Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].CO.[C:5]([NH:8][C:9]1[S:10][C:11]2[C:17]([C:18]#[N:19])=[C:16]([O:20][C:21]3[CH:22]=[CH:23][C:24]([F:34])=[C:25]([NH:27]C(=O)C(F)(F)F)[CH:26]=3)[CH:15]=[CH:14][C:12]=2[N:13]=1)(=[O:7])[CH3:6]>C(O)C>[NH2:27][C:25]1[CH:26]=[C:21]([CH:22]=[CH:23][C:24]=1[F:34])[O:20][C:16]1[CH:15]=[CH:14][C:12]2[N:13]=[C:9]([NH:8][C:5](=[O:7])[CH3:6])[S:10][C:11]=2[C:17]=1[C:18]#[N:19]
Reactant: CC(=O)Nc1nc2ccc(Oc3ccc(F)c(NC(=O)C(F)(F)F)c3)c(C#N)c2s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: CC(=O)Nc1nc2ccc(Oc3ccc(F)c(N)c3)c(C#N)c2s1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 47.5 %

Procedure:
To a solution of sodium borohydride (3.0 g, 79.4 mmol) in is ethanol (30 mL) was added dropwise methanol (6 mL). To this suspension was added N-(5-{[2-(acetylamino)-7-cyano-1,3-benzothiazol-6-yl]oxy}-2-fluorophenyl)-2,2,2-trifluoroacetamide (700 mg, 1.60 mmol). The reaction mixture was stirred at room temperature for 20 min, and concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate (150 mL), washed successively with saturated aqueous sodium hydrogen carbonate solution (100 mL) and saturated brine (100 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=50/50→100/0). The obtained solution was concentrated under reduced pressure to give the title compound (260 mg, 48%) as a white powder.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[C:26]([C:28]([NH:30][CH2:31][CH:32]([OH:35])[CH2:33][OH:34])=[O:29])[CH:25]=[C:24]([N+:36]([O-])=O)[CH:23]=2)=[O:20])[CH:7]=[C:8]([C:10]([NH:12][CH2:13][CH:14]([OH:17])[CH2:15][OH:16])=[O:11])[CH:9]=1)([O-])=O.Cl>CO.O.[Pd]>[NH2:36][C:24]1[CH:23]=[C:22]([NH:21][C:19]([NH:18][C:6]2[CH:7]=[C:8]([C:10]([NH:12][CH2:13][CH:14]([OH:17])[CH2:15][OH:16])=[O:11])[CH:9]=[C:4]([NH2:1])[CH:5]=2)=[O:20])[CH:27]=[C:26]([C:28]([NH:30][CH2:31][CH:32]([OH:35])[CH2:33][OH:34])=[O:29])[CH:25]=1
Reactant: O=C(Nc1cc(C(=O)NCC(O)CO)cc([N+](=O)[O-])c1)Nc1cc(C(=O)NCC(O)CO)cc([N+](=O)[O-])c1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CO
Product: Nc1cc(NC(=O)Nc2cc(N)cc(C(=O)NCC(O)CO)c2)cc(C(=O)NCC(O)CO)c1
Yield: 112.7 %

Procedure:
N,N'-bis[3-nitro-5-(2,3-dihydroxypropylaminocarbonyl)phenyl]urea (0.103 g, 0.19 mmol) was dissolved in a mixture of methanol (14 ml) and water (6 ml) containing 2M aqueous HCl (0.2 ml) and a Pd/C catalyst (10%, 0.1 g). Hydrogenation was carried out at 60 psi. The catalyst was filtered off and the solvents were evaporated. The residue was redissolved in water and lyophilized giving 0.102 g (97%) of the product.
Reaction SMILES: C(O[C:4]([C:6]1[C:10]([I:11])=[C:9]([CH3:12])[S:8][C:7]=1[NH:13][C:14](=[O:18])[CH2:15][C:16]#[N:17])=[O:5])C.[H-].[Na+].CO>C1COCC1>[OH:5][C:4]1[C:6]2[C:10]([I:11])=[C:9]([CH3:12])[S:8][C:7]=2[NH:13][C:14](=[O:18])[C:15]=1[C:16]#[N:17]
Reactant: CCOC(=O)c1c(NC(=O)CC#N)sc(C)c1I
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1sc2[nH]c(=O)c(C#N)c(O)c2c1I
Yield: 22.9 %

Procedure:
2-(2-Cyano-acetylamino)-4-iodo-5-methyl-thiophene-3-carboxylic acid ethyl ester (189 mg, 0.5 mmol) was cyclized by NaH in THF at room temperature for 12 h as described in Example 29D. After reaction was finished, methanol (2 mL) was added and the mixture was evaporated. The residue was purified on HPLC to give 4-hydroxy-3-iodo-2methyl-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-cabonitrile (38 mg, 22.9%). This compound (33 mg, 0.1 mmol) was taken up in a Smith Process Vial (2–5 mL), CuI (7.6 mg, 0.04 mmol), Pd(PPh3)2Cl2 (14 mg, 0.02 mmol), DMF (2 ml), diisopro pylamine (1 mL) and phenylacetylene (20.4 mg, 0.2 mmol) were then added sequentially. After degassed, the vial was sealed and stirred at 70° C. for 2 h. The resulting mixture was filtered and the solid was washed with methanol (5 mL×2). The combined organic layers were concentrated under vacuum and purification on HPLC to give title compound (20 mg, 65%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 11.0 (s, 1H), 7.52–7.38 (m, 5H), 2.44 (s, 3H, MS (ESI) m/e 307 (M+H)+, 305 (M−H)−.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH2:8][C@H:9]([O:27][CH2:28][C:29]([N:31]([CH2:35][CH2:36][CH3:37])[CH2:32][CH2:33][CH3:34])=[O:30])[C@H:10]([O:16][CH2:17][C:18]([N:20]([CH2:24][CH2:25][CH3:26])[CH2:21][CH2:22][CH3:23])=[O:19])[CH2:11]2.[C:38]([NH2:42])([CH3:41])([CH3:40])[CH3:39]>CO>[CH3:39][C:38]([NH:42][CH2:3][CH:2]([OH:1])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH2:8][C@H:9]([O:27][CH2:28][C:29]([N:31]([CH2:32][CH2:33][CH3:34])[CH2:35][CH2:36][CH3:37])=[O:30])[C@H:10]([O:16][CH2:17][C:18]([N:20]([CH2:24][CH2:25][CH3:26])[CH2:21][CH2:22][CH3:23])=[O:19])[CH2:11]2)([CH3:41])[CH3:40]
Reactant: CCCN(CCC)C(=O)CO[C@H]1Cc2c(cccc2OCC2CO2)C[C@H]1OCC(=O)N(CCC)CCC
Reactant: CC(C)(C)N
Solvent: CO
Product: CCCN(CCC)C(=O)CO[C@H]1Cc2c(cccc2OCC(O)CNC(C)(C)C)C[C@H]1OCC(=O)N(CCC)CCC

Procedure:
A solution of 1.5 g (0.0029 M) of cis-2,2'-[[1,2,3,4-tetrahydro-5-(oxiranyl-methoxy)-2,3-naphthalenediyl]bis(oxy)]bis-[N,N-dipropylacetamide] in 5 ml of methanol and 20 ml of t-butylamine is stirred at room temperature overnight. The solution is evaporated in vacuo to give 1.7 g of oil. This material is dissolved in ether and extracted with 5% aqueous HCl. The aqueous layer is basified with aqueous NaOH and extracted with ether. The ether is washed (saturated NaCl solution), dried (Na2SO4), filtered and evaporated in vacuo to give the title compound as a dense oil, 1.52 g.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C@H:4]([CH2:5][C:6]([Cl:9])([Cl:8])[Cl:7])[C@@H:3]1[C:10](Cl)=[O:11].[C:14]([CH:16]([OH:30])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:18]=1)#[N:15].N1C=CC=CC=1.O>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:13])[C@H:4]([CH2:5][C:6]([Cl:9])([Cl:8])[Cl:7])[C@@H:3]1[C:10]([O:30][CH:16]([C:14]#[N:15])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:18]=1)=[O:11]
Reactant: N#CC(O)c1cccc(Oc2ccccc2)c1
Reactant: CC1(C)[C@H](CC(Cl)(Cl)Cl)[C@@H]1C(=O)Cl
Solvent: O
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CC1(C)[C@H](CC(Cl)(Cl)Cl)[C@@H]1C(=O)OC(C#N)c1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.8 %

Procedure:
To a solution of 10.0 g of cis-2,2-dimethyl-3-(2,2,2-trichloroethyl)cyclopropanecarbonyl chloride in 80 ml of dry benzene, there were added first 8.5 g of α-cyano-3-phenoxybenzyl alcohol and then gradually 4.5 g of pyridine. The mixture was stirred at room temperature overnight. About 70 ml of water was added to the reaction mixture, the benzene layer was separated, washed with water and dried over anhydrous magnesium sulfate, and low-boiling fractions were distilled off under reduced pressure. The oily product thus obtained was purified by preparative liquid chromatography following the procedure of SYNTHESIS EXAMPLE 1 to give 12.1 g (70% yield) of α-cyano-3-phenoxybenzyl cis-2,2-dimethyl-3-(2,2,2-trichloroethyl)cyclopropanecarboxylate with a ratio of racemic modifications D1 /D2 of about 50/50.
Reaction SMILES: Cl[C:2]1[S:3][C:4]([C:7]([N:9]([C:19]2[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:26])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[O:8])=[CH:5][N:6]=1.[NH2:27][C:28]1[CH:33]=[C:32]([Cl:34])[N:31]=[C:30]([CH3:35])[N:29]=1.[H-].[Na+]>O1CCCC1>[Cl:26][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]([CH3:25])[C:19]=1[N:9]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=1)[C:7]([C:4]1[S:3][C:2]([NH:27][C:28]2[CH:33]=[C:32]([Cl:34])[N:31]=[C:30]([CH3:35])[N:29]=2)=[N:6][CH:5]=1)=[O:8]
Reactant: COc1ccc(CN(C(=O)c2cnc(Cl)s2)c2c(C)cccc2Cl)cc1
Reactant: Cc1nc(N)cc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(CN(C(=O)c2cnc(Nc3cc(Cl)nc(C)n3)s2)c2c(C)cccc2Cl)cc1

Procedure:
The first step of the process involves reacting 2-chlorothiazole with 2-chloro-6-methylphenylisocyanate in the presence of n-butyl lithium in tetrahydrofuran to obtain 2-chloro-N-(2-chloro-6-methylphenyl)-1,3-thiazole-5-carboxamide. The second step involves reacting 2-chloro-N-(2-chloro-6-methylphenyl)-1,3-thiazole-5-carboxamide with 4-methoxybenzylchloride in the presence of sodium hydride in tetrahydrofuran to obtain 2-chloro-N-(2-chloro-6-methylphenyl)-N-(4-methoxybenzyl)-1,3-thiazole-5-carboxamide. The third step involves reacting 2-chloro-N-(2-chloro-6-methylphenyl)-N-(4-methoxybenzyl)-1,3-thiazole-5-carboxamide with 4-amino-6-chloro-2-methylpyrimidine in the presence of sodium hydride in tetrahydrofuran at reflux temperature to obtain N-(2-chloro-6-methylphenyl)-2-[(6-chloro-2-methylpyrimidin-4-yl)amino]-N-(4-methoxybenzyl)-1,3-thiazole-5-carboxamide. The fourth step involves reacting N-(2-chloro-6-methylphenyl)-2-[(6-chloro-2-methylpyrimidin-4-yl)amino]-N-(4-methoxybenzyl)-1,3-thiazole-5-carboxamide with trifluoromethanesulfonic acid and trifluoroacetic acid in dichloromethane to obtain N-(2-chloro-6-methylphenyl)-2-[(6-chloro-2-methylpyrimidin-4-yl)amino]-1,3-thiazole-5-carboxamide (Formula 1d).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[C:29]5[O:28][CH2:27][O:26][C:25]=5[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.Cl[C:37]([O:39][CH2:40][CH3:41])=[O:38]>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[CH:24][C:25]3[O:26][CH2:27][O:28][C:29]=3[C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:35])=[C:12]([C:10]([NH:9][C@@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:37](=[O:38])[O:39][CH2:40][CH3:41])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:34][CH2:33]1
Reactant: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc2c1C(=O)N[C@H]1CC[C@@H](N)CC1
Reactant: CCOC(=O)Cl
Agent: Cl
Product: CCOC(=O)N[C@H]1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[5-(cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f3) and commercially available ethyl chloroformate the title compound is obtained as colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][C:3]=1[CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1.Cl[Sn]Cl>C1COCC1.Cl>[F:1][C:2]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:3]=1[CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: O=[N+]([O-])c1ccc(F)c(CN2CCCC2)c1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: C1CCOC1
Product: Nc1ccc(F)c(CN2CCCC2)c1
Yield: 63.2 %

Procedure:
To a solution of 1-(2-fluoro-5-nitro-benzyl)-pyrrolidine (420 mg, 1.87 mmol) in THF (20 mL) was added a solution of SnCl2 (1421 mg, 7.49 mmol) in THF (5 mL) and HCl 1M (2.1 mL). The reaction mixture was refluxed for 4 h and concentrated. Saturated solution of NaHCO3 was added until pH8. Aqueous layer was extracted with CH2Cl2 (5×50 mL). The organic layer was dried over MgSO4, filtered, evaporated. Expected compound was precipited with MeOH and purified by TLC (DCM/MeOH/NH4OH//9.5/0.5/0.35) and obtained as a yellow oil (229.5 mg, 63% yield). MALDI-TOF: m/z 195.2 [M+H]+. 1H NMR (300 MHz, CDCl3) δ6.76; (dd, J=9.5 Hz and 8.7 Hz, 1H), 6.69; (dd, J=6.1 Hz and 2.9 Hz, 1H), 6.46; (ddd, J=8.7 Hz, 4.1 Hz and 2.9 Hz, 1H), 3.57; (d, J=1.6 Hz, 2H), 3.3-3.5; (s large, 2H), 2.5-2.6; (m, 2H), 1.7-1.8; (m, 4H). 13C NMR (75 MHz, CDCl3) δ117.5; (CH, d, J=3.5 Hz), 115.7; (CH, d, J=23.6 Hz), 115.0; (CH, d, J=7.7 Hz), 54.1; (CH2), 52.8; (CH2), 23.6; (CH2).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([C:13]#[N:14])=[C:6]2[CH2:15][CH2:16][CH2:17][CH3:18])=O.COC1C=CC(/C=[C:34]2/[C:35]([NH:37][C:38]([S:40]/2)=[NH:39])=[O:36])=CC=1OC1CCCC1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[NH2:39][C:38]1[S:40]/[C:34](=[CH:1]\[C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][CH:12]=2)[N:9]=[CH:8][C:7]([C:13]#[N:14])=[C:6]3[CH2:15][CH2:16][CH2:17][CH3:18])/[C:35](=[O:36])[N:37]=1
Reactant: CCCCc1c(C#N)cnc2ccc(C=O)cc12
Reactant: COc1ccc(/C=C2\SC(=N)NC2=O)cc1OC1CCCC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCCCc1c(C#N)cnc2ccc(/C=C3\SC(N)=NC3=O)cc12

Procedure:
Similar procedure as described in example 38 was used, starting from 6-formyl-4-butyl-quinoline-3-carbonitrile (example 49c), pseudothiohydantoin, sodium acetate and acetic acid to give 6-[2-amino-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-4-butyl-quinoline-3-carbonitrile. LC-MS m/e 337 (MH+).
Reaction SMILES: [CH2:1]([NH:4][C:5]1[N:10]=[C:9]([OH:11])[C:8]([C:12]([O:14]CC)=[O:13])=[CH:7][N:6]=1)[CH:2]=[CH2:3].[OH-].[Na+]>O>[CH2:1]([NH:4][C:5]1[N:10]=[C:9]([OH:11])[C:8]([C:12]([OH:14])=[O:13])=[CH:7][N:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCNc1ncc(C(=O)OCC)c(O)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=CCNc1ncc(C(=O)O)c(O)n1

Procedure:
2-Allylamino-5-ethoxycarbonyl-4-hydroxypyrimidine (585 mg, 2.5 mmol) was hydrolysed in boiling water with NaOH (300 mg, 7.5 mmol) for 2 hours. Cooling and acidification to pH 2 yielded the title acid (321 mg, 66%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[C:15]([O:19][C:20](=[O:28])[NH:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)([CH3:18])([CH3:17])[CH3:16]>>[C:15]([O:19][C:20](=[O:28])[NH:21][CH:22]1[CH2:27][CH2:26][N:25]([C:2]2[CH:7]=[CH:6][C:5]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:4][CH:3]=2)[CH2:24][CH2:23]1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: Ic1ccc(Oc2ccccc2)cc1
Product: CC(C)(C)OC(=O)NC1CCN(c2ccc(Oc3ccccc3)cc2)CC1
Yield: 29.9 %

Procedure:
The title compound (1.1 g, 30%) was prepared from 1-iodo-4-phenoxy-benzene (2.9 g, 10 mmol) and piperidin-4-yl-carbamic acid tert-butyl ester (2 g, 10 mmol) by the procedure described in step 1 of Example 4: MS (ESI) m/z 368 (M+H); 1H NMR (400 MHz, CDCl3) δ 1.46 (s, 9H), 1.51-1.61 (m, 3H), 2.05 (br, 2H), 2.81 (dd, J=1.6, 12 Hz, 2H), 3.52 (m, 2H), 3.60 (br, 1H), 4.47 (br, 1H), 6.90-6.96 (m, 6H), 7.03 (m, 1H), 7.28 (m, 2).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]([NH2:23])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH3:22])[CH:9]=2)=[O:5])[CH3:2].[C:24](Cl)(=[O:26])[CH3:25].C(N(CC)CC)C>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]([NH:23][C:24](=[O:26])[CH3:25])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH3:22])[CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccc(OC)cc2C1N
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1=C(c2ccccc2)c2ccc(OC)cc2C1NC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.9 %

Procedure:
1-Amino-6-methoxy-3-phenyl-1H-indene-2-carboxylic acid ethyl ester (60 mg, 0.19 mmol) prepared in Example 20 was dissolved in dichloromethane (10 mL), and acetyl chloride (76.15 mg, 70.0 μl, 0.97 mmol) and triethylamine (130.00 mg, 0.18 mL, 128 mmol) were added thereto in order at 0° C. The mixture was stirred for 1 hr at RT, washed with saturated saline and extracted with dichloromethane. The organic layer was separated, dried over anhydrous MgSO4 and concentrated under a reduced pressure. The resulting residue was purified by flash chromatography to obtain 48 mg of the titled compound (yield: 71%).
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.ClC(N(C)C)=C(C)C.[Br:21][C:22]1[C:23]([CH3:29])=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25].CCN(C(C)C)C(C)C>C(Cl)Cl.C([O-])(O)=O.[Na+]>[Br:21][C:22]1[C:23]([CH3:29])=[C:24]([NH:25][C:7](=[O:9])[C:6]2[CH:5]=[CH:4][C:3]([N:2]([CH3:1])[CH3:12])=[CH:11][CH:10]=2)[CH:26]=[CH:27][CH:28]=1
Reactant: CN(C)c1ccc(C(=O)O)cc1
Reactant: Cc1c(N)cccc1Br
Agent: CC(C)=C(Cl)N(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1c(Br)cccc1NC(=O)c1ccc(N(C)C)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 53.5 %

Procedure:
A suspension of 4-(dimethylamino)benzoic acid (100 mg, 0.605 mmol) in DCM (3 mL) was treated with 1-chloro-N,N,2-trimethylprop-1-en-1-amine (0.120 mL, 0.908 mmol) and the resulting solution was stirred at rt for 1.5 h. 3-Bromo-2-methylaniline (0.053 mL, 0.432 mmol) was added, followed by DIEA (0.264 mL, 1.513 mmol). The mixture was stirred at rt for 1 h, then was diluted with DCM and NaHCO3 (aq). The layers were separated and the organic phase was washed with brine, dried and concentrated. The residue was purified by column chromatography (eluting with a gradient from 85:15 to 65:35 hexane-EtOAc) to provide N-(3-bromo-2-methylphenyl)-4-(dimethylamino)benzamide as a light yellow solid (77 mg, 53%). 1H NMR (400 MHz, DMSO-d6) δ 9.75 (s, 1H) 7.85 (d, J=9.0 Hz, 2H) 7.49 (dd, J=8.0, 1.0 Hz, 1H) 7.30 (dd, J=7.9, 0.9 Hz, 1H) 7.15 (t, J=7.9 Hz, 1H) 6.75 (d, J=9.0 Hz, 2H) 2.99 (s, 6H) 2.25 (s, 3H). Mass spectrum m/z 331, 333 (M−H)−.
Reaction SMILES: [F:1][C:2]([F:9])([CH2:6][CH:7]=[CH2:8])[C:3](O)=[O:4].[Cl:10]CCl.C1(C)C=CC=CC=1>CN(C)C=O>[F:1][C:2]([F:9])([CH2:6][CH:7]=[CH2:8])[C:3]([Cl:10])=[O:4]
Reactant: C=CCC(F)(F)C(=O)O
Reactant: ClCCl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: C=CCC(F)(F)C(=O)Cl

Procedure:
For example, 2,2-difluoro-4-pentenoic acid 12c is contacted with about 1.0 to 1.5 molar equivalents of an appropriate chlorinating agent. The reaction is carried out in a suitable solvent, such as dichloromethane, toluene or dimethylformamide. The reaction is carried out at a temperature of from about 20° C. to about 35° C. and generally requires about 4 to 24 hours. The product, 2,2-difluoro-4-pentenoyl chloride 12a, can be isolated by fractional distillation and purified by techniques well known in the art, such as chromatography.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH3:9].[N+:10]([O-])([OH:12])=[O:11]>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]([F:8])=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1cc(F)ccc1Br
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1cc(F)c([N+](=O)[O-])cc1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 104.8 %

Procedure:
Combine 1-bromo-4-fluoro-2-methylbenzene (30.0 g, 159 mmol) in concentrated sulfuric acid (100 mL), cool to about −5° C., and treat dropwise with nitric acid (11.00 mL, 174 mmol) over 20 minutes. Allow reaction mixture to warm to RT and stir for 30 min. Pour onto crushed ice with stiffing and partition with tert-butyl methyl ether (MTBE) (200 mL). Separate the aqueous layer and extract with MTBE (2×50 mL). Combine organic layers, dry and concentrate under reduced pressure to provide 1-bromo-4-fluoro-2-methyl-5-nitrobenzene as an orange-colored viscous oil (39.0 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:29]([F:32])([F:31])[F:30])[O:13][N:12]=[C:11]([C:14]3[CH:27]=[CH:26][C:17]([C:18]([NH:20][CH:21]4[CH2:24][S:23](=[O:25])[CH2:22]4)=[O:19])=[C:16]([CH3:28])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[F:33][C:34]([F:39])([F:38])[C:35]([NH2:37])=[O:36].[O-2].[Mg+2].C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>ClCCl.CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O.[Rh+2].[Rh+2]>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:29]([F:31])([F:30])[F:32])[O:13][N:12]=[C:11]([C:14]3[CH:27]=[CH:26][C:17]([C:18]([NH:20][CH:21]4[CH2:22][S:23](=[O:25])(=[N:37][C:35](=[O:36])[C:34]([F:39])([F:38])[F:33])[CH2:24]4)=[O:19])=[C:16]([CH3:28])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: NC(=O)C(F)(F)F
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NC1CS(=O)C1
Agent: [Rh+2]
Agent: CC(=O)[O-]
Agent: [Mg+2]
Solvent: Ic1ccccc1
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NC1CS(=O)(=NC(=O)C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 42 h
Yield: 24.6 %

Procedure:
To a solution of 4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N-(1-oxo-thietan-3-yl)-benzamide (Example P2) (0.2 g) in dichloromethane (20 ml) was added trifluoroacetamide (0.09 g), rhodium(II) acetate dimer (0.02 g), magnesium oxide (0.07 g) and iodobenzene diacetate (0.19 g). The reaction mixture was stirred at ambient temperature for 42 hours. The reaction mixture was concentrated and the residue purified by chromatography on silica gel (eluent: ethyl acetate/heptane 1:1) to give 4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N-[1-oxo-1-(2,2,2-trifluoro-acetylimino)-thietan-3-yl]-benzamide (0.06 g) as an off-white powder. HPLC-MS: RT 2.14 min and 2.18 min (two isomers) MH+ 616.
Reaction SMILES: [CH:1]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][CH:4]=[C:3]([OH:10])[CH:2]=1.[C:11](O)(=[O:14])[CH:12]=[CH2:13].C1C2NC3C(=CC=CC=3)SC=2C=CC=1.F>>[N+:7]([C:6]1[CH:5]=[C:4]2[C:3](=[CH:2][CH:1]=1)[O:10][CH2:13][CH2:12][C:11]2=[O:14])([O-:9])=[O:8]
Reactant: C=CC(=O)O
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: F
Agent: c1ccc2c(c1)Nc1ccccc1S2
Product: O=C1CCOc2ccc([N+](=O)[O-])cc21

Procedure:
Following the same procedure as Example 1, p-nitrophenol (34.8 grams), acrylic acid (27 grams), and an inhibitor, phenothiazine (0.02 grams was added to the pressure reactor. The anhydrous hydrogen fluoride (110 grams) was added before the system was warmed. When the reaction temperature was attained, a pressure of 140 psig was noted, similar to previous reactions. Work-up was carried out as previous examples and the 6-Nitro-4-Chromanone was isolated and characterized.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=2[S:21]([CH3:24])(=[O:23])=[O:22])[C:3]=1[CH3:25].[O:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:33]=[C:34]([NH2:38])[CH:35]=[N:36][CH:37]=2)[CH2:28][CH2:27]1>C1(C)C=CC=CC=1>[F:12][C:10]1[CH:9]=[C:8]([F:13])[CH:7]=[C:6]2[C:11]=1[C:2]([NH:38][C:34]1[CH:35]=[N:36][CH:37]=[C:32]([N:29]3[CH2:30][CH2:31][O:26][CH2:27][CH2:28]3)[CH:33]=1)=[C:3]([CH3:25])[C:4]([C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=1[S:21]([CH3:24])(=[O:23])=[O:22])=[N:5]2
Reactant: Nc1cncc(N2CCOCC2)c1
Reactant: Cc1ccc(S(C)(=O)=O)c(-c2nc3cc(F)cc(F)c3c(Cl)c2C)c1
Solvent: Cc1ccccc1
Product: Cc1ccc(S(C)(=O)=O)c(-c2nc3cc(F)cc(F)c3c(Nc3cncc(N4CCOCC4)c3)c2C)c1

Procedure:
Essentially prepared according to Procedure H using 4-chloro-5,7-difluoro-3-methyl-2-(5-methyl-2-(methylsulfonyl)phenyl)quinoline (60.0 mg, 0.16 mmol) and 5-morpholinopyridin-3-amine in toluene to give 5,7-difluoro-3-methyl-2-(5-methyl-2-(methylsulfonyl)phenyl)-N-(5-morpholinopyridin-3-yl)quinolin-4-amine. 1H NMR (CDCl3) δ ppm 8.05 (1H, d, J=8.0 Hz), 7.83-7.92 (2H, m), 7.44-7.52 (2H, m), 7.00-7.24 (3H, m), 6.54-6.59 (1H, m), 3.79 (3H, t, J=4.9 Hz), 3.09-3.25 (4H, m), 3.07 (2H, s), 2.50 (2H, s), 2.04 (1H, s), 1.89 (3H, s), 1.26 (2H, t, J=7.1 Hz). Mass Spectrum (ESI) m/e=525.3 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:22])[NH:10][CH:11]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:12]([OH:14])=O)[CH:5]=[CH:6][CH:7]=1.[NH:23]([CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>ClCCCl.S(Cl)(Cl)=O>[CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:22])[NH:10][CH:11]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:12]([N:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:35])[CH3:36])=[O:32])=[O:14])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(NC(=O)NC(Cc2ccccc2)C(=O)O)c1
Reactant: CC(C)(C)OC(=O)CNc1ccccc1
Solvent: ClCCCl
Solvent: O=S(Cl)Cl
Product: Cc1cccc(NC(=O)NC(Cc2ccccc2)C(=O)N(CC(=O)OC(C)(C)C)c2ccccc2)c1
Yield: 41.2 %

Procedure:
Working as in Example 15, but starting with (RS)-2-[3-(3-methylphenyl)ureido]-3-phenylpropanoic acid (4.8 g) and tert-butyl anilinoacetate (3.3 g) in anhydrous 1,2-dichloroethane (300 cc) and thionyl chloride (1.16 cc), and recrystallizing successively in diethyl ether and then in isopropanol, tert-butyl (RS)-N-{2-[3-(3-methylphenyl)ureido]-3-phenylpropionyl}-N-phenylglycinate (3.2 g), m.p. 198° C., is obtained.