Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[CH3:27][C:28]([CH3:42])([CH3:41])[CH2:29][S:30]([C:33]1[CH:40]=[CH:39][C:36]([CH2:37][NH2:38])=[CH:35][CH:34]=1)(=[O:32])=[O:31].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:14])([F:13])[F:15])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:38][CH2:37][C:36]1[CH:35]=[CH:34][C:33]([S:30]([CH2:29][C:28]([CH3:42])([CH3:41])[CH3:27])(=[O:32])=[O:31])=[CH:40][CH:39]=1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: CC(C)(C)CS(=O)(=O)c1ccc(CN)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)CS(=O)(=O)c1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1
Yield: 80 %

Procedure:
Use a method similar to the General Procedure 5-2 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (158 mg, 0.37 mmol) with 4-(2,2-dimethyl-propane-1-sulfonyl)-benzylamine (166 mg, 0.73 mmol) by using tris(dibenzylideneacetone)dipalladium(0) (68 mg, 0.074 mmol), BINAP (92 mg, 0.148 mmol) and cesium carbonate (169 mg, 0.518 mmol) in anhydrous toluene (15 mL). Purify by chromatography on silica gel eluting with hexane/EtOAc (8:2) and then by reversed HPLC [Zorbax Bonus RP, 5 □M 21.2×100 mm, eluting with water/acetonitrile (0.05% TFA in each), UV detector (230 nm)] to give 7-chloro-6-[4-(2,2-dimethyl-propane-1-sulfonyl)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as an oil (153 mg, 80%). MS (ES+) m/z: 517 (M+H)+.
Reaction SMILES: [O:1]1[CH2:3][C:2]21[C:16]1[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:10]1([CH2:18][O:17]1)[C:9]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]2=1.B(F)(F)F.C(=O)(O)[O-].[Na+]>CCOCC>[OH:17][CH2:18][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:2]([CH:3]=[O:1])=[C:16]2[C:11]=1[CH:12]=[CH:13][CH:14]=[CH:15]2
Reactant: c1ccc2c(c1)C1(CO1)c1ccccc1C21CO1
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: O=Cc1c2ccccc2c(CO)c2ccccc12
Temperature: -45 °C
Reaction time: 0.17 h

Procedure:
To a solution of 500 mg. of the product of Example 1 in 50 ml. of anhydrous ether maintaining at -45° C. is added dropwise a solution of 0.060 ml. of boron trifluoride in 2.0 ml. of anhydrous ether. The reaction mixture is stirred at -45° C. for 10 minutes and then allowed to warm to -30° C. in 5 minutes. The reaction mixture is poured into a mixture of 20 ml. of cool saturated sodium bicarbonate solution and 30 ml. of ether. The ethereal solution is washed with an additional 20 ml. of saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate and filtered. The ether is removed to provide a yellow solid. The solid is recrystallized from acetonitrile to give 259 mg. of the desired product as yellow crystals, mp. 182°-184° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:4]=[C:3]1[CH:13]=[O:14].C(O)C.[BH4-].[Na+].O>O1CCCC1>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:4]=[C:3]1[CH2:13][OH:14]
Reactant: Cn1cc(-c2ccccc2)nc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: Cn1cc(-c2ccccc2)nc1CO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
To a solution of 1-methyl-4-phenyl-1H-imidazole-2-carbaldehyde (7.24 g) in tetrahydrofuran (50 mL)-ethanol (10 mL) was gradually added sodium borohydride (1.47 g) at room temperature and the mixture was stirred at room temperature for 30 min. Water was added to the reaction mixture and the precipitated crystals were collected by filtration to give (1-methyl-4-phenyl-1H-imidazol-2-yl)methanol as colorless crystals (5.71 g, yield 78%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 191-192° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:23]=[C:22]([F:24])[C:21]([Cl:25])=[CH:20][C:16]=2[C:17](Cl)=[O:18])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:26][NH2:27]>ClCCl>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:23]=[C:22]([F:24])[C:21]([Cl:25])=[CH:20][C:16]=2[C:17]([NH:26][NH2:27])=[O:18])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NN
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2cc(F)c(Cl)cc2C(=O)Cl)cc1
Solvent: ClCCl
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2cc(F)c(Cl)cc2C(=O)NN)cc1
Temperature: -10 °C
Yield: 70.2 %

Procedure:
The crude 2-(4-tert-butyl-benzenesulfonylamino)-5-chloro-4-fluoro-benzoyl chloride (57.0 mmol) was dissolved in dichloromethane (100 mL) and transferred to an addition funnel. Anhydrous hydrazine (44 mL, 1.38 mol), dissolved in 300 mL dichloromethane in a one liter Erlenmeyer flask, was cooled to −10° C. in a dry ice-acetone bath and the acyl chloride solution was added in a slow stream to the stirring hydrazine solution over a 15 minute period. The cold bath was subsequently removed following the addition and LCMS analysis at 15 minutes indicated the reaction was complete. The resultant reaction mixture was quenched with water (200 mL), resulting in a voluminous white precipitate that was collected by vacuum filtration. The precipitate was slurried in 500 mL ethyl acetate and acetic acid was added while stirring until a homogeneous solution was formed. The solution was transferred to a separatory funnel and extracted with 2×50 mL of water. The aqueous phases were discarded and the organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo to produce 4-tert-butyl-N-(4-chloro-5-fluoro-2-hydrazinocarbonyl-phenyl)-benzenesulfonamide (16 g) in a 71% yield: HPLC retention time=2.63 minutes; MS (ES) M+H expected 400.0, found 400.0.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[F:7][C:8]([F:23])([F:22])[C:9]1[CH:10]=[C:11]([C:15](=[O:21])[CH2:16][CH2:17][CH2:18][CH2:19]Cl)[CH:12]=[CH:13][CH:14]=1.[CH3:24][CH:25]([CH3:41])[C:26]([NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH:30]=1)=[O:27]>>[CH3:24][CH:25]([CH3:41])[C:26]([NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]2[CH2:40][CH2:39][N:38]([CH2:19][CH2:18][CH2:17][CH2:16][C:15](=[O:21])[C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([C:8]([F:23])([F:22])[F:7])[CH:10]=3)[CH2:37][CH2:36]2)[CH:30]=1)=[O:27]
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=C(CCCCCl)c1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3cccc(C(F)(F)F)c3)CC2)c1

Procedure:
Prepared by Procedure K and Scheme B1 (K2CO3) using 1-[3-(trifluoromethyl)phenyl]-5-chloro-1-pentanone and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 475.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][C@:11]([OH:15])([CH3:14])[CH2:12][OH:13])[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.C(N(CC)C(C)C)(C)C.[Cl:25][C:26]1[CH:41]=[CH:40][C:29]([CH2:30][N:31]2[CH2:36][CH2:35][N:34]([C:37](Cl)=[O:38])[CH2:33][CH2:32]2)=[CH:28][CH:27]=1>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:25][C:26]1[CH:41]=[CH:40][C:29]([CH2:30][N:31]2[CH2:32][CH2:33][N:34]([C:37]([O:13][CH2:12][C@@:11]([OH:15])([CH3:14])[CH2:10][N:3]3[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=[C:2]3[Cl:1])=[O:38])[CH2:35][CH2:36]2)=[CH:28][CH:27]=1
Reactant: O=C(Cl)N1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: C[C@](O)(CO)Cn1cc([N+](=O)[O-])nc1Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C[C@](O)(COC(=O)N1CCN(Cc2ccc(Cl)cc2)CC1)Cn1cc([N+](=O)[O-])nc1Cl
Temperature: 100 °C
Reaction time: 3 h
Yield: 47.9 %

Procedure:
(R)-2-Chloro-1-(2,3-dihydroxy-2-methyl)propyl-4-nitroimidazole prepared in Example 10 (2.28 g, 9.66 mmol), N,N-diisopropylethylamine (2.81 ml, 16.10 mmol) and 4-dimethylaminopyridine (0.20 g, 1.61 mmol) were added to a suspension of 4-(4-chlorobenzyl)piperazine-1-carbonylchloride (2.20 g, 8.05 mmol) in toluene (30 ml) followed by stirring 100° C. for 3 hours. The reaction mixture was diluted with ethyl acetate, washed with water, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=9/1) to afford (R)-3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl 4-(4-chlorobenzyl)piperazine-1-carboxylate (1.82 g, yield 48%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[N:15]1[CH:20]=[CH:19][N:18]=[CH:17][C:16]=1[C:21]([NH:23][NH2:24])=O.Cl.C(N(CC)CC)C>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][C:5]2[N:4]([C:21]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][N:15]=3)=[N:23][N:24]=2)[N:3]=1
Reactant: Clc1cc(-c2ccccc2)c(Cl)nn1
Reactant: NNC(=O)c1cnccn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1C
Product: Clc1nn2c(-c3cnccn3)nnc2cc1-c1ccccc1

Procedure:
The product from Example 1 step b) (1 g, 4.46 mmol) was suspended in xylene (25 ml) with pyrazine-2-hydrazide (0.74 g, 5.35 mmol) and triethylamine hydrochloride (0.61 g, 4.46 mmol) and the reaction mixture was heated at reflux for 2 days. The solvent was removed under high vacuum, and the residue was dissolved in dichloromethane, basified with sodium bicarbonate and the aqueous extracted with dichloromethane (2×150 ml). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated. The residue was purified by silica gel chromatography using 0-40% ethyl acetate in dichloromethane as eluent to give the required product (0.249 g). 1H NMR (250 MHz, DMSO) δ 7.56 (5H, m), 8.43 (1H, s), 8.87 (1H, d, J=2.5 Hz), 8.96 (1H, d, J=2.5 Hz), 9.49 (1H, d, J=2.5 Hz); MS (ES+) m/e 309 [MH+].
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:9][C@H:10]([CH3:15])[C:11]([CH3:14])([OH:13])[CH3:12])=[N:4][C:5](Cl)=[N:6][CH:7]=1.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([CH:35]2[CH2:37][CH2:36]2)(=[N:25][S:26]([CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])(=[O:28])=[O:27])=[O:24])=[CH:19][CH:18]=1.Cl>C(#N)C.O1CCOCC1.O>[Br:1][C:2]1[C:3]([NH:9][C@H:10]([CH3:15])[C:11]([OH:13])([CH3:14])[CH3:12])=[N:4][C:5]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH:35]3[CH2:37][CH2:36]3)(=[N:25][S:26]([CH2:29][CH2:30][Si:31]([CH3:33])([CH3:34])[CH3:32])(=[O:27])=[O:28])=[O:24])=[CH:19][CH:18]=2)=[N:6][CH:7]=1
Reactant: C[C@@H](Nc1nc(Cl)ncc1Br)C(C)(C)O
Reactant: C[Si](C)(C)CCS(=O)(=O)N=S(=O)(c1ccc(N)cc1)C1CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Solvent: CC#N
Product: C[C@@H](Nc1nc(Nc2ccc(S(=O)(=NS(=O)(=O)CC[Si](C)(C)C)C3CC3)cc2)ncc1Br)C(C)(C)O

Procedure:
95 mg (0.32 mmol) of (R)-3-[(5-bromo-2-chloropyrimidin-4-yl)amino]-2-methyl-butan-2-ol is dissolved in 2 ml of acetonitrile and mixed with 116 mg (0.32 mmol) of (RS)—S-(4-aminophenyl)-S-cyclopropyl-N-[2-(trimethylsilyl)ethylsulfonyl]sulfoximide. After 0.08 ml of an approximately 4N solution of HCl in dioxane and 0.08 ml of water are added, the mixture is heated in a sealed vessel for 16 hours to 75° C. The suspension is filtered, and the filtrate is separated by flash chromatography (dichloromethane—dichloromethane/ethanol 95:5, 15 ml/min) The fractions, 43-51 min, contain 50 mg (25% of theory) of the desired product.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([OH:27])([CH3:26])[C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[C@@H:11]([CH2:28][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH:30]2[CH2:35][C:36]([OH:38])=O)[CH2:10]1)(=[O:8])=[O:7].[CH3:39][NH:40][CH3:41].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:39][N:40]([CH3:41])[C:36](=[O:38])[CH2:35][CH:30]1[CH2:31][O:32][CH2:33][CH2:34][N:29]1[CH2:28][C@H:11]1[CH2:10][N:9]([S:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)(=[O:7])=[O:8])[CH2:14][CH2:13][N:12]1[C:15]1[CH:20]=[CH:19][C:18]([C:21]([OH:27])([CH3:26])[C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=1
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CN2CCOCC2CC(=O)O)cc1)C(F)(F)F
Reactant: CNC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)CC1COCCN1C[C@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ccc(C(C)(O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.3 %

Procedure:
A 25-mL round-bottomed flask was charged with (4-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-morpholinyl)acetic acid (65 mg, 0.113 mmol), dimethylamine (2.0 M in MeOH, 1.69 mL, 3.38 mmol, Sigma-Aldrich, St. Louis, Mo.), Hünig's base (0.039 mL, 0.225 mmol), HATU (471 mg, 1.24 mmol) and DMF (3 mL). After stirring at room temperature for 1 h, the reaction was concentrated onto silica gel and purified via column chromatography (12 g silica gel, 0 to 100% hexanes in EtOAc) to give N,N-dimethyl-2-(4-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-morpholinyl)acetamide (20 mg) as a mixture of four isomers.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:12][CH2:13][NH2:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:26][C:27]1[CH:37]=[CH:36][C:30]([NH:31][CH2:32][C:33](O)=[O:34])=[CH:29][CH:28]=1>C1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:12][CH2:13][NH:14][C:33](=[O:34])[CH2:32][NH:31][C:30]2[CH:36]=[CH:37][C:27]([Cl:26])=[CH:28][CH:29]=2)[CH:15]=[CH:16][C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CNc1ccc(Cl)cc1
Reactant: NCCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Solvent: c1ccccc1
Product: O=C(CNc1ccc(Cl)cc1)NCCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Temperature: 190 °C
Reaction time: 3 h
Yield: 50.4 %

Procedure:
A mixture of 3,4-dibenzyloxyphenethylamine (36.2 g) and p-chloroanilinoacetic acid (20 g) was stirred for 3 hours at 190° C. The reaction mixture was dissolved in benzene. The solution was washed with a diluted potassium carbonate aqueous solution and dried. The solvent was distilled off from the benzene solution and the residue obtained was purified by column chromatography on silica gel to give N-[2-(3,4-dibenzyloxyphenyl)ethyl] -2-(p-chloroanilino)acetamide (27.2 g), mp 121° C.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[OH:15][CH2:16][C:17]1[CH:21]=[C:20]([C:22]2[CH:23]=[C:24]([C:28]([NH:31][S:32]([CH2:35][C:36]([F:39])([F:38])[F:37])(=[O:34])=[O:33])([CH3:30])[CH3:29])[CH:25]=[CH:26][CH:27]=2)[N:19]([CH3:40])[N:18]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[F:60][C:61]1[CH:66]=[CH:65][C:64](O)=[CH:63][CH:62]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[F:37][C:36]([F:39])([F:38])[CH2:35][S:32]([NH:31][C:28]([C:24]1[CH:25]=[CH:26][CH:27]=[C:22]([C:20]2[N:19]([CH3:40])[N:18]=[C:17]([CH2:16][O:15][C:64]3[CH:65]=[CH:66][C:61]([F:60])=[CH:62][CH:63]=3)[CH:21]=2)[CH:23]=1)([CH3:30])[CH3:29])(=[O:34])=[O:33]
Reactant: Cn1nc(CO)cc1-c1cccc(C(C)(C)NS(=O)(=O)CC(F)(F)F)c1
Reactant: Oc1ccc(F)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cn1nc(COc2ccc(F)cc2)cc1-c1cccc(C(C)(C)NS(=O)(=O)CC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Diisopropyl azodicarboxylate (57 mg, 0.27 mmol) was added dropwise to a stirred solution of the alcohol from Step 5 (75 mg, 0.19 mmol), PPh3 (75 mg, 0.27 mmol) and 4-fluorophenol (26 mg, 0.23 mmol) in THF (10 mL) under N2 and the resulting mixture was stirred at RT for 2 hours. Further DIAD (19 mg, 0.09 mmol), PPh3 (25 mg, 0.09 mmol) and 4-fluorophenol (11 mg, 0.09 mmol) were added and stirring was continued for a further 30 min. The reaction mixture was then concentrated under reduced pressure while loading on to MgSO4 and then purified by column chromatography on silica eluting with 100% Et2O to yield the desired ether (19 mg, 20%). 1H NMR (CDCl3, 360 MHz) δ 7.58-7.53 (2H, s), 7.49 (1H, t, J=7.5 Hz), 7.37 (1H, d, J=7.5 Hz), 6.97 (4H, app. d, J=6.1 Hz), 6.41 (1H, s), 5.05 (2H, s), 4.99 (1H, s), 3.88 (3H, s), 3.48 (2H, q, J=8.9 Hz), 1.81 (6H, s). MS (ES+) C22H23F4N3O3S requires: 485, found: 486 (M+H+, 100%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[C:12](O)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].S([O-])(O)(=O)=O.[K+]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][OH:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1C(=O)O
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H]1CO
Temperature: 25 °C
Reaction time: 48 h
Yield: 96 %

Procedure:
To an ice-cooled solution of the compound of step 7a (9.39 g, 46.72 mmol) in tetrahydrofuran (100 mL) was added borane/THF complex (1 M, 210 mL, 4.5 eq.) under nitrogen. The reaction was gradually warmed to room temperature and stirred for 48 hours, after which a 10% aqueous potassium hydrogen sulfate solution (60 mL) was added gradually, then the volatiles were evaporated in vacuo. The remaining slurry was diluted with ethyl acetate (100 mL), and triturated two additional times. The organic phase was then washed with a saturated solution of sodium hydrogen carbonate (3×75 mL), dried (MgSO4), filtered and concentrated in vacuo, yielding a colorless oil (8.4 g, 96% yield). This material was carried forward without further purification. MS (DCI/NH3) m/e 188 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ: 4.49-4.40 (ddd, J=9.0 Hz, J=9.0 Hz, J=3.0 Hz, 1H), 3.95-3.68 (m, 4H), 2.23-2.12 (m, 1H), 1.99-1.87 (m, 1H), 1.46 (s, 9H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]1[S:11][C:10]2[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:9]=2[O:8][CH2:7][CH:6]1[OH:18].[C:19]1([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>O.CN(C)C=O>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:9]2[O:8][CH2:7][C@@H:6]([OH:18])[C@@H:5]([CH2:4][CH2:3][CH2:2][N:28]3[CH2:29][CH2:30][N:25]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:26][CH2:27]3)[S:11][C:10]=2[CH:12]=1
Reactant: COc1ccc2c(c1)SC(CCCCl)C(O)CO2
Reactant: c1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)S[C@H](CCCN1CCN(c3ccccc3)CC1)[C@H](O)CO2
Temperature: 80 °C

Procedure:
A mixture of 4-(3-chloropropyl)-7-methoxy-3,4-dihydro-2H-1,5-benzoxathiepin-3-ol 500 mg, N-phenylpiperazine (500 mg), potassium iodide (50 mg), potassium carbonate (400 mg) and N,N-dimethylformamide (10 ml) is heated at 80° C. for 8 hours with stirring. The reaction mixture is poured into water, extracted with ethyl acetate. The organic layer is washed with water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The residue is submited to column chromatography on silica gel eluting with hexane-ethyl acetate-methanol (10:10:1) to give cis-7-methoxy-4-[3-(4-phenylpiperazin-1-yl)propyl]-3,4-dihydro-2H-1,5-benzoxathiepin-3-ol (colorless oil) which is isolated as the dihydrochloride (amorphous powder).
Reaction SMILES: CN(C)[CH2:3][C:4]1[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:7]2[NH:6][CH:5]=1.O.[C-:15]#[N:16].[Na+]>C1COCC1>[NH:6]1[C:7]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[C:4]([CH2:3][C:15]#[N:16])=[CH:5]1
Reactant: CN(C)Cc1c[nH]c2cccnc12
Reactant: [C-]#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: N#CCc1c[nH]c2cccnc12
Yield: 68 %

Procedure:
A stirred solution of dimethyl-(1H-pyrrolo[3,2-b]pyridin-3-yl)methylamine (0.828 g, 4.73 mmol) in dry THF (20 mL) under nitrogen is treated with a solution of (CH3O)2SO2 (0.49 mL) in THF, heated at reflux temperature for 0.5 h, cooled in an ice bath, and decanted. The gummy residue is washed with ether, treated with water (15 mL) and NaCN (0.39 g, 6.2 mmol), heated at reflux temperature for 0.75 h, cooled and extracted with 4:1 CH2Cl2:ethanol. The combined extracts are dried over MgSO4 and concentrated in vacuo. The resultant residue is chromatographed (silica gel, ethyl acetate as eluent) to afford the title compound as a white solid, 0.51 g (68% yield), mp 201-202° C., identified by NMR and mass spectral analyses.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:8][N:7]([CH2:9][C:10]2[N:11]=[CH:12][N:13](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:14]=2)[C:6](=[O:34])[CH2:5]1)[CH2:2][CH3:3]>CC(O)=O.O>[NH:13]1[CH:14]=[C:10]([CH2:9][N:7]2[CH2:8][CH:4]([CH2:1][CH2:2][CH3:3])[CH2:5][C:6]2=[O:34])[N:11]=[CH:12]1
Reactant: CCCC1CC(=O)N(Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)C1
Solvent: CC(=O)O
Solvent: O
Product: CCCC1CC(=O)N(Cc2c[nH]cn2)C1
Temperature: 25 °C
Reaction time: 36 h
Yield: 88 %

Procedure:
In a 50 ml reaction flask fitted with a magnetic stirrer, 4-propyl-1-[(1-trityl-1H-imidazol-4-yl)methyl]pyrrolidin-2-one x45 (1.8 g, 4 mmol) is dissolved in a 1/1 mixture of CH3CO2H/H2O (30 ml) and the solution is stirred for 36 h at room temperature. Most of the solvents are removed under vacuum and the residue is dissolved in 1N HCl and diluted with CH2Cl2. The first organic phase is removed and pH of the aqueous phase is adjusted to 9 by addition of solid Na2CO3. Then CH2Cl2 is added and the second organic phase is separated, dried over MgSO4 and concentrated to dryness, affording 730 mg of 1-(1H-imidazol-4-ylmethyl)-4-propylpyrrolidin-2-one 110.
Reaction SMILES: [C:1]([C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7][C:6]=2[CH:5]=1)([OH:3])=[O:2].C[C:18](C)([O-:20])C.[K+].C(OCC)=O>CN(C)C=O>[C:1]([C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:7]([CH:18]=[O:20])[C:6]=2[CH:5]=1)([OH:3])=[O:2]
Reactant: O=C(O)c1ccc2c(c1)Cc1ccccc1-2
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC=O
Solvent: CN(C)C=O
Product: O=CC1c2ccccc2-c2ccc(C(=O)O)cc21
Temperature: 60 °C
Reaction time: 3 h

Procedure:
2-Carboxyfluorene (2.8 g, 0.014 mole) was dissolved in anhydrous dimethylformamide (DMF, 133 mL). Potassium t-butoxide (12.5 g, 0.11 mole) and ethyl formate (400 mL) were added to the reaction solution. The temperature of the solution was increased to 60° C. for 5-10 minutes. The reaction solution was cooled to room temperature. Total reaction time was three hours. Ethyl formate was distilled off and 1M hydrochloric acid (150 mL) was added to the reaction mixture. The solid was filtered and washed with distilled water. The precipitate was dried overnight under reduced pressure with phosphorous pentoxide present. NMR confirmed the structure by the appearance of one new proton at δ11.47 ppm (aldehyde hydrogen).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:4]=1[C:5](OC)=[O:6].CC(C[AlH]CC(C)C)C>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]([CH2:5][OH:6])=[CH:9][C:10]([C:13]([F:16])([F:14])[F:15])=[CH:11][N:12]=1
Reactant: COC(=O)c1cc(C(F)(F)F)cnc1OC
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: COc1ncc(C(F)(F)F)cc1CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.1 %

Procedure:
To a solution of methyl 2-methoxy-5-(trifluoromethyl)nicotinate (13) (0.5 g, 2.12 mmol) dissolved in DCM was added DIBAL-H (6.38 ml, 1M in Toluene) at 0° C. The reaction mixture was stirred for 2 h at RT. Then the reaction mixture was quenched with saturated NH4Cl solution and extracted with ethyl acetate (2×25 mL). The combined organic layer was washed with water, brine, dried over sodium sulfate, and concentrated at reduced pressure to yield (2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methanol (14) as a pale yellow liquid (0.4 g, 90%).