Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C@@H:4]1[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([CH2:19][CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:23])[CH2:14][CH2:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1)[CH3:3].[CH3:24]C(C)([O-])C.[K+].CI>>[CH3:24][C:12]1[C:13](=[O:23])[CH2:14][CH2:15][C@@:16]2([CH3:17])[C:11]=1[CH2:10][CH2:9][C@@H:8]1[C@@H:18]2[CH2:19][CH2:20][C@@:21]2([CH3:22])[C@H:7]1[CH2:6][CH2:5][C@@H:4]2[CH:2]([OH:1])[CH3:3]
Reactant: CC(O)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Product: CC1=C2CC[C@H]3[C@@H]4CC[C@H](C(C)O)[C@@]4(C)CC[C@@H]3[C@@]2(C)CCC1=O

Procedure:
With reference to Scheme 4, alkylation of 1a, such as 20-hydroxy-4-pregnen-3-one, using potassium t-butoxide and methyl iodide yields 4-methyl-20-hydroxy-4-pregnen-3-one 1b. Allylic bromination of N-bromosuccinimide in carbon tetrachloride yields the 6β-bromo derivative. Protection of the C-20 alcohol as its t-butyldimethyl silyl derivative yields 3. Lithium aluminum hydride reduction of the ketone in 3 with concomitant double bond migration and loss of bromide should yield 4. Protection of the C-3 alcohol as a tetrahydropyranyl ether, followed by deprotection and oxidation of the C-17 alcohol should yield the C-17 ketone 7. Removal of the C-3 tetrahydropyranyl ether yields 4α-methyl-5-pregnen-20-one.
Reaction SMILES: [C:1]([O:4][C@@H:5]([C@H:8]([C@@H:13]([C@@H:18]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[O:19][C:20](=[O:22])[CH3:21])[O:14][C:15](=[O:17])[CH3:16])[O:9][C:10](=O)C)C=O)(=[O:3])[CH3:2].C1C=CN=CC=1.[FH:34]>ClCCl>[C:25]([O:24][C@H:23]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:13]([O:14][C:15](=[O:17])[CH3:16])[C@@H:8]([CH2:5][O:4][C:1](=[O:3])[CH3:2])[O:9][C@@H:10]1[F:34])(=[O:27])[CH3:26]
Reactant: F
Reactant: CC(=O)OC[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](C=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@H](F)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 40 °C

Procedure:
Mannose pentaacetate (100 g) was stirred with dichloromethane (10 mL) in a FEP Erlenmeyer. Cold HF-pyridine (100 g) was added and the resulting solution stirred at 40° C., sealed, overnight. The solution was poured into a FEP separating funnel containing water and chloroform and shaken. The chloroform layer was washed once with water and once with saturated sodium bicarbonate. The aqueous layers were neutralized with sodium hydroxide. The organic solution was dried over magnesium sulfate and concentrated under reduced pressure. The product was purified by plug chromatography (silica, eluent hexane/EtOAc). Yield 74.06 g, 80%.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1.[CH2:20]([NH2:25])[CH2:21][CH:22]([CH3:24])[CH3:23]>>[Cl:1][C:2]1[CH:17]=[C:16]([CH2:18][NH:25][CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2Cl)cn1
Reactant: CC(C)CCN
Product: CC(C)CCNCc1ccc(Oc2ccc(C(N)=O)nc2)c(Cl)c1
Yield: 65.7 %

Procedure:
Using a method similar to Example 405, a reaction of 5-(2-chloro-4-formylphenoxy)pyridine-2-carboxamide (0.0388 g, 0.140 mmol) and isoamylamine (0.012 g, 0.140 mmol) gives the title compound (0.0320 g, 65.6%): TOF MS ES+ 348.1 (M+H)+, HRMS calcd for C18H23N3O2Cl 348.1479 (M+H)+, found 348.1466, time 0.39 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min], tR=7.4 min, 100% purity.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([CH:23]([CH3:25])[CH3:24])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33]([OH:37])[CH:34]=2)[CH2:29]1)=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:38][N:39]([CH3:43])[CH2:40][CH2:41]Cl.Cl.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([CH:23]([CH3:25])[CH3:24])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33]([O:37][CH2:41][CH2:40][N:39]([CH3:43])[CH3:38])[CH:34]=2)[CH2:29]1)=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1cc(C(=O)N2Cc3ccc(O)cc3C2)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)c1cc(C(=O)N2Cc3ccc(OCCN(C)C)cc3C2)c(OCc2ccccc2)cc1OCc1ccccc1

Procedure:
A mixture of (2,4-bis-benzyloxy-5-isopropyl-phenyl)-(5-hydroxy-1,3-dihydro-isoindol-2-yl)-methanone (100 mg, 0.2 mmol), 2-dimethylaminoethylchloride.HCl (72 mg, 0.5 mmol) and K2CO3 (173 mg, 1.25 mmol) in DMF (5 ml) was heated at 90° C. for 16 hours. Dilute reaction mixture with EtOAc and filtered. The reaction mixture was diluted with EtOAc and filtered. The filtrate was reduced in vacuo and purified by flash column chromatography, eluting 100% DCM then 90% DMAW 90 to give the title compound as an off white gel (79 mg). MS: [M+H]+ 565.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:37][NH:38][CH2:39][CH2:40]O.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:37][NH:38][CH2:39][CH2:40][O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][CH2:9][NH:8][C:1](=[O:2])[O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[CH:12][CH:13]=1
Reactant: CNCCO
Reactant: CC(C)(C)OC(=O)NCCc1ccc(O)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CNCCOc1ccc(CCNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 43.8 %

Procedure:
To a solution of N-Boc-tyramine (750 mg, 3.16 mmol) and triphenylphosphine (1.655 g, 6.308 mmol) in THF (30 mL) was added 2-(methylamino)ethanol (0.38 mL, 4.75 mmol) followed by DIAD (1.25 mL, 6.31 mmol). After stirring at room temperature for 72 h, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (gradient elution 1:20 to 1:3 MeOH/DCM) to afford the title compound (407 mg, 44%) as an oily white solid. ES/MS calcd. for C16H27N2O3+ 295.2. Found m/z=295.2 (M+H)+.
Reaction SMILES: [C:1]([CH2:3][CH2:4][O:5][CH2:6][O:7][C@@H:8]1[C@H:12]([OH:13])[C@@H:11]([CH2:14][OH:15])[O:10][C@H:9]1[N:16]1[CH:23]=[CH:22][C:20](=[O:21])[NH:19][C:17]1=[O:18])#[N:2].N1C=CC=CC=1.[CH3:30][O:31][C:32]1[CH:53]=[CH:52][C:35]([C:36](Cl)([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)=[CH:34][CH:33]=1>CO>[CH3:44][O:43][C:40]1[CH:39]=[CH:38][C:37]([C:36]([O:15][CH2:14][C@H:11]2[O:10][C@@H:9]([N:16]3[CH:23]=[CH:22][C:20](=[O:21])[NH:19][C:17]3=[O:18])[C@H:8]([O:7][CH2:6][O:5][CH2:4][CH2:3][C:1]#[N:2])[C@@H:12]2[OH:13])([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)[C:35]2[CH:52]=[CH:53][C:32]([O:31][CH3:30])=[CH:33][CH:34]=2)=[CH:42][CH:41]=1
Reactant: N#CCCOCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc(=O)[nH]c1=O
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: CO
Solvent: c1ccncc1
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](OCOCCC#N)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reaction time: 0.17 h
Yield: 97.9 %

Procedure:
2′-O-(2-Cyanoethoxymethyl)uridine (14 g, 43 mmol) was subjected to azeotropic distillation with pyridine, and then was dried with a vacuum pump for 30 minutes. The residue was dissolved in 300 mL of THF, and 68 g of pyridine (856 mmol), and 20 g of molecular sieve 4 A was added under an argon atmosphere, and the mixture was stirred for 10 minutes. To the solution was added 19.6 g of 4,4′-dimethoxytritylchloride (57.8 mmol) by 3 portions every 1 hour, and the mixture was further stirred for 1 hour. After 10 mL of methanol was added and the reaction solution was stirred for 2 minutes, the reaction solution was filtrated with a celite, and was washed with ethyl acetate. After concentrating the filtrate, the residue was dissolved in ethyl acetate, and was washed with a saturated aqueous sodium bicarbonate solution. After the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, the solvent was distilled off. The obtained residue was purified by silica gel chromatography to obtain the objective compound (26.5 g, yield 98%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([S:22][CH2:23][C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)[NH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.Br[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33].[H-].[Na+]>>[CH3:21][O:20][C:17]1[CH:16]=[CH:15][C:14]([C:13]2[N:12]=[C:11]([S:22][CH2:23][C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)[N:10]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:9]=2[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[CH:19][CH:18]=1
Reactant: COc1ccc(-c2nc(SCc3cccnc3)[nH]c2-c2ccc(OC)cc2)cc1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)Cn1c(SCc2cccnc2)nc(-c2ccc(OC)cc2)c1-c1ccc(OC)cc1

Procedure:
Starting substances: 500 mg (1.2 mmol) of T70 from Example 31; 270 mg (1.6 mmol) of ethyl bromoacetate; 72 mg (3 mmol) of NaH
Reaction SMILES: Cl.[NH2:2][OH:3].[CH2:4]([C:6]([CH:10]([N+:12]([O-:14])=[O:13])[CH3:11])=[CH:7][CH:8]=O)[CH3:5]>C(Cl)(Cl)Cl.CO>[CH2:4]([C:6]([CH:10]([N+:12]([O-:14])=[O:13])[CH3:11])=[CH:7][CH:8]=[N:2][OH:3])[CH3:5]
Reactant: NO
Reactant: CCC(=CC=O)C(C)[N+](=O)[O-]
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCC(=CC=NO)C(C)[N+](=O)[O-]
Yield: 73 %

Procedure:
Hydroxylamine hydrochloride (100 mg) was added to a solution of 3-ethyl-4-nitro-2-pentenal (100 mg) in chloroform (3 ml) and methanol (2 ml) with stirring. The resulting mixture was stirred at room temperature overnight. The reaction mixture was evaporated to dryness and the residue was diluted with water and extracted with ethyl acetate (50 ml×2). The combined extracts were washed successively with water, 5% sodium bicarbonate and brine, and then dried over magnesium sulfate. Removal of the solvent gave an oil which was purified by a preparative thin layer chromatography (5% methanol-chloroform) to give 3-ethyl-4-nitro-2-pentenal oxime (80 mg).
Reaction SMILES: [F:1][C:2]1[C:11]2[O:10][CH2:9][C:8]3[CH:12]=[C:13]([C:15]([OH:17])=O)[S:14][C:7]=3[C:6]=2[CH:5]=[C:4]([F:18])[CH:3]=1.[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[NH:22][CH3:23]>>[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[N:22]([CH3:23])[C:15]([C:13]1[S:14][C:7]2[C:6]3[CH:5]=[C:4]([F:18])[CH:3]=[C:2]([F:1])[C:11]=3[O:10][CH2:9][C:8]=2[CH:12]=1)=[O:17]
Reactant: O=C(O)c1cc2c(s1)-c1cc(F)cc(F)c1OC2
Reactant: CNc1ccccc1Cl
Product: CN(C(=O)c1cc2c(s1)-c1cc(F)cc(F)c1OC2)c1ccccc1Cl

Procedure:
Following the procedure of Example 70 and General Procedure B, 142bp was prepared from 6,8-difluoro-4H-thieno[3,2-c]chromene-2-carboxylic acid and 2-chloro-N-methylaniline. MS: (ESI+)=392.1
Reaction SMILES: C([N:8]([C@H:16]([C@@H:24]([OH:30])[CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)CC1C=CC=CC=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.O.[C].[Pd]>[NH2:8][C@H:16]([C@@H:24]([OH:30])[CH2:25][CH2:26][CH:27]([CH3:28])[CH3:29])[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)CC[C@H](O)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: CC(C)CC[C@H](O)[C@@H](N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 101.6 %

Procedure:
2(S)-(N,N-Dibenzylamino)-1-phenyl-3(S)-hydroxy- 6-methylheptane (25 g) was dissolved in methanol (250 ml), and 10% palladium-carbon (1.25 g) suspended in water (10 ml) was added thereto. Then, ammonium formate (15.70 g) was added thereto, and the mixture was stirred at ambient temperature for 5 hours, followed by concentration under reduced pressure. The residue was dissolved in methylene chloride and washed with water. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give 14.0 g of 2(S)-amino-1-phenyl-3(S)-hydroxy-6-methylheptane.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]=[O:11])[C:5]=1[N:12]([S:21]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)(=[O:23])=[O:22])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[BH4-].[Na+]>CO.C1COCC1>[CH3:1][O:2][C:3](=[O:32])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][OH:11])[C:5]=1[N:12]([S:21]([C:24]1[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=1)(=[O:23])=[O:22])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCN(c1c(C=O)cccc1C(=O)OC)S(=O)(=O)c1ccc(OC)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCCCN(c1c(CO)cccc1C(=O)OC)S(=O)(=O)c1ccc(OC)cc1
Reaction time: 2 h

Procedure:
To a solution of 0.547 g (1.187 mmol) of the product of Example 322 in 10 mL of methanol and 3 mL of THF was added 0.045 g (1.187 mmol) of sodium borohydride. The reaction was stired for 2 h at room temperature and then concentrated in vacuo. The residue was diluted with ether and washed with 5% HCl and water, dried over MgSO4, filtered and concentrated in vacuo to provide 0.549 g (100%) as a colorless oil. Electrospray Mass Spec: 464.2 (M+H)+.
Reaction SMILES: [CH:1]([NH:3][NH2:4])=[O:2].C1(C)C=CC=CC=1.[CH2:12]([O:19][C@@H:20]([CH3:23])[CH:21]=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CO>[CH2:12]([O:19][C@@H:20]([CH3:23])[CH:21]=[N:4][NH:3][CH:1]=[O:2])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NNC=O
Reactant: C[C@@H](C=O)OCc1ccccc1
Solvent: CO
Solvent: Cc1ccccc1
Product: C[C@@H](C=NNC=O)OCc1ccccc1
Temperature: 27.5 °C
Reaction time: 4 h

Procedure:
To a pre-cooled solution of formyl hydrazine (40.3 g) in methanol (290 ml) at 0-5° C., toluene layer containing (S)-2-(benzyloxy)propanal compound of formula-15 obtained in step-b) was added. Slowly raised the temperature of reaction mixture to 25-30° C. and stirred for 4 hours at 25-30° C. After completion of the reaction, distilled off the solvent under reduced pressure to get title compound. Ethyl acetate (210 ml) was added to the obtained compound and stirred for 1 hour at 25-30° C. Filtered the reaction mixture to remove the unwanted solid and washed with ethyl acetate. Distilled off the solvent completely from the filtrate under reduced pressure to get semi-solid. Petroleum ether (210 ml) was added to the obtained semi-solid and stirred for 2 hours at 25-30° C. Filtered the precipitated solid, washed with petroleum ether and then dried to get title compound.
Reaction SMILES: [CH2:1]([CH:8]1[NH:14][CH2:13][CH2:12][S:11](=[O:15])[C:10]2[C:16](=[O:21])[N:17]([CH3:20])[N:18]=[CH:19][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:22]O>C(O)(=O)C>[CH2:1]([CH:8]1[NH:14][CH2:13][CH2:12][S:11](=[O:22])(=[O:15])[C:10]2[C:16](=[O:21])[N:17]([CH3:20])[N:18]=[CH:19][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1ncc2c(c1=O)S(=O)CCNC2Cc1ccccc1
Reactant: OO
Solvent: CC(=O)O
Product: Cn1ncc2c(c1=O)S(=O)(=O)CCNC2Cc1ccccc1
Yield: 55 %

Procedure:
A mixture of 0.60 g (1.98 mmol) of 5-benzyl-8-methyl-2,3,4,5-tetrahydro-9(8H)-pyridazino[4,5-b][1,5]thiazepinone-1-oxide, 1.92 ml of glacial acetic acid and 1.2 ml of 30% aqueous hydrogen peroxide are left to stand for a day. The precipitated crystals are filtered, washed acid free with water and dried in an exsiccator. In this way 0.35 g (55%) of the title compound are obtained with a melting point of 288-290° C.
Reaction SMILES: ClCC([O:5][C:6]1[CH:14]=[CH:13][C:12]2[N:11]([CH3:15])[C:10]3[C:16](=[O:19])[CH2:17][CH2:18][C:9]=3[C:8]=2[CH:7]=1)=O.[OH-].[Na+]>CCO>[OH:5][C:6]1[CH:14]=[CH:13][C:12]2[N:11]([CH3:15])[C:10]3[C:16](=[O:19])[CH2:17][CH2:18][C:9]=3[C:8]=2[CH:7]=1
Reactant: Cn1c2c(c3cc(OC(=O)CCl)ccc31)CCC2=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1c2c(c3cc(O)ccc31)CCC2=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
7-Chloroacetyloxy-1,4-dihydro-4-methylcyclopent[b]indol3(2H)-one (5.0 g) was suspended in EtOH (100 ml), and thereafter 10% NaOH solution (50 ml) was added and the mixture was stirred at room temperature for 3 hours. The mixture was concentrated in vacuo, CH2Cl2 (100 ml) was added followed by 10% HCl until the aqueous layer was neutralized. The layers were separated and the aqueous phase extracted with CH2Cl2 (2×100 ml). The organic portion was dried (Na2SO4) and concentrated and the residue was recrystallized from 95% EtOH to provide 1,4-dihydro-7-hydroxy-4-methylcyclopent[b]indol-3(2H)-one as an off-white solid. The phenol was dissolved in CH2Cl2 (100 ml), and thereafter 1,8-diazabicyclo[5.4.0]undec-7-ene (0.4 g) was added followed by methyl isocyanate (1.4 g) and the mixture was stirred overnight. The mixture was concentrated in vacuo to afford an oily solid which was crystallized from EtOH to provide 1,4-dihydro-7-methylaminocarbonyloxy-4-methylcyclopent[b] indol-3(2H)-one (1.1 g).
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[N:13][C:14]([C:16]([OH:18])=O)=[CH:15][C:10]=3[N:9]=[CH:8]2)=[CH:4][CH:3]=1.Cl.[O:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[N:13][C:14]([C:16]([NH:29][O:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[O:18])=[CH:15][C:10]=3[N:9]=[CH:8]2)=[CH:19][CH:20]=1
Reactant: NOc1ccccc1
Reactant: O=C(O)c1cc2ncn(Cc3ccc(F)cc3)c2cn1
Agent: Cl
Product: O=C(NOc1ccccc1)c1cc2ncn(Cc3ccc(F)cc3)c2cn1

Procedure:
The title compound was prepared by coupling of 3-(4-fluoro-benzyl)-3H-imidazo[4,5-c]pyridine-6-carboxylic acid and N-phenoxyamine hydrochloride under the same conditions as those in step (c) of example 1. 1H NMR (300 MHz, MeOH-d4) δ: 8.82 (s, 1H), 8.53 (s, 1H), 8.43 (s, 1H), 8.24 (d, 2H, J=7.9 Hz), 7.38-7.33 (m, 2H), 7.07-7.01 (m, 2H), 6.88-6.74 (m, 3H), 5.57 (s, 2H). LCMS (API-ES, M+H+): 363.1. HRMS calcd for C20H6FN4O2 (M+H) 363.1257, found 363.1256. HPLC: >85% purity.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[CH3:7][C:8]1([CH3:36])[C@@H:10](/[CH:11]=[CH:12]\[C:13](=[O:15])Cl)[C@H:9]1[C:16]([O:18][C@H:19]([C:34]#[N:35])[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[C:22]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:21]=1)=[O:17].P(O)(O)([O-])=O.[Na+]>C(Cl)Cl>[CH3:7][C:8]1([CH3:36])[C@@H:10](/[CH:11]=[CH:12]\[C:13](=[O:15])[O:4][CH2:3][C:2]([F:6])([F:5])[F:1])[C@H:9]1[C:16]([O:18][C@H:19]([C:34]#[N:35])[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[C:22]([O:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:21]=1)=[O:17]
Reactant: OCC(F)(F)F
Reactant: CC1(C)[C@H](C(=O)O[C@H](C#N)c2ccc(F)c(Oc3ccccc3)c2)[C@@H]1/C=C\C(=O)Cl
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C)[C@H](C(=O)O[C@H](C#N)c2ccc(F)c(Oc3ccccc3)c2)[C@@H]1/C=C\C(=O)OCC(F)(F)F
Reaction time: 1.5 h

Procedure:
2 ml of 2,2,2-trifluoroethanol were added at 20° C. to a solution of 2.14 g of the product of Step D in 8 ml of methylene chloride and the mixture was stirred for 90 minutes and was poured into aqueous monosodium phosphate solution. The decanted organic phase was washed with water, dried and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with a 1--1 cyclohexane-ethyl acetate mixture to obtain 2.33 g of (S)α-cyano-3-phenoxy-4-fluoro-benzyl (1R,cis,Z) 2,2-dimethyl-3-[3-oxo-3-(2,2,2-trifluoroethoxy)-1-propenyl]-cyclopropane-carboxylate melting at 56° C. and having a specific rotation of [αD20 =+42°±1° (c=1% in CHCl3).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:12]2C(=O)O[C:15](C)([CH3:19])[O:14][C:13]2=[O:21])[C:9]#[C:10][CH3:11])=[CH:4][CH:3]=1>N1C=CC=CC=1.C(O)C>[CH2:15]([O:14][C:13](=[O:21])[CH2:12][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1)[C:9]#[C:10][CH3:11])[CH3:19]
Reactant: CC#CC(c1ccc(O)cc1)C1C(=O)OC(C)(C)OC1=O
Solvent: c1ccncc1
Solvent: CCO
Product: CC#CC(CC(=O)OCC)c1ccc(O)cc1
Temperature: 90 °C
Yield: 94.7 %

Procedure:
Phenol 1.2 (1.2 g, 4 mmol) was dissolved in pyridine (3 mL) and ethanol (1 mL). The mixture was heated to 90° C. for 16 h and then concentrated to an oil which was purified by column chromatography (elution with 1-3% MeOH in dichloromethane). Phenol 16 (0.88 g, 91%) was obtained as an oil. 1H NMR (500 MHz)(acetone-d6) δ 8.24 (s, 1H); 7.21 (d, 2H, J=9.5 Hz); 6.78 (d, 2H, J=9.0 Hz); 4.06 (m, 2H); 3.98 (m, 1H); 2.68-2.59 (m, 2H); 1.78 (d, 3H, J=2.5 Hz); 1.75 (t, 3H, J=7.0 Hz). MS ESI (pos.) m/e: 233.1 (M+H); 255.1 (M+Na).
Reaction SMILES: [F:1][C:2]1([F:27])[CH2:5][CH:4]([C:6]2[CH:11]=[CH:10][C:9]([N:12]3[CH2:25][CH2:24][C:14]4([CH2:23][CH2:22][C:17]5(OCC[O:18]5)[CH2:16][CH2:15]4)[C:13]3=[O:26])=[CH:8][CH:7]=2)[CH2:3]1.Cl.CCOC(C)=O>CCCCCCC>[F:27][C:2]1([F:1])[CH2:3][CH:4]([C:6]2[CH:11]=[CH:10][C:9]([N:12]3[CH2:25][CH2:24][C:14]4([CH2:15][CH2:16][C:17](=[O:18])[CH2:22][CH2:23]4)[C:13]3=[O:26])=[CH:8][CH:7]=2)[CH2:5]1
Reactant: O=C1N(c2ccc(C3CC(F)(F)C3)cc2)CCC12CCC1(CC2)OCCO1
Agent: Cl
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: O=C1CCC2(CC1)CCN(c1ccc(C3CC(F)(F)C3)cc1)C2=O

Procedure:
The title compound was prepared in analogy to example 133 step 5 from 10-[4-(3,3-Difluoro-cyclobutyl)-phenyl]-1,4-dioxa-10-aza-dispiro[4.2.4.2]tetradecan-9-one (described in example 340, step 2) by treatment with 2M HCl. White solid (89%). Rf 0.53 (4:1 AcOEt:heptane)
Reaction SMILES: [F:1][CH:2]([F:19])[CH2:3][NH:4][CH:5]1[CH2:11][CH2:10][C:9]2[C:12]([O:17][CH3:18])=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[N:34]2[CH:38]=[CH:37][CH:36]=[N:35]2)[C:24]([Cl:39])=[CH:23][N:22]=1>>[Cl:39][C:24]1[C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[N:34]2[CH:38]=[CH:37][CH:36]=[N:35]2)=[N:26][C:21]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][CH:5]([NH:4][CH2:3][CH:2]([F:19])[F:1])[CH2:11][CH2:10][C:9]=3[C:12]=2[O:17][CH3:18])=[N:22][CH:23]=1
Reactant: COc1c(N)ccc2c1CCC(NCC(F)F)CC2
Reactant: Clc1ncc(Cl)c(Nc2ccccc2-n2cccn2)n1
Product: COc1c(Nc2ncc(Cl)c(Nc3ccccc3-n3cccn3)n2)ccc2c1CCC(NCC(F)F)CC2
Yield: 58 %

Procedure:
In an analogous procedure to Example 651, part c, N*7*-(2,2-Difluoro-ethyl)-1-methoxy-6,7,8,9-tetrahydro-5H-benzocycloheptene-2,7-diamine was combined with (2,5-Dichloro-pyrimidin-4-yl)-(2-pyrazol-1-yl-phenyl)-amine to yield 5-Chloro-N*2*-[7-(2,2-difluoro-ethylamino)-1-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yl]-N*4*-(2-pyrazol-1-yl-phenyl)-pyrimidine-2,4-diamine (57.74, 58% yield) as a red glass. 1H-NMR (CDCl3) δ 10.17 (s, 1H), 8.52 (d, J=8.3 Hz, 1H), 8.02 (m, 2H), 7.82 (d, J=18.3 Hz, 2H), 7.38 (m, 3H), 7.19 (m, 1H), 6.82 (d, J=8.1 Hz, 1H), 6.60 (m, 1H), 6.52 (m, 2H), 5.82 (m, 1H), 3.70 (s, 3H), 3.21 (m, 1H), 3.02 (m, 2H), 2.98-2.30 (m, 6H), 2.06 (m, 2H), 1.23 (m, 2H).
Reaction SMILES: S([O:5][CH2:6][CH2:7][N:8]1[C:12]([NH2:13])=[C:11]([NH2:14])[CH:10]=[N:9]1)(O)(=O)=O.[C:15]([O:19][C:20]([NH:22][CH2:23][CH2:24][C@H:25]([OH:29])[C:26](O)=[O:27])=[O:21])([CH3:18])([CH3:17])[CH3:16].C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>O>[NH2:13][C:12]1[N:8]([CH2:7][CH2:6][OH:5])[N:9]=[CH:10][C:11]=1[NH:14][C:26](=[O:27])[C@@H:25]([OH:29])[CH2:24][CH2:23][NH:22][C:20](=[O:21])[O:19][C:15]([CH3:16])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)NCC[C@H](O)C(=O)O
Reactant: Nc1cnn(CCOS(=O)(=O)O)c1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)NCC[C@H](O)C(=O)Nc1cnn(CCO)c1N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(4,5-diamino-1H-pyrazol-1-yl)ethanol sulfate (2 g) and (2S)-4-[(tert-butoxycarbonyl)amino]-2-hydroxybutanoic acid (1.92 g) in water (8 ml) were added triethylamine (2.32 ml) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.76 g), and the mixture was stirred at room temperature for 3 hours. The whole mixture was extracted with ethyl acetate-tetrahydrofuran (1:1) and the solvent was evaporated under reduced pressure to give a crude product of tert-butyl ((3S)-4-{[5-amino-1-(2-hydroxyethyl)-1H-pyrazol-4-yl]amino}-3-hydroxy-4-oxobutyl)carbamate. The obtained crude product was used for Preparation 38 without further purification.