21][C:22]3[C:27]([C:28]=2[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[CH:26][CH:25]=[CH:24][C:23]=3[C:35]([F:38])([F:37])[F:36])=[O:18])[CH:7]=[CH:6][CH:5]=1
Reactant: CON(C)C(=O)c1cnc2c(C(F)(F)F)cccc2c1-c1ccccc1
Reactant: Cc1cccc(Br)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cccc(C(=O)c2cnc3c(C(F)(F)F)cccc3c2-c2ccccc2)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 24 %

Procedure:
3-Bromotoluene (0.078 mL, 0.64 mmol) was taken into THF (3 mL) and cooled to −78° C. Next, BuLi (0.32 mL of a 2.0 M Solution, 0.64 mmol) was added dropwise and then stirred for 30 minutes. Next, N-methoxy-N-methyl-4-phenyl-8-(trifluoromethyl)quinoline-3-carboxamide (0.231 g, 0.64 mmol) in THF (2 mL) was added quickly via syringe and allowed to stir overnight. MeOH and 2 N HCl were added and stirred for 5 minutes. Then the mixture was extracted with ethyl acetate and dried over magnesium sulfate and concentrated. The resulting material was purified via column chromatography using 10% ethyl acetate in hexane as the eluent to afford 0.060 g of desired product as an off white solid. MS (ESI) m/z 392 ([M+H]+); Anal. Calcd. for C24H16F3NO: C, 73.65; H, 4.12; N, 3.58. Found: C, 73.34; H, 4.08; N, 3.31.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]3[N:14]=[C:15]([C:19]4[CH:24]=[CH:23][C:22]([O:25][C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)=[CH:21][CH:20]=4)[C:16]([C:17]#[N:18])=[C:12]3[N:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[BH4-].[Na+]>C(O)C>[NH2:1][C:2]1[CH:3]=[C:4]([CH:8]2[N:13]3[N:14]=[C:15]([C:19]4[CH:24]=[CH:23][C:22]([O:25][C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=5)=[CH:21][CH:20]=4)[C:16]([C:17]#[N:18])=[C:12]3[NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)nn2c(-c3cccc(N)c3)ccnc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCCC2c1cccc(N)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 89.1 %

Procedure:
To a solution of 7-(3-aminophenyl)-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (150 mg, 0.372 mmol) in ethanol (10 mL) was added NaBH4 (70 mg, 1.86 mmol). The mixture was stirred at rt for 16 hr and 60° C. for 2 hr. Then the reaction mixture was concentrated to a residue and partitioned between EA (50 mL) and brine (40 mL). Organic layer was separated from aqueous layer, washed with brine (50 mL×2), dried over Na2SO4 and concentrated to afford 135 mg (crude) of 7-(3-aminophenyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile as a yellow solid. MS (ESI) m/e [M+1]+ 408.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][O:12]2)[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10]
Reactant: CC(=O)c1ccc(O)cc1F
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(=O)c1ccc(OC2CCCCO2)cc1F
Yield: 74 %

Procedure:
A solution of 1-(2-fluoro-4-hydroxy-phenyl)-ethanone (130 mmol), 3,4-dihydro-2H-pyran (260 mmol) and a catalytic amount of pyridinium p-toluenesulfonate in CH2Cl2 (200 mL) was left overnight at room temperature. The organic phase was washed with 1 N NaOH (aq) (1×50 mL) and dried (K2CO3). Evaporation in vacuo gave a brown oil, that was purified by vacuumdistillation. The desired product was isolated as clear oil in 74% yield:
Reaction SMILES: [CH3:1][S:2][C:3]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2C(=O)C3=CC=CC=C3C2=O)=[C:11]([Cl:26])[CH:10]=1)([CH3:8])[C:4]([O:6][CH3:7])=[O:5].O.NN>CO>[CH3:1][S:2][C:3]([C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([Cl:26])[CH:10]=1)([CH3:8])[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)C(C)(SC)c1ccc(N2C(=O)c3ccccc3C2=O)c(Cl)c1
Agent: NN
Solvent: CO
Solvent: O
Product: COC(=O)C(C)(SC)c1ccc(N)c(Cl)c1
Temperature: 25 °C
Yield: 92 %

Procedure:
Methyl α-methylthio-α-(3-chloro-4-phthalimidophenyl)propionate was suspended in 7 ml of methanol, and 97 mg of hydrazine hydrate was added. The mixture was stirred at room temperature, and then heated under reflux for 1 hour. The mixture was concentrated under reduced pressure, and an aqueous solution of ammonium chloride and methylene chloride were added. The organic layer was separated, and dried over anhydrous sodium sulfate. Concentration under reduced pressure yielded 231 mg of methyl α-methylthio-α-(3-chloro-4-aminophenyl)propionate as a pale yellow oil. Yield 92%.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7](B(O)O)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].Br[C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([CH:27]=[O:28])[CH:21]=[CH:20]2.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.C(OCC)(=O)C.[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]([C:5]1[CH:6]=[C:7]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[CH:23]=[C:22]([CH:27]=[O:28])[CH:21]=[CH:20]3)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(B(O)O)cc1C(C)(C)C
Reactant: O=Cc1ccc2cc(Br)ccc2c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc(-c2ccc3cc(C=O)ccc3c2)cc1C(C)(C)C
Temperature: 25 °C
Yield: 92.4 %

Procedure:
A mixture of 3-(t-butyl)-4-methoxyphenyl boronic acid (0.424 g, 2.04 mmol), 6-bromo-2-naphthaldehyde (0.400 g, 1.70 mmol) and sodium carbonate (0.541 g, 5.10 mmol) in 10 mL of toluene:ethanol (4:1) and water (1 mL) was degassed with argon for 30 minutes. Tetrakis(triphenylphosphine) palladium(0) (0.059 g, 0.05 mmol) was added and the mixture heated at reflux for 17 hours. The solution was cooled to room temperature, diluted with ethyl acetate and washed successively with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified on silica gel (eluent: hexane:EtOAc, 9:1) to give 0.50 g of 6-[3-(t-butyl)-4-methoxyphenyl]-2-naphthaldehyde (76%) as a solid. 1H NMR (300 MHz; DMSO-d6, 300 MHz): 1.46 (s, 9H), 3.92 (s, 3H), 7.02 (d, J=8.7 Hz, 1H), 7.57 (dd, J1=8.7 Hz, J2=2.4 Hz, 1H), 7.66 (d, J=2.4 Hz, 1H), 7.84 (dd, J1=8.4 Hz, J2=1.8 Hz, 1H), 7.97 (brs, 2H), 8.04 (s, 1H), 8.05 (d, J=8.7 Hz, 1H), 8.35 (s, 1H), 10.16 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][N:18]=2)[C:12]([O:14][CH3:15])=[O:13])=[CH:5][CH:4]=1>C(O)(=O)C.[Pt](=O)=O>[F:19][C:2]([F:1])([F:20])[C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:10][CH:11]([C:12]([O:14][CH3:15])=[O:13])[CH2:16][CH2:17][NH:18]2)=[CH:7][CH:8]=1
Reactant: COC(=O)c1ccnc(-c2ccc(C(F)(F)F)cc2)c1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: COC(=O)C1CCNC(c2ccc(C(F)(F)F)cc2)C1
Reaction time: 5 h
Yield: 99 %

Procedure:
Methyl 2-(4-(trifluoromethyl)phenyl)isonicotinate (4.985 g, 17.73 mmol) was dissolved in acetic acid (45 mL) and platinum(IV) oxide (0.232 g, 1.02 mmol) added. The resulting mixture was hydrogenated in a Büchi hydrogenator at room temperature and 5 bar for 5 h. More platinum(IV) oxide (0.116 g, 0.51 mmol) was added and the hydrogenation continued at 5 bar for 1 h. The catalyst was filtered off and washed with MeOH and the eluate evaporated. DCM and 10% K2CO3 were added and the phases separated. The organic layer was washed with brine, passed through a phase separator and evaporated to yield methyl 2-(4-(trifluoromethyl)phenyl)piperidine-4-carboxylate (5.04 g, 99%) as a brown oil. MS m/z 288 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Cl:25])=[C:5]([CH:10]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)[O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[C:6]=1[C:7](O)=[O:8].[Cl-].[CH3:27][O:28][C:29]([C:31]1[CH:36]=[CH:35][C:34]([C@@H:37]([NH3+:39])[CH3:38])=[CH:33][CH:32]=1)=[O:30]>>[Cl:1][C:2]1[S:3][C:4]([Cl:25])=[C:5]([CH:10]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)[O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[C:6]=1[C:7]([NH:39][C@H:37]([C:34]1[CH:35]=[CH:36][C:31]([C:29]([O:28][CH3:27])=[O:30])=[CH:32][CH:33]=1)[CH3:38])=[O:8]
Reactant: COC(=O)c1ccc([C@H](C)[NH3+])cc1
Reactant: O=C(O)c1c(Cl)sc(Cl)c1C(OC1CCCCO1)c1cccc(Cl)c1
Agent: [Cl-]
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2c(Cl)sc(Cl)c2C(OC2CCCCO2)c2cccc(Cl)c2)cc1

Procedure:
2,5-Dichloro-4-[(3-chlorophenyl)(tetrahydro-2H-pyran-2-yloxy)methyl]thiophene-3-carboxylic acid from Example 8, Step 3 (207 mg, 0.491 mmol) was reacted with (1S)-1-[4-(methoxycarbonyl)phenyl]ethanaminium chloride from Example 1, Step 9 under conditions similar to Example 1, Step 10. The crude product was purified by Combi Flash chromatography system (2-8% EtOAc/toluene in 20 min.) to afford the desired product as a white foam.
Reaction SMILES: [NH2:1][C:2]([NH:4][C@H:5]([C:9]([N:11]1[CH2:19][C@H:18]([O:20][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[C:28]([CH:31]=[CH2:32])[CH:29]=3)[CH:24]=[CH:23][N:22]=2)[CH2:17][C@H:12]1[C:13]([O:15][CH3:16])=[O:14])=[O:10])[CH:6]([CH3:8])[CH3:7])=[S:3].Br[CH2:34][C:35](=O)[CH2:36][CH2:37][CH:38]=[CH2:39]>O1CCOCC1>[CH2:36]([C:35]1[N:1]=[C:2]([NH:4][C@H:5]([C:9]([N:11]2[CH2:19][C@H:18]([O:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([CH:31]=[CH2:32])[CH:29]=4)[CH:24]=[CH:23][N:22]=3)[CH2:17][C@H:12]2[C:13]([O:15][CH3:16])=[O:14])=[O:10])[CH:6]([CH3:8])[CH3:7])[S:3][CH:34]=1)[CH2:37][CH:38]=[CH2:39]
Reactant: C=CCCC(=O)CBr
Reactant: C=Cc1ccc2ccnc(O[C@@H]3C[C@@H](C(=O)OC)N(C(=O)[C@@H](NC(N)=S)C(C)C)C3)c2c1
Solvent: C1COCCO1
Product: C=CCCc1csc(N[C@H](C(=O)N2C[C@H](Oc3nccc4ccc(C=C)cc34)C[C@H]2C(=O)OC)C(C)C)n1

Procedure:
A solution of thiourea from Step 3 and Intermediate 3 (1.5 eq) in dioxane was stirred at 65° C. for 1 h. The volatiles were then removed under reduced pressure and the residue was purified by SiO2 gel chromatography (DCM/MeOH=98/2) to give the title compound as a pale brown oil. MS (ES+) C29H34N4O4S requires: 534. Found: 535 (M+H+).