Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(O)[C:5](=[O:6])[C:3](=O)[C:2]=1[OH:7].[CH3:9][N:10]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:15]=1)[CH2:11][CH2:12][OH:13].[CH3:25][CH2:26][CH2:27][CH2:28][OH:29]>C1(C)C=CC=CC=1>[CH2:21]([O:20][C:16]1[CH:15]=[C:14]([N:10]([CH2:11][CH2:12][OH:13])[CH3:9])[CH:19]=[CH:18][C:17]=1[C:3]1[C:2]([OH:7])=[C:1]([C:27]2[CH:26]=[CH:25][C:14]([N:10]([CH2:11][CH2:12][OH:13])[CH3:9])=[CH:15][C:28]=2[O:29][CH2:19][CH2:18][CH2:17][CH3:16])[C:5]=1[OH:6])[CH2:22][CH2:23][CH3:24]
Reactant: O=c1c(O)c(O)c1=O
Reactant: CCCCOc1cccc(N(C)CCO)c1
Reactant: CCCCO
Solvent: Cc1ccccc1
Product: CCCCOc1cc(N(C)CCO)ccc1C1=C(O)C(c2ccc(N(C)CCO)cc2OCCCC)=C1O
Temperature: 120 °C

Procedure:
342 mg of squaric acid and 2.14 g of 2-(methyl(3-butoxyphenyl)amino)ethan-1-ol was put in a 100 mL 3-necked round bottom flask, and 40 mL of n-BuOH and 20 mL of toluene were added thereto. The mixture was heated and refluxed at 120° C. for 7 hour. Then, a Dean-Stark trap set was used to remove water generated from the reactant during the reaction and kept being reacted. When the reaction was complete, the reactant was cooled down, producing crystals. The crystals was filtered, several times washed with hexanes, and once more recrystallized, obtaining a desired compound.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:12](=[O:19])[NH:11][C:10]2[CH:20]=[CH:21][CH:22]=[N:23][C:9]1=2)=[O:7].C(=O)([O-])[O-].[Na+].[Na+].[CH3:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>C(O)C>[CH3:30][N:31]1[CH2:36][CH2:35][N:34]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12](=[O:19])[NH:11][C:10]3[CH:20]=[CH:21][CH:22]=[N:23][C:9]2=3)=[O:7])[CH2:33][CH2:32]1
Reactant: O=C1Nc2cccnc2N(C(=O)CCCCCl)c2ccccc21
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CN1CCN(CCCCC(=O)N2c3ccccc3C(=O)Nc3cccnc32)CC1
Yield: 37 %

Procedure:
A mixture of 5.0 g of 11-(5-chlorovaleryl)-5,11-dihydro-6H-pyrido-[2,3-b][1,4]-benzodiazepine-6-one, 1.6 g of sodium carbonate and 3 ml of 1-methylpiperazine in 100 ml of ethanol was refluxed for 20 hours and then the hot mixture was vacuum filtered. The filtrate was evaporated to dryness in vacuo and the residue was chromatographed over silica gel to obtain a 37% yield of 5,11-dihydro-11-[5-(4-methyl-1-piperazinyl)-valeryl]-6H-pyrido-[2,3-b][1,4]-benzodiazepine-6-one melting at 151°-153° C. after crystallization from ethyl acetate.
Reaction SMILES: C(#N)C.Cl[S:5]([N:8]=C=O)(=[O:7])=[O:6].C(O)=O.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C@H:21]1[O:25][C:24]([CH3:27])([CH3:26])[O:23][C@@H:22]1[CH2:28][OH:29].CN(C)C(=O)C>>[S:5](=[O:6])(=[O:7])([O:29][CH2:28][C@@H:22]1[C@@H:21]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[Cl:14])[O:25][C:24]([CH3:27])([CH3:26])[O:23]1)[NH2:8]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CC1(C)O[C@H](c2ccccc2Cl)[C@@H](CO)O1
Solvent: CC#N
Solvent: CC(=O)N(C)C
Solvent: O=CO
Product: CC1(C)O[C@H](c2ccccc2Cl)[C@@H](COS(N)(=O)=O)O1
Temperature: 0 °C
Reaction time: 6 h
Yield: 72.3 %

Procedure:
To a 100 ml flask, Acetonitrile (2.26 ml, 43.2 mmol) was added and cooled to 0° C. Chlorosulfonyl isocyanate (1.5 ml, 17.3 mmol), and formic acid (0.65 ml, 17.3 mmol) was added dropwise and stirred at room temperature for 6 hours. ((4R,5R)-5-(2-chlorophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methanol (Preparation example 6, 1.05 g, 4.3 mmol) in N,N-dimethyl acetamide (13.2 ml, 142.7 mmol) was slowly added at 0° C. and stirred at room temperature for 1 hours. The reaction mixture was quenched with H2O, extracted with EtOAc, and washed with H2O. The organic layer was dried over anhydrous magnesium sulfate (MgSO4), filtered and concentrated. The crude compound was purified by a silica gel column to produce the title compound (1.00 g, 50˜80%).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([N:17]3[C:25]4[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=4)[CH:19]=[N:18]3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([N:17]3[C:25]4[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=4)[CH:19]=[N:18]3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-n3ncc4cc(F)ccc43)nc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)NC(=O)c1c[nH]c2ncc(-n3ncc4cc(F)ccc43)nc12
Reaction time: 15 h
Yield: 27.8 %

Procedure:
To a stirred solution of N-tert-butyl-2-(5-fluoro-1H-indazol-1-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (120 mg, 249 μmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL). After 15 h, the mixture was concentrated in vacuo then 25 mL Jan. 10, 1960 of a solution of ammonium hydroxide/methanol/dichloromethane was added. After 1 h the mixture was concentrated in vacuo then purified by chromatography (silica, 24 g Analogix column, 0-5% methanol containing 10% ammonium hydroxide in dichloromethane) to give 2-(5-fluoro-indazol-1-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (24.4 mg, 28%). MS: (M+H)+=353; 1H NMR (DMSO-d6) δ: 9.02 (s, 1H), 8.56-8.61 (m, 2H), 8.53 (d, J=0.8 Hz, 2H), 8.42 (d, J=3.0 Hz, 1H), 7.78 (dd, J=8.8, 2.3 Hz, 1H), 7.62 (s, 1H), 7.49 (d, J=2.5 Hz, 1H), 1.50 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[S:12]([NH:15][CH2:16][CH3:17])(=[O:14])=[O:13].[F:18][C:19]1[CH:24]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH:22]=[CH:21][C:20]=1[C:34]1[CH:35]=[N:36][C:37]([NH2:40])=[N:38][CH:39]=1>>[NH2:40][C:37]1[N:38]=[CH:39][C:34]([C:20]2[CH:21]=[CH:22][C:23]([C:2]3[C:3]([S:12]([NH:15][CH2:16][CH3:17])(=[O:14])=[O:13])=[CH:4][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:7]=3)=[CH:24][C:19]=2[F:18])=[CH:35][N:36]=1
Reactant: CCNS(=O)(=O)c1cc(C(F)(F)F)ccc1Br
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Product: CCNS(=O)(=O)c1cc(C(F)(F)F)ccc1-c1ccc(-c2cnc(N)nc2)c(F)c1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using 2-bromo-N-ethyl-5-(trifluoromethyl)benzenesulfonamide and 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine. MS (ESI): mass calcd. for C19H16F4N4O2S, 440.09; m/z found, 441.0 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.56-8.53 (d, J=1.4, 2H), 8.34-8.31 (m, 1H), 7.99-7.95 (m, 1H), 7.63-7.59 (d, J=8.0, 1H), 7.59-7.53 (m, 1H), 7.36-7.34 (dd, J=7.1, 1.6, 1H), 7.34-7.32 (m, 1H), 2.97-2.71 (q, J=7.2, 2H), 1.15-0.84 (t, J=7.2, 3H).
Reaction SMILES: [C:1]1([S:7]([CH2:9][C:10]([OH:12])=O)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:28][CH:29]1[C:47](=[O:48])[N:31]2[C:32]([C:44]([OH:46])=[O:45])=[C:33]([CH2:36][S:37][C:38]3[S:42][C:41]([CH3:43])=[N:40][N:39]=3)[CH2:34][S:35][C@H:30]12>C(Cl)Cl.C(N(CC)CC)C.C(O)C>[C:1]1([S:7]([CH2:9][C:10]([NH:28][CH:29]2[C:47](=[O:48])[N:31]3[C:32]([C:44]([OH:46])=[O:45])=[C:33]([CH2:36][S:37][C:38]4[S:42][C:41]([CH3:43])=[N:40][N:39]=4)[CH2:34][S:35][C@H:30]23)=[O:12])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CS(=O)c1ccccc1
Reactant: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)s1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(NC(=O)CS(=O)c4ccccc4)[C@H]3SC2)s1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 16.6 %

Procedure:
To 8 ml of methylene chloride were added 0.37 g of phenylsulfinylacetic acid of the R form ([α]D20 :+183°, C=1.00, ethanol) and 0.41 g of dicyclohexylcarbodiimide, and the mixture was agitated at room temperature for 1.5 hours. Then, a solution consisting of 0.69 g of 7-amino-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid, 0.28 ml of triethylamine and 8 ml of methylene chloride was added to the above mixture, and the resulting mixture was agitated at room temperature overnight. The reaction mixture was filtered, and the filtrate was post-treated in the same manner as described in Example 19 to obtain 0.17 g of 7-(phenylsulfinylacetamido)-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid of the R form, the IR and NMR spectra of which were found to be in agreement with those of the intended product.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:24][NH2:25].O>C(O)(=O)C>[C:2]1([C:1]2[C:9]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:25][N:24]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: O=C(c1ccccc1)c1ccccc1C(=O)c1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: c1ccc(-c2nnc(-c3ccccc3)c3ccccc23)cc1
Yield: 100 %

Procedure:
To a cooled solution of 1,2-bis(benzoyl)benzene (286.32, 0.5 g, 1.75 mmol) in glacial acetic acid (12 ml) was added hydrazine monohydrate (3.5 mL) dropwise. The reaction mixture was refluxed for 4 hours. The resulting bright brown solution was added with water to produce pale yellow precipitate, yield 100%. This was used to the next reaction for complex without further purification. MS: m/z 283.0 (M+).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9]([CH3:37])[C@H:10]([CH3:36])[CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:24](=[O:25])[C:23]2[NH:22][C:21]([CH2:26][NH:27]C(OC(C)(C)C)=O)=[N:20][C:19]=2[N:18]([CH3:35])[C:16]1=[O:17]>ClCCl>[CH3:37][N:9]([CH3:8])[C@H:10]([CH3:36])[CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:24](=[O:25])[C:23]2[NH:22][C:21]([CH2:26][NH2:27])=[N:20][C:19]=2[N:18]([CH3:35])[C:16]1=[O:17]
Reactant: C[C@H](CCCCn1c(=O)c2[nH]c(CNC(=O)OC(C)(C)C)nc2n(C)c1=O)N(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](CCCCn1c(=O)c2[nH]c(CN)nc2n(C)c1=O)N(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.6 %

Procedure:
To a 50% solution of trifluoroacetic acid in dichloromethane (15 ml) was added (R)-1-(5-dimethylaminohexyl)-8-(N-BOC-aminomethyl)-3-methylxanthine (0.16 g, 0.38 mmol). After stirring at room temperature for 3 hours, the solvent and excess reagent were evaporated under reduced pressure. The residue was treated with ammonia-methanol solution (2.0 M, 10 ml) and stirred for 1 hour. Concentration under reduced pressure gave the crude product which was purified by flash chromatography on silica gel eluting with ammonium hydroxide (37% in water)-methanol-ethyl acetate (2:10:1). (R)-1-(5-Dimethylaminohexyl)-8-aminomethyl-3-methylxanthine (0.062 g, 50% yield) was obtained as an oil.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:9]([O:11][SiH:12]([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[CH3:10].C(OC(=O)C)(=O)C.C([Si](C=C)(C)O[Si](C)(C)C)=C>C1(C)C=CC=CC=1>[CH2:1]([Si:12]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])[O:11][CH2:9][CH3:10])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=Cc1ccccc1
Reactant: CCO[SiH](OCC)OCC
Agent: C=C[Si](C)(C=C)O[Si](C)(C)C
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: CCO[Si](CCc1ccccc1)(OCC)OCC
Temperature: 50 °C
Yield: 13 %

Procedure:
130 mg Of styrene and 217 mg of triethoxysilane were placed in a glass reaction tube and 0.0015 ml of acetic anhydride was added. Next, 0.0045 ml of a toluene solution of a 0-valent platinum complex of divinyltetramethyldisiloxane (platinum content: 0.04 Wt. %) was added to this mixture. The reaction tube was sealed with Teflon tape and heated for 30 minutes in an oil bath at 50° C. When the tube contents were analyzed by GC-MS following cooling, the conversion rate of styrene was 16% and phenethyltriethoxysilane was produced at a yield of 13%. The yield of (α-methylbenzyl) triethoxysilane was 2%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:39][CH3:40])=[C:6]([C:8]([CH3:38])([CH3:37])[CH2:9][C:10]([OH:36])([C:32]([F:35])([F:34])[F:33])[CH2:11][NH:12][C:13]2[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]3[C:14]=2[CH:15]=[N:16][N:17]3[C:23]2[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=2)[C:26](O)=[O:27])[CH:7]=1.[NH:41]1[CH2:48][CH2:47][CH2:46][C@H:42]1[C:43]([NH2:45])=[O:44]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:39][CH3:40])=[C:6]([C:8]([CH3:37])([CH3:38])[CH2:9][C:10]([OH:36])([C:32]([F:34])([F:35])[F:33])[CH2:11][NH:12][C:13]2[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]3[C:14]=2[CH:15]=[N:16][N:17]3[C:23]2[CH:24]=[C:25]([C:26]([N:41]3[CH2:48][CH2:47][CH2:46][C@H:42]3[C:43]([NH2:45])=[O:44])=[O:27])[CH:29]=[CH:30][CH:31]=2)[CH:7]=1
Reactant: NC(=O)[C@@H]1CCCN1
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cc(C)cc2c1cnn2-c1cccc(C(=O)O)c1)C(F)(F)F
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cc(C)cc2c1cnn2-c1cccc(C(=O)N2CCC[C@H]2C(N)=O)c1)C(F)(F)F

Procedure:
Prepared similarly to Example 1 from 3-(4-{[4-[5-fluoro-2-(methyloxy)phenyl]-2-hydroxy-4-methyl-2-(trifluoromethyl)pentyl]amino}-6-methyl-1H-indazol-1-yl)benzoic acid and L-prolinamide with System A used for purification by mass directed autopreparation
Reaction SMILES: C(O)CCC.CC(C)([O-])C.[K+].CCOC([CH:17]([C:20]1([C:25]#[N:26])[CH2:24][CH2:23][CH2:22][CH2:21]1)C#N)=O.[C:27]([N:29](C1C=CC=CC=1)[C:30]([NH2:32])=[NH:31])#[N:28].[C:39]([OH:42])(=O)[CH3:40]>O>[NH2:28][C:27]1[CH:40]=[C:39]([OH:42])[N:31]=[C:30]([NH:32][C:22]2[CH:21]=[CH:17][C:20]([C:25]#[N:26])=[CH:24][CH:23]=2)[N:29]=1
Reactant: CCOC(=O)C(C#N)C1(C#N)CCCC1
Reactant: CC(=O)O
Reactant: N#CN(C(=N)N)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCCCO
Solvent: O
Product: N#Cc1ccc(Nc2nc(N)cc(O)n2)cc1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
2000 ml of n-butanol and 192.8 g of potassium-tert-butoxide were added to the reaction vessel at 45±5° C. and stirred for 30 mins. To the reaction mixture was added 194.42 g of ethylcyano acetate over 15 min and added 250 ml of n-butanol. The reaction mixture was heated to 60±5° C. under stirring and 250 g of N-cyanophenyl guanidine was added, followed by 250 ml of n-butanol and further heated to 93±3° C., maintained the same at 4 hrs with stirring. After completion of the reaction, the reaction mixture was cooled to 75±5° C. and 1750 ml of water was added and stirred at the same temperature for 30 mins. Further to the reaction mass was added 250 ml of glacial acetic acid; stirred and cooled to room temperature (RT). The resulting solid was filtered and washed with 500 ml of water, followed by washing with methanol and drying to yield the titled compound.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][NH2:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl[C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][N:14]=1.C(=O)(O)[O-].[K+].O>CN(C=O)C>[C:17]([C:16]1[CH:19]=[CH:20][C:13]([NH:11][CH2:10][CH2:9][NH:8][C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[N:14][CH:15]=1)#[N:18]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: N#Cc1ccc(Cl)nc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NCCNc1ccc(C#N)cn1
Temperature: 90 °C

Procedure:
3.0 g (18.73 mmol) of N-Boc-ethylenediamine, 5.19 g (37.45 mmol) of 6-chloronicotinonitrile and 3.75 g (37.45 mmol) of potassium bicarbonate are suspended in 360 ml of DMF and heated at 90° C. for 16 h. Water is added to the mixture, which is then extracted three times with ethyl acetate. The combined organic phases are washed with saturated aqueous sodium chloride solution. After drying over magnesium sulphate, the solvent is removed. Drying under high vacuum results in 3.58 g (68% of theory) of the product.
Reaction SMILES: O.NN.[CH3:4][O:5][C:6]1[N:7]=[C:8]2[C:17](=[CH:18][CH:19]=1)[N:16]=[CH:15][C:14]1[N:13](C)[C:12](=[O:21])[CH:11]([C@H:22]3[CH2:27][CH2:26][C@H:25]([N:28]4C(=O)C5C(=CC=CC=5)C4=O)[CH2:24][CH2:23]3)[O:10][C:9]2=1>ClCCl.CO>[NH2:28][C@H:25]1[CH2:26][CH2:27][C@H:22]([CH:11]2[O:10][C:9]3[C:8]4[C:17](=[CH:18][CH:19]=[C:6]([O:5][CH3:4])[N:7]=4)[N:16]=[CH:15][C:14]=3[NH:13][C:12]2=[O:21])[CH2:23][CH2:24]1
Reactant: COc1ccc2ncc3c(c2n1)OC([C@H]1CC[C@H](N2C(=O)c4ccccc4C2=O)CC1)C(=O)N3C
Agent: NN
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: COc1ccc2ncc3c(c2n1)OC([C@H]1CC[C@H](N)CC1)C(=O)N3
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Hydrazine hydrate (2M solution in methanol, 3.56 mL, 7.12 mmol, 8.0 eq) is added at room temperature to a stirred solution of 2-[trans-4-(6-methoxy-1-methyl-2-oxo-2,3-dihydro-1H-4-oxa-1,5,9-triaza-phenanthren-3-yl)-cyclohexyl]-isoindole-1,3-dione (420 mg, 0.89 mmol, 1.0 eq) in dichloromethane (10 mL) and methanol (20 mL). After 16 hours stirring at room temperature and 2 hours stirring at 55° C., solvent is removed and the residue is purified by preparative HPLC to afford 3-(trans-4-amino-cyclohexyl)-6-methoxy-1H-4-oxa-1,5,9-triaza-phenanthren-2-one as a light grey solid (160 mg, 56% yield).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[O:6][CH:7]1[CH2:10][N:9]([C:11](Cl)=[O:12])[CH2:8]1.C(=O)([O-])[O-].[K+].[K+].Cl.[C:26]1([C:32]2[CH2:33][CH2:34][NH:35][CH2:36][CH:37]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCCC1.O>[C:26]1([C:32]2[CH2:37][CH2:36][N:35]([C:11]([N:9]3[CH2:10][CH:7]([O:6][C:5]4[CH:14]=[CH:15][CH:16]=[C:3]([C:2]([F:18])([F:17])[F:1])[CH:4]=4)[CH2:8]3)=[O:12])[CH2:34][CH:33]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: C1=C(c2ccccc2)CCNC1
Reactant: O=C(Cl)N1CC(Oc2cccc(C(F)(F)F)c2)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(N1CC=C(c2ccccc2)CC1)N1CC(Oc2cccc(C(F)(F)F)c2)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 111.8 %

Procedure:
A mixture of 2.8 g (0.01 mole) of 3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarbonyl chloride and 2.8 g (0.02 mole) of potassium carbonate in 25 ml of tetrahydrofuran was stirred for 10 min and treated with 2 g (0.01 mole) 4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride. After stirring for 30 min, approximately 2 g of ice was added and stirring continued for 18 hr. The reaction mixture was diluted with 200 ml of water and the oil which separated was extracted into methylene chloride (2×50 ml). The extracts were combined, dried and concentrated in vacuo to yield 4.5 g of orange-yellow oil which solidified when cooled to -78° C. Recrystallization from isopropyl ether after charcoaling yielded 2.6 g (65%) of fine white crystals, m.p. 100°-102° C.
Reaction SMILES: [F:1][C@@H:2]1[C:22]2[C@:17]([CH3:24])([CH:18]=[CH:19][C:20](=[O:23])[CH:21]=2)[C@@H:16]2[C@H:4]([C@H:5]3[C@:13]([CH3:26])([CH2:14][C@@H:15]2[OH:25])[C@@H:8]([C:9](=[O:12])[CH:10]=[O:11])[C@H:7]([CH3:27])[CH2:6]3)[CH2:3]1.ClCC[OH:31]>>[F:1][C@@H:2]1[C:22]2[C@:17]([CH3:24])([CH:18]=[CH:19][C:20](=[O:23])[CH:21]=2)[C@@H:16]2[C@H:4]([C@H:5]3[C@:13]([CH3:26])([CH2:14][C@@H:15]2[OH:25])[C@@H:8]([C:9](=[O:12])[C:10]([OH:31])=[O:11])[C@H:7]([CH3:27])[CH2:6]3)[CH2:3]1
Reactant: C[C@@H]1C[C@H]2[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@]2(C)[C@H]1C(=O)C=O
Reactant: OCCCl
Product: C[C@@H]1C[C@H]2[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@]2(C)[C@H]1C(=O)C(=O)O

Procedure:
5.0 g. of 6α-fluoro-11β-hydroxy-3,20-dioxo-16α-methyl-1,4-pregnadien-21-al is reacted, under the conditions set forth in Example 46, but with 2-chloroethanol in place of 2-fluoroethanol, and then worked up. The crude product is chromatographed on silica gel. With 25-29% acetone-hexane, 2.19 g. of the 2-chloroethyl ester of 6α-fluoro-11β-hydroxy-3,20-dioxo-16α-methyl-1,4-pregnadien-21-oic acid is obtained, m.p. 174.8° C. [α]D25 = +135°. UV: ε242 = 17,100 (methanol).
Reaction SMILES: [CH2:1]([C:4]1[N:5]=[N:6][N:7]([CH2:9][C:10]([N:12]2[CH2:17][CH2:16][O:15][CH:14]([C:18]([OH:20])=O)[CH2:13]2)=[O:11])[CH:8]=1)[CH2:2][CH3:3].[Li].[NH2:22][C@@H:23]([CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C@H:24]([OH:40])[CH2:25][NH:26][C@@H:27]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([Br:37])[CH:35]=2)[O:30][C:29]([CH3:39])([CH3:38])[CH2:28]1.[CH3:48]N(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:37][C:34]1[CH:35]=[C:36]2[C:31](=[CH:32][CH:33]=1)[O:30][C:29]1([CH2:39][CH2:48][CH2:38]1)[CH2:28][C@@H:27]2[NH:26][CH2:25][C@@H:24]([OH:40])[C@@H:23]([NH:22][C:18]([C@@H:14]1[O:15][CH2:16][CH2:17][N:12]([C:10](=[O:11])[CH2:9][N:7]2[CH:8]=[C:4]([CH2:1][CH2:2][CH3:3])[N:5]=[N:6]2)[CH2:13]1)=[O:20])[CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CCCc1cn(CC(=O)N2CCOC(C(=O)O)C2)nn1
Reactant: CC1(C)C[C@H](NC[C@@H](O)[C@@H](N)Cc2ccccc2)c2cc(Br)ccc2O1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Li]
Solvent: CN(C)C=O
Product: CCCc1cn(CC(=O)N2CCO[C@@H](C(=O)N[C@@H](Cc3ccccc3)[C@H](O)CN[C@H]3CC4(CCC4)Oc4ccc(Br)cc43)C2)nn1
Reaction time: 14 h

Procedure:
In a 15-mL RBF, the 4-(2-(4-propyl-1H-1,2,3-triazol-1-yl)acetyl)morpholine-2-carboxylic acid (0.034 g, 0.11 mmol) as the crude lithium salt and (2R,3S)-3-amino-1-((S)-6-bromo-2,2-dimethylchroman-4-ylamino)-4-phenylbutan-2-ol (0.046 g, 0.11 mmol) were taken up in DMF (1.5 mL). When the solids had dissolved, HATU (0.041 g, 0.11 mmol) was added. After 14 h, the reaction was concentrated, and the residue was taken up in EtOAc (60 mL) and the organic layer was extracted with water (5 mL), dried over sodium sulfate and concentrated. The residue was purified through silica gel (15 mL) which had been deactivated with TEA (2.0 mL) eluting with 4% MeOH-EtOAc, to afford the title compound as a 1:1 mixture of diastereomers. MS m/z 695/697 (M+1).
Reaction SMILES: [F:1][C:2]1([F:33])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[F:34][C:35]([F:46])([F:45])[C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:33][C:2]1([F:1])[CH2:3][CH2:4][N:5]([C:8]([C:10]2[N:11]([C:40]3[CH:39]=[CH:38][CH:37]=[C:36]([C:35]([F:46])([F:45])[F:34])[CH:41]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]4[CH2:28][CH2:29][O:30][CH2:31][CH2:32]4)[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:6][CH2:7]1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCC(N2CCOCC2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2-c1cccc(C(F)(F)F)c1)N1CCC(N2CCOCC2)CC1
Yield: 60 %

Procedure:
The title compound was synthesized in analogy to example 66, from [2-(4,4-difluoro-piperidine-1-carbonyl)-1H-indol-5-yl]-(4-morpholin-4-yl-piperidin-1-yl)-methanone (example 170), 3-(trifluoromethyl)phenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a brown oil (60%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:31]=[CH:30][C:8]([O:9][C:10]([CH3:29])([CH3:28])[C:11](=[O:27])[CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[CH:16][CH:15]=2)=[CH:7][CH:6]=1.C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>ClCCl>[CH3:39][S:40]([O:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:9][C:10]([CH3:29])([CH3:28])[C:11](=[O:27])[CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]([O:22][C:23]([CH3:26])([CH3:24])[CH3:25])=[O:21])=[CH:18][CH:19]=2)=[CH:30][CH:31]=1)(=[O:42])=[O:41]
Reactant: CC(C)(C)OC(=O)c1ccc(OCC(=O)C(C)(C)Oc2ccc(CCCO)cc2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)c1ccc(OCC(=O)C(C)(C)Oc2ccc(CCCOS(C)(=O)=O)cc2)cc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 99.8 %

Procedure:
A solution of 3-[4-(3-hydroxypropyl)phenoxy]-1-[4-(tert-butoxycarbonyl)phenoxy]-3-methyl-2-butanone (0.312 g, 0.73 mmol) in dry dichloromethane (15 ml) was cooled to 0-5° C. and treated with triethylamine (0.23 ml, 1.65 mmol) followed with methanesulfonyl chloride (0.10 ml, 1.29 mmol) added dropwise over 2 minutes. The reaction mixture was stirred at 0° C. for 45 minutes and then quenched by the addition of ethyl acetate and water. The organic phase was washed with brine, dried (magnesium sulfate) and concentrated. The residue was chromatographed on silica gel (elution toluene-ethyl acetate, 85:15) to give 0.369 g (100%) of the title material as a clear oil.