Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[C:10]([N+:15]([O-:17])=[O:16])[CH:9]=2)=[C:6]([C:18]([F:21])([F:20])[F:19])[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH:24]1([CH:30]=[CH:31][C:32](Cl)=[O:33])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.[Cl-].[NH4+]>CN(C=O)C>[CH:24]1([CH:30]=[CH:31][C:32]([NH:14][C:11]2[CH:12]=[CH:13][C:8]([C:7]3[C:2]([F:1])=[CH:3][CH:4]=[CH:5][C:6]=3[C:18]([F:19])([F:20])[F:21])=[CH:9][C:10]=2[N+:15]([O-:17])=[O:16])=[O:33])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: Nc1ccc(-c2c(F)cccc2C(F)(F)F)cc1[N+](=O)[O-]
Reactant: O=C(Cl)C=CC1CCCCC1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: O=C(C=CC1CCCCC1)Nc1ccc(-c2c(F)cccc2C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 6′-fluoro-3-nitro-2′-trifluoromethyl-biphenyl-4-yl-amine (150 mg, 0.500 mmol, prepared as in STEP A above) in DMF (10 mL) was added 60% NaH (120 mg, 3 mmol) portion wise. The resulting mixture was stirred at room temperature for 15 min. and treated with 3-cyclohexyl-acryloyl chloride (172 mg, 1.00 mmol) in DMF (2 mL). The resulting mixture was stirred overnight and poured into saturated aqueous ammonium chloride solution (10 mL). The aqueous layer was extracted thrice with EtOAc (10 mL). The EtOAc layers were combined, dried over Na2SO4 and concentrated. The residue was purified on silica (EtOAc/hexane, 0:100 to 100:0, v/v) to yield 3-cyclohexyl-N-(6′-fluoro-3-nitro-2′-trifluoromethyl-biphenyl-4-yl)-acrylamide.
Reaction SMILES: [CH2:1]([O:8][C@H:9]([CH3:15])[C@@H:10]([C:12]([OH:14])=[O:13])[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O.O1CCCC1>[C:22]([NH:11][C@H:10]([C:12]([OH:14])=[O:13])[C@@H:9]([CH3:15])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C[C@@H](OCc1ccccc1)[C@H](N)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](OCc1ccccc1)[C@H](NC(=O)c1ccccc1)C(=O)O
Temperature: 25 °C

Procedure:
A mixture containing 10 mmoles of O-benzyl-threonine, 10 mmoles of Na2CO3 in water and tetrahydrofuran (THF) is stirred at room temperature. Benzoyl chloride (10 mmoles), dissolved in anhydrous THF, is added gradually with continued stirring at room temperature. The reaction mixture is stirred until the reaction is completed as judged by thin layer chromatography (TLC). The solvent is removed by a rotary evaporator at 30° C. An excess of water is added and the reaction mixture extracted several times with ethyl acetate. The aqueous phase is adjusted to pH 2 with 1N HCl. The precipitate is recovered by filtration and washed with dilute HCl and then with cold water. The precipitate is dried over P2O5 in a vacuum desiccator. The precipitate is homogeneous as judged by TLC. In this reaction sequence, the racemate is obtained.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:46])[C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]3[N:24]=[CH:25][C:26]4[N:32]([CH3:33])[C:31](=[O:34])[C:30]([F:36])([F:35])[CH2:29][N:28]([CH:37]5[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]5)[C:27]=4[N:43]=3)=[C:18]([O:44][CH3:45])[CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH:37]1([N:28]2[CH2:29][C:30]([F:36])([F:35])[C:31](=[O:34])[N:32]([CH3:33])[C:26]3[CH:25]=[N:24][C:23]([NH:22][C:19]4[CH:20]=[CH:21][C:16]([C:15]([NH:14][CH:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]5)=[O:46])=[CH:17][C:18]=4[O:44][CH3:45])=[N:43][C:27]2=3)[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]1
Reactant: COc1cc(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(=O)NC2CCNCC2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Reaction time: 1 h
Yield: 78.8 %

Procedure:
A mixture of 0.090 g (0.14 mmole) of 4-[4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoylamino]-piperidine-1-carboxylic acid tert-butyl ester (I-250) 1 mL of trifluoroacetic acid and 5 mL of dichloromethane was stirred for 1 hour and then concentrated under reduced pressure. The residue was taken up in 30 mL of ethyl acetate, washed twice with 30 mL of saturated aqueous sodium bicarbonate and then brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was triturated with ether, to give 0.060 g of 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-piperidin-4-yl-benzamide (I-251).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[CH:14][CH:13]=3)=[CH:9][S:8][C:7]=2[CH:27]=1.Br[C:29]1[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=1.CC(C)(C)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])=[CH:14][CH:13]=3)=[C:9]([C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=3)[S:8][C:7]=2[CH:27]=1
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: COc1ccc2c(Oc3ccc(/C=C/C(=O)OC(C)(C)C)cc3)csc2c1
Agent: CC(C)(C)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1ccc2c(Oc3ccc(/C=C/C(=O)OC(C)(C)C)cc3)c(-c3ccc(C(F)(F)F)cc3)sc2c1
Yield: 84.6 %

Procedure:
To a 5 mL microwave vial, added a solution of (E)-tert-butyl 3-(4-((6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (50 mg, 0.13 mmol) in anhydrous DMA (1.5 mL), followed by 1-bromo-4-(trifluoromethyl)benzene (35.3 mg, 0.16 mmol), chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2′,4′,6′-tri-i-propyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl]palladium(II) (BrettPhos palladacycle 1st generation, 10.4 mg, 0.013 mmol), trimethylacetic acid (40.1 mg, 0.392 mmol) and potassium carbonate (54.2 mg, 0.392 mmol). The microwave vial was scaled, purged and back-filled with nitrogen. The reaction mixture subjected to microwave irradiation for 2 h at 150° C. Upon completion the reaction was diluted with EtOAc, and washed with water and brine. The combined organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo to give a red brown residue which was purified by column chromatography (SiO2, 0-30% EtOAc/heptane) to afford (E)-tert-butyl 3-(4-((6-methoxy-2-(4-(trifluoromethyl)phenyl)benzo[b]thiophen-3 yl)oxy)phenyl)acrylate (59.4 mg, 0.11 mmol, 86% yield). 1H NMR (400 MHz, CD3OD) δ ppm=1.42-1.61 (m, 9 H), 3.77-3.98 (m, 3 H), 6.31 (d, J=15.66 Hz, 1 H), 6.87-7.04 (m, 3 H), 7.28 (d, J=9.09 Hz, 1 H), 7.46 (d, J=2.53 Hz, 1 H), 7.47-7.57 (m, 3 H), 7.65 (d, J=8.08 Hz, 2 H), 7.89 (d, J=8.08 Hz, 2 H), LC/MS (m/z, MH+): 471.40.
Reaction SMILES: C[O-].[Na+].[C:4](#[N:7])[CH:5]=[CH2:6].Cl.[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][NH2:24])=[C:19]([F:25])[CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CO.CCOC(C)=O>[NH2:7][C:4]1[NH:24][N:23]([C:20]2[CH:21]=[CH:22][C:17]([O:16][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:18][C:19]=2[F:25])[CH2:6][CH:5]=1
Reactant: NNc1ccc(OCc2ccccc2)cc1F
Reactant: C=CC#N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: NC1=CCN(c2ccc(OCc3ccccc3)cc2F)N1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
NaOMe (25 wt. % solution in MeOH, 7.75 mL) and acrylonitrile (2.1 mL) were added to a solution of 4-benzyloxy-2-fluorophenylhydrazine hydrochloride (4.15 g) in MeOH (40 mL) at room temperature. The mixture was stirred at room temperature for 30 minutes and refluxed overnight. Additional NaOMe (25 wt. % solution in MeOH, 3.9 mL) and acrylonitrile (1.05 ml) were added to the reaction mixture and refluxed for 7.5 hours. The mixture was diluted with EtOAc and washed with sat. NaHCO3 and brine. The organic layer was dried over anhydrous MgSO4 and concentrated. The residue was crystallized from CHCl3/hexane to yield 3.86 g of the title compound.
Reaction SMILES: Cl.N[C@H](C(OC)=[O:9])CC(C)C.N[C@H](C(O)=O)CC(C)C.CCC(OC(C[N+](C)(C)C)CC([O-])=O)=O.[CH:36]1([N:42]=[C:43]=[N:44][CH:45]2[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>CC(C)=O.N1C=CC=CC=1>[C:43]([NH:42][CH:36]1[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]1)([NH:44][CH:45]1[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1)=[O:9]
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC(C)C[C@H](N)C(=O)O
Agent: CCC(=O)OC(CC(=O)[O-])C[N+](C)(C)C
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: O=C(NC1CCCCC1)NC1CCCCC1

Procedure:
To 1.82 grams (0.01 moles) of methyl leucinate hydrochloride 0.8 cc (0.01 moles) of pyridine in 15 cc of acetone were added. Pyridine hydrochloride precipitated, which was filtered off. To the methyl ester of leucine free base was added an aqueous solution of 2.54 grams (0.01 moles) of propionyl carnitine in 3.5 cc. Then, 4.12 grams of dicyclohexyl carbodiimide dissolved in 5 cc of acetone were slowly added under stirring to the solution. A precipitate of dicyclohexylurea formed which after 16 hours was filtered off. The mother liquors were concentrated under vacuum. The raw product thus obtained was crystallized from methanol-acetone, furnishing a solid, very hygroscopic product (yield: 75%).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH3:12])(=[O:11])=[O:10])=[CH:5][C:4]=1Cl.FC1C=CC(C=O)=CC=1[C:23]([F:26])([F:25])[F:24]>>[Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH3:12])(=[O:11])=[O:10])=[C:5]([C:23]([F:26])([F:25])[F:24])[CH:4]=1
Reactant: O=Cc1ccc(F)c(C(F)(F)F)c1
Reactant: CS(=O)(=O)c1ccc(CBr)c(Cl)c1
Product: CS(=O)(=O)c1ccc(CBr)cc1C(F)(F)F

Procedure:
The titled compound is prepared analogously to 1-bromomethyl-2-chloro-4-methanesulfonyl-benzene by replacing 2-chloro-4-fluorobenzaldehyde (step 90a) with 4-fluoro-3-trifluoromethylbenzaldehyde.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:11](Br)[N:12]2[CH:17]([CH3:18])[CH2:16][N:15]([CH3:19])[C:14](=[O:20])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:27]([Sn](CCCC)(CCCC)C=C)[CH2:28]CC>C1(C)C=CC=CC=1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH2:1]([O:8][C:9]1[C:10]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:11]([CH:27]=[CH2:28])[N:12]2[CH:17]([CH3:18])[CH2:16][N:15]([CH3:19])[C:14](=[O:20])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(OCc2ccccc2)c2n(c1Br)C(C)CN(C)C2=O
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1
Product: C=Cc1c(C(=O)OCC)c(OCc2ccccc2)c2n1C(C)CN(C)C2=O
Temperature: 100 °C

Procedure:
A mixture of ethyl 8-(benzyloxy)-6-bromo-2,4-dimethyl-1-oxo-1,2,3,4-tetrahydro-pyrrolo[1,2-a]-pyrazine-7-carboxylate (0.5 g, 1.19 mmol), tri-n-butyl vinyltin (0.46 mL, 1.42 mmol), and bis(tri-tert-butylphosphine)palladium(0) (0.12 g, 0.24 mmol) in toluene (6 mL) was purged with nitrogen for 2 minutes and sealed. The mixture was heated in a microwave oven at 100° C. for 10 minutes. The reaction mixture was concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluted with a hexanes and ethyl acetate gradient to provide titled product.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([O:10][CH3:11])[N:3]=1.[CH:12]([O:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[S:24]([N:27]=[C:28]=[O:29])(=[O:26])=[O:25])=[O:17])([CH3:14])[CH3:13]>C(Cl)Cl>[CH3:9][O:8][C:6]1[N:5]=[C:4]([O:10][CH3:11])[N:3]=[C:2]([NH:1][C:28]([NH:27][S:24]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[C:16]([O:15][CH:12]([CH3:14])[CH3:13])=[O:17])(=[O:26])=[O:25])=[O:29])[N:7]=1
Reactant: COc1nc(N)nc(OC)n1
Reactant: CC(C)OC(=O)c1ccccc1S(=O)(=O)N=C=O
Solvent: ClCCl
Product: COc1nc(NC(=O)NS(=O)(=O)c2ccccc2C(=O)OC(C)C)nc(OC)n1
Yield: 26.2 %

Procedure:
To 0.7 g of 2-amino-4,6-dimethoxy-1,3,5-triazine suspended in 5.0 ml anhydrous methylene chloride was added 1.6 g of 2-isopropoxycarbonylbenzenesulfonyl isocyanate in 5.0 ml anhydrous methylene chloride. The resulting mixture was filtered to remove some unreacted 2-amino-4,6-dimethoxytriazine, the methylene chloride filtrate was evaporated at reduced pressure and the residue triturated with chlorobutane to yield 0.5 g of desired product melting at 192°-195° C. The solid showed infrared absorption peaks at 1705 and 1715 cm-1 consistent for N-[(4,6-dimethoxy-1,3,5-triazin-2-yl)aminocarbonyl]-2-(isopropoxycarbonyl)benzenesulfonamide.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][CH2:32]Cl)(=[O:29])=[O:28])[CH2:23][CH2:22]2)[N:3]=1.[NH2:34][C:35]([CH3:39])([CH3:38])[CH2:36][OH:37]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][CH2:32][NH:34][C:35]([CH3:39])([CH3:38])[CH2:36][OH:37])(=[O:29])=[O:28])[CH2:23][CH2:22]2)[N:3]=1
Reactant: CC(C)(N)CO
Reactant: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCCl)CC2)nc1N
Product: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCNC(C)(C)CO)CC2)nc1N

Procedure:
The compound was prepared from [4-amino−2-[1-(3-chloro-propane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(2,3-difluoro-6-methoxy-phenyl)-methanone (Example 226) and 2-amino-2-methyl-1-propanol (Aldrich) in an analogous manner as described in Example 227. HR-MS (ES, m/z) calculated for C24H35N6O5SF2 [(M+H)+] 557.2352, observed 557.2359.
Reaction SMILES: [CH:1]1([C:5](Cl)=[O:6])[CH2:4][CH2:3][CH2:2]1.[CH2:8]([O:10][C:11]([C:13]1([CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)[CH2:17][CH2:16][NH:15][CH2:14]1)=[O:12])[CH3:9]>>[CH2:8]([O:10][C:11]([C:13]1([CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)=[CH:22][CH:21]=2)[CH2:17][CH2:16][N:15]([C:5]([CH:1]2[CH2:4][CH2:3][CH2:2]2)=[O:6])[CH2:14]1)=[O:12])[CH3:9]
Reactant: O=C(Cl)C1CCC1
Reactant: CCOC(=O)C1(COc2ccc(-c3ccc(F)cc3)cc2)CCNC1
Product: CCOC(=O)C1(COc2ccc(-c3ccc(F)cc3)cc2)CCN(C(=O)C2CCC2)C1

Procedure:
The title compound was prepared according to the method described for Preparation using cyclobutanecarbonyl chloride and 3-(4′-fluoro-biphenyl-4-yloxymethyl)-pyrrolidine-3-carboxylic acid ethyl ester (Preparation 65) to afford the racemate as a colourless oil (105 mg, 85%)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1CCCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1.Br[CH2:39][C:40]([O:42][CH3:43])=[O:41]>C1C=CC=CC=1.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[C:10]([CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)([CH2:39][C:40]([O:42][CH3:43])=[O:41])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(Cc2ccccc2)C1
Reactant: COC(=O)CBr
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Solvent: C1CCNC1
Product: COC(=O)CC1(Cc2ccccc2)CN(C(=O)OC(C)(C)C)CCC1=O
Temperature: 25 °C

Procedure:
A solution of the product from Step A of Example 21 above (1320 mg, 4.56 mmol), pyrrolidine (972 mg, 13 mmol) and p-toluenesulfonic acid (33 mg) in benzene (30 mL) was refluxed through 3 Å molecular sieves for about 17 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was dissolved in benzene (10 mL) and cooled to about 0° C. Methyl bromoacetate (1530 mg, 10 mmol) was added dropwise. The reaction mixture was slowly allowed to warm to room temperature and then was heated under reflux for about 17 h at which point H2O (5 mL) was added. After refluxing for about another 2 h, the reaction mixture was cooled to room temperature and extracted with EtOAc (3×100 mL). The combined organic extracts were dried and concentrated in vacuo. The crude residue was chromatographed on SiO2-gel using 15% ethyl acetate/hexanes to give 280 mg of product 1H NMR (250 MHz, CDCl3): d 7.35 (m, 5H), 4.5 (m, 1H), 3.8 (s, 3H), 3.4 (dd, 1H), 3.1 (m, 1H), 2.85 (m, 4H), 2.6 (m, 1H), 2.4 (m, 1H), 1.5 (s, 9H); MS (APCI): 362 (M+1).
Reaction SMILES: CO[C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[N:14][O:15][C:16]=2[C:17]([F:20])([F:19])[F:18])=[N:6][CH:5]=1.[CH:29]1([CH2:32][NH2:33])[CH2:31][CH2:30]1>>[CH:29]1([CH2:32][NH:33][C:3](=[O:28])[C:4]2[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]3[C:13]([C:21]4[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=4)=[N:14][O:15][C:16]=3[C:17]([F:20])([F:19])[F:18])=[N:6][CH:5]=2)[CH2:31][CH2:30]1
Reactant: NCC1CC1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2C(F)(F)F)nc1
Product: O=C(NCC1CC1)c1ccc(OCc2c(-c3ccc(F)cc3)noc2C(F)(F)F)nc1
Yield: 87 %

Procedure:
As described for example 137, 6-[3-(4-fluoro-phenyl)-5-trifluoromethyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (100 mg, 0.25 mmol) was converted, using cyclopropanemethylamine instead of methylamine, to the title compound (96 mg, 87%) which was obtained as an off white solid. MS: m/e=436.0 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:32])[C:17]1[CH:22]=[CH:21][C:20](B2OC(C)(C)C(C)(C)O2)=[CH:19][CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:33]1([NH:39][C:40](=[O:49])[O:41][CH2:42][C:43]2[S:47][C:46](Cl)=[N:45][CH:44]=2)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>C(OCC)(=O)C>[CH:33]1([NH:39][C:40](=[O:49])[O:41][CH2:42][C:43]2[S:47][C:46]([C:20]3[CH:19]=[CH:18][C:17]([C:16]([NH:15][C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[O:32])=[CH:22][CH:21]=3)=[N:45][CH:44]=2)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: O=C(NC1CCCCC1)OCc1cnc(Cl)s1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(-c2ncc(COC(=O)NC3CCCCC3)s2)cc1

Procedure:
Using an analogous procedure to that described in Method 4, N-(2-t-butoxycarbonylaminophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (Method 13, 219 mg, 0.5 mmol) was reacted with (2-chloro-1,3-thiazol-5-yl)methyl cyclohexylcarbamate (138 mg, 0.5 mmol). The crude residue was stirred in ethyl acetate for 16 hours before being filtered, mixed with water and the aqueous removed using a Varian Chem Elut Column (CE1010). The resulting solution was concentrated and purified by flash chromatography on silica, eluting with methanol/dichloromethane (0-30%) to give the title compound; Mass Spectrum: M+H+ 551.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:16][C:15]2[C:6]([CH3:25])([CH:7]3[CH:12]([CH2:13][CH:14]=2)[CH:11]2[CH2:17][CH2:18][CH:19]4[CH:20]([CH3:24])[N:21]([CH3:23])[CH2:22][C:10]24[CH2:9][CH2:8]3)[CH2:5][CH2:4]1.[C:26]([N:33]([CH3:41])[C@@H:34]([C:38]([OH:40])=O)[CH:35]([CH3:37])[CH3:36])([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>C1COCC1.ClCCl>[C:29]([O:28][C:26](=[O:27])[N:33]([CH3:41])[CH:34]([C:38](=[O:40])[N:2]([CH3:1])[CH:3]1[CH2:16][C:15]2[C:6]([CH3:25])([CH:7]3[CH:12]([CH2:13][CH:14]=2)[CH:11]2[CH2:17][CH2:18][CH:19]4[CH:20]([CH3:24])[N:21]([CH3:23])[CH2:22][C:10]24[CH2:9][CH2:8]3)[CH2:5][CH2:4]1)[CH:35]([CH3:36])[CH3:37])([CH3:30])([CH3:31])[CH3:32]
Reactant: CNC1CCC2(C)C(=CCC3C2CCC24CN(C)C(C)C2CCC34)C1
Reactant: CC(C)[C@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)C(C(=O)N(C)C1CCC2(C)C(=CCC3C2CCC24CN(C)C(C)C2CCC34)C1)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.3 %

Procedure:
A mixture of compound 7B (240 mg, 0.702 mmol), Boc-N-methyl-D-valine (176 mg, 0.762 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (208 mg, 1.085 mmol), 1-hydroxybenzotriazole (146 mg, 1.085 mmol), dichloromethane (5 mL) and THF (2.5 mL) was stirred at room temperature overnight. The solvent was evaporated under reduced pressure and the residue was dissolved in minimum amount of dichloromethane and purified on silica gel column, which was eluted with 0.5% ammonium hydroxide and 5% methanol in dichloromethane to give the desired product (282 mg, 72% yield).
Reaction SMILES: [Cl:1][C:2]1[C:11]([OH:12])=[C:10]([N+:13]([O-:15])=[O:14])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][CH2:7]2.[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:16]([O:12][C:11]1[C:2]([Cl:1])=[C:3]2[C:8](=[CH:9][C:10]=1[N+:13]([O-:15])=[O:14])[CH2:7][CH2:6][CH2:5][CH2:4]2)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=[N+]([O-])c1cc2c(c(Cl)c1O)CCCC2
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc2c(c(Cl)c1OCc1ccccc1)CCCC2
Temperature: 25 °C
Reaction time: 24 h
Yield: 69.2 %

Procedure:
5-Chloro-6-hydroxy-7-nitrotetralin (2.28 g, 10.0 mmol) was dissolved in dry DMF (40 mL) and flushed with argon. Benzyl chloride (11.5 mL, 100.0 mmol) n-Bu4NI (95 mg, 0.25 mmol) and K2CO3 (41.5 g, 30.0 mmol) were added. The reaction mixture was stirred for 24 h at room temperature, protected from light. The salts were filtered off and the solvent and excess of BnCl were co-evaporated with xylene (3×200 mL) and CH2Cl2 (200 mL), followed by vacuum-drying. The crude product (5.8 g) was purified by flash column chromatography (SiO2, CHCl3 -Hexane 1:1) and afforded the title compound (2.20 g). Mp 80°-82° C.; 1H NMR (DMSO-d6): δ 7.73 (s, 1 H), 7.48-7.37 (m, 5 H), 5.06 (s,2 H), 2.79-2.75 (m, 4 H), 1.79-1.69 (dm, 4 H); 13C NMR (DMSO-d6): δ 144.81, 142.14, 135.79, 135.56, 129.55, 128.42, 123.40, 106.20, 105.51, 75.80, 28.63, 27.65, 21.55, 21.36; MS (TSP): m/z (rel.int.) 337/335 (M+NH4, 30/100).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=2)[CH:7]=[C:6](I)[CH:5]=1.[CH:19]([C:22]1[NH:23][CH:24]=[CH:25][N:26]=1)([CH3:21])[CH3:20].C([O-])([O-])=O.[K+].[K+]>CS(C)=O.O.[Cu]I>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=2)[CH:7]=[C:6]([N:23]2[CH:24]=[CH:25][N:26]=[C:22]2[CH:19]([CH3:21])[CH3:20])[CH:5]=1
Reactant: CC(C)c1ncc[nH]1
Reactant: COC(=O)c1cc(I)cc(-c2ccc(C)cn2)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1cc(-c2ccc(C)cn2)cc(-n2ccnc2C(C)C)c1
Temperature: 100 °C
Yield: 56.7 %

Procedure:
To a solution of 3-iodo-5-(5-methyl-pyridin-2-yl)-benzoic acid methyl ester (500 mg, 1.42 mmol) in DMSO (10 ml) was added 2-Isopropylimidazole (312 mg, 2.83 mmol), CuI (54 mg, 0.283 mmol), N,N′-dimethylglycine HCl salt (79 mg, 0.567 mmol) and K2CO3 (391 mg, 2.83 mmol) under N2 atmosphere. The mixture was heated to 100° C. overnight. After cooling to room temperature, the mixture was diluted with H2O (15 ml). The mixture was extracted with EtOAc. The combined organic layers were washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure. The residue was purified by flash chromatography (30%-75% EtOAc in hexanes) to afford 3-(2-isopropyl-imidazol-1-yl)-5-(5-methyl-pyridin-2-yl)-benzoic acid methyl ester as an off-white solid (270 mg, 57%).