Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C:9]1[C:10]([C:18]([O:20][CH3:21])=[O:19])=[N:11][C:12]([CH2:15][O:16][CH3:17])=[CH:13][CH:14]=1)=O)(C)(C)C.FC(F)(F)C(O)=O.C([O-])([O-])=O.[Na+].[Na+]>ClCCl>[CH3:21][O:20][C:18]([C:10]1[C:9]([NH2:8])=[CH:14][CH:13]=[C:12]([CH2:15][O:16][CH3:17])[N:11]=1)=[O:19]
Reactant: COCc1ccc(NC(=O)OC(C)(C)C)c(C(=O)OC)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCc1ccc(N)c(C(=O)OC)n1
Temperature: 50 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
To a stirred solution of methyl 3-(tert-butoxycarbonylamino)-6-(methoxymethyl)picolinate (695 mg, 2.35 mmol) at r.t. in dichloromethane (10 ml) under an argon atmosphere was added 2,2,2-trifluoroacetic acid (903 μl, 11.7 mmol) in one portion. The mixture was stirred at 50° C. overnight, then cooled to r.t. and treated carefully with 10% aq. Na2CO3 (10 ml). The aqueous solution was extracted with CH2Cl2 (10 ml). The combined organics were washed with brine (10 ml), dried over MgSO4, filtered and concentrated to leave the product as a light brown solid (424 mg, 92%) which was used for the next step without further purification.
Reaction SMILES: Br[CH:2]([CH:5]=O)[CH:3]=[O:4].C([O-])(=O)C.[Na+].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([NH:26][C:27]([NH2:29])=[S:28])[CH:17]=[CH:18][C:19]=1[N:20]1[CH:24]=[C:23]([CH3:25])[N:22]=[CH:21]1>>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([NH:26][C:27]2[S:28][C:2]([CH:3]=[O:4])=[CH:5][N:29]=2)[CH:17]=[CH:18][C:19]=1[N:20]1[CH:24]=[C:23]([CH3:25])[N:22]=[CH:21]1
Reactant: O=CC(Br)C=O
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(C)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Product: COc1cc(Nc2ncc(C=O)s2)ccc1-n1cnc(C)c1
Yield: 56 %

Procedure:
The title compound was prepared in analogy to example 1 step e) from 78 mg (0.5 mmol) bromomalonaldehyde, 82 mg (1 mmol) sodium acetate and 131 mg (0.5 mmol) [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea. The solvent was evaporated. The reaction was diluted with water and extracted twice with ethyl acetate and twice with methylene chloride/methanol 9/1. The combined organic layers were washed with brine, dried over sodium sulphate, filtered and the solvent was evaporated under reduced pressure. The crude product was stirred diethyl ether to yield 88 mg (56%) of 2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-thiazole-5-carbaldehyde as a yellow solid. MS ISP (m/e): 315.1 (100) (M+H)+. 1H NMR (DMSO-D6, 250 MHz): δ (ppm)=11.35 (br s, 1H), 9.80 (s, 1H), 8.27 (s, 1H), 7.70 (s, 1H), 7.55 (s, 1H), 7.38 (d, 1H), 7.33 (d, 1H), 7.07 (s, 1H), 3.82 (s, 3H), 2.15 (s, 3H).
Reaction SMILES: Cl.[Cl:2][CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[CH:5]=1.[CH3:18][C:19]1[NH:20][CH:21]=[CH:22][N:23]=1>>[ClH:2].[Cl:17][C:12]1[CH:11]=[C:10]([C:6]2[CH:5]=[C:4]([CH2:3][N:20]3[CH:21]=[CH:22][N:23]=[C:19]3[CH3:18])[CH:9]=[CH:8][N:7]=2)[CH:15]=[CH:14][C:13]=1[Cl:16]
Reactant: ClCc1ccnc(-c2ccc(Cl)c(Cl)c2)c1
Reactant: Cc1ncc[nH]1
Agent: Cl
Product: Cc1nccn1Cc1ccnc(-c2ccc(Cl)c(Cl)c2)c1

Procedure:
The title compound, MS: m/e=317.0 (M+) was obtained as a beige solid (51% yield) by the reaction of 4-chloromethyl-2-(3,4-dichloro-phenyl)-pyridine hydrochloride (1:1) with 2-methylimidazole, using sodium hydride and triethylamine as base followed by formation of the hydrochloride salt.
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH:11]1[N:16]2[C:17]3[CH:18]=[CH:19][CH:20]=[C:21]([F:24])[C:22]=3[CH:23]=[C:15]2[C:14]2[N:25]=[C:26]([C:29]3[C:30]([N:49]([CH3:54])[S:50]([CH3:53])(=[O:52])=[O:51])=[CH:31][C:32]4[O:36][C:35]([C:37]5[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=5)=[C:34]([C:44]([NH:46][CH3:47])=[O:45])[C:33]=4[CH:48]=3)[CH:27]=[CH:28][C:13]=2[O:12]1)C1C=CC=CC=1>CO.[Pd]>[F:24][C:21]1[C:22]2[CH:23]=[C:15]3[C:14]4[N:25]=[C:26]([C:29]5[C:30]([N:49]([CH3:54])[S:50]([CH3:53])(=[O:52])=[O:51])=[CH:31][C:32]6[O:36][C:35]([C:37]7[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=7)=[C:34]([C:44]([NH:46][CH3:47])=[O:45])[C:33]=6[CH:48]=5)[CH:27]=[CH:28][C:13]=4[O:12][CH:11]([CH2:10][CH2:9][OH:8])[N:16]3[C:17]=2[CH:18]=[CH:19][CH:20]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3C(CCOCc3ccccc3)O4)cc12
Agent: [Pd]
Solvent: CO
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3C(CCO)O4)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.8 %

Procedure:
To a solution of 5-(6-(2-(benzyloxy)ethyl)-11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (85 mg, 0.11 mmol) in MeOH (3 mL) was added Pd/C (30 mg, 10%) under H2 protection The mixture was stirred at room temperature overnight. The it was filtered to remove Pd/C, the filtrate was concentrated in vacuo, the resulting residue was purified using prep-TLC (dichloromethane:MeOH=20:1) to provide 5-(11-fluoro-6-(2-hydroxyethyl)-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (60 mg, yield: 85%). And after SFC separation, two enantiomers were obtained. Column: Chiralpak AD-3 50*4.6 mm I.D., 3 um Mobile phase: 60% ethanol (0.05% DEA) in CO2 Flow rate: 3 mL/min Wavelength: 220 nm. Compound 99: RT=0.529 min, Compound 100: RT=1.909 min
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][C:9]2[O:12][C:13]3[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[C:15]([C:21]([OH:23])=[O:22])[C:14]=3[C:8]=2[CH2:7]1)=O)C.[OH-].[K+]>CO.O>[CH3:20][O:19][C:18]1[C:13]2[O:12][C:9]3[CH2:10][CH2:11][NH:6][CH2:7][C:8]=3[C:14]=2[C:15]([C:21]([OH:23])=[O:22])=[CH:16][CH:17]=1
Reactant: CCOC(=O)N1CCc2oc3c(OC)ccc(C(=O)O)c3c2C1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(C(=O)O)c2c3c(oc12)CCNC3

Procedure:
2-ethoxycarbonyl-6-methoxy-1,2,3,4-tetrahydro[1]benzofuro[3,2-c]pyridine-9-carboxylic acid (from step 9 of example 9) (1.8 g, 6.10 mmol) was dissolved in methanol (10 ml). To this KOH (6.8 g, 122.03 mmol) dissolved in 10 ml water was added and reaction mixture was refluxed overnight. Reaction mixture was concentrated and residue was diluted with water (25 ml) and neutralized with (15 ml) saturated ammonium chloride solution. The precipitate obtained was filtered and dried under vacuum. Yield=1.6 g (pale yellow solid).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[C:4]#[N:5].[CH3:12][C:13]1[N:14]=[CH:15][NH:16][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:2]([N:16]2[CH:17]=[C:13]([CH3:12])[N:14]=[CH:15]2)=[C:3]([CH:6]=1)[C:4]#[N:5]
Reactant: COc1ccc(F)c(C#N)c1
Reactant: Cc1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(-n2cnc(C)c2)c(C#N)c1
Yield: 72 %

Procedure:
In analogy to example 5a, 2-fluoro-5-methoxy-benzonitrile was reacted with 4-methylimidazole and potassium carbonate for 48 h at 100° C. After aqueous workup and crystallization from Ethyl acetate/diisopropylether the title compound was obtained as a white solid (yield: 72%). MS: m/e=214.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[C:6](Cl)[N:5]2[N:16]=[C:17]([CH:19]3[CH2:21][CH2:20]3)[N:18]=[C:4]2[N:3]=1.O.C1COCC1.[NH4+].[Cl-]>C(O)C.[Zn]>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[CH:6][N:5]2[N:16]=[C:17]([CH:19]3[CH2:21][CH2:20]3)[N:18]=[C:4]2[N:3]=1
Reactant: Fc1ccc(-c2c(Cl)nc3nc(C4CC4)nn3c2Cl)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: Fc1ccc(-c2cn3nc(C4CC4)nc3nc2Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 10.9 %

Procedure:
7.78 g (24.1 mmol) 5,7-Dichloro-2-cyclopropyl-6-(4-fluorophenyl)-[1,2,4]triazolo[1,5-a]pyrimidine are given in 612 mL ethanol, 435 mL water and 234 mL THF. After addition of 6.1 g (114 mmol) NH4Cl, 10.1 g (154 mmol) zinc powder are added and the mixture is stirred at room temperature for 3 h. Stirring is continued over night. The reaction mixture is filtered via a glass microfibre filter and the filter is washed with plenty of methanol. The zinc slurry is stirred twice with ethylacetate/methanol (250 mL each) and the combined organic filtrates are evaporated. The residue is extracted with ethyl acetate (1 L). The organic phase is washed twice with brine and dried over Na2SO4. After evaporation of the solvent, the residue is purified by chromatography on silicagel (eluents dichloromethane/methanol) yielding 0.76 g (10.4%) of the desired product. Additionally 3.57 g are obtained which are a mixture of the desired product and the bis deschloro derivate (ratio 6:4).
Reaction SMILES: Cl.[NH:2]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[NH2:3].C([O-])(O)=O.[Na+].[CH3:15][C:16]([CH3:23])([CH3:22])[C:17](=O)[CH2:18][C:19]#[N:20]>CCO>[NH2:20][C:19]1[N:2]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:3]=[C:17]([C:16]([CH3:23])([CH3:22])[CH3:15])[CH:18]=1
Reactant: CCOC(=O)CNN
Reactant: CC(C)(C)C(=O)CC#N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)Cn1nc(C(C)(C)C)cc1N
Temperature: 60 °C
Yield: 81.9 %

Procedure:
A mixture of ethyl 2-hydrazinylacetate hydrochloride (0.309 g, 2 mmol), NaHCO3 (0.185 g, 2.2 mmol), and 4,4-dimethyl-3-oxopentanenitrile (0.250 g, 2 mmol) in EtOH (10 mL) was heated at 60° C. overnight. The reaction was quenched with water and extracted with CH2Cl2. Extracts were dried over MgSO4 and concentrated under reduced pressure to afford ethyl 2-(5-amino-3-tert-butyl-1H-pyrazol-1-yl)acetate as solid (0.369 g, 82%). 1H NMR (300 MHz, CDCl3) δ 5.50 (s, 1H), 4.75 (s, 2H), 4.23 (q, 2H), 3.57 (br, 2H), 1.29 (t, 3H), 1.25 (s, 9H); LC-MS (ESI) m/z 226 (M+H)+.
Reaction SMILES: [NH:1]([C:5]1[CH:28]=[CH:27][C:8]([C:9]([N:11]2[CH2:18][CH:17]3[CH2:19][CH:13]([CH2:14][N:15](CC4C=CC=CC=4)[CH2:16]3)[CH2:12]2)=[O:10])=[CH:7][CH:6]=1)[C:2]([CH3:4])=[O:3].[H][H]>CO.[Pd]>[NH:1]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([N:11]2[CH2:12][CH:13]3[CH2:19][CH:17]([CH2:16][NH:15][CH2:14]3)[CH2:18]2)=[O:10])=[CH:27][CH:28]=1)[C:2]([CH3:4])=[O:3]
Reactant: CC(=O)Nc1ccc(C(=O)N2CC3CC(CN(Cc4ccccc4)C3)C2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(=O)Nc1ccc(C(=O)N2CC3CNCC(C3)C2)cc1

Procedure:
78.0 g (0.21 mole) of 3-(4-acetaminobenzoyl)-7-benzyl-3,7-diazabicyclo[3.3.1]nonane (cf. Example 1) were dissolved in 1.3 l of methanol, and 3.0 g of 10% strength palladium/carbon were added. Hydrogenation was carried out until an equimolar amount of hydrogen had been consumed. The reaction mixture was filtered and the filtrate was evaporated down under reduced pressure. Crystalline 3-(4-acetaminobenzoyl)-3,7-diazabicyclo[3.3.1]nonane was obtained. Yield: 59 g, mp.: 186°-189° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-])=O)[CH:24]=2)[NH:10][C@@H:11]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=2)[CH3:12])=[CH:5][CH:4]=1.[BH4-].[Na+]>O.O.O.O.O.O.[Ni](Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:10][C@@H:11]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=2)[CH3:12])[C:23]2[CH:24]=[C:25]([NH2:29])[CH:26]=[CH:27][CH:28]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(N[C@H](C)c2ccc3ccccc3c2)c2cccc([N+](=O)[O-])c2)cc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: COc1ccc(C(N[C@H](C)c2ccc3ccccc3c2)c2cccc(N)c2)cc1
Yield: 92 %

Procedure:
Following a similar procedure to that described in Example (1b), 6.13 g of N-[(4-methoxyphenyl)-(3-nitrophenyl)methyl]-N-[(R)-1-(naphthalen-2-yl)ethyl]amine [prepared as described in step (a) above], 7.06 g of nickel chloride hexahydrate and 2.25 g of sodium borohydride were reacted, to obtain 5.23 g of the title compound as a pale yellow oil.
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:5]=[C:6](/[CH:15]=[CH:16]/[C:17]([NH:19][CH:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22][CH2:21]2)=[O:18])[CH:7]=[CH:8][C:9]=1[N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1)[CH3:3]>[O-2].[O-2].[Mn+4].C(Cl)(Cl)Cl>[C:2]([C:4]1[CH:5]=[C:6](/[CH:15]=[CH:16]/[C:17]([NH:19][CH:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22][CH2:21]2)=[O:18])[CH:7]=[CH:8][C:9]=1[N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1)(=[O:1])[CH3:3]
Reactant: CC(O)c1cc(/C=C/C(=O)NC2CCc3ccccc32)ccc1-n1ccnc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CC(=O)c1cc(/C=C/C(=O)NC2CCc3ccccc32)ccc1-n1ccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 127.4 %

Procedure:
To a chloroform (0.5 mL) solution of (E)-3-(3-(1-hydroxyethyl)-4-(1H-imidazol-1-yl)phenyl)-N-indan-1-ylacrylamide (3 mg) obtained in Example 440, activated manganese dioxide (14 mg) was added and the reaction mixture was agitated at room temperature overnight. The reaction solution was filtered through a filter paper and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate), and 3.8 mg of the title compound was obtained.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[CH:29]=3)=[C:20]([C:36]([F:39])([F:38])[F:37])[CH:19]=2)[CH2:13][O:12]C(C)(C)[O:10][CH2:9]1)(C)(C)C.[ClH:41]>C(O)C>[ClH:41].[NH2:7][C:8]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[CH:29]=2)=[C:20]([C:36]([F:37])([F:38])[F:39])[CH:19]=1)([CH2:13][OH:12])[CH2:9][OH:10]
Reactant: COc1cccc(CCCOc2ccc(CCC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)cc2C(F)(F)F)c1
Agent: Cl
Solvent: CCO
Product: COc1cccc(CCCOc2ccc(CCC(N)(CO)CO)cc2C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Compound 16-3 (800 mg) was dissolved in ethanol (20 ml), concentrated hydrochloric acid (2 ml) was added, and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (560 mg) as a white powder.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:18]=[C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:20]=1[OH:21])[NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=[O:13])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:27][N:28]([CH3:32])[CH2:29][CH2:30]Cl.C(N(CC)CC)C>CN(C)C=O.C(OCC)C>[C:22]([C:19]1[CH:18]=[C:7]([CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:20]=1[OH:21])[NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([O:14][CH2:30][CH2:29][N:28]([CH3:32])[CH3:27])=[O:13])([CH3:25])([CH3:24])[CH3:23]
Reactant: CN(C)CCCl
Reactant: CC(C)(C)c1cc(Nc2cccc(C(=O)O)c2)cc(C(C)(C)C)c1O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CN(C)CCOC(=O)c1cccc(Nc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c1
Temperature: 100 °C
Reaction time: 28 h
Yield: 23.4 %

Procedure:
Under a nitrogen atmosphere, 6.0 g (0.0176 mole) of 3-(3,5-di-tertiary-butyl-4-hydroxyanilino)benzoic acid (from Example 13) and 2.53 g (0.0176 mole) of 2-dimethylaminoethyl chloride hydrochloride were dissolved in 17 ml of N,N-dimethylformamide. To this mixture was added 4.9 ml (0.035 mole) of triethylamine and the reaction was heated at 100° C. for 25 hours. The reaction temperature was then raised to 120° C. and heating was continued for an additional 28 hours. The reaction mixture was diluted with 10 ml of diethyl ether, then filtered to remove triethylamine hydrochloride. The filtrate was diluted with additional diethyl ether and then shaken with cold 10% hydrochloric acid. A middle layer contained most of the product hydrochloride. It was diluted with water and ether, and basified with solid sodium carbonate. The ether extract was washed with saturated aqueous sodium chloride and then concentrated to give 1.7 g of a tan solid, m.p. 119°-120° C. This material was recrystallized first from 20 ml of cyclohexane and then from a mixture of 10 ml of ethanol and 3 ml of water to give 1.48 g of light yellow prisms of N,N-dimethyl-2-aminoethyl 3-(3,5-di-t-butyl-4-hydroxyanilino)benzoate m.p. 123°-124° C. Analysis: Calculated for C25H36N2O3 : % C, 72.8; % H, 8.8; % N, 6.8. Found: % C, 73.0; % H, 8.8; % N, 6.7.
Reaction SMILES: Cl.[C:2]1([C:8]2([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C@@H:16]3[C@@H:12]([CH2:13][NH:14][CH2:15]3)[C@@:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])([OH:17])[CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH2:40][C:41](O)=[O:42]>>[C:26]1([C:8]2([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C@@H:16]3[C@@H:12]([CH2:13][N:14]([C:41](=[O:42])[CH2:40][C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=4[O:33][CH3:32])[CH2:15]3)[C@@:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])([OH:17])[CH2:10][CH2:9]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COc1ccccc1CC(=O)O
Reactant: COc1ccccc1[C@]1(O)CCC(c2ccccc2)(c2ccccc2)[C@H]2CNC[C@H]21
Agent: Cl
Product: COc1ccccc1CC(=O)N1C[C@@H]2[C@H](C1)C(c1ccccc1)(c1ccccc1)CC[C@@]2(O)c1ccccc1OC
Yield: 44.1 %

Procedure:
By working in accordance with Example 4, starting from 1.13 g of (3aS,4S,7aS)-7,7-diphenyl-4-(2-methoxyphenyl)perhydroisoindol-4-ol hydrochloride and 0.42 g of (2-methoxyphenyl)acetic acid, 0.61 g of (3aS,4S,7aS)-7,7-diphenyl-4-(2-methoxyphenyl)-2-[(2-methoxyphenyl)acetyl]perhydroisoindol-4-ol is obtained in the form of white crystals which melt at 204° C.
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+].[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=1[S:33](Cl)(=[O:35])=[O:34]>CN(C=O)C>[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=1[S:33]([N:12]1[C:13]2[C:9](=[C:8]3[CH:2]([CH3:1])[N:3]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:4][CH2:5][O:6][C:7]3=[CH:15][CH:14]=2)[CH:10]=[CH:11]1)(=[O:35])=[O:34]
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
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)c2c(F)cccc2F)OCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.8 %

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 2,6-difluorobenzenesulfonyl chloride (26 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 8-[(2,6-difluorophenyl)sulfonyl]-1-methyl-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (17 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 HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give the title compound (6 mg). MS m/z 379 [M+H]+.
Reaction SMILES: [OH-:1].[Na+].[CH2:3]([CH:5]1[O:7][CH2:6]1)Cl>>[CH2:3]([O:1][CH2:3][CH:5]1[O:7][CH2:6]1)[CH:5]1[O:7][CH2:6]1
Reactant: [OH-]
Reactant: ClCC1CO1
Agent: [Na+]
Product: C(OCC1CO1)C1CO1
Temperature: 118 °C
Reaction time: 0.5 h
Yield: 651.6 %

Procedure:
To a 5-liter, 4-necked round-bottomed flask fitted with a condenser, addition funnel, stirrer, and thermometer were charged 1260 g (1.71 moles) above polyisopropylphenol. A 50% NaOH solution (137.3 g, 1.71 moles) was then added and the mixture heated with stirring to reflux (118° C.) and held there for 0.5 hours. The mixture was vacuum stripped at 100° (0.5 mm) to remove water, recharged with 50 g toluene, and restripped (105°, 0.2 mm) to azeotropically remove the last traces of water. The reaction was then cooled to 65° C. and 792 g (8.55 moles) epichlorohydrin was added and the reaction heated to reflux (~120° C.) for three hours. The excess epichlorohydrin was then vacuum stripped at 120° (0.05 mm) to yield ~1450 g of the crude glycidyl ether.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:16]1[N:20]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23](Br)[CH:22]=2)[N:19]=[C:18]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH:17]=1)C(OC(C)(C)C)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.CC(C)([O-])C.[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>C1COCC1.O.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]>[C:1]([O:5][C:6](=[O:7])[NH:8][C:16]1[N:20]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[CH:22]=2)[N:19]=[C:18]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH:17]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1cc(C(C)(C)C)nn1-c1cccc(Br)c1
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cc(C(C)(C)C)nn1-c1cccc(N2CCOCC2)c1
Yield: 40.2 %

Procedure:
A mixture of Intermediate 23b (900 mg, 1.80 mmol), morpholine (240 mg, 2.70 mmol), potassium-tert-butoxide (303 mg, 2.70 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropyl biphenyl (87 mg, 0.18 mmol), and tris(dibenzylideneacetone)dipalladium(0) (81 mg, 0.09 mmol) in THF (9 mL) was irradiated in the microwave at 100° C. for 20 min. The reaction was diluted with water and extracted with EtOAc (×2). The combined organics were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-100% EtOAc in cyclohexane, to give the title compound (290 mg, 40%). LCMS (Method 7): Rt 3.94 min, m/z 401 [MH+].
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C@H:15]2[C@@H:21]([OH:22])[C:20](=[O:23])[NH:19][C:18]3[CH:24]=[CH:25][CH:26]=[CH:27][C:17]=3[S:16]2)=[CH:11][CH:10]=1.Cl.[CH3:29][N:30]([CH2:33][CH2:34][Cl:35])[CH2:31][CH3:32].CC(C)=O>C(OCC)(=O)C.O>[ClH:35].[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C@H:15]2[C@@H:21]([OH:22])[C:20](=[O:23])[N:19]([CH2:32][CH2:31][N:30]([CH3:29])[CH2:33][CH3:34])[C:18]3[CH:24]=[CH:25][CH:26]=[CH:27][C:17]=3[S:16]2)=[CH:13][CH:14]=1
Reactant: COc1ccc([C@@H]2Sc3ccccc3NC(=O)[C@@H]2O)cc1
Reactant: CCN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: O
Product: CCN(C)CCN1C(=O)[C@H](O)[C@H](c2ccc(OC)cc2)Sc2ccccc21
Reaction time: 8 h
Yield: 87.5 %

Procedure:
5.05 g of potassium carbonate are added to a mixture of 10.0 g of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 5.52 g of 2-(N-methyl-N-ethylamino)ethyl chloride hydrochloride and 100 ml of acetone. The mixture is refluxed under stirring overnight. After the reaction, the mixture is condensed under reduced pressure. The residue is dissolved in a mixture of ethyl acetate and water. The ethyl acetate layer is collected, dried and then evaporated to remove solvent. The residue is converted to its hydrochloride and then recrystallized from isopropanol. 12.28 g of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(N-methyl-N-ethylamino)ethyl]-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride are thereby obtained as colorless prisms. Yield: 87%.