Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:4]([N:6]([CH3:12])[C:7](=[O:11])[C:8]=1OC)=[O:5])#[N:2].[NH3:13]>>[NH2:13][C:8]1[C:7](=[O:11])[N:6]([CH3:12])[C:4](=[O:5])[C:3]=1[C:1]#[N:2]
Reactant: COC1=C(C#N)C(=O)N(C)C1=O
Reactant: N
Product: CN1C(=O)C(N)=C(C#N)C1=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 83 %

Procedure:
120 parts of 2-cyano-3-methoxy-N-methylmaleimide are dissolved in 600 parts of methylglycol and 13.5 parts of ammonia are then passed into the ice-cooled solution. Stirring is then continued for 3 hours at room temperature, and the resulting precipitate is filtered off under suction, washed with methanol and then with water, and dried to give 90 parts (83% of theory) of 3-amino-2-cyano-N-methylmaleimide.
Reaction SMILES: N1C=CC=CC=1.Cl.CN(C)CCCN=C=NCC.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[OH:26].[N:27]1([C:33]2[N:34]=[C:35]([CH2:40][C:41]([O-])=[O:42])[NH:36][C:37](=[O:39])[CH:38]=2)[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.[Na+]>CN(C)C=O>[OH:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[NH:19][C:41](=[O:42])[CH2:40][C:35]1[NH:36][C:37](=[O:39])[CH:38]=[C:33]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[N:34]=1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: Nc1ccccc1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1ccccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.5 %

Procedure:
4 ml of pyridine, 550 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride and 700 mg of 2-aminophenol are added to a solution of 500 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate in 4 ml of dimethylformamide. The reaction mixture is stirred at ambient temperature overnight, and is then concentrated under reduced pressure. Water and ethyl acetate are added and the resulting mixture is thus stirred for 30 minutes. The precipitate formed is filtered off, and rinsed with water, ethyl ether and petroleum ether. The solid obtained is dried under vacuum. 370 mg of N-(2-hydroxyphenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are thus obtained in the form of a beige solid, the characteristics of which are the following:
Reaction SMILES: CC1C=C(C)C=C(C)N=1.[C:10]([C:14]1[CH:30]=[CH:29][CH:28]=[CH:27][C:15]=1[O:16][C:17]1[N:22]=[C:21](O)[CH:20]=[CH:19][C:18]=1[N+:24]([O-:26])=[O:25])([CH3:13])([CH3:12])[CH3:11].O.P(Cl)(Cl)([Cl:34])=O>>[C:10]([C:14]1[CH:30]=[CH:29][CH:28]=[CH:27][C:15]=1[O:16][C:17]1[C:18]([N+:24]([O-:26])=[O:25])=[CH:19][CH:20]=[C:21]([Cl:34])[N:22]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)c1ccccc1Oc1nc(O)ccc1[N+](=O)[O-]
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: Cc1cc(C)nc(C)c1
Product: CC(C)(C)c1ccccc1Oc1nc(Cl)ccc1[N+](=O)[O-]
Temperature: 130 °C
Yield: 77 %

Procedure:
2,4,6-Trimethylpyridine (1.6 mL) was added dropwise into 136a (2.32 g, 8.0 mmol) in phosphorus oxychloride (3.2 mL) at 0° C. The reaction mixture was heated at 130° C. for 20 h. The reaction was stopped at ˜70% conversion as determined by HPLC. The dark brown solution was poured into water (40 mL) with stirring, and stirred for 15 min. The brown precipitate was filtered, air dried, and purified by SiO2 chromatography (120 g), loaded with a CH2Cl2 and eluted using a gradient of ethyl acetate in hexanes to afford 136b (1.91 g, 77% yield) as an amber colored oil; HPLC purity 100%, 3.95 min (Method A); 1H NMR (500 MHz, CDCl3) δ ppm 8.36 (d, 1H, J, J=10.0 Hz), 7.47 (d, 1H, J=5.0 Hz), 7.23 (m, 2H), 7.16 (d, 1H, J=10.0 Hz), 6.95 (d, 1H, J=10.0 Hz), 1.36 (s, 9H); 13C (125 MHz, CDCl3) δ (ppm), 155.30, 153.23, 150.87, 141.45, 137.72, 133.22, 127.59, 126.91, 125.79, 123.04, 118.39, 34.60, 30.25.
Reaction SMILES: [C:1]([N:9]1[CH2:13][CH:12]2[CH2:14][S:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:11]2=[N:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:30])C=1>ClCCl>[C:1]([N:9]1[CH2:13][CH:12]2[CH2:14][S:15](=[O:30])[CH:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]3=[C:11]2[NH:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(c1cccnc1)N1CC2CSc3ccccc3C2=N1
Solvent: ClCCl
Product: O=C(c1cccnc1)N1CC2CS(=O)C3C=CC=CC3=C2N1
Yield: 50.7 %

Procedure:
To a solution of 2-nicotinoyl-3,3a-dihydro-2H,4H-[1]-benzothiopyrano[4,3-c]pyrazole (6 g) synthesized in Example 37, dissolved in dichloromethane (50 ml) was added m-chloroperbenzoic acid (2.5 g, purity: 70%) with ice-cooling, to give rise to a reaction. After the completion of the reaction, the reaction mixture was washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution. The organic layer was dried and concentrated under vacuum. The residue was purified by silica gel column chromatography (methanol:chloroform=1/40) to obtain 2.3 g of a title compound (yield: 73%).
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.Br.[Br:8][CH2:9][CH2:10][CH2:11][NH2:12].C(N(CC)CC)C>C1COCC1>[Br:8][CH2:9][CH2:10][CH2:11][NH:12][C:4](=[O:5])[CH2:3][C:2]([CH3:1])=[O:6]
Reactant: C=C1CC(=O)O1
Reactant: NCCCBr
Agent: Br
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)CC(=O)NCCCBr
Reaction time: 1 h

Procedure:
Diketene (1.22 mL, 15.7 mmol 1.50 equiv) was added at room temperature to a stirred mixture of 3-bromopropylamine hydrobromide (2.30 g, 10.5 mmol, 1.00 equiv) and triethylamine (1.46 mL, 10.5 mmol, 1.00 equiv) in anhydrous THF (20 mL) under argon, and stirring was continued at room temperature for 1 hour. The solvent was removed and the residue was purified by flash chromatography (SiO2, MeOH—CH2Cl2 0:1 to 1:18) to afford a light yellow oil, 2.10 g (90%), which was characterized spectroscopically.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-:3])=[O:2].C([O-])(=O)C.[NH4+].[N+:17]([CH2:20][CH3:21])([O-:19])=[O:18]>CC(O)=O.CCOC(C)=O>[N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[C:20]([N+:17]([O-:19])=[O:18])[CH3:21])([O-:3])=[O:2]
Reactant: CC[N+](=O)[O-]
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(=Cc1ccccc1[N+](=O)[O-])[N+](=O)[O-]

Procedure:
A solution of 2-nitrobenzaldehyde (5.0 g, 33.1 mmol) and ammonium acetate (2.55 g, 33.1 mmol) in AcOH (20 mL) was treated dropwise at 20° C. with nitroethane (2.84 mL, 39.7 mmol). The resulting solution was heated under reflux for 2 h, then cooled and diluted with EtOAc. The organic layer was washed with saturated aqueous NaHCO3 solution and brine, then dried over Na2SO4. Filtration and removal of the volatiles gave a residue that was purified on silica gel (gradient elution, 0-40% EtOAc/hexanes) to give the title compound as an oil. (2.3 g, 33%). LCMS (ES+) m/z 209 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH:8]([OH:10])[CH3:9])[CH:5]=[CH:4][N:3]=1.[H-].[Na+].F[C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([N+:24]([O-:26])=[O:25])=[CH:16][CH:15]=1>CN(C=O)C>[N+:24]([C:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:14]([O:10][CH:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[CH:7]=2)[CH3:9])=[CH:15][CH:16]=1)([O-:26])=[O:25]
Reactant: CC(O)c1ccnc(N)c1
Reactant: O=[N+]([O-])c1ccc(F)c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(Oc1ccc([N+](=O)[O-])c2ccccc12)c1ccnc(N)c1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 57.9 %

Procedure:
To a stirred solution of 1-(2-aminopyridin-4-yl)ethanol (22) (73 mg, 0.528 mmol) in DMF (1.5 mL), under nitrogen at 0° C., was added sodium hydride (32 mg, 0.793 mmol, 60 wt %). The resulting mixture was stirred at 0° C. for 40 min, and a solution of 1-fluoro-4-nitronaphthalene (101 mg, 0.528 mmol) in DMF (1.5 mL) was added dropwise. The resulting dark-red mixture was stirred at 0° C. for a further 5 min, and then at RT. After a further 40 min, the reaction was quenched by the addition of 1.0 mL of NH4Cl solution. Water (20 mL) and EtOAc (20 mL) were added, and the layers were separated. The aqueous layer was extracted with EtOAc (15 mL×3). The combined organic extracts were washed with brine, dried and the solvents removed under reduced pressure. The crude material was purified by column chromatography (12 g), eluting with 0 to 80% EtOAc in iso-hexane, to give 4-(1-(4-nitronaphthalen-1-yloxy)ethyl)pyridin-2-amine (23) (94.6 mg, 57%) as an orange gum: m/z 310 (M+H)+ (ES+).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12](Br)=[CH:11][C:10]=1[F:16])(C)(C)C.[F:18][C:19]1[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=1>>[F:16][C:10]1[CH:11]=[C:12]([O:25][C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([F:18])[CH:20]=2)[CH:13]=[CH:14][C:9]=1[CH2:8][NH2:7]
Reactant: Oc1cccc(F)c1
Reactant: CC(C)(C)OC(=O)NCc1ccc(Br)cc1F
Product: NCc1ccc(Oc2cccc(F)c2)cc1F
Yield: 28.4 %

Procedure:
Use a method similar to Preparation 30, using (4-bromo-2-fluorobenzyl)-carbamic acid tert-butyl ester (2.12 g, 7.0 mmol) and m-fluorophenol (1.57 g, 14 mmol) to give the title compound (468 mg, 47% overall).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:4]=[C:5]3[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH2:21][CH2:22][Cl:23])=[CH:14][C:6]3=[N:7][C:8]=2[N:9]=[CH:10][C:11]=1[C:12]#[N:13].[Cl:24][C:25]1[CH:31]=[C:30]([Cl:32])[C:29]([O:33][CH3:34])=[CH:28][C:26]=1[NH2:27]>C(OCCO)C>[Cl:23][CH2:22][CH2:21][O:20][C:15]1[C:16]([O:18][CH3:19])=[CH:17][C:5]2[C:6]([CH:14]=1)=[N:7][C:8]1[N:9]=[CH:10][C:11]([C:12]#[N:13])=[C:2]([NH:27][C:26]3[CH:28]=[C:29]([O:33][CH3:34])[C:30]([Cl:32])=[CH:31][C:25]=3[Cl:24])[C:3]=1[CH:4]=2
Reactant: COc1cc2cc3c(Cl)c(C#N)cnc3nc2cc1OCCCl
Reactant: COc1cc(N)c(Cl)cc1Cl
Solvent: CCOCCO
Product: COc1cc(Nc2c(C#N)cnc3nc4cc(OCCCl)c(OC)cc4cc23)c(Cl)cc1Cl
Temperature: 25 °C
Yield: 41.2 %

Procedure:
A mixture of 4-chloro-8-(2-chloroethoxy)-7-methoxybenzo[b][1,8]naphthyridine-3-carbonitrile (500 mg, 1.43 mmol) and 2,4-dichloro-5-methoxyaniline (460 mg, 2.39 mmol) in 40 mL of 2-ethoxyethanol is heated at reflux for 20 minutes then cooled to room temperature. The solution is partitioned between ethyl acetate and saturated sodium bicarbonate. The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is partitioned between ethyl acetate and an aqueous solution of sodium hydroxide and sodium bicarbonate (pH 14). The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo. Ethyl acetate and diethyl ether are added to the residue and the resultant orange solid is collected by filtration to provide 297 mg (41%) of 8-(2-chloroethoxy)-4-(2,4-dichloro-5-methoxyanilino)-7-methoxybenzo[b][1,8]naphthyridine-3-carbonitrile, mp 227-230° C. dec.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[C:23]1([CH2:29][CH2:30][CH2:31][C:32](O)=[O:33])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:11][C:8]1[CH:7]=[CH:6][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:32](=[O:33])[CH2:31][CH2:30][CH2:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:20])[F:21])[CH:14]=2)=[CH:10][CH:9]=1
Reactant: NC(Cc1cccc(C(F)(F)F)c1)C(O)c1ccc(F)cc1
Reactant: O=C(O)CCCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: O=C(CCCc1ccccc1)NC(Cc1cccc(C(F)(F)F)c1)C(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.3 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(3-(trifluoromethyl)phenyl)-1-propanol (450 mg, 1.44 mmol) in acetonitrile (30 ml) were added 4-phenyl-n-butyric acid (236 mg, 1.44 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (358 mg, 1.87 mmol) and 1-hydroxy-1H-benzotriazole (220 mg, 1.44 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate). Recrystallization from ethyl acetate-hexane gave the title compound (432 mg, 65%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([N+:12]([O-:14])=[O:13])=[CH:4][N:3]=1.[CH3:15][CH2:16][OH:17].[H-].[Na+].O>C1COCC1>[CH2:16]([O:17][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([N+:12]([O-:14])=[O:13])=[CH:4][N:3]=1)[CH3:15]
Reactant: O=[N+]([O-])c1cnc(Cl)c(C(F)(F)F)c1
Reactant: CCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOc1ncc([N+](=O)[O-])cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 20.7 %

Procedure:
To a mixture of 2-chloro-5-nitro-3-(trifluoromethyl)pyridine (500 mg, 2.207 mmol) in THF (10 mL) was added EtOH (0.155 mL, 2.65 mmol) and NaH (132 mg, 3.31 mmol). Then the mixture was stirred at 0° C. for 30 min, then warmed to rt and stirred for 16 h. The mixture was added to H2O and extracted with EA (2×50 mL) to give the organic layer. The combined organic extract was washed with brine, dried over Na2SO4, filtered, and concentrated to yield a brown oil of 2-ethoxy-5-nitro-3-(trifluoromethyl)pyridine (120 mg, 0.457 mmol, 20.7% yield): 1H NMR (400 MHz, CD3OD) δ 9.27 (d, J=2.5 Hz, 1H), 8.75 (d, J=2.5 Hz, 1H), 4.67 (m, 2H), 1.47 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)=O.[CH2:16]([NH:19][C:20]1[CH2:24][S:23][C:22](=[O:25])[N:21]=1)[C:17]#[CH:18].C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[O:25]=[C:22]1[N:21]=[C:20]([NH:19][CH2:16][C:17]#[CH:18])/[C:24](=[CH:1]/[CH:3]2[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]2)/[S:23]1
Reactant: C#CCNC1=NC(=O)SC1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: C#CCNC1=NC(=O)S/C1=C\C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 76.3 %

Procedure:
To a solution of tert-butyl 4-formylpiperidine-1-carboxylate (11.2 g) in 2-propanol (230 mL) were added 4-(prop-2-yn-1-ylamino)-1,3-thiazol-2(5H)-one (16.3 g) and piperidinium acetate (3.90 g). The reaction mixture was stirred at 60° C. overnight, and the solvent was evaporated under reduced pressure. Ethyl acetate was added to the residue, the precipitate was removed, and the filtrate was concentrated. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (14.0 g).
Reaction SMILES: [F:1][C:2]([F:30])([O:9][C:10]([F:29])([F:28])[C:11]([F:27])([F:26])[O:12][C:13]([F:25])([F:24])[C:14]([F:23])([F:22])[C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]O.[C:31]1([CH3:41])[C:32]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:34]=[CH:35][CH:36]=1.C(N(CC)C(C)C)(C)C>ClCCl>[C:31]1([CH3:41])[C:32]([S:37]([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]([F:1])([F:30])[O:9][C:10]([F:28])([F:29])[C:11]([F:26])([F:27])[O:12][C:13]([F:24])([F:25])[C:14]([F:22])([F:23])[C:15]([F:20])([F:21])[C:16]([F:17])([F:18])[F:19])(=[O:39])=[O:38])=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: OCCCCCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccccc1S(=O)(=O)CCCCCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 10 h

Procedure:
This hexanol (1.2 g, 2.45 Moles)was combined with toluene sulfonyl chloride (0.5 g, 2.58 mmoles), N,N-diisopropylethyl amine (0.85 mL, 4.9 mmoles), and N,N-dimethylaminopyridine (12 mg, 0.98 mmole) in dichloromethane (10 mL). After stirring for 10 hours at room temperature, the desired product, 1-toluenesulfonyl-6,6-difluoro-6-(perfluoro-2-butoxyethoxy)hexane, was isolated by column chromatography (and its structure confirmed by infrared spectroscopy).
Reaction SMILES: [CH2:1]([NH:3][CH:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)[CH3:2].C(N(CC)CC)C.[C:17](Cl)([Cl:19])=[O:18]>ClCCl>[CH2:1]([N:3]([CH:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)[C:17]([Cl:19])=[O:18])[CH3:2]
Reactant: CCNC1CCOCC1
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(C(=O)Cl)C1CCOCC1
Temperature: 25 °C

Procedure:
At −30° C., a solution of 19 g (0.15 mol) of ethyl(tetrahydro-2H-pyran-4-yl)amine and 14.8 g (0.15 mol) of triethylamine in 10 ml of dichloromethane was slowly added dropwise to a solution of 44 g (0.44 mol) of phosgene in 100 ml of dichloromethane. The mixture was slowly warmed to room temperature (over a period of approximately 3 hours) and then heated under reflux for 30 minutes, excess phosgene was removed using a nitrogen stream, and the solution was concentrated. 200 ml of hexane were added, the solids were filtered off and the filtrate was concentrated. Yield 25.3 g. MS (m/z): 192 [M+H]+, 156 [M−Cl]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[NH2:12].C1C(=O)N([Br:20])C(=O)C1>CC#N>[Br:20][C:5]1[CH:6]=[C:7]([N+:9]([O-:11])=[O:10])[CH:8]=[C:3]([O:2][CH3:1])[C:4]=1[NH2:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc([N+](=O)[O-])ccc1N
Solvent: CC#N
Product: COc1cc([N+](=O)[O-])cc(Br)c1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 2 L round bottom flask with a stir bar was added 2-methoxy-4-nitro-phenylamine (50.0 g, 297.4 mmol), CH3CN (1 L), and NBS (53.5 g, 297.4 mmol). The reaction was stirred at room temperature for 2 hours while protected from light. The reaction was concentrated and then 500 mL water was added. The product was extracted with ethyl acetate and concentrated. The solid which precipitated from the aqueous washes was combined with the solid which resulted from the organic concentration to give I-229 (59.6 g) which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]([F:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:14][NH:15][CH3:16]>>[Cl:1][C:2]1[N:11]=[C:10]([N:15]([CH3:16])[CH3:14])[C:9]([F:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: CNC
Reactant: COC(=O)c1cc(F)c(Cl)nc1Cl
Product: COC(=O)c1cc(F)c(N(C)C)nc1Cl

Procedure:
Methyl 2,6-dichloro-5-fluoronicotinate was treated with dimethylamine in a sealed tube to obtain methyl 2-chloro-6-(dimethylamino)-5-fluoronicotinate, which was then reacted under a hydrogen atmosphere in the presence of palladium/carbon to obtain methyl 6-(dimethylamino)-5-fluoronicotinate.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[NH2:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1
Reactant: Nc1cccnc1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Product: O=C(N1CCc2ccc(Cl)c(Nc3cccnc3)c2CC1)C(F)(F)F
Yield: 7.7 %

Procedure:
Use a method similar to the General Procedure 5-1 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (300 mg, 0.7 mmol) with 3-aminopyridine (75 mg, 0.85 mmol). Purify by chromatography on silica gel eluting with hexane/EtOAc (4:1) to give 7-chloro-6-[(3-pyridyl)amino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as an off-white solid (20 mg, 8%). MS (ES+) m/z: 370 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)[CH:7]=[C:6]([CH3:17])[C:3]=1[C:4]#[N:5].Cl.[F:19][C:20]1[CH:21]=[C:22]([CH:27]=[C:28]([F:30])[CH:29]=1)[O:23][CH2:24][CH2:25][NH2:26].C(=O)([O-])O.[Na+].CS(C)=O>O>[ClH:1].[F:19][C:20]1[CH:21]=[C:22]([CH:27]=[C:28]([F:30])[CH:29]=1)[O:23][CH2:24][CH2:25][NH:26][C:2]1[N:9]=[C:8]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)[CH:7]=[C:6]([CH3:17])[C:3]=1[C:4]#[N:5]
Reactant: Cc1cc(Nc2cc(C)c(C#N)c(Cl)n2)n[nH]1
Reactant: NCCOc1cc(F)cc(F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(Nc2cc(C)c(C#N)c(NCCOc3cc(F)cc(F)c3)n2)n[nH]1
Temperature: 100 °C
Reaction time: 27 h
Yield: 10.9 %

Procedure:
Compound A (300 mg, 1.22 mmol), 2-(3,5-difluorophenoxy)ethylamine hydrochloride (767 mg) and sodium hydrogencarbonate (1.02 g) were added to DMSO (10 ml), and the mixture was stirred at 100° C. for 27 hr. After stirring, the reaction mixture was added to cold water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and concentrated, and the residue was washed by suspending in ethyl acetate. This was converted to hydrochloride to give the object compound of 2-(2-(3,5-difluorophenoxy)ethylamino)-6-(5-methyl-1H-pyrazol-3-ylamino)-4-methylnicotinonitrile hydrochloride (56 mg).
Reaction SMILES: [Na].[CH3:2][C:3]12[C:9]([CH3:11])([CH3:10])[CH:6]([CH2:7][CH2:8]1)[CH2:5][C:4]2=[N:12][OH:13].[CH2:14](Br)[C:15]#[CH:16]>CO>[CH2:16]([O:13][N:12]=[C:4]1[CH2:5][CH:6]2[C:9]([CH3:10])([CH3:11])[C:3]1([CH3:2])[CH2:8][CH2:7]2)[C:15]#[CH:14]
Reactant: CC12CCC(CC1=NO)C2(C)C
Reactant: C#CCBr
Agent: [Na]
Solvent: CO
Product: C#CCON=C1CC2CCC1(C)C2(C)C
Reaction time: 1 h
Yield: 80.9 %

Procedure:
4.6 g (0.2 mole) of metallic sodium are dissolved in 200 ml of methanol, and 33.4 g (0.2 mole) of (±)-1,7,7-trimethyl-bicyclo[2,2,1]heptane-2-one-oxime are added to the solution. After one hour of boiling 23.8 g (0.2 mole) of propargyl bromide are introduced, and the reaction is continued for a further hour. The mixture is cooled, the separated sodium bromide is filtered off, the filtrate is concentrated, and the concentrate is subjected to fractional distillation in vacuo. 33.2 g (81%) of (±)-2-(propargyloxyimino)-1,7,7-trimethyl-bicyclo[2,2,1]heptane are obtained as a light yellow oil; b.p.: 94° C./1.5 mm Hg, nD20 =1.4955.
Reaction SMILES: [CH2:1]([NH:7][C:8](=S)[NH:9][NH2:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Cl:12][CH:13]([C:19]([CH3:21])=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15].Cl>C(O)C>[ClH:12].[CH2:1]([NH:7][C:8]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:19]([CH3:21])[NH:10][N:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCNC(=S)NN
Reactant: CCOC(=O)C(Cl)C(C)=O
Agent: Cl
Solvent: CCO
Product: CCCCCCNc1n[nH]c(C)c1C(=O)OCC
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 28.4 %

Procedure:
A stirred solution of 15.8 g (0.091 mole) of 4-hexyl-3-thiosemicarbazide in 150 mL of absolute ethanol under nitrogen atmosphere was treated with 14.8 g (0.091 mole) of ethyl 2-chloroacetoacetate, stirred for 2.5 hr at ambient temperature, treated with 50 mL of 2N ethanolic hydrogen chloride, heated at reflux for 1 hr, and stirred at ambient temperature ~16 hr. The reaction mixture was heated to dissolve most of the solids, filtered to remove the insoluble sulfur and concentrated in vacuo to give a deep red-orange oil. After standing for 3 weeks at ambient temperature, the oil began to crystallize. Trituration with ethyl acetate and filtration gave 13 g of crude product, which was recrystallized from acetone/diethyl ether to give 7.5 g of white granular product, mp 108°-109° C.