Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([OH:11])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].[CH3:15][O:16][C:17](=[O:37])[CH2:18][O:19][C:20]1[C:25]([C:26](=[O:28])[CH3:27])=[CH:24][CH:23]=[C:22]([O:29][CH2:30][CH2:31][CH2:32]Br)[C:21]=1[CH2:34][CH2:35][CH3:36].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C)C=O>[CH3:15][O:16][C:17](=[O:37])[CH2:18][O:19][C:20]1[C:25]([C:26](=[O:28])[CH3:27])=[CH:24][CH:23]=[C:22]([O:29][CH2:30][CH2:31][CH2:32][O:11][C:6]2[CH:5]=[CH:4][C:3]([C:12](=[O:14])[CH3:13])=[C:2]([OH:1])[C:7]=2[CH2:8][CH2:9][CH3:10])[C:21]=1[CH2:34][CH2:35][CH3:36]
Reactant: CCCc1c(OCCCBr)ccc(C(C)=O)c1OCC(=O)OC
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCCc1c(OCCCOc2ccc(C(C)=O)c(OCC(=O)OC)c2CCC)ccc(C(C)=O)c1O
Yield: 32.7 %

Procedure:
A mixture of 1.72 g of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, 3.43 g of [6-acetyl-3-(3-bromopropoxy)-2-propylphenoxy]acetic acid methyl ester, 2.44 g of anhydrous potassium carbonate in 50 ml of anhydrous acetone and 25 ml of anhydrous dimethylformamide was stirred at reflux for 18 hours. The reaction mixture was concentrated in vacuo and the residue was purified by high pressure liquid chromatography to give 1.45 g (33%) of [6-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-2-propylphenoxy]acetic acid methyl ester as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:34]=[CH:33][C:5]2[N:6]=[C:7]([O:9][C:10]3[C:15]([Cl:16])=[CH:14][C:13]([NH:17][S:18]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=4[Cl:31])(=[O:20])=[O:19])=[CH:12][C:11]=3[Cl:32])[S:8][C:4]=2[CH:3]=1.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>>[Cl:31][C:22]1[CH:23]=[C:24]([C:27]([F:28])([F:30])[F:29])[CH:25]=[CH:26][C:21]=1[S:18]([NH:17][C:13]1[CH:14]=[C:15]([Cl:16])[C:10]([O:9][C:7]2[S:8][C:4]3[CH:3]=[C:2]([NH:1][S:36]([CH3:35])(=[O:38])=[O:37])[CH:34]=[CH:33][C:5]=3[N:6]=2)=[C:11]([Cl:32])[CH:12]=1)(=[O:20])=[O:19]
Reactant: Nc1ccc2nc(Oc3c(Cl)cc(NS(=O)(=O)c4ccc(C(F)(F)F)cc4Cl)cc3Cl)sc2c1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)Nc1ccc2nc(Oc3c(Cl)cc(NS(=O)(=O)c4ccc(C(F)(F)F)cc4Cl)cc3Cl)sc2c1

Procedure:
2-Chloro-N-[3,5-dichloro-4-(6-methanesulfonylamino-benzothiazol-2-yloxy)-phenyl]-4-trifluoromethyl-benzenesulfonamide was synthesized from N-[4-(6-Amino-benzothiazol-2-yloxy)-3,5-dichloro-phenyl]-2-chloro-4-trifluoromethyl-benzenesulfonamide (439) and methanesulfonyl chloride (Aldrich) in a similar manner as described in Examples 70-91. 1H NMR (400 MHz, DMSO-d6) δ 11.64 (s, 1H), 9.87 (s, 1H), 8.38 (d, J=8.3 Hz, 1H), 8.22 (s, 1H), 8.00 (d, J=8.2 Hz, 1H), 7.83 (d, J=1.8 Hz, 1H), 7.62 (d, J=8.8 Hz, 1H), 7.31 (s, 2H), 7.23 (dd, J=8.8, 1.5 Hz, 1H). MS (EI): m/z 644 (M−H).
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]2[CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:19][CH:18]=2)=[CH:5][CH:4]=1.[CH2:27](Br)[CH2:28][CH3:29]>>[ClH:1].[CH2:27]([N:12]1[CH2:13][CH2:14][C@@H:9]([C:6]2[CH:7]=[CH:8][C:3]([F:2])=[CH:4][CH:5]=2)[C@H:10]([CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:21][CH:22]=2)[CH2:11]1)[CH2:28][CH3:29]
Reactant: CC(C)(C)c1ccc(OC[C@@H]2CNCC[C@H]2c2ccc(F)cc2)cc1
Reactant: CCCBr
Agent: Cl
Product: CCCN1CC[C@@H](c2ccc(F)cc2)[C@H](COc2ccc(C(C)(C)C)cc2)C1

Procedure:
trans-1-propyl-4-(4-fluorophenyl)-3-(4-t-butylphenoxymethyl)-piperidine hydrochloride M.p. 221.1° C. was prepared exactly as described in example 1 from trans-4-(4-fluorophenyl)-3-(4-t-butylphenoxymethyl)-piperidine hydrochloride and propyl bromide by refluxing for 96 hours.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH:4]([OH:32])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:31]=[CH:30][C:14]2[NH:15][C:16]([CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1.CO.[OH-].[Li+].Cl>CCOC(C)=O.O>[OH:32][CH:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:31]=[CH:30][C:14]2[NH:15][C:16]([CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:28])([F:29])[F:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)[C:3]([OH:33])=[O:2]
Reactant: COC(=O)C(O)c1ccccc1-c1ccc2[nH]c(COc3ccc(C(F)(F)F)cc3)nc2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)C(O)c1ccccc1-c1ccc2[nH]c(COc3ccc(C(F)(F)F)cc3)nc2c1
Reaction time: 12 h
Yield: 97.8 %

Procedure:
To a solution of hydroxy-{2-[2-(4-trifluoromethyl-phenoxymethyl)-1H-benzoimidazol-5-yl]-phenyl}-acetic acid methyl ester (0.312 g, 0.684 mmol) in mixed solvent (14 mL, MeOH: H2O=3:1) at rt was added lithium hydroxide (LiOH) (0.098 g, 4.10 mmol). After stirring for 12 hours, the reaction mixture was diluted with EtOAc and acidified with aqueous 3N HCl. The organic layer was washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to afford the title compound as a white solid (0.296 g, 98%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:14][C:15]([CH3:30])([CH3:29])[C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:24]([CH3:28])([CH3:27])[C:25]#[CH:26])[CH2:20][CH2:19]1)=[O:17].C(N(CC)CC)C>O1CCCC1.C(OCC)(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:4]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=[C:2]([C:26]#[C:25][C:24]([N:21]2[CH2:20][CH2:19][N:18]([C:16](=[O:17])[C:15]([CH3:30])([CH3:29])[CH3:14])[CH2:23][CH2:22]2)([CH3:28])[CH3:27])[CH:3]=1
Reactant: C#CC(C)(C)N1CCN(C(=O)C(C)(C)C)CC1
Reactant: Brc1cccc(-c2ccccc2)c1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)N1CCN(C(C)(C)C#Cc2cccc(-c3ccccc3)c2)CC1
Reaction time: 0.25 h
Yield: 61.7 %

Procedure:
1.05 g (4.5 mmol) of 3-bromobiphenyl and 0.9 g (3.6 mmol) of 1-(2,2-dimethylpropanoyl)-4-(1,1-dimethylprop-2-yn-1-yl)piperazine, prepared in step 5.1., 0.75 ml (5.38 mmol) of triethylamine and 0.028 g (0.11 mmol) of triphenylphosphine are dissolved in 8 ml of tetrahydrofuran. Under an argon atmosphere, 0.126 g (0.18 mmol) of the dichloride complex of bis(triphenylphosphine) palladium is added. The mixture is stirred for 15 minutes and then 0.014 g (0.07 mmol) of cuprous iodide is added. The mixture is stirred at ambient temperature for 4 hours and then at 60° C. overnight. After cooling to temperature it is diluted with 25 ml of ethyl acetate and filtered on paper. The solid is rinsed with 4 times 10 ml of ethyl acetate. 4 g of silica are added to the filtrate, which is evaporated to dryness. The residue is purified by chromatography on silica gel, eluting with a 90/10 then 80/20 and 70/30 mixture of cyclohexane and ethyl acetate, to give 0.90 g (2.22 mmol) of product in the form of a orange-colored oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[CH:6][C:5]=1[CH3:19].[Br:21]N1C(=O)CCC1=O.C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>CCOCC>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[CH:6][C:5]=1[CH2:19][Br:21]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(Oc2ccc(OC)cc2)cc1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOCC
Product: COC(=O)c1ccc(Oc2ccc(OC)cc2)cc1CBr
Temperature: 25 °C
Yield: 82.9 %

Procedure:
To a mixture of 4-(4-Methoxy-phenoxy)-2-methyl-benzoic acid methyl ester (2.8 grams, 10.3 mmol), N-bromosuccinimide (2.14 grams, 12 mmol) and carbon tetrachloride (12 mL) was added a crystal of benzoyl peroxide. The mixture was heated to reflux for 2 hours, and an additional 2.1 grams of N-bromosuccinimide was added. After refluxing for an additional 4 hours, the mixture was cooled to room temperature, diluted with ether, and the organic phase was washed with water, dried over magnesium sulfate, filtered and concentrated, affording 3 grams of 2-Bromomethyl-4-(4-methoxy-phenoxy)-benzoic acid methyl ester as a colorless oil. 1H NMR (CDCl3, 500 MHz): δ 7.96 (d, 1H, J=8.8 Hz), 7.05-6.90 (m, 6H), 6.87 (dd, 1H, J=2.6, 8.3 Hz), 4.92 (s, 2H), 3.93 (s, 3H), 3.85(s, 3H) ppm.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=4[F:29])=[C:13]([O:31][CH3:32])[CH:12]=3)[C:3]=12.Cl.O1CCOCC1>C(O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[NH:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:27])([F:28])[F:26])=[CH:21][C:20]=4[F:29])=[C:13]([O:31][CH3:32])[CH:12]=3)[C:3]=12
Reactant: COc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ncnc(N)c23)ccc1NC(=O)c1ccc(C(F)(F)F)cc1F
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: COc1cc(-c2n[nH]c3ncnc(N)c23)ccc1NC(=O)c1ccc(C(F)(F)F)cc1F
Temperature: 50 °C
Yield: 44.6 %

Procedure:
A mixture of N1-[4-(4-amino-1-trityl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxyphenyl]-2-fluoro-4-trifluoromethylbenzamide (2.10 g, 1.75 mmol), 6 N aqueous hydrochloric acid (10 mL), p-dioxane (10 mL) and ethanol (8 mL) was heated at 50° C. for 6 hours. The mixture was filtered and the solid was washed with ethanol, dried in a vacuum oven over the weekend, and purified by flash column chromatography on silica to provide N1-[4-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxyphenyl]-2-fluoro-4-trifluoromethylbenzamide (0.35 g, 0.78 mmol). The filtrate was concentrated and purified by flash column chromatography on silica and preparative HPLC to provide the same product N1-[4-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxyphenyl]-2-fluoro-4-trifluoromethylbenzamide (0.67 g, 1.51 mmol) as a white solid: 1H NMR (DMSO-d6, 400 MHz) δ 13.58 (s, 1H), 9.90 (dd, 1H), 8.30(d, 1H), 8.23 (s, 1H), 8.05 (t, 1H), 7.90 (d, 1H), 7.75 (d, 1H), 7.36 (s, 1H), 7.24 (d, 1H), 3.94 (s, 3H); MS: MH+ 447.
Reaction SMILES: [O:1]=[C:2]([CH3:15])[CH2:3][CH:4]([C:10](OCC)=[O:11])[C:5](OCC)=[O:6].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[OH:6][CH2:5][CH:4]([CH2:3][CH:2]([OH:1])[CH3:15])[CH2:10][OH:11]
Reactant: CCOC(=O)C(CC(C)=O)C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(O)CC(CO)CO
Temperature: 25 °C
Yield: 100.1 %

Procedure:
A solution of 11.4 g of diethyl 2-oxopropylmalonate in 30 ml of tetrahydrofuran was added dropwise under ice-cooling over 20 minutes to a suspension of 5.00 g of lithium aluminum hydride in 100 ml of tetrahydrofuran. The reaction fluid was stirred for an hour under ice-cooling and for 4.5 hours at room temperature, and 10 ml of water was added thereto dropwise under ice-cooling over 20 minutes. The reaction fluid was refluxed for an hour and filtrated. The unfiltered solid was suspended in 200 ml of ethanol and the suspension was refluxed. The suspension was filtrated, and the filtrate combined with the foregoing filtrate was concentrated under a reduced pressure to obtain 7.08 g of 2-hydroxymethyl-1,4-pentanediol as a colorless oily matter.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[NH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]1.CCN(C(C)C)C(C)C>C(O)CCC>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:9][CH:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(N)C1
Reactant: Clc1cc(Cl)ncn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N1CCCC(Nc2cc(Cl)ncn2)C1

Procedure:
A solution of 4,6-dichloropyrimidine (0.1 g, 0.671 mmol), 3-amino-Boc-piperidine (0.16 g, 0.80 mmol) and DIPEA (0.086 g, 6.71 mmol) in n-butanol (5.0 mL) was heated in a pressure tube (120° C., 12 h). The solution was cooled, was quenched with water (2 mL) and was extracted with EtOAc (2×15 mL). The combined EtOAc extract was washed with water (5 mL), brine (5 mL), was dried over Na2SO4 and was concentrated under reduced pressure to give tert-butyl 3-(6-chloropyrimidin-4-ylamino)piperidine-1-carboxylate, which was dried under high vacuum and was used as such for next step without further purification.
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([CH:12]=NC(C)(C)C)[CH:6]=1)=[O:4].[CH3:18][C:19]([CH3:22])([NH2:21])[CH3:20].Cl.CC([OH:27])C>>[ClH:1].[CH3:18][C:19]([NH:21][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([CH:6]=1)[CH:12]=[O:27])=[O:4])([CH3:22])[CH3:20]
Reactant: CC(C)(C)N
Reactant: CC(C)(C)N=Cc1cc(C(=O)CCl)ccc1O
Reactant: CC(C)O
Agent: Cl
Product: CC(C)(C)NCC(=O)c1ccc(O)c(C=O)c1
Temperature: 25 °C

Procedure:
2-Chloro-1-[3-[[(1,1-dimethylethyl)imino]methyl]-4-hydroxyphenyl]ethanone (10 g) is suspended in 2-propanol (60 ml) with stirring at room temperature under an inert atmosphere. This slurry is treated with 1,1-dimethylethanamine (16.4 ml) and heated at reflux for 1 hour then treated with a mixture of 12M hydrochloric acid (13.0 ml) and 2-propanol (20 ml). The reaction mixture is allowed to cool to room temperature and stir for an additional 18 hours. Filtration of the reaction mixture affords (6.2 g) of 5-[[(1,1-dimethylethyl) amino]acetyl]-2-hydroxybenzaldehyde hydrochloride after washing with diethylether (50 ml) and drying in vacuo at 50°.
Reaction SMILES: C(N(C(C)C)C(C)C)C.[F:10][C:11]([F:24])([F:23])[S:12]([O:15]S(C(F)(F)F)(=O)=O)(=[O:14])=[O:13].[CH:25]([N:28]([CH:44]([CH3:46])[CH3:45])[C:29](=[O:43])[CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35](O)=[C:34]([C:39]#[N:40])[C:33]=1[C:41]#[N:42])([CH3:27])[CH3:26]>C(#N)C>[CH:44]([N:28]([CH:25]([CH3:27])[CH3:26])[C:29](=[O:43])[CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([O:15][S:12]([C:11]([F:24])([F:23])[F:10])(=[O:14])=[O:13])=[C:34]([C:39]#[N:40])[C:33]=1[C:41]#[N:42])([CH3:46])[CH3:45]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CC(C)N(C(=O)COc1ccc(O)c(C#N)c1C#N)C(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)N(C(=O)COc1ccc(OS(=O)(=O)C(F)(F)F)c(C#N)c1C#N)C(C)C

Procedure:
0.58 ml of ethyl diisopropylamine and 0.59 ml of trifluoro-methanesulfonic anhydride were added to a solution of 900 mg of the product of Stage A in 50 ml of acetonitrile and the reaction medium was refluxed for one hour. Then, the solvent was evaporated under reduced pressure and the crude product obtained was chromatographed on silica, eluting with a cyclohexane-ethyl acetate mixture (50-50) to obtain 600 mg of the expected product.
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[C:6](O)=[N:7][C:8]([S:11][CH3:12])=[N:9][CH:10]=1.O=P(Cl)(Cl)[Cl:21].CC(=O)OCC>[N+](C)(C)(C)C.[Cl-].CC#N>[Cl:21][C:6]1[C:5]([O:4][C:3]2[CH:14]=[CH:15][C:16]([F:18])=[CH:17][C:2]=2[F:1])=[CH:10][N:9]=[C:8]([S:11][CH3:12])[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CSc1ncc(Oc2ccc(F)cc2F)c(O)n1
Agent: C[N+](C)(C)C
Agent: [Cl-]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CSc1ncc(Oc2ccc(F)cc2F)c(Cl)n1
Temperature: 0 °C
Yield: 70.6 %

Procedure:
The title compound of step 1 (5.30 g, 19.63 mmol), POCl3 (18.06 g, 117.78 mmol), (Me)4NCl (3.23 g, 29.47 mmol) in dry CH3CN (60 mL) was refluxed for 12 h. The mixture was poured into ice-water (50 mL) and subjected to EA extractive work up. Concentration under vacuum gave impure title compound (4.0 g), which was carried on to the next step.
Reaction SMILES: [CH:1]([C:4]1[C:19]([O:20][C:21]2([CH3:32])[CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22]2)=[CH:18][C:7]2[N:8]3[C@@H:13]([CH3:14])[C:12](=[O:15])[NH:11][N:10]=[C:9]3[CH2:16][O:17][C:6]=2[CH:5]=1)([CH3:3])[CH3:2].[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34]>C(Cl)Cl>[F:36][C:35]([F:38])([F:37])[C:33]([OH:39])=[O:34].[CH:1]([C:4]1[C:19]([O:20][C:21]2([CH3:32])[CH2:22][NH:23][CH2:24]2)=[CH:18][C:7]2[N:8]3[C@@H:13]([CH3:14])[C:12](=[O:15])[NH:11][N:10]=[C:9]3[CH2:16][O:17][C:6]=2[CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1cc2c(cc1OC1(C)CN(C(=O)OC(C)(C)C)C1)N1C(=NNC(=O)[C@@H]1C)CO2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1cc2c(cc1OC1(C)CNC1)N1C(=NNC(=O)[C@@H]1C)CO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
To a solution of (S)-tert-butyl 3-((8-isopropyl-1-methyl-2-oxo-1,2,3,5-tetrahydrobenzo[5,6][1,4]oxazino[3,4-c][1,2,4]triazin-9-yl)oxy)-3-methylazetidine-1-carboxylate (enantiomer 1, SFC (Table 1, Method 24), Rt=8.741 min., 0.095 g, 0.213 mmol) in DCM (3 mL) was added TFA (0.5 mL) and the mixture was stirred at ambient temperature for 2 h. The solvent was removed in vacuo to give (S)-8-isopropyl-1-methyl-9-((3-methylazetidin-3-yl)oxy)-3,5-dihydrobenzo[5,6][1,4]oxazino[3,4-c][1,2,4]-triazin-2(1H)-one trifluoroacetic acid (Example #121-1, Enantiomer 1, SFC (Table 1, Method 24), Rt=3.745 min, 0.085 g, 97%). LC/MS (Table 1, Method 5) Rt=2.175 min.; MS m/z: 345 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][C:10]([F:13])([F:12])[F:11])[C:7]2[CH:14]=[CH:15][CH:16]=[CH:17][C:6]=2[C:5]2[CH:18]=[CH:19][CH:20]=[CH:21][C:4]=2[C@@H:3]1[NH:22][C:23]([C@@H:25]([O:27][C:28](=O)[O:29]C1C=CC([N+]([O-])=O)=CC=1)[CH3:26])=[O:24].[F:40][C:41]([F:48])([C:44]([F:47])([F:46])[F:45])[CH2:42][NH2:43]>ClCCl.C(OC(=O)C)C>[O:1]=[C:2]1[N:8]([CH2:9][C:10]([F:12])([F:13])[F:11])[C:7]2[CH:14]=[CH:15][CH:16]=[CH:17][C:6]=2[C:5]2[CH:18]=[CH:19][CH:20]=[CH:21][C:4]=2[C@@H:3]1[NH:22][C:23]([C@@H:25]([O:27][C:28](=[O:29])[NH:43][CH2:42][C:41]([F:48])([F:40])[C:44]([F:47])([F:46])[F:45])[CH3:26])=[O:24]
Reactant: NCC(F)(F)C(F)(F)F
Reactant: C[C@H](OC(=O)Oc1ccc([N+](=O)[O-])cc1)C(=O)N[C@@H]1C(=O)N(CC(F)(F)F)c2ccccc2-c2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C[C@H](OC(=O)NCC(F)(F)C(F)(F)F)C(=O)N[C@@H]1C(=O)N(CC(F)(F)F)c2ccccc2-c2ccccc21
Yield: 86 %

Procedure:
0.065 g (0.12 mmol) carbonic acid 4-nitro-phenyl ester (S)-1-[(S)-6-oxo-5-(2,2,2-trifluoro-ethyl)-6,7-dihydro-5H-dibenzo[b,d]azepin-7-ylcarbamoyl]-ethyl ester and 0.26 ml 2,2,3,3,3. pentafluoropropylamine were stirred at room temperature over night. Chromatography on silicagel with dichloromethane/ethylacetate (100-40/0-60) yielded 0.06 g (86%) (2,2,3,3,3-Pentafluoro-propyl)-carbamic acid (S)-1-[(S)-6-oxo-5-(2,2,2-trifluoro-ethyl)-6,7-dihydro-5H-dibenzo[b,d]azepin-7-ylcarbamoyl]-ethyl ester as white foam, MS: m/e: 554.3 (M+H+), [α] 589=−4.40° (0.75% in CHCl3).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]#[N:12])=[C:6]([F:13])[CH:5]=1.Br[CH2:15][CH2:16]Br>CN(C=O)C.C1COCC1.CCOC(C)=O>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:11]#[N:12])[CH2:16][CH2:15]2)=[C:6]([F:13])[CH:5]=1
Reactant: BrCCBr
Reactant: N#CCc1ccc(Br)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#CC1(c2ccc(Br)cc2F)CC1

Procedure:
To a slurry of sodium hydride (60% dispersion in mineral oil, 0.82 g, 20.6 mmol) in DMF (20 mL) cooled to 0° C. was added a solution of (4-bromo-2-fluoro-phenyl)-acetonitrile (2.0 g, 9.35 mmol) from Step 1 above dissolved in THF (10 mL). The reaction was stirred till gas evolution ceased, and then 1,2-dibromoethane (1.8 mL, 20.6 mmol) was added slowly. The reaction was stirred for 30 minutes, and then diluted with 100 mL EtOAc. The solids were removed by filtration, and the organic layer was washed with 100 mL water. The organic layer was dried over MgSO4, and then filtered. The mother liquor was concentrated by rotary evaporation, and the product was distilled under high vacuum (0.3 torr, 45° C.). Yield: 0.98 g, 44%.
Reaction SMILES: [CH2:1](CN)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10](Cl)(=[O:13])[CH:11]=[CH2:12].[CH2:15]([N:17](CC)CC)C>CCOCC>[CH2:1]([N:17]([CH3:15])[C:10](=[O:13])[CH:11]=[CH2:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCc1ccccc1
Reactant: C=CC(=O)Cl
Reactant: CCN(CC)CC
Solvent: CCOCC
Product: C=CC(=O)N(C)Cc1ccccc1
Yield: 69 %

Procedure:
A quantity of 121 g of N-benzylmethylamine was reacted with 100 g of acryloyl chloride in the presence of 111 g of triethylamine in ether at 0° C. to 25° C. for 16 hours. The product was filtered, the solvent was removed, and N-benzyl-N-methylacrylamide was isolated in 69% yield by distillation under vacuum Cop 83°-85° C./0.04 mm--Hg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=[O:9])[CH:3]=1.[CH2:10]([S:12]Cl)[CH3:11].Cl>C1(C)C=CC=CC=1>[CH2:10]([S:12][C:3]1[C:4](=[O:9])[O:5][C:6]([CH3:8])=[CH:7][C:2]=1[OH:1])[CH3:11]
Reactant: CCSCl
Reactant: Cc1cc(O)cc(=O)o1
Agent: Cl
Solvent: Cc1ccccc1
Product: CCSc1c(O)cc(C)oc1=O
Temperature: 25 °C

Procedure:
A mixture of 37.2 g. (0.295 mole) of 4-hydroxy-6-methyl-2-pyrone and 28.4 g. (0.295 mole) of ethanesulfenyl chloride in 900 ml. of toluene was heated under reflux with stirring at 75°C. for two hours, during which time hydrogen chloride evolved. The reaction mixture was cooled to room temperature and filtered to remove 24.2 g. of a solid (m. 170°-172°C. - probably a mixture of starting pyrone and an unknown substance). The filtrate was concentrated to give 13.3 g. (25 percent) of the product as a white solid, m. 94°-95°C. Recrystallization from cyclohexane gave the pure product as white crystals, m. 101°-102°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.Cl[C:24](Cl)([O:26]C(=O)OC(Cl)(Cl)Cl)Cl.[N:35]1([CH2:41][CH2:42][CH:43]([OH:47])[CH2:44][CH2:45][CH3:46])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:24](=[O:26])[O:47][CH:43]([CH2:42][CH2:41][N:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)[CH2:44][CH2:45][CH3:46])=[CH:18][CH:17]=1
Reactant: CCCC(O)CCN1CCCCC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(CCN1CCCCC1)OC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1
Yield: 66.5 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (77 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 1-piperidino-3-hexanol (48 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, and the extract was washed with water and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (57 mg, yield 58%).
Reaction SMILES: [Cl:1]C[C@H:3]1[C:7]2=[C:8]3[C:12](=[C:13](O)[CH:14]=[C:6]2[N:5](C(C2NC4C(C=2)=CC(NC(C2OC5C(OC)=CC=CC=5C=2)=O)=CC=4)=O)[CH2:4]1)[NH:11][C:10]([C:16]([F:19])([F:18])[F:17])=[C:9]3[C:20]([O:22]C)=[O:21].OCCN1CCNCC1>>[ClH:1].[F:19][C:16]([F:17])([F:18])[C:10]1[NH:11][C:12]2[C:8]([C:9]=1[C:20]([OH:22])=[O:21])=[C:7]1[CH2:3][CH2:4][NH:5][C:6]1=[CH:14][CH:13]=2
Reactant: COC(=O)c1c(C(F)(F)F)[nH]c2c(O)cc3c(c12)[C@H](CCl)CN3C(=O)c1cc2cc(NC(=O)c3cc4cccc(OC)c4o3)ccc2[nH]1
Agent: OCCN1CCNCC1
Product: Cl
Product: O=C(O)c1c(C(F)(F)F)[nH]c2ccc3c(c12)CCN3

Procedure:
Methyl (1S)-1-chloromethyl-5-[4-(2-hydroxyethyl)piperazin-1-ylcarbonyl)oxy-3-[5-(7-methoxybenzofuran-2-ylcarbonyl)amino]-1H-indol-2-ylcarbonyl]-7-trifluoromethyl-1,2,3,6-tetrahydropyrrolo[3,2-e]indole-8-carboxylate hydrochloride was prepared by using 25.6 mg (37 μmol) of methyl (1S)-1-chloromethyl-5-hydroxy-3-[5-(7-methoxybenzofuran-2-ylcarbonyl)amino-1H-indol-2-ylcarbonyl]-7-trifluoromethyl-1,2,3,6-tetrahydropyrrolo[3,2-e]indole-8-carboxylate and 6.8 μl (56 μmol) of 1-(2-hydroxyethyl)piperazine in the same manner as in Example 46 in a yield of 22.2 mg (69%).