Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14](=[O:15])[CH:13]2[CH2:16][CH2:17][CH2:18][C:11](=[CH:12]2)C1=O.[NH3:20].C[C:22](C)=[O:23]>>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:14](=[O:15])[C:13]1[CH2:12][CH2:11][CH2:18][CH2:17][C:16]=1[C:22]([NH2:20])=[O:23]
Reactant: O=C1C2=CC(CCC2)C(=O)N1c1ccc(Cl)cc1F
Reactant: N
Reactant: CC(C)=O
Product: NC(=O)C1=C(C(=O)Nc2ccc(Cl)cc2F)CCCC1
Reaction time: 0.5 h

Procedure:
In acetone (100 ml) was dissolved N-(2-fluoro-4-chlorophenyl)-3,4,5,6-tetrahydroisophthalimide (22.5 g), and under cooling, 25% aqueous ammonia (5.8 g) was added dropwise over a period of about one minute, the temperature of the system being maintained below 25° C. The mixture was further stirred for 30 minutes, after which the precipitate was recovered by filtration and washed with a small amount of cold acetone. Yield 22.2 g; m.p. 150°-151° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=O)=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([OH:21])=[O:20])=[CH:15][CH:14]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C(=O)([O-])O.[Na+].[CH:42]([NH2:44])=[O:43]>CCCCCC.C(OCC)(=O)C.O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([S:19]([C:16]3[CH:17]=[CH:18][C:13]([CH3:12])=[CH:14][CH:15]=3)(=[O:21])=[O:20])[NH:44][CH:42]=[O:43])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: NC=O
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: Cc1ccc(S(=O)O)cc1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1ccc(S(=O)(=O)C(NC=O)c2ccc3c(c2)OCO3)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 33 %

Procedure:
A solution of benzo[1,3]dioxole-5-carbaldehyde (1.0 g, 6.66 mmol), 4-methyl-benzenesulfinic acid (1.1 g, 7.24 mmol, 1.09 equiv), and 10-camphorsulfonic acid (0.4 g, 1.72 mmol, 0.25 equiv) in formamide (2.8 mL) was heated to 75° C. for four hours. The resulting reaction mixture was cooled to ambient temperature, poured into a mixture of saturated aqueous sodium hydrogen carbonate (100 mL), water (100 mL), ethyl acetate (20 mL) and hexane (20 mL), and stirred at ambient temperature for 20 minutes. The resulting white solid was filtered off and azeotroped with toluene (2×50 mL) to provide N-[Benzo[1,3]dioxol-5-yl-(toluene-4-sulfonyl)-methyl]-formamide (740 mg, 33%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>CC(C)=O>[CH2:23]([O:22][C:20](=[O:21])[CH2:19][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][C:9](=[O:11])[CH3:10])[CH:3]=1)[CH3:24]
Reactant: CC(=O)Nc1cccc(O)c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1cccc(NC(C)=O)c1
Temperature: 100 °C

Procedure:
To a solution of N-(3-hydroxy-phenyl)-acetamide (0.5 g, 3.3 mmol) in acetone (5 ml) was added K2CO3 (0.46 g, 3.3 mmol), ethyl bromoacetate (0.67 g, 4.0 mmol) and 10 4A molecular sieves. The reaction mixture was then heated in the microwave for 1 h at 100° C. (150 W, 200 psi). The reaction mixture was filtered and the acetone layer evaporated in vacuo. This residue was dissolved in EtOAc (10 ml) and washed with 2M KOH (5 ml×2). The organic layer was dried (Na2SO4), filtered and the solvent removed in vacuo to give the title compound as a colourless oil which solidified upon standing.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10]([NH:13][C:14]2[CH:15]=[C:16]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:17]=[CH:18][CH:19]=2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-])=O>O.CO.C(O)(=O)C.[Fe]>[NH2:1][C:4]1[CH:5]=[C:6]([S:10]([NH:13][C:14]2[CH:15]=[C:16]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])[CH:17]=[CH:18][CH:19]=2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(NS(=O)(=O)c2cccc([N+](=O)[O-])c2)c1
Agent: [Fe]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)Nc1cccc(NS(=O)(=O)c2cccc(N)c2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97.4 %

Procedure:
To a solution tert-butyl (3-{[(3-nitrophenyl)sulfonyl]amino}phenyl)carbamate (0.51 g, 0.0013 mol) in water (1 mL), methanol (5 mL) and acetic acid (2 mL) was added iron (290 mg, 5.2 mmol) powder in one batch. The mixture was stirred at 0° C. for 0.5 h. The reaction mixture was mixed with celite, filtered, and the cake was washed with EtOAc. The brown filtrate was concentrated, followed by the addition of EtOAc and NaHCO3/water. The aqueous phase was extracted with EtOAc. The organics were combined, dried over Na2SO4 and concentrated to give the desired product as a yellow powder (0.46 g, 98%). LCMS for C17H21N3O4S (M-tBu+H)+: m/z=308.0. 1H NMR (400 MHz, DMSO-d6): δ 10.02 (s, 1H), 9.31 (s, 1H), 7.33 (br, 1H), 7.10 (t, J=8.0 Hz, 1H), 7.02 (m, 1H), 6.93 (t, J=2.0 Hz, 1H), 6.85 (ddd, J=7.6, 1.8, 1.0 Hz, 1H), 6.67 (m, 1H), 5.53 (s, 1H), 1.43 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH2:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1B(O)O.C(N(CC)CC)C>ClCCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH:9][C:19]1[CH:18]=[CH:17][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: OB(O)c1ccc2ccccc2c1
Reactant: CC(C)(C)OC(=O)N(N)Cc1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N(Cc1ccccc1)Nc1ccc2ccccc2c1
Temperature: 50 °C
Yield: 49 %

Procedure:
A mixture of N-benzyl-hydrazinecarboxylic acid tert-butyl ester (Intermediate 27; 1.21 g, 5.44 mmol), 2-naphthaleneboronic acid (Lancaster; 1.00 g, 5.8 mmol), copper(II) acetate (990 mg, 5.45 mmol) and triethylamine (1.9 mL, 13.6 mmol) in 1,2-dichloroethane (30 mL) was heated in an oil bath at 50° C. for 1.5 h. The mixture was allowed to cool, and it was then adsorbed onto silica gel and purified by chromatography using an ISCO 120 g column, eluting with 15-30% ethyl acetate/hexanes, to give N-benzyl-N′-naphthalen-2-yl-hydrazinecarboxylic acid tert-butyl ester (929 mg, 49%) as a yellow oil that solidified on standing.
Reaction SMILES: S(=O)(=O)(O)O.[BrH:6].[CH:7]1([CH2:13][CH2:14]O)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1>>[Br:6][CH2:14][CH2:13][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: OCCC1CCCCC1
Reactant: Br
Agent: O=S(=O)(O)O
Product: BrCCC1CCCCC1
Temperature: 25 °C
Yield: 85.1 %

Procedure:
In a 1 l-roundbottom flask equipped with a reflux condenser 164 g concentrated sulphuric acid and 200 g hydrobromic acid (48% in water) were added subsequently under cooling with an ice bath to 88.7 g (0.693 mole) 2-cyclohexyl-ethanol. The mixture was refluxed for 6 h and after cooling to room temperature given to 400 g of ice. The aqueous phase was extracted with 400 ml pentane. The organic layer was washed with a 2 M NaOH-solution and with water, dried over magnesium sulphate, and the solvent was removed in vacuo. The product was distilled in vacuo to yield 112.7 g (85%) of (2-bromo-ethyl)-cyclohexane as a colourless oil. 1H-NMR (400 MHz, CDCl3): δ=3.40 (2H, t, CH2Br), 1.73-1.61 (m, 7H), 1.44 (m, 1H), 1.26-1.11 (m, 3H), 0.92-0.84 (m, 2H) ppm.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:5]=[CH:4][CH:3]=1.[OH:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C(OCC)(=O)C.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>[OH:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[N:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:5]=[CH:4][CH:3]=2)=[CH:16][CH:15]=1
Reactant: OB(O)c1ccc(O)cc1
Reactant: CCOC(=O)c1cccc(Br)n1
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: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1cccc(-c2ccc(O)cc2)n1
Temperature: 150 °C
Yield: 69.9 %

Procedure:
To a solution of ethyl 6-bromo-2-pyridinecarboxylate (D1, 460 mg, 2.0 mmol) in dioxane (4 ml) were added 4-hydroxy-phenyl boronic acid (414 mg, 3.0 mmol), Pd(PPh3)4 (450 mg, 0.4 mmol) and potassium carbonate (420 mg, 4.0 mmol) dissolved in water (2 ml). The reaction mixture was heated in a microwave synthesizer for 15 min at 150° C. The reaction mixture was diluted with ethyl acetate (150 ml) and washed with saturated aqueous ammonium chloride (40 ml). The resulting crude material was purified by chromatography on silica gel using ethyl acetate/cyclohexanes (1:1) to afford the title compound (340 mg, 72%); 1H-NMR (300 MHz, CDCl3) δ (ppm): 8.05 (d, 2H), 8.0 (m, 1H), 7.80 (d, 2H), 7.05 (d, 2H), 6.80 (bt, 1H), 4.50 (q, 2H), 1.45 (t, 3H).
Reaction SMILES: Cl.[CH:2]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([OH:16])[CH:10]=1)=[O:8])([CH3:4])[CH3:3].[Cl:17][C:18]1[C:26]([O:27][CH3:28])=[C:25]([CH3:29])[CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>>[CH:2]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:20](=[O:21])[C:19]2[CH:23]=[CH:24][C:25]([CH3:29])=[C:26]([O:27][CH3:28])[C:18]=2[Cl:17])=[C:11]([OH:16])[CH:10]=1)=[O:8])([CH3:4])[CH3:3]
Reactant: CC(C)NCC(=O)c1ccc(O)c(O)c1
Reactant: COc1c(C)ccc(C(=O)Cl)c1Cl
Agent: Cl
Product: COc1c(C)ccc(C(=O)Oc2ccc(C(=O)CNC(C)C)cc2O)c1Cl

Procedure:
Following the procedure described above in Example 58A but using 3,4-dihydroxyphenyl isopropylaminomethyl ketone hydrochloride instead of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride and 2-chloro-3-methoxy-4-methylbenzoyl chloride instead of isovaleryl chloride, there is obtained 3-hydroxy-4-(2-chloro-3-methoxy-4-methylbenzoyloxy)phenyl isopropylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using a procedure similar to that described above in Example 2B, there is obtained 3-hydroxy-4-(2-chloro-3-methoxy-4-methylbenzoyloxy)-apha-(isopropylaminomethyl)benzyl alcohol hydrochloride.
Reaction SMILES: [ClH:1].CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O.C(O)=O.[C:29]([C:31]1[CH:56]=[CH:55][C:34]([CH2:35][N:36]2[CH2:43][CH:42]3[O:44][CH:38]([CH2:39][N:40]([CH2:45][CH2:46][NH:47]C(=O)OC(C)(C)C)[CH2:41]3)[CH2:37]2)=[CH:33][CH:32]=1)#[N:30]>C(OCC)(=O)C>[ClH:1].[NH2:47][CH2:46][CH2:45][N:40]1[CH2:41][CH:42]2[O:44][CH:38]([CH2:37][N:36]([CH2:35][C:34]3[CH:33]=[CH:32][C:31]([C:29]#[N:30])=[CH:56][CH:55]=3)[CH2:43]2)[CH2:39]1
Reactant: CC(C)(C)OC(=O)NCCN1CC2CN(Cc3ccc(C#N)cc3)CC(C1)O2
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: Cl
Solvent: O=CO
Solvent: CCOC(C)=O
Product: N#Cc1ccc(CN2CC3CN(CCN)CC(C2)O3)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96 %

Procedure:
A saturated solution of HCl in ethyl acetate (200 mL) was added to an ice-cooled slurry of the acetic and formic acid salt of tert-butyl {2-[7-(4-cyanobenzyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]ethyl}carbamate (7.00 g, 14.2 mmol). The reaction mixture was stirred at room temperature for 3 hours after which it was filtered and the resultant solid was washed with ethyl acetate. Drying in vacuo gave 6.12 g (96%) of the title compound with one equivalent of residual ethyl acetate.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([OH:9])=[CH:7][CH:6]=[CH:5][N:4]=1)[CH3:2].[H-].[Na+].Br[C:13]1[CH:14]=[C:15]([N+]([O-])=O)[C:16]([C:19]#[N:20])=[N:17][CH:18]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[SH:30]>CN(C=O)C.O>[CH2:1]([C:3]1[C:8]([O:9][C:15]2[C:16]([C:19]#[N:20])=[N:17][CH:18]=[C:13]([S:30][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=3)[CH:14]=2)=[CH:7][CH:6]=[CH:5][N:4]=1)[CH3:2]
Reactant: CCc1ncccc1O
Reactant: N#Cc1ncc(Br)cc1[N+](=O)[O-]
Reactant: Sc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1ncccc1Oc1cc(Sc2ccccn2)cnc1C#N
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 58 %

Procedure:
To a solution of 2-ethylpyridin-3-ol (2.5 g, 20.3 mmol)in DMF (20 ml) at 0° C. was added sodium hydride (0.512 g, 21.3 mmol). After 15 minutes, 5-bromo-3-nitropicolinonitrile (4.63 g, 20.3 mmol) was added and the mixture was allowed to warm slowly to ambient temperature and stirred for 2 hours. Pridine-2-thiol (0.804 g, 7.23 mmol) was added followed by sodium hydride (0.182 g, 7.60 mmol) and the mixture was stirred at ambient temperature overnight. Water (200 ml) was added and the mixture was extracted with diethyl ether (3×100 mL), washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified over silica gel (25 to 75% EtOAc in Hexanes) to afford 3-(2-ethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)picolinonitrile (1.4 g, 4.19 mmol).
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[CH:13]([OH:22])([C:18]([F:21])([F:20])[F:19])[C:14]([F:17])([F:16])[F:15].N1C(C)=CC=CC=1C.[F:31][C:32]1[CH:33]=[C:34]([N:45]2[CH2:50][CH2:49][O:48][CH2:47][CH2:46]2)[CH:35]=[CH:36][C:37]=1[CH2:38][N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1.ClC([O-])=O.C(=O)(O)[O-].[Na+]>ClCCl>[F:31][C:32]1[CH:33]=[C:34]([N:45]2[CH2:46][CH2:47][O:48][CH2:49][CH2:50]2)[CH:35]=[CH:36][C:37]=1[CH2:38][N:39]1[CH2:40][CH2:41][N:42]([C:2]([O:22][CH:13]([C:18]([F:21])([F:20])[F:19])[C:14]([F:17])([F:16])[F:15])=[O:4])[CH2:43][CH2:44]1
Reactant: Fc1cc(N2CCOCC2)ccc1CN1CCNCC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OC(C(F)(F)F)C(F)(F)F
Agent: O=C([O-])Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: O=C(OC(C(F)(F)F)C(F)(F)F)N1CCN(Cc2ccc(N3CCOCC3)cc2F)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A 10 mL screw cap vial equipped with a magnetic stir bar was charged with triphosgene (22 mg, 0.233 mmol, 0.35 equiv) and dichloromethane (1 mL) under nitrogen and cooled to 0° C. 1,1,1,3,3,3-Hexafluoroisopropanol (29 uL, 0.23 mmol) was added via syringe over 1 min followed by addition of 2,6-lutidine, (52 uL, 0.44 mmol, 2.1 equiv) over 1 min. The latter addition is exothermic and the internal temperature was maintained below 5° C. during the addition. N,N-dimethylaminopyridine (2 mg, 0.1 equiv) was then added to the reaction mixture. The solution remained colorless and the ice bath was removed. The resulting clear solution was allowed to stir at room temperature for 1 h. A separate 10 mL vial, equipped with a magnetic stir bar, was charged with 4-(3-fluoro-4-(piperazin-1-ylmethyl)phenyl)morpholine (59.1 mg, 0.212 mmol) and dichloromethane (1 mL). The chloroformate solution was re-cooled to 0° C. and the amine solution was added to the chloroformate solution over 1 min via syringe. The amine-containing flask was rinsed with dichloromethane (0.25 mL) and the rinsing solution was added to the reaction flask. The ice bath was removed and the clear, colorless reaction was stirred at room temperature overnight. Saturated aqueous sodium bicarbonate (1 mL) was added and the layers were separated. The aqueous layer was washed with dichloromethane (1 mL). The organic layers were combined, concentrated and applied to a 40 g silica gel column to afford 1,1,1,3,3,3-hexafluoropropan-2-yl 4-(2-fluoro-4-morpholinobenzyl)piperazine-1-carboxylate, 54 mg (58%). 1H NMR 400 MHz (CDCl3) δ 7.18 (t, J=8.5 Hz, 1H), 6.65 (dd, J=8.5, 2.2 Hz, 1H), 6.56 (dd, J=13.0, 2.2 Hz, 1H), 5.73 (hep, J=6.2 Hz, 1H), 3.88-3.81 (m, 4H), 3.53 (bs, 6H), 3.18-3.07 (m, 4H), 2.52-2.43 (m, 4H). LCMS (ESI, m/z): 194.1 (4-morpholino-2-fluorobenzyl cation).
Reaction SMILES: Cl[S:2]([CH2:5][C@H:6]([CH3:17])[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])(=[O:4])=[O:3].[CH3:18][NH:19][CH3:20]>C(Cl)Cl>[CH3:18][N:19]([CH3:20])[S:2]([CH2:5][C@H:6]([CH3:17])[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])(=[O:4])=[O:3]
Reactant: C[C@@H](CS(=O)(=O)Cl)C(=O)OCc1ccccc1
Reactant: CNC
Solvent: ClCCl
Product: C[C@@H](CS(=O)(=O)N(C)C)C(=O)OCc1ccccc1
Temperature: -78 °C

Procedure:
A 100 mL round bottomed flask equipped with magnetic stir bar was charged with 1.7 g benzyl 3-chlorosulfonyl-2(R)-methylpropionate from Example 3 in 25 mL CH2Cl2. The solution was cooled to −78° C. and 15 mL of anhydrous dimethylamine was slowly added. After 30 minutes the reaction was concentrated in vacuo and the residue was partioned between EA/H2O. The organic phase was dried, concentrated in vacuo to yield 1.4 g of benzyl 3-[(dimethylamino)sulfonyl]-2(R)-methylpropionate as a clear amber oil which was used directly in the next step.
Reaction SMILES: OC(C(F)(F)F)=O.[NH2:8][C:9]1[CH:10]=[C:11]([NH:18][C:19]2[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[N:20]=2)[C:12]([C:15]([NH2:17])=[O:16])=[N:13][CH:14]=1.[CH2:27]([N:29]=[C:30]=[O:31])[CH3:28].C(N(CC)CC)C>C1COCC1>[CH3:25][C:23]1[CH:22]=[C:21]([CH3:26])[N:20]=[C:19]([NH:18][C:11]2[C:12]([C:15]([NH2:17])=[O:16])=[N:13][CH:14]=[C:9]([NH:8][C:30](=[O:31])[NH:29][CH2:27][CH3:28])[CH:10]=2)[CH:24]=1
Reactant: CCN=C=O
Reactant: Cc1cc(C)nc(Nc2cc(N)cnc2C(N)=O)c1
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CCNC(=O)Nc1cnc(C(N)=O)c(Nc2cc(C)cc(C)n2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-amino-3-[(4,6-dimethylpyridin-2-yl)amino]pyridine-2-carboxamide TFA salt (50 mg, 0.13 mmol) in THF (1 mL) was added ethyl isocyanate (12 mg, 0.18 mmol) and triethylamine (0.075 mL, 0.54 mmol), and the reaction mixture was stirred for 2 hours at room temperature. Additional ethyl isocyanate (12 mg, 0.18 mmol) and triethylamine (0.075 mL, 0.54 mmol) were added, and the reaction mixture was heated to 55° C. for 18 hours. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (acetonitrile/water with 0.1% TFA, linear gradient) to afford 3-[(4,6-dimethylpyridin-2-yl)amino]-5-[(ethylcarbamoyl)amino]pyridine-2-carboxamide. MS ESI calc'd. for C16H21N6O2 [M+H]+ 329. found 329. 1H NMR (500 MHz, DMSO-d6) δ 11.61 (s, 1H), 9.24 (s, 1H), 8.86 (s, 1H), 8.23 (d, J=2.2 Hz, 1H), 8.13 (s, 1H), 7.57 (s, 1H), 6.63 (s, 1H), 6.53 (s, 1H), 6.33 (t, J=5.3 Hz, 1H), 3.20-3.07 (m, 2H), 2.40 (s, 3H), 2.23 (s, 3H), 1.06 (t, J=7.2 Hz, 3H).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[Si:11]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([OH:32])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[C:22]([O:33][CH3:34])[CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].C(N(CC)CC)C>C(Cl)Cl>[Si:11]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26](=[O:32])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[C:22]([O:33][CH3:34])[CH:21]=1)([C:14]([CH3:15])([CH3:17])[CH3:16])([CH3:12])[CH3:13]
Reactant: CCCCCC(O)c1ccc(CO[Si](C)(C)C(C)(C)C)cc1OC
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCCCCC(=O)c1ccc(CO[Si](C)(C)C(C)(C)C)cc1OC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 91.4 %

Procedure:
A solution of 14.0 ml (0.20 mol) of dimethyl sulfoxide in 50 ml of methylene chloride was added dropwise over a period of 35 minutes to a solution of 9.0 ml (0.10 mol) of oxalyl chloride in 100 ml of methylene chloride cooled to -78° C., whilst the internal temperature of the mixture was kept below -60° C. The resulting mixture was then stirred at -78° C. for 30 minutes, after which a solution of 30.65 g (86.9 mmol) of 1-(4-t-butyldimethylsilyloxymethyl-2-methoxyphenyl)hexyl alcohol [prepared as described in step (i) above] in 60 ml of methylene chloride was added dropwise at the same temperature over a period of 35 minutes. The mixture was then stirred for 30 minutes. 60 ml (0.43 mol) of triethylamine were added dropwise to the mixture at the same temperature over a period of 17 minutes, and then the reaction mixture was stirred for 10 minutes, after which the dry ice-acetone bath was removed and the mixture was stirred for a further 50 minutes. At the end of this time, the reaction was terminated by adding water. The reaction mixture was then diluted with methylene chloride, and the organic phase was separated and then washed with 2 N aqueous hydrochloric acid, with water and with a saturated aqueous solution of sodium hydrogencarbonate, in that order, after which it was dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through 250 g of silica gel, using a 1:9 by volume mixture of ethyl acetate and hexane as the eluent, to give 27.84 g (yield 91%) of the title compound as an oily substance.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([Cl:20])=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:35]=[CH:34][C:25]2[CH2:26][CH2:27][CH2:28][C:29](=[O:33])[N:30]([CH2:31][CH3:32])[C:24]=2[CH:23]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C(O)(C)C>[Cl:20][C:5]1[C:6]([NH:8][C:9]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])=[N:7][C:2]([NH:21][C:22]2[CH:35]=[CH:34][C:25]3[CH2:26][CH2:27][CH2:28][C:29](=[O:33])[N:30]([CH2:31][CH3:32])[C:24]=3[CH:23]=2)=[N:3][CH:4]=1
Reactant: CCN1C(=O)CCCc2ccc(N)cc21
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Product: CCN1C(=O)CCCc2ccc(Nc3ncc(Cl)c(Nc4c(F)cccc4C(=O)NC)n3)cc21
Temperature: 120 °C
Reaction time: 2 h
Yield: 74.7 %

Procedure:
A microwave vessel was charged with 2-(2,5-dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide (57.5 mg, 0.182 mmol), 8-amino-1-ethyl-1,3,4,5-tetrahydro-1-benzazepin-2-one (44.7 mg, 0.219 mmol), 10-camphorsulfonic acid (5.0 mg, 0.022 mmol) and isopropyl alcohol (2 mL) and heated at 120° C. for 60 minutes in a microwave reactor (sealed vessel). The reaction mixture was quenched with a slurry of saturated, aqueous NaHCO3 and stirred for 2 h. The resulting precipitate was filtered, washed with water (5×2 mL), ether (2×2 mL) and dried under vacuum to afford product 65.7 mg, 69%) as a tan solid that had the following properties: mp: 228-235° C.; LC/MS (ESI+): 483 (M+H); 1H-NMR (DMSO-d6, 400 MHz): δ 9.38-9.35 (m, 2H), 8.53 (m, 1H), 8.19 (s, 1H), 7.48-7.45 (m, 2H), 7.36-7.26 (m, 3H), 6.98 (d, J=8.3, 1H), 3.55 (br s, 2H), 2.74 (d, J=4.1, 3H), 2.50 (m, 2H), 2.10-1.85 (m, 4H), 0.93 (t, J=7.0, 3H).
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH3:7])[CH:4]=[O:5])[CH3:2].[CH2:8](O)[CH:9]=[CH:10][CH2:11][OH:12].C1CCCCC1>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[CH3:2][CH2:1][CH:3]([CH:4]1[O:12][CH2:11][CH:10]=[CH:9][CH2:8][O:5]1)[CH2:6][CH3:7]
Reactant: OCC=CCO
Reactant: CCC(C=O)CC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCCCC1
Solvent: O
Product: CCC(CC)C1OCC=CCO1
Temperature: 25 °C
Yield: 86 %

Procedure:
To a one liter flask equipped with heating jacket, agitator and condenser fitted with a Dean-Stark trap was charged 100 grams (1.0 mole), 2-ethyl-butanal, 97 grams(1.1 mole) 2-butene-1,4-diol, 80 grams cyclohexane and 0.2 grams p-toluenesulfonic acid monohydrate. The mixture was heated with vigorous agitation at reflux (84° - 99°C.) until water no longer continued to be distilled from the reaction mixture (1.2 hours). The reaction mixture was cooled to room temperature and the p-toluenesulfonic acid neutralized by washing with reaction mixture with a 5% aqueous solution of sodium hydroxide. The reaction mixture was then washed neutral with water and distilled to remove the cyclohexane. The oil was vacuum distilled to obtain 146 grams (86% of theoretical) of 4,7-dihydro-2-(3-pentyl)-1,3-dioxepin having a boiling point of 47°C. at a pressure of 1.0 millimeter of mercury, (refractive index, ND20 = 1.457). Analysis for carbonyl content of IR showed 0.0% carbonyl and VPC analysis showed the compound to have a purity of 100%.