Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]([CH3:55])([CH3:54])[C:20]([NH:22][CH2:23][CH2:24][O:25][C:26]2[CH:31]=[CH:30][C:29]([CH2:32][C:33]3[C:34]([O:41][C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)=[N:35][NH:36][C:37]=3[CH:38]([CH3:40])[CH3:39])=[C:28]([CH3:53])[CH:27]=2)=[O:21])=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>CC(O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][N:14]([C:17]([C:19]([CH3:55])([CH3:54])[C:20]([NH:22][CH2:23][CH2:24][O:25][C:26]2[CH:31]=[CH:30][C:29]([CH2:32][C:33]3[C:34](=[O:41])[NH:35][NH:36][C:37]=3[CH:38]([CH3:39])[CH3:40])=[C:28]([CH3:53])[CH:27]=2)=[O:21])=[O:18])[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(OCCNC(=O)C(C)(C)C(=O)N2CCN(C(=O)OCc3ccccc3)CC2)ccc1Cc1c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)n[nH]c1C(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: Cc1cc(OCCNC(=O)C(C)(C)C(=O)N2CCN(C(=O)OCc3ccccc3)CC2)ccc1Cc1c(C(C)C)[nH][nH]c1=O
Temperature: 50 °C
Reaction time: 48 h
Yield: 99.2 %

Procedure:
A mixture of 4-[(4-{2-[2-{[4-(benzyloxycarbonyl)-piperazin-1-yl]carbonyl}-2-(methyl)propionylamino]ethoxy}-2-methylphenyl)methyl]-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole (0.23 g), p-toluenesulfonic acid monohydrate (0.41 g) and 2-propanol (10 mL) was stirred at 50° C. for 2 days. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1) to give the title compound (0.18 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10]O)[CH:5]=[CH:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:31]N1C(=O)CCC1=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][Br:31])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: OCCCc1cccc(Br)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCCCc1cccc(Br)c1
Reaction time: 12 h
Yield: 37.3 %

Procedure:
Compound 40-2 (2.78 g) was dissolved in methylene chloride (40 ml), triphenylphosphine (3.72 g) and N-bromosuccinimide (2.53 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 2 hr, and at room temperature for 12 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (1.34 g) as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([N:15]([CH3:18])[CH:16]=[O:17])=[CH:10][C:11]=3[NH:12]2)=[CH:4][CH:3]=1.[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37]F)(=[O:28])=[O:27])=[CH:22][CH:21]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN1C(=O)CCC1.CCOC(C)=O>[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][O:1][C:2]2[CH:3]=[CH:4][C:5]3[C:6]4[C:11](=[CH:10][C:9]([N:15]([CH3:18])[CH:16]=[O:17])=[CH:8][CH:7]=4)[NH:12][C:13]=3[CH:14]=2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: CN(C=O)c1ccc2c(c1)[nH]c1cc(O)ccc12
Reactant: Cc1ccc(S(=O)(=O)OCCOCCOCCF)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)OCCOCCOCCOc2ccc3c(c2)[nH]c2cc(N(C)C=O)ccc23)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 48.7 %

Procedure:
To N-(7-hydroxy-9H-carbazol-2-yl)-N-methylformamide (45 mg, 0.187 mmol) and 2-(2-(2-fluoroethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (172 mg, 0.38 mmol) in 0.5 mL NMP was added Cs2CO3 (65 mg, 0.2 mmol). The mixture was stirred at rt for 15 h under Ar atmosphere and diluted with EtOAc (50 mL). It was washed with water (2×50 mL), 0.5 M HCl (50 mL) and brine (50 mL), and dried over MgSO4. Solvent was removed under reduced pressure and the crude product was purified with silica chromatography (hexane/EtOAc) to afford 2-(2-(2-(7-(N-methylformamido)-9H-carbazol-2-yloxy)ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (AD-CB-004 Pa-WZ01179) as a light-brown oil (48 mg, 48%). 1H NMR (400 MHz, CDCl3) δ 8.52 (s, 1H), 8.45 (s, 1H), 7.95 (d, J=8.4 Hz, 1H), 7.90 (d, J=8.8 Hz, 1H), 7.80-7.77 (m, 2H), 7.30 (d, J=8.0 Hz, 2H), 7.17 (d, J=2.4 Hz, 1H), 7.02 (d, J=2.0 Hz, 1H), 7.01 (dd, J=8.0, 2.0 Hz, 1H), 6.89 (dd, J=8.8, 2.4 Hz, 1H), 4.23 (m, 1H), 4.17 (m, 2H), 3.88 (m, 2H), 3.72-3.68 (m, 4H), 3.66-3.61 (m, 2H), 3.39 (s, 3H), 2.41 (s, 3H); MS (ESI) m/z 527 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C@H:11]2[CH2:16][O:15][C@H:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:13][O:12]2)[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=O.N.O=P(Cl)(Cl)Cl>CN(C=O)C>[F:1][C:2]1[CH:10]=[C:9]([C@H:11]2[CH2:16][O:15][C@H:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:13][O:12]2)[CH:8]=[CH:7][C:3]=1[C:4]#[N:6]
Reactant: CCCCC[C@@H]1CO[C@@H](c2ccc(C(N)=O)c(F)c2)CO1
Agent: N
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CCCCC[C@@H]1CO[C@@H](c2ccc(C#N)c(F)c2)CO1

Procedure:
A solution of 29.5 g. trans-2-fluoro-4-(5-pentyl-1,4-dioxan-2-yl)-benzamide (obtainable from the acid chloride and NH3) in 500 ml. DMF is mixed dropwise at 50°, while stirring, with 65 g. POCl3. After a further one hour stirring, one pours on to ice, works up as usual and obtains trans-2-fluoro-4-(5-pentyl-1,4-dioxan-2-yl)-benzonitrile.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:10][CH:11]([O:17][CH:18]([CH3:20])[CH3:19])[C:12]([O:14]CC)=[O:13])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[Cl:21][C:22]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:23]=1[O:24][CH2:25][C:26](O)=[O:27].C(N1C=CN=C1)(N1C=CN=C1)=O.C(N(CC)CC)C>O1CCCC1>[Cl:21][C:22]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:23]=1[O:24][CH2:25][C:26]([NH:1][C:2]1[CH:3]=[C:4]([CH2:10][CH:11]([O:17][CH:18]([CH3:19])[CH3:20])[C:12]([OH:14])=[O:13])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9])=[O:27]
Reactant: CCOC(=O)C(Cc1ccc(OC)c(N)c1)OC(C)C
Reactant: O=C(O)COc1ccc(Cl)cc1Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(CC(OC(C)C)C(=O)O)cc1NC(=O)COc1ccc(Cl)cc1Cl
Temperature: 50 °C
Reaction time: 4 h
Yield: 8.2 %

Procedure:
30 mg of Ethyl 3-(3-amino-4-methoxyphenyl)-2-isopropoxypropanoate and 20 mg of 2,4-dichlorophenoxyacetic acid were dissolved in 0.5 ml of tetrahydrofuran, and 30 mg of carbonyldiimidazole and 0.05 ml of triethylamine were added, and the mixture was stirred at 50° C. for 4 hours. The reaction mixture was then partitioned between water and ethyl acetate, and the organic layer was concentrated. The residue was dissolved in 0.6 ml of ethanol, and 0.12 ml of 5N sodium hydroxide was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was neutralized with dilute hydrochloric acid, and extracted with ethyl acetate. The organic layer was concentrated, and the residue was purified by HPLC using a reverse-phase column and a water-acetonitrile-trifluoroacetic acid elution solvent, to give 3.4 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[S:11]1[CH2:17][C:15](=[O:16])[NH:14][C:12]1=[S:13].C([O-])(=O)C.[Na+]>C(O)(=O)C>[Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[C:17]1[S:11][C:12](=[S:13])[NH:14][C:15]1=[O:16]
Reactant: O=C1CSC(=S)N1
Reactant: O=Cc1cccc(Cl)c1Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1NC(=S)SC1=Cc1cccc(Cl)c1Cl
Temperature: 0 °C
Yield: 40 %

Procedure:
A mixture of 2,3-dichlorobenzaldehyde (4.6 g, mmoles), rhodanine (3.5 g, 25 mmoles), sodium acetate (7.5 g, 91 mmoles), and acetic acid (40 ml) is stirred under an inert atmosphere and heated to reflux. After 2.5 hours the mixture is stirred into ice-water (250 ml) and the precipitate is filtered off, rinsed three times with water and dried. Recrystallization from methanol gave the pure product (2.9 g), mp 203°-204° C.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[S:24][C:23]([C:25](=O)[CH2:26][CH2:27][C:28](=O)[CH:29]([C:37]2[CH:42]=[CH:41][C:40]([S:43]([CH:46]3[CH2:48][CH2:47]3)(=[O:45])=[O:44])=[CH:39][CH:38]=2)[CH2:30][CH:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[N:22][N:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:55].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(OCC)(=O)C>[Si:1]([O:18][CH2:19][C:20]1[S:24][C:23]([C:25]2[NH:55][C:28]([CH:29]([C:37]3[CH:42]=[CH:41][C:40]([S:43]([CH:46]4[CH2:47][CH2:48]4)(=[O:44])=[O:45])=[CH:39][CH:38]=3)[CH2:30][CH:31]3[CH2:32][CH2:33][O:34][CH2:35][CH2:36]3)=[CH:27][CH:26]=2)=[N:22][N:21]=1)([C:14]([CH3:16])([CH3:15])[CH3:17])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](OCc1nnc(C(=O)CCC(=O)C(CC2CCOCC2)c2ccc(S(=O)(=O)C3CC3)cc2)s1)(c1ccccc1)c1ccccc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)(C)[Si](OCc1nnc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)s1)(c1ccccc1)c1ccccc1
Temperature: 110 °C
Reaction time: 1 h
Yield: 74.6 %

Procedure:
To a solution of 1-[5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-1,3,4-thiadiazol-2-yl]-5-[4-(cyclopropylsulfonyl)phenyl]-6-(tetrahydro-2H-pyran-4-yl)hexane-1,4-dione (168 mg) in acetic acid (2.3 mL) was added ammonium acetate (283 mg), and the mixture was stirred at 110° C. for 1 hr. After cooling to room temperature, the mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution. The reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (122 mg, yield 74%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (4:1, volume ratio).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].CCN(C(C)C)C(C)C.Cl[C:22](=[O:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24]>C1COCC1>[C:4]([C:3]1[CH:7]=[CH:8][C:9]([Cl:11])=[CH:10][C:2]=1[NH:1][C:22](=[O:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])(=[O:5])[NH2:6]
Reactant: CCOC(=O)C(=O)Cl
Reactant: NC(=O)c1ccc(Cl)cc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)Nc1cc(Cl)ccc1C(N)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.5 %

Procedure:
To a solution of 2-amino-4-chlorobenzamide (393 mg, 2.30 mmol) and DIEA (0.60 mL, 3.45 mmol) in THF (15 mL) at 0° C. was added ethyl chlorooxoacetate (0.28 mL, 2.53 mmol). The solution was allowed to warm to rt and stir for 2 h. The mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with 10-50% EtOAc/hexanes to afford ethyl 2-(2-carbamoyl-5-chlorophenylamino)-2-oxoacetate as a solid (545 mg, 88%). 1H NMR (300 MHz, DMSO-d6) δ 1.32 (t, J=6.97 Hz, 3H), 4.31 (q, J=6.97 Hz, 2H), 7.34 (d, J=8.48 Hz, 1H), 7.86-8.03 (m, 2H), 8.44 (br s, 1H), 8.62 (s, 1H), 13.24 (s, 1H)
Reaction SMILES: Cl.[CH3:2][C:3]1[S:4][C:5]2[CH:11]=[CH:10][C:9]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH:18]([O:21][C:22]1[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][C:23]=1[C:24](O)=[O:25])([CH3:20])[CH3:19]>C(#N)C.C(OCC)C>[CH:18]([O:21][C:22]1[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][C:23]=1[C:24]([N:15]1[CH2:14][CH2:13][N:12]([C:9]2[CH:10]=[CH:11][C:5]3[S:4][C:3]([CH3:2])=[N:7][C:6]=3[CH:8]=2)[CH2:17][CH2:16]1)=[O:25])([CH3:20])[CH3:19]
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: Cc1nc2cc(N3CCNCC3)ccc2s1
Agent: Cl
Solvent: CC#N
Solvent: CCOCC
Product: Cc1nc2cc(N3CCN(C(=O)c4cc(S(C)(=O)=O)ccc4OC(C)C)CC3)ccc2s1

Procedure:
Prepared in analogy to example 1.1(b) from 2-methyl-5-piperazin-1-yl-benzothiazole hydrochloride and 2-isopropoxy-5-methanesulfonyl-benzoic acid (example 2.2) in acetonitrile. Trituration in diethyl ether yields the title compound as a yellowish solid.
Reaction SMILES: [C:1]([CH:6]=[C:7]1[CH:11]2[CH2:12][CH2:13][CH:8]1[CH2:9][CH2:10]2)([O:3]CC)=[O:2].C(O)C.[H][H].[OH-].[K+]>[Pd].O>[CH:8]12[CH:7]([CH2:6][C:1]([OH:3])=[O:2])[CH:11]([CH2:10][CH2:9]1)[CH2:12][CH2:13]2
Reactant: CCOC(=O)C=C1C2CCC1CC2
Reactant: [H][H]
Agent: [Pd]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CC1C2CCC1CC2

Procedure:
A mixture containing 0.05 mole of 7-carbethoxymethylene-bicyclo[2.2.1]heptane and 5 g. of 5% palladium on carbon catalyst and 250 ml. of ethanol is stirred under hydrogen until no more hydrogen is absorbed (about 1.2 liters are absorbed). The catalyst is removed by filtration and a solution containing 0.1 mole of potassium hydroxide in 20 ml. of water is added to the filtrate. The solution is then refluxed until no more starting material is observed by thin-layer chromatographic monitoring. The solvent is then removed by evaporation under vacuum and the resulting residue dissolved in 200 ml. of water and extracted three times with ethyl ether. The remaining aqueous phase is acidified with dilute aqueous hydrochloric acid and then extracted three times with ethyl acetate. The combined organic extracts are washed with water, then dried with anhydrous magnesium sulfate and filtered. The filtrate is evaporated to dryness, under vacuum, affording bicyclo[2.2.1]hept-7-yl acetic acid.
Reaction SMILES: [CH2:1]([C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10](O)=[Se:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.[Cl:39][C:40]1[CH:46]=[CH:45][C:43]([NH2:44])=[CH:42][CH:41]=1>ClCCl>[Cl:39][C:40]1[CH:46]=[CH:45][C:43]([NH:44][C:10](=[Se:11])[C:9]2[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=2[CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:42][CH:41]=1
Reactant: OC(=[Se])c1ccccc1Cc1ccccc1
Reactant: Nc1ccc(Cl)cc1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Clc1ccc(NC(=[Se])c2ccccc2Cc2ccccc2)cc1

Procedure:
To a solution of 6 g (0.0206 mol) 2-benzylselenobenzoic acid and 2.1 g (0.0206 mol) triethylamine in 100 ml dichloromethane at 0°-5° C. is added in one portion 5.24 g (0.0206 mol) bis[2-oxo-3-oxazolidinyl]phosphoryl chloride. After stirring for 30 minutes a solution of 2.63 g (0.0206 mol) 4-chloroaniline at 0° C. is added and after 15 minutes a solution of 2.1 g (0.0206 mol) triethylamine in 30 ml dichloromethane (within 21/2 hours). The reaction mixture is then immediately extracted with 100 ml 1N aqueous hydrochloroic acid solution, 100 ml 1N caustic soda solution and 100 ml distilled water. The organic phase is dried with sodium sulfate and the solvent removed under vacuum. The residue is purified by recrystallization from 80 ml 2-propanol.
Reaction SMILES: [CH3:1][CH:2]1[C:8]2=[C:9]3[C:13](=[CH:14][CH:15]=[C:7]2[O:6][CH2:5][CH2:4][N:3]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[NH:12][CH:11]=[CH:10]3.[H-].[Na+].[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[S:30](Cl)(=[O:32])=[O:31]>CN(C=O)C>[CH3:1][CH:2]1[C:8]2=[C:9]3[C:13](=[CH:14][CH:15]=[C:7]2[O:6][CH2:5][CH2:4][N:3]1[C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[N:12]([S:30]([C:26]1[S:25][CH:29]=[CH:28][CH:27]=1)(=[O:32])=[O:31])[CH:11]=[CH:10]3
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: CC1c2c(ccc3[nH]ccc23)OCCN1C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1c2c(ccc3c2ccn3S(=O)(=O)c2cccs2)OCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.6 %

Procedure:
tert-Butyl 1-methyl-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 42, 25 mg, 0.083 mmol) was dissolved in DMF (1 mL) and sodium hydride (60% in mineral oil, 4.0 mg, 0.17 mmol) was added. The reaction mixture was stirred at room temperature for 15 minutes before 2-thiophenesulfonyl chloride (21 mg, 0.11 mmol) was added. The reaction mixture was allowed to stir at room temperature overnight. The reaction was quenched by addition of water and the crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give tert-butyl 1-methyl-8-(2-thienylsulfonyl)-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (14 mg) which was dissolved in DCM (1 mL) and TFA (1 mL) was added. The reaction mixture was stirred at room temperature for 1 hour and the solvent was removed under reduced pressure. The crude material was purified by preparative preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give the title compound (5 mg). MS m/z 349 [M+H]+.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=1)[CH:2]([CH3:4])[CH3:3].[Cl-].[Al+3].[Cl-].[Cl-].COC[C:21]([Cl:23])=O>[N+](C)([O-])=O>[Cl:23][CH2:21][C:13]1[CH:12]=[C:9]([CH:8]=[CH:7][C:6]=1[O:5][CH2:1][CH:2]([CH3:4])[CH3:3])[CH:10]=[O:11]
Reactant: COCC(=O)Cl
Reactant: CC(C)COc1ccc(C=O)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Product: CC(C)COc1ccc(C=O)cc1CCl
Temperature: 0 °C
Yield: 59.5 %

Procedure:
To a mixture of 4-isobutoxybenzaldehyde (6.9 g, 38.7 mmol), aluminum chloride (12.9 g, 96.8 mmol) and nitromethane (39 mL) was added methoxyacetyl chloride (4.1 mL, 44.5 mmol) under stirring at 0° C., and the mixture was stirred at the same temperature for 3 hr. After completion of the reaction, the reaction mixture was poured into ice water, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-4/1) to give the title compound (5.22 g, yield 60%) as colorless crystals.
Reaction SMILES: C[O-].[Na+].CO.[OH:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:18])[N:15]([CH3:17])[CH3:16])=[CH:9][CH:8]=1.[Na].[Cl:20][C:21]1[N:26]=[C:25](Cl)[CH:24]=[C:23]([CH3:28])[N:22]=1>CS(C)=O>[Cl:20][C:21]1[N:26]=[C:25]([O:6][C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14](=[O:18])[N:15]([CH3:16])[CH3:17])=[CH:11][CH:12]=2)[CH:24]=[C:23]([CH3:28])[N:22]=1
Reactant: CN(C)C(=O)Nc1ccc(O)cc1
Reactant: Cc1cc(Cl)nc(Cl)n1
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Solvent: CS(C)=O
Product: Cc1cc(Oc2ccc(NC(=O)N(C)C)cc2)nc(Cl)n1

Procedure:
4-Hydroxyphenyl-N,n-dimethylurea (14.4 grams; 0.08 mole) was mixed with a solution of sodium methylate (prepared by mixing sodium metal (1.84 grams) in 50 milliliters (ml) of methanol) and the resulting sodium 4-hydroxyphenyl-N,N-dimethylurea solution added gradually over a period of about one hour to a solution of 2,4-dichloro-6-methylpyrimidine (13.04 grams; 0.08 mole) in 70 ml. of dimethylsulfoxide. During the addition, the reaction temperature rose from about 52°C. to a temperature from between about 60° to about 65°C. The resulting reaction mixture was maintained at temperatures from between about 60° to about 70°C. for a period of about 80 minutes. Following the reaction period, the reaction mixture was poured into about 400 ml. of cold water and the resulting tan product precipitate recovered by filtration and washed with additional portions of water. The product precipitate was dissolved in boiling benzene and the resulting solution treated with activated charcoal. Approximately one-half of the solvent was removed by evaporation and the remaining portion was cooled to crystallize the product. As a result of these operations, the desired title product was obtained as a light tan crystalline solid having a melting point of 176°-178°C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:20](O)=[O:21])[CH2:10][C:11]1[C:16]([CH3:17])=[CH:15][C:14]([OH:18])=[CH:13][C:12]=1[CH3:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.Cl.[CH3:31][O:32][C:33](=[O:37])[C@H:34]([CH3:36])[NH2:35]>C(Cl)Cl>[CH3:2][C:1]([CH3:3])([O:5][C:6]([NH:8][CH:9]([C:20]([NH:35][C@@H:34]([C:33]([O:32][CH3:31])=[O:37])[CH3:36])=[O:21])[CH2:10][C:11]1[C:12]([CH3:19])=[CH:13][C:14]([OH:18])=[CH:15][C:16]=1[CH3:17])=[O:7])[CH3:4]
Reactant: COC(=O)[C@H](C)N
Reactant: Cc1cc(O)cc(C)c1C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)[C@@H](C)NC(=O)C(Cc1c(C)cc(O)cc1C)NC(=O)OC(C)(C)C
Temperature: -30 °C
Reaction time: 16 h
Yield: 98.9 %

Procedure:
Racemic t-butoxycarbonyl 2,6-dimethyltyrosine (3.9 g, 10 mmoles) was dissolved in 30 ml of CH2Cl2 by adding 1.12 ml (10 mmoles) of NMM. After bringing this mixture to reflux it was cooled to -30° C. and 1.32 ml (10 mmoles) of IBCF were added to this stirred solution. The temperature was allowed to rise to -15° C. and then lowered to -50° C. (D) alanine methyl ester hydrochloride (1.54 g, 11 mmoles) was added to the solution followed by 1.3 ml (11 mmoles) of NMM. The mixture was allowed to warm to room temperature and stand for 16 hours. The majority of the CH2Cl2 was removed under reduced pressure. Ethyl acetate (200 ml) was added and this solution was washed twice with 100 ml portions of 0.5 molar KHSO4, once with 100 ml of H2O and dried over MgSO4. Removal of all solvent gave 3.9 g of the mixture of diastereomers. Recrystallization of this material from Skelly B/CH2Cl2 produced 1.6 g (4.2 mmoles) of diastereomer F. Removal of the solvent from the filtrate gave 1.3 g (3.3 mmoles) of diastereomer S contaminated by less than 10% of diastereomer F.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]([O:22][CH3:23])=[O:21])[CH:18]=2)[CH:13]=[CH:12]1.[Cl-].C([Al+]CC)C>ClCCCl>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([C:13]2[C:14]3[C:19](=[CH:18][C:17]([C:20]([O:22][CH3:23])=[O:21])=[CH:16][CH:15]=3)[NH:11][CH:12]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Agent: CC[Al+]CC
Agent: [Cl-]
Solvent: ClCCCl
Product: COC(=O)c1ccc2c(C(=O)c3ccc(F)cc3)c[nH]c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.1 %

Procedure:
A solution of 4-fluorobenzoyl chloride 43b (2 mmol, 0.24 mL) in 8 mL of DCE was added dropwise to an ice-cold solution of methyl 1H-indole-6-carboxylate 43a (1.43 mmol, 250 mg) and diethylaluminum chloride (1 M in hexanes, 1.86 mmol, 1.86 mL) in 8 mL of DCE. After 2 h at 0° C., the mixture was warmed to room temperature and was stirred overnight. To the mixture was added pH 7 buffer; the resulting solid was filtered and washed with CH2Cl2 to give 162 mg (38%) of methyl 3-(4-fluorobenzoyl)-1H-indole-6-carboxylate 43c. MS m/z (M+H+) 298.0.