Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8](=[O:18])[N:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[CH3:10])[N:6]=1.N1C=CC=CC=1.[C:25](Cl)(=[O:28])[CH2:26][CH3:27]>COCCOC>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([N:9]([CH3:10])[C:8]([CH2:7][C:5]2[N:6]=[C:2]([NH:1][C:25](=[O:28])[CH2:26][CH3:27])[S:3][CH:4]=2)=[O:18])=[CH:12][CH:13]=1
Reactant: CCC(=O)Cl
Reactant: CN(C(=O)Cc1csc(N)n1)c1ccc(Cl)cc1
Solvent: COCCOC
Solvent: c1ccncc1
Product: CCC(=O)Nc1nc(CC(=O)N(C)c2ccc(Cl)cc2)cs1
Yield: 52.2 %

Procedure:
A 300 ml reaction flask was charged with 6.0 g (0.021 mole) of 2-amino-4-[N-4-chlorophenyl-N-methyl(carbamoylmethyl)] thiazole, 100 ml of 1,2-dimethoxyethane and 2.6 g (0.03 mole) of pyridine. The propionyl chloride (2.8 g, 0.03 mole) which was dissolved in 15 ml of 1,2-dimethoxyethane was added portionwise and the reaction solution was heated at 65° for two hours. The solvent was evaporated and the residue was dissolved in ethyl acetate. The organic phase was extracted with water and dried over sodium sulfate. After evaporating most of the ethyl acetate, hexane was added. There was obtained 3.7 g (51%) of product, M.P. 153°-5°. N.M.R. (CDCl3) ∂1.2-1.4 (CH3), 2.3-2.5 (CH2), 3.3 (NCH3), 3.5 (0=CCH2), 6.5 (hetero-aromatic) 7.2-7.4 (aromatic).
Reaction SMILES: C([NH:11][S:12]([NH:15][CH:16]([CH2:20][CH2:21][CH3:22])[C:17]([OH:19])=[O:18])(=[O:14])=[O:13])(OCC1C=CC=CC=1)=O.[CH3:23]O>[Pd]>[CH3:23][O:19][C:17](=[O:18])[CH:16]([NH:15][S:12]([NH2:11])(=[O:14])=[O:13])[CH2:20][CH2:21][CH3:22]
Reactant: CCCC(NS(=O)(=O)NC(=O)OCc1ccccc1)C(=O)O
Reactant: CO
Agent: [Pd]
Product: CCCC(NS(N)(=O)=O)C(=O)OC
Reaction time: 2 h
Yield: 90 %

Procedure:
A mixture of 2-(N-carbobenzyloxyaminosulfonyl)aminopentanoic acid (46.7 g), methanol (350 mL) and 10% palladium on carbon (3.0 g) was hydrogenated at 55 psi for about 2 hours. The catalyst was removed by filtration through CELITE®, the solvent was removed in vacuo and the residue was purified by column chromatography on silica eluting with 50% ethyl acetate/hexane to afford 25.6 g (90%) of 2-(aminosulfonylamino)pentanoic acid methyl ester (Formula V: R=CH3 ; R1 =propyl; R2 =H; R3 =H), m.p. 63°-64° C.
Reaction SMILES: [C:1]1(=O)[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH2:3][CH2:2]1.Cl.[NH2:16]O.C([O-])(=O)C.[Na+]>C(O)C.O>[CH:1]1([NH2:16])[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH2:3][CH2:2]1
Reactant: NO
Reactant: O=C1CCCc2c1[nH]c1ccccc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: NC1CCCc2c1[nH]c1ccccc21
Reaction time: 0.25 h

Procedure:
To a solution of 2,3,4,9-tetrahydro-1H-carbazol-1-one (1.5 g, 8.10 mmol) in ethanol (20 mL) was added a solution of hydroxylamine hydrochloride (1.13 g, 16.2 mmol) in water (10 mL) and a solution of sodium acetate (2.19 g, 26.7 mmol) in water (10 mL). The reaction mixture was heated at reflux for 2 h, cooled, and concentrated. The residue was diluted with water and extracted with ethyl acetate (2×100 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated to a brown solid. The oxime was dissolved in THF (80 mL) and lithium aluminum hydride (1.0 M in THF, 24.3 mL) was added dropwise. The reaction was heated at reflux for 7 h and cooled in an ice bath. Methanol was added dropwise until bubbling ceased. The mixture was diluted with aqueous Na/K tartrate, stirred vigorously for 15 min and extracted with ethyl acetate (2×100 mL). The extracts were combined, dried over sodium sulfate, filtered and concentrated. The crude amine was purified by flash chromatography on silica (2% to 5% methanol/methylene chloride gradient) to provide 2,3,4,9-tetrahydro-1H-carbazol-1-amine as a brown oil. The oil was diluted in diethyl ether and HCl (1.0 M in diethyl ether) was added. The resulting precipitate was collected by filtration to provide 2,3,4,9-tetrahydro-1H-carbazol-1-amine hydrochloride (760 mg, 42%) as a light brown solid. 1H-NMR (CD3OD): δ 7.54 (d, 1H), 7.42 (d, 1H), 7.22 (t, 1H), 7.09 (t, 1H), 4.66 (t, 1H), 2.95-2.73 (m, 2H), 2.39-2.28 (m, 1H), 2.18-2.03 (m, 3H); MS m/z (M+1) 170.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:26])[C:5]([CH3:25])=[C:6]([CH2:12][C:13]2[CH:14]=[C:15]([CH2:19][CH2:20][CH2:21][C:22]([OH:24])=O)[CH:16]=[CH:17][CH:18]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH3:1][O:2][C:3]1[C:4](=[O:26])[C:5]([CH3:25])=[C:6]([CH2:12][C:13]2[CH:14]=[C:15]([CH2:19][CH2:20][CH2:21][C:22]([N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[O:24])[CH:16]=[CH:17][CH:18]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2cccc(CCCC(=O)O)c2)=C(C)C1=O
Reactant: C1CCNCC1
Product: COC1=C(OC)C(=O)C(Cc2cccc(CCCC(=O)N3CCCCC3)c2)=C(C)C1=O
Yield: 19 %

Procedure:
4-[3-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]-n-butyric acid (73 mg, 0.20 mmol) obtained in Example 62 and piperidine (0.030 ml, 0.30 mmol) were used, and a method similar to that described in Example 46 was employed to obtain the title compound (16 mg, 0.038 mmol, yield 19%).
Reaction SMILES: [OH-].[K+].[C:3]([O:7][C@@H:8]([C:15]1[C:16]([CH3:47])=[N:17][C:18]([CH3:46])=[C:19]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH2:38][C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=3)=[CH:32][CH:31]=2)[C:20]=1[N:21]1[CH2:26][CH2:25][C:24]([O:28][CH3:29])([CH3:27])[CH2:23][CH2:22]1)[C:9]([O:11]C(C)C)=[O:10])([CH3:6])([CH3:5])[CH3:4].Cl>C(O)C>[C:3]([O:7][C@@H:8]([C:15]1[C:16]([CH3:47])=[N:17][C:18]([CH3:46])=[C:19]([C:30]2[CH:31]=[CH:32][C:33]([O:36][CH2:37][CH2:38][C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=3)=[CH:34][CH:35]=2)[C:20]=1[N:21]1[CH2:22][CH2:23][C:24]([O:28][CH3:29])([CH3:27])[CH2:25][CH2:26]1)[C:9]([OH:11])=[O:10])([CH3:6])([CH3:5])[CH3:4]
Reactant: COC1(C)CCN(c2c(-c3ccc(OCCc4ccc(F)cc4)cc3)c(C)nc(C)c2[C@H](OC(C)(C)C)C(=O)OC(C)C)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COC1(C)CCN(c2c(-c3ccc(OCCc4ccc(F)cc4)cc3)c(C)nc(C)c2[C@H](OC(C)(C)C)C(=O)O)CC1
Temperature: 90 °C
Reaction time: 6 h
Yield: 21.5 %

Procedure:
The potassium hydroxide (230 mg, 4.1 mmol) was added to a gave (S)-isopropyl 2-(tert-butoxy)-2-(5-(4-(4-fluorophenethoxy)phenyl)-4-(4-methoxy-4-methylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetate (255 mg, 0.41 mmol) in ethanol (4 mL) and stirred for 6 h at 90° C. The reaction mixture was neutralized with 1N HCl solution, extracted with EtOAc, and the organic layer was washed with brine, and dried (MgSO4). The crude material was purified by prep to give (S)-2-(tert-butoxy)-2-(5-(4-(4-fluorophenethoxy)phenyl)-4-(4-methoxy-4-methylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid 51 mg (21%) as a mixture of diastereomers. 1H NMR (500 MHz, DMSO-d6) δ 7.39-7.36 (m, 2H), 7.19-7.12 (m, 3H), 7.02-6.99 (m, 3H), 5.81 (s, 1H), 4.24-4.21 (m, 2H), 3.49 (br. s, 4H), 3.07-3.04 (m, 2H), 2.89/2.81 (s, 3H), 2.44 (s, 3H), 2.04 (s, 3H), 1.59-1.45 (m, 3H), 1.32-1.25 (m, 1H), 1.12 (br. s, 9H), 0.99/0.81 (s, 3H). UPLC (M+H)=579.5.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([O:15][CH2:16][C:17]2[CH:26]=[CH:25][C:24]3[C:23]([CH3:28])([CH3:27])[CH2:22][CH2:21][C:20]([CH3:30])([CH3:29])[C:19]=3[CH:18]=2)=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=[O:11])(=O)=O.[C:33]1([Sn](CCCC)(CCCC)CCCC)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH3:27][C:23]1([CH3:28])[CH2:22][CH2:21][C:20]([CH3:29])([CH3:30])[C:19]2[CH:18]=[C:17]([CH2:16][O:15][C:8]3[C:9]([CH:10]=[O:11])=[CH:12][CH:13]=[CH:14][C:7]=3[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:26]=[CH:25][C:24]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(COc3c(C=O)cccc3OS(=O)(=O)C(F)(F)F)ccc21
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Product: CC1(C)CCC(C)(C)c2cc(COc3c(C=O)cccc3-c3ccccc3)ccc21
Yield: 53.6 %

Procedure:
3-Trifluoromethylsulphonyloxy-2-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl]methoxy benzaldehyde (46) (0.844 g., 1.79 mmol) is coupled with phenyltributylstannane (0.760 g., 2.06 mmol) via the method of Example 3 to afford 2-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl]methoxy-[1,1'-biphenyl]-3-carboxaldehyde (47) (0.380 g., 0.96 mmol, 54%): chromatographed on silica gel using CH2Cl2 /hexane to afford an oil; 1H NMR (300 MHz, CDCl3) 10.32 (s, 1H, CHO), 7.81 (dd, J=2, 8 Hz, 1H, ArH), 7.61 (m, 3H, ArH), 7.44 (m, 3H, ArH), 7.28 (dd, J=8, 8 Hz, 1H, ArH), 7.20 (d, J=8 Hz, 1H, ArH), 6.88 (d, J=2 Hz, 1H, ArH), 6.84 (dd, J=2, 8 Hz, 1H, ArH), 4.46 (s, 2H, ArCH2O), 1.67 (s, 4H, CH2CH2), 1.22 (s, 6H, 2×CH3), 1.17 (s, 6H, 2×CH3); 13C NMR (75 MHz, CDCl3) δ 190.30 (C=0), 159.90, 145.01, 137.32, 137.23, 136.56, 132.38, 130.29, 129.23, 128.62, 127.86, 127.31, 127.18, 126.83, 126.18, 124.62, 34.96, 34.93, 34.15, 31.78, 31.75; IR (film) 2958, 2926, 1688, 1584, 1458, 1364, 1244, 1210, 764, 700 cm-1 ; MS (DCI) m/e 398 (MH+), 201 (C15H21+).
Reaction SMILES: [BH4-].[Na+].[C:3]([O:11][C@@H:12]1[CH2:19][C@H:18]2[C@H:14]([CH2:15][C:16](=[O:20])[O:17]2)[C@H:13]1/[CH:21]=[CH:22]/[C:23](=[O:29])[CH2:24][C:25]#[C:26][CH2:27][CH3:28])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO>[C:3]([O:11][C@@H:12]1[CH2:19][C@H:18]2[C@H:14]([CH2:15][C:16](=[O:20])[O:17]2)[C@H:13]1/[CH:21]=[CH:22]/[C@@H:23]([OH:29])[CH2:24][C:25]#[C:26][CH2:27][CH3:28])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCC#CCC(=O)/C=C/[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCC#CC[C@H](O)/C=C/[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1
Temperature: -40 °C
Reaction time: 3 h
Yield: 46.1 %

Procedure:
5.81 g of sodium borohydride are introduced into a solution of 9.5 g of the ketone prepared in Example (23c) in 307 ml of absolute methanol cooled to -40° C. and the mixture is stirred at that temperature for 3 hours. Excess sodium borohydride is then removed by adding 9.62 ml of glacial acetic acid and the mixture is concentrated to dryness at 30° C. in vacuo. Water is added to the residue and the solution is extracted several times with methylene chloride. The combined organic phases are washed with semi-saturated sodium chloride solution, dried over magnesium sulphate and concentrated. To separate the epimeric alcohols, the crude product (9.75 g) is carefully chromatographed on silica gel by gradient elution in pentane/ether. 4.4 g of the title compound are obtained.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[NH:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14](O)=O>C(=O)(O)[O-].[Na+]>[NH:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14]1[NH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[N:8]=1
Reactant: O=C(O)c1ccc[nH]1
Reactant: Nc1ccccc1N
Agent: O=C([O-])O
Agent: [Na+]
Product: c1c[nH]c(-c2nc3ccccc3[nH]2)c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 27.3 %

Procedure:
A mixture of 1.08 g (10 mmol) of o-phenylenediamine and 20 g of polyophosphate esters was heated gently at 80° C. and was added portionwise 1.11 g (10 mmol) of pyrrole-2-carboxylic acid. After the mixture was stirred at 100° C. for 30 minutes, it was poured into a saturated solution of sodium bicarbonate (500 mL) and stirred until polyphosphate esters was decomposed. It was then extracted with two 400 mL portions of ethyl acetate. the separated organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product. After purification by column chromatography on silica gel with 30% ethyl acetate in hexane, the desired product, 2-(pyrrol-2-yl)benzimidazole (0.50 g, 25%) was obtained as a pale yellow solid, m.p. 250° C.; 1H-NMR (Acetone-d6) 6.25-6.27 (m, 1H, ArH), 6.90-6.92 (m, 1H, ArH), 7.02-7.03 (m, 1H, ArH), 7.14-7.19 (m, 2H, 2xArH), 7.52 (bs, 2H, 2xArH).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:31]1[CH:36]=[CH:35][N:34]=[CH:33][N:32]=1)[S:7]([C:10]1[CH:15]=[C:14]([CH:16]=[CH2:17])[C:13]([O:18][C@H:19]2[CH2:23][CH2:22][CH2:21][C@@H:20]2[C:24]2[N:28]([CH3:29])[N:27]=[CH:26][CH:25]=2)=[CH:12][C:11]=1[F:30])(=[O:9])=[O:8].C([SiH](CC)CC)C>ClCCl.FC(F)(F)C(O)=O>[CH2:16]([C:14]1[C:13]([O:18][C@H:19]2[CH2:23][CH2:22][CH2:21][C@@H:20]2[C:24]2[N:28]([CH3:29])[N:27]=[CH:26][CH:25]=2)=[CH:12][C:11]([F:30])=[C:10]([S:7]([NH:6][C:31]2[CH:36]=[CH:35][N:34]=[CH:33][N:32]=2)(=[O:8])=[O:9])[CH:15]=1)[CH3:17]
Reactant: C=Cc1cc(S(=O)(=O)N(Cc2ccc(OC)cc2OC)c2ccncn2)c(F)cc1O[C@H]1CCC[C@@H]1c1ccnn1C
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1cc(S(=O)(=O)Nc2ccncn2)c(F)cc1O[C@H]1CCC[C@@H]1c1ccnn1C
Reaction time: 1 h

Procedure:
To a solution of the N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)-5-vinylbenzenesulfonamide (29 mg, 0.05 mmol) prepared in Example 61c and triethylsilane (0.10 mL) in dichloromethane (4.0 mL), trifluoroacetic acid (0.5 mL) was added at room temperature, and the mixture was stirred for 1 hour. The reaction mixture was concentrated to yield a mixture of the title compound and a vinyl derivative.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=O.[NH2:13][C@H:14]1[C:18](=[O:19])[N:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:16][C@H:15]1[CH2:26][C:27]([O:29]CC)=[O:28]>CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([NH:13][C@H:14]1[C:18](=[O:19])[N:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:16][C@H:15]1[CH2:26][C:27]([OH:29])=[O:28])=[O:12]
Reactant: CCOC(=O)C[C@@H]1CN(c2ccccc2)C(=O)[C@@H]1N
Reactant: O=C(O)c1cc2ccccc2[nH]1
Solvent: CN(C)C=O
Product: O=C(O)C[C@@H]1CN(c2ccccc2)C(=O)[C@@H]1NC(=O)c1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of indole-2-carboxylic acid in DMF is added 1 equivalent of 1,1-carbonyldiimidazole. After stirring for 4 h at room temperature a solution of the aminopyrrolidinone of Example 68 in DMF is added. After stirring for 12 h at room temperature the reaction mixture is evaporated in vacuo to give a residue which is chromatographed on silica gel to give the desired amide. To a solution of the amide in 1:4 EtOH/THF is added a solution of lithium hydroxide (1.4 equiv) in H2O and the resulting solution is stirred for 2 h at room temperature. The reaction mixture is then acidified to pH=2 with 1N HCl. Removal of the solvent gives a residue which is chromatographed on silica gel to give the title carboxylic acid as a single enantiomer.
Reaction SMILES: [CH2:1]1[CH:8]2[N:4]([C:5](=[O:9])[CH2:6][CH2:7]2)[C:3](=[O:10])[CH2:2]1.Cl.[Cl:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15][OH:16]>C(OCC)C>[Cl:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15][O:16][C:5](=[O:9])[CH2:6][CH2:7][CH:8]1[CH2:1][CH2:2][C:3](=[O:10])[NH:4]1
Reactant: OCc1ccccc1Cl
Reactant: O=C1CCC2CCC(=O)N12
Agent: Cl
Solvent: CCOCC
Product: O=C1CCC(CCC(=O)OCc2ccccc2Cl)N1
Temperature: 100 °C

Procedure:
Five grams of dihydro-1H-pyrrolizine-3,5(2H,6H)-dione (III) are dissolved in 31 g of o-chlorobenzyl alcohol and 0.2 ml of concentrated hydrochloric acid is added. The solution is heated at 100° C. for 71 hours. The mixture is cooled and dissolved in 150 ml of anhydrous diethylether. The solution is cooled to induce crystallization and the resulting crystals are isolated by filtration. Recrystallization from toluene-diethyl ether yields 5-oxo-2-pyrrolidinepropanoic acid o-chlorobenzyl ester with a melting point of 99°-100° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:17])[N:9]([CH3:16])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][CH:15]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[Br:18]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:18][C:15]1[N:14]=[CH:13][N:12]2[C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[C:7]=3[C:8](=[O:17])[N:9]([CH3:16])[CH2:10][C:11]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: CN1Cc2cncn2-c2cccc(Cl)c2C1=O
Solvent: CN(C)C=O
Solvent: O
Product: CN1Cc2c(Br)ncn2-c2cccc(Cl)c2C1=O

Procedure:
12.38 g (50 mmol) of 7-chloro-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one was stirred at room temperature for 40 minutes with 9.80 g (55 mmol) of N-bromosuccinimide in 80 ml of N,N-dimethylformamide. The reaction mixture was poured into 800 ml of water and the suspension obtained was filtered. The filter residue was rinsed with water and taken up in methylene chloride. The organic phase was dried over magnesium sulphate and evaporated. After chromatography of the residue on silica gel while eluting with ethyl acetate and recrystallization from ethyl acetate and hexane there was obtained 3-bromo-7-chloro-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 178°-179°.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[N+:11]([O-:13])=[O:12])=[N+]=[N-].[C:14]1([P:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1.O>[F:10][C:6]1[C:5]([N+:11]([O-:13])=[O:12])=[C:4]([N:1]=[P:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: [N-]=[N+]=Nc1cccc(F)c1[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1c(F)cccc1N=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 73.7 %

Procedure:
To a solution of 1-azido-3-fluoro-2-nitrobenzene (500 mg, 2.75 mmol) in THF (4 mL) and water (1 mL) was added triphenylphosphine (720 mg, 2.75 mmol). The reaction mixture was stirred at room temperature for 45 min then partitioned between water and EtOAc. The organic layer was separated and washed with brine, dried over Na2SO4, filtered and concentrated. The residue was subjected to flash chromatography (Si—PCC, Et2O) to give the desired product as a yellow solid (844 mg, 73%). LCMS (Method A): RT 4.36 min; [M+H]+ 417
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:10]([C@@H:12]([NH2:14])[CH3:13])[N:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]=2[C:21]=1[CH3:22].Cl[C:24]1[N:32]=[CH:31][N:30]=[C:29]2[C:25]=1[N:26]=[CH:27][N:28]2C1CCCCO1.CCN(C(C)C)C(C)C.Cl>C(O)CCC.O1CCOCC1>[F:3][C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:10]([C@@H:12]([NH:14][C:24]3[N:32]=[CH:31][N:30]=[C:29]4[C:25]=3[N:26]=[CH:27][NH:28]4)[CH3:13])[N:9]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:8]=2[C:21]=1[CH3:22]
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: Cc1c(F)ccc2nc([C@H](C)N)n(-c3ccccc3)c12
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1c(F)ccc2nc([C@H](C)Nc3ncnc4[nH]cnc34)n(-c3ccccc3)c12
Temperature: 90 °C
Yield: 69.9 %

Procedure:
A mixture of (S)-1-(6-fluoro-7-methyl-1-phenyl-1H-benzoimidazol-2-yl)ethylamine dihydrochloride (330 mg, 1.23 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (351 mg, 1.47 mmol) and DIPEA (320 μL, 2.45 mmol) in n-butanol (6 mL) was heated at 90° C. in a sealed vial for 18 h. After cooling to RT, the volatiles were removed under reduced pressure and the resulting residue purified by column chromatography (Si—PCC, gradient 0-10% MeOH in EtOAc). A solution of the compound thus obtained in MeOH (5 mL) and 4N HCl in dioxane (1 ml) was stirred at RT for 1 h then the volatiles were removed under reduced pressure. The resulting residue was partitioned between EtOAc and a saturated solution of NaHCO3. A white solid precipitated and was collected by filtration to afford 183 (333 mg, 70%). LCMS (Method K): RT 3.46 min [M+H]+ 388.1. 1H NMR (DMSO-d6, 400 MHz): δ 12.55 (1H, s), 8.06-8.00 (2H, m), 7.71-7.39 (7H, m), 7.05 (1H, dd, J=10.58, 8.77 Hz), 5.30 (1H, br s), 1.70 (3H, d, J=1.84 Hz), 1.53 (3H, d, J=6.84 Hz)
Reaction SMILES: CC(N=NC(C#N)(C)C)(C#N)C.[C:13](I)([C:16]([C:19]([C:22]([F:25])([F:24])[F:23])([F:21])[F:20])([F:18])[F:17])([F:15])[F:14].[CH2:27]=[CH:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][OH:38]>C(O)C.[Zn]>[C:13]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][OH:38])([C:16]([C:19]([C:22]([F:25])([F:24])[F:23])([F:21])[F:20])([F:18])[F:17])([F:15])[F:14]
Reactant: C=CCCCCCCCCCO
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)I
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: [Zn]
Solvent: CCO
Product: OCCCCCCCCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F

Procedure:
C4F9(CH2)11OAcr was prepared essentially as described above starting with the AIBN catalyzed addition of C4F9I to CH2═CH(CH2)9OH. The resulting iodohydrin was reduced with zinc in ethyl alcohol to give the desired C4F9(CH2)11OH and olefinic products in about an 80:20 ratio as follows.
Reaction SMILES: [NH2:1][CH:2]([CH2:10][NH:11][C:12]1[C:17]([CH2:18][CH3:19])=[C:16]([N:20]2[CH2:25][CH2:24][CH:23]([C:26]3[CH:35]=[CH:34][C:33]4[CH2:32][CH2:31][CH2:30][NH:29][C:28]=4[N:27]=3)[CH2:22][CH2:21]2)[N:15]=[CH:14][N:13]=1)[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[N+:36]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[N:45]=[C:46]=[O:47])([O-:38])=[O:37]>O1CCCC1>[CH2:18]([C:17]1[C:12]([NH:11][CH2:10][CH:2]([NH:1][C:46]([NH:45][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=2[N+:36]([O-:38])=[O:37])=[O:47])[C:3]([O:5][C:6]([CH3:8])([CH3:7])[CH3:9])=[O:4])=[N:13][CH:14]=[N:15][C:16]=1[N:20]1[CH2:21][CH2:22][CH:23]([C:26]2[CH:35]=[CH:34][C:33]3[CH2:32][CH2:31][CH2:30][NH:29][C:28]=3[N:27]=2)[CH2:24][CH2:25]1)[CH3:19]
Reactant: O=C=Nc1ccccc1[N+](=O)[O-]
Reactant: CCc1c(NCC(N)C(=O)OC(C)(C)C)ncnc1N1CCC(c2ccc3c(n2)NCCC3)CC1
Solvent: C1CCOC1
Product: CCc1c(NCC(NC(=O)Nc2ccccc2[N+](=O)[O-])C(=O)OC(C)(C)C)ncnc1N1CCC(c2ccc3c(n2)NCCC3)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.5 %

Procedure:
A mixture of 240 mg (0.50 mmole) of tert-butyl 2-amino-3-{5-ethyl-6-[4-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-piperidin-1-yl]-pyrimidin-4-ylamino}-propionate and 82 mg (0.50 mmole) of 2-nitrophenylisocynate in 15 ml of tetrahydrofuran is stirred for 3 hours at ambient temperature. The reaction mixture is evaporated to dryness under reduced pressure (2 kPa) and the residue is taken up in ethyl acetate and water. The organic phase is separated, dried over magnesium sulphate and the solvent evaporated off under reduced pressure (2 kPa). The residue is chromatographed on alumina eluting with a gradient of ethyl acetate-methylene chloride-methanol from 50-50-0 to 50-50-10. 260 mg of expected product is obtained in the form of a yellow solid.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][CH2:11][C:12]([NH2:14])=O)=[CH:4][C:3]=2[O:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+]>O1CCCC1.O>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][CH2:11][CH2:12][NH2:14])=[CH:4][C:3]=2[O:2]1
Reactant: NC(=O)CCc1ccc2c(c1)OCO2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: NCCCc1ccc2c(c1)OCO2
Yield: 84.6 %

Procedure:
6.0 g of the above amide was dissolved in 100 ml of dry tetrahydrofuran, which was added dropwise to a suspension of 2.4 g of LiAlH4 in 150 ml of dry tetrahydrofuran. The reaction mixture was refluxed for 2 hours and 10 ml of 1N NaOH was added thereto. The mixture was filtered through a Celite layer to give solids, which were dissolved in 200 ml of distilled water. This solution was extracted twice with 200 ml of ethyl ether. The combined organic phase was dried over magnesium sulfate, concentrated and distilled under reduced pressure to provide 4.71 g(yield 85%) of 3-(3,4-methylenedioxyphenyl) propylamine, having the characteristics of: NMR(CDCl3, 200 MHz) δ1.34 (br s, 2H, NH2), 1.72(m, J=7 Hz, 2H, CH2), 2.57(t, J=7 Hz, 2H, CH2), 2.71(t, J=7 Hz, 2H, CH2N), 5.91(s, 2H, CH2O2), 6.59-6.74(s, 3H, ArH).