Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:13]([CH3:14])=[C:12]([OH:15])[C:11]2[C:6](=[CH:7][C:8]([Cl:17])=[C:9]([F:16])[CH:10]=2)[N:5]=1.C(C1C(C)=C([O:31][C:32]([CH:34]2[CH2:36][CH2:35]2)=O)C2C(=CC(F)=C(F)C=2)N=1)C.[CH2:39]([C:41]1[C:50]([CH3:51])=[C:49]([O:52][C:53]([CH:55]2[CH2:57][CH2:56]2)=[O:54])[C:48]2[C:43](=[CH:44][CH:45]=[C:46]([F:59])[C:47]=2F)[N:42]=1)C>CN(C)C=O.O>[CH3:3][C:4]1[C:13]([CH3:14])=[C:12]([O:15][C:32]([CH:34]2[CH2:36][CH2:35]2)=[O:31])[C:11]2[C:6](=[CH:7][C:8]([Cl:17])=[C:9]([F:16])[CH:10]=2)[N:5]=1.[CH3:39][C:41]1[C:50]([CH3:51])=[C:49]([O:52][C:53]([CH:55]2[CH2:57][CH2:56]2)=[O:54])[C:48]2[C:43](=[CH:44][CH:45]=[C:46]([F:59])[C:47]=2[Cl:17])[N:42]=1
Reactant: CCc1nc2cc(F)c(F)cc2c(OC(=O)C2CC2)c1C
Reactant: CCc1nc2ccc(F)c(F)c2c(OC(=O)C2CC2)c1C
Reactant: Cc1nc2cc(Cl)c(F)cc2c(O)c1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc2cc(Cl)c(F)cc2c(OC(=O)C2CC2)c1C
Product: Cc1nc2ccc(F)c(Cl)c2c(OC(=O)C2CC2)c1C
Reaction time: 1 h

Procedure:
3-Chloro-4-fluoroaniline (5.0 g) and 4.9 g of ethyl-2-methyl acetoacetate were refluxed in toluene (50 ml) in the presence of 0.3 ml of boron trifluoride etherate for 3 hr. The reaction mixture was washed with a saturated sodium hydrogencarbonate solution and saturated brine and was dried over anhydrous sodium sulfate, and the solvent was then removed by evaporation. The resultant intermediate was refluxed in diphenyl ether for 30 min. The reaction mixture was allowed to stand for cooling, and the precipitate was then collected by filtration under the reduced pressure to give 1.7 g of a mixture of 2,3-dimethyl-4-hydroxy-6-fluoro-7-chloroquinoline with 2,3-dimethyl-4-hydroxy-5-chloro-6-fluoroquinoline. In 50 ml of dimethyl formamide was suspended 350 mg of 60% sodium hydride. Separately, the mixture of 2,3-dimethyl-4-hydroxy-6-fluoro-7-chloroquinoline with 2,3-dimethyl-4-hydroxy-5-chloro-6-fluoroquinoline (starting material 1) (1.7 g) was suspended in 30 ml of dimethyl formamide, and this suspension was added dropwise to the above suspension under ice cooling. After stirring for one hr, 940 μl of cyclopropanecarbonyl chloride (starting material 2) was added thereto, and the mixture was stirred at room temperature for 13 hr. The reaction solution was poured into water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine and was then dried over anhydrous sodium sulfate. The solvent was then removed by evaporation under the reduced pressure. The crude product thus obtained was purified on Wako Gel C-200 (100 ml; elution solvent=n-hexane-ethyl acetate (10:1)) to give 480 mg of 2,3-dimethyl-4-cyclopropanecarbonyloxy-6-fluoro-7-chloroquinoline (compound 26) and 350 mg of 2,3-dimethyl-4-cyclopropanecarbonyloxy-5-chloro-6-fluoro -quinoline (compound 27). 1H-NMR data are shown in Table 3.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:38]([C:39]([F:42])([F:41])[F:40])=[CH:37][CH:36]=[CH:35][C:4]=1[CH2:5][N:6]([CH2:21][CH:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[C:13]([CH2:17][C:18]([OH:20])=[O:19])[CH:14]=[CH:15][CH:16]=1.[CH3:43]O>S(=O)(=O)(O)O>[CH3:43][O:19][C:18](=[O:20])[CH2:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([O:10][CH2:9][CH2:8][CH2:7][N:6]([CH2:5][C:4]2[CH:35]=[CH:36][CH:37]=[C:38]([C:39]([F:40])([F:41])[F:42])[C:3]=2[Cl:2])[CH2:21][CH:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:12]=1
Reactant: O=C(O)Cc1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Reactant: CO
Agent: Cl
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Yield: 93 %

Procedure:
To a solution of (3-{3[(2-Chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-acetic acid hydrochloride salt (Example 1d, 0.1 g, 0.2 mmol) in methanol (2 ml) was added concentrated sulfuric acid (2 drops). After the resulting mixture was heated to reflux for 2 h solvent was removed under vacuum. The residue was dissolved in water and neutralized to pH=7. The aqueous layer was extracted with ethyl acetate three times. The combined organic layers were washed with, brine, dried over magnesium sulfate, and concentrated in vacco to give 900 mg (93%) of the title compound as an oil. MS m/e 596.2 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:15][CH2:14][N:13]([C:16]2[C:17]3[CH:24]=[CH:23][NH:22][C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:12][C:9]21[CH2:11][CH2:10]2)=O)(C)(C)C.Cl>C(OCC)C.O1CCOCC1>[CH2:11]1[C:9]2([CH2:12][N:13]([C:16]3[C:17]4[CH:24]=[CH:23][NH:22][C:18]=4[N:19]=[CH:20][N:21]=3)[CH2:14][CH2:15][NH:8]2)[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncnc3[nH]ccc23)CC12CC2
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: c1nc(N2CCNC3(CC3)C2)c2cc[nH]c2n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To 7-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4,7-diazaspiro[2.5]octane-4-carboxylic acid tert-butyl ester (intermediate 1) (0.5 g, mmol) dissolved in diethyl ether (20 ml) was added HCl in dioxane (ml, M) and the reaction mixture was stirred for 5 hours at room temperature. The precipitate was isolated by filtration, and washed with diethyl ether (2×5 ml). The precipitate was suspended in THF (50 ml) and stirred vigorously with K2CO3 (5 gram) for 3 hours. After filtration and evaporation of the solvent in vacuo, the product was obtained as an off-white compound.
Reaction SMILES: CC1N=C(N2C(=O)N(CC3C=CC(C(F)(F)F)=CC=3)N=C2)SC=1C(O)=O.[F:27][C:28]1[CH:49]=[CH:48][C:31]([CH2:32][N:33]2[C:37](=[O:38])[N:36]([C:39]3[S:40][C:41]([C:45](O)=[O:46])=[C:42]([CH3:44])[N:43]=3)[CH:35]=[N:34]2)=[CH:30][CH:29]=1.Cl.[S:51]1[CH:55]=[CH:54][N:53]=[C:52]1[CH2:56][NH2:57]>>[F:27][C:28]1[CH:49]=[CH:48][C:31]([CH2:32][N:33]2[C:37](=[O:38])[N:36]([C:39]3[S:40][C:41]([C:45]([NH:57][CH2:56][C:52]4[S:51][CH:55]=[CH:54][N:53]=4)=[O:46])=[C:42]([CH3:44])[N:43]=3)[CH:35]=[N:34]2)=[CH:30][CH:29]=1
Reactant: Cc1nc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)O
Reactant: NCc1nccs1
Agent: Cc1nc(-n2cnn(Cc3ccc(C(F)(F)F)cc3)c2=O)sc1C(=O)O
Agent: Cl
Product: Cc1nc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)NCc1nccs1
Yield: 66 %

Procedure:
Following the procedure as described in Example 21, making variations as required to replace 4-methyl-2-(5-oxo-1-(4-(trifluoromethyl)benzyl)-1H-1,2,4-triazol-4(5H)-yl)thiazole-5-carboxylic acid with 2-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methylthiazole-5-carboxylic acid to react with thiazol-2-ylmethanamine hydrochloride, the title compound was obtained as a white solid in 66% yield: mp 189-190° C. (ethyl acetate/hexane); 1H NMR (300 MHz, CDCl3) δ 8.25 (s, 1H), 7.74 (br s, 1H), 7.40-7.31 (m, 3H), 7.06-6.97 (m, 2H), 6.78 (t, J=5.4 Hz, 1H), 4.97 (s, 2H), 4.92 (d, J=5.4 Hz, 2H), 2.67 (s, 3H); MS (ES+) m/z 431.1 (M+1).
Reaction SMILES: N[C:2]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:3]=1[CH:4]([OH:20])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:6]=1.C(OC1C=CC(C=O)=CC=1)C1C=CC=CC=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[C:16]([O:15][C:13]([NH:12][CH2:11][C:7]1[CH:6]=[C:5]([CH:4]([OH:20])[C:3]2[CH:21]=[C:22]([O:25][CH3:26])[CH:23]=[CH:24][CH:2]=2)[CH:10]=[CH:9][CH:8]=1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: COc1ccc(N)c(C(O)c2cccc(CNC(=O)OC(C)(C)C)c2)c1
Agent: O=Cc1ccc(OCc2ccccc2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1cccc(C(O)c2cccc(CNC(=O)OC(C)(C)C)c2)c1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
In methanol (6 ml) were dissolved 2-amino-α-(3-tert-butoxycarbonylaminomethylphenyl)-5-methyloxybenzyl alcohol (0.18 g), 4-benzyloxy-benzaldehyde (0.12 g) and acetic acid (0.02 g). To the solution was added sodium cyano borohydride (0.02 mg). The mixture was stirred for 30 minutes at 60° C. The reaction mixture was concentrated, to which were added ethyl acetate (30 ml) and water (50 ml). The mixture was shaken. The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by means of a silica gel column chromatography to give 2-(4-benzyloxybenzyl)-α-(3-tert-butoxycarbonylaminomethylphenyl-5-methyloxybenzyl alcohol as a colorless crystalline product (0.17 g). m.p.:86-87° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]=[C:8]([Cl:19])[N:9]=[C:10]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[NH:20]1[CH2:25][CH2:24][CH:23]([C:26]([OH:29])([CH3:28])[CH3:27])[CH2:22][CH2:21]1>>[Cl:19][C:8]1[N:9]=[C:10]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:11]2[N:12]=[C:3]([CH2:2][N:20]3[CH2:25][CH2:24][CH:23]([C:26]([OH:29])([CH3:28])[CH3:27])[CH2:22][CH2:21]3)[CH:4]=[CH:5][C:6]=2[N:7]=1
Reactant: CC(C)(O)C1CCNCC1
Reactant: Clc1nc(N2CCOCC2)c2nc(CBr)ccc2n1
Product: CC(C)(O)C1CCN(Cc2ccc3nc(Cl)nc(N4CCOCC4)c3n2)CC1

Procedure:
Following General Procedure B, 4-(6-(bromomethyl)-2-chloropyrido[3,2-d]pyrimidin-4-yl)morpholine 7 and 2-(piperidin-4-yl)propan-2-ol were reacted to give 2-(1-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)propan-2-ol. LCMS (MH+)=406.1. 1H-NMR (DMSO-d6): δ 8.02 (d, 1H), 7.83 (d, 1H), 4.46 (s, br, 4H), 4.01 (s, 1H), 3.78 (m, 4H), 3.68 (s, 2H), 2.88 (m, 2H), 1.96 (m, 2H), 1.65 (m, 2H), 1.25 (m, 3H), 1.03 (s, 6H)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=[CH:5]2.[Cu][C:18]#[N:19]>>[N:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:6]2[NH:7][C:8]3[C:4]([CH:5]=2)=[CH:3][C:2]([C:18]#[N:19])=[CH:10][CH:9]=3)[CH:12]=1
Reactant: Brc1ccc2[nH]c(-c3cccnc3)cc2c1
Reactant: N#C[Cu]
Product: N#Cc1ccc2[nH]c(-c3cccnc3)cc2c1
Temperature: 160 °C
Reaction time: 8 h

Procedure:
5-Bromo-2-pyridin-3-yl-1H-indole (7.0 g, 21.8 mmol) and copper (I) cyanide (2.3 g, 26.1 mmol) are placed in a round bottom flask which is flushed with N2. N-Methylpyrrolidinone (40 mL) is added via syringe. The resulting mixture is heated to 160° C. under N2 with vigorous stirring overnight. The mixture is cooled to room temperature and poured into 10% aqueous ammonia in saturated aqueous ammonium chloride (300 mL). The aqueous phase is extracted with dichloromethane (100 mL) five times. The combined organic phase is dried over sodium sulfate and concentrated. The residue is purified by silica gel flash chromatography (ethyl acetate-heptane, 0:1 to 1:0) to give 2-pyridin-3-yl-1H-indole-5-carbonitrile. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.20 (s, 1H), 7.48 (dd, J=8.3, 1.5 Hz, 1H), 7.51-7.55 (m, 1H), 7.59 (d, J=8.6 Hz, 1H), 8.12 (s, 1H), 8.25-8.29 (m, 1H), 8.56 (dd, J=4.8, 1.5 Hz, 1H), 9.14 (d, J=1.8 Hz, 1H), 12.27 (s, 1H). HRMS (ESI) m/z 220.0869 [(M+H)+ Calcd for C14H9N3, 220.0875].
Reaction SMILES: [NH2:1][C:2]1[N:14]=[C:13]2[N:4]([C:5]([CH2:18][C:19]3[CH:27]=[CH:26][C:22]4[O:23][CH2:24][O:25][C:21]=4[CH:20]=3)=[N:6][C:7]3[CH:8]=[C:9]([C:15](O)=[O:16])[CH:10]=[CH:11][C:12]=32)[N:3]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:59][CH2:60][CH2:61][OH:62]>ClCCl>[OH:62][CH2:61][CH2:60][NH:59][C:15]([C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:4]([N:3]=[C:2]([NH2:1])[N:14]=3)[C:5]([CH2:18][C:19]3[CH:27]=[CH:26][C:22]4[O:23][CH2:24][O:25][C:21]=4[CH:20]=3)=[N:6][C:7]=2[CH:8]=1)=[O:16]
Reactant: NCCO
Reactant: Nc1nc2c3ccc(C(=O)O)cc3nc(Cc3ccc4c(c3)OCO4)n2n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Nc1nc2c3ccc(C(=O)NCCO)cc3nc(Cc3ccc4c(c3)OCO4)n2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.7 %

Procedure:
To a solution of 2-amino-5-benzo[1,3]dioxol-5-ylmethyl-[1,2,4]triazolo[1,5-c]quinazoline-8-carboxylic acid (0.05 g, 0.14 mmol) prepared as described in Example 19, and N,N-diisopropylethylamine (0.14 mL, 0.81 mmol) in anhydrous dichloromethane (5 mL), TBTU (0.05 g, 0.17 mmol) was added. The reaction was stirred at room temperature for 30 minutes, then 2-aminoethanol (0.02 mL, 0.28 mmol) was added. After stirring for 1 h, the solution washed with NaHCO3 satured solution, then with water and brine. The organic phase was dried over Na2SO4 and evaporated to give a crude that was purified by flash column chromatography on silica gel eluting with DCM/MeOH/NH4OH 8/2/1, to provide the title compound (0.03 g, 53% yield).
Reaction SMILES: [CH:1]([C:13]([O:15]C)=O)([C:9]([O:11]C)=O)[CH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:17]1(/[CH:23]=[CH:24]/[C:25](=[NH:27])[NH2:26])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C.C[O-].[Na+].CO>CCO>[OH:15][C:13]1[N:26]=[C:25](/[CH:24]=[CH:23]/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[NH:27][C:9](=[O:11])[C:1]=1[CH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: N=C(N)/C=C/c1ccccc1
Reactant: CCOC(=O)CCC(C(=O)OC)C(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Solvent: CCN(CC)CC
Product: CCOC(=O)CCc1c(O)nc(/C=C/c2ccccc2)[nH]c1=O
Temperature: 25 °C

Procedure:
3-Ethyl 1,1-dimethyl 1,1,3-propanetricarboxylate (1.65 g, 7.1 mmol) and (2E)-3-phenyl-2-propenimidamide (1.04 g, 7.11 mmol) were combined in EtOH (36 mL). Triethylamine (1.98 mL, 14.2 mmol) was added and the solution was heated at reflux for 3 h with no change based on LCMS. The solution was cooled to room temperature and treated with NaOMe in MeOH (1.0 mL, 5.33 mmol, 25% wt solution) and the solution was refluxed for an additional 4 h. Another portion of NaOMe in MeOH (1.0 mL, 5.33 mmol, 25% wt solution) was added and the solution was refluxed for 16 h. After this time, a yellow precipitate had formed which was filtered off The mother liquor was acidified to pH2 with 1N HCl, and the solution was concentrated under vacuum. The resulting material was combined with the yellow solid and used without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[NH2:23][CH:24]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[CH:35][CH:34]=1)[C:25]([NH:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]>CN(C=O)C>[CH2:40]([O:39][C:36]1[CH:37]=[CH:38][C:33]([CH2:32][CH:24]([NH:23][C:9](=[O:11])[C:8]2[CH:7]=[CH:6][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:13][CH:12]=2)[C:25](=[O:26])[NH:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[CH:34][CH:35]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: CC(C)(C)NC(=O)C(N)Cc1ccc(OCc2ccccc2)cc1
Reactant: CC(C)(C)c1ccc(C(=O)O)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)C(Cc1ccc(OCc2ccccc2)cc1)NC(=O)c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 0.589 g (3.026 mmol) 4-tert-butylbenzoic acid (Aldrich, Milwaukee Wis.) 1.06 mL (6.5 mmol) N,N-diisopropylethylamine, and 1.15 g (3.026 mmol) O-Benzotriazol-1-yl-N,N,N′,N′-bis(tetramethylene)-uronium hexafluorophosphate in 6 mL dry DMF was stirred in an ice bath for 35 minutes, when 1.00 g (3.026 mmol) of 2-Amino-3-(4-benzyloxy-phenyl)-N-tert-butyl-propionamide (Example 1, Step B) was added. The resulting solution was warmed to 25° C. and stirred for 60 minutes. The mixture was poured into 20 mL diethyl and washed sequentially with 25 mL each of saturated aqueous sodium bicarbonate solution and twice with brine. The mixture was then dried over anhydrous sodium sulfate and concentrated at reduced pressure giving a pale amber solid that was purified by column chromatography on silica gel with 30% ethyl acetate in hexane to give N-[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-4-tert-butyl-benzamide as a white solid; mp 124-131° C.
Reaction SMILES: [S:1]([O:8]S(C(F)(F)F)(=O)=O)([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2].CN(C1C=CC=CN=1)C.[CH:25]1([CH2:28][O:29][C:30]2[CH:31]=[C:32]([C:36]3[C:44]4[C:39](=[CH:40][CH:41]=[C:42](O)[CH:43]=4)[N:38]([CH2:46][C:47]4[CH:52]=[CH:51][CH:50]=[C:49]([O:53][CH3:54])[CH:48]=4)[C:37]=3[C:55]([O:57][CH2:58][CH3:59])=[O:56])[CH:33]=[CH:34][CH:35]=2)[CH2:27][CH2:26]1>ClCCl.N1C=CC=CC=1.C(OCC)(=O)C>[CH:25]1([CH2:28][O:29][C:30]2[CH:31]=[C:32]([C:36]3[C:44]4[C:39](=[CH:40][CH:41]=[C:42]([O:8][S:1]([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2])[CH:43]=4)[N:38]([CH2:46][C:47]4[CH:52]=[CH:51][CH:50]=[C:49]([O:53][CH3:54])[CH:48]=4)[C:37]=3[C:55]([O:57][CH2:58][CH3:59])=[O:56])[CH:33]=[CH:34][CH:35]=2)[CH2:27][CH2:26]1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CCOC(=O)c1c(-c2cccc(OCC3CC3)c2)c2cc(O)ccc2n1Cc1cccc(OC)c1
Agent: CN(C)c1ccccn1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1c(-c2cccc(OCC3CC3)c2)c2cc(OS(=O)(=O)C(F)(F)F)ccc2n1Cc1cccc(OC)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 89.1 %

Procedure:
Triflic anhydride (0.84 mL, 1.4 g, 5.0 mmol) and dimethylaminopyridine (25 mg, 0.20 mmol) were added to a cooled (0° C.) and stirred solution of ethyl 3-[3-(cyclopropylmethoxy)phenyl]-5-hydroxy-1-(3-methoxybenzyl)-1H-indole-2-carboxylate (Example 66, 1.00 g, 2.12 mmol) in dichloromethane (10 mL) and pyridine (2 mL). The reaction was warmed to rt and then stirred an additional 2 h. The solution was diluted with ethyl acetate (100 mL), washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. Flash chromatography of the residue over silica gel using 15% ethyl acetate/hexane afforded 1.14 g (89%) of desired product. The product had: 1H NMR (300 MHz, acetone-D6) δ 7.73 (d, 1 H), 7.54 (d, 1 H), 7.35-7.42 (m, 3 H), 7.20 (dd, 1 H), 7.00-7.07 (m, 2 H), 6.68-6.83 (m, 3 H), 5.88 (s, 2 H), 4.16 (q, 2 H), 3.91 (d, 2 H), 3.72 (s, 3 H), 1.25-1.35 (m, 1 H), 10.5 (t, 3 H), 0.55-0.65 (m, 2 H), 0.32-0.42 (m, 2 H); mass spectroscopy gave M+=603.1 (exact mass calc'd for C20H28F3NO7S=603.15).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[CH2:15][C:16]([CH3:18])=[CH2:17])(C)(C)C.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.CS(O)(=O)=O>ClCCl>[CH3:17][C:16]1([CH3:18])[CH2:15][C:9]2[C:8](=[CH:13][CH:12]=[C:11]([F:14])[CH:10]=2)[NH:7]1
Reactant: C=C(C)Cc1cc(F)ccc1NC(=O)OC(C)(C)C
Agent: CS(=O)(=O)O
Solvent: COc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)Cc2cc(F)ccc2N1
Temperature: 170 °C
Reaction time: 4 h
Yield: 65.8 %

Procedure:
A sample of [4-Fluoro-2-(2-methyl-allyl)-phenyl]-carbamic acid tert-butyl ester (1.10 g, 4.14 mmol) was treated with anisole (5 mL), dichloromethane (5 mL) and trifluoroacetic acid (5 mL) and stirred for 4 hours. The solvent was removed and the reaction was transferred to a microwave reaction vial using methanesulfonic acid (3 mL). The reaction was heated to 170° C. for 10 minutes. The reaction was cooled to room temperature and quenched into excess stirring 1 M NaOH. The aqueous phase was extracted twice with ethyl acetate and the combined organics were dried over MgSO4 and filtered. The resulting oil was purified on silica gel using a gradient of 0-70% t-butyl ethyl ether and hexane to afford 450 mg (66% yield) of 2,2-dimethyl-5-fluoroindoline; 1H NMR (CDCl3, 400 MHz) δ 1.08 (s, 6H), 2.58 (s, 2H), 6.24 (dd, 1H, J1=4.4, J2=8.4), 6.43-6.48 (m, 1H), 6.53-6.56 (m, 1H); HPLC-MS calcd. for C10H12FN (M+H+) 166.1, found 166.4.
Reaction SMILES: C([O:5][C:6](=[O:37])[CH2:7][C@H:8]([NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:23])[NH2:22])=[CH:17][C:16]=1[O:24][CH2:25][CH2:26][C:27]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:28]=1[CH:29]=[CH:30][CH:31]=[N:32]2)(=[O:14])=[O:13])[C:9]#[N:10])(C)(C)C.C1(C)C=CC=CC=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[C:21]([C:18]1[CH:19]=[CH:20][C:15]([S:12]([NH:11][C@H:8]([C:9]#[N:10])[CH2:7][C:6]([OH:37])=[O:5])(=[O:14])=[O:13])=[C:16]([O:24][CH2:25][CH2:26][C:27]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:28]=2[CH:29]=[CH:30][CH:31]=[N:32]3)[CH:17]=1)(=[O:23])[NH2:22]
Reactant: CC(C)(C)OC(=O)C[C@@H](C#N)NS(=O)(=O)c1ccc(C(N)=O)cc1OCCc1cccc2ncccc12
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#C[C@H](CC(=O)O)NS(=O)(=O)c1ccc(C(N)=O)cc1OCCc1cccc2ncccc12
Yield: 106.7 %

Procedure:
A solution of (S)-3-[4-carbamoyl-2-(2-quinolin-5-yl-ethoxy)-benzenesulfonylamino]-3-cyano-propionic acid tert-butyl ester (0.13 g, 0.20 mmol) in TFA (2 mL) and CH2Cl2 (20 mL) was stirred for 9 h. Toluene (50 mL) was added and the solvents were removed under vacuum. The residue was lyophilized to yield 100 mg (99%) of (S)-3-[4-carbamoyl-2-(2-quinolin-5-yl-ethoxy)-benzenesulfonylamino]-3-cyano-propionic acid as a pale yellow solid. MS m/z 469.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:38]=[CH:37][C:18]([CH2:19][C:20]2[O:21][C:22]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[C:23]([CH2:25][CH2:26][C:27]([O:29]C)=[O:28])[N:24]=2)=[CH:17][CH:16]=1.O.[OH-].[Li+].O1CCCC1.Cl>CO.O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:38]=[CH:37][C:18]([CH2:19][C:20]2[O:21][C:22]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[C:23]([CH2:25][CH2:26][C:27]([OH:29])=[O:28])[N:24]=2)=[CH:17][CH:16]=1
Reactant: COC(=O)CCc1nc(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)oc1-c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(Cc2nc(CCC(=O)O)c(-c3ccccc3)o2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84.6 %

Procedure:
A mixture of methyl 3-[2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-5-phenyl-4-oxazolyl]propionate (192 mg), lithium hydroxide hydrate (47.6 mg), tetrahydrofuran (6 ml), water (4 ml) and methanol (4 ml) was stirred at room temperature for 1.5 hrs. 1N Hydrochloric acid (1.2 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 to give 3-[2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-5-phenyl-4-oxazolyl]propionic acid (158 mg, yield 85%) as colorless crystals. The crystals were recrystallized from ethyl acetate-hexane. melting point: 136–137° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19](Br)[CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:19]2[CH:18]=[N:17][CH:16]=[C:15]([Br:14])[CH:20]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Brc1cncc(Br)c1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1cncc(N2CCN(Cc3ccccc3)CC2)c1
Temperature: 200 °C
Yield: 11.4 %

Procedure:
A mixture of 1-benzyl-piperazine (1.49 g, 8.44 mmol), 3,5-dibromo-pyridine (2.00 g, 8.44 mmol), and potassium carbonate (1.17 g, 8.44 mmol) in 15 ml DMF was heated at 200° C. for 1 h under a nitrogen atmosphere. Then the mixture was diluted with 100 ml of water and was extracted twice with ethyl acetate. The combined organic layers were extracted with aqueous HCl solution. The pH of the aqueous solution was adjusted to pH 10 with aqueous NaOH. After extraction with diethylether the combined organic phases were dried with magnesium sulfate, filtered and the solvent was evaporated under reduced pressure. The so obtained oil was purified via silica gel chromatography with cyclohexane/ethyl acetate (2:1) as eluent to give 0.32 g of the product.
Reaction SMILES: Cl.[Cl:2][C:3]([Cl:11])([Cl:10])[C:4]1[CH:5]=[NH+:6][CH:7]=[CH:8][CH:9]=1.C(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>O>[Cl:2][C:3]([Cl:11])([Cl:10])[C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: ClC(Cl)(Cl)c1ccc[nH+]c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: ClC(Cl)(Cl)c1cccnc1
Yield: 80.2 %

Procedure:
The 3-trichloromethylpyridinium hydrochloride salt (2836 g, 12.17 moles) was placed in a 22-liter pot with 2800 ml of methylene chloride and 2600 ml of water. A solution of 1000 g of sodium carbonate in 4300 ml of water was then added slowly so that the gassing could be controlled. The temperature was maintained with an ice bath between 15°-20° C. The lower organic phase was then separated and was dried with magnesium sulfate. The mixture was filtered and the methylene chloride was removed by rotary evaporation. The concentrated material was distilled at 77°-79° C. and 0.5 mm Hg giving 1918 g of the desired 3-trichloromethylpyridine product. The yield was 80%.