Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[C:3]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C@H:20]3[NH:24][C:23](=[O:25])[C@H:22]([CH2:26][C:27]([O:29][CH3:30])=[O:28])[CH2:21]3)=[CH:14][CH:13]=2)=[N:10][CH:11]=1)(=[NH:5])[NH2:4].Cl.Cl[C:33]([O:35][CH3:36])=[O:34]>C(Cl)Cl.O>[CH3:36][O:35][C:33]([NH:5][C:3]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C@H:20]3[NH:24][C:23](=[O:25])[C@H:22]([CH2:26][C:27]([O:29][CH3:30])=[O:28])[CH2:21]3)=[CH:14][CH:13]=2)=[N:10][CH:11]=1)=[NH:4])=[O:34]
Reactant: COC(=O)Cl
Reactant: COC(=O)C[C@@H]1C[C@@H](COc2ccc(-c3ccc(C(=N)N)cn3)cc2)NC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: COC(=O)C[C@@H]1C[C@@H](COc2ccc(-c3ccc(C(=N)NC(=O)OC)cn3)cc2)NC1=O
Temperature: 25 °C

Procedure:
3 ml of 0.2M sodium hydroxide solution are added dropwise to 100 mg of (3S,5S)-5-[[4-(5-amidino-2-pyridyl)phenyl]oxymethyl]-3-[(methoxycarbonyl)methyl]-2-pyrrolidinone×1.6 HCl×1.5 H2O and 19.4 μl of methyl chloroformate in 10 ml of methylene chloride with vigorous stirring at ambient temperature. Then the mixture is stirred for a further 21/2 hours at ambient temperature. It is diluted with methylene chloride, the organic phase is separated off, dried and evaporated down.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:21])[CH2:9][N:10]([CH2:18][CH2:19]O)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][C:3]=1[Cl:22].C(N(CC)CC)C.CS(Cl)(=O)=O>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:21][CH2:19][CH2:18][N:10]([C:11]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:17])[CH2:9]2)=[CH:4][C:3]=1[Cl:22]
Reactant: CC(C)(C)OC(=O)N(CCO)CC(O)c1ccc(Br)c(Cl)c1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(Br)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.9 %

Procedure:
To a stirred solution of tert-butyl (RS)-2-(4-bromo-3-chlorophenyl)-2-hydroxyethyl(2-hydroxyethyl)carbamate (12.7 g) and triethylamine (6.72 ml) in THF (150 ml) at 0-5° C. was added dropwise methanesulfonyl chloride (2.76 ml). The reaction mixture was then stirred at room temperature for 60 min to afford a white suspension. The reaction mixture was then filtered to remove triethylamine hydrochloride, washing the filter with THF (20 ml). The filtrate was cooled to 0-5° C. and potassium 2-methyl-2-butoxide (28.4 ml, 1.7 M solution in toluene) was added. The reaction mixture was stirred at room temperature for 30 min and then poured into EtOAc and washed sequentially with dilute aq. HCl, water and saturated brine. The organic phase was separated and was then dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel; gradient: 0% to 50% EtOAc in hexanes) to afford tert-butyl (RS)-2-(4-bromo-3-chlorophenyl)morpholine-4-carboxylate (9.32 g, 77%) as a yellow oil. MS (ISP): 324.0 ([{81Br37Cl}M+H—C4H8]+), 321.9 ([{81Br35Cl or 79Br37Cl}M+H—C4H8]+), 319.9 ([{79Br35Cl}M+H—C4H8]+), 279.9 ([{81Br37Cl}M+H—C4H8—CO2]+), 277.9 ([{81Br35Cl or 79Br37Cl}M+H]—C4H8]—CO2]+), 276.0 ([{79Br35Cl}M+H—C4H8—CO2]+).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH2:18])[CH:15]([CH3:17])[CH3:16])[N:5]=[C:4]([CH3:19])[C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21].[O:25]1[CH2:30][CH2:29][O:28][C:27]2[CH:31]=[C:32]([C:35](O)=[O:36])[CH:33]=[CH:34][C:26]1=2>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH:18][C:35]([C:32]2[CH:33]=[CH:34][C:26]3[O:25][CH2:30][CH2:29][O:28][C:27]=3[CH:31]=2)=[O:36])[CH:15]([CH3:17])[CH3:16])[N:5]=[C:4]([CH3:19])[C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)c1c(C)nc2cccc(OC[C@@H](N)C(C)C)c2c1N
Reactant: O=C(O)c1ccc2c(c1)OCCO2
Product: CCOC(=O)c1c(C)nc2cccc(OC[C@@H](NC(=O)c3ccc4c(c3)OCCO4)C(C)C)c2c1N

Procedure:
Prepared as in Example 24a from (S)-ethyl 4-amino-5-(2-amino-3-methylbutoxy)-2-methylquinoline-3-carboxylate (Example 95b) and 2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylic acid as brown solid (29%). MS 494 (MH+).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][CH2:14][C:15]([O:17]CC)=[O:16])[C:10]([O:20][CH2:21][C:22]2[CH:23]=[N:24][C:25]([O:28][CH2:29][C:30]3[N:31]=[C:32]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[O:33][C:34]=3[CH3:35])=[CH:26][CH:27]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])[C:10]([O:20][CH2:21][C:22]2[CH:23]=[N:24][C:25]([O:28][CH2:29][C:30]3[N:31]=[C:32]([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)[O:33][C:34]=3[CH3:35])=[CH:26][CH:27]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2nn(Cc3ccccc3)cc2CCC(=O)O)cn1
Temperature: 25 °C
Yield: 90.2 %

Procedure:
A mixture of ethyl 3-[1-benzyl-3-[6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3-pyridylmethoxy]-1H-pyrazol-4-yl]propionate (746 mg), 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature. 1N Hydrochloric acid (3 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to give 3-[1-benzyl-3-[6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3-pyridylmethoxy]-1H-pyrazol-4-yl]propionic acid (639 mg, yield 90%), which was then recrystallized from acetone-hexane. melting point: 130–131° C.
Reaction SMILES: [OH:1][CH2:2][C:3](=[O:13])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1.N1C=CN=C1.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>CN(C=O)C>[Si:19]([O:1][CH2:2][C:3](=[O:13])[CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([CH3:12])=[CH:10][CH:11]=1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1ccc(CCC(=O)CO)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1ccc(CCC(=O)CO[Si](C)(C)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.9 %

Procedure:
To an ice cooled solution of 1-hydroxy-4-(p-tolyl)butan-2-one in DMF (5 ml) was added imidazole (264 mg, 3.88 mmol) followed by tert-butyldimethylsilyl chloride (234 mg, 1.55 mmol). After 30 minutes the ice-bath was removed and then the mixture was stirred overnight at room temperature. The reaction mixture was poured into water (50 ml) and extracted with ethyl acetate. The organic layer was washed with brine, dried (magnesium sulfate), and concentrated in vacuo. The residue was purified by silica gel (8 g) column chromatography eluting with hexane/ethyl acetate (50:1) to give 1-(tert-butyldimethylsilyloxy)-4-(4-methylphenyl)butan-2-one (350 mg, 67.9%) as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[C:11]([O:13][CH2:14][CH3:15])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=O)[CH3:2].C(OC([NH:23][CH2:24][C:25]1[CH:26]=[C:27]([CH2:33][CH:34]([O:38][CH:39]([CH3:41])[CH3:40])[C:35]([O-:37])=[O:36])[CH:28]=[CH:29][C:30]=1[O:31][CH3:32])=O)(C)(C)C>>[CH2:1]([O:3][C:4]1[CH:12]=[C:11]([O:13][CH2:14][CH3:15])[CH:10]=[CH:9][C:5]=1[C:6]([NH:23][CH2:24][C:25]1[CH:26]=[C:27]([CH2:33][CH:34]([O:38][CH:39]([CH3:41])[CH3:40])[C:35]([OH:37])=[O:36])[CH:28]=[CH:29][C:30]=1[O:31][CH3:32])=[O:8])[CH3:2]
Reactant: CCOc1ccc(C(=O)O)c(OCC)c1
Reactant: COc1ccc(CC(OC(C)C)C(=O)[O-])cc1CNC(=O)OC(C)(C)C
Product: CCOc1ccc(C(=O)NCc2cc(CC(OC(C)C)C(=O)O)ccc2OC)c(OCC)c1

Procedure:
Using 2,4-diethoxybenzoic acid and 3-[3-([(tert-butoxycarbonyl)amino]methyl)-4-methoxyphenyl)-2-isopropoxypropanoate, 3-(3-[(2,4-diethoxybenzoyl)amino]methyl-4-methoxyphenyl)-2-isopropoxypropanoic acid was obtained in the same method as in Example 38).
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]2[N:10](S(C3C=CC=CC=3)(=O)=O)[C:11]([CH3:13])=[CH:12][C:5]=12>O1CCOCC1>[Br:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]2[NH:10][C:11]([CH3:13])=[CH:12][C:5]=12
Reactant: Cc1cc2c(Br)ccnc2n1S(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1cc2c(Br)ccnc2[nH]1
Temperature: 60 °C
Yield: 105 %

Procedure:
2M Sodium hydroxide solution (114 ml) was added to a solution of 4-bromo-2-methyl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (16 g) in 1,4-dioxane (320 ml) and the reaction heated at 60° C. overnight. After cooling, the aqueous layer was separated and washed with ethyl acetate. The combined organics were washed with brine, dried over magnesium sulphate, filtered, and then evaporated to give title compound (10.1 g) as a cream coloured solid.
Reaction SMILES: [CH:1]1([C:4]2([CH2:23]O)[CH2:8][CH2:7][N:6]([C:9]3[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]4[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=4)[N:10]=3)[C:5]2=[O:22])[CH2:3][CH2:2]1.CS(Cl)(=O)=O.[CH2:30]([N:32](CC)CC)C.C(=O)([O-])O.[Na+]>O1CCCC1>[CH:1]1([C:4]2([CH2:23][C:30]#[N:32])[CH2:8][CH2:7][N:6]([C:9]3[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]4[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=4)[N:10]=3)[C:5]2=[O:22])[CH2:3][CH2:2]1
Reactant: CCN(CC)CC
Reactant: Cn1cc(Nc2nccc(N3CCC(CO)(C4CC4)C3=O)n2)cn1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1cc(Nc2nccc(N3CCC(CC#N)(C4CC4)C3=O)n2)cn1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 3-cyclopropyl-3-(hydroxymethyl)-1-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)pyrrolidin-2-one (45 mg) obtained in Example 393 in tetrahydrofuran (1.0 mL) were added methanesulfonyl chloride (15 μL) and triethylamine (29 μL) at 0° C., and the mixture was stirred at 0° C. for 1 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. To a solution of the residue in N,N-dimethylformamide (1.0 mL) were added potassium cyanide (36 mg) and sodium iodide (82 mg) at room temperature, and the mixture was stirred overnight at 120° C. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (17 mg).
Reaction SMILES: [Br-].[C:2]1([CH2:8][CH2:9][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[CH:34]1([CH:46]=O)[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>CCOCC>[C:2]1([CH2:8][CH:9]=[CH:46][CH:34]2[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=CC1CCCCCCCCCCC1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCOCC
Product: C(=CC1CCCCCCCCCCC1)Cc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 88.2 %

Procedure:
To 11.4 g (25.5 mmol) of phenylethyl triphenylphosphonium bromide in 50 mL of dry ether at 0° C. is added 10.2 mL (25.5 mmol) of 2.5M butyllithium. The suspension is stirred at 0° C. for 1 hour followed by the addition of 5.0 g (25.5 mmol) of cyclododecane carboxaldehyde. The mixture is stirred at room temperature for 3 hours after which time no starting material is evident by TLC. The reaction mixture is quenched with 1N HCl. The layers are separated and the aqueous layer is washed twice with ethyl ether. The combined organic layers are dried over a MgSO4 and the ether is evaporated. The residue is flash chromatographed on silica gel using hexanes to give 6.4 g of a colorless oil: NMR (CDCl3) δ 1.0-1.6 (m, 10H), 2.6 (m, 1H), 3.4 (d, 2H, J=8 Hz,), 5.3 (t, 1H, J=7 Hz), 5.45 (q, 1H, J=7 Hz), 7.2 ppm (m, 5
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[NH2:15][C:16]1[CH:20]=[CH:19][S:18][C:17]=1[C:21]([O:23][CH3:24])=[O:22].N1C=CC=CC=1>ClCCl>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:15][C:16]2[CH:20]=[CH:19][S:18][C:17]=2[C:21]([O:23][CH3:24])=[O:22])(=[O:13])=[O:12])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: COC(=O)c1sccc1N
Reactant: CCCCc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCc1ccc(S(=O)(=O)Nc2ccsc2C(=O)OC)cc1

Procedure:
Synthesized as described for 52 using commercially available 4-n-butylbenzenesulfonyl chloride (0.47 g; 2 mmol), methyl 3-aminothiophene-2-carboxylate (314 mg; 2 mmol), pyridine (0.2 mL; 2.4 mmol), and anhydrous dichloromethane (10 mL). This afforded the title compound as a clear oil which later solidified (0.6 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][NH2:11].C[O:13][C:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21]Br.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][N:11]1[CH2:21][C:16]2[C:15](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:14]1=[O:13]
Reactant: COC(=O)c1ccccc1CBr
Reactant: NCCCc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2CN1CCCc1ccccc1Br
Reaction time: 2 h
Yield: 57.5 %

Procedure:
A mixture of 3-(2-bromophenyl)-propylamine (6.9 g, 30 mmol), 2-bromomethyl-benzoic acid methyl ester (6.42 g, 30 mmol), and K2CO3 (6.91 g, 50 mmol) in toluene (100 mL) was heated at reflux with stirring for 2 h. Workup and silica gel column chromatography using a gradient of hexanes to 50% ethyl acetate in hexanes afforded 2-[3-(2-bromophenyl)-propyl]-2,3-dihydroisoindol-1-one (5.7 g, 58%). GC/MS gave: m/z (rel.int.) 331 (M+, 3), 329 (M+, 3), 250 (42), 147 (82), 146 (100) 119 (27), and 91 (47). 1H NMR (300 MHz, CDCl3): δ 2.00 (dt, 2H), 2.80 (t, 2H), 3.74 (t, 2H), 4.40 (s, 2H), 7.04 (dt, 1H), 7.19-7.27 (m, 3H), 7.43-7.53 (m, 3H), 7.76 (dd, 1H). 13C NMR (300 MHz, CDCl3): δ 28.7, 33.7, 42.1, 50.0, 122.8, 123.8, 124.4, 127.7, 127.9, 128.1, 130.6, 131.3, 132.9, 133.1, 140.8, 141.3, 168.7.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2.[Li]C(C)(C)C.Br[CH2:16][CH2:17][CH2:18][CH3:19]>C1COCC1>[CH2:16]([C:5]1[S:1][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=1)[CH2:17][CH2:18][CH3:19]
Reactant: c1ccc2sccc2c1
Reactant: CCCCBr
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CCCCc1cc2ccccc2s1

Procedure:
2-n-Butylbenzo[b]thiophene was prepared by the method of Example 40A with benzo[b]thiophene (7.5 mmoles, 1.0 g), t-BuLi (1.7 M, 9.7 mmoles, 5.7 ml), 1-bromobutane (9.7 mmoles, 1.0 ml) and THF (20 ml). 0.65 g (46%) of a yellow liquid was isolated.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:11][C:12](=[O:14])[CH:13]=2)=[O:10])=[CH:4][CH:3]=1.[F-].[Cs+].[C:17]([Si](C)(C)C)([F:20])([F:19])[F:18]>C(#N)C.C(OCC)C>[F:18][C:17]([F:20])([F:19])[C:9](=[O:10])[C:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)=[CH:13][C:12]([OH:11])=[O:14]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=C1C=C(c2ccc(F)cc2)C(=O)O1
Agent: [Cs+]
Agent: [F-]
Solvent: CCOCC
Solvent: CC#N
Product: O=C(O)C=C(C(=O)C(F)(F)F)c1ccc(F)cc1
Reaction time: 1 h
Yield: 72.3 %

Procedure:
To a stirred solution of 4-fluorophenylmaleic anhydride (1.42 g, 7.39 mmol) (prepared by procedures similar to those described in Dean, W. D.; Bum, D. M. J. Org. Chem. 1993, 58, 7916-7917), in acetonitrile (15 ml) at 0° C. (ice/water/sodium chloride bath—temperature of the bath −10° C.), was added CsF (1.1 g, 7.39 mmol), followed by the drop-wise addition of CF3SiMe3 (1 ml, 7.39 mmol), under nitrogen. The reaction mixture was stirred for 1 h, and then diluted with diethyl ether and extracted with 2M sodium hydroxide (200 ml). The organic layer was removed and the aqueous layer acidified to pH=1 by the addition of conc. hydrochloric acid. The mixture was extracted with dichloromethane and the organic layer removed, dried (Na2SO4), and the solvent evaporated in vacuo to yield D5 (1.4 g, 72%) as a mixture of isomers. C11H6F4O3 requires 262 Found 261 (M-H−).
Reaction SMILES: [CH:1]1([CH:7]([N:11]2[C:15]3[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=3[N:13]=[C:12]2[C@H:21]([O:28][CH3:29])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:8](O)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:62][C@H:63]1[CH2:68][CH2:67][C@H:66]([OH:69])[CH2:65][CH2:64]1>CN(C=O)C>[CH:1]1([CH:7]([N:11]2[C:15]3[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=3[N:13]=[C:12]2[C@H:21]([O:28][CH3:29])[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:8]([NH:62][CH:63]2[CH2:68][CH2:67][CH:66]([OH:69])[CH2:65][CH2:64]2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CO[C@H](c1ccccc1)c1nc2cc(F)ccc2n1C(C(=O)O)C1CCCCC1
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CO[C@H](c1ccccc1)c1nc2cc(F)ccc2n1C(C(=O)NC1CCC(O)CC1)C1CCCCC1
Temperature: 40 °C
Reaction time: 0.25 h
Yield: 40.5 %

Procedure:
To a solution of cyclohexyl-[5-fluoro-2-((R)-methoxy-phenyl-methyl)-benzoimidazol-1-yl]-acetic acid (100 mg, 0.25 mmol, 1.0 equiv) in DMF (1.5 mL) was added triethylamine (51.1 mg, 70.0 μL, 0.50 mmol, 2.0 equiv) and HATU (124.7 mg, 0.33 mmol, 1.3 equiv) and the mixture stirred at 40° C. After 15 min, trans-4-amino-cyclohexanol hydrochloride (50.03 mg, 0.33 mmol, 1.3 equiv; [CAS RN 50910-54-8]) was added and stirring continued at 50° C. for 2 h. Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 50 mg (40%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.[CH2:9]([N:13]1[N:17]=[C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]2=[N:14]1)[CH2:10][C:11]#[CH:12]>>[CH3:8][C:4]1[N:3]=[C:2]([C:12]#[C:11][CH2:10][CH2:9][N:13]2[N:14]=[C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]3=[N:17]2)[CH:7]=[CH:6][CH:5]=1
Reactant: C#CCCn1nc2ccccc2n1
Reactant: Cc1cccc(Br)n1
Product: Cc1cccc(C#CCCn2nc3ccccc3n2)n1
Yield: 51.7 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-6-methylpyridine (55 mg, 0.32 mmol) and 2-(but-3-ynyl)-2H-benzo[d][1,2,3]triazole (50 mg, 0.29 mmol, Example 109(D)). Reaction time: 13 hours. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 40 mg (0.15 mmol, 53%) of 2-(4-(6-methylpyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole as a yellow solid.
Reaction SMILES: C1([C:4]2([N:7]([CH2:40][C:41]3[CH:46]=[C:45]([CH2:47][CH2:48][CH2:49][O:50][CH3:51])[CH:44]=[C:43]([OH:52])[CH:42]=3)[C:8](=[O:39])[CH:9]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][O:29][C:30]4[C:35]([Cl:36])=[CH:34][C:33]([CH3:37])=[CH:32][C:31]=4[Cl:38])=[CH:22][CH:21]=3)[CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:6][CH2:5]2)CC1.[CH2:53]([N:55]=[C:56]=[O:57])[CH3:54].C(N(CC)CC)C>ClCCl.CN(C1C=CN=CC=1)C>[CH2:53]([NH:55][C:56](=[O:57])[O:52][C:43]1[CH:44]=[C:45]([CH2:47][CH2:48][CH2:49][O:50][CH3:51])[CH:46]=[C:41]([CH2:40][N:7]([C:8](=[O:39])[CH:9]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([O:26][CH2:27][CH2:28][O:29][C:30]3[C:31]([Cl:38])=[CH:32][C:33]([CH3:37])=[CH:34][C:35]=3[Cl:36])=[CH:24][CH:25]=2)[CH2:10][NH:11][C:12]([O:13][C:14]([CH3:17])([CH3:15])[CH3:16])=[O:18])[CH:4]2[CH2:6][CH2:5]2)[CH:42]=1)[CH3:54]
Reactant: COCCCc1cc(O)cc(CN(C(=O)C(CNC(=O)OC(C)(C)C)Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2(C3CC3)CC2)c1
Reactant: CCN=C=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCNC(=O)Oc1cc(CCCOC)cc(CN(C(=O)C(CNC(=O)OC(C)(C)C)Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of tert-butyl (3-{cyclopropyl[3-hydroxy-5-(3-methoxypropyl)benzyl] (cyclopropyl)amino}-2-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl}-3-oxopropyl)carbamate from Example 70, Step 2 (1 eq.) in dichloromethane (0.08 M) was added ethyl isocyanate (3 eq.), triethylamine (3 eq.) and a few crystals of DMAP. The resulting solution was stirred at RT for 1.5 h. The reaction mixture was concentrated in vacuo and directly subjected to purification by way of column chromatography (SiO2, 3:2 (v/v) Hex:EtOAc→2:3 (v/v) Hex:EtOAc). The title compound was isolated as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]([OH:15])[C:12]2[C:7](=[CH:8][C:9]([CH3:16])=[CH:10][CH:11]=2)[N:6]=1)=[O:4].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:23]([O:30][C:31](=[O:34])[CH2:32]Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C.O>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]([O:15][CH2:32][C:31]([O:30][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:34])[C:12]2[C:7](=[CH:8][C:9]([CH3:16])=[CH:10][CH:11]=2)[N:6]=1)=[O:4]
Reactant: O=C(CBr)OCc1ccccc1
Reactant: COC(=O)c1cc(O)c2ccc(C)cc2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OCC(=O)OCc2ccccc2)c2ccc(C)cc2n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 5.00 g 4-Hydroxy-7-methyl-quinoline-2-carboxylic acid methyl ester in 35 ml of DMF, 8.25 g of cesium carbonate and 5.80 g of Bromo-acetic acid benzyl ester were added and the reaction mixture was stirred for 12 h at RT. Then, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over MgSO4 and the solvents were removed under reduced pressure. The isolated crude product was pure enough for the next reaction step. Yield: 10.00 g.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[N:13]=[C:14]([CH3:24])[S:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)=[O:11].Cl[C:26]1[N:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1>>[F:23][C:20]1[CH:19]=[CH:18][C:17]([C:16]2[S:15][C:14]([CH3:24])=[N:13][C:12]=2[C:10]([N:4]2[CH2:5][CH2:6][CH2:7][C@H:8]([CH3:9])[C@@H:3]2[CH2:2][NH:1][C:26]2[N:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=2)=[O:11])=[CH:22][CH:21]=1
Reactant: Cc1nc(C(=O)N2CCC[C@H](C)[C@H]2CN)c(-c2ccc(F)cc2)s1
Reactant: FC(F)(F)c1cnc(Cl)nc1
Product: Cc1nc(C(=O)N2CCC[C@H](C)[C@@H]2CNc2ncc(C(F)(F)F)cn2)c(-c2ccc(F)cc2)s1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1 using ((2S,3S)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-(4-fluorophenyl)-2-methylthiazol-4-yl)methanone and 2-chloro-5-(trifluoromethyl)pyrimidine. ESI-MS (m/z): 494 [M+1]+.
Reaction SMILES: [NH2:1][C@H:2]([CH:5]([CH3:7])[CH3:6])[CH2:3][OH:4].[Cl:8][C:9]1[CH:14]=[N:13][CH:12]=[C:11](Cl)[N:10]=1>>[Cl:8][C:9]1[N:10]=[C:11]([NH:1][C@H:2]([CH:5]([CH3:7])[CH3:6])[CH2:3][OH:4])[CH:12]=[N:13][CH:14]=1
Reactant: CC(C)[C@@H](N)CO
Reactant: Clc1cncc(Cl)n1
Product: CC(C)[C@H](CO)Nc1cncc(Cl)n1

Procedure:
In analogy to the procedures described for the preparation of intermediate A-20 and A-3 [C]: i) (R)-2-amino-3-methyl-butan-1-ol has been reacted with 2,6-dichloropyrazine to give (R)-2-(6-chloro-pyrazin-2-ylamino)-3-methyl-butan-1-ol; ii) subsequent condensation with 1-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one (intermediate A-1) gave the title compound as a light yellow solid. MS: 341.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:32])[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH:19]([OH:31])[CH2:20][O:21][CH:22]2CC3C(=CC=CC=3)C2)[CH2:14][CH2:13]1.[F:33][C:34]([F:44])([F:43])[C:35]1[CH:42]=[CH:41][C:38](CO)=[CH:37][CH:36]=1>CC(O)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:32])[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH:19]([OH:31])[CH2:20][O:21][CH2:22][C:38]2[CH:41]=[CH:42][C:35]([C:34]([F:44])([F:43])[F:33])=[CH:36][CH:37]=2)[CH2:14][CH2:13]1
Reactant: OCc1ccc(C(F)(F)F)cc1
Reactant: Cc1cccc(C)c1NC(=O)CN1CCN(CC(O)COC2Cc3ccccc3C2)CC1
Solvent: CC(C)O
Product: Cc1cccc(C)c1NC(=O)CN1CCN(CC(O)COCc2ccc(C(F)(F)F)cc2)CC1

Procedure:
Compound 17 was prepared in a similar manner to compound 7, substituting the commercially available 4-trifluoromethyl-benzylalcohol for 2-propanol in part C. MS (M+1)=480.37