Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]=[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH3:11])=[C:4]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:3]1[NH:19][C:20]([NH:22][C:23]([O:25][CH3:26])=[O:24])=[S:21].[OH-].[Ca+2].[OH-].[CH3:30]I>CC(C)=O.O>[NH:1]=[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH3:11])=[C:4]([CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:3]1[NH:19][C:20](=[N:22][C:23]([O:25][CH3:26])=[O:24])[S:21][CH3:30]
Reactant: CI
Reactant: CCCSC1=C(Cc2ccccc2)C(NC(=S)NC(=O)OC)C(=N)C=C1
Agent: [Ca+2]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CCCSC1=C(Cc2ccccc2)C(NC(=NC(=O)OC)SC)C(=N)C=C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 1-iminophenylmethyl-2-(3-carbomethoxythioureido)-4-propylthiobenzene (3.88 g.; 0.01 mol) in acetone (40 ml.) and water (10 ml.) there is added calcium hydroxide (0.74 g.; 0.01 mol). The mixture is stirred at room temperature for 4 hours and then is added methyl iodide (1.42 g.; 0.01 mol). The mixture is stirred at room temperature for 4 hours and the precipitate collected and dried to afford 1-iminophenylmethyl-2-(3-carbomethoxy-S-methylisothioureido)-4-propylthiobenzene.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[N:5]2[N:25]=[CH:26][C:27]([C:28]3[CH:29]=[N:30][C:31]4[C:36]([CH:37]=3)=[CH:35][C:34]([F:38])=[CH:33][CH:32]=4)=[C:4]2[N:3]=1.[NH2:39][CH:40]1[CH2:45][CH2:44][N:43]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:42][CH2:41]1.C([O-])(O)=O.[Na+]>CN1C(=O)CCC1.O>[CH3:14][Si:13]([CH3:16])([CH3:15])[CH2:12][CH2:11][O:10][CH2:9][N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:6]1[N:5]2[N:25]=[CH:26][C:27]([C:28]3[CH:29]=[N:30][C:31]4[C:36]([CH:37]=3)=[CH:35][C:34]([F:38])=[CH:33][CH:32]=4)=[C:4]2[N:3]=[C:2]([NH:39][CH:40]2[CH2:41][CH2:42][N:43]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:44][CH2:45]2)[CH:7]=1
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(Cl)nc2c(-c3cnc4ccc(F)cc4c3)cnn12
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4cnc5ccc(F)cc5c4)c3n2)CC1
Temperature: 130 °C

Procedure:
A mixture of 5-chloro-3-(6-fluoroquinolin-3-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (531.3 mg, 0.93 mmol), tert-butyl 4-aminopiperidine-1-carboxylate (556.6 mg, 2.78 mmol), NaHCO3 (467.2 mg, 5.56 mmol) in NMP (10 mL) was heated at 130° C. overnight. The mixture was cooled to room temperature and diluted with H2O and then extracted with ethyl acetate (×2). The combined organic layers were washed with brine and dried with Na2SO4. Evaporation of solvent afforded the crude displacement compound. Purification by column chromatography afforded tert-butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6-fluoroquinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-ylamino)piperidine-1-carboxylate: LCMS tR=3.24 Min (5 min run, UV254nm), Mass calculated for M+737.4, observed m/z 738.3 (M+H).
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[F:13][C:14]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=O.Cl.[F:25][CH2:26][C:27]([NH2:30])([CH3:29])[CH3:28].C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>C(Cl)Cl>[F:25][CH2:26][C:27]([NH:30][C:16](=[O:18])[C:15]1[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:14]=1[F:13])([CH3:29])[CH3:28]
Reactant: CC(C)(N)CF
Reactant: O=C(O)c1ccc(F)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(CF)NC(=O)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 44 %

Procedure:
WSC HCl (1.15 g, 6 mmol) was added to a mixture of 2,4-difluorobenzoic acid (0.95 g, 6 mmol), 2-fluoro-1,1-dimethylethylamine hydrochloride (J. Med. Chem., 34, 29-37(1991): 0.77 g, 6 mmol), HOBt (0.81 g, 6 mmol) and triethylamine (0.91 g, 9 mmol) in methylene chloride (15 ml), and stirred at room temperature for 3 hours. The reaction mixture was concentrated, diluted with ethyl acetate and washed with saturated aqueous NaHCO3, 1N hydrochloric acid, saturated aqueous NaHCO3 and brine, successively, dried over MgSO4 and concentrated under a reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=20/1) to give the title compound (0.61 g: 44%).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].C[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=1C.ClC1CCCCC1=O>O>[CH2:1]([N:3]1[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2]
Reactant: CCNc1ccccc1
Reactant: Cc1ccccc1C
Agent: O=C1CCCCC1Cl
Solvent: O
Product: CCn1c2c(c3ccccc31)CCCC2
Temperature: 100 °C

Procedure:
266.2 g N-ethyl aniline was charged in a reactor along with 200 ml o-xylene. To this 132.5 g of 2-chloro-cyclohexanone was added over a period of 2 hours to obtain a clear solution which was then heated to 100° C. and stirred for 2 hours with water removal. The contents were further heated to 150-160° C. with simultaneous water removal by applying mild vacuum. The reaction mass was worked up as above to get 136 g crude 9-ethyl tetrahydrocarbazole with 96.8% GC purity.
Reaction SMILES: [C:1]([C:3]([C:10]#[N:11])=[C:4]([CH3:9])[CH:5]=[CH:6]OC)#[N:2].S(=O)(=O)(O)[OH:13]>O>[C:1]([C:3]1[C:10](=[O:13])[NH:11][CH:6]=[CH:5][C:4]=1[CH3:9])#[N:2]
Reactant: COC=CC(C)=C(C#N)C#N
Reactant: O=S(=O)(O)O
Solvent: O
Product: Cc1cc[nH]c(=O)c1C#N
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 90.6 %

Procedure:
The mixture of 4,4-dicyano-3-methyl-3-butenal dimethyl acetatal (1) and 1, 1-dicyano-4-methoxy-2-methyl-1,3-butadiene (2) produced by the preceding step was added to a stirred solution of concentrated sulfuric acid (1 09.8 g, 1.12 moles) at a rate so that the reaction contents did not exceed 30° C. The reaction mixture was then heated to 50° C. and held at that temperature for 1.5 hours. The reaction mixture was cooled to ambient temperature followed by the addition of water (150 mL). The product was filtered from the reaction mixture, washed with water (20 mL) and dried in a vacuum oven at 70° C. and full vacuum for 12 hours to give 40.7 g of 3-cyano-4-methyl-2-pyridone (3).
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1.Br[CH2:11][CH2:12][O:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1>CN(C=O)C.O>[O:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH:14]1[O:13][CH2:12][CH2:11][S:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1
Reactant: BrCCOC1CCCCO1
Reactant: Sc1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: c1cc(SCCOC2CCCCO2)ccn1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 61.6 %

Procedure:
Sodium hydride (890 mg of a 50% suspension in mineral oil, 19 mmol) was added to a solution of 4-mercaptopyridine (2.34 g, 21 mmol) in DMF (75 ml) and the mixture stirred for 30 minutes. 2-(2-Bromoethoxy)tetrahydropyran (4.0 g, 19 mmol), (J. Am. Chem. Soc. 1948, 70, 4187), was added and the mixture heated at 100° C. for 3 hours and then stirred at ambient temperature for 18 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed with water, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol mixtures (100/0 increasing to 97/3) to give 4-(2-(tetrahydropyran-2-yloxy)ethylthio)pyridine (2.8 g, 56%).
Reaction SMILES: C(OC(C)C)(=O)CCCCCCCCCCCCCCCCC.C([O:43][CH:44]([CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[CH3:45])(=O)CCCCCCCCCCCCCCCCC>O>[CH3:45][C@H:44]([OH:43])[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53]
Reactant: CCCCCCCCCCCCCCCCCC(=O)OC(C)CCCCCCCC
Agent: CCCCCCCCCCCCCCCCCC(=O)OC(C)C
Solvent: O
Product: CCCCCCCC[C@H](C)O
Temperature: 95 °C
Reaction time: 0.02 h
Yield: 73.5 %

Procedure:
In a 300 ml separable flask were put 1 g of Lipase QL and 40 g of (R,S)-2-decanol, and the mixture was subjected to ultrasonication with the same ultrasonic wave generating equipment as used in Example 1 at room temperature and 90 kHz for 1 minute. To the dispersion was added 60 g of isopropyl stearate, followed by stirring at 95° C. and 250 rpm for 20 hours to carry out interesterification while evaporating by-produced isopropyl alcohol under reduced pressure. The water content of the reaction system was 0.02% by weight, and 96% of the lipase particles had a particle size of 10 to 40 μm. Gas chromatographic analysis of the reaction mixture revealed that 58 mol % of (R,S)-2-decanol had been converted to 2-decyl stearate. Lipase was removed by filtration in the same manner as in Example 1, and the filtrate was subjected to simple distillation at 70° C. under reduced pressure of 5 mmHg to give (S)-(+)-2-decanol (yield: 73.5%; chemical purity: 99.9%; optical purity: 98.5% ee). The residue, i.e., a mixture of (R)-(-)-2-decanol stearic acid ester and unreacted isopropyl stearate was acid-hydrolyzed in the same manner as in Example 2, and 1000 ml of acetone was added to the reaction mixture, followed by cooling to 5° C. The precipitated stearic acid was removed by filtration, and methanol was evaporated from the filtrate under reduced pressure to give (R)-(-)-2-decanol (yield: 72%; chemical purity: 99.6%; optical purity: 84% ee).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[CH:23]=[CH:22][C:12]([C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[O:14])=[C:11]([Cl:24])[CH:10]=1.[C:25](=O)([O:36]C1C=CC([N+]([O-])=O)=CC=1)[O:26][CH2:27][O:28][C:29](=[O:35])[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].ON1C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CN(C=O)C>[Cl:24][C:11]1[CH:10]=[C:9]([NH:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][C:25](=[O:36])[O:26][CH2:27][O:28][C:29](=[O:35])[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:23]=[CH:22][C:12]=1[C:13](=[O:14])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21]
Reactant: Cc1ccccc1C(=O)c1ccc(Nc2ccccc2N)cc1Cl
Reactant: CCCCCC(=O)OCOC(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCCC(=O)OCOC(=O)Nc1ccccc1Nc1ccc(C(=O)c2ccccc2C)c(Cl)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 4-(2-aminophenylamino)-2-chloro-2′-methylbenzophenone (305 mg, 1.0 mmol) and hexanoyloxymethyl 4-nitrophenyl carbonate (Compound 207) (3.3 g, 10 mmol) in DMF (50 ml) was added 1-hydroxybenzotriazole (270 mg, 2.0 mmol) followed by N-ethyl di-iso-propylamine (0.18 ml, 1.05 mmol). The reaction mixture was stirred at room temperature. After 72 hours, the reaction mixture was poured into ice/water and extracted with diethylether. The etheral extracts were washed with a saturated sodium carbonate solution, water, and brine and dried over anhydrous sodium sulphate. Filtration and concentration in vacuo afforded the crude product. This was further purified by chromatography using Et2O/hexane 2:1 as eluent.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1([CH3:18])[CH2:11][O:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:8]1.[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[CH:29]=[O:30]>O1CCCC1.C1(C(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:6][C:7]1([CH3:18])[CH2:11][O:10][C:9]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=2[CH:29]([C:20]2[CH:21]=[CH:22][C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:19]=2)[OH:30])=[N:8]1
Reactant: O=Cc1ccc2ccccc2c1
Reactant: CC1(C)COC(c2ccccc2)=N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: c1ccc(C(c2ccccc2)c2ccccc2)cc1
Product: CC1(C)COC(c2ccccc2C(O)c2ccc3ccccc3c2)=N1
Temperature: -30 °C
Reaction time: 1 h
Yield: 58.7 %

Procedure:
At −78° C., 104 ml of a 1.6M solution of butyl lithium were slowly added dropwise to 25 g (0.14 mol) of 4,4-dimethyl-2-phenyl-2-oxazolin and 0.1 g of triphenylmethane in 400 ml of anhydrous tetrahydrofuran. The mixture was stirred for 1 h. The mixture was then allowed to warm to −30° C. and a solution of 20.3 g (0.13 mol) of 2-naphthaldehyde in 200 ml of anhydrous tetrahydrofuran was added dropwise. Stirring was continued for about 1 h at −20 to −30° C. The reaction solution was then allowed to warm to room temperature and the solvent was removed under reduced pressure. The residue was introduced into ice-water which was then extracted with ether. The organic phase was dried and concentrated under reduced pressure. This residue was purified chromatographically (eluent: n-heptane/acetone=40/3), affording 25.3 g (54%) of the product.
Reaction SMILES: Cl[C:2]1[CH:9]=[N:8][CH:7]=[C:6]([Cl:10])[C:3]=1[C:4]#[N:5].[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=1[NH:22][C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][CH:27]=1)=[O:24].C([O-])(O)=O.[Na+]>O1CCOCC1.O.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>[Cl:10][C:6]1[C:3]([C:4]#[N:5])=[C:2]([C:29]2[CH:28]=[CH:27][C:26]([NH:25][C:23]([NH:22][C:13]3[CH:14]=[C:15]([C:18]([F:19])([F:21])[F:20])[CH:16]=[CH:17][C:12]=3[F:11])=[O:24])=[CH:31][CH:30]=2)[CH:9]=[N:8][CH:7]=1
Reactant: N#Cc1c(Cl)cncc1Cl
Reactant: CC1(C)OB(c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1c(Cl)cncc1-c1ccc(NC(=O)Nc2cc(C(F)(F)F)ccc2F)cc1
Reaction time: 8 h
Yield: 33.4 %

Procedure:
To a solution of 346 mg of 3,5-dichloroisonicotinonitrile and 959 mg of 1-(2-fluoro-5-trifluoromethylphenyl)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea in 24 mL of dioxane are added 462 mg of NaHCO3 in 14.4 mL of water. 462 mg of tetrakis(triphenylphosphine)palladium are then added and the reaction is refluxed for 5 hours and then left overnight at 20° C. 20 mL of water are then added and the mixture is extracted with 2×60 mL of ethyl acetate. The organic phase is dried over magnesium sulfate and then concentrated under reduced pressure. The brown oil is purified on a prepacked Merck cartridge of 30 g of SiO2 15-40 μm (dichloromethane and then 99/1 dichloromethane/methanol). 290 mg of yellow crystals of 1-[4-(5-chloro-4-cyanopyrid-3-yl)phenyl]-3-(2-fluoro-5-trifluoromethylphenyl)urea are obtained.
Reaction SMILES: C(O)(=O)C.S(=O)(=O)(O)O.[O:10]=[C:11]1[C:20]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[O:14][C:13]2[CH:21]=[CH:22][C:23]([C:25]([CH:27](C(OCC)=O)C(OCC)=O)=[O:26])=[CH:24][C:12]1=2>O>[C:25]([C:23]1[CH:22]=[CH:21][C:13]2[O:14][C:15]3=[N:16][CH:17]=[CH:18][CH:19]=[C:20]3[C:11](=[O:10])[C:12]=2[CH:24]=1)(=[O:26])[CH3:27]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)c1ccc2oc3ncccc3c(=O)c2c1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)c1ccc2oc3ncccc3c(=O)c2c1

Procedure:
A mixture of 7.5 ml of glacial acetic acid, 0.9 ml of concentrated sulfuric acid, 4.5 ml of water and 4.6 g of diethyl 2-(5-oxo-5H-[1]benzopyrano[2,3-b]pyridin-7-yl-carbonyl)malonate is stirred under reflux for 2 hours. The reaction mixture is poured into 50 ml of cool water. The crystalline precipitate is filtered off, and suspended in water. The suspension is alkalified with 10% sodium hydroxide under ice cooling, and extracted with chloroform. The extract is washed thoroughly with water, dried, and concentrated. The residue is recrystallized from toluene to give 7 -acetyl-5-oxo-5H-[1]benzopyrano[2,3-b]pyridine melting at 194°-195°C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:12]([NH:13][C:14]3[C:23]4[C:18](=[CH:19][C:20]([F:24])=[CH:21][CH:22]=4)[N:17]=[C:16]([C:25]4[CH:30]=[C:29]([N+:31]([O-:33])=[O:32])[CH:28]=[CH:27][C:26]=4F)[C:15]=3[CH3:35])=[CH:11][C:10]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)=[CH:9][N:8]=2)[CH2:3][CH2:2]1.[CH3:42][S:43]([OH:45])=[O:44].[Na]>CC(N(C)C)=O>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:12]([NH:13][C:14]3[C:23]4[C:18](=[CH:19][C:20]([F:24])=[CH:21][CH:22]=4)[N:17]=[C:16]([C:25]4[CH:30]=[C:29]([N+:31]([O-:33])=[O:32])[CH:28]=[CH:27][C:26]=4[S:43]([CH3:42])(=[O:45])=[O:44])[C:15]=3[CH3:35])=[CH:11][C:10]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)=[CH:9][N:8]=2)[CH2:3][CH2:2]1
Reactant: CS(=O)O
Reactant: Cc1c(-c2cc([N+](=O)[O-])ccc2F)nc2cc(F)ccc2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Agent: [Na]
Solvent: CC(=O)N(C)C
Product: Cc1c(-c2cc([N+](=O)[O-])ccc2S(C)(=O)=O)nc2cc(F)ccc2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Reaction time: 2 h

Procedure:
The N-(2,5-dimorpholinopyridin-3-yl)-7-fluoro-2-(2-fluoro-5-nitrophenyl)-3-methylquinolin-4-amine (66 mg, 0.112 mmol) and methanesulfinic acid, sodium salt (12.0 mg, 0.112 mmol) was added to dimethylacetamide (0.24 mL) and placed in a microwave reactor for 2 h at 150° C. An LCMS was taken and ˜35% of starting material had converted to desired product. The mixture was reheated and stirred at 150° C. for 4 h. The reaction was then diluted with water (20 mL) and extracted with EtOAc (2×30 mL). The combined organic layers were washed with water (1×30 mL) and brine (1×30 mL) and dried over magnesium sulfate. The mixture was purified by reverse-phase preparative HPLC using a Phenomenex Gemini™ column, 10 micron, C18, 100 Å, 150×30 mm, 0.1% TFA in CH3CN/H2O, gradient 10% to 90% over 20 minutes to provide N-(2,5-dimorpholinopyridin-3-yl)-7-fluoro-3-methyl-2-(2-(methylsulfonyl)-5-nitrophenyl)-quinolin-4-amine after extraction with satd sodium bicarbonate. 1H NMR (CDCl3) δ ppm 8.48-8.56 (1H, m), 8.40-8.47 (1H, m), 8.31 (1H, s), 7.88-8.04 (1H, m), 7.67 (1H, dd, J=9.5, 2.6 Hz), 7.62 (1H, d, J=2.0 Hz), 7.38-7.47 (1H, m), 7.01 (1H, br. s.), 6.38 (1H, br. s.), 3.89-4.06 (4H, m), 3.76 (4H, t, J=4.6 Hz), 3.37-3.56 (2H, m), 2.93-3.28 (9H, m), 2.03 (3H, s). Mass Spectrum (ESI) m/e=623.3.3 (M+1).
Reaction SMILES: [CH2:1]([S:3][C:4]1[NH:13][C:7]2=[N:8][CH:9]=[CH:10][C:11]([CH3:12])=[C:6]2[N:5]=1)[CH3:2].[H-].[Na+].Br[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]2[C:30]#[N:31])=[CH:20][CH:19]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH2:1]([S:3][C:4]1[N:13]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([N:24]3[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]3[C:30]#[N:31])=[CH:22][CH:23]=2)[C:7]2=[N:8][CH:9]=[CH:10][C:11]([CH3:12])=[C:6]2[N:5]=1)[CH3:2]
Reactant: N#Cc1cc(Cl)cn1-c1ccc(CBr)cc1
Reactant: CCSc1nc2c(C)ccnc2[nH]1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCSc1nc2c(C)ccnc2n1Cc1ccc(-n2cc(Cl)cc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28.1 %

Procedure:
To a solution of 2-ethylthio-7-methyl-3H-imidazo[4,5-b]pyridine (1.50 g) in dimethylformamide (15 ml) was added sodium hydride (341 mg) at room temperature under nitrogen atmosphere. The mixture was stirred for 30 minutes at the same room temperature under nitrogen atmosphere. To the mixture was added a solution of 1-(4-bromomethylphenyl)-4-chloropyrrole-2-carbonitrile (2.19 g) in dimethylformamide (15 ml). The mixture was stirred for 3 hours at room temperature. The mixture was treated with aqueous sodium bicarbonate solution, extracted twice with ethyl acetate. The extracts were washed with water, dried over magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (eluted by n-hexane/ethyl acetate=1/1) to yield 2-ethylthio-3-[4-(4-chloro-2-cyano-1-pyrrolyl)benzyl]-7-methyl-3H-imidazo-[4,5-b]pyridine (850 mg) as a yellow oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][C:4]([NH:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:3]1.[CH3:24][C:25]1([NH2:29])[CH2:28][O:27][CH2:26]1>>[CH3:1][N:2]1[C:6]([C:7]([NH:29][C:25]2([CH3:24])[CH2:28][O:27][CH2:26]2)=[O:9])=[CH:5][C:4]([NH:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:3]1
Reactant: CC1(N)COC1
Reactant: Cc1onc(-c2ccccn2)c1CNc1cc(C(=O)O)n(C)n1
Product: Cc1onc(-c2ccccn2)c1CNc1cc(C(=O)NC2(C)COC2)n(C)n1
Yield: 70 %

Procedure:
As described for example 160c, 1-methyl-3-((5-methyl-3-(pyridin-2-yl)isoxazol-4-yl)methylamino)-1H-pyrazole-5-carboxylic acid (80 mg, 255 μmol) was converted, using 3-methyl-3-oxetanamine instead of isopropylamine, to the title compound (68 mg, 70%) which was obtained as a white solid. MS: m/e=383.3 [M+H]+.
Reaction SMILES: [Si:1]([O:8][C@H:9]([CH2:26][O:27][Si](C(C)(C)C)(C)C)[C@@H:10]([NH:19][S@](C(C)(C)C)=O)[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.COC1C=CC(C=O)=CC=1.[O:46](C(OC(C)(C)C)=O)[C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=O>C(OCC)C.CCO>[Si:1]([O:8][C@H:9]([CH2:26][OH:27])[C@@H:10]([NH:19][C:47](=[O:46])[O:49][C:50]([CH3:53])([CH3:52])[CH3:51])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[S@](=O)N[C@@H](Cc1cccc(F)c1)[C@@H](CO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: COc1ccc(C=O)cc1
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cccc(F)c1)[C@@H](CO)O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a 500 mL RBF containing (S)—N-((2S,3S)-3,4-bis(tert-butyldimethylsilyloxy)-1-(3-fluorophenyl)butan-2-yl)-2-methylpropane-2-sulfinamide (2.600 g, 4.9 mmol) was added EtOH (25 ml) and the mixture was allowed to stir at 0° C. for 15 min. At this time, HCl (4N in dioxane) (3.7 ml, 15 mmol) was added via syringe. The reaction was monitored at 1 h by LC/MS 76877-2-1 and tlc (100% EtOAC amino bis TBS; Rf=0.80 UV active stains orange to anisaldehyde amine with primary alcohol deprotected Rf=0.45 to 0.1 streak, UV active and stains white to anisaldehyde). The reaction was allowed to stir for 3 h at 0° C. and then TEA (4.1 ml, 29 mmol) was added fast dropwise and a white solid formed. An LC/Ms was obtained to confirm that the secondary TBS ether was not removed during the TEA neutralization process. Approximately 15 mL of EtOH were removed by rotary evaporator and then DCM (10 mL) was added and the solid went into solution. At this time, (BOC)2O (2.3 ml, 9.8 mmol) was added in one portion and the reaction was allowed to stir for 1 h and then poured into diethyl ether (300 ml). The organic layer was washed with ammonium chloride (3×150 mL, sat) and brine. The organic layer was dried with magnesium sulfate, filtered and concentrated to give a colorless crude oil. The desired product has an Rf=0.40 in 35% EtOAc in hexanes, UV active, stains white to anisaldehyde and purple to moly stain. The crude oil was purified on a 120 g Isco column (10 to 35% EtOAc in hexanes) to give the title compound as a colorless oil.