Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.Cl[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9]>[OH-].[K+]>[OH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:3]1
Reactant: OC1CCNC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [K+]
Agent: [OH-]
Product: O=C(OCc1ccccc1)N1CCC(O)C1
Yield: 81 %

Procedure:
A solution of 4.29 g (48.9 mmol) of 3-hydroxypyrrolidine in 30 mL of 2N potassium hydroxide was cooled to 0° C. and 10.2 mL of benzyl chloroformate were added with stirring. The reaction was stirred for four hours at 0° C. and then extracted with ethyl acetate (3×100 mL). The extracts were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacua. The residue was chromatographed on silica gel with 70/30 hexanes/ethyl acetate. The correct fractions were combined and concentrated in vacuo to give 8.87 g (81%) of benzyl 3-hydroxypyrrolidine-1-carboxylate as a viscous clear oil. Rf=0.11 in 50/50 hexanes/ethyl acetate Mass Spectrum (FD+): M+221; IR (CHCl3, cm-1): 913, 977, 993, 1100, 1117, 1175, 1236, 1360, 1427, 1454, 1498, 1694, 2884, 2954, 3013, 3020, 3436 (broad), 3610; UV (C2H5OH) λmax =205 (ε=9112), 264 (ε=142); 1H NMR (300 MHz, CDC13) δ: 1.91-2.05 (m-, 2H); 3.00 (broad s, 1H); 3.39-3.61 (m, 4H); 4.41 (s, 1H); 5.12 (s, 2H); 7.30-7.43 (m, 5H).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[N:12]=[C:11]([NH:13][NH2:14])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:15])[CH:9]=2)[N:4]=1.[CH:16](OCC)(OCC)OCC>>[Cl:1][CH2:2][C:3]1[N:12]2[CH:16]=[N:14][N:13]=[C:11]2[C:10]2[CH:9]=[C:8]([CH3:15])[CH:7]=[CH:6][C:5]=2[N:4]=1
Reactant: Cc1ccc2nc(CCl)nc(NN)c2c1
Reactant: CCOC(OCC)OCC
Product: Cc1ccc2nc(CCl)n3cnnc3c2c1
Temperature: 100 °C

Procedure:
4. 58.2 g of 2-(chloromethyl)-4-hydrazino-6-methylquinazoline in 870 ml of triethyl orthoformate are heated to reflux temperature while stirring in an oil bath pre-heated to 100° C. and stirred at this temperature for a further 0.5 h. (bath temperature 140°-145° C.). About 40 ml of ethanol are distilled off during the heating. Thereafter, the mixture is concentrated in a vacuum to a volume of about 150 ml. 150 ml of diethyl ether are then added thereto, the mixture is cooled to 0° to 5° C. and the crystals are filtered off. The product is washed with ethanol/diethyl ether 1:2 and with diethyl ether and dried in a vacuum. 55.1 g of crude 5-(chloro-methyl)-9-methyl-1,2,4-triazolo[4,3-c]quinazoline of m.p. 175° C. are obtained.
Reaction SMILES: Cl[C:2]1[N:24]=[C:5]2[C:6]([NH:10][C:11]3[CH:23]=[CH:22][CH:21]=[CH:20][C:12]=3[CH2:13][N:14]([CH3:19])[S:15]([CH3:18])(=[O:17])=[O:16])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:25][N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=2)[CH2:28][CH2:27]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:19][N:14]([CH2:13][C:12]1[CH:20]=[CH:21][CH:22]=[CH:23][C:11]=1[NH:10][C:6]1[C:5]2[N:4]([N:3]=[C:2]([NH:38][C:35]3[CH:34]=[CH:33][C:32]([N:29]4[CH2:28][CH2:27][N:26]([CH3:25])[CH2:31][CH2:30]4)=[CH:37][CH:36]=3)[N:24]=2)[CH:9]=[CH:8][CH:7]=1)[S:15]([CH3:18])(=[O:17])=[O:16]
Reactant: CN(Cc1ccccc1Nc1cccn2nc(Cl)nc12)S(C)(=O)=O
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(c2ccc(Nc3nc4c(Nc5ccccc5CN(C)S(C)(=O)=O)cccn4n3)cc2)CC1

Procedure:
171 c) N-[2-(2-Chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-benzyl]-N-methyl-methanesulfonamide was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (500.0 mg, 2.151 mmol) and N-(2-amino-benzyl)-N-methyl-methanesulfonamide (507.0 mg, 2.366 mmol) in a manner analogous to Example 2d. Product isolated as a tan foam (0.53 g, 67%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.01 (d, J=6.4 Hz, 1H), 7.48-7.41 (m, 2H), 7.38 (t, J=7.4 Hz, 1H), 7.21 (t, J=7.4 Hz, 1H), 7.10 (s, 1H), 6.90-6.81 (m, 2H), 4.36 (s, 2H), 3.02 (s, 3H), 2.76 (s, 3H). MS=366 (MH)+. 171 d) N-Methyl-N-(2-{2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino}-benzyl)-methanesulfonamide was prepared from N-[2-(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-benzyl]-N-methyl-methanesulfonamide (75.0 mg, 0.205 mmol) and 4-(4-methyl-piperazin-1-yl)-phenylamine (44.0 mg, 0.230 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a brown foam (0.019 g, 18%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.94 (d, J=6.5 Hz, 1H), 7.51 (d, J=8.7 Hz, 2H), 7.45-7.39 (m, 2H), 7.35 (t, J=7.2 Hz, 1H), 7.13 (t, J=7.4 Hz, 1H), 7.00-6.94 (m, 3H), 6.81 (d, J=7.7 Hz, 1H), 6.68 (t, J=7.2 Hz, 1H), 6.60 (s, 1H), 4.36 (s, 2H), 3.18-3.13 (m, 4H), 2.91 (s, 3H), 2.78 (s, 3H), 2.62-2.57 (m, 4H), 2.36 (s, 3H). MS=521 (MH)+.
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]1[CH2:12][CH2:11][CH:10]([C:13]2[O:14][C:15]3[CH:21]=[CH:20][C:19](Br)=[CH:18][C:16]=3[CH:17]=2)[CH2:9][CH2:8]1.[C:23]1(=[O:29])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>C(OCC)C>[CH3:6][N:7]1[CH2:12][CH2:11][CH:10]([C:13]2[O:14][C:15]3[CH:21]=[CH:20][C:19]([C:23]4([OH:29])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)=[CH:18][C:16]=3[CH:17]=2)[CH2:9][CH2:8]1
Reactant: O=C1CCCCC1
Reactant: CN1CCC(c2cc3cc(Br)ccc3o2)CC1
Agent: [Li]CCCC
Solvent: CCOCC
Product: CN1CCC(c2cc3cc(C4(O)CCCCC4)ccc3o2)CC1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
480 ml of a 1.35 N solution of n-butyl lithium in abs. diethyl ether is added dropwise within 30 minutes at -5° to a solution of 60 g of 1-methyl-4-(5-bromo-2-benzofuranyl)-piperidine [cp. Example 19] in 300 ml of diethyl ether. The reaction temperature during the dropwise addition is maintained at between -50° and 0° by external cooling. The solution is afterwards stirred for a further 90 minutes at 5° to 10°. There is then added dropwise within 30 minutes a solution of 85 ml of cyclohexanone in 100 ml of abs. diethyl ether, with the reaction temperature being kept at 0° to 5° by external cooling. The reaction solution is subsequently stirred for 15 hours at room temprature, and then poured, with stirring, onto 300 g of ice, and the aqueous phase extracted three times with 500 ml of ethyl acetate each time. The combined organic extracts are dried over sodium sulphate, filtered, and concentrated by evaporation. The residue is dissolved in 300 ml of 2 N hydrochloric acid, and the acid solution washed with ether. The aqueous solution is then adjusted by addition of 10% sodium hydroxide solution to pH 12, and extracted with 1000 ml of chloroform. The chloroform solution is dried with sodium sulphate, filtered off, and concentrated by evaporation to obtain crude 1-methyl-4-[5-(1-hydroxycyclohexyl)-2-benzofuranyl]-piperidine. The free base melts at 155° to 157° after recrystallisation from cyclohexane. The hydrochloride is prepared with hydrogen chloride in ethyl acetate, and recrystallised from acetone, whereupon it melts at 226°-229°.
Reaction SMILES: [C@@H:1]12[O:6][C@@H:5]1[CH2:4][CH:3]([C:7]([O:9][CH3:10])=[O:8])[CH2:2]2.N1C=CC=CC=1.[FH:17]>ClC(Cl)C>[F:17][C@H:1]1[C@H:5]([OH:6])[CH2:4][C@@H:3]([C:7]([O:9][CH3:10])=[O:8])[CH2:2]1
Reactant: F
Reactant: COC(=O)C1C[C@@H]2O[C@@H]2C1
Solvent: c1ccncc1
Solvent: CC(Cl)Cl
Product: COC(=O)[C@@H]1C[C@@H](O)[C@H](F)C1
Reaction time: 6 h

Procedure:
To a solution of methyl (1S,5R)-6-oxabicyclo[3.1.0]hexane-3-carboxylate (300 mg, 2.110 mmol) in 3 ml of dichloroethane in a Teflon tube was added hydrogen fluoride-pyridine (0.190 ml, 2.110 mmol and allowed to stir at ambient for 6 hrs. Carefully poured onto 5 ml ice/NaHCO3 and extracted with three portions of DCM. Dried over sodium sulfate followed by Silica gel chromatgraphy with 30-50% Acetone-hexane to give title compound. 1H NMR (500 MHz, CDCl3) δ 1.96-2.03 (m, 1H), δ 2.12-2.32 (m, 3H), δ 2.38-2.52 (m, 1H), δ 3.12 (m, 1H), δ 3.72 (s, 3H), δ 4.34 (m, 1H), δ 4.86 (d of m, J=51.5 Hz, 1H)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH2:5][CH:6]1[O:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[O:8][CH2:7]1.C(N(C(C)C)CC)(C)C.[CH3:25][C:26]1([CH3:39])[C:30]2([CH2:34][S:35](Cl)(=[O:37])=[O:36])[C:31]([CH2:33][CH:27]1[CH2:28][CH2:29]2)=[O:32]>ClCCl>[O:11]1[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[O:8][CH2:7][CH:6]1[CH2:5][NH:4][CH2:3][CH2:2][NH:1][S:35]([CH2:34][C@:30]12[C:26]([CH3:25])([CH3:39])[CH:27]([CH2:28][CH2:29]1)[CH2:33][C:31]2=[O:32])(=[O:37])=[O:36]
Reactant: CC1(C)C2CCC1(CS(=O)(=O)Cl)C(=O)C2
Reactant: NCCNCC1COc2ccccc2O1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)C2CC[C@@]1(CS(=O)(=O)NCCNCC1COc3ccccc3O1)C(=O)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.4 %

Procedure:
To a solution of 2.1 g (10 mmole) of 2-{N-(2-aminoethyl)]aminomethyl-2,3-dihydrobenzodioxin and 1.3 g (10 mmole) of diisopropylethylamine in 100 ml of dichloromethane stored in an ice bath was added 2.5 g (10 mmole) (+)-10-camphorsulfonyl chloride. The mixture was allowed to stir overnight at room temperature. The reaction was next washed with saturated aqueous sodium bicarbonate, with saturated sodium chloride, dried over sodium sulfate, filtered and evaporated in vacuum. Column chromatography on 75 g of silica gel with chloroform as eluant, followed by crystallization from 100 ml of isopropanol with the addition of 5 ml of 4 N HCl/isopropyl alcohol and 300 ml of diethyl ether gave 1.2 g of the title compound as a monohydrochloride, m.p. 143°-146° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH2:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:14][C:15]1[O:19][C:18]([CH:20]=O)=[CH:17][CH:16]=1.[BH4-].[Na+]>CCO.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][CH2:20][C:18]2[O:19][C:15]([CH3:14])=[CH:16][CH:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: Cc1ccc(C=O)o1
Reactant: COc1ccc(CCN)cc1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: COc1ccc(CCNCc2ccc(C)o2)cc1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4.82 g (26.6 mmol) of 2-(3,4-dimethoxyphenyl)ethylamine and 3.0 g (27.2 mmol) of 5-methylfuran-2-carbaldehyde in 65 ml of EtOH, 18.3 g of molecular sieves (0.3 nm) were added and the mixture was refluxed for 4 hours. After this time the reaction mixture was cooled to room temperature and filtered. The solution obtained was concentrated in vacuo to obtain an oil. This oil was dissolved in 65 ml of MeOH and 1.01 g (26.6 mmol) of NaBH4 were added in small portions, maintaining the temperature of the reaction at room temperature. The mixture was stirred at this temperature for 16 hours more. After this time the solvent was evaporated in vacuo and the residue was treated with 150 ml of water and extracted twice with ether.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([OH:23])=O)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].[CH2:24]([O:26][C:27]([C:29]1[CH:34]=[CH:33][C:32]([C:35]#[C:36][CH:37]2[CH2:41][CH2:40][CH2:39][NH:38]2)=[CH:31][CH:30]=1)=[O:28])[CH3:25].C(Cl)CCl.Cl>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([N:38]2[CH2:39][CH2:40][CH2:41][CH:37]2[C:36]#[C:35][C:32]2[CH:33]=[CH:34][C:29]([C:27]([O:26][CH2:24][CH3:25])=[O:28])=[CH:30][CH:31]=2)=[O:23])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11]
Reactant: CCOC(=O)c1ccc(C#CC2CCCN2)cc1
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(C#CC2CCCN2C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)cc1
Reaction time: 8 h
Yield: 88.6 %

Procedure:
A mixture of 3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetic acid (1.45 g, 4.6 mmol), 2-(2-(4-ethoxycarbonylphenyl)ethynyl)pyrrolidine (1.12 g, 4.6 mmol), EDC 1.32 g (6.9 mmol), DMAP (562 mg, 4.6 mmol) in DMF (20 mL) was stirred overnight. The mixture was poured into 1 N HCl and the solid was collected with suction. The solid was dissolved in CHCl3 and died over MgSO4. After removal of the solvent, the residue was chromatographed on silica-gel with CHCl3—MeOH (100:1, v/v) as eluent to give 2.20 g (89%) ethyl 4-[2-[1-[3-methoxy-4-(N′-(2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinyl]ethynyl]benzoate as a white amorphous solid. 1H-NMR (CDCl3) δ1.37-1.41 (3 H, m), 1.94-2.22 (4 H, m), 2.29 (3 H, s), 3.41-3.89 (2 H, m), 3.62 (3 H, s), 3.69 (2 H, s), 4.34-4.40 (2 H, m), 4.72-5.01 (1 H, m), 6.33 (1 H, br s), 6.80-8.06 (12 H, m).
Reaction SMILES: [CH2:1]([SH:3])[CH3:2].[CH2:4]([CH:9]1[CH2:14][CH2:13][CH:12]([CH:15]2[CH2:20][CH2:19][C:18]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])(O)[CH2:17][CH2:16]2)[CH2:11][CH2:10]1)[CH2:5][CH2:6][CH2:7][CH3:8].C(OC(=O)C)(=O)C.Cl(O)(=O)(=O)=O.[Cl-].[Na+]>C(O)(=O)C>[CH2:4]([CH:9]1[CH2:14][CH2:13][CH:12]([CH:15]2[CH2:20][CH2:19][C:18]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])([S:3][CH2:1][CH3:2])[CH2:17][CH2:16]2)[CH2:11][CH2:10]1)[CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCC1(O)CCC(C2CCC(CCCCC)CC2)CC1
Reactant: CCS
Agent: [Cl-]
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CCCCCCCC1(SCC)CCC(C2CCC(CCCCC)CC2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
7.2 g of ethanethiol and 35 g of 4-pentyl-4'heptyl-4'-hydroxybicyclohexane in 70 ml of glacial acetic acid are added dropwise to a mixture of 30 ml of glacial acetic acid, 11.1 g of acetic anhydride and 7 g of 72% aqueous perchloric acid solution at -20°. The mixture is stirred at room temperature for 24 hours, poured into 250 ml of saturated sodium chloride solution, extracted with petroleum ether and worked up in the customary manner. 4-Pentyl-4'-heptyl-4'-ethylthiobicyclohexane is obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18]([OH:20])=O)[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[OH:28]>>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:13][CH2:14][C@H:15]([C:18]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[OH:28])=[O:20])[CH2:16][CH2:17]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccccc1O
Reactant: O=C(N[C@H]1CC[C@H](C(=O)O)CC1)OCc1ccccc1
Product: O=C(N[C@H]1CC[C@H](C(=O)Nc2ccccc2O)CC1)OCc1ccccc1

Procedure:
By treating trans-4-(benzyloxycarbonylamino)cyclohexanecarboxylic acid and 2-aminophenol in the same manner as in Reference Example 8-40, trans-4-benzyloxycarbonylamino-N-(2-hydroxyphenyl)cyclohexanecarboxamide was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=2[CH2:24][NH:25][CH2:26][CH3:27])[CH:7]=1)[CH3:2].C(N(CC)CC)C.Cl[C:37]([O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:38]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=2[CH2:24][N:25]([C:37]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:38])[CH2:26][CH3:27])[CH:7]=1)[CH3:2]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCNCc1cc([N+](=O)[O-])ccc1Oc1cc(CC(=O)OCC)ccc1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc([N+](=O)[O-])cc2CN(CC)C(=O)OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To [3-(2-ethylaminomethyl-4-nitro-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester (0.5 g, 1.29 mmol) in CH2Cl2 (20 mL) was added triethylamine (1 mL, 7.17 mmol), followed by benzyl chloroformate (0.25 g, 1.5 mmol), and the reaction was stirred at room temperature for 30 minutes. After work-up, the crude material was purified by silica gel chromatography (0-40% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [BH4-].[Na+].[N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.[C:13](O)(=[O:15])[CH3:14]>C(OC(=O)C)(=O)C>[C:13]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH2:4]1)(=[O:15])[CH3:14]
Reactant: CC(=O)O
Reactant: c1ccc2ncccc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N1CC=Cc2ccccc21
Temperature: 0 °C
Reaction time: 8 h

Procedure:
23.43 g of sodium borohydride are introduced, in portions, into a solution of 20 g of quinoline in 200 ml of acetic acid and 77.5 ml of acetic anhydride, cooled to 0° C. The mixture is then heated for 2 hours at 60° C. and is stirred overnight at ambient temperature. The mixture is concentrated, diluted with water, adjusted to pH=10 with sodium hydroxide solution and extracted with ether. The combined ethereal phases are washed with 1N hydrochloric acid and then at neutral pH and after conventional treatment the expected product is isolated.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:18]=[C:17]([C:19]([OH:21])=O)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.Cl.[OH:23][C:24]1[C:33]([O:34][CH3:35])=[CH:32][CH:31]=[C:30]2[C:25]=1[CH2:26][CH2:27][NH:28][CH2:29]2>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:18]=[C:17]([C:19]([N:28]2[CH2:27][CH2:26][C:25]3[C:30](=[CH:31][CH:32]=[C:33]([O:34][CH3:35])[C:24]=3[OH:23])[CH2:29]2)=[O:21])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1
Reactant: O=C(O)c1nc(-c2ccc(F)cc2F)nc2ccccc12
Reactant: COc1ccc2c(c1O)CCNC2
Agent: Cl
Product: COc1ccc2c(c1O)CCN(C(=O)c1nc(-c3ccc(F)cc3F)nc3ccccc13)C2
Yield: 11 %

Procedure:
Reaction of 2-(2,4-difluorophenyl)quinazoline-4-carboxylic acid with 5-hydroxy-6-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 57 (11% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 2.62 and 2.88 (2t, 2H), 3.49 and 4.01 (2t, 2H), 3.74 and 3.79 (2s, 3H), 4.39 and 4.90 (2s, 2H), 6.34 and 6.76 (2d, 1H), 6.72 and 6.90 (2d, 1H), 7.27-7.31 (m, 1H), 7.42-7.46 (m, 1H), 7.82-7.84 (m, 1H), 7.89 and 7.99 (2s, 1H), 8.09-8.26 (m, 3H), 8.68 and 8.73 (2s, 1H); MS (ESI) m/z 448 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C:4]1[C:9]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15]C(OC(C)(C)C)=O)=[CH:8][CH:7]=[CH:6][C:5]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH3:1][O:2][C:3](=[O:31])[C:4]1[C:5]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:6][CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][CH2:13][CH2:14][NH2:15]
Reactant: COC(=O)c1c(OCCCCNC(=O)OC(C)(C)C)cccc1OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1c(OCCCCN)cccc1OCc1ccccc1

Procedure:
A solution of 2-benzyloxy-6-(4-tert-butoxycarbonylaminobutoxy)-benzoic acid methyl ester (1.6 g, 3.7 mmol) in 30 mL of methylene chloride/TFA (2:1) is stirred at RT for 20 min. The solvent is removed under reduced pressure and the residue is re-dissolved in methylene chloride, washed with sat. NaHCO31 water and brine, and dried over sodium sulfate. The solvent is removed under reduced pressure to afford the title compound as a colorless liquid: (M+1)+=330.
Reaction SMILES: [CH2:1]([C:3]1([C:39]2[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=2)[CH:12]([CH2:13][CH2:14][CH2:15]CCCCCC(CCCCCCC(F)(F)C(F)(F)F)C(O)=O)[C:11]2[C:6](=[CH:7][C:8]([OH:38])=[CH:9][CH:10]=2)[S:5][CH2:4]1)[CH3:2].[F:46][C:47]([F:70])([C:66]([F:69])([F:68])[F:67])[CH2:48][CH2:49][CH2:50][CH2:51][CH:52]([CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63]C=C)[C:53]([O:55]CC)=[O:54]>>[CH2:1]([C:3]1([C:39]2[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=2)[CH:12]([CH2:13][CH2:14][CH2:15][CH2:63][CH2:62][CH2:61][CH2:60][CH2:59][CH2:58][CH:52]([CH2:51][CH2:50][CH2:49][CH2:48][C:47]([F:46])([F:70])[C:66]([F:67])([F:68])[F:69])[C:53]([OH:55])=[O:54])[C:11]2[C:6](=[CH:7][C:8]([OH:38])=[CH:9][CH:10]=2)[S:5][CH2:4]1)[CH3:2]
Reactant: C=CCCCCCCC(CCCCC(F)(F)C(F)(F)F)C(=O)OCC
Reactant: CCC1(c2ccc(O)cc2)CSc2cc(O)ccc2C1CCCCCCCCC(CCCCCCC(F)(F)C(F)(F)F)C(=O)O
Product: CCC1(c2ccc(O)cc2)CSc2cc(O)ccc2C1CCCCCCCCCC(CCCCC(F)(F)C(F)(F)F)C(=O)O

Procedure:
Starting with the allyl compound prepared in Example 13 and the ethyl 2-(5,5,6,6,6-pentafluorohexyl)-9-decenoate prepared in Example 5, the same procedure as shown in Example 13 was repeated to give 11-[(3RS,4RS)-3-ethyl-7-hydroxy-3-(4-hydroxyphenyl)thiochroman-4-yl]-2-(5,5,6,6,6-pentafluorohexyl)undecanoic acid.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8](OS(C(F)(F)F)(=O)=O)[CH:9]=2)[C:4](=[O:19])[CH2:3]1.[Cl:21][C:22]1[S:26][C:25](B(O)O)=[CH:24][CH:23]=1>>[Cl:21][C:22]1[S:26][C:25]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[C:4](=[O:19])[CH2:3][C:2]3([CH3:1])[CH3:20])=[CH:24][CH:23]=1
Reactant: CC1(C)CC(=O)c2ccc(OS(=O)(=O)C(F)(F)F)cc21
Reactant: OB(O)c1ccc(Cl)s1
Product: CC1(C)CC(=O)c2ccc(-c3ccc(Cl)s3)cc21

Procedure:
The title compound was prepared from trifluoro-methanesulfonic acid 3,3-dimethyl-1-oxo-indan-5-yl ester and 5-chlorothien-2-yl boronic acid according to the procedure described in example 21. MS m/z 277; HRMS: calcd for C15H13ClOS+H+, 277.04484; found (ESI, [M+H]+), 277.0444.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH3:24])[N:9]=2)[CH:5]=[N:6][CH:7]=1.[C:25]([NH:29][S:30]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)(=[O:32])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([NH:29][S:30]([C:33]1[CH:34]=[CH:35][CH:36]=[C:37]([C:2]2[CH:3]=[C:4]([C:8]3[CH:13]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=4)[CH:11]=[C:10]([CH3:24])[N:9]=3)[CH:5]=[N:6][CH:7]=2)[CH:38]=1)(=[O:32])=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cncc(Br)c2)n1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cncc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)c2)n1

Procedure:
The title compound was prepared from 5′-bromo-6-methyl-4-(4-trifluoromethylphenyl)-[2,3′]bipyridinyl (example E.24) (0.200 g, 0.5 mmol) and commercially available 3-(tert-butylsulfamoyl)-benzeneboronic acid (0.157 g, 0.6 mmol) according to the general procedure VI. Obtained as an off-white solid (0.182 g, 68%). MS (ISP) 526.3 [(M+H)+].
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:10]2[CH:15]=[C:14]([CH3:16])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:10]3[CH:15]=[C:14]([CH3:16])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: Cc1cc2c(NCc3ccccc3)nc(Cl)nc2s1
Product: Cc1cc2c(NCc3ccccc3)nc(-n3cncn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-6-methyl-4-benzylamino-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-6-methyl-4-benzylamino-thieno-[2,3-d]-pyrimidine.
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].[N+:12]([O-])([O-:14])=[O:13].[K+]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10]
Reactant: O=[N+]([O-])[O-]
Reactant: CC(=O)c1ccc(O)cc1F
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CC(=O)c1cc([N+](=O)[O-])c(O)cc1F
Temperature: 0 °C
Reaction time: 3 h
Yield: 70.9 %

Procedure:
To a mixture of 1-(2-fluoro-4-hydroxy-phenyl)-ethanone (Alfa, 5 g, 32.5 mmol) in concentrated sulfuric acid (50 mL) at −5° C. was added KNO3 (3.29 g, 32.6 mmol) and the reaction mixture was stirred for 3 h. The reaction mixture was poured into ice water (500 mL) carefully and the aqueous solution was extracted with EtOAc (3×150 mL). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was evaporated in vacuo and the residue was purified by column chromatography on silica gel (eluting with 2-10% EtOAc in petroleum ether) to give 1-(2-fluoro-4-hydroxy-5-nitro-phenyl)-ethanone as yellow solid (4.59 g, 71%). 1H NMR (CDCl3, 400 MHz): δ 10.95 (s, 1H), 8.79 (d, J=7.2 Hz, 1H), 6.92 (d, J=11.2 Hz, 1H), 2.63 (d, J=5.2 Hz, 3H).