Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]1[C@H:20]([OH:21])[C@@H:19]([CH3:22])[C:17](=[O:18])[C:16]([CH3:24])([CH3:23])[C@@H:15]([OH:25])[CH2:14][C:12](=[O:13])[O:11][C@H:10](/[C:26](/[CH3:35])=[CH:27]/[C:28]2[N:32]=[C:31]([CH2:33]O)[S:30][CH:29]=2)[CH2:9][C@@H:7]2[O:8][C@:6]2([CH3:36])[CH2:5][CH2:4][CH2:3]1.C1(P([N:51]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2.CP(C)C.[NH4+].[OH-]>O1CCCC1.O>[NH2:51][CH2:33][C:31]1[S:30][CH:29]=[C:28]([CH:27]=[C:26]([CH:10]2[O:11][C:12](=[O:13])[CH2:14][CH:15]([OH:25])[C:16]([CH3:24])([CH3:23])[C:17](=[O:18])[CH:19]([CH3:22])[CH:20]([OH:21])[CH:2]([CH3:1])[CH2:3][CH2:4][CH2:5][C:6]3([CH3:36])[CH:7]([O:8]3)[CH2:9]2)[CH3:35])[N:32]=1
Reactant: C/C(=C\c1csc(CO)n1)[C@@H]1C[C@@H]2O[C@]2(C)CCC[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: CP(C)C
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(=Cc1csc(CN)n1)C1CC2OC2(C)CCCC(C)C(O)C(C)C(=O)C(C)(C)C(O)CC(=O)O1
Reaction time: 0.17 h

Procedure:
THF was dried over 3A molecular sieves prior to use. To a stirred suspension of epothilone F (10 g, 19.1 mmol) in dry tetrahydrofuran (200 ml) under argon, was added diphenylphosphoryl azide (6.20 ml, 7.90 g, 28.6 mmol, 1.5 equivalents). The mixture was stirred for about 10 min. 1,8-diazabicyclo[5.4.0]undec-7-ene (3.43 ml, 3.53 g, 22.8 mmol, 1.2 equivalents) was added gradually, at a rate that maintained the temperature of the mixture below 30° C. The mixture was stirred for 12 to 24 hours (overnight). To the reaction mixture was added a solution of 1.0 M trimethylphosphine in tetrahydrofuran (21 ml, 18.3 g, 21.04 mmol, 1.1 equivalents), at a rate that maintained the temperature of the mixture below 27° C. The mixture was stirred at room temperature for 30 minutes, and water (52 ml) was added. After 30 minutes, 28% aqueous NH4OH (26.5 ml) was added, and the mixture stirred for 30 minutes. Water (100 ml) was added, and the mixture was extracted with methylene chloride (3×100 ml). The combined organic extracts were washed with 1.0M aqueous ammonium hydroxide (2×100 ml). NMR analysis was used to determine the presence of residual diphenylphosphate in the organic phase, and an additional wash with 1.0 M aqueous ammonium hydroxide (100 ml) was carried out. The organic phase was then washed with half-saturated aqueous sodium chloride (100 ml), the solvents were removed on a rotary evaporator, and the residual solid was dried in vacuo for 18 hours. The crude product was purified within 24 hours, or stored at −15° C. or below.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([C:8]([O:10][CH3:11])=[O:9])=[C:5](C)[N:6]=1.N[C:13](N)=[S:14].Br[CH2:17][CH2:18][CH:19]=[C:20]([F:22])[F:21].C(=O)([O-])[O-].[K+].[K+]>C(O)C.CC(C)=O>[F:21][C:20]([F:22])=[CH:19][CH2:18][CH2:17][S:14][CH2:13][C:2]1[O:3][C:4]([C:8]([O:10][CH3:11])=[O:9])=[CH:5][N:6]=1
Reactant: NC(N)=S
Reactant: COC(=O)c1oc(Cl)nc1C
Reactant: FC(F)=CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCO
Product: COC(=O)c1cnc(CSCCC=C(F)F)o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product from Step 2 (0.176 g) and thiourea (0.084 g) were stirred in ethanol (5 cm3) and heated to reflux under an atmosphere of nitrogen for 5 hours. The reaction was cooled and solvent removed by evaporation under reduced pressure to give a yellow gum which was dissolved in acetone containing 4-bromo-1,1-difluorobut-1-ene (0.17 g) and potassium carbonate (0.2 g). This mixture was stirred for 1 hour under an atmosphere of nitrogen at ambient temperature and stored for 18 hours. The solvent was evaporated under reduced pressure and the residue treated with water and diethyl ether. The organic phase was separated, dried (MgSO4) and evaporated to give Compound VI.32 (0.095 g); M+ =175. 1H NMR: δ 2.45(5H,m); 3.22 (2H,t); 3.90(3H,s); 4.25(1H,m); (oil).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH3:14].[C:21](OCC)(=[O:29])[C:22]1[C:23](=[CH:25][CH:26]=[CH:27][CH:28]=1)[OH:24]>C1COCC1>[OH:24][C:23]1[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=1[C:21](=[O:29])[CH2:14][C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: CC(=O)OC(C)(C)C
Reactant: CCOC(=O)c1ccccc1O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(=O)c1ccccc1O
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 74.8 %

Procedure:
To a N2 purged 250 mL RBF is added 30 mL of THF and diisopropylamine (12.0 mL, 86 mmol). The solution is cooled to −78° C. and nBuLi (50 mL, 1.6 M) is added and the solution is warmed to 0° C. for 45 min. The solution is cooled to −78° C. and t-butyl acetate (7.1 mL, 53 mmol) in 12 mL THF is added dropwise over 10 minutes. After 90 min., ethyl salicylate (2.2 mL, 15 mmol) in 15 mL of THF is added. The solution is allowed to warm to RT overnight and quenched with 90 mL of aq. NH4Cl (sat.), extracted with EtOAc (2×25 mL), washed brine (40 mL), dried Na2SO4, filtered, concentrated in vacuo. Purified via column chromatography (silica gel, 10% EtOAc/hex) to give 2.65 g of pale yellow oil (75% yield). IR (film) 2980.2; 2934.9; 1733.6; 1643.7; 1146.6; 757.0 cm−1; 1H NMR (500 MHz, CDCl3) δ 11.93 (s, 1H); 7.68 (d, J=7.9 Hz, 1H); 7.51 (t, J=7.3, 1H); 7.01 (d, J=8.2 Hz, 1H); 6.93 (t, J=7.3 Hz, 1H); 3.93 (s, 2H); 1.47 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 198.7, 165.8, 162.3, 136.6, 130.3, 118.8, 118.7, 118.3, 82.1, 46.9, 27.6; LRMS (electrospray): Mass calculated for C13H16O4, [M]+, 236.10. Found, [M+23]+259.5.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8]([O:14][CH2:15][CH3:16])(=[O:13])[CH2:9][CH2:10][C:11]#[CH:12]>C(N(CC)CC)C.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:12]#[C:11][CH2:10][CH2:9][C:8]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: C#CCCC(=O)OCC
Reactant: Ic1ccccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Product: CCOC(=O)CCC#Cc1ccccn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 91.4 %

Procedure:
In a dry reaction tube containing in suspension copper iodide (60 mg, 0.315 mmol) and triethylamine (17.70 mL, 126 mmol), were added 2-iodopyridine (1.29 g, 6.30 mmol) and the Pd(PPh3)2Cl2 (202mg, 0.315 mmol). A yellow suspension is obtained and after a few minutes of stirring at room temperature, was added ethyl pent-4-ynoate (790 mg, 6.30 mmol) in solution in 2 mL of triethylamine. Immediately the color of the reaction turns to black. The mixture was stirred at room temperature for 30 min and then at 80° C. for 20h. Triethylamine was concentrated under reduce pressure and the residue was dissolved in DCM. The organic layer was washed with saturated NH4Cl, water and brine. The solvent was removed under reduced pressure and the crude product was purified by flash chromatography system (prepacked silicagel column 25 g, DCM/MeOH:98/2 as eluent) to afford 1.17 g of ethyl 5-(pyridin-2-yl)pent-4-ynoate (Yield: 78%) as brownish oil.
Reaction SMILES: Cl[C:2]1[C:3]2[N:11]=[C:10](Cl)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[N:13]1[C:21]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[S:15][C:14]=1[NH2:22].[SH:23][C:24]1[N:28]([CH3:29])[CH:27]=[N:26][N:25]=1>>[CH3:29][N:28]1[CH:27]=[N:26][N:25]=[C:24]1[S:23][C:10]1[CH:9]=[CH:8][C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH:22][C:14]3[S:15][C:16]4[C:21]([N:13]=3)=[CH:20][CH:19]=[CH:18][N:17]=4)[C:3]=2[N:11]=1
Reactant: Nc1nc2cccnc2s1
Reactant: Cn1cnnc1S
Reactant: Clc1ccc2ncnc(Cl)c2n1
Product: Cn1cnnc1Sc1ccc2ncnc(Nc3nc4cccnc4s3)c2n1

Procedure:
The compound of Example 34 was manufactured by the same method as in Example 31, by a similar method thereto or by a combination of such a method with a conventional method using 4,6-dichloro-pyrido[3,2-d]pyrimidine, thiazolo[5,4-b]-pyridin-2-yl-amine and 3-mercapto-4-methyl-1,2,4-triazole.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH3:35])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH3:36][O:37][C:38]1[CH:44]=[C:43]([CH:45]2[CH2:50][CH2:49][N:48]([CH2:51][CH:52]([CH3:54])C)[CH2:47][CH2:46]2)[CH:42]=[CH:41][C:39]=1[NH2:40].[C:55]1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>C(Cl)Cl.CC(O)C>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:40][C:39]3[CH:41]=[C:42]([CH3:55])[C:43]([CH:45]4[CH2:46][CH2:47][N:48]([CH2:51][CH2:52][CH3:54])[CH2:49][CH2:50]4)=[CH:44][C:38]=3[O:37][CH3:36])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH3:35]
Reactant: COc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Reactant: COc1cc(C2CCN(CC(C)C)CC2)ccc1N
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClCCl
Product: CCCN1CCC(c2cc(OC)c(Nc3nccc(-c4c(-c5ccc(OC)c(C(=O)Nc6c(F)cccc6F)c5)nc5ccccn45)n3)cc2C)CC1
Temperature: 120 °C
Yield: 40 %

Procedure:
5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamide (Intermediate Example 2) (100 mg, 0.2 mmol), 2-(methyloxy)-4-[1-(2-methylpropyl)-4-piperidinyl]aniline (48 mg, 0.18 mmol), and p-toluenesulfonic acid (93 mg, 0.49 mmol) were weighed into a 20 mL vial. 7 mL of iPrOH was added and the mixture was heated to 120° C. for 48 h. The mixture was transferred to a 50 mL round bottom and neutralized with 3 mL of 0.5 N sodium methoxide. The solvent was rotovaped down. The residue was taken up in 10 mL of DCM. 1 g of silica gel was added. The solvent was rotovaped down and the pre-adsorbed solids were purified by flash chromatography to give the title compound (52 mg, 0.072 mmol, 40%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.78 (s, 1H), 9.37 (d, J=6.59 Hz, 1H), 8.50 (s, 1H), 8.24 (d, J=5.13 Hz, 1H), 8.10 (d, J=2.01 Hz, 1H), 7.76 (dd, J=8.61, 2.20 Hz, 1H), 7.69 (d, J=8.97 Hz, 1H), 7.65 (d, J=8.06 Hz, 1H), 7.40-7.46 (m, 1H), 7.32-7.40 (m, 1H), 7.27 (d, J=8.79 Hz, 1H), 7.17 (t, J=8.06 Hz, 2H), 6.93-6.98 (m, 2H), 6.78 (dd, J=8.24, 1.47 Hz, 1H), 6.58 (d, J=5.31 Hz, 1H), 3.97 (s, 3H), 3.82 (s, 3H), 2.90 (d, J=10.07 Hz, 2H), 2.38-2.46 (m, 1H), 1.98-2.08 (m, 2H), 1.87-1.98 (m, 2H), 1.65-1.76 (m, 5H), 0.84 (d, J=6.41 Hz, 6H). MS (ESI): 718 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:23]3[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=3)=[N:10][N:11]([CH2:17][C:18]([O:20]CC)=[O:19])[C:12]=2[C:13]([F:16])([F:15])[F:14])=[CH:4][CH:3]=1.[OH-].[Li+]>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:23]3[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:30])=[O:31])=[CH:25][CH:24]=3)=[N:10][N:11]([CH2:17][C:18]([OH:20])=[O:19])[C:12]=2[C:13]([F:16])([F:14])[F:15])=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cn1nc(-c2ccc(S(C)(=O)=O)cc2)c(-c2ccc(F)cc2)c1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(-c2nn(CC(=O)O)c(C(F)(F)F)c2-c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.7 %

Procedure:
To a solution of ethyl [4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5 -(trifluoromethyl)-1H-pyrazol-1-yl]acetate (Example 8 ) (0.48 g, 1.0 mmol) in tetrahydrofuran (THF) (10 mL) was added 1.5 mL of 1N aqueous lithium hydroxide at 25° C. under nitrogen and the mixture stirred for 24 hours at 25° C. The reaction mixture was extracted with two portions diethyl ether and the aqueous layer was acidified with dilute aqueous HCl. This was extracted with two portions ethyl acetate which was washed with brine, dried over MgSO4 and concentrated in vacuo. Recrystallization from chloroform/acetone gave [4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)-1H-pyrazol-1-yl]acetic acid as a white crystalline solid (0.41 g, 93%). Elemental analysis for C19H14N2F4SO4Calc'd: C, 51.58, H, 3.19, N, 6.33. Found: C, 51.18, H, 3.23, N, 6.19; .
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].NC1C=CC=CN=1.S(Cl)([Cl:19])=O>C1(C)C=CC=CC=1>[Cl:19][C:7]1[CH:6]=[CH:5][C:4]([OH:9])=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1ccccc1O
Reactant: O=S(Cl)Cl
Agent: Nc1ccccn1
Solvent: Cc1ccccc1
Product: COc1cc(Cl)ccc1O
Temperature: 25 °C

Procedure:
2-Methoxyphenol (5.0 g), 2-aminopyridine (0.3 g), and thionyl chloride (3.24 mL) were stirred at 70° C. in toluene (100 mL) for 19 hours. The reaction mixture was cooled to room temperature, and then the solvent was evaporated under reduced pressure to obtain the title compound as an oil (6.6 g).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7][C:6]=2[CH:19]=1.[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O.O>C(O)C.C(=O)([O-])[O-].[Na+].[Na+].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>[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7][C:6]=2[CH:19]=1
Reactant: Cc1ccccc1B(O)O
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(Br)cc2C1
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: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1ccccc1-c1ccc2c(c1)CN(C(=O)OC(C)(C)C)CCO2
Yield: 96.8 %

Procedure:
A mixture of tert-butyl 7-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (200 mg, 0.609 mmol), a solution of 2-methylphenylboronic acid (124 mg, 0.912 mmol) in ethanol (0.7 ml), 2N aqueous sodium carbonate solution (2.5 ml), and tetrakis(triphenylphosphine)palladium(0) (84.2 mg, 0.0729 mmol) in toluene (5 ml) was stirred under a nitrogen atmosphere at 95° C. for 12 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give the desired product (200 mg, 96.6%) as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[CH2:17]([O:19][C:20](=[O:32])[CH2:21][O:22][C:23](OC1C=CC=CC=1)=[O:24])[CH3:18]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][CH2:10][CH:11]2[CH2:12][CH2:13][N:14]([C:23]([O:22][CH2:21][C:20]([O:19][CH2:17][CH3:18])=[O:32])=[O:24])[CH2:15][CH2:16]2)=[CH:6][CH:7]=1
Reactant: Brc1ccc(OCCC2CCNCC2)cc1
Reactant: CCOC(=O)COC(=O)Oc1ccccc1
Product: CCOC(=O)COC(=O)N1CCC(CCOc2ccc(Br)cc2)CC1
Yield: 54.6 %

Procedure:
The procedure described in Example 4.3. is repeated. Starting from 1.76 g (6.19 mmol) of 4-{2-[(4 bromophenyl)oxy]ethyl} prepared in Step 9.2., and 1.39 g (6.19 mmol) of ethyl{[(phenyloxy)carbonyl]oxy}-acetate, prepared in accordance with Example 1.1., gives 1.4 g of product in oil form.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[N+:8]([C:11]1[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=1)([O-:10])=[O:9]>>[N+:8]([C:11]1[CH:12]=[C:13]([CH:14]=[CH:15][CH:16]=1)[O:17][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])([O-:10])=[O:9]
Reactant: CCOC(=O)CBr
Reactant: O=[N+]([O-])c1cccc(O)c1
Product: CCOC(=O)COc1cccc([N+](=O)[O-])c1

Procedure:
Ethyl bromoacetate is reacted with meta-nitrophenol under standard conditions to afford ethyl 2-(3-nitrophenoxy)acetate, which is elaborated to ethyl 2-(3-hydrazinophenoxy)acetate using the reduction/oxidation sequence described for Example Y.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[NH:13][CH2:14][CH3:15])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[N:16]([O-])=O.[Na+].O.N.C(OCC)(=O)C>C(O)(=O)C>[CH2:14]([N:13]1[C:12]2[CH:11]=[CH:10][C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:3][C:2]=2[N:1]=[N:16]1)[CH3:15]
Reactant: O=N[O-]
Reactant: CCNc1ccc(C(=O)OCC)cc1N
Agent: N
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc2c(c1)nnn2CC
Reaction time: 0.17 h
Yield: 68.9 %

Procedure:
Ethyl 3-amino-4-ethylaminobenzoate (1.80 g, 9.27 mmol) prepared in the same manner as in the Step 1-1-3 was dissolved in acetic acid (5 ml), and under an ice cooling sodium nitrite (1.28 g, 18.5 mmol) was added to the solution little by little. The mixture was stirred for 10 minutes under a water cooling. The mixture was cooled by ice again and neutralized with a 25% ammonia water. Thereafter, ethyl acetate was added to the mixture, and the resulting mixture was washed with a saturated saline solution and water in order. The washed mixture was dried over anhydrous magnesium sulfate and then concentrated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1 to 1:1) to give the title compound (1.40 g, 69%) as a brown powder.
Reaction SMILES: Br[CH2:2][C:3]1[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:11]=[CH:10][C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH2:18][C:19]1[C:20]([CH3:48])=[C:21]([C:25]2[N:26]=[C:27]([NH:33][C:34]3[CH:39]=[CH:38][C:37]([C:40]([N:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)=[O:41])=[CH:36][CH:35]=3)[C:28](=[O:32])[N:29]([CH3:31])[CH:30]=2)[CH:22]=[CH:23][CH:24]=1.C(N(C(C)C)CC)(C)C.C([O-])([O-])=O.[Na+].[Na+]>CCO>[C:14]([C:12]1[CH:11]=[CH:10][C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[C:3]([CH2:2][NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]3[N:26]=[C:27]([NH:33][C:34]4[CH:35]=[CH:36][C:37]([C:40]([N:42]5[CH2:47][CH2:46][O:45][CH2:44][CH2:43]5)=[O:41])=[CH:38][CH:39]=4)[C:28](=[O:32])[N:29]([CH3:31])[CH:30]=3)[C:20]=2[CH3:48])[CH:13]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CCOC(=O)c1ccc(C(C)(C)C)cc1CBr
Reactant: Cc1c(N)cccc1-c1cn(C)c(=O)c(Nc2ccc(C(=O)N3CCOCC3)cc2)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1ccc(C(C)(C)C)cc1CNc1cccc(-c2cn(C)c(=O)c(Nc3ccc(C(=O)N4CCOCC4)cc3)n2)c1C
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A 48-mL sealed tube equipped with a magnetic stirring bar was charged with bromide 101c (120 mg, 0.4 mmol), aniline 101g (168 mg, 0.4 mmol), diisopropyethylamine (0.08 mL, 0.48 mmol) in EtOH (3 mL). After the mixture was stirred at 100° C. for 16 h, aqueous Na2CO3 (5 mL) was added. The aqueous phase was extracted with EtOAc (2×5 mL), and the combined organic extracts were washed with brine (5 mL), dried with Na2SO4 and concentrated. The residue was chromatographed with (gradient, 50%-100% EtOAc/hexanes) to afford 100 mg (42%) of 101h.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:16]2[C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:24]3[C:19]([C:20]4[CH:32]=[CH:31][O:30][C:21]=4[CH2:22][O:23]3)=[CH:18][CH:17]=2)C(OC)=O)(=[O:10])=[O:9])=[C:4](/[CH:33]=[CH:34]\[CH2:35]O)[CH:3]=1.C(N(C(C)C)CC)(C)C.CS(Cl)(=O)=O.FC(F)(F)C(O)=O.[NH:58]1[CH2:61][CH:60]([O:62][C:63](=[O:65])[CH3:64])[CH2:59]1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:16]2[C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:24]3[C:19]([C:20]4[CH:32]=[CH:31][O:30][C:21]=4[CH2:22][O:23]3)=[CH:18][CH:17]=2)(=[O:10])=[O:9])=[C:4](/[CH:33]=[CH:34]\[CH2:35][N:58]2[CH2:61][CH:60]([O:62][C:63](=[O:65])[CH3:64])[CH2:59]2)[CH:3]=1
Reactant: COC(=O)c1c(N(C(=O)OC)S(=O)(=O)c2ccc(F)cc2/C=C\CO)ccc2c1OCc1occc1-2
Reactant: CC(=O)OC1CNC1
Agent: CS(=O)(=O)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2/C=C\CN2CC(OC(C)=O)C2)ccc2c1OCc1occc1-2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 40.1 %

Procedure:
To a suspension of methyl 7-{N-[4-fluoro-2-((Z)-3-hydroxy-prop-1-enyl)-benzenesulfonyl]-N-(methoxycarbonyl)amino}-4H-furo[2,3-c]chromene-6-carboxylate (Intermediate 92, 0.220 g) in DCM (10 mL) was added N,N-di-isopropyl-N-ethylamine (1.10 g) and methanesulfonyl chloride (0.059 g). The mixture was stirred at room temperature for 1.5 hours. A solution of acetic acid azetidin-3-yl ester trifluoroacetate salt (1.40 g) in DCM (5 mL) was added and the resultant mixture was stirred at room temperature for 30 minutes. The mixture was diluted with DCM and washed with water, dried (MgSO4) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of 2M ammonia in methanol and DCM, with a gradient of 0-10% to give methyl 7-{4-fluoro-2-[(Z)-3-(3-acetoxyazetidin-1-yl)-prop-1-enyl]-benzenesulfonylamino]-4H-furo[2,3-c]chromene-6-carboxylate (0.095 g) as a white foam.
Reaction SMILES: [CH2:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6]([O:12][CH:13]2[CH2:15][CH2:14]2)[CH:5]=1)[CH:2]=C.N1C=CC=CC=1.[O:22]=[O+][O-]>C(Cl)Cl.CO>[CH:13]1([O:12][C:6]2[CH:5]=[C:4]([CH2:1][CH:2]=[O:22])[CH:11]=[CH:10][C:7]=2[C:8]#[N:9])[CH2:15][CH2:14]1
Reactant: O=[O+][O-]
Reactant: C=CCc1ccc(C#N)c(OC2CC2)c1
Solvent: c1ccncc1
Solvent: CO
Solvent: ClCCl
Product: N#Cc1ccc(CC=O)cc1OC1CC1
Temperature: -78 °C
Reaction time: 8 h

Procedure:
A solution of 4-allyl-2-(cyclopropyloxy)benzonitrile (100 mg, 0.5 mmol) in 1:1 CH2Cl2/MeOH (15 mL) containing pyridine (0.5 mL, 6 mmol) was cooled to −78° C., and O3 was passed through until a blue color was present. N2 was then bubbled through to discharge the blue color and Me2S (5 ml) was added. The reaction mixture was allowed to warm and left overnight. The mixture was washed with 1 N HCl and aqueous NaHCO3 and then dried and concentrated to give crude 2-(cyclopropyloxy)-4-(2-oxoethyl)benzonitrile.
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1.C1COCC1.[OH-].[Na+]>CO>[O:25]1[CH2:24][CH2:23][CH:22]([C:15]2[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:13]([S:10]([C:7]3[CH:6]=[CH:5][C:4]([C:3]([OH:28])=[O:2])=[CH:9][CH:8]=3)(=[O:12])=[O:11])[CH:14]=2)[CH2:27][CH2:26]1
Reactant: COC(=O)c1ccc(S(=O)(=O)n2cc(C3CCOCC3)c3ccccc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(S(=O)(=O)n2cc(C3CCOCC3)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
Add to a suspension of 4-[3-(tetrahydro-pyran-4-yl)-indole-1-sulfonyl]-benzoic acid methyl ester (16.7 g, 41.83 mmol) in methanol (200 mL) with stirring THF (600 mL). Treat the solution with 5N NaOH (23.5 ml, 2.8 eq.) and stir for 2 h at room temperature. Concentrate the solution to near dryness and treat with 1N HCl (125 mL), a solid separates. Dilute to 500 mL total volume with water, filter, back-wash with water, and dry (20 mm Hg, 60° C.) to give a resulting solid found to be pure title compound (15.8 g, 98%); 1H NMR (DMSO-d6) 13.57 (s, 1H), 8.08 (m, 4H), 7.93 (d, J=8.2 Hz, 1H), 7.68 (d, J=8.2 Hz, 1H), 7.57 (s, 1H), 7.37 (t, J=8.2 Hz, 1H), 7.27 (t, J=7.1 Hz, 1H), 3.95 (m, 2H), 3.47 (t, J=12.0 Hz, 2H), 3.03 (m, 1H), 1.85 (m, 2H), 1.70 (m, 2H); MS (ESI) m/z 384 (m−H).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.Cl[CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:30]=[C:29]2[C:25]([CH:26]=[CH:27][NH:28]2)=[CH:24][C:23]=1[O:31][CH3:32].C(#N)C>O>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:18][CH2:19][CH2:20][O:21][C:22]4[CH:30]=[C:29]5[C:25]([CH:26]=[CH:27][NH:28]5)=[CH:24][C:23]=4[O:31][CH3:32])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: COc1cc2cc[nH]c2cc1OCCCCl
Solvent: CC#N
Solvent: O
Product: COc1cc2cc[nH]c2cc1OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Yield: 90.8 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.5 g, 11.5 mmol), 6-(3-chloropropoxy)-5-methoxyindole (2.5 g, 10.4 mmol), K2 CO3 (1.6 g, 11.5 mmol), KI (200 mg) and acetonitrile (100 ml) was stirred at reflux under nitrogen for 40 hours. The cooled reaction was poured into water and extracted with ethyl acetate. The ethyl acetate extract was washed with water, washed with brine, dried with MgSO4 and concentrated to yield 4.0 g of a solid. The compound was recrystallized from ethanol to afford 3.3 g. Another recrystallization from ethanol (utilizing a charcoal treatment) provided 2.9 g (66%) of 6-fluoro-3-[1-[3-[(5-methoxy-1 H-indol-6-yl)oxy]-propyl]piperdinyl]-1,2-benzisoxazole as a beige solid, m.p.=156°-158° C.