Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([O:6][CH2:7][C:8](Cl)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:11]([C:14]1[C:15]([NH2:23])=[N:16][N:17]2[CH:22]=[CH:21][CH:20]=[N:19][C:18]=12)([CH3:13])[CH3:12].CO>N1C=CC=CC=1>[CH:1]1([O:6][CH2:7][C:8]([NH:23][C:15]2[C:14]([CH:11]([CH3:13])[CH3:12])=[C:18]3[N:19]=[CH:20][CH:21]=[CH:22][N:17]3[N:16]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)c1c(N)nn2cccnc12
Reactant: O=C(Cl)COC1CCCC1
Solvent: CO
Solvent: c1ccncc1
Product: CC(C)c1c(NC(=O)COC2CCCC2)nn2cccnc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The product from Example 133C (1.5 mL of solution in CH2Cl2) was added to a solution of the product from Example 112C (86 mg, 0.49 mmol) in pyridine (1.0 mL) in a 4 mL vial. The reaction mixture was stirred at room temperature for 2 h. Methanol (0.5 mL) was added, and the solution was stirred for 30 minutes and then concentrated under vacuum. The residue was purified by flash chromatography (silica gel, eluted with hexanes-EtOAc, 70:30-0:100) to provide the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.45 (d, J=7.1 Hz, 6H) 1.57-1.69 (m, 2H) 1.70-1.87 (m, 6H) 3.24 (hept, J=7.1 Hz, 1H) 4.10-4.13 (m, 1H) 4.11-4.12 (m, 2H) 6.72 (dd, J=6.8, 4.1 Hz, 1H) 8.39 (dd, J=4.1, 1.7 Hz, 1H) 8.58 (dd, J=6.8, 1.7 Hz, 1H) 8.60 (s, 1H); MS (ESI) m/z 303 (M+H)+; Anal. Calculated for C16H22N4O2: C, 63.71; H, 7.44; N, 18.20. Found: C, 63.56; H, 7.33; N, 18.53.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:4][OH:5].Br[C:11]1[N:16]=[CH:15][CH:14]=[CH:13][N:12]=1>CN(C=O)C>[CH2:8]([O:7][C:3](=[O:6])[CH2:4][O:5][C:11]1[N:16]=[CH:15][CH:14]=[CH:13][N:12]=1)[CH3:9]
Reactant: CCOC(=O)CO
Reactant: Brc1ncccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ncccn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 51.5 %

Procedure:
To a slurry of sodium hydride (60% dispersion in mineral oil), 280 mg (5.76 mmol) in 10 mL of DMF at 0° C. was added 0.52 mL (4.8 mmol) of ethyl glycolate. After 10 minutes, 0.92 g (5.76 mmol) of 2-bromopyrimidine was added. The reaction mixture was stirred 15 min at 0° C. then ice bath was removed. After four hours, reaction mixture was quenched with methanol and concentrated to dryness. The residue was partitioned between 20% isopropanol/chloroform and water, then extracted with 20% isopropanol/chloroform. The combined organics were washed with saturated aqueous sodium bicarbonate, washed with brine, dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by radial chromatography using a methanol/chloroform gradient as eluent and concentrated to dryness to yield 0.45 g (52%) of the desired product as a colorless oil. MS (ion spray) 183.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[C:18](O)(=[O:27])[CH:19]=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:18]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)(=[O:27])[CH:19]=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(O)C=Cc1ccccc1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)C=Cc4ccccc4)cc23)CC1
Yield: 40.1 %

Procedure:
Beginning with 12.0 mg (0.05 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 15.0 mg (0.10 mMol) cinnamic acid, 7.2 mg (40%) of the title compound were recovered.
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([CH3:18])=[C:8]([CH:15]=[CH:16][CH:17]=1)[CH2:9][C:10]1NN=N[N:11]=1.[C-]#N.[Na+]>CN(C=O)C.CCOC(C)=O>[CH3:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([CH3:18])=[C:8]([CH2:9][C:10]#[N:11])[CH:15]=[CH:16][CH:17]=1
Reactant: Cc1cccc(C)c1COc1cccc(Cc2nnn[nH]2)c1C
Agent: [C-]#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1COc1cccc(CC#N)c1C

Procedure:
The solution of 1-(bromomethyl)-3-(2,6-dimethylbenzyloxy)-2-methylbenzene (Step D, 4.28 g, 13.41 mmol) and NaCN (0.789 g, 16.10 mmol) in dry DMF (20 ml) was heated at 120° C. for 3 hours then cooled and diluted with EtOAc (50 ml). The organic layer was washed with water (30 ml), brine, dried over Na2SO4, filtered, concentrated, and purified by flash chromatography on a silica gel column (hex:ethyl acetate 4:1) to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:6]2[C:7]([O:9][C:10](=[O:12])[NH:11][C:5]2=[CH:4][CH:3]=1)=O.[C:14]([CH2:16]C(OC)=O)#[N:15].C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[CH:13]=[C:6]2[C:5](=[CH:4][CH:3]=1)[N:11]=[C:10]([OH:12])[C:16]([C:14]#[N:15])=[C:7]2[OH:9]
Reactant: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Reactant: COC(=O)CC#N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#Cc1c(O)nc2ccc(Cl)cc2c1O
Temperature: 90 °C
Reaction time: 1 h

Procedure:
A 300 ml, three neck flask, equipped as described in Example 1, was charged with 39.5 g 5-chloroisatoic anhydride (molecular weight 198.5:assay 95 percent), 21.8 g methyl cyanoacetate, 150 ml triethylamine and four drops of DMF. Agitation was commenced, and continued until reaction was discontinued. A slight exotherm caused the temperature of the reaction mixture to increase from 20° C. to about 38° C., and to remain at about 38° C. for approximately one hour, during which time there was a steady and vigorous evolution of gas. At the end of one hour the temperature began to drop, and the rate of gas evolution slowed as the consistency of the reaction mixture became jelly-like. The reaction mixture was then heated to a temperature of 90° C. and maintained at a temperature within the range of 85° to 90° C. for one-half hour. The heating to 90° C. occurred over a period of one-half hour. The temperature of the reaction mixture was then raised to approximately 100° C., and maintained at about such temperature for an additional 30 minutes. Gas evolution reached a maximum during the time that the reaction mixture was at a temperature between 85° and 100° C. and then gradually decreased and stopped. The reaction mixture became jelly-like and gummy during the time that the temperature was being maintained between 85° and 90° C.; to facilitate stirring a 20 ml addition of DMF was made when this occurred. After the reaction mixture had been maintained at approximately 100° C. for one-half hour, agitation was stopped and the reaction mixture separated into an upper colorless layer consisting mainly of triethylamine and a lower layer of a tan oil. The excess of triethylamine was recovered by distillation, after which the oily remainder was dissolved in 700 ml water and treated with 3 g activated charcoal at reflux. Concentrated hydrochloric acid at a temperature of 60° to 70° C. was then added to the beaker to bring the pH to 1.0 and to form a precipitate. The precipitate was recovered by filtration; the filter cake was washed with water, was reslurried in warm water, refiltered, and finally dried at 60° C. The yield was 39.34 g (93.9 percent of theory based upon the pure 5-chloro-isatoic anhydride charged) 6-chloro-3-cyano-2,4-dihydroxyquinoline, melting point 275°-277° C. Examination of the product by infrared spectroscopy and nuclear magnetic resonance indicated that it was of high purity.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[N:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[C:18](OC(=O)C)(=[O:20])[CH3:19]>ClCCl>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[N:16]=[CH:15][C:14]([NH:17][C:18](=[O:20])[CH3:19])=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: Nc1ccc(C2CCC3(CC2)OCCO3)nc1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)Nc1ccc(C2CCC3(CC2)OCCO3)nc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
6-(1,4-Dioxa-spiro[4.5]dec-8-yl)-pyridin-3-ylamine (0.158 g, 0.675 mmol, prepared as described in Example 3: Steps A-B from 5-amino-2-bromopyridine, Aldrich) was dissolved in anhydrous dichloromethane (10 mL), treated with acetic anhydride (Aldrich, 0.080 mL, 0.846 mmol), and stirred at ambient temperature under Ar for 18 h. The reaction was quenched with saturated aqueous NaHCO3, extracted thrice with dichloromethane, and the combined organic layers washed with brine, dried over Na2SO4, filtered, and the filtrate concentrated in vacuo giving the title compound as a pale solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:21]([CH3:22])=[CH:20][C:19]([NH2:23])=[CH:18][C:17]=1[CH3:24].[CH2:25]([N:27]1[CH:32]=[C:31]([C:33](O)=[O:34])[C:30](=[O:36])[N:29]([C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=2)[C:28]1=[O:44])[CH3:26]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:17]([CH3:24])=[CH:18][C:19]([NH:23][C:33]([C:31]2[C:30](=[O:36])[N:29]([C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)[C:28](=[O:44])[N:27]([CH2:25][CH3:26])[CH:32]=2)=[O:34])=[CH:20][C:21]=1[CH3:22]
Reactant: CCn1cc(C(=O)O)c(=O)n(-c2ccc(F)cc2)c1=O
Reactant: COc1cc2nccc(Oc3c(C)cc(N)cc3C)c2cc1OC
Product: CCn1cc(C(=O)Nc2cc(C)c(Oc3ccnc4cc(OC)c(OC)cc34)c(C)c2)c(=O)n(-c2ccc(F)cc2)c1=O

Procedure:
This compound was synthesized using 4-(6,7-dimethoxy-quinolin-4-yloxy)-3,5-dimethyl-phenylamine and 1-ethyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid using the procedure for example 1. mp=240-242° C.; LCMS m/z=585 (M+1); 1H NMR (DMSO-d6) δ: 10.90 (s, 1H), 8.84 (s, 1H), 8.41 (d, 1H, J=5 Hz), 7.61 (s, 1H), 7.55 (s, 1H), 7.45-7.33 (m, 6H), 6.19 (d, 1H, J=6 Hz), 4.01 (q, 2H, J=8 Hz), 3.95 (d, 6H, J=5 Hz), 2.07 (s, 6H), 1.30 (t, 3H, J=7 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[C:4]([NH:6][C:7]1[C:8](Cl)=[N:9][C:10]([CH3:18])=[N:11][C:12]=1[NH:13][C@H:14]([CH3:17])[CH2:15][OH:16])=O.[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(N(C(C)C)CC)(C)C>CC(O)C>[Cl:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[C:4]1[N:13]([C@H:14]([CH3:17])[CH2:15][OH:16])[C:12]2[C:7]([N:6]=1)=[C:8]([N:28]1[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]1)[N:9]=[C:10]([CH3:18])[N:11]=2
Reactant: CN1CCNCC1
Reactant: Cc1nc(Cl)c(NC(=O)c2ccccc2Cl)c(N[C@H](C)CO)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Cc1nc(N2CCN(C)CC2)c2nc(-c3ccccc3Cl)n([C@H](C)CO)c2n1
Temperature: 160 °C

Procedure:
Combine 2-chloro-N-[4-chloro-6-[[(1R)-2-hydroxy-1-methyl-ethyl]amino]-2-methyl-pyrimidin-5-yl]benzamide (13.0 g), IPA (11 mL), of N-methylpiperizine (7.1 mL) and diisopropylethylamine (7.0 mL) in a 300 mL Parr autoclave with mechanical stirrer. Seal the reaction vessel and heat to 160° C. for 24 h. Evaporate all volatile materials, dissolve in dichloromethane (100 mL) to give a dark solution. Wash with water (2×50 mL), dry using a hydrophobic frit, and evaporate all the solvent under reduced pressure. Take the resulting solid and dissolve in acetonitrile (85 mL) and stir. After 1.5 h collect the solids by filtration and air dry, before dying under vacuum to provide the title compound (10.73 g). Determine optical purity by chiral SFC to show a single enantiomer. ES/MS m/z 401.2 (M+1). Chiral HPLC conditions: Diacel AD-H, 10% IPA, 0.2% isopropylamine, 89.8% supercritical carbon dioxide, UV (220 nm), TR=4.22 min, 100% ee.
Reaction SMILES: [Li+].[OH-].[NH2:3][C@H:4]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:19](Br)[C:20]#[CH:21]>CN(C=O)C.C1(C)C=CC=CC=1>[C:15]([O:14][C:12](=[O:13])[C@H:4]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[NH:3][CH2:21][C:20]#[CH:19])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccccc1
Reactant: C#CCBr
Agent: [Li+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: C#CCN[C@@H](Cc1ccccc1)C(=O)OC(C)(C)C
Reaction time: 0.33 h
Yield: 82.5 %

Procedure:
A solution of LiOH (400 mg, 16.7 mmol, 2.15 eq) in dry DMF (44 mL) containing activated 4 Å molecular sieves was stirred vigorously for 20 min, treated with Phe-Ot-Bu*HCl (2 g, 7.76 mmol, 1 eq), stirred for 45 min, treated with a solution 80% propargyl bromide (1.4 mL, 9.4 mmol, 1.21 eq) in toluene, stirred for 16 h and filtered through a pad of Celite™, which was washed with EtOAc (Cho, J. H. and B. M. Kim, Tetrahedron Lett. 2002, 43 1273-1276). The filtrate was washed three times with water, dried over MgSO4 and the volatiles were evaporated to provide an oil, which was purified by chromatography on silica gel using 30% EtOAc in hexane as eluent. Evaporation of the collected fractions gave ester 41 as yellow oil (1.66 g, 83%): Rf=0.53 (8:2 hexane/EtOAc); 1H NMR (400 MHz, CDCl3) δ 7.32-7.28 (m, 2H), 7.24 (m, 3H), 3.62 (t, J=6.9 Hz, 1H), 3.47-3.36 (m, 2H), 2.96 (m, 2H), 2.20 (m, 1H), 1.77 (s, 1H), 1.39 (s, 9H); 13C NMR (300 MHz, CDCl3) δ 172.9, 137, 129.2, 128.1, 126.4, 81.3, 81.0, 71.6, 61.5, 39.4, 36.5, 27.8. IR (thin film) v 3297, 2981, 2942, 1723, 1370, 1152, 700 cm−1; HRMS (LC-ESI) m/z calcd for C16H22NO2 [MH]+ 260.1645. Found 260.1634.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]2[CH:7]=[C:8]([C:11](=[O:13])[CH3:12])[CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1.[Al+3].[Cl-].[Cl-].[Cl-].[Br:19]Br.Cl>ClCCl>[Br:19][C:10]1[C:5]2[O:4][CH2:3][C:2]([CH3:14])([CH3:1])[C:6]=2[CH:7]=[C:8]([C:11](=[O:13])[CH3:12])[CH:9]=1
Reactant: CC(=O)c1ccc2c(c1)C(C)(C)CO2
Reactant: BrBr
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1cc(Br)c2c(c1)C(C)(C)CO2
Temperature: 25 °C
Reaction time: 6 h
Yield: 81.2 %

Procedure:
To a solution of 1-(3,3-dimethyl-2,3-dihydro-benzofuran5-yl)-ethanone (1.69 g, 8.88 mmol) in dichloromethane (25 mL) was slowly added a suspension of AlCl3 (2.96 g, 22.2 mmol) in dichloromethane (30 mL). Bromine (1.61 g, 10.7 mmol) was added dropwise and the mixture was stirred at room temperature for 6 hours then cooled to 0° C. and aqueous HCl (1N) was added and the mixture extracted with dichloromethane, washed with brine, dried over MgSO4, filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane: EtOAc/10:1 to 2:1) to give 1.94 g 1-(7-Bromo-3,3-dimethyl-2,3-dihydro-benzofuran5-yl)-ethanone (81%). 1H NMR (300 MHz, CDCl3, ppm): δ: 1.39 (s, 6H), 2.56 (s, 3H), 4.37 (s, 2H), 7.69 (d, J=1.76 Hz, 1H), 7.95 (d, J=1.76 Hz, 1H).
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[C:25]([CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)=[O:26])[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.[CH3:42][Mg]Br>O1CCCC1>[F:41][C:2]([F:1])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:37])([F:38])[F:39])[CH:35]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[C:25]([CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)([OH:26])[CH3:42])[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1
Reactant: C[Mg]Br
Reactant: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2C(=O)C2CCCCC2)n1
Solvent: C1CCOC1
Product: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2C(C)(O)C2CCCCC2)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 108 %

Procedure:
To a solution of (2-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-cyclohexyl-methanone (143 mg; 0.241 mmol) in tetrahydrofuran (2.5 mL) at 0° C. was added 3.0M methylmagnesium bromide in tetrahydrofuran (0.25 mL; 0.75 mmol). After 15 minutes, the bath was removed and reaction was stirred at room temperature for 3 hours. The reaction was quenched with 2 drops of water. The reaction was diluted with ethyl acetate and dried over sodium sulfate and concentrated under reduced pressure. The residue was purified over 12 g RediSep column (Teledyne Isco Inc., Lincoln Nebr.) (eluted with 10-50% ethyl acetate in heptane) to give 158 mg (108% yield) of a colorless oil. MS (ES+): Calc: 609.5, Found: 610.4 (M+H). 1H NMR (400 MHz, CDCl3) δ ppm 7.77 (s, 1H), 7.74 (s, 1H) 7.42 (m, 2H), 7.34 (d, J=8.30 Hz, 1H), 5.46 (d, J=16.18 Hz, 1H), 4.93 (d, J=16.60 Hz, 1H), 4.82 (q, J=16.18 Hz, 2H), 4.18 (s, 3H), 1.78-1.6 (m, 6H), 1.58 (s, 3H), 1.40 (m, 1H), 1.13-0.94 (m, 4H).
Reaction SMILES: C([O:3][C:4](=[O:23])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[C:11]([C:19]([F:22])([F:21])[F:20])[CH:10]=1)C.[OH-].[Na+].Cl>O.C(O)C>[F:16][C:15]([F:17])([F:18])[C:13]1[CH:14]=[C:9]([CH:10]=[C:11]([C:19]([F:21])([F:22])[F:20])[CH:12]=1)[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:23])=[O:3]
Reactant: CCOC(=O)CCCOc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CCCOc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 5 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
A stirred charge containing 0.05 mole of ethyl-4-[3,5-bis-(trifluoromethyl)phenoxy]butyrate, 150 ml of ethyl alcohol, 8 g (0.1 mole) of 50% aqueous solution of sodium hydroxide and 25 ml of water was heated at reflux for 5 hours and at 25°-30° C. for 18 hours. After cooling to 5° C., 800 ml of water containing 15 g (0.15 mole) of concentrated hydrochloric acid was added slowly. After stirring at 0°-10° C. for one hour, the resulting solid was collected by filtration, washed with cold water and air dried at 25°-30° C. A product with a melting point of 85°-87° C. was obtained with a yield of 87%.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[OH:12][CH2:13][C@H:14]([CH3:23])[CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C(N(CC)CC)C>ClCCl>[CH3:23][C@@H:14]([CH2:13][O:12][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8])[CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]
Reactant: C[C@@H](CO)CC(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OC[C@H](C)CC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 96.5 %

Procedure:
p-Toluenesulphonyl chloride (13.2 g) was added portionwise to a stirred mixture of tert-butyl (3R)-4-hydroxy-3-methylbutyrate (11 g), triethylamine (21 ml) and dichloromethane (120 ml) and the mixture was stirred at room temperature for 20 hours. The mixture was washed in turn with water and with a dilute aqueous sodium carbonate solution. The organic solution was filtered through phase separating paper and evaporated to give tert-butyl (3R)-3-methyl-4-(p-toluenesulphonyloxy)-butyrate as an oil (20 g): NMR(CDCl3) δ 7.6(2H,d), 7.33(2H,d), 3.92(2H,d), 2.45(3H,s), 2.18.2.47(2H,m), 2.0-2.15(1H,m), 1.42(9H,s), 0.95(3H,d).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[NH:10][S:9]1(=[O:18])=[O:17].C(=O)([O-])[O-].[Cs+].[Cs+].[Br:25][CH2:26]/[CH:27]=[CH:28]/[CH2:29]Br>>[Br:25][CH2:26]/[CH:27]=[CH:28]/[CH2:29][N:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[S:9]1(=[O:18])=[O:17]
Reactant: O=S1(=O)Nc2ccccc2N1c1ccccc1F
Reactant: BrC/C=C/CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=S1(=O)N(C/C=C/CBr)c2ccccc2N1c1ccccc1F

Procedure:
In an analogous manner to general procedure IV, 1-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (prepared in an analogous manner as described in general procedure I, 0.264 g, 1.0 mmol) was treated with cesium carbonate (0.49 g, 1.5 mmol) and (E)-1,4-dibromobut-2-ene (1.07 g, 5.0 mmol) to give 0.26 g of 1-[(2E)-4-bromobut-2-en-1-yl]-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:12](I)=[C:13]2[C:20]3[CH2:21][CH2:22][CH2:23][CH2:24][C:19]=3[S:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].[Cl:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[C:29]([F:36])[CH:28]=1>>[C:1]([O:5][C@@H:6]([C:11]1[C:12]([C:30]2[CH:31]=[CH:32][C:27]([Cl:26])=[CH:28][C:29]=2[F:36])=[C:13]2[C:20]3[CH2:21][CH2:22][CH2:23][CH2:24][C:19]=3[S:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccc(Cl)cc1F
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2sc3c(c2c1I)CCCC3
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2sc3c(c2c1-c1ccc(Cl)cc1F)CCCC3

Procedure:
The title compound was prepared from Methyl (2S)-tert-butoxy(4-iodo-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl)acetate (Preparation 16, 100 mg, 212 μmol) and (4-chloro-2-fluorophenyl) boronic acid (74 mg, 424 μmol) using the same method as described in Example 44, Step 1 to yield 57 mg, 56%. Material obtained was a mixture of atropisomers, in a 3:1 ratio. 1H NMR (400 MHz, CDCl3) δ ppm 1.01 (s, 9 H), 1.48-1.55 (m, 1 H), 1.69-1.75 (m, 3 H), 1.95-2.03 (m, 1 H), 2.72 (s, 3 H), 2.80-2.86 (m, 3 H), 3.66 (s, 3 H), 4.98 (s, 1 H), 7.19-7.21 (m, 1 H), 7.25-7.27 (m, 1 H), 7.35-7.37 (m, 1 H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][C:9]2[C:10]([NH:19][C:20]3[S:24][N:23]=[C:22]([CH:25]4[CH2:31][CH:30]5[N:32](C(OCC)=O)[CH:27]([CH2:28][CH2:29]5)[CH2:26]4)[N:21]=3)=[N:11][CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[OH-].[K+]>CC(O)C.O>[CH:30]12[NH:32][CH:27]([CH2:28][CH2:29]1)[CH2:26][CH:25]([C:22]1[N:21]=[C:20]([NH:19][C:10]3[C:9]([O:8][C:7]4[C:2]([CH3:1])=[N:3][CH:4]=[CH:5][CH:6]=4)=[CH:14][C:13]([C:15]([F:16])([F:17])[F:18])=[CH:12][N:11]=3)[S:24][N:23]=1)[CH2:31]2
Reactant: CCOC(=O)N1C2CCC1CC(c1nsc(Nc3ncc(C(F)(F)F)cc3Oc3cccnc3C)n1)C2
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: Cc1ncccc1Oc1cc(C(F)(F)F)cnc1Nc1nc(C2CC3CCC(C2)N3)ns1
Yield: 74.8 %

Procedure:
Ethyl 3-(5-(3-(2-methylpyridin-3-yloxy)-5-(trifluoromethyl)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (69.5 mg, 0.130 mmol) was dissolved in iPrOH (5 mL) and potassium hydroxide (72.9 mg, 1.30 mmol) was added. The reaction was heated to reflux for 3 days. More KOH (72.9 mg, 1.30 mmol) was added and the reaction was heated for another 2 days. Water (˜10 drops) was added and the reaction was heated for 1 week. The solution was partitioned between saturated aqueous NH4Cl and CH2Cl2. The aqueous layer was extracted 3 times with CH2Cl2, dried over sodium sulfate, filtered and concentrated to afford crude 3-(8-azabicyclo[3.2.1]octan-3-yl)-N-(3-(2-methylpyridin-3-yloxy)-5-(trifluoromethyl)pyridin-2-yl)-1,2,4-thiadiazol-5-amine (45 mg, 0.0973 mmol, 74.8% yield).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:9][OH:10])=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.O[C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1>>[Cl:1][C:2]1[C:3]([CH2:9][O:10][C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=2)=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1
Reactant: OCc1nc(Cl)ccc1Cl
Reactant: COC(=O)c1ccc(O)cc1
Product: COC(=O)c1ccc(OCc2nc(Cl)ccc2Cl)cc1

Procedure:
The title compound was prepared from the intermediate from Step A and methyl 4-hydroxybenzoate using the Mitsunobu conditions described in EXAMPLE 4. 1H NMR (500 MHz, CDCl3): δ 8.054 (d, J=8.8 Hz, 2H); 7.74 (d, J=8.4 Hz, 1H); 7.35 (d, J=8.4 Hz, 1H); 7.07 (d, J=8.7 Hz, 2H); 5.31 (s, 2H); 3.93 (s, 3H). LCMS2 2.29 min. (M+H)=312
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:6][C:5]=1[NH:15][C:16](=[O:32])[NH:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]1)([O-:3])=[O:2].C(O)(C(F)(F)F)=O>ClCCl>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:6][C:5]=1[NH:15][C:16]([NH:17][CH2:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:32])([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CNC(=O)Nc2cc(-c3cccs3)ccc2[N+](=O)[O-])CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NCC1CCNCC1)Nc1cc(-c2cccs2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.4 %

Procedure:
To a solution of tert-butyl 4-((3-(2-nitro-5-(thiophen-2-yl)phenyl)ureido)methyl)piperidine-1-carboxylate (0.30 g, 0.65 mmol) in dichloromethane (15 mL) was added TFA (3 mL) at 0° C. The reaction was warmed to room temperature and stirred for 2 h. The reaction was concentrated. The crude residue was diluted with a saturated aqueous solution of sodium bicarbonate. The obtained solid was filtered, washed with water then washed with ether and pentane to afford 1-(2-nitro-5-(thiophen-2-yl)phenyl)-3-(piperidin-4-ylmethyl)urea (0.20 g, 85% yield).