Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:18]=[CH:17][C:9]([CH2:10][N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:8][C:7]=2[CH3:19])[CH2:2]1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[O:32][C:31]([C:33](OCC)=[O:34])=[N:30][N:29]=2)=[CH:24][CH:23]=1>C(O)C>[CH3:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[O:32][C:31]([C:33]([N:1]3[CH2:4][CH:3]([O:5][C:6]4[CH:18]=[CH:17][C:9]([CH2:10][N:11]5[CH2:12][CH2:13][O:14][CH2:15][CH2:16]5)=[CH:8][C:7]=4[CH3:19])[CH2:2]3)=[O:34])=[N:30][N:29]=2)=[CH:26][CH:27]=1
Reactant: Cc1cc(CN2CCOCC2)ccc1OC1CNC1
Reactant: CCOC(=O)c1nnc(-c2ccc(OC)cc2)o1
Solvent: CCO
Product: COc1ccc(-c2nnc(C(=O)N3CC(Oc4ccc(CN5CCOCC5)cc4C)C3)o2)cc1
Temperature: 120 °C
Yield: 71.8 %

Procedure:
A mixture of 12B (0.18 g, 0.69 mmol) and ethyl 5-(4-methoxyphenyl)-1,3,4-oxadiazole-2-carboxylate (0.19 g, 0.75 mmol) was heated to 120° C. for 3 h using an oil-bath. Ethanol (0.1 mL) was added and the mixture was further heated to 120° C. for 30 min. The product was purified by column chromatography eluting with DCM and then with MeOH/DCM (0.5-2%). There was obtained 0.23 g (71%) of 12 as a solid. 1H NMR (600 MHz, CDCl3): δ 2.22 (s, 3H), 2.33-2.50 (m, 4H), 3.39 (s, 2H) 3.60-3.77 (m, 4H), 3.86 (s, 3H), 4.26-4.36 (m, 1H), 4.57-4.78 (m, 2H), 4.99-5.16 (m, 2H), 6.42 (d, 1H), 6.99 (d, 2H), 7.05 (d, 1H), 7.12 (s, 1H), 8.07 (d, 2H), MS (APCI+) m/z 465 [M+H]+, LC purity: 99%.
Reaction SMILES: C(OC([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]1[C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[O:28][CH2:29][C:30]1[O:34][N:33]=[C:32]([O:35]CC2C=CC=CC=2)[CH:31]=1)=O)C1C=CC=CC=1>Br.C(O)(=O)C>[Cl:27][C:25]1[CH:24]=[CH:23][C:22]([O:28][CH2:29][C:30]2[O:34][N:33]=[C:32]([OH:35])[CH:31]=2)=[C:21]([CH:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:19][CH2:20][NH:11]2)[CH:26]=1
Reactant: O=C(OCc1ccccc1)N1CCc2ccccc2C1c1cc(Cl)ccc1OCc1cc(OCc2ccccc2)no1
Agent: Br
Solvent: CC(=O)O
Product: Oc1cc(COc2ccc(Cl)cc2C2NCCc3ccccc32)on1

Procedure:
A solution of (±)-1-[2-(3-benzyloxy-isoxazol-5-ylmethoxy)-5-chloro-phenyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (70 mg, 0.12 mmol, 1 eq.) in 33% hydrobromic acid in acetic acid (0.64 mL) was stirred at r.t. for 1.5 hours. The solvent was removed in vacuo. The residue, redissolved in MeCN/MeOH, was purified by prep. HPLC (column: Waters XBridge, 30×75 mm, 10 um, UV/MS, acidic conditions) and evaporated (genevac) to give (±)-5-[4-chloro-2-(1,2,3,4-tetrahydro-isoquinolin-1-yl)-phenoxymethyl]-isoxazol-3-ol.
Reaction SMILES: C([O:3][C:4](=[O:37])[CH:5]([C:10]1[CH:11]=[C:12]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:18][CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])C.[OH-].[Na+]>CO>[CH3:8][CH:7]([CH3:9])[CH2:6][CH:5]([C:10]1[CH:11]=[C:12]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:29][CH:28]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH:24]([CH3:25])[CH3:26])[CH2:18][CH2:17]2)[CH:15]=1)[C:4]([OH:37])=[O:3]
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCN(CCC(C)C)CC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)CCN1CCC(c2cc(-c3ccc(C(F)(F)F)cc3)cc(C(CC(C)C)C(=O)O)c2)CC1
Temperature: 50 °C

Procedure:
To a solution of a mixture of 4-methyl-2-{5-[1-(3-methyl-butyl)-piperidin-4-yl]-4′-trifluoromethyl-biphenyl-3-yl}-pentanoic acid ethyl ester and methyl ester (67 mg, 0.13 mmol) in MeOH (1 mL) was added 3N NaOH (0.130 mL) and heated to 50° C. for 2 h. The reaction was concentrated in vacuo to remove MeOH. The thick liquid was acidified to pH=2 by 2N HCl. The resulting acidic solution was extracted with EtOAc. The organic fraction was dried (MgSO4) and concentrated in vacuo. The crude mixture was purified by Gilson reverse phase column chromatography to obtain 4-methyl-2-{5-[1-(3-methyl-butyl)-piperidin-4-yl]-4′-trifluoromethyl-biphenyl-3-yl}-pentanoic acid.
Reaction SMILES: [NH2:1][C:2]1[C:12]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=1.C(=O)([O-])O.[Na+].[C:28](O)(=O)[CH3:29]>>[Cl:22][C:16]1[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=1[CH2:14][N:13]1[C:12]2[C:2](=[N:3][CH:4]=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:11]=2)[N:1]=[C:28]1[CH3:29]
Reactant: CC(=O)O
Reactant: CCOC(=O)c1cnc(N)c(NCc2ccc(Cl)cc2Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)c1cnc2nc(C)n(Cc3ccc(Cl)cc3Cl)c2c1
Temperature: 100 °C
Yield: 89.7 %

Procedure:
A suspension of ethyl 6-amino-5-(2,4-dichlorobenzylamino)nicotinate (300 mg) and acetic acid (132 mg) in polphosphoric acid (6 g) was heated to 100° C. Two hours later, the reaction mixture was cooled and ice (5 g) was added. The mixture was neutralized with a saturated aqueous sodium hydrogencarbonate and extracted with dichloromethane. The organic layer was washed with water, dried over anhydrous sulfate and filtrated. The filtrate was concentrated and the residue was crystallized from isopropyl ether to give the objective compound (288 mg) as pale-brown crystals.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH:16][CH:17]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][NH:25][C:26](=[O:35])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[NH:33][CH3:34])[CH2:19][CH2:18]1.C(N(CC)CC)C.[C:43](Cl)(Cl)=[S:44].O>ClCCl>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH:16][CH:17]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][N:25]2[C:26](=[O:35])[C:27]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:33]([CH3:34])[C:43]2=[S:44])[CH2:19][CH2:18]1
Reactant: S=C(Cl)Cl
Reactant: CNc1ccccc1C(=O)NCCN1CCC(Nc2nc3ccccc3n2Cc2ccco2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cn1c(=S)n(CCN2CCC(Nc3nc4ccccc4n3Cc3ccco3)CC2)c(=O)c2ccccc21
Reaction time: 8 h
Yield: 27.5 %

Procedure:
To a stirred mixture of 4.7 parts of N-[2-[4-[[1-(2-furanylmethyl)-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]-2-(methylamino)benzamide, 2.02 parts of N,N-diethylethanamine and 195 parts of dichloromethane was added dropwise a solution of 1.14 parts of carbonothioic dichloride in dichloromethane. Upon completion, stirring was continued overnight at room temperature. The reaction mixture was poured into water. The layers were separated. The organic layer was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (96:4 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile, yielding 1.4 parts (27.5%) of 3-[2-[4-[[1-(2-furanylmethyl)-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]-2,3-dihydro-1-methyl-2-thioxo-4(1H)-quinazolinone; mp. 188.4° C. (compound 129).
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)[N:15]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:27][C:24]1[CH:23]=[CH:22][C:21]([S:20][C:16]2[N:15]=[C:14]([C:12]3[S:4][C:3]4[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=4[C:1](=[O:10])[N:13]=3)[CH:19]=[CH:18][CH:17]=2)=[CH:26][CH:25]=1
Reactant: COC(=O)c1ccccc1S
Reactant: Cc1ccc(Sc2cccc(C#N)n2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc(Sc2cccc(-c3nc(=O)c4ccccc4s3)n2)cc1
Yield: 12.5 %

Procedure:
A mixture of methyl thiosalicylate (0.37 g, 2.2 mmol), 2-cyano-6-(4-methylphenyl)thiopyridine (0.50 g, 2.2 mmol), triethylamine (0.46 ml, 3.3 mmol) and toluene (30 ml) was refluxed for 48 hrs as described in Example 1. The solvent was concentrated under reduced pressure. The residue was recrystallized from ethanol to give the titled compound (0.10 g, 13%) as crystals.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:10][CH:9]1[CH:11]1[CH2:13][CH2:12]1.[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])(C)(C)C.[Na+].C(OCC)(=O)C>C(COC)OC>[CH2:14]([NH:21][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:10][CH:9]1[CH:11]1[CH2:13][CH2:12]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NCc1ccccc1
Reactant: Clc1ccccc1C1CC1C1CC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: c1ccc(CNc2ccccc2C2CC2C2CC2)cc1
Reaction time: 24 h
Yield: 87.1 %

Procedure:
3 g of 2-(2-chlorophenyl)bicyclopropyl (15.6 mmol, trans/cis ratio of about 2:1), 2.5 g of benzylamine (23.4 mmol), 2.4 g of sodium tert-butanolate (25 mmol), 35 mg of Pd(II) acetate (0.16 mmol) and 60 mg of R(−)-di-tert-butyl-[1-[(S)-2-(dicyclohexylphosphanyl)-ferrocenyl]ethyl]phosphine (0.11 mmol) are dissolved in 30 ml of dimethoxyethane. The reaction mixture is heated to the reflux temperature of the solvent and is stirred for 24 hours. After cooling, ethyl acetate is added and the organic phase is washed with water. The solvent is removed using a water jet vacuum and the residue is dried. The product is purified by column chromatography on silica gel (eluant:ethyl acetate/hexane 1:15). 3.58 g of benzyl(2-bicyclopropyl-2-yl-phenyl)amine (87% of theory) are obtained in the form of a brown oil (trans/cis ratio of about 2:1).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[N:8]=[CH:7][C:6]([OH:9])=[CH:5][N:4]=1.[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([F:22])[C:20]=1F)[CH:16]=[O:17].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([F:22])[C:20]=1[O:9][C:6]1[CH:7]=[N:8][C:3]([C:2]([F:1])([F:10])[F:11])=[N:4][CH:5]=1)[CH:16]=[O:17]
Reactant: O=Cc1cc(F)c(F)c(F)c1
Reactant: Oc1cnc(C(F)(F)F)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cc(F)c(Oc2cnc(C(F)(F)F)nc2)c(F)c1
Temperature: 130 °C
Yield: 98.2 %

Procedure:
To a solution of 2-(trifluoromethyl)pyrimidin-5-ol (1.5 g, 9.14 mmol) and 3,4,5-trifluorobenzaldehyde (1.464 g, 9.14 mmol) in DMF (18 mL), was added K2CO3 (1.642 g, 11.88 mmol). The mixture was heated with a microwave condition at 130° C. for 1 h. After cooling, the reaction mixture was diluted in water, extracted with EA. The organic phase was washed with water and brine, dried over Na2SO4, concentrated to afford the title compound (2.73 g, 8.98 mmol, 98% yield) as brown oil. LCMS: rt=3.16 min, [M+H+]=305
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=2)=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1.[CH2:21]([NH:23][CH2:24][CH3:25])[CH3:22]>C(Cl)Cl>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:15]=[CH:14][C:10]([C:11]([N:23]([CH2:24][CH3:25])[CH2:21][CH3:22])=[O:12])=[CH:9][CH:8]=2)=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1
Reactant: O=C(Cl)c1ccc(Oc2ccc(Cl)cc2[N+](=O)[O-])cc1
Reactant: CCNCC
Solvent: ClCCl
Product: CCN(CC)C(=O)c1ccc(Oc2ccc(Cl)cc2[N+](=O)[O-])cc1
Reaction time: 12 h

Procedure:
The compound from Example 126c (1.0 g, 3.2 mmol) in CH2Cl2 was added to a mixture of diethylamine (469 mg, 6.41 mmol) in CH2Cl2. Mixture was stirred for 12 hours. Mixture was concentrated under vacuum giving the title compound, which was purified by silica gel column chromatography eluting with 50% EtOAc/hexane giving a yellow oil (1.1 g, 100%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[N:17]([CH2:32][CH2:33][NH:34][CH2:35][CH:36]4[CH2:38][CH2:37]4)[CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[C:23]([C:28](F)(F)F)[CH:22]=4)[N:20]=3)[CH2:12][CH2:11]2)[N:5]=[CH:4][N:3]=1.NC1N=CN=C(N2CCC(C3N(CCOS(C)(=O)=O)C=C(C4C=CC(F)=C(C)C=4)N=3)CC2)C=1C#N>>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:11][CH2:12][CH:13]([C:16]3[N:17]([CH2:32][CH2:33][NH:34][CH2:35][CH:36]4[CH2:37][CH2:38]4)[CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[C:23]([CH3:28])[CH:22]=4)[N:20]=3)[CH2:14][CH2:15]2)[N:5]=[CH:4][N:3]=1
Reactant: N#Cc1c(N)ncnc1N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2CCNCC2CC2)CC1
Agent: Cc1cc(-c2cn(CCOS(C)(=O)=O)c(C3CCN(c4ncnc(N)c4C#N)CC3)n2)ccc1F
Product: Cc1cc(-c2cn(CCNCC3CC3)c(C3CCN(c4ncnc(N)c4C#N)CC3)n2)ccc1F

Procedure:
The title compound was prepared in an analogous manner as 4-Amino-6-{4-[1-[2-(cyclopropylmethyl-amino)-ethyl]-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile using methanesulfonic acid 2-[2-[1-(6-amino-5-cyano-pyrimidin-4-yl)-piperidin-4-yl]-4-(4-fluoro-3-methyl-phenyl)-imidazol-1-yl]-ethyl ester instead of methanesulfonic acid 2-[2-[1-(6-amino-5-cyano-pyrimidin-4-yl)-piperidin-4-yl]-4-(4-fluoro-3-trifluoromethyl-phenyl)-imidazol-1-yl]-ethyl ester. LC-MS: (M+1=475, obsd.=475).
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[O:17]1[CH2:18][CH2:19][N:14]([S:2]([C:5]2[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=2)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3])[CH2:15][CH2:16]1
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(O)c1cccc(S(=O)(=O)N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 52.1 %

Procedure:
3-(Chlorosulfonyl)benzoic acid (250 mg, 1.133 mmol) was added to morpholine (99 mg, 1.133 mmol) in the presence of potassium carbonate (313 mg, 2.266 mmol) in THF (5 mL) at room temperature, and reaction mixture allowed to stirred for 12 h at rt. The reaction was monitored by TLC. After completion of the reaction, the solvent was removed by vacuum, and then compound was purified by column chromatography (3% CH3OH/CH2Cl2) affording the title compound (160 mg) as a solid. 1H NMR (400 MHz, CD3OD): δ 8.34 (m, 1H), 8.32 (d, 1H, J=8.0 Hz), 7.99 (m, 1H), 7.76 (t, 1H, J=8.0 Hz), 3.70 (m, 4H), 2.98 (m, 4H). ESI-MS: 272.0 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.[CH3:16]O>>[CH3:16][O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([F:11])=[C:2]([NH2:1])[CH:3]=1
Reactant: Nc1cc(C(=O)O)ccc1F
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(F)c(N)c1
Temperature: 25 °C

Procedure:
To a stirred solution of 3-amino-4-fluoro-benzoic acid (25 g, 161 mmol) in methanol (300 mL) was added thionyl chloride (30 mL, 403 mmol) dropewise at 0° C. Then the mixture solution was refluxed for 12 hours before cooling to room temperature. Then the reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (500 mL), washed with saturated aqueous sodium bicarbonate solution (3×100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford 3-amino-4-fluoro-benzoic acid methyl ester (27.5 g, quant.) as a pale-white solid: LC/MS m/e calcd for C8H8FNO2 (M+H)+: 170.16, observed: 169.9.
Reaction SMILES: [NH2:1][CH:2](C(F)(F)F)[CH2:3][C:4]([NH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH3:17])[CH:15]=2)[N:10]=[C:9]([N:18]2[CH2:24][C:23]3[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=3[S:21](=[O:30])(=[O:29])[CH2:20][CH2:19]2)[CH:8]=1)=[O:5].O=S1(=O)C2C=CC=CC=2CN(C2C=C(N)C3C(=CC=C(C)C=3)N=2)CC1.O=C1C2C(=CC=CC=2)C(=O)N1CCC(Cl)=O>>[O:30]=[S:21]1(=[O:29])[C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[CH2:24][N:18]([C:9]2[CH:8]=[C:7]([NH:6][C:4](=[O:5])[CH2:3][CH2:2][NH2:1])[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH3:17])[CH:15]=3)[N:10]=2)[CH2:19][CH2:20]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NC(=O)CC(N)C(F)(F)F)c2c1
Agent: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(N)c2c1
Agent: O=C(Cl)CCN1C(=O)c2ccccc2C1=O
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NC(=O)CCN)c2c1

Procedure:
The title compound was prepared in analogy to 3-amino-N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-4,4,4-trifluorobutanamide in Example 42-1 in Scheme 19 by using 2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine and 3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propanoyl chloride. MS obsd. (ESI+) [(M+H)+] 425, 1H NMR (400 MHz, CDCl3) δ ppm 8.00 (d, J=7.83 Hz, 1 H), 8.29 (s, 1 H), 7.85 (d, J=7.33 Hz, 1 H), 7.61-7.47 (m, 4 H), 7.34 (d, J=12.13 Hz, 2 H), 5.12 (s, 2 H), 3.55 (brs, 2 H), 3.23 (d, J=5.56 Hz, 2 H), 2.62 (brs, 2 H), 2.44 (brs, 3 H), 1.66-2.10 (m, 2 H).
Reaction SMILES: [F:1][C:2]([F:32])([C:19]1[CH:24]=[CH:23][C:22]([CH:25]([CH3:31])[C:26]([O:28]CC)=[O:27])=[CH:21][CH:20]=1)[C:3]([F:18])([F:17])[C:4]([F:16])([F:15])[C:5]([F:14])([F:13])[C:6]([F:12])([F:11])[C:7]([F:10])([F:9])[F:8].Cl>C(O)C.[OH-].[Na+]>[F:1][C:2]([F:32])([C:19]1[CH:20]=[CH:21][C:22]([CH:25]([CH3:31])[C:26]([OH:28])=[O:27])=[CH:23][CH:24]=1)[C:3]([F:17])([F:18])[C:4]([F:15])([F:16])[C:5]([F:13])([F:14])[C:6]([F:12])([F:11])[C:7]([F:10])([F:9])[F:8]
Reactant: CCOC(=O)C(C)c1ccc(C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C(=O)O)c1ccc(C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc1
Temperature: 25 °C
Yield: 57.7 %

Procedure:
Ethyl 2-(4-[perfluorohexyl]phenyl)propionate (100 mg, 0.20 mmol) was dissolved in 5 mL of ethanol and 5 mL of 1N NaOH. The solution was heated to reflux for 1 hour, cooled to room temperature, poured into 30 mL of 1N HCl and extracted with three 10-mL portions of dicholormethane. Combination, drying (MgSO4), and concentration of the organic layers gave a residue which was purified by PTLC (one 2 mm silica gel plate eluted with 15% methanol-85% dichloromethane) to give 54 mg (57% yield) of 2-(4-[perflurohexyl]phenyl)propionic acid as a white powder.
Reaction SMILES: [S:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH2:10]O.O=S(Cl)[Cl:14]>ClCCl>[Cl:14][CH2:10][C:2]1[S:1][C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1
Reactant: OCc1cc2ncccc2s1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: ClCc1cc2ncccc2s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of thieno[3,2-b]pyridin-2-ylmethanol (C-4) (17 mg, 0.1 mmol) in anhydrous dichloromethane (10 mL) was added SOCl2 (120 mg). After the mixture was stirred at room temperature for 2 hours, it was concentrated and used for the next step without further purification. MS (m/z): 184 (M+1)+.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[C:12]1=[N:13][O:14][C:15]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH3:24])=[CH:18][CH:17]=3)=[C:11]1[CH2:10][CH2:9]2)[C:3](O)=[O:4].CN1CCOCC1.[NH2:35][CH2:36][C:37]#[N:38].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>[C:36]([CH2:37][NH:38][C:3](=[O:4])[CH:2]([OH:1])[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[C:12]1=[N:13][O:14][C:15]([C:16]3[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][CH3:24])=[CH:20][CH:21]=3)=[C:11]1[CH2:10][CH2:9]2)#[N:35]
Reactant: N#CCN
Reactant: CCCc1ccc(-c2onc3c2CCc2cc(C(O)C(=O)O)ccc2-3)cc1
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: CN1CCOCC1
Product: CCCc1ccc(-c2onc3c2CCc2cc(C(O)C(=O)NCC#N)ccc2-3)cc1
Reaction time: 8 h
Yield: 47.3 %

Procedure:
To a solution of 2-hydroxy-2-(3-(4-propylphenyl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)acetic acid (Example 127, 20 mg, 0.055 mmol) in DMF (1 mL) was added 4-methylmorpholine (0.036 mL, 0.33 mmol), 2-aminoacetonitrile (5.55 mg, 0.1 mmol) and BOP (43.8 mg, 0.1 mmol). The reaction mixture was stirred overnight and was then purified by preparative HPLC (Phenomenex Luna 5 u C18 21.2×100 mm, Solvent A: 90% water with 10% MeOH and 0.1% TFA, Solvent B: 90% MeOH with 10% water and 0.1% TFA, Gradient: 0% B to 100% B over 10 min, 20 mL/min, 220 nM, product retention time=11.9 min) to give N-(cyanomethyl)-2-hydroxy-2-(3-(4-propylphenyl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)acetamide (11.2 mg, 0.026 mmol, 46.9% yield): product HPLC ret. time=9.89 min. (condition G); LC/MS M+1=402.1; 1H NMR (400 MHz, CD3OD) δ ppm 7.88 (1H, d, J=7.92 Hz), 7.72 (2H, d, J=8.36 Hz), 7.43-7.53 (2H, m), 7.37 (2H, d, J=8.36 Hz), 5.13 (1H, s), 4.19 (2H, d, J=1.76 Hz), 3.06 (4H, s), 2.67 (2H, t, J=7.59 Hz), 1.62-1.77 (2H, m), 0.97 (3H, t, J=7.37 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][C@H:12]([NH:15]C(=O)OCC1C=CC=CC=1)[CH2:13][OH:14])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[NH2:15][C@H:12]([CH2:13][OH:14])[CH2:11][CH2:10][CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCC[C@@H](CO)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCC[C@H](N)CO

Procedure:
A solution of 169 mg (0.48 mmol) of benzyl [(1S)-4-[(tert -butoxycarbonyl)amino]-1-(hydroxymethyl)butyl]carbamate (Example Z4) in 50 ml of ethanol is hydrogenated after the addition of 17 mg of palladium on activated carbon (10%) under atmospheric pressure at RT for 4 h. The mixture is filtered through kieselguhr, and the residue is washed with ethanol. The filtrate is evaporated to dryness in vacuo. The product is reacted without further purification.
Reaction SMILES: [C:1](Cl)(=O)[C:2](Cl)=O.[Na].[Cl:8][C:9]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:10]=1[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][C:19]([OH:21])=[O:20]>C1C=CC=CC=1>[N:11]1[CH:10]=[CH:9][CH:25]=[CH:24][C:1]=1[CH2:2][O:20][C:19](=[O:21])[CH2:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[NH:11][C:10]1[C:9]([Cl:8])=[CH:25][CH:24]=[CH:23][C:22]=1[Cl:26]
Reactant: O=C(O)Cc1ccccc1Nc1c(Cl)cccc1Cl
Reactant: O=C(Cl)C(=O)Cl
Agent: [Na]
Solvent: c1ccccc1
Product: O=C(Cc1ccccc1Nc1c(Cl)cccc1Cl)OCc1ccccn1

Procedure:
While stirring, a mixture of 10 ml of oxalyl chloride and 20 ml of anhydrous benzene is added at 5°-10°C to a suspension of 10.0 g of the sodium salt of [o-(2,6-dichloro-anilino)-phenyl]-acetic acid in 100 ml of anhydrous benzene. The reaction mixture is then stirred for 3 hours at room temperature and the suspension is concentrated to dryness at 40°C and 11 Torr. The residue is treated with 40 ml of anhydrous benzene and the mixture is concentrated to dryness under 11 Torr. The residue, [o-(2,6-dichloro-anilino)-phenyl]-acetic acid chloride contaminated with sodium chloride, is treated with 50 ml of anhydrous benzene and, with stirring, subsequently with 2.5 g of 2-hydroxymethyl-pyridine at 10°C. The mixture is stirred for 1 hour at room temperature and concentrated at 40°C/11 Torr. the residue is treated with 150 ml of ether and 30 ml of 2 normal hydrochloric acid. The hydrochloric acid solution is isolated and shaken twice with 50 ml of ether and then made alkaline with 2 normal sodium hydroxide solution. The precipitated oil is dissolved in 50 ml of ether, the ether phase washed twice with 10 ml of water, dried over magnesium sulphate, and concentrated under 11 Torr at 40°C. The residue, [o-(2,6-dichloro-anilino)-phenyl]-acetic acid-(2-pyridyl)-methyl ester, is crystallised from ether/petroleum ether; m.p. 80°-81°C.
Reaction SMILES: CC1(C)C2C=C(C#CC3C=CC(C(O)=O)=CC=3)C=CC=2C(=O)CC1.[CH3:25][C:26]1([CH3:50])[C:35]2[CH:34]=[CH:33][C:32]([C:36]#[C:37][C:38]3[CH:48]=[CH:47][C:41]([C:42]([O:44]CC)=[O:43])=[CH:40][N:39]=3)=[CH:31][C:30]=2[C:29](=[O:49])[CH2:28][CH2:27]1>>[CH3:25][C:26]1([CH3:50])[C:35]2[CH:34]=[CH:33][C:32]([C:36]#[C:37][C:38]3[CH:48]=[CH:47][C:41]([C:42]([OH:44])=[O:43])=[CH:40][N:39]=3)=[CH:31][C:30]=2[C:29](=[O:49])[CH2:28][CH2:27]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(=O)CCC3(C)C)nc1
Agent: CC1(C)CCC(=O)c2ccc(C#Cc3ccc(C(=O)O)cc3)cc21
Product: CC1(C)CCC(=O)c2cc(C#Cc3ccc(C(=O)O)cn3)ccc21

Procedure:
Employing the same general procedure as for the preparation of 4-[[5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl]ethynyl]benzoic acid (Compound 7), 300 mg (0.86 mmol) of ethyl 6-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-3 -yl)ethynyl]nicotinate (Compound 3) was converted into the title compound (pale yellow solid) using 8.6 ml (8.6 mmol) of LiOH (1M aqueous solution) .