Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:21]3[S:22][C:23]4[C:29]([O:30][CH3:31])=[CH:28][C:27]([CH3:32])=[CH:26][C:24]=4[CH:25]=3)[C:9]([CH2:13][N:14]3[CH2:19][CH2:18][NH:17][C:16](=[O:20])[CH2:15]3)=[C:10]([CH2:11][OH:12])[N:6]2[N:5]=[CH:4][N:3]=1.S(Cl)(Cl)=O.[CH3:37]O.C[O-].[Na+]>ClCCl>[NH2:1][C:2]1[C:7]2=[C:8]([C:21]3[S:22][C:23]4[C:29]([O:30][CH3:31])=[CH:28][C:27]([CH3:32])=[CH:26][C:24]=4[CH:25]=3)[C:9]([CH2:13][N:14]3[CH2:19][CH2:18][NH:17][C:16](=[O:20])[CH2:15]3)=[C:10]([CH2:11][O:12][CH3:37])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CO
Reactant: COc1cc(C)cc2cc(-c3c(CN4CCNC(=O)C4)c(CO)n4ncnc(N)c34)sc12
Agent: C[O-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COCc1c(CN2CCNC(=O)C2)c(-c2cc3cc(C)cc(OC)c3s2)c2c(N)ncnn12
Temperature: 25 °C
Reaction time: 1.08 h
Yield: 21 %

Procedure:
A suspension of Example 125 (88 mg, 194 μmol) in dichloromethane (5 ml) was treated with thionyl chloride (29 μl, 389 μmol), and the mixture was stirred at rt for 65 min. Another portion of thionyl chloride (29 μl, 389 μmol) was added, and stirring was continued for 1.5 h. An excess of methanol was then added, followed by dropwise addition of a 5.4 M solution of sodium methylate in methanol (84 mg, 1.56 mmol) until pH 8 was reached. After stirring for 3 days, the volatiles were evaporated under reduced pressure, and the residue was separated by preparative RP-HPLC (Reprosil C18, gradient 20-40% acetonitrile/0.2% aq. trifluoroacetic acid). The product fractions were evaporated to yield 19 mg of the title compound (21% of th.).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:36]=[CH:35][C:9]2[C:10]3[C:27]4([O:32][CH2:31][C:30]([CH3:34])([CH3:33])[CH2:29][O:28]4)[C:11]=3[C:12]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][OH:26])=[CH:16][C:13]=3[CH2:14][CH2:15][C:8]=2[CH:7]=1)[CH2:2][CH2:3][CH3:4].N1C=CC=CC=1.Cl[C:44]([O:46][C:47]1[CH:52]=[CH:51][C:50]([N+:53]([O-:55])=[O:54])=[CH:49][CH:48]=1)=[O:45]>C(Cl)Cl>[C:44](=[O:45])([O:46][C:47]1[CH:48]=[CH:49][C:50]([N+:53]([O-:55])=[O:54])=[CH:51][CH:52]=1)[O:26][CH2:25][CH2:24][O:23][CH2:22][CH2:21][O:20][C:17]1[CH:18]=[CH:19][C:12]2[C:11]3[C:27]4([O:32][CH2:31][C:30]([CH3:34])([CH3:33])[CH2:29][O:28]4)[C:10]=3[C:9]3[CH:35]=[CH:36][C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:7][C:8]=3[CH2:15][CH2:14][C:13]=2[CH:16]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCCCOc1ccc2c(c1)CCc1cc(OCCOCCO)ccc1C1=C2C12OCC(C)(C)CO2
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCOc1ccc2c(c1)CCc1cc(OCCOCCOC(=O)Oc3ccc([N+](=O)[O-])cc3)ccc1C1=C2C12OCC(C)(C)CO2
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of alcohol 11 (0.439 g, 0.89 mmol) and pyridine (0.25 g, 3.21 mmol) in CH2Cl2 (approximately 5 mL) was added to a solution of 4-nitrophenyl chloroformate (0.30 g, 1.49 mmol) in CH2Cl2 (25 mL) at room temperature, and the reaction mixture was stirred for 20 minutes at room temperature. Solvent was evaporated under reduced pressure, and the residue was separated by chromatography (Hex:ExOAc 4:1+1.5% of Et3N) to provide 0.317 g (0.48 mmol 80%) of 12 as and 0.113 g (0.23 mmol) of starting 11. 1H NMR: 8.25 (d, J=8.8 Hz, 2 H) 7.65 (dd, J=8.4, 2.0 Hz, 2 H), 7.35, (d, J=9.2, 2 H), 6.92-6.82 (m, 4 H), 4.43 (t, J=4.4 Hz, 2 H), 4.19 (t, J=6.4 Hz, 2 H), 3.98 (t, J=4.4 Hz, 2 H), 3.92 (m, 7 H), 3.22 (d, J=10.8 Hz, 2 H), 2.43 (d, J=10.8 Hz, 2 H), 1.75 (p, J=7.2 Hz, 2 H), 1.51 (six, J=7.6 Hz, 2 H), 1.21 (s, 3H), 1.19 (s, 3 H), 0.98 (t, J=−7.2 Hz, 3 H); 13C NMR: 159.9, 159.2, 155.7, 152.7, 150.0 147.4, 145.6, 131.77, 131.63, 125.5, 124.6, 123.4, 122.0, 119.8, 119.1, 116.25, 116.19, 112.2, 112, 15, 84.1, 79.4, 70.0, 69.1, 68.4, 70.0, 67.8, 37.1, 31.5, 30.8, 22.87, 22.79, 19.5, 14.1.
Reaction SMILES: COC1C=CC=CC=1[C@H]1C(C)(C)COP(=O)([O-])O1.[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[C@@H:33]([NH3+:35])[CH3:34].C(N(CC)CC)C.[CH3:43][O:44][C:45]1[CH:50]=[CH:49][C:48]([S:51](Cl)(=[O:53])=[O:52])=[CH:47][CH:46]=1>C(#N)C.COC1C=CC(S(Cl)(=O)=O)=CC=1>[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[C@@H:33]([NH:35][S:51]([C:48]1[CH:47]=[CH:46][C:45]([O:44][CH3:43])=[CH:50][CH:49]=1)(=[O:53])=[O:52])[CH3:34]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: C[C@H]([NH3+])c1cc(F)ccc1-c1ccccc1F
Agent: COc1ccccc1[C@@H]1OP(=O)([O-])OCC1(C)C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(S(=O)(=O)N[C@@H](C)c2cc(F)ccc2-c2ccccc2F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.2 %

Procedure:
A stirred suspension of (1S)-1-(2′,4-difluoro-1,1′-biphenyl-2-yl)ethanaminium (4R)-4-(2-methoxyphenyl)-5,5-dimethyl-1,3,2-dioxaphosphinan-2-olate 2-oxide (2.53 g, 5.0 mmol) in acetonitrile (50 mL) was treated sequentially with triethylamine (1.39 mL, 10 mmol) and 4-methoxybenzenesulfonyl chloride (1.04 g, 5.05 mmol). The progress of the reaction was monitored by LCMS. After eight hours, approximately 5% of the starting amine was still present. An additional aliquot of 4-methoxybenzenesulfonyl chloride (52 mg, 0.25 mmol, 5 mole %) was added, and the reaction was stirred at ambient temperature for an additional 16 hours. Monitoring by LCMS indicated complete formation of a single product. The solvent was removed in vacuo. The residue was dissolved in dichloromethane and washed with a 5% aqueous sodium bicarbonate solution. The aqueous phase was extracted with dichloromethane. The combined organic phase was washed with a 2 N hydrochloric acid solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to a residue. The residue was purified by preparative liquid chromatography on a Biotage® 40 Mi column of pre-packed silica gel (90 g), eluting with a gradient of 30%-50% methyl tert-butylether in hexane, to afford N-[(1S)-1-(2′,4-difluoro-1,1′-biphenyl-2-yl)ethyl]-4-methoxybenzenesulfonamide (1.8 g, 89%, 99.2% ee), m.p. 133-135° C.;
Reaction SMILES: [CH:1]12[O:6][CH:5]1[CH2:4][N:3]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2]2.[F:14][C:15]1[CH:20]=[CH:19][C:18]([Mg]Br)=[CH:17][CH:16]=1>>[C:10]([O:9][C:7]([N:3]1[CH2:2][C@@H:1]([C:18]2[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=2)[C@H:5]([OH:6])[CH2:4]1)=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: CC(C)(C)OC(=O)N1CC2OC2C1
Product: CC(C)(C)OC(=O)N1C[C@@H](O)[C@H](c2ccc(F)cc2)C1

Procedure:
The title compound was prepared from tert-butyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate and 4-fluorophenylmagnesium bromide according to the procedure for Example 1, step A. 1H-NMR (CDCl3): δ: 1.49 (s, 9H), 3.2-3.4 (m, 3H), 3.50 (m, 1H), 3.7-3.95 (m, 2H), 4.32 (q, 1H, 5 Hz), 7.05 (t, 2H), 7.23 (m, 2H) ppm.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[S:12](Cl)([CH3:15])(=[O:14])=[O:13].O>C(Cl)Cl>[C:1]([NH:5][S:12]([CH3:15])(=[O:14])=[O:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)NS(C)(=O)=O
Reaction time: 0.5 h

Procedure:
To a solution of tert-butylamine (6.8 ml) and pyridine (7.8 ml) in methylene chloride (50 ml) was added dropwise mesyl chloride (5.0 ml) at 0° C. The mixture was stirred for 30 minutes. The reaction mixture was poured into water and then extracted with methylene chloride. The organic layer was concentrated. The residue was purified by column chromatography to give the title compound (5.2 g) having the following physical data.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][NH:21][C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]=3)[CH:15]=2)[C:3]=1[O:4][CH2:5][C:6]#N.C1COCC1.[OH-:37].[Na+].Cl.C[OH:41]>>[CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][NH:21][C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]=3)[CH:15]=2)[C:3]=1[O:4][CH2:5][C:6]([OH:41])=[O:37]
Reactant: CO
Reactant: Cc1cccc(COc2cccc(CNc3ccc4ccccc4n3)c2)c1OCC#N
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cccc(COc2cccc(CNc3ccc4ccccc4n3)c2)c1OCC(=O)O
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a solution of {2-methyl-6-[3-(quinolin-2-ylaminomethyl)-phenoxymethyl]-phenoxy}-acetonitrile (134 mg, 0.31 mmol, example 35a) in methanol (1 mL) is added THF (1 mL) followed by sodium hydroxide solution (0.2 mL, 10 N). The resulting mixture is warmed to 60° C. and stirred at this temperature for 3 h. The reaction mixture is then cooled to room temperature and acidified to ca. pH 5 with hydrochloric acid (1 mL, 2N), then extracted with ethyl acetate, washed with brine, dried over MgSO4 and concentrated. The residue is purified by flash chromatography (silica, 10% methanol in dichloromethane) to give the title compound. 1H NMR (300 MHz, CDCl3) δ 8.10 (d, 1H), 7.80 (d, 1H), 7.68 (t, 2H), 7.40 (t, 1H), 7.25 (m, 2H), 7.04 (m, 3H), 6.90 (m, 3H), 6.6 (bs, 0.1H), 5.15 (s, 2H), 4.60 (d, 2H), 4.50 (s, 2H), 2.27 (s, 3H). MS (ESI) 429 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:7])([CH2:5][NH2:6])[CH2:3][NH2:4].C(N(CC)CC)C.[Cl:15][C:16]1[N:25]=[C:24](Cl)[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([CH3:27])[CH:22]=2)[N:17]=1.O>ClCCl>[Cl:15][C:16]1[N:25]=[C:24]([NH:4][CH2:3][C:2]([F:7])([F:1])[CH2:5][NH2:6])[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([CH3:27])[CH:22]=2)[N:17]=1
Reactant: Cc1ccc2nc(Cl)nc(Cl)c2c1
Reactant: NCC(F)(F)CN
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: Cc1ccc2nc(Cl)nc(NCC(F)(F)CN)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 6.2 %

Procedure:
To a solution of 2,2-difluoropropane-1,3-diamine (1.1 g, 10 mmol) and triethylamine (1.4 mL, 10 mol) in dichloromethane (15 mL) was added a solution of 2,4-dichloro-6-methylquinazoline (500 mg, 2.36 mmol) in dichloromethane (5 mL) dropwise. After being stirred at room temperature overnight, the resulting mixture was poured into water (50 mL) and extracted with dichloromethane (50 mL×2). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (eluting with 10-25% methanol in dichloromethane) to afford 41.8 mg of the desired product as a white solid (yield was 62%). MS obsd. (ESI+) [(M+H)+] 287.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27]([C:30]2[CH:38]=[CH:37][C:33]([C:34]([OH:36])=O)=[CH:32][CH:31]=2)(=[O:29])=[O:28])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:39][C@@H:40]([CH2:43][CH3:44])[CH2:41][NH2:42]>>[N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27]([C:30]2[CH:31]=[CH:32][C:33]([C:34]([NH:42][CH2:41][C@@H:40]([CH3:39])[CH2:43][CH3:44])=[O:36])=[CH:37][CH:38]=2)(=[O:29])=[O:28])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC[C@H](C)CN
Reactant: O=C(O)c1ccc(S(=O)(=O)Cc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Product: CC[C@H](C)CNC(=O)c1ccc(S(=O)(=O)Cc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Yield: 100 %

Procedure:
Using the method in Example 172, 4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoic acid (53 mg, 0.10 mmol, 0.20M in DMF) and (S)-2-methylbutylamine (26 mg, 0.30 mmol, 0.6M in DMF) were combined to give 60 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 600 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([O:10]O)=O)[CH:3]=1.[CH3:12][S:13][C:14]1[N:23]2[C:17](CC3C=CC=CC=3[CH:21]=[CH:22]2)=[N:16][N:15]=1.S([O-])([O-])=[O:29].[Na+].[Na+].C(=O)([O-])O.[Na+]>ClCCl>[CH3:12][S:13]([C:14]1[N:23]2[C:17]([C:8](=[O:10])[C:4]3[CH:3]=[CH:2][CH:7]=[CH:6][C:5]=3[CH:21]=[CH:22]2)=[N:16][N:15]=1)=[O:29]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=S([O-])[O-]
Reactant: CSc1nnc2n1C=Cc1ccccc1C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)c1nnc2c(=O)c3ccccc3ccn12

Procedure:
Under ice-cooling and stirring, 0.224 g of m-chloroperbenzoic acid was added to a solution of 0.243 g of 3-methylthio-11H-s-triazolo[3,4-b][3]benzazepine in 4 ml of dichloromethane. The mixture was stirred for 30 minutes, after which 0.035 g of m-chloroperbenzoic acid was further added. After additional stirring for 1 hour, the reaction mixture was shaken well with an aqueous solution of sodium sulfite and a saturated aqueous solution of sodium hydrogen carbonate. The dichloromethane layer was washed with water and dried over Na2SO4. The solvent was evaporated off and the crystalline precipitate was recovered by filtration and washed with ethyl acetate. The above procedure gave 3-methylsulfinyl-11H-s-triazolo[3,4-b][3]benzazepin-11-one as crystals. Recrystallization from chloroform-methanol yielded colorless needles, m.p. 208°-211° C.
Reaction SMILES: CN(C)S([N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:20][CH2:21]C(C)(C)N=2)=[CH:15][CH:14]=1)[OH:12])(=O)=O.[OH-:27].[K+]>C(O)C>[NH:6]1[CH:10]=[CH:9][N:8]=[C:7]1[C:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([O:20][CH3:21])=[O:27])=[CH:15][CH:14]=1)=[O:12].[NH:6]1[CH:10]=[CH:9][N:8]=[C:7]1[CH:11]([OH:12])[C:13]1[CH:18]=[CH:17][C:16]([C:19]([O:20][CH3:21])=[O:27])=[CH:15][CH:14]=1
Reactant: CN(C)S(=O)(=O)n1ccnc1C(O)c1ccc(C2=NC(C)(C)CO2)cc1
Reactant: [OH-]
Agent: [K+]
Solvent: CCO
Product: COC(=O)c1ccc(C(=O)c2ncc[nH]2)cc1
Product: COC(=O)c1ccc(C(O)c2ncc[nH]2)cc1

Procedure:
To a solution of 1.70 g of N,N-dimethyl-2-[[4-(4,4-dimethyl-2-oxazolin-2-yl)phenyl]hydroxymethyl]imidazole-1-sulfonamide in ethanol was added 50 ml of a 2% aqueous solution of potassium hydroxide and the resulting mixture was heated under reflux for 15 hours. After distilling off the solvent under reduced pressure, 50 ml of methanol and 5 ml of conc. sulfuric acid were added to the residue and the resulting mixture was heated under reflux for 10 hours. After distilling off methanol under reduced pressure, the residue was distributed into ethyl acetate and an aqueous solution of sodium bicarbonate. The organic layer was extracted, washed successively with water and a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluted with dichloromethane/methanol) to thereby give 0.38 g of methyl 4-[(imidazol-2-yl)carbonyl]benzoate and 0.21 g of methyl 4-[(imidazol-2-yl)hydroxymethyl]benzoate each as a colorless oily substance.
Reaction SMILES: [Cl:1][C:2]1[C:12]([Br:13])=[CH:11][C:10]([N+:14]([O-:16])=[O:15])=[CH:9][C:3]=1[C:4]([O:6]CC)=[O:5].C1COCC1.[OH-].[Na+].Cl>C(O)C.O>[Cl:1][C:2]1[C:12]([Br:13])=[CH:11][C:10]([N+:14]([O-:16])=[O:15])=[CH:9][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])cc(Br)c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc([N+](=O)[O-])cc(Br)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
26.63 g (86.3 mmol ) of ethyl 2-chloro-3-bromo-5-nitrobenzoate was dissolved in a mixture comprising 150 ml of ethanol and 80 ml. of THF, followed by the addition of 55 ml of a 2N aqueous solution of sodium hydroxide. The obtained mixture was stirred at room temperature for one hour, followed by the addition of water and 19 ml. of 6N hydrochloric acid. The obtained mixture was concentrated under reduced pressure and extracted with ethyl acetate. The ethyl acetate phase was washed with a saturated aqueous solution of common salt, dried and distilled to remove the solvent, giving 24.11 g of the title compound (yield: quantitative).
Reaction SMILES: [CH2:1]([C:5]1([CH3:22])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([OH:15])=[C:7](C(OCC)=O)[C:6]1=[O:21])[CH2:2][CH2:3][CH3:4].Cl>O1CCOCC1>[CH2:1]([C:5]1([CH3:22])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([OH:15])=[CH:7][C:6]1=[O:21])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1(C)C(=O)C(C(=O)OCC)=C(O)c2ccccc21
Agent: Cl
Solvent: C1COCCO1
Product: CCCCC1(C)C(=O)C=C(O)c2ccccc21
Temperature: 25 °C
Yield: 36 %

Procedure:
A solution of Example 27D (1.92 g, 6.35 mmol) in 1,4-dioxane (25 mL) was treated with aqueous 1N hydrochloric acid solution (25 mL) and refluxed for 3 hours. The mixture was cooled to 25° C. and partitioned between ethyl acetate and water. The ethyl acetate layer was washed with water and brine, dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was triturated in hot hexane and filtered. The precipitate was dried to give the title compound (0.527 g, 36%). 1H NMR (300 MHz, CDCl3) δ ppm 0.56 (m, 0.5 H) 0.70 (t, 1.5 H) 0.81 (t, 1.5 H) 0.92 (m, 1 H) 1.16 (m, 2.5 H) 1.53 (s, 1.5 H) 1.56 (s, 1.5 H) 1.85 (m, 1 H) 2.03 (m, 0.5 H) 2.26 (m, 0.5 H) 3.74 (s, 0.5 H) 3.75 (s, 0.5 H) 6.22 (s, 0.5 5 H) 7.44 (m, 2 H) 7.62 (m, 1 H) 8.08 (0.5, 1 H) 8.14 (m, 0.5 H). MS (DCI NH3+) m/z 248 (M+NH4)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH3:22])[C:6]=1[F:23])[CH3:2].Br[C:26]1[CH:27]=[N:28][CH:29]=[C:30]([CH2:32][CH3:33])[CH:31]=1>>[CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[N:14]([C:26]3[CH:27]=[N:28][CH:29]=[C:30]([CH2:32][CH3:33])[CH:31]=3)[C:13]=2[CH3:22])[C:6]=1[F:23])[CH3:2]
Reactant: CCc1cncc(Br)c1
Reactant: CCOC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1F
Product: CCOC(=O)c1cccc(Sc2c(C)n(-c3cncc(CC)c3)c3cc(Cl)ccc23)c1F

Procedure:
Prepared according to the procedure described in Example 42, Step 4, using the following starting materials: 3-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-2-fluoro-benzoic acid ethyl ester and 3-bromo-5-ethylpyridine.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.O.CCN=C=NCCCN(C)C.[NH2:23][C:24]1[N:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26]([OH:28])=O.CCN(C(C)C)C(C)C.[F:42][C:43]1[CH:48]=[CH:47][C:46]([NH2:49])=[CH:45][CH:44]=1>O.CN(C=O)C>[NH2:23][C:24]1[N:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26]([NH:49][C:46]1[CH:47]=[CH:48][C:43]([F:42])=[CH:44][CH:45]=1)=[O:28]
Reactant: Nc1ncccc1C(=O)O
Reactant: Nc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Nc1ncccc1C(=O)Nc1ccc(F)cc1
Reaction time: 0.5 h

Procedure:
A 1 L round-bottomed flask was charged with HOBT-H2O (20.37 g, 133.0 mmol), EDCI (25.50 g, 133.0 mmol), 2-aminonicotinic acid (12.25 g, 88.69 mmol), and DMF (750 mL). The reaction mixture was stirred for 30 minutes, then Hunig's base (30.90 ml, 177.4 mmol) and 4-fluorobenzenamine (10.65 ml, 110.9 mmol) were added. The reaction mixture was stirred for 18 hours, then diluted with water. After 30 minutes the resulting precipitate was collected by filtration and dried to provide the product. LRMS M+1 (231.9) observed.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1([C:14]([OH:16])=O)[CH2:13][CH2:12]1)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.[Br-:29].[Br-].[NH3+:31][CH2:32][CH2:33][CH2:34][P+:35]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CN(C)C=O.C(Cl)Cl>[Br-:29].[C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1([C:14]([NH:31][CH2:32][CH2:33][CH2:34][P+:35]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:16])[CH2:12][CH2:13]1)[CH3:9])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(CC1(C(=O)O)CC1)C(=O)OC(C)(C)C
Reactant: [NH3+]CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Br-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(CC1(C(=O)NCCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)CC1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.2 %

Procedure:
1-{[(tert-butoxycarbonyl)(methyl)amino]methyl}cyclopropanecarboxylic acid (680 mg, 3.0 mmol) was dissolved in N,N-dimethylformamide (6.8 mL) and treated with N,N-carbonyldiimidazole (571 mg, 3.52 mmol). The mixture was stirred at room temperature for 30 minutes. To the solution was added (3-ammoniopropyl)(triphenyl)phosphonium dibromide (1.93 g, 4.00 mmol). The mixture was stirred overnight at room temperature and then diluted with methylene chloride and washed with 5% aqueous lithium chloride (3 times), 1N aqueous hydrogen chloride, and saturated sodium bicarbonate. The organic solution was dried over anhydrous sodium sulfate, filtered, and concentrated to give crude title compound. The crude product was purified on a silica gel column eluting with a gradient of 0-20% methanol with methylene chloride to isolate the title compound (810 mg, 40%, 91% pure).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[C:16]3[S:17][CH:18]=[CH:19][C:15]=3[O:14][N:13]=2)[CH:9]=[CH:10][CH:11]=1.ClCCCOC1C=C(C2[C:35]3[S:36][CH:37]=[CH:38][C:34]=3ON=2)C=CC=1.S1C=CC([CH2:44][NH2:45])=C1.C(=O)([O-])[O-].[K+].[K+]>>[O:14]1[C:15]2[CH:19]=[CH:18][S:17][C:16]=2[C:12]([C:8]2[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=2)[O:5][CH2:4][CH2:3][CH2:2][N:45]([C:34]2[CH:38]=[CH:37][S:36][CH:35]=2)[CH3:44])=[N:13]1
Reactant: NCc1ccsc1
Reactant: BrCCCOc1cccc(-c2noc3ccsc23)c1
Reactant: ClCCCOc1cccc(-c2noc3ccsc23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CN(CCCOc1cccc(-c2noc3ccsc23)c1)c1ccsc1
Yield: 86 %

Procedure:
The title compound is prepared from a mixture of 3-[3-(3-bromo-propoxy)-phenyl]-thieno[2,3-d]isoxazole, 3-[3-(3-chloro-propoxy)-phenyl]-thieno[2,3-d]isoxazole, 3-thiophenemethylamine and potassium carbonate essentially as described above in example 4. Combine the appropriate fractions and concentrate to give the title compound (0.32 g, 86% Yield) as an oil. Purity by LC/MS (APCI)=98%, [M+H]+=371 m/e.
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[O:5])[CH3:2].[CH2:6]([NH:8][C:9](=[O:32])[C:10]1[CH:15]=[C:14]([C:16]2[CH:24]=[C:23]3[C:19]([C:20]([CH:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)=[N:21][NH:22]3)=[CH:18][CH:17]=2)[C:13]([CH3:31])=[CH:12][CH:11]=1)[CH3:7]>CN(C=O)C>[CH2:1]([NH:3][C:4]([N:28]1[CH2:29][CH2:30][CH:25]([C:20]2[C:19]3[C:23](=[CH:24][C:16]([C:14]4[CH:15]=[C:10]([C:9]([NH:8][CH2:6][CH3:7])=[O:32])[CH:11]=[CH:12][C:13]=4[CH3:31])=[CH:17][CH:18]=3)[NH:22][N:21]=2)[CH2:26][CH2:27]1)=[O:5])[CH3:2]
Reactant: CCN=C=O
Reactant: CCNC(=O)c1ccc(C)c(-c2ccc3c(C4CCNCC4)n[nH]c3c2)c1
Solvent: CN(C)C=O
Product: CCNC(=O)c1ccc(C)c(-c2ccc3c(C4CCN(C(=O)NCC)CC4)n[nH]c3c2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ethyl isocyanate (4 μL) was added to N-ethyl-4-methyl-5-[3-(4-piperidinyl)-1H-indazol-6-yl]benzamide (Intermediate 16, 20 mg) in DMF (3 mL) at room temperature under nitrogen and the reaction mixture was stirred at room temperature for 30 min. The product was concentrated under vacuum and the residue was purified by preparative HPLC to give the title compound as a white solid (13 mg).