Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:22]=[C:5]2[C:6]([C:10]3[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=3[O:20][CH3:21])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[C:23]([O:27][C:28]([N:30]1[CH2:36][CH2:35][C:34]2[CH:37]=[CH:38][C:39]([NH2:41])=[CH:40][C:33]=2[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>>[C:23]([O:27][C:28]([N:30]1[CH2:36][CH2:35][C:34]2[CH:37]=[CH:38][C:39]([NH:41][C:2]3[N:22]=[C:5]4[C:6]([C:10]5[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=5[O:20][CH3:21])=[CH:7][CH:8]=[CH:9][N:4]4[N:3]=3)=[CH:40][C:33]=2[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: COc1ccc(C(F)(F)F)cc1-c1cccn2nc(Cl)nc12
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(N)cc2CC1
Product: COc1ccc(C(F)(F)F)cc1-c1cccn2nc(Nc3ccc4c(c3)CCN(C(=O)OC(C)(C)C)CC4)nc12

Procedure:
7-[8-(2-Methoxy-5-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butyl ester was prepared from 2-chloro-8-(2-methoxy-5-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (0.630 g, 1.92 mmol) and 7-amino-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butyl ester (0.605 g, 2.31 mmol) in a manner analogous to Example 311b to give product (0.750 g, 71%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.56 (s, 1H), 8.79 (d, 1H), 7.95 (s, 1H), 7.82 (d, 1H), 7.65 (d, 1H), 7.42 (m, 3H), 7.05 (m, 2H), 3.85 (s, 3H), 3.42 (m, 4H), 2.75 (m, 4H), 1.41 (s, 9H): MS=554 (MH)+.
Reaction SMILES: [OH-].[Na+].S([O:8][CH3:9])(OC)(=O)=O.[OH:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][C:15](O)=[CH:16][CH:17]=2)[CH:12]=1>ClCCl.O>[OH:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][C:15]([O:8][CH3:9])=[CH:16][CH:17]=2)[CH:12]=1
Reactant: COS(=O)(=O)OC
Reactant: Oc1ccc2ccc(O)cc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: COc1ccc2ccc(O)cc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.1 %

Procedure:
Sodium hydroxide (20 ml, 1M) and dimethyl sulfate (15.0 ml, 158 mmol) were added dropwise to a solution of 2,7-dihydroxynaphthalene (6.6 g, 40 mmol) in dichloromethane (100 ml) and water (60 ml). Additional sodium hydroxide (20 ml, 1M) and dimethyl sulfate (15.0 ml, 158 mmol) were added and the resulting mixture was stirred at room temperature for 2 hours. The two phases were separated and the aqueous layer was extracted with dichloromethane twice. The combined organic extracts were washed with 1 M HCl, dried over magnesium sulfate and concentrated under vacuum. The crude material was purified by column chromatography (5:1 heptane/ethyl acetate) to give 2-hydroxy-7-methoxynaphthalene (2.1 g, 30%, 100% AUC HPLC): 1H NMR (300 MHz, CDCl3) δ 7.66-7.70 (m, 2H), 6.94-7.08 (m, 4H), 4.90 (s, 1H), 3.92 (s, 3H).
Reaction SMILES: [C:1]1([CH:7]2[C:11]3([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:10](=[O:17])[NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:18]12[O:24][CH:23]1[CH2:22][CH2:21][CH2:20][CH2:19]2>C(O)C>[O:24]=[C:23]1[CH2:18][CH2:19][CH2:20][CH2:21][CH:22]1[N:14]1[CH2:13][CH2:12][C:11]2([C:10](=[O:17])[NH:9][CH2:8][CH:7]2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:16][CH2:15]1
Reactant: O=C1NCC(c2ccccc2)C12CCNCC2
Reactant: C1CCC2OC2C1
Solvent: CCO
Product: O=C1CCCCC1N1CCC2(CC1)C(=O)NCC2c1ccccc1
Temperature: 25 °C
Yield: 97.7 %

Procedure:
A suspension of rac-4-phenyl-2,8-diaza-spiro[4.5]decan-1-one (13.10 g, 56.9 mmol) and 7-oxa-bicyclo[4.1.0]heptane (5.58 g, 56.9 mmol) in ethanol (250 mL) was heated under reflux for 3 days. After cooling to room temperature the mixture was filtered and the filtrate evaporated to afford the title compound (18.14 g, 97%) which was obtained as off-white solid. MS: m/e=329.3 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:10][CH2:11][CH2:12][CH:13]=O)=[O:9])[NH:5][C:6]=1[Br:7]>CS(O)(=O)=O.CCOCC>[Br:7][C:6]1[NH:5][C:4]2[C:8](=[O:9])[NH:10][CH2:11][CH:12]=[CH:13][C:3]=2[C:2]=1[Br:1]
Reactant: O=CCCNC(=O)c1cc(Br)c(Br)[nH]1
Agent: CS(=O)(=O)O
Solvent: CCOCC
Product: O=C1NCC=Cc2c1[nH]c(Br)c2Br
Yield: 67.4 %

Procedure:
A solution of 12 (1.0 g, 3.3 mmol) in 10 mL of methanesulfonic acid was stirred at room temperature for 7 d. The reaction mixture was diluted with ether (500 mL), washed with sat. NaHCO3 (100 mL ×3) and sat. NaCl (100 mL). The organic layer was dried (MgSO4) and evaporated under reduced pressure. The resulting residue was purified by flash chromatography (CH2Cl2/MeOH 19:1) to give 13 (0.68 g, 80%) as a colorless solid: mp 170-175° C.; 1H NMR (CD3OD) d 3.57 (d, 2H, J=6.4), 6.01 (dt, 1H, J=10.1, 6.4), 6.65 (d, 1H, J=10.1); (DMSO-d6) d 3.46 (dd, 2H, J=6.4, 4.9), 6.03 (dt, 1H, J=10.0, 6.4), 6.54 (d, 1H, J=10.0), 7.75 (t, 1H, J=4.9), 13.04 (s, 1H); 13C NMR (CD3OD) d 39.6 (e), 100.2 (e), 108.4 (e), 126.4 (o), 126.7 (e), 126.8 (o), 127.0 (e), 164.6 (e); IR (nujol) 3184, 1639, 1603, 1541 cm−1; UV (CH3OH) 1max 288, 227 nm; MS, m/z (relative intensity) 308 (M++4, 30), 306 (M++2, 60), 304 (M+, 30), 225 (100), 200 (80), 182 (40), 170 (40); HRMS, calcd for C8H6N2OBr2 (M+) 303.8847, found 303.8833. Anal. Calcd for C8H6N2OBr2: C, 34.41; H, 1.98; N, 9.16; Found: C, 34.75; H, 2.09; N, 9.07.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:17]N1C(=O)CCC1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][Br:17])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: OCc1ccc(OCc2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 92.6 %

Procedure:
To 4-benzyloxybenzyl alcohol (8.1 g, 37.8 mmol) in dichloromethane (160 mL) was added N-bromosuccinimide (7.4 g, 41.6 mmol) followed by portionwise addition of triphenylphosphine (10.9 g, 41.6 mmol). The reaction mixture was stirred at room temperature for 5 minutes, and was then concentrated in vacuo. Purification by flash chromatography, eluting with 80:20 hexanes/ethyl acetate, provided 9.7 g (92%) of 1 as a white solid.
Reaction SMILES: C(OC(C([C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([O:17][CH2:18][C:19]1[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=1)=[CH:12][CH:11]=2)C)=O)C.[OH2:29].[OH-].[Li+].[O:32]1[CH2:36][CH2:35][CH2:34]C1>>[N:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:27]=[CH:28][C:19]=1[CH2:18][O:17][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:34][CH2:35][C:36]([OH:32])=[O:29])[CH:8]=[CH:16]2
Reactant: CCOC(=O)C(C)c1cc2cc(OCc3ccc4ccccc4n3)ccc2[nH]1
Reactant: C1CCOC1
Reactant: O
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)CCn1ccc2cc(OCc3ccc4ccccc4n3)ccc21

Procedure:
A mixture of 1-ethoxycarbonylethyl-5-(2-quinolylmethoxy)indole (2.0 g) and lithium hydroxide monohydrate (0.9 g) in aqueous tetrahydrofuran was refluxed for 3 hours. The cooled mixture was extracted with ethyl acetate and the organic layer was washed with water, dried over magnesium sulfate, and concentrated in vacuo. The crude product was chromatographed on silica gel eluting with 50%-ethyl acetate in n-hexanes to yield the titled product, m.p. 157°-160° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]=[O:11])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:12][C:13]([OH:16])([CH3:15])[CH3:14]>>[C:13]([O:16][C:10](=[O:11])[NH:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=1)([CH3:15])([CH3:14])[CH3:12]
Reactant: CC(C)(C)O
Reactant: O=C=Nc1ccc(F)c(F)c1
Product: CC(C)(C)OC(=O)Nc1ccc(F)c(F)c1
Yield: 100 %

Procedure:
A solution of 3,4-difluorophenyl isocyanate (2 g, 10.55 mmol) in t-BuOH (50 mL) was heated at 80° C. for 16 h. The mixture was concentrated by rotary evaporation to give a white solid which was triturated with toluene and evaporated to dryness. Addition of toluene (20 mL) and concentration under vacuum gave (3,4-difluorophenyl)-carbamic acid-tert-butyl ester as a white solid (2.43 g, 100%).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]([OH:12])=[O:11])[CH2:6][CH2:5]1.Cl.CCN(C(C)C)C(C)C.Br[C:24]1[N:29]=[CH:28][C:27]([Br:30])=[CH:26][N:25]=1>CC(N(C)C)=O>[Br:30][C:27]1[CH:26]=[N:25][C:24]([N:2]([CH2:3][C@H:4]2[CH2:9][CH2:8][C@H:7]([C:10]([OH:12])=[O:11])[CH2:6][CH2:5]2)[CH3:1])=[N:29][CH:28]=1
Reactant: Brc1cnc(Br)nc1
Reactant: CNC[C@H]1CC[C@H](C(=O)O)CC1
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CN(C[C@H]1CC[C@H](C(=O)O)CC1)c1ncc(Br)cn1
Temperature: 120 °C

Procedure:
A mixture of 0.42 g (2.0 mmol) of trans-4-methylaminomethyl-cyclohexanecarboxylic acid•HCl, 1.85 mL (1.1 mmol) of Huenig's base and 0.57 g (2.4 mmol) of 2,5-dibromo-pyrimidine [Brown and Arantz, J. Chem. Soc. C Issue 10, 1889-1891 (1971)] in 2 mL of DMA was placed in the microwave and heated to 120° C. for 1 h. The solvent was evaporated, partitioned between Et2O (×3)/aqueous 10% KH2PO4, dried over Na2SO4 and evaporated to yield 0.604 g (92%) of trans-4-{[(5-bromo-pyrimidin-2-yl)-methyl-amino]-methyl}-cyclohexanecarboxylic acid, MS: 326 (M−H−, 1Br), MP: 172-174° C.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C:13]3[CH2:14][CH2:15][C:16]4[C@:21]([C:23]=3[CH2:24][CH2:25]2)([CH3:22])[CH2:20][CH2:19][C:18](=[O:28])[CH:17]=4)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].CCC(C)[BH-](C(C)CC)C(C)CC.[Li+].Cl>O1CCCC1>[CH3:3][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C:13]3[CH2:14][CH2:15][C:16]4[C@:21]([C:23]=3[CH2:24][CH2:25]2)([CH3:22])[CH2:20][CH2:19][C@H:18]([OH:28])[CH:17]=4)[CH2:11][CH2:10]1)[CH3:8])[CH3:1].[CH3:3][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C:13]3[CH2:14][CH2:15][C:16]4[C@:21]([C:23]=3[CH2:24][CH2:25]2)([CH3:22])[CH2:20][CH2:19][C@@H:18]([OH:28])[CH:17]=4)[CH2:11][CH2:10]1)[CH3:8])[CH3:1]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2C3=C(CC[C@]12C)[C@@]1(C)CCC(=O)C=C1CC3
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2C3=C(CC[C@]12C)[C@@]1(C)CC[C@@H](O)C=C1CC3
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2C3=C(CC[C@]12C)[C@@]1(C)CC[C@H](O)C=C1CC3
Temperature: 25 °C

Procedure:
To a solution of 520 mg cholesta-4,8-dien-3-one in 45 ml tetrahydrofuran 1.70 ml of a L-Selectride solution (1 N, in tetrahydrofuran) are added dropwise at −75° C. The reaction mixture is warmed to room temperature within 4 hours, poured into hydrochloric acid (1 N) and extracted with ethyl acetate. The organic layer is separated, washed with brine, dried over anhydrous sodium sulphate and filtered. After evaporation of the solvent the residue is chromatographed with a mixture of hexane and ethyl acetate to give 286 mg cholesta-4,8-dien-3β-ol and 20 mg cholesta-4,8-dien-3α-ol as white solids.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:23][CH2:24][CH:25]3[CH2:27][CH2:26]3)[CH2:13][CH2:12][C:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[F:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(=O)OCC>[CH:25]1([CH2:24][O:23][C:8]2([C:5]3[CH:4]=[CH:3][C:2]([C:32]4[CH:33]=[CH:34][C:29]([F:28])=[CH:30][CH:31]=4)=[CH:7][CH:6]=3)[CH2:9][CH2:10][C:11]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)([C:14]([OH:16])=[O:15])[CH2:12][CH2:13]2)[CH2:27][CH2:26]1
Reactant: O=C(O)C1(c2ccccc2)CCC(OCC2CC2)(c2ccc(Br)cc2)CC1
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)C1(c2ccccc2)CCC(OCC2CC2)(c2ccc(-c3ccc(F)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 9.7 %

Procedure:
19 mg of tetrakis(triphenylphosphine)palladium(0) were added to a solution of 200 mg of 4-(4-bromophenyl)-4-cyclopropylmethoxy-1-phenylcyclohexanecarboxylic acid in 4 ml of degassed toluene under argon in a two-necked flask and the mixture was stirred for 10 min at room temperature. Subsequently, 65.1 mg of 4-fluorobenzeneboronic acid and 0.341 ml of a 2 M sodium carbonate solution were added and the reaction mixture was heated for 24 h at 100° C. After cooling, water and EA were added, the organic phase was separated and the aqueous phase was extracted twice with EA. The combined organic phases were dried over magnesium sulfate and the solvent was removed in vacuo. After purification of the residue by preparative HPLC, 20 mg of the title compound were obtained as a white lyophilizate.
Reaction SMILES: [CH2:1]([C:5]1[O:9][N:8]=[C:7]([CH2:10][Cl:11])[N:6]=1)[C:2]([CH3:4])=O.[CH2:12]([NH2:15])[CH2:13][CH3:14]>C1C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[CH2:12]([NH:15][C:2]([CH3:4])=[CH:1][C:5]1[O:9][N:8]=[C:7]([CH2:10][Cl:11])[N:6]=1)[CH2:13][CH3:14]
Reactant: CC(=O)Cc1nc(CCl)no1
Reactant: CCCN
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CCCNC(C)=Cc1nc(CCl)no1
Reaction time: 1 h

Procedure:
To a stirred solution of 350 mg of 5-acetonyl-3-chloromethyl-1,2,4-oxadiazole in 10 ml of dry benzene-ether (3:1) was added dropwise with ice-cooling a solution of 190 mg of titanium tetrachloride in 1 ml of dry benzene. After the mixture was stirred for 1 hour, there was added dropwise 360 mg of n-propylamine with ice-cooling. The stirring was continued for 3 hours and then at room temperature for additional 3 hours. After the filtration of the reaction mixture, the filtrate was concentrated in vacuo. The residue was chromatographed on silica gel using benzene-acetonitrile (10:1) as eluent to give 5-[2-(n-propylamino)-1-propenyl]-3-chloromethyl-1,2,4-oxadiazole as an oil.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[O:14]1[CH2:17][C:16](=O)[CH2:15]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.C(Cl)Cl>[O:14]1[CH2:17][CH:16]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)[CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C1COC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCN(C2COC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
A solution of tert-butyl piperazine-1-carboxylate (10.8 g, 1.2 eq, 58.0 mmol) and oxetan-3-one (3.5 g, 1.0 eq, 14 mmol) in 1,2-dichloroethane (100 mL) was stirred at room temperature. Sodium triacetoxyborohydride (16.4 g, 1.6 eq, 77.3 mmol) was added in portions to the above solution and the heterogeneous mixture was stirred at room temperature overnight. The reaction mixture was diluted with CH2Cl2 (200 mL) and pardoned with aqueous saturated NaHCO3 solution (100 mL). The layers were separated and the organic layer was washed with brine solution (2×50 mL). The combined organic layers were dried over Na2SO4. Removal of the solvents and purification of the crude mixture by column chromatography on silica gel (ISCO System) using 20% MeOH in CH2Cl2/CH2Cl2 (gradient system from 0:1 to 1:9) as eluent gave tert-butyl 4-(oxetan-3-yl)piperazine-1-carboxylate in 84% yield.
Reaction SMILES: [C:1]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([NH:18][CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])=[O:17])=[CH:11][CH:10]=2)=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:38])C=1>CC(C)=O>[C:1]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:2]=[CH:3][C:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([NH:18][CH2:19][CH2:20][N+:21]([CH3:23])([CH3:22])[O-:38])=[O:17])=[CH:11][CH:10]=2)=[CH:5][CH:6]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CN(C)CCNC(=O)Cc1ccc(OCc2ccc(-c3ccccc3)cc2)cc1
Solvent: CC(C)=O
Product: C[N+](C)([O-])CCNC(=O)Cc1ccc(OCc2ccc(-c3ccccc3)cc2)cc1
Reaction time: 18 h
Yield: 48 %

Procedure:
To a solution of 2-(4-([1,1′-biphenyl]-4-ylmethoxy)phenyl)-N-(2-(dimethylamino)ethyl)acetamide (0.2 g) in acetone (30 ml) was added m-chloroperbenzoic acid (0.2 g) and stirring was continued at room temperature for 18 hr. The reaction mixture was concentrated. The residue was recrystallized twice from ethyl acetate to obtain the titled compound (0.1 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].CN(C)C(=O)C.Cl[C:18]([O:20][CH3:21])=[O:19].C(=O)(O)[O-].[Na+]>O>[CH3:21][O:20][C:18]([NH:7][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:10]=[CH:9][CH:8]=1)=[O:19]
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COC(=O)Nc1cccc([N+](=O)[O-])c1
Yield: 93 %

Procedure:
A mixture of 10 g of 3-nitroaniline and 100 ml of N,N-dimethylacetamide was stirred under ice cooling and 8.2 g of methyl chloroformate was added dropwise to the mixture. After stirring the mixture for 30 minutes, 300 ml of water was added to the reaction mixture and then the reaction mixture was neutralized by the addition of sodium bicarbonate to deposit crystals, which were recovered by filtration, washed with water, and dried. The amount of the product was 13.1 g (yield: 93%).
Reaction SMILES: [CH3:1][CH:2]1[O:7][C:6]2[N:8]=[C:9]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26][CH2:25]4)=[CH:20][CH:19]=3)[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:11][C:5]=2[NH:4][C:3]1=[O:36].C(=O)([O-])[O-].[K+].[K+].Br[CH2:44][C:45]#[N:46]>CN(C=O)C.C(OCC)(=O)C>[C:31]([O:30][C:29](=[O:35])[NH:28][C:24]1([C:21]2[CH:22]=[CH:23][C:18]([C:9]3[C:10]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)=[CH:11][C:5]4[N:4]([CH2:44][C:45]#[N:46])[C:3](=[O:36])[CH:2]([CH3:1])[O:7][C:6]=4[N:8]=3)=[CH:19][CH:20]=2)[CH2:25][CH2:26][CH2:27]1)([CH3:32])([CH3:34])[CH3:33]
Reactant: CC1Oc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc2NC1=O
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1Oc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc2N(CC#N)C1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 83.3 %

Procedure:
A solution of tert-butyl 1-(4-(3-methyl-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutylcarbamate (50 mg, 0.103 mmol) in DMF (2 ml) was added potassium carbonate (42.7 mg) and 2-bromoacetonitrile (22 μl, 0.309 mmol). The reaction mixture was stirred at room temperature for 48 h then was diluted with ethyl acetate (20 ml). Washed with water, brine, and dried with Na2SO4, filtered and concentrated to give crude product which was purified by column (biotage, 25 g) eluted with ethyl acetate and cyclohexane to afford product (45 mg). 1H NMR (500 MHz, CDCl3): 7.35 (s, 1H), 7.20-7.32 (m, 9H), 4.98 (q, 1H), 4.87 (dd, 2H), 2.44-2.49 (m, 4H), 2.06 (m, 1H), 1.80 (m, 1H), 1.75 (d, 3H), 1.24-1.36 (br, 9H).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:15]=[C:16]=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl.[CH3:19][O:20][C:21](=[O:31])[C@H:22]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[NH2:23].O>O1CCCC1>[CH2:8]([NH:15][C:16](=[O:17])[NH:23][CH:22]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:21]([O:20][CH3:19])=[O:31])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C=NCc1ccccc1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)C(Cc1ccccc1)NC(=O)NCc1ccccc1
Reaction time: 12 h
Yield: 95 %

Procedure:
Triethylamine (1.86 mmol, 0.26 ml) and benzyl isocyanate (1.86 mmol, 0.23 mL) were added at 0° C. to a solution of phenylalanine methylester hydrochloride (0.93 mmol, 0.2 g) in tetrahydrofuran, and the mixture was stirred over a period of 12 h. The reaction was poured into water (30 mL) and extracted with ethyl acetate (5×30 mL). The organic layers were washed with saturated sodium chloride solution (3×30 mL), dried with anhydrous sodium sulfate and concentrated. The residue was purified by chromatographic column on silica gel eluting with ethyl acetate/n-hexane 1/2 to afford the pure compound as a colorless oil, 95% yield; 1H NMR (CDCl3, 400 MHz, δ; ppm) δ 2.91-2.92 (dd, 1H, PhCHHCHCOO), 2.96-2.97 (dd, 1H, PhCHHCHCOO), 3.56 (s, 3H, COOCH3), 4.70-4.71 (m, 1H, PhCHHCHCOO), 4.17-4.19 (dd, 1H, PhCHHNHCONH), 4.22-4.24 (dd, 1H, PhCHHNHCONH), 5.46 (bs, 2H, NHCONH), 7.03-7.04 (2H, aromatic protons), 7.17-7.25 (m, 8H, aromatic protons); 13C NMR (CDCl3, 400 MHz, δ; ppm) δ 36.3, 44.4, 51.9, 57.3, 125.9, 126.7, 126.9 (2C), 127.7 (2C), 128.5 (2C), 128.6 (2C), 136.6, 137.9, 157.9, 171.5; MS (ESI) m/z: 312.14 [M]+.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([Cl:18])=[C:13]([CH:17]=1)[C:14]([OH:16])=O)=[O:7].ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.[C:42]([O:46][C:47]([N:49]1[CH2:54][CH2:53][CH:52]([S:55]([C:58]2[CH:63]=[CH:62][C:61]([NH:64][C:65]3[N:70]=[CH:69][C:68]([NH2:71])=[CH:67][N:66]=3)=[CH:60][CH:59]=2)(=[O:57])=[O:56])[CH2:51][CH2:50]1)=[O:48])([CH3:45])([CH3:44])[CH3:43]>C(Cl)Cl>[C:42]([O:46][C:47]([N:49]1[CH2:50][CH2:51][CH:52]([S:55]([C:58]2[CH:59]=[CH:60][C:61]([NH:64][C:65]3[N:70]=[CH:69][C:68]([NH:71][C:14](=[O:16])[C:13]4[CH:17]=[C:9]([NH:8][C:6](=[O:7])[C:5]5[CH:19]=[CH:20][CH:21]=[C:3]([C:2]([F:23])([F:22])[F:1])[CH:4]=5)[CH:10]=[CH:11][C:12]=4[Cl:18])=[CH:67][N:66]=3)=[CH:62][CH:63]=2)(=[O:56])=[O:57])[CH2:53][CH2:54]1)=[O:48])([CH3:45])([CH3:43])[CH3:44]
Reactant: CC(C)(C)OC(=O)N1CCC(S(=O)(=O)c2ccc(Nc3ncc(N)cn3)cc2)CC1
Reactant: O=C(Nc1ccc(Cl)c(C(=O)O)c1)c1cccc(C(F)(F)F)c1
Agent: COc1nc(Cl)nc(OC)n1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(S(=O)(=O)c2ccc(Nc3ncc(NC(=O)c4cc(NC(=O)c5cccc(C(F)(F)F)c5)ccc4Cl)cn3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25.8 %

Procedure:
Intermediate 1 (Example 2) (0.098 g, 0.286 mmol) was combined with 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) (0.060 g, 0.343 mmol) and diluted with DCM (4 mL). This was immediately treated with 4-methyl morpholine (0.063 mL, 0.55 mmol) and allowed to stir at ambient temperature for 1 h. Intermediate 13 (Example 20) (0.130 g, 0.3 mmol) was then added in one portion. Stirring was continued overnight. After 18 h, reaction solvents were removed and resulting crude solids were purified via HPLC to afford the title compound as a white solid (0.056 g, 26%).
Reaction SMILES: C([O:4][C:5]([C:7]1[N:8]([NH:12][CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[CH:9]=[CH:10][CH:11]=1)=[O:6])C=C.Cl.C(ON)C1C=CC=CC=1>ClCCl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:16][CH:15]([CH3:17])[CH2:14][CH2:13][NH:12][N:8]1[CH:9]=[CH:10][CH:11]=[C:7]1[C:5]([OH:6])=[O:4]
Reactant: C=CCOC(=O)c1cccn1NCCC(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: NOCc1ccccc1
Solvent: ClCCl
Product: CC(C)CCNn1cccc1C(=O)O
Temperature: 25 °C
Yield: 81.3 %

Procedure:
To a solution of 1-(3-methyl-butylamino)-1H-pyrrole-2-carboxylic acid allyl ester (Example 1c, 2.8 g, 16 mmol) in dichloromethane (70 mL) was added O-benzylhydroxylamine hydrochloride (2.56 g, 16 mmol). Tetrakis(triphenylphosphine)palladium(0) (3.6 g, 3.2 mmol) was added and the reaction mixture was heated at reflux for 16 h. The crude mixture was allowed to cool to 25° C. The solvent was removed in vacuo and redissolved in ethyl acetate (150 mL) and then washed with 10% aqueous hydrochloric acid solution (3×50 mL) and water (50 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (Merck silica gel 60, 40-63 μm, ethyl acetate/hexane, 20-60%) to afford the desired product, 1-(3-methyl-butylamino)-1H-pyrrole-2-carboxylic acid (2.5 g, 13 mmol, 82% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 0.94 (6H, d, J=6.4 Hz), 1.41-1.47 (2H, q, J=15.2 Hz, J2=6.8 Hz), 1.68 (1H, m), 6.18 (1H, dd, J1=4.0 Hz, J2=2.8 Hz), 6.98-7.02 (2H, m).