Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH3:23])[CH:9]=[C:10]([F:15])[CH:11]=2)[O:6]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO>O1CCCC1.O.C(C(Cl)Cl)C.[NH4+].[OH-]>[F:15][C:10]1[CH:11]=[C:12]2[C:7](=[C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH3:23])[CH:9]=1)[O:6][C@@H:5]([CH2:4][NH2:1])[CH2:14][CH2:13]2
Reactant: COc1ccccc1-c1cc(F)cc2c1O[C@@H](CN=[N+]=[N-])CC2
Agent: CCC(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1ccccc1-c1cc(F)cc2c1O[C@@H](CN)CC2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of (R)-2-(azidomethyl)-6-fluoro-8-(2-methoxyphenyl)-chroman (210 mg, 0.67 mmol) in tetrahydrofuran (15 mL) and water (0.5 mL) was added triphenylphosphine (0.21 g, 0.80 mmol) and the reaction mixture stirred at room temperature for 24 hours. Chromatography with 0–10% methanol in ethyl methylene chloride plus 1% NH4OH afforded [(R)-6-fluoro-8-(2-methoxyphenyl)-3,4-dihydro-2H-chromen-2-yl]methanamine as a colorless oil. The oil was dissolved in ethyl acetate and made into its hydrochloride salt (0.95 g, 69%) as a white solid using excess ethereal hydrochloric acid, mp 100° C. decomposed; MS (ES) m/z 288.1 ([M+H]+); [α]D25=−34.64° (c=5.7 mg/0.7 mL MeOH).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[CH:12][C:13](=[O:16])[NH:14][CH:15]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pd].CN(C)C=O>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:11]=[CH:12][C:13](=[O:16])[NH:14][CH:15]=2)=[CH:8][CH:9]=1
Reactant: O=c1cnc(-c2ccc([N+](=O)[O-])cc2)c[nH]1
Reactant: [H][H]
Agent: [Pd]
Solvent: CN(C)C=O
Product: Nc1ccc(-c2c[nH]c(=O)cn2)cc1
Yield: 81.2 %

Procedure:
5-(4-Nitrophenyl)-2-(1H)-pyrazinone (0.1 g) was hydrogenated over 10% Palladium on Charcoal (0.01 g) at atmospheric pressure in 50% aqueous dimethylformamide containing 2N sodium hydroxide (0.46 ml). Once the theoretical quantity of hydrogen uptake had been observed, the reaction mixture was filtered and the filtrate treated with HCl to pH6 and evaporated. Trituration of the residue with water afforded the title compound 0.07 g, m.p. 269°-271.5° C. (with decomposition).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]1([C@:13](C)(O)[C:14]([OH:16])=O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O.[OH-].[Na+].[O:22]1CCC[CH2:23]1>>[OH:22][CH2:23][C@@H:14]([OH:16])[CH2:13][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: C1CCOC1
Reactant: C[C@@](O)(C(=O)O)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Product: OC[C@@H](O)Cc1ccccc1
Reaction time: 2 h

Procedure:
There were dropped into a suspension of 50 grams of LiAlH4 in 750 ml of tetrahydrofuran (THF) cooled to 0° C. within 3 hours 83.1 grams of (S)-phenyl lactic acid dissolved in 250 ml of THF. The reaction mixture was boiled for 2 hours under reflux, after cooling treated portionwise with water and 43 ml of 4 N-NaOH and boiled for 0.5 hour under reflux. The white precipitate was filtered off and carefully washed with hot THF. The solvent was distilled off from the combined filtrates and the crude product fractionally distilled. There were obtained 64.6 grams of (S)-1,2-dihydroxy-3-phenyl-propane of boiling point 101°-102° C. (0.001 mbar).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:11][C@@H:10]([CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[N:9]([C:21](=[O:44])[C:22]2[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][Si:31]([CH:38]([CH3:40])[CH3:39])([CH:35]([CH3:37])[CH3:36])[CH:32]([CH3:34])[CH3:33])=[CH:24][C:23]=2[N+:41]([O-:43])=[O:42])[CH:8]=1)(=O)=O.[CH:47](/B(O)O)=[CH:48]\[CH3:49].P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(OCC)(=O)C>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Si:14]([O:13][CH2:12][C@@H:10]1[CH2:11][C:7](/[CH:47]=[CH:48]/[CH3:49])=[CH:8][N:9]1[C:21]([C:22]1[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][Si:31]([CH:32]([CH3:34])[CH3:33])([CH:38]([CH3:39])[CH3:40])[CH:35]([CH3:36])[CH3:37])=[CH:24][C:23]=1[N+:41]([O-:43])=[O:42])=[O:44])([C:17]([CH3:18])([CH3:19])[CH3:20])([CH3:16])[CH3:15]
Reactant: C/C=C/B(O)O
Reactant: COc1cc(C(=O)N2C=C(OS(=O)(=O)C(F)(F)F)C[C@H]2CO[Si](C)(C)C(C)(C)C)c([N+](=O)[O-])cc1O[Si](C(C)C)(C(C)C)C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C/C=C/C1=CN(C(=O)c2cc(OC)c(O[Si](C(C)C)(C(C)C)C(C)C)cc2[N+](=O)[O-])[C@H](CO[Si](C)(C)C(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.5 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (0.41 g, 0.35 mmol, 0.03 eq) was added to a mixture of the triflate 5 (8.4 g, 11.8 mmol, 1.0 eq), E-1-propene-1-ylboronic acid (1.42 g, 16.5 mmol, 1.4 eq) and potassium phosphate (5.0 g, 23.6 mmol, 2.0 eq) in dry dioxane (60 mL) under a nitrogen atmosphere. The mixture was stirred at 25° C. for 120 mins when LC/MS indicated complete reaction. Ethyl acetate (120 mL) and water (120 mL) were added, the organic phase was removed, washed with brine (20 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 95/5 v/v n-hexane/EtOAc to 90/10 v/v n-hexane/EtOAc) to afford the product as a yellow foam (4.96 g, 70%). LC/MS (4.477 min (ES+)), m/z: 605.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.67 (s, 1H), 6.74 (s, 1H), 5.93 (d, 1H, J=15.4 Hz), 5.67 (s, 1H), 4.65 (m, 1H), 4.04 (m, 2H), 3.86 (s, 3H), 2.85 (m, 1H), 2.71 (m, 1H), 1.72 (dd, 3H, J=6.8, 1.0 Hz), 1.30-1.22 (m, 3H), 1.07 (d, 18H, J=7.2 Hz), 0.87 (s, 9H), 0.08 (s, 3H), 0.07 (s, 3H).
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH3:4][O:5][C:6]1[CH:15]=[C:14]([CH:16]=[C:17]([CH2:20][O:21][CH3:22])[C:18]#[N:19])[C:9]2[CH:10]=[CH:11][CH2:12][O:13][C:8]=2[C:7]=1[O:23][CH3:24]>CO.O>[CH3:4][O:5][C:6]1[CH:15]=[C:14]([CH2:16][CH:17]([CH:20]([O:2][CH3:1])[O:21][CH3:22])[C:18]#[N:19])[C:9]2[CH:10]=[CH:11][CH2:12][O:13][C:8]=2[C:7]=1[O:23][CH3:24]
Reactant: C[O-]
Reactant: COCC(C#N)=Cc1cc(OC)c(OC)c2c1C=CCO2
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cc(CC(C#N)C(OC)OC)c2c(c1OC)OCC=C2
Yield: 62.2 %

Procedure:
A mixture of sodium methoxide (8.86 g, 0.164 mole), and 3-(7,8-dimethoxy-2H-1-benzopyran-5-yl)-2-methoxymethylpropenenitrile (Example 37A, 23.1 g, 0.080 mole) in methanol (60 mL) was heated at reflux for 24 hr, allowed to cool and diluted with water (200 mL). The resultant mixture was extracted with toluene (1×200 mL and 2×100 mL). The combined toluene portions were extracted with water (3×100 mL) and dried over magnesium sulfate. The toluene solution was concentrated leaving a brown oil which was distilled under reduced pressure to give 15.9 g (62%) of a yellow oil which was used without further purification.
Reaction SMILES: CN(C)C1C=CC=CC=1.[C:10]([Cl:13])(Cl)=[O:11].[Cl:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18]>C1(C)C=CC=CC=1.C1(C)C(C)=CC=CC=1>[Cl:14][C:15]1[CH:16]=[C:17]([NH:18][C:10]([Cl:13])=[O:11])[CH:19]=[CH:20][CH:21]=1
Reactant: O=C(Cl)Cl
Reactant: Nc1cccc(Cl)c1
Solvent: Cc1ccccc1
Solvent: Cc1ccccc1C
Solvent: CN(C)c1ccccc1
Product: O=C(Cl)Nc1cccc(Cl)c1

Procedure:
Other of the ureas and thioureas of this invention are prepared by reacting arylamines with activated derivatives of carbonic acid such as phosgene or thiophosgene to yield an intermediate, for instance, an arylcarbamyl chloride. This intermediate is then reacted with a secondary amine to yield the urea or thiourea. The preparation of this intermediate is conducted in an aprotic solvent such as toluene or xylene at temperatures from about room temperature up to the boiling point of the solvent in the presence of a base, for example, N,N-dimethylaniline. The intermediate is then reacted with a secondary amine in an aprotic solvent such as toluene at temperatures from room temperature or below up to the boiling point of the solvent. An example of this process is the reaction of phosgene with 3-chloroaniline to yield the intermediate N-(3-chlorophenyl)carbamyl chloride which is then reacted with di-(n-butyl)amine to yield 1,1-di-(n-butyl)-3-(3-chlorophenyl)urea.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:36]([O:38][CH3:39])=[O:37])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:35])[CH2:19][NH:20][C:21](=[O:34])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][N:27]2[C:31](=[O:32])[CH:30]=[CH:29][C:28]2=[O:33])=[CH:13][CH:12]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[O:33]=[C:28]1[CH:29]=[CH:30][C:31](=[O:32])[N:27]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][C:21]([NH:20][CH2:19][C:18]([NH:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][C@@H:9]([C:36]([O:38][CH3:39])=[O:37])[NH2:8])=[CH:12][CH:13]=1)=[O:35])=[O:34]
Reactant: COC(=O)[C@H](Cc1ccc(NC(=O)CNC(=O)CCCCCN2C(=O)C=CC2=O)cc1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@@H](N)Cc1ccc(NC(=O)CNC(=O)CCCCCN2C(=O)C=CC2=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 122.4 %

Procedure:
To a solution of #251 (800 mg, 1.47 mmol, 1 eq.) in dichloromethane (16 mL) was added TFA (4.8 mL) at 0° C. The mixture was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo. The residue was dissolved in water and filtered. The filtrate was lyophilized to afford #252 (800 mg, 97.5%) as a white solid. HPLC (Protocol Q3) [M+H+] 445.4, retention time=0.90 min.
Reaction SMILES: [O:1]([CH2:5][CH3:6])[C:2]([S-])=[S:3].[K+].Br[NH:9][C:10](=[NH:15])[C:11]([Cl:14])([Cl:13])[Cl:12]>O.C(Cl)Cl>[Cl:12][C:11]([Cl:14])([Cl:13])[C:10]1[N:15]=[C:2]([O:1][CH2:5][CH3:6])[S:3][N:9]=1
Reactant: N=C(NBr)C(Cl)(Cl)Cl
Reactant: CCOC(=S)[S-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CCOc1nc(C(Cl)(Cl)Cl)ns1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.5 %

Procedure:
32 g (0.2 mole) of potassium ethyl xanthate was dissolved in 175 ml of water. This was stirred rapidly while a solution of 48 g (0.2 mole) of N-bromotrichloroacetamidine in 150 ml of methylene chloride was added over 15 minutes. Then, the mixture was stirred one hour at room temperature. The dark methylene chloride layer was separated and the water layer extracted with 100 ml of methylene chloride. The combined methylene chloride fractions were dried over magnesium sulfate and filtered. Next, the solvent was evaporated and then the crude product was distilled at 75° C. under a vacuum of 0.9mm to give 26 g of 3-trichloromethyl-5-ethoxy-1,2,4-thiadiazole.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH:13]([C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])=[O:17])[C:14]#[N:15])=[N:6][C:7]=1[S:8]([CH2:11]C)(=O)=O.[H-].[Na+]>CN(C=O)C>[F:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:16](=[O:17])[CH:13]([C:5]1[N:6]=[C:7]2[S:8][C:11]([NH:1][CH:2]([CH3:3])[CH3:7])=[N:1][C:2]2=[CH:3][CH:4]=1)[C:14]#[N:15]
Reactant: CCS(=O)(=O)c1nc(C(C#N)C(=O)c2ccccc2F)ccc1N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Nc1nc2ccc(C(C#N)C(=O)c3ccccc3F)nc2s1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 2-(5-amino-6-(ethylsulfonyl)pyridin-2-yl)-3-(2-fluorophenyl)-3-oxopropanenitrile (presumed 0.951 mmol, 1.0 eq.) and iPrNCS (0.15 mL, 1.43 mmol, 1.5 eq.) in DMF (4.8 mL) under nitrogen at 0° C. was added NaH (95%; 0.0982 g, 3.89 mmol, 4.1 eq.). After 0.75 hr, the cold bath was removed and the reaction was stirred to room temperature for 0.5 hr. At 0° C., iPrNCS (0.1 mL) and NaH (0.050 g) were added and stirred for 0.25 hr. The cold bath was removed, and the reaction was stirred to room temperature overnight. At 0° C., water and EtOAc were added, and separated. The aqueous layer was washed with EtOAc (2×). The aqueous layer was concentrated in vacuo. Silica gel chromatrography using CH2Cl2:MeOH (100:1) as eluent afforded 3-(2-fluorophenyl)-2-(2-(isopropylamino)thiazolo[5,4-b]pyridin-5-yl)-3-oxopropanenitrile as a burgundy solid (0.10 g, 29%).
Reaction SMILES: O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20](=[O:22])[CH3:21].[OH-].[Na+]>C1C=[N+]([C@@H]2O[C@H](COP(OP(OC[C@H]3O[C@@H](N4C5N=CN=C(N)C=5N=C4)[C@H](OP(O)(O)=O)[C@@H]3O)(O)=O)(O)=O)[C@@H](O)[C@H]2O)C=C(C(N)=O)C=1>[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]([OH:22])[CH3:21]
Reactant: CC(=O)c1ccccc1F
Agent: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Na+]
Product: CC(O)c1ccccc1F
Temperature: 30 °C
Reaction time: 24 h
Yield: 80.8 %

Procedure:
The culture of the recombinant Escherichia coli HB101(pNTRGG1) as obtained in Example 9 was subjected to ultrasonic cell disruption using SONIFIRE 250 (product of BRANSON). To 100 ml of this cell disruption fluid, there were added 15 g of glucose, 5 g of 1-(2′-fluorophenyl)ethanone and 15 mg of NADP. This reaction mixture was stirred at 30° C. for 24 hours while adjusting the pH to 6.5 with 5 M sodium hydroxide. After completion of the reaction, this reaction mixture was extracted with ethyl acetate, the solvent was then removed, and the extract was distilled (54° C./1 mm Hg) to obtain 4.1 g of 1-(2′-fluorophenyl)ethanol as a colorless oil. Its specific rotation showed a value of [α] (25,D)=−45.3 (c=0.794, methanol) and it was the S form with an optical purity of 99.9% ee.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:23][C@@H:24]([C:37]1[N:41]2[C:42]3[S:56][C:55]([CH2:57][CH3:58])=[CH:54][C:43]=3[C:44]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=3[Cl:53])=[N:45][CH2:46][C:40]2=[N:39][N:38]=1)[CH2:25][CH2:26][C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28].[CH3:59][O:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][C:62]=1[N:67]=[C:68]=[O:69].C(N(CC)CC)C.O>CN(C=O)C>[Cl:53][C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=1[C:44]1[C:43]2[CH:54]=[C:55]([CH2:57][CH3:58])[S:56][C:42]=2[N:41]2[C:37]([C@H:24]([NH:23][C:68]([NH:67][C:62]3[CH:63]=[CH:64][CH:65]=[CH:66][C:61]=3[O:60][CH3:59])=[O:69])[CH2:25][CH2:26][C:27]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[O:28])=[N:38][N:39]=[C:40]2[CH2:46][N:45]=1
Reactant: CCc1cc2c(s1)-n1c(nnc1[C@H](N)CCC(=O)OCc1ccccc1)CN=C2c1ccccc1Cl
Reactant: COc1ccccc1N=C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCc1cc2c(s1)-n1c(nnc1[C@@H](CCC(=O)OCc1ccccc1)NC(=O)Nc1ccccc1OC)CN=C2c1ccccc1Cl

Procedure:
Benzyl (R)-4-amino-4-(4-(2-chlorophenyl)-2-ethyl-6H-thieno[3,2-f] [1,2,4]triazolo[4,3-a] [1,4]diazepin-9-yl)butanoate di-p-toluenesulfonate (2.0 g) and 2-methoxyphenyl isocyanate (0.34 ml) were dissolved in DMF (20 ml). Triethylamine (0.97 ml) was added and the mixture was stirred. Water was added to the reaction mixture. The mixture was washed with an aqueous citric acid solution, saturated brine, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography using ethyl acetate as an eluent to give 1.19 g of benzyl (R)-4-(4-(2-chlorophenyl)-2-ethyl-6H-thieno[3,2-f] [1,2,4]triazolo[4,3-a] [1,4]diazepin-9-yl)-4-(3-(2-methoxyphenyl)ureido)butanoate.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]1[C:12](=[O:36])[N:13]([CH2:22][C:23]([NH:25][CH:26]([CH:33]([CH3:35])[CH3:34])[CH:27]([OH:32])[C:28]([F:31])([F:30])[F:29])=[O:24])[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:15][C:8]2=1)#N.O.[PH2]([O-])=[O:39].[Na+].O>N1C=CC=CC=1.C(O)(=O)C.[Ni].CO>[CH:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]1[C:12](=[O:36])[N:13]([CH2:22][C:23]([NH:25][CH:26]([CH:33]([CH3:35])[CH3:34])[C:27](=[O:32])[C:28]([F:31])([F:29])[F:30])=[O:24])[C:14]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:15][C:8]2=1)=[O:39]
Reactant: O=[PH2][O-]
Reactant: CC(C)C(NC(=O)Cn1c(-c2ccccc2)cc2c([nH]c3c(C#N)cccc32)c1=O)C(O)C(F)(F)F
Agent: [Ni]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CO
Solvent: O
Product: CC(C)C(NC(=O)Cn1c(-c2ccccc2)cc2c([nH]c3c(C=O)cccc32)c1=O)C(=O)C(F)(F)F
Temperature: 60 °C
Yield: 79.8 %

Procedure:
To a solution of 2-(8-cyano-1-oxo-3-phenyl-1,2-dihydropyrido[3,4-b]indol-2-yl)-N-(3,3,3-trifluoro-2-hydroxy-1-isopropylpropyl)acetamide (0.5 g) and sodium hypophosphite hydrate (0.35 g) in pyridine (3 mL), acetic acid (1.5 mL), and H2O (1.5 mL) was added a small amount of Raney nickel (50% slurry in water, pH greater than 9) and the resulting mixture was heated at 60° C. for 1 hour. Additional sodium hypophosphite hydrate (0.1 g) was added and the mixture was heated at 60° C. for 1 hour. The reaction mixture was diluted with methanol, filtered through diatomaceous earth, evaporated, and diluted with ethyl acetate. The resulting solution was washed with 1N hydrochloric acid, dried, and evaporated to give the aldehyde (0.4 g) as a yellow solid; TLC: Rf =0.45, methanol:dichloromethane (5:95);
Reaction SMILES: [Li]CCCC.[CH3:6][C:7]1[O:8][CH:9]=[CH:10][CH:11]=1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[O-2].[Al+3].[O-2].[O-2].[Al+3].[NH4+].[Cl-]>C1COCC1>[CH3:6][C:7]1[O:8][C:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:10][CH:11]=1
Reactant: BrCc1ccccc1
Reactant: Cc1ccco1
Agent: [Al+3]
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(Cc2ccccc2)o1
Temperature: 25 °C
Reaction time: 3 h
Yield: 45.9 %

Procedure:
n-BuLi (1.8 mL, 4.51 mmol, 2.5 M in hexane) was added to a solution of 2-methylfuran (0.37 mL, 4.10 mmol) in anhydrous THF (3 mL) at −25° C. The resulting solution was stirred at room temperature for 3 h and then cooled to −15° C. Benzyl bromide (0.59 mL, 4.92 mmol), which was passed through a plug of aluminum oxide, was added and the solution was warmed to rt and stirred overnight. Saturated NH4Cl solution (5 mL) was added and the mixture was stirred for 1 h. The reaction mixture was then extracted with ether (2×5 mL) and the combined organic extracts were dried and concentrated under reduced pressure. Purification by flash chromatography on silica gel eluting with hexanes gave 323 mg (1.88 mmol, 46%) of compound 205A as colorless oil. HPLC: 95% at 3.72 min (retention time) (YMC S5 ODS column 4.6×50 mm, 10-90% aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm) and about 400 mg mixture of product and benzyl bromide (˜2:1 by HPLC).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:13]=[C:14]([C@H:19]2[C@H:25]([CH2:26][OH:27])[O:24][CH2:23][CH2:22][N:21]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:20]2)[CH:15]=[CH:16][C:17]=1[Cl:18].O>C1COCC1.C(N(CC)CC)C>[Cl:11][C:12]1[CH:13]=[C:14]([C@H:19]2[C@H:25]([CH:26]=[O:27])[O:24][CH2:23][CH2:22][N:21]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:20]2)[CH:15]=[CH:16][C:17]=1[Cl:18]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](CO)[C@H](c2ccc(Cl)c(Cl)c2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCO[C@@H](C=O)[C@H](c2ccc(Cl)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 96.9 %

Procedure:
To a solution of oxalyl chloride (1.52 g) in THF (20 mL) was added dimethyl sulfoxide (1.87 g) at −78° C., and the mixture was stirred for 20 min. A solution of tert-butyl (6R,7R)-6-(3,4-dichlorophenyl)-7-(hydroxymethyl)-1,4-oxazepane-4-carboxylate (3.0 g) in THF (10 mL) and triethylamine (7.78 mL) were added at −78° C., and the mixture was warmed to room temperature and stirred for 1 hr. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate (0%-50%)) to give the title compound (2.89 g) as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH2:14])=[CH:4][CH:3]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25](=O)[CH3:26])=[CH:19][CH:18]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:25]([CH3:26])[CH2:24][CH2:23][C:20]2[CH:19]=[CH:18][C:17]([O:16][CH3:15])=[CH:22][CH:21]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(CCC(C)=O)cc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1N
Product: COc1ccc(CCC(C)Nc2c(C)noc2-c2ccc(Br)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 8, Step 1, using 5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylamine and 4-(4-methoxy-phenyl)-butan-2-one.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[CH3:15])[N:5]=[C:4]([NH2:16])[N:3]=1.[Cl:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1>>[Cl:14][C:12]1[CH:11]=[CH:10][C:9]([CH3:15])=[C:8]([C:6]2[N:5]=[C:4]([NH2:16])[N:3]=[C:2]([NH:22][C:21]3[CH:23]=[CH:24][C:18]([Cl:17])=[CH:19][CH:20]=3)[CH:7]=2)[CH:13]=1
Reactant: Cc1ccc(Cl)cc1-c1cc(Cl)nc(N)n1
Reactant: Nc1ccc(Cl)cc1
Product: Cc1ccc(Cl)cc1-c1cc(Nc2ccc(Cl)cc2)nc(N)n1
Yield: 78 %

Procedure:
Following the method described in Example 26, 4-chloro-6-(5-chloro-2-methyl-phenyl)-pyrimidin-2-yl-amine and 4-chloroaniline provided the title compound (78% yield). 1H NMR (DMSO-d6) δ 2.34 (s, 3H, CH3), 6.10 (s, 1H, Ar), 6.45 (s, 2H, NH2), 7.30-7.33 (m, 3H, Ar), 7.37 (dd, 1H, J=8.1 Hz, J=2.3 Hz, Ar), 7.41 (d, 1H, J=2.2 Hz, Ar), 7.80-7.83 (m, 2H, Ar), 9.35 (s, 1H, NH).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]=[N:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)=[CH:7][C:6]=1[C:21]#[N:22].C(N(CC)CC)C.[C:30](Cl)(=[O:34])[C:31]([CH3:33])=[CH2:32]>O1CCOCC1>[C:30]([O:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]=[N:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)=[CH:7][C:6]=1[C:21]#[N:22])(=[O:34])[C:31]([CH3:33])=[CH2:32]
Reactant: C=C(C)C(=O)Cl
Reactant: N#Cc1ccc(N=Nc2ccc(OCCO)c(C#N)c2)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OCCOc1ccc(N=Nc2ccc(C#N)cc2)cc1C#N
Temperature: 65 °C
Reaction time: 2 h

Procedure:
5.8 g (4-(2-hydroxyethyloxy)-3,4′-dicyanoazobenzene are dissolved in 15 ml dioxane at 65° C.; 2.4 g triethylamine are added. A solution of 3.1 g methacrylic acid chloride in 3 ml dioxane is added and the reaction mixture is stirred at 65° C. for 2 h and then introduced into 350 ml ice-water. The precipitate is filtered off with suction and dried. Purification is carried out by chromatography on silica gel in toluene/THF (½). The yield of 4-(2-methacryloyloxyethyloxy)-3,4′-dicyanoazobenzene is 5.9 g. M.p.=110° C.; max=352 nm (DMF).