Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([NH2:17])=[N:14][CH:13]=[N:12][C:11]=3[N:10]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH:9]=2)=[CH:4][C:3]=1[O:23][CH3:24].N1C=CC=CC=1.[C:31]1([CH2:37][C:38](Cl)=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C1(CS(Cl)(=O)=O)C=CC=CC=1>ClCCl>[NH2:17][C:15]1[C:16]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:38](=[O:39])[CH2:37][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[C:3]([O:23][CH3:24])[CH:4]=3)=[CH:9][N:10]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: COc1cc(-c2cn(C3CCCC3)c3ncnc(N)c23)ccc1N
Reactant: O=C(Cl)Cc1ccccc1
Agent: O=S(=O)(Cl)Cc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(-c2cn(C3CCCC3)c3ncnc(N)c23)ccc1NC(=O)Cc1ccccc1
Reaction time: 8 h
Yield: 18.4 %

Procedure:
5-(4-Amino-3-methoxyphenyl)-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (28 mg, 0.086 mmol) was dissolved in dichloromethane (1 mL). Pyridine (1 mL) was added followed by 2-phenylethanoyl chloride (14 uL, 0.105 mmol). After stirring overnight, another 14 uL of phenylmethanesulfonyl chloride was added and the reaction mixture was stirred overnight. The solvent was removed and the residue was purified by preparative thin layer chromatogram eluted with dichlormethane/methanol (95:5) to give N1-[4-(4-amino-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]-2-phenylacetamide (7 mg, 0.0158 mmol). 1H NMR (DMSO-d6) δ 1.89 (m, 6H), 2.25 (m, 2H), 3.77 (s, 3H), 3.79 (s, 2H), 5.21 (m, 1H), 5.56 (bs, 2H), 6.89 (s, 1H), 6.99 (s, 1H), 7.05 (d, J=8.22, 1H), 7.36 (m, 5H), 7.81 (s, 1H), 8.27 (s, 1H), 8.43 (d, J=8.23 Hz, 1H). LC/MS MH+=442.
Reaction SMILES: C[C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.B(Br)(Br)Br.C([O-])([O-])=[O:16].[Na+].[Na+]>C(Cl)Cl>[OH:16][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1
Reactant: Cc1ccc2occc2c1
Reactant: O=C([O-])[O-]
Agent: BrB(Br)Br
Agent: [Na+]
Solvent: ClCCl
Product: Oc1ccc2occc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 79.6 %

Procedure:
To an ice-cooled solution of 5-methylbenzofuran (0.5 g, 3.37 mmol) in DCM (7 mL) was added boron tribromide (3.4 mL, 3.37 mmol, 1M in DCM). The light brown solution was stirred at 0° C. for 1 h, another equivalent of boron tribromide (3.4 mL) was then added. The mixture was stirred at room temperature for 2 h. TLC analysis indicated the completion of the reaction. The mixture was poured into ice and the pH was adjusted to 7 with Na2CO3. The aqueous was extracted with DCM (×2). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The resulting light brown sold gave the satisfactory purity without further purification for next step: 0.36 g (79.6% yield), 1H NMR (400 MHz, CD3OD) δ 7.59 (d, J=2.0 Hz, 1H), 7.35 (d, J=9.2 Hz, 1H), 7.01 (d, J=2.4 Hz, 1H), 6.82 (dd, J=8.8 Hz, J=2.8 Hz, 1H), 6.67 (m, 1H), 4.73 (s, 1H).
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=O)[CH2:4][CH2:3][CH2:2]1.C(O)(=O)C.[CH2:13]([O:15][P:16]([CH2:36][NH2:37])([CH2:18][CH:19]([C:24](=[O:35])[NH:25][C@H:26]([C:31](=[O:34])[NH:32][CH3:33])[CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:20][CH:21]([CH3:23])[CH3:22])=[O:17])[CH3:14]>>[CH2:13]([O:15][P:16]([CH2:36][N:37]1[C:1](=[O:8])[CH2:2][CH2:3][CH2:4][C:5]1=[O:7])([CH2:18][CH:19]([C:24](=[O:35])[NH:25][C@H:26]([C:31](=[O:34])[NH:32][CH3:33])[CH2:27][CH:28]([CH3:29])[CH3:30])[CH2:20][CH:21]([CH3:23])[CH3:22])=[O:17])[CH3:14]
Reactant: CCOP(=O)(CN)CC(CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)NC
Reactant: O=C1CCCC(=O)O1
Solvent: CC(=O)O
Product: CCOP(=O)(CC(CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)NC)CN1C(=O)CCCC1=O
Yield: 27.9 %

Procedure:
In a manner analogous to that described in Example 24(A), from 0.161 g (1.41 mmol) of glutaric anhydride and 0.41 g (0.94 mmol) of (aminomethyl)[(RS)-4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]pentyl]phosphinic acid ethyl ester acetate, there was obtained 0.124 g of (glutarimidomethyl)[(RS)-4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]pentyl]phosphinic acid ethyl ester.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10](=[O:12])[S:9][C:8]=2[CH:13]=1.[CH3:14]I.[Cl-].[NH4+]>COCCOC>[CH3:14][O:3][C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10](=[O:12])[S:9][C:8]=2[CH:13]=1
Reactant: O=c1oc2ccc(O)cc2s1
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: COCCOC
Product: COc1ccc2oc(=O)sc2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 72 %

Procedure:
With cooling with ice, 60% oily sodium hydride (3.14 g) was added to a 1,2-dimethoxyethane (100 mL) solution of 5-hydroxy-1,3-benzoxathiol-2-one (10 g, 59.5 mmol), and stirred for 10 minutes. With cooling with ice, methyl iodide (37 mL) was added to the reaction liquid, and stirred for 2 hours with cooling with ice and further for 6 hours at room temperature. Aqueous saturated ammonium chloride solution was added to the reaction liquid, and extracted three times with chloroform. The organic layer was dried with magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/2) to obtain the intended compound (7.8 g, 72%) as a white solid.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([C:19]([O:21]C)=[O:20])[CH:16]=[CH:15][N:14]=2)[N:10]=[CH:9]1)(=O)=O.Cl.[C:24]([C:26]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:27]=1[CH2:28][NH:29][CH2:30]2)#[N:25]>>[C:24]([C:26]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:27]=1[CH2:28][N:29]([CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]3[CH:18]=[C:17]([C:19]([OH:21])=[O:20])[CH:16]=[CH:15][N:14]=3)[N:10]=[CH:9]1)[CH2:30]2)#[N:25]
Reactant: N#Cc1cccc2c1CNC2
Reactant: COC(=O)c1ccnc(-c2cn(CCOS(C)(=O)=O)cn2)c1
Agent: Cl
Product: N#Cc1cccc2c1CN(CCn1cnc(-c3cc(C(=O)O)ccn3)c1)C2
Yield: 11 %

Procedure:
The title compound was prepared in 11% yield from methyl 2-(1-{2-[(methylsulfonyl)oxy]ethyl}-1H-imidazol-4-yl)pyridine-4-carboxylate (PREPARATION 6) and 4-cyanoisoindoline hydrogen chloride according to the procedure for the preparation of Example 58. 1HNMR (400 MHz, DMSO): δ 3.13 (2H, t, J=6.0 Hz), 4.03 (2H, s), 4.13 (2H, s), 4.23 (2H, t, J=4.5 Hz), 7.41 (1H, d, J=7.6 Hz), 7.55 (2H, m), 7.66 (1H, d, J=5.7 Hz), 7.80 (1H, s), 7.87 (1H, s), 8.26 (1H, s), 8.57 (1H, d, J=4.9 Hz). [M+H] Calc'd for C20H17N5O2, 360. Found, 360.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#[N:13])=[O:2].[C:17]1([Mg]Br)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[OH:2][CH:1]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#[N:13]
Reactant: Br[Mg]c1ccccc1
Reactant: N#Cc1cccc(-c2ccncc2C=O)c1
Solvent: C1CCOC1
Product: N#Cc1cccc(-c2ccncc2C(O)c2ccccc2)c1

Procedure:
To a solution of 3-(3-formyl-pyridin-4-yl)-benzonitrile (21 mg, 0.1 mmol) in THF (1 mL) at −78° C. was added 3.0 M phenylmagnesium bromide in THF (0.1 mL). The reaction mixture was quenched with ammonium chloride and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated, and the residue purified by flash chromatography to yield 3-[3-(hydroxy-phenyl-methyl)-pyridin-4-yl]-benzonitrile as a colorless oil.
Reaction SMILES: [N:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][N:16]1[C:24]2[C:23]([CH3:25])=[C:22]([CH3:26])[N:21]=[C:20]([NH2:27])[C:19]=2[N:18]=[C:17]1[CH3:28]>>[NH2:27][C:20]1[C:19]2[N:18]=[C:17]([CH3:28])[N:16]([CH2:15][CH2:14][O:13][CH2:12][CH2:11][NH:10][C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:8])[C:24]=2[C:23]([CH3:25])=[C:22]([CH3:26])[N:21]=1
Reactant: Cc1nc(N)c2nc(C)n(CCOCCN)c2c1C
Reactant: O=C(Cl)N1CCOCC1
Product: Cc1nc(N)c2nc(C)n(CCOCCNC(=O)N3CCOCC3)c2c1C

Procedure:
Using the method of Examples 54–68, 4-morpholinecarbonyl chloride was reacted with 1-[2-(2-aminoethoxy)ethyl]-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-4-amine to provide the desired compound. The product was purified using Method A. The observed accurate mass was 377.2295.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])(C)(C)C.C(O[C:28](=[O:44])[CH2:29][C:30](=O)[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:42]=[CH:41][N:40]=[CH:39][N:38]=2)[CH:32]=1)(C)(C)C>>[CH3:15][N:14]([CH3:16])[C:12]1[C:11]([C:17]([F:18])([F:19])[F:20])=[CH:10][C:9]2[NH:21][C:28](=[O:44])[CH2:29][C:30]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]4[CH:42]=[CH:41][N:40]=[CH:39][N:38]=4)[CH:32]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccncn2)c1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccncn3)c1)=N2

Procedure:
The title compound was prepared from (2-amino-5-dimethylamino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J1) (160 mg, 0.5 mmol) and 3-oxo-3-(3-pyrimidin-4-yl-phenyl)-propionic acid tert-butyl ester (Example K43) (179 mg, 0.6 mmol) according to the general procedure M and subsequent treatment of the crude product according to the general procedure N. Obtained as a light yellow solid (112 mg).
Reaction SMILES: O.[OH-].[Li+].[CH2:4]([N:7]1[C:15]2[C:10](=[CH:11][C:12](/[CH:16]=[C:17](/[C:19](=[O:24])[NH:20][CH2:21][CH2:22][CH3:23])\[CH3:18])=[CH:13][CH:14]=2)[C:9]([CH2:25][C:26]2[CH:35]=[CH:34][C:29]([C:30]([O:32]C)=[O:31])=[CH:28][C:27]=2[O:36][CH3:37])=[CH:8]1)[CH:5]=[CH2:6]>O.CO>[CH2:4]([N:7]1[C:15]2[C:10](=[CH:11][C:12](/[CH:16]=[C:17](/[C:19](=[O:24])[NH:20][CH2:21][CH2:22][CH3:23])\[CH3:18])=[CH:13][CH:14]=2)[C:9]([CH2:25][C:26]2[CH:35]=[CH:34][C:29]([C:30]([OH:32])=[O:31])=[CH:28][C:27]=2[O:36][CH3:37])=[CH:8]1)[CH:5]=[CH2:6]
Reactant: C=CCn1cc(Cc2ccc(C(=O)OC)cc2OC)c2cc(/C=C(\C)C(=O)NCCC)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C=CCn1cc(Cc2ccc(C(=O)O)cc2OC)c2cc(/C=C(\C)C(=O)NCCC)ccc21
Reaction time: 18 h
Yield: 88 %

Procedure:
A solution of lithium hydroxide monohydrate (0.16 g) in water (2 ml) was added to a stirred solution of methyl E-4[1-allyl-5-[2-(propylcarbamoyl)- 1-propenyl]indol-3-ylmethyl]-3-methoxybenzoate (0.34 g) in methanol (5 ml), and the mixture was stirred for 18 hr under an atmosphere of nitrogen. The solution was concentrated to remove methanol, acidified with 1M hydrochloric acid (30 ml), diluted with water (30 ml), and the precipitate which formed (0.31 g) was isolated by filtration and dried. The product was dissolved in methanol (2 ml) and water (2 ml), and triethylamine (0.1 ml) was added. The salt that formed was purified by reverse-phase flash chromatography on octadecylsilyl (ODS, J. T. Baker) 40 micron packing material (40 g), eluting with 1:1 methanol:water. The fraction containing the purified salt was evaporated and acidified with 1M hydrochloric acid, extracted with methylene chloride (3×50 ml), and the organic phase washed with 1M hydrochloric acid and brine, and dried (MgSO4). The solvent was evaporated to give the title compound (0.29 g, 88%) as a solid glass, mp 84°-90°.
Reaction SMILES: [C:1]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7](=O)[C:6]2=[CH:16][S:17][CH:18]=[C:5]12)(=O)[CH3:2].O1CCCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O>[CH2:1]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][CH2:7][C:6]2=[CH:16][S:17][CH:18]=[C:5]12)[CH3:2]
Reactant: CC(=O)N1c2ccccc2NC(=O)c2cscc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCN1c2cscc2CNc2ccccc21

Procedure:
A reaction mixture comprising 5 g. of 4-acetyl-4,9-dihydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-one in 225 ml. of dried tetrahydrofuran and 6.4 g. of lithium aluminum hydride in 150 ml. of dried tetrahydrofuran under nitrogen is stirred with heating to reflux overnight. A 6.5 ml. portion of water is added cautiously with stirring and cooling followed by 6.5 ml. of 15% sodium hydroxide and 19 ml. of water. The complex is filtered and washed thoroughly with ether. The combined filtrate and washings is dried over sodium sulfate and concentrated to a dark brown viscous oil. The oil is crystallized by treatment with 50 ml. of ether:hexane (50:50). The crystalline product is dissolved in 15 ml. of 40% methylene chloride in hexane and chromatographed on an alumina column eluting with 40% methylene chloride in hexane. Fractions 2-8 (50 ml. each) are combined and concentrated giving olive green crystals. These crystals are triturated in hexane, washed with hexane and dried giving the desired product, mp. 85°-87° C.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([N:22]5[C:29](=[O:30])[CH2:28][C@@H:27]6[NH:31][C@@H:24]([CH2:25][CH2:26]6)[CH2:23]5)=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:37][C:38]([CH3:40])=O>>[CH3:35][N:34]([CH3:36])[C:32]([C:7]1[N:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[C:10]2[N:11]=[C:12]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[C:29](=[O:30])[CH2:28][C@@H:27]5[N:31]([CH:38]([CH3:40])[CH3:37])[C@@H:24]([CH2:25][CH2:26]5)[CH2:23]4)=[CH:18][N:17]=3)[N:13]=[CH:14][C:9]=2[CH:8]=1)=[O:33]
Reactant: CC(C)=O
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4C[C@@H]5CC[C@H](CC4=O)N5)cn3)nc2n1C1CCCC1
Product: CC(C)N1[C@@H]2CC[C@H]1CN(c1ccc(Nc3ncc4cc(C(=O)N(C)C)n(C5CCCC5)c4n3)nc1)C(=O)C2
Yield: 86.4 %

Procedure:
Following general reductive alkylation method 1, 7-Cyclopentyl-N,N-dimethyl-2-(5-((1S,6R)-4-oxo-3,9-diazabicyclo[4.2.1]nonan-3-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (65 mg, 0.133 mmol) was combined with acetone (0.05 mL, 0.665 mmol) which gave 7-cyclopentyl-2-[5-((1S,6R)-9-isopropyl-4-oxo-3,9-diaza-bicyclo[4.2.1]non-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (61 mg) in 86% yield. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.67 (s, 1H), 8.44 (d, J=8.59 Hz, 1H), 8.12 (s, 1H), 8.08 (d, J=2.53 Hz, 1H), 7.46 (dd, J=8.59, 2.53 Hz, 1H), 6.38 (s, 1H), 4.73 (t, J=9.09 Hz, 1H), 4.24 (d, J=14.65 Hz, 1H), 3.59 (m, 2H), 3.21 (br. s., 1H), 3.08 (m, 7H), 2.97 (br. s., 1H), 2.53 (m, 3H), 1.95 (m, 6H), 1.66 (m, 3H), 1.07 (t, J=5.81 Hz, 6H).
Reaction SMILES: [C:1]([C@H:6]1[CH2:23][CH2:22][C@@:21]2([CH3:24])[C:8](=[CH:9][C:10](=[O:26])[C@@H:11]3[C@@H:20]2[CH2:19][CH2:18][C@@:16]2([CH3:17])[C@H:12]3[CH2:13][CH2:14][C:15]2=[O:25])[CH2:7]1)([O:3][CH2:4][CH3:5])=[O:2].O.O.O.O.O.O.O.[Cl-].[Ce+3].[Cl-].[Cl-].[BH4-].[Na+]>ClCCl.CO>[C:1]([C@H:6]1[CH2:23][CH2:22][C@@:21]2([CH3:24])[C:8](=[CH:9][C@H:10]([OH:26])[C@@H:11]3[C@@H:20]2[CH2:19][CH2:18][C@@:16]2([CH3:17])[C@H:12]3[CH2:13][CH2:14][C@@H:15]2[OH:25])[CH2:7]1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)[C@H]1CC[C@@]2(C)C(=CC(=O)[C@@H]3[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]32)C1
Agent: [BH4-]
Agent: [Ce+3]
Agent: [Cl-]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)[C@H]1CC[C@@]2(C)C(=C[C@H](O)[C@H]3[C@@H]4CC[C@H](O)[C@@]4(C)CC[C@@H]32)C1
Reaction time: 0.5 h
Yield: 75.9 %

Procedure:
3β-Carbomethoxyandrost-5-ene-7,17-dione (44) (0.3 g, 0.8 mmol) in 5 mL dichloromethane and 10 mL methanol was treated with cerium (III) chloride heptahydrate (0.3 g, 0.8 mmol). To this cold solution, finely powdered sodium borohydride (0.09 g, 2.4 mmol) was added slowly. After 15 minutes the solvent was evaporated to complete dryness, the solid crude was taken up in dichloromethane, stirred for 30 minutes and filtered on a small bed of celite. The organic layer was washed once with water, dried and the solvent was removed. The product was crystallized from acetone-petroleum ether to afford 0.22 g (73%) of 3β-carboethoxyandrost-5-ene-7β,17β-diol (50) as a white solid, m.p. 170-71° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](Cl)=[O:8])([O-:3])=[O:2].[CH:13]1[CH:14]=[CH:15][N:16]2[C:21]=1[CH:20]=[CH:19][CH:18]=[CH:17]2.C(OCC)(=O)C.O>ClCCl>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([C:15]1[N:16]2[C:21]([CH:20]=[CH:19][CH:18]=[CH:17]2)=[CH:13][CH:14]=1)=[O:8])([O-:3])=[O:2]
Reactant: c1ccn2cccc2c1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: O=C(c1cccc([N+](=O)[O-])c1)c1ccc2ccccn12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.9 %

Procedure:
A mixture of 3-nitrobenzoyl chloride (4.50 g) and indolizine (2.84 g) in dichloromethane (30 ml) was stirred at room temperature for 30 minutes. The reaction mixture was poured into a mixture of ethyl acetate and water. The organic phase was separated, washed with brine, dried over magnesium sulfate and concentrated. The resultant solid was collected and washed with ethyl acetate to give 3-(3-nitrobenzoyl)indolizine (4.51 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].C(N([CH2:21][CH3:22])CC)C>ClCCl>[CH2:12]([O:11][C:9]([NH:1][CH2:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:10])[C:22]1[CH:21]=[CH:8][CH:4]=[CH:3][CH:2]=1
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CCN
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CCNC(=O)OCc1ccccc1
Yield: 177.5 %

Procedure:
A mixture of Example 535B (560 mg, 2.62 mmol), benzyloxycarbonylsuccinimide ester (0.783 g, 3.93 mmol, and triethylamine (0.55 mL, 3.93 mmol) in 10 mL of dichloromethane was stirred overnight, concentrated, treated with ethyl acetate, washed with brine, 10% potassium hydrogen sulfate (3×), and brine (3×), dried (MgSO4), filtered, concentrated, and purified by silica gel column chromatography, eluting with 20% ethyl acetate in n-hexane to provide 0.81 g of the desired product. MS (ESI(+)) m/e 347 (M+H)+; 1H NMR (300 MHz, CDCl3) δ 7.28-7.39 (m, 5H), 7.23 (br, 1H), 5.00 (s, 2H), 3.62-3.74 (m, 1H), 3.19-3.29 (m, 2H), 2.92-3.05 (m, 2H), 1.73-1.91 (m, 5H), 1.54-1.62 (m, 1H), 1.38 (s, 9H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10]([O-:14])(=[O:13])[CH2:11][CH3:12].[Na+].C(OC(=O)CC)(=O)CC>O>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[C:11]([CH3:12])[C:10]([OH:14])=[O:13])=[CH:4][CH:3]=1
Reactant: CCC(=O)[O-]
Reactant: O=Cc1ccc(O)cc1
Agent: CCC(=O)OC(=O)CC
Agent: [Na+]
Solvent: O
Product: CC(=Cc1ccc(O)cc1)C(=O)O
Reaction time: 40 h
Yield: 75.4 %

Procedure:
A mixture of 4-hydroxybenzaldehyde (60 g), sodium propionate (104 g) and propionic anhydride (190 ml) was stirred at 135°-140° C. for 40 hours. After the mixture was allowed to cool, water (600 ml) was added thereto, and stirred under ice cooling for 2-3 hours. The precipitate was collected by filtration, and washed well with water. Sodium hydroxide (60 g) was completely dissolved in water (800 ml) with stirring under ice cooling, and thereto was added the above-mentioned precipitate, and the mixture was stirred at the same temperature for 30 minutes. The insoluble materials were filtered off, and the filtrate was acidified with 5N hydrochloric acid under ice cooling. The resulting precipitate was collected by filtration, washed well with water to give 4-hydroxy-α-methylcinnamic acid (66 g). mp. 204°-205° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([CH2:13][N:14]3C(=O)C4C(=CC=CC=4)C3=O)=[C:11]([CH3:25])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.FC1C=CC(C2C(CN3C(=O)C4C(=CC=CC=4)C3=O)=C(C)ON=2)=CC=1>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([CH2:13][NH2:14])=[C:11]([CH3:25])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1onc(-c2cccc(F)c2)c1CN1C(=O)c2ccccc2C1=O
Agent: Cc1onc(-c2ccc(F)cc2)c1CN1C(=O)c2ccccc2C1=O
Product: Cc1onc(-c2cccc(F)c2)c1CN
Yield: 75.3 %

Procedure:
As described for example 78b, 2-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-isoindole-1,3-dione (6.26 g, 19 mmol) was converted, instead of 2-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-isoindole-1,3-dione, to the title compound (2.95 g, 77%) which was obtained as a yellow oil. MS: m/e=207.3 [M+H]+.
Reaction SMILES: C([O:8][C:9]1[CH:22]=[CH:21][C:12]([CH2:13][NH:14][C:15]([CH:17]2[CH2:20][NH:19][CH2:18]2)=[O:16])=[CH:11][C:10]=1[O:23][CH3:24])C1C=CC=CC=1>C(O)C.C(O)(=O)C.CO.[Pd]>[OH:8][C:9]1[CH:22]=[CH:21][C:12]([CH2:13][NH:14][C:15]([CH:17]2[CH2:18][NH:19][CH2:20]2)=[O:16])=[CH:11][C:10]=1[O:23][CH3:24]
Reactant: COc1cc(CNC(=O)C2CNC2)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Solvent: CCO
Product: COc1cc(CNC(=O)C2CNC2)ccc1O
Reaction time: 1 h
Yield: 96.6 %

Procedure:
The N-(4-benzyloxy-3-methoxybenzyl)-3-azetidinecarboxamide (386 mg) of Example 14 (3) was dissolved in a mixture of ethanol (10 ml), acetic acid (0.5 ml) and methanol (5 ml), and 10% palladium on carbon (30 mg) was added thereto to carry out catalytic hydrogenation at room temperature. After 1 hour, the catalyst was filtered and the solvent was evaporated to obtain 270 mg of N-(4-hydroxy-3-methoxybenzyl)-3-azetidinecarboxamide.
Reaction SMILES: Br[C:2]1[C:11]2[NH:12][S:13](=O)(=O)[C:9]3[C:10]=2[C:5]([CH:6]=[CH:7][CH:8]=3)=[CH:4][C:3]=1CC(O)C.[H-].[Na+].[Br:22][CH2:23][CH:24]([OH:27])[CH2:25]Br>CN(C)C=O>[Br:22][CH2:23][CH:24]([OH:27])[CH2:25][N:12]1[C:11]2[CH:2]=[CH:3][CH:4]=[C:5]3[CH:6]=[CH:7][CH:8]=[C:9]([C:10]=23)[S:13]1
Reactant: CC(O)Cc1cc2cccc3c2c(c1Br)NS3(=O)=O
Reactant: OC(CBr)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: OC(CBr)CN1Sc2cccc3cccc1c23
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
2-(3-Bromo-2-hydroxypropylnaphtho[1,8-cd]isothiazole 1,1-dioxide may be prepared in the following manner: a solution of naphtho[18-cd]isothiazole 1,1-dioxide (41 g) in dimethylformamde (1000 cc) is added over 2 hours under a current of argon to a suspension of sodium hydride (9.6 g) in a 50% dispersion in vaseline oil in dimethylformamide (100 cc), maintaining the temperature between 20 and 35° C. The reaction medium is stirred for 30 minutes at a temperature of about 20° C., then 1,3-dibromo-2-hydroxypropane (20.5 cc) in dimethylformamide (500 cc) is added over 10 minutes. Stirring is maintained for 15 hours at a temperature of about 20° C. The reaction mixture is concentrated to dryness at 70° C under reduced pressure (0.5 mm Hg; 0.07 kPa). The residue is purified by chromatography on a silica column, under a current of argon with a mixture of dichloromethane and methanol (95-5 vol) as eluant. 2-(3-Bromo-2-hydroxypropyl)naphtho[1,8-cd]isothiazole 1, -dioxide (62.1 g) is obtained, in the form of a green oil which is used in the crude state in the subsequent synthesis.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9]2)[CH:5]=[N:6][CH:7]=1.[Cl:22]N1C(C)(C)C(=O)N(Cl)C1=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9]2)[CH:5]=[N:6][C:7]=1[Cl:22]
Reactant: CC(C)(C)OC(=O)N1CCCN(c2cncc(Cl)c2)CC1
Reactant: CC1(C)C(=O)N(Cl)C(=O)N1Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCN(c2cnc(Cl)c(Cl)c2)CC1
Reaction time: 3 h

Procedure:
A mixture of 1-(5-chloro-3-pyridyl)-4-tert-butoxycarbonylhomopiperazine (1.56, 5.0 mmol), 1,3-dichloro-5,5-dimethylhydantoin (0.985 g, 5.0 mmol) and dichloromethane (50 ml) was stirred for 180 minutes. The crude mixture was evaporated and purified by chromatography on silica gel using ethyl acetate:petroleum (3:1) as solvent. Yield 0.46 g, 27%.
Reaction SMILES: O.S(=O)(O)[O-].[Na+].[CH:7]([CH:9]=O)=O.[NH2:11][C:12]1[C:17]([NH2:18])=[CH:16][CH:15]=[CH:14][C:13]=1[O:19][CH3:20]>O.C(O)C.Cl>[CH3:20][O:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:12]=1[N:11]=[CH:7][CH:9]=[N:18]2
Reactant: COc1cccc(N)c1N
Reactant: O=CC=O
Agent: Cl
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1cccc2nccnc12
Reaction time: 1 h
Yield: 77.9 %

Procedure:
Glyoxal sodium bisulphite hydrate (10.0 g) in water (80 ml) was warmed to 60° C. then a solution of 2,3-diaminoanisole (3.40 g) in ethanol (40 ml) was added. The stirred mixture was then heated to 80° C. for 1 h before addition of concentrated hydrochloric acid (6 drops). Heating was continued for 1 h. It was allowed to cool overnight, concentrated in vacuo and poured into aqueous potassium carbonate (40 ml). Ethyl acetate (3×100 ml) extracts were washed with water (100 ml) and saturated brine (50 ml) then dried over anhydrous magnesium sulphate, filtered and evaporated in vacuo to afford the title compound as a yellow solid (3.07 g).