Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.[CH2:10]([O:17][C:18]1[CH:30]=[CH:29][C:21]([C:22]([NH:24][CH2:25][C:26]([OH:28])=O)=[O:23])=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[N:54]1([C:60]([C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][C:63]=2[C:68]([F:71])([F:70])[F:69])=[O:61])[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]1>CN(C=O)C.O>[CH2:10]([O:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([NH:24][CH2:25][C:26](=[O:28])[N:57]2[CH2:58][CH2:59][N:54]([C:60](=[O:61])[C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][C:63]=3[C:68]([F:71])([F:69])[F:70])[CH2:55][CH2:56]2)=[O:23])=[CH:29][CH:30]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(O)CNC(=O)c1ccc(OCc2ccccc2)cc1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 104.1 %

Procedure:
DIPEA (98 mg, 0.76 mmol) was added to a stirred solution of (4-benzyloxy-benzoylamino]-acetic acid (50 mg, 0.17 mmol) in DMF (3 mL). HOBT (25.8 mg, 0.19 mmol) and EDCI.HCl (83 mg, 0.43 mmol) were added at room temperature. After 2 minutes, piperazine-1-yl-(2-trifluoromethyl-phenyl)-methanone hydrochloride (61.5 mg, 0.21 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was diluted with cold water and the resulting precipitate was filtered, washed with hexane and dried to afford 93 mg (99% yield) of 4-benzyloxy-N-{2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-benzamide. LC-MS purity: 87%, 1H NMR (DMSO): δ 8.5 (s, 1H,), 7.8 (m, 5H), 7.5 (s, 1H), 7.4 (m, 4H), 7.1 (d, 2H), 5.2 (s, 2H), 4.2 (d, 2H), 3.7 (m, 4H), 3.5 (s, 2H), 3.4 (s, 2H), 3.3 (s, 2H).
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[C:4]([C:11]2[N:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:3]=1.Cl.[NH2:18][CH:19]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)[C:20]1[CH:25]=[CH:24][C:23]([PH:26](=[O:28])[OH:27])=[CH:22][CH:21]=1>S(Cl)(Cl)=O.ClCCl>[OH:1][C:2]1[C:7]([C:8]([NH:18][CH:19]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)[C:20]2[CH:25]=[CH:24][C:23]([PH:26](=[O:27])[OH:28])=[CH:22][CH:21]=2)=[O:10])=[CH:6][N:5]=[C:4]([C:11]2[N:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:3]=1
Reactant: O=C(O)c1cnc(-c2cccnn2)nc1O
Reactant: COc1ccc(C(N)c2ccc([PH](=O)O)cc2)cc1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(C(NC(=O)c2cnc(-c3cccnn3)nc2O)c2ccc([PH](=O)O)cc2)cc1
Reaction time: 3 h
Yield: 12 %

Procedure:
4-hydroxy-2-(pyridazin-3-yl)pyrimidine-5-carboxylic acid, 30-ie, (545 mg, 2.5 mmol) in 5 ml of thionyl chloride was heated at reflux overnight. Then it was concentrated under vacuum and the residue was dissolved in 10 ml of dichloromethane. To the mixture was added 4-(amino(4-methoxyphenyl)methyl)phenylphosphinic acid hydrochloride (1-1-e, 782.5 mg, 2.5 mmol) and TEA (505 mg, 5 mmol) in 10 ml of dichloromethane at 0° C. The mixture was stirred for 3 hours and then it was washed with sat. NH4Cl. The organic layer was concentrated under vacuum and the residue was purified on prep-HPLC to provide the product 9-2 (150 mg, 12%). 1H NMR (CD3OD, 300 MHz,): δ 9.37 (m, 1H), 8.83 (s, 1H), 8.51 (m, 1H), 8.15 (m, 1H), 7.80 (m, 2H), 7.53 (m, 2H), 7.23 (m, 2H), 6.79 (m, 2H), 6.56 (s, 1H), 6.34 (s, 1H), 3.77 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:26][CH3:27])=[C:9]([O:12][CH2:13][C@@H:14]3[CH2:18][CH2:17][CH2:16][N:15]3C(OC(C)(C)C)=O)[CH:10]=2)[N:5]=[CH:4][N:3]=1.[Cl:28][C:29]1[C:30]([F:36])=[C:31]([CH:33]=[CH:34][CH:35]=1)[NH2:32].Cl>C(#N)C>[ClH:1].[Cl:28][C:29]1[C:30]([F:36])=[C:31]([CH:33]=[CH:34][CH:35]=1)[NH:32][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:26][CH3:27])=[C:9]([O:12][CH2:13][C@@H:14]3[CH2:18][CH2:17][CH2:16][NH:15]3)[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: COc1cc2ncnc(Cl)c2cc1OC[C@@H]1CCCN1C(=O)OC(C)(C)C
Reactant: Nc1cccc(Cl)c1F
Agent: Cl
Solvent: CC#N
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC[C@@H]1CCCN1
Temperature: 25 °C
Yield: 100 %

Procedure:
To a solution of 4-chloro-7-methoxy-6-{[(2S)-1-tert-butoxycarbonylpyrrolidin-2-yl]methoxy}quinazoline in acetonitrile (120 ml), 3-chloro-2-fluoroaniline (1.4 ml, 12.7 mmole) and hydrogen chloride (4.0M in 1,4-dioxane) (13 ml, 52 mmole) were added. This mixture was heated to reflux for one hour. After cooling to ambient temperature the precipitate was filtered off, washed with acetonitrile followed by diethylether and dried under vacuum to give 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-{[(2S)-pyrrolidin-2-yl]methoxy}quinazoline hydrochloride as a yellow solid (5.73 g, 100%); 1H NMR Spectrum: (DMSO d6) 1.70-2.10 (m, 3H); 2.10-2.30 (m, 1H); 3.00-3.80 (m, 2H); 3.97-4.10 (m, 4H); 4.45-4.57 (m, 2H); 7.32-7.38 (m, 1H); 7.46 (s, 1H); 7.49-7.55 (m, 1H); 7.59-7.65 (m, 1H); 8.65 (s, 1H); 8.81 (s, 1H); 9.31 (bs, 1H); 9.67 (bs, 1H); 12.09 (bs, 1H); Mass Spectrum: (M+H)+ 403.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:21])[NH:9][CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18]CC)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].C(O)C.Cl>O>[Cl:1][C:2]1[C:7]2[C:8](=[O:21])[NH:9][CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([OH:18])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ncn2c1CNC(=O)c1c(Cl)cccc1-2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ncn2c1CNC(=O)c1c(Cl)cccc1-2

Procedure:
A mixture of 9 g (29.4 mmol) of ethyl 7-chloro-5,6-dihydro-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate, 1.434 g (35.9 mmol) of sodium hydroxide, 30 ml of ethanol and 15 ml of water is heated to boiling under reflux for 70 minutes. The mixture is then diluted with 80 ml of water, filtered, the filtrate is neutralized by the addition of 8.9 ml (35.9 mmol) of 4N hydrochloric acid and the ethanol is distilled off in vacuo. The residue is subsequently cooled to about 0°, the product is filtered off under suction, rinsed with water and dried at 80°-90° in a high vacuum. There is obtained 7-chloro-5,6-dihydro-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid of decomposition point 289°.
Reaction SMILES: [CH3:1][Si:2]([CH3:11])([CH3:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].N1C=CC=CC=1.Cl[C:19]([C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=1)=[O:20].O>C1C=CC=CC=1>[CH3:1][Si:2]([CH3:11])([CH3:10])[C:3]1[CH:4]=[C:5]([NH:6][C:19]([C:21]2[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=2)=[O:20])[CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Reactant: C[Si](C)(C)c1cccc(N)c1
Solvent: c1ccncc1
Solvent: c1ccccc1
Solvent: O
Product: COC(=O)c1ccc(C(=O)Nc2cccc([Si](C)(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 101.7 %

Procedure:
To a solution of 135 mg (0.817 mmol) of m-trimethylsilylaniline in 8 ml of dry benzene were added 1.0 ml of dry pyridine and 179 mg (0.900 mmol) of methyl p-chloroformylbenzoate, successively. The mixture was stirred at room temperature for 20 hours. To the reaction mixture was added water and the aqueous solution was extracted with AcOEt. The extract was washed successively with water, sat.eq.NaHCO3 and sat.ag.NaCl, dried and evaporated to give 272 mg of white powder, which was purified by column chlomatography on silica gel (eluent: methylene chloride) to give 266 mg of white powder (yield: 99%). Recrystallization of the powder from a mixture of methylene chloride, n-hexane and chloroform gave 120 mg of white needles, m.p. 125°-126° C. (yield 45%).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)[N:8]=1)=O.[F:26][C:27]1([F:38])[O:31][C:30]2[CH:32]=[CH:33][C:34]([NH:36]N)=[CH:35][C:29]=2[O:28]1.N([O-])=O.[Na+].[Sn](Cl)Cl>>[F:38][C:27]1([F:26])[O:31][C:30]2[CH:32]=[CH:33][C:34]([N:36]3[C:5]([C:7]4[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]5[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=5)[N:8]=4)=[CH:4][CH:3]=[N:2]3)=[CH:35][C:29]=2[O:28]1
Reactant: NNc1ccc2c(c1)OC(F)(F)O2
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)(F)F)c2)ccc1=O
Agent: Cl[Sn]Cl
Agent: O=N[O-]
Agent: [Na+]
Product: O=c1ccn(-c2cccc(OC(F)(F)F)c2)nc1-c1ccnn1-c1ccc2c(c1)OC(F)(F)O2

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-6) and 2,2-difluoro-benzo[1,3]dioxol-5-yl-hydrazine (prepared from the corresponding amino derivative using sodium nitrite and tin(II) chloride as described in J. Med. Chem. 2003, 46, 4676-4686) according to the method described for example 91. MS: M=479.1 (M+H)+
Reaction SMILES: Cl[C:2]1[CH:12]=[C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=1.[CH2:20]([NH:22][C:23]([NH2:25])=[O:24])[CH3:21].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH2:20]([NH:22][C:23](=[O:24])[NH:25][C:2]1[CH:12]=[C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=1)[CH3:21]
Reactant: CCOC(=O)c1cnc(Cl)cc1Nc1ccccc1
Reactant: CCNC(N)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: CCNC(=O)Nc1cc(Nc2ccccc2)c(C(=O)OCC)cn1
Temperature: 80 °C
Yield: 92 %

Procedure:
To a solution of ii (6.40 g, 23.18 mmol) in 1,4-dioxane (200 mL) was added N-ethylurea (2.60 g, 29.0 mmol) followed by Cs2CO3 (11.50 g, 34.80 mmol). The resulting solution was purged with nitrogen for 15 min followed by addition of Pd(OAc)2 (0.16 g, 0.70 mmol) and Xantphos (0.81 g, 1.40 mmol). The reaction mixture was again purged with nitrogen for 15 min and then heated at 80° C. for 16 h. The reaction mass was cooled to room temperature and filtered through a celite bed. The celite bed was washed with EtOAc and the combined filtrates concentrated under reduced pressure. Water was added to the residue and extracted with EtOAc (3×20 mL). The combined organic phase was washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude residue was purified over silica gel (60-120 M, 50-75% EtOAc-hexane) to obtain a solid residue. This was purified further by trituration with 25% ether-hexane to afford compound iii as an off-white solid (7.0 g, 92%). 1H-NMR (400 MHz, DMSO-d6): δ 9.14 (s, 1H) and 9.64 (s, 1H), 8.61 (s, 1H), 7.70 (br s, 1H), 7.27-7.45 (m, 5H), 7.21 (t, J=7.20 Hz, 1H), 4.32 (q, J=7.20 Hz, 2H), 3.11 (m, 2H), 1.34 (t, J=7.20 Hz, 3H), 1.04 (t, J=7.20 Hz, 3H). [M+H]+ m/z=329.14.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:14]([F:15])=[CH:13][N:12]=[C:11]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH3:29])=[CH:19][CH:18]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:30](Cl)(=[O:33])[CH:31]=[CH2:32].C(Cl)(Cl)Cl.CO.C(=O)(O)[O-].[Na+]>C(Cl)Cl.O>[F:15][C:14]1[C:9]([NH:8][C:4]2[CH:3]=[C:2]([NH:1][C:30](=[O:33])[CH:31]=[CH2:32])[CH:7]=[CH:6][CH:5]=2)=[N:10][C:11]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH3:29])=[CH:19][CH:18]=2)=[N:12][CH:13]=1
Reactant: C=CC(=O)Cl
Reactant: COCCOCOc1ccc(Nc2ncc(F)c(Nc3cccc(N)c3)n2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: C=CC(=O)Nc1cccc(Nc2nc(Nc3ccc(OCOCCOC)cc3)ncc2F)c1
Temperature: -30 °C
Reaction time: 0.67 h

Procedure:
In a 50 mL, 3-neck RBF equipped with a magnetic stirrer, calcium chloride guard tube and thermo pocket was charged N4-(3-aminophenyl)-5-fluoro-N2-(4-((2-methoxyethoxy)methoxy)phenyl)pyrimidine-2,4-diamine (0.380 g) in DCM (10 mL) and was cooled to −30° C. To the reaction mixture was slowly added acryloyl chloride solution in DCM (0.090 g in 5.0 mL DCM) and the reaction mixture was stirred at −30° C. for approx. 40 minutes. The reaction was monitored on TLC using chloroform:methanol (9.6:0.4) as mobile phase. The reaction mixture was poured into water (100 mL) and basified using sodium bicarbonate. The reaction mixture was extracted with DCM (25 mL×2) and the combined organic layers were washed with 50 mL brine solution. The organic layer was dried over sodium sulfate and concentrated completely under reduce pressure at 40° C. The crude product was purified by column chromatography eluting in 35% of ethyl acetate in hexane to give 0.36 g of N-(3-((5-fluoro-2-((4-((2-methoxyethoxy)methoxy)phenyl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide.
Reaction SMILES: [NH2:1][C:2]1[C:9]([I:10])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.CC(C)([O-])C.[K+].[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C1COCC1>[C:6]([C:5]1[C:4]([C:11]([F:14])([F:12])[F:13])=[CH:3][C:2]([NH:1][S:22]([CH3:21])(=[O:24])=[O:23])=[C:9]([I:10])[CH:8]=1)#[N:7]
Reactant: CS(=O)(=O)Cl
Reactant: N#Cc1cc(I)c(N)cc1C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1cc(C(F)(F)F)c(C#N)cc1I

Procedure:
4-Amino-5-iodo-2-trifluoromethyl-benzonitrile (8.04 g, 25.77 mmoles) was dissolved in anhydrous THF (60 mL), stirred under a nitrogen atmosphere and cooled in an ice/brine bath for 20 min. 1.0 M potassium tert-butoxide in THF (82 mL, 82 mmoles) was added and the reaction mixture was stirred for 20 min. Methanesulfonyl chloride (3.2 mL, 41.18 mmoles) was then added and the reaction mixture was stirred at ambient temperature overnight. The reaction mixture was quenched with 1N HCl (90 mL) and extracted with dichloromethane (3×100 mL). The organic extracts were diluted with diethyl ether and a white solid precipitated. The solid was filtered, washed and dried to yield the title compound. The filtrate was concentrated to a crude orange solid. The compound was purified by column chromatography (SiO2, 100% CH2Cl2).
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:31])[C:4](=[O:30])[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12](C(OC(C)(C)C)=O)[C@H:13]2[CH2:18][CH2:17][C@H:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]2)=[CH:7][CH:6]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][N:3]([CH3:31])[C:4](=[O:30])[C:5]1[CH:6]=[CH:7][C:8]([CH2:11][NH:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([C:19]([CH3:20])([CH3:21])[CH3:22])[CH2:15][CH2:14]2)=[CH:9][CH:10]=1
Reactant: CON(C)C(=O)c1ccc(CN(C(=O)OC(C)(C)C)[C@H]2CC[C@H](C(C)(C)C)CC2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CON(C)C(=O)c1ccc(CN[C@H]2CC[C@H](C(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-Methoxy-N-methyl-trans-4-{[tert-butoxycarbonyl-(4-tert-butylcyclohexyl)amino]methyl}benzamide (1.0 g, 2.3 mmol) was dissolved in DCM (10 ml), and TFA (10 ml) was added. The reaction mixture was stirred at ambient temperature for 2 hours and then taken to dryness by rotary evaporation. The crystal-line residue was then dissolved in ethyl acetate (100 ml), and the organic phase was washed with saturated aqueous sodium carbonate solution (2×100 ml). The combined water phases were back extracted once with ethyl acetate (100 ml); and the combined organic phases dried with anhydrous sodium sulphate. Solvent was removed by rotary evaporation, to leave the title product as fine white crystals. Yield: 760 mg (99%).
Reaction SMILES: [C:1]([C:9]1[CH:41]=[CH:40][C:12]([CH2:13][N:14]2[CH2:18][CH2:17][C@@H:16]([N:19]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:20]3[N:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]([O:30]CC)=[O:29])=[CH:22][CH:21]=3)[CH2:15]2)=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].O.[ClH:45]>O1CCOCC1>[ClH:45].[ClH:45].[C:1]([C:9]1[CH:10]=[CH:11][C:12]([CH2:13][N:14]2[CH2:18][CH2:17][C@@H:16]([N:19]([C:33]([O:35][C:36]([CH3:37])([CH3:39])[CH3:38])=[O:34])[C:20]3[N:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29])=[CH:22][CH:21]=3)[CH2:15]2)=[CH:40][CH:41]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)/C=C/c1ccc(N(C(=O)OC(C)(C)C)[C@@H]2CCN(Cc3ccc(C(=O)c4ccccc4)cc3)C2)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N(c1ccc(/C=C/C(=O)O)cn1)[C@@H]1CCN(Cc2ccc(C(=O)c3ccccc3)cc2)C1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl (2E)-3-{6-[[(3R)-1-(4-benzoylbenzyl)-3-pyrrolidinyl](tert-butoxycarbonyl)amino]-3-pyridyl}acrylate (111 mg) in dioxane (2 mL) was added 1N sodium hydroxide (0.6 mL). After stirring at 60° C. for 2 hours, the reaction mixture was added H2O(10 mL) and acidified with 1N hydrochloric acid (to pH 1). A resulting mixture was extracted with CHCl3, and the organic layer was dried over MgSO4, filtered, and evaporated in vacuo to give (2E)-3-{6-[[(3R)-1-(4-benzoylbenzyl)-3-pyrrolidinyl](tert-butoxycarbonyl)amino]-3-pyridyl}acrylic acid dihydrochloride (97 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8](Br)[CH:7]=[CH:6]2.C([Sn](CCCC)(CCCC)[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=1[N+:27]([O-:29])=[O:28])CCC.[Cl-].[Li+].N>CS(C)=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.[Cu]Cl.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=3[N+:27]([O-:29])=[O:28])[CH:9]=2)[CH:4]=1
Reactant: COc1ccc2cc(Br)ccc2c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(OC)cc1[N+](=O)[O-]
Agent: Cl[Cu]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COc1ccc(-c2ccc3cc(OC)ccc3c2)c([N+](=O)[O-])c1
Temperature: 60 °C
Reaction time: 5 h
Yield: 63.2 %

Procedure:
The title compound was synthesized by referring to J. Am. Chem. Soc., 1999, 121, 760. A suspension of 6-methoxy-2-bromonaphthalene (500 mg), tributyl(4-methoxy-2-nitrophenyl)tin (1.1 g), tetrakis(triphenylphosphine)palladium(0) (250 mg), copper(I) chloride (1.0 g) and lithium chloride (540 mg) in dimethylsulfoxide (15 ml) was stirred at 60° C. for 5 hours under a nitrogen atmosphere. Ethyl acetate and aqueous ammonia were sequentially added thereto, the solution was filtered through celite pad, extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was washed with a hexane-diethyl ether system to provide the title compound (412 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[CH:12]=[C:11](Br)[CH:10]=[C:9]([C:14]([O:16][CH3:17])=[O:15])[C:8]2=[O:18])=[CH:4][CH:3]=1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1>>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[CH:12]=[C:11]([C:26]3[CH:27]=[CH:28][C:23]([O:22][CH3:21])=[CH:24][CH:25]=3)[CH:10]=[C:9]([C:14]([O:16][CH3:17])=[O:15])[C:8]2=[O:18])=[CH:4][CH:3]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: COC(=O)c1cc(Br)cn(Cc2ccc(Cl)cc2)c1=O
Product: COC(=O)c1cc(-c2ccc(OC)cc2)cn(Cc2ccc(Cl)cc2)c1=O
Yield: 82 %

Procedure:
According to Scheme 3 Method A: The title compound was prepared from methyl 1-(4-chlorobenzyl)-5-bromo-2-oxo-1,2-dihydropyridine-3-carboxylate (1 eq, 7.00 mmol, 2.50 g) and 4-methoxyphenyl boronic acid (1.5 eq, 11.0 mmol, 1.60 g) according to the procedure described for Example 1 Step 3. Reaction conditions: 4 hours at 80° C. The crude product was purified by flash chromatography over silica gel (AIT Flashsmart prepacked column 80 g SiO2) using CH2Cl2/AcOEt 80/20 and by recrystallization with Et2O/pentane to afford methyl 1-(4-chlorobenzyl)-5-(4-methoxyphenyl)-2-oxo-1,2-dihydropyridine-3-carboxylate (5.74 mmol, 2.22 g, 82%) as a beige solid.
Reaction SMILES: [ClH:1].O1CCOCC1.[C:8]12([CH2:18][CH2:19][N:20]([CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:21]([C@H:23]3[CH2:27][CH2:26][CH2:25][N:24]3C(OC(C)(C)C)=O)=[O:22])[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2>>[ClH:1].[C:8]12([CH2:18][CH2:19][N:20]([CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:21]([C@H:23]3[CH2:27][CH2:26][CH2:25][NH:24]3)=[O:22])[CH2:9][CH:10]3[CH2:11][CH:12]([CH2:13][CH:14]([CH2:16]3)[CH2:15]1)[CH2:17]2
Reactant: CCCCCN(CCC12CC3CC(CC(C3)C1)C2)C(=O)[C@H]1CCCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCCCCN(CCC12CC3CC(CC(C3)C1)C2)C(=O)[C@H]1CCCN1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Next, 4 N hydrogen chloride/dioxane (20 ml, 81 mmol) was added to (R)-1-(t-butoxycarbonyl)-2-pyrrolidinecarboxylic acid N-[2-(1-adamantyl)ethyl]-N-pentylamide (1.8 g, 4.0 mmol) under ice-cooling, then the temperature was raised to room temperature, and the mixture was stirred for 1.5 hours. The reaction mixture was concentrated under reduced pressure to give 1.5 g (quantitatively) of (R)-2-pyrrolidinecarboxylic acid N-[2-(1-adamantyl)ethyl]-N-pentylamide hydrochloride as a noncrystalline solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:9]1[CH:14]=[CH:13][C:12](Br)=[CH:11][C:10]=1[Cl:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:24]1([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:9]1[CH:14]=[CH:13][C:12]([N:27]2[CH2:26][CH2:25][N:24]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:29][CH2:28]2)=[CH:11][C:10]=1[Cl:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ccc(Br)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(Cl)c2)CC1
Temperature: 100 °C

Procedure:
A mixture of the product of EXAMPLE 42A (280 g, 0.9 mmol), tert-butyl piperazine-1-carboxylate (205 mg, 1.09 mmol), palladium acetate (21 mg, 0.092 mmol), (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (86 mg, 0.14 mmol) and cesium carbonate (900 mg, 2.76 mmol) in toluene (10 mL) under nitrogen was heated at 100° C. for 16 hours. After cooling to ambient temperature, the mixture was concentrated and the residue was diluted with dichloromethane (300 mL), washed with water and brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (200-300 mesh) eluting with 5/1 petroleum ether/ethyl acetate to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[CH2:9][OH:10].Cl[C:12](Cl)([O:14]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[Br:8][C:4]1[C:3]2[CH2:9][O:10][C:12](=[O:14])[NH:1][C:2]=2[CH:7]=[CH:6][CH:5]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1cccc(Br)c1CO
Solvent: C1CCOC1
Product: O=C1Nc2cccc(Br)c2CO1
Temperature: 25 °C
Yield: 268.6 %

Procedure:
A solution of (2-Amino-6-bromo-phenyl)-methanol (549 mg, 2.72 mmol) and triphosgen (282 mg, 0.95 mmol) in THF (20 ml) was heated at 50° C. for an hours. After cooling to room temperature, the reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed by water and brine. After drying over MgSO4, the solution was concentrated under vacuum to give 5-bromo-1,4-dihydro-benzo[d][1,3]oxazin-2-one (582 mg, 94%) as a white solid. MS: 226.1 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]([OH:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[CH:12]=1.[C:20](OCC)(=[O:22])C>>[Cl:8][C:4]1[C:3]2[CH:9]([CH2:10][C:11]3[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[CH:12]=3)[O:19][C:20](=[O:22])[NH:1][C:2]=2[CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(C)=O
Reactant: Nc1cccc(Cl)c1C(O)Cc1ccc(F)c(F)c1
Product: O=C1Nc2cccc(Cl)c2C(Cc2ccc(F)c(F)c2)O1
Yield: 64 %

Procedure:
This compound was prepared using General Method 2 (EXAMPLE 1) from (±)-1-(2-amino-6-chlorophenyl)-2-(3,4-difluorophenyl)ethanol (0.28 g, 1.1 mmol) to afford 0.21 g (64%) of (±)-5-chloro-4-(3,4-difluorobenzyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one after flash chromatography (4:1 hexanes:ethyl acetate).