Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:17])[CH:7]=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:9]2)=[CH:4][CH:3]=1.N1CCCCC1.[Cl:24][CH2:25][CH:26]1[O:28][CH2:27]1>>[Cl:24][CH2:25][CH:26]([OH:28])[CH2:27][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:17])[CH:7]=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(=O)c2ccc(O)cc2o1
Reactant: ClCC1CO1
Solvent: C1CCNCC1
Product: CCOC(=O)c1cc(=O)c2ccc(OCC(O)CCl)cc2o1
Reaction time: 1 h

Procedure:
A mixture of 4.7 g of ethyl 7-hydroxychromone-2-carboxylate and 20 ml of 1-chloro-2,3-epoxypropane is heated at an external temperature of 100° C. for 8 hours in the presence of 0.2 ml of piperidine. The mixture is evaporated under reduced pressure and the residue is taken up with 15 ml of ethyl acetate. After filtration, the solution is evaporated under reduced pressure, the residue is taken up with 30 ml of chloroform and 10 ml of N hydrochloric acid, concentrated and stirred for one hour. The organic layer is washed with water, dried on anhydrous sodium sulfate and evaporated. The residue, crystallized from ethanol, gives 4 g of ethyl 7-(3-chloro-2-hydroxypropoxy)chromone-2-carboxylate. An amount of 1.65 g of the product thus obtained is dissolved in 40 mg of methylene chloride and to the solution thus obtained there is added 0.2 g of hexadecyltributylphosphonium bromide. To the organic solution there is added a solution of CH3SNa in 20 ml of water. The mixture is stirred for two hours at the room temperature, the aqueous layer is separated and acidified with N hydrochloric acid. The precipitate which forms, consisting of 7-(2-hydroxy-3-methylthiopropoxy)chromone2-carboxylic acid, is filtered and dried; m.p. 200°-202° C.
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][C:7]2[NH:8][CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.[C:22]([O:26][C:27](=[O:36])[NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31](I)[CH:30]=1)([CH3:25])([CH3:24])[CH3:23]>>[C:22]([O:26][C:27](=[O:36])[NH:28][C:29]1[CH:30]=[CH:31][CH:32]=[C:33]([N:8]2[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=[C:7]2[CH2:6][C:5]2[CH:20]=[CH:21][C:2]([Br:1])=[CH:3][CH:4]=2)[CH:34]=1)([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)Nc1cccc(I)c1
Reactant: Clc1ccc(-c2c[nH]c(Cc3ccc(Br)cc3)n2)c(Cl)c1
Product: CC(C)(C)OC(=O)Nc1cccc(-n2cc(-c3ccc(Cl)cc3Cl)nc2Cc2ccc(Br)cc2)c1

Procedure:
2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-1H-imidazole (1 g, 2.6 mmol) was treated with (3-iodo-phenyl)-carbamic acid tert-butyl ester following general procedure R to provide {3-[2-(4-bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-carbamic acid tert-butyl ester. The bromophenyl product (370 mg, 0.64 mmol) was treated as described in general procedure G using 4-ethoxycarbonylphenyl boronic acid to provide 4′-[1-(3-tert-butoxycarbonylamino-phenyl)-4-(2,4-dichloro-phenyl)-1H-imidazol-2-ylmethyl]-biphenyl-4-carboxylic acid ethyl ester.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]1[CH2:14][S:13][CH:12](OCC)[S:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:18]([O:20][P:21]([O:25]CC)[O:22][CH2:23][CH3:24])[CH3:19].P(Cl)(Cl)Cl>ClCCl.[Cl-].[Zn+2].[Cl-]>[Si:1]([O:8][CH2:9][C@@H:10]1[CH2:14][S:13][C@@H:12]([P:21]([O:22][CH2:23][CH3:24])([O:20][CH2:18][CH3:19])=[O:25])[S:11]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CCOP(OCC)OCC
Reactant: CCOC1SCC(CO[Si](C)(C)C(C)(C)C)S1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClP(Cl)Cl
Solvent: ClCCl
Product: CCOP(=O)(OCC)[C@@H]1SC[C@@H](CO[Si](C)(C)C(C)(C)C)S1
Temperature: 0 °C
Reaction time: 18 h
Yield: 31 %

Procedure:
To a solution of 4-(t-butyldimethylsilyloxymethyl)-2-ethoxy-1,3-dithiolane (example 48) (37.1 g, 126 mmol) and triethylphosphite (14.3 mL, 83.0 mmol, 0.66 eq) in dichloromethane (100 mL) were added phosphorus trichloride (3.6 mL, 42.0 mmol, 0.33 eq) and zinc chloride (catalytic) at 0° c. The solution was stirred at 0° C. for 2 hr and at room temperature for 18 hr. The solvent was evaporated and the crude material was purified by flash chromatography with a mixture of hexane and ethyl acetate (80:20 to 60:40) to give 3.64 g of the cis isomer, 8.62 g of the trans isomer and 9.95 g of the mixture (2:1 trans:cis) for a total yield of 46%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([O:11][CH3:12])=[CH:4][C:3]=1[N:13]1[CH2:18][CH2:17][CH:16]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH2:15][CH2:14]1.[CH3:25][S:26]([CH:29]=[CH2:30])(=[O:28])=[O:27].CS(C)=O>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([O:11][CH3:12])=[CH:4][C:3]=1[N:13]1[CH2:18][CH2:17][CH:16]([N:19]2[CH2:20][CH2:21][N:22]([CH2:30][CH2:29][S:26]([CH3:25])(=[O:28])=[O:27])[CH2:23][CH2:24]2)[CH2:15][CH2:14]1
Reactant: COc1cc(N2CCC(N3CCNCC3)CC2)c(Cl)cc1[N+](=O)[O-]
Reactant: C=CS(C)(=O)=O
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: COc1cc(N2CCC(N3CCN(CCS(C)(=O)=O)CC3)CC2)c(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.9 %

Procedure:
1-{1-[2-Chloro-5-(methyloxy)-4-nitrophenyl]-4-piperidinyl}piperazine (Example 112, step D) (0.050 g, 1.41 mmol) was taken up in THF (10 mL) and methylvinylsulfone (0.371 mL, 4.23 mmol) was added. DMSO was added to solubilize the starting material. Reaction was stirred overnight at rt. Reaction was not complete and over the next 3 days, 30 equivalents more methylvinylsulfone were added. Reaction was then stirred over the weekend. Poured reaction mixture onto prepackaged silica gel cartridge, dried by vacuum suction of air through cartridge and then flash chromatographed to give the title compound of step A (0.370 g, 57%). MS (M+H, ES+) 461.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[CH2:9]([O:11][C:12]([C:14]1[C:15](=[O:37])[N:16]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:17]2[C:22]([C:23]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)=[CH:21][CH:20]=[CH:19][N:18]=2)=[O:13])[CH3:10]>N1C=CC=CC=1>[CH2:9]([O:11][C:12]([C:14]1[C:15](=[O:37])[N:16]([CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:17]2[C:22]([C:23]=1[N:24]1[CH2:25][CH2:26][N:27]([C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[O:7])[CH2:28][CH2:29]1)=[CH:21][CH:20]=[CH:19][N:18]=2)=[O:13])[CH3:10]
Reactant: O=C(Cl)c1cccs1
Reactant: CCOC(=O)c1c(N2CCNCC2)c2cccnc2n(Cc2ccccc2)c1=O
Solvent: c1ccncc1
Product: CCOC(=O)c1c(N2CCN(C(=O)c3cccs3)CC2)c2cccnc2n(Cc2ccccc2)c1=O
Temperature: 0 °C
Reaction time: 18 h
Yield: 50.9 %

Procedure:
2-Thiophene carbonyl chloride (0.16 mL, 1.5 mmol) was added to a stirred solution of 1-benzyl-2-oxo-4-piperazin-1-yl-1,2-dihydro-[1,8]-naphthyridine-3-carboxylic acid ethyl ester (5) (392 mg, 1 mmol) in pyridine (5 mL) at 0° C. under inert atmosphere. The solution was allowed to come at room temperature and further stirred for 18 h. The solution was poured into ice water, the solids formed were filtered, washed by water, dried, and recrystallized by ether and ethyl acetate to yield 256 mg (51%) of 1-benzyl-4-[4-(thiophene-2-carbonyl)-piperazin-1-yl]-2-oxo-1,2-dihydro-[1,8]-naphthyridine-3-carboxylic acid ethyl ester (6) as white solids. MP: 168° C.; 1H-NMR (DMSO-d6): δ 1.29 (t, J=6.9 Hz, 3H), 3.16 (m, 4H), 3.88 (m, 4H), 4.31 (q, J=6.9 Hz, 2H), 5.56 (s, 2H), 7.15 (dd, J=3.5, 4.9 Hz, 1H), 7.20-7.29 (m, 5H), 7.38 (dd, J=4.6, 8.2 Hz, 1H), 7.97 (d, J=4.9 Hz, 1H), 8.35 (dd, J=1.5, 7.5 Hz, 1H), 8.66 (dd, J=1.5, 7.5 Hz, 1H); EIMS: 503 (M+1), 525 (M+23). Anal. C27H26N4O4S (C,H,N).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([SH:11])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:27][CH2:28][O:29][CH2:30][CH2:31][OH:32]>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:27][CH2:28][O:29][CH2:30][CH2:31][OH:32])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OCCOCCCl
Reactant: Nc1nc(S)nc2c1nc(O)n2Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nc(SCCOCCO)nc2c1nc(O)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 25.9 %

Procedure:
Crude 6-amino-9-benzyl-8-hydroxy-2-mercaptopurine (470 mg, 1.7 mmol) was suspended in dimethylformamide (100 ml). To the suspension were added potassium carbonate (350 mg, 2.5 mmol) and 2-(2-chloroethoxy)ethanol (0.27 ml, 2.6 mmol) in order. The mixture was stirred at room temperature for 4 hours. The solvent was removed in vacuo and the residue was purified by silica gel chromatography (7% methanol/chloroform) to give the subject compound (159 mg, yield 27%).
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[Br:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH:12]=[CH:13][C:14](=[O:29])[N:15]2[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1>CS(C)=O>[Br:9][C:10]1[C:11]2[CH:12]3[CH2:4][CH:13]3[C:14](=[O:29])[N:15]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=3)[C:16]=2[CH:17]=[CH:18][CH:19]=1
Reactant: C[S+](C)(C)=O
Reactant: COc1ccc(Cn2c(=O)ccc3c(Br)cccc32)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc(CN2C(=O)C3CC3c3c(Br)cccc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.1 %

Procedure:
To a suspension of sodium hydride (136 mg, 3.40 mmol) in DMSO (5 mL) at room temperature was added trimethylsulfoxonium iodide (661 mg, 3.00 mmol) slowly under nitrogen. The reaction mixture was stirred at room temperature for 1 h, and then 5-bromo-1-(4-methoxybenzyl)quinolin-2(1H)-one (689 mg, 2.00 mmol) in 1 mL DMSO was added. Upon completion of addition, the reaction mixture was stirred at room temperature for 2 h, and then heated to 90° C. for 2 d. After cooling to room temperature, the reaction mixture was quenched with water and extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The resulting residue was purified by flash chromatography (0 to 30% ethyl acetate:hexanes) to afford the title compound (330 mg, 45% yield) as a white powder. LCMS, [M+H]+=358.0. 1H NMR (400 MHz, CDCl3) δ 7.21 (d, J=7.7 Hz, 1H), 7.08 (d, J=8.2 Hz, 2H), 6.91 (t, J=8.0 Hz, 1H), 6.85-6.75 (m, 3H), 4.97-5.25 (m, 2H), 3.75 (s, 3H), 2.90 (td, J=8.1, 5.2 Hz, 1H), 2.40 (ddd, J=9.6, 8.0, 4.9 Hz, 1H), 1.74 (td, J=9.1, 4.4 Hz, 1H), 0.69 (q, J=4.8 Hz, 1H).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[N:8]=[C:7](O)[CH:6]=[CH:5][N:4]=1.P(Br)(Br)[Br:13]>>[Br:13][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([C:2]([F:11])([F:10])[F:1])[N:8]=1
Reactant: BrP(Br)Br
Reactant: Oc1ccnc(C(F)(F)F)n1
Product: FC(F)(F)c1nccc(Br)n1
Temperature: 150 °C

Procedure:
The 2-(trifluoromethyl)pyrimidin-4-ol (328 mg, 2.0 mmol) and PBr3 (0.188 mL, 2.0 mmol) were mixed and heated at 150° C. for 3 h. The reaction was cooled down and quenched with ice water, extracted with DCM (20 mL×2) to yield the titled compound. The organic phase was concentrated and crude material was purified by preparative TLC with 20% Acetone:Hexane to yield titled compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1F)[NH:7][C:6](=[O:12])[C:5]2=[O:13].[CH3:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>CS(C)=O.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N:18]1[CH2:19][CH2:20][N:15]([CH3:14])[CH2:16][CH2:17]1)[NH:7][C:6](=[O:12])[C:5]2=[O:13]
Reactant: O=C1Nc2cc(F)c(F)cc2C1=O
Reactant: CN1CCNCC1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CN1CCN(c2cc3c(cc2F)C(=O)C(=O)N3)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 72 %

Procedure:
To a solution of 5,6-difluoroisatin (1.0 g, 5 mmol) in 50 mL of dimethyl sulfoxide was added N-methylpiperazine (5.47 g, 50 mmol). The mixture was stirred for 4 h at room temperature and the crude reaction mixture was diluted with ethyl acetate. The organic solution was washed with saturated sodium bicarbonate. The organic layers were separated and concentrated to give the title compound in 72% yield: mp 150° C. (dec); 1H NMR (300 MHz, DMSO-d6) δ 10.8 (br s, 1H), 7.3 (d, 1H), 6.4 (d, 1H), 2.25 (s, 3H), 2.2 (m, 4H), 2.1 (m, 4H).
Reaction SMILES: [OH:1][C:2]1([C:5]([OH:7])=O)[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:41][N:42]1[C:51]2[C:46](=[CH:47][N:48]=[C:49]([CH3:52])[CH:50]=2)[CH:45]=[C:44]([C:53]2[CH:54]=[C:55]([NH:60]/[C:61](/[NH2:64])=[N:62]/O)[CH:56]=[CH:57][C:58]=2[CH3:59])[C:43]1=[O:65]>CN(C=O)C>[OH:1][C:2]1([C:5]2[O:7][N:62]=[C:61]([NH:60][C:55]3[CH:56]=[CH:57][C:58]([CH3:59])=[C:53]([C:44]4[C:43](=[O:65])[N:42]([CH3:41])[C:51]5[C:46]([CH:45]=4)=[CH:47][N:48]=[C:49]([CH3:52])[CH:50]=5)[CH:54]=3)[N:64]=2)[CH2:4][CH2:3]1
Reactant: Cc1cc2c(cn1)cc(-c1cc(N/C(N)=N/O)ccc1C)c(=O)n2C
Reactant: O=C(O)C1(O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc2c(cn1)cc(-c1cc(Nc3noc(C4(O)CC4)n3)ccc1C)c(=O)n2C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1-hydroxycyclopropanecarboxylic acid (6 mg, 0.06 mmol) in DMF (1 mL) were added DIPEA (31 μL, 0.18 mmol) and HATU (23 mg, 0.06 mmol). After stirring at rt for 15 min, 17 (20 mg, 0.06 mmol) was added as a solution in DMF (0.5 mL). The reaction was stirred at rt until complete consumption of 17 was determined by LC/MS and then heated at 100° C. for 1 h. Subsequently the reaction was cooled to rt, filtered and purified by preparative LC/MS to give 3-(5-(5-(1-hydroxycyclopropyl)-1,2,4-oxadiazol-3-ylamino)-2-methylphenyl)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one (A57). MS m/z 404.4 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:14]2[N:15]=[C:16]([NH:19][CH:20]([CH3:22])[CH3:21])[S:17][CH:18]=2)[CH:3]=1.C(C1N=C(C2C=C(O[CH:42]3[CH2:60][CH:59]4[N:44]([C:45](=[O:65])[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH:52]=[CH:53][CH:54]5[C:56]([C:62]([OH:64])=[O:63])([NH:57][C:58]4=[O:61])[CH2:55]5)[CH2:43]3)C3C(=CC(OC)=CC=3)N=2)SC=1)(C)C>>[CH:20]([NH:19][C:16]1[S:17][CH:18]=[C:14]([C:4]2[CH:3]=[C:2]([O:1][CH:42]3[CH2:60][CH:59]4[N:44]([C:45](=[O:65])[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH:52]=[CH:53][CH:54]5[C:56]([C:62]([OH:64])=[O:63])([NH:57][C:58]4=[O:61])[CH2:55]5)[CH2:43]3)[C:11]3[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[N:5]=2)[N:15]=1)([CH3:22])[CH3:21]
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCCCC(=O)N4C3)cc(-c3nc(C(C)C)cs3)nc2c1
Reactant: COc1ccc2c(O)cc(-c3csc(NC(C)C)n3)nc2c1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCCCC(=O)N4C3)cc(-c3csc(NC(C)C)n3)nc2c1

Procedure:
The title compound was prepared from 4-hydroxy-2-[2-(isopropylamino)thiazol-4-yl]-7-methoxyquinoline and intermediate 7 following the procedure (Step F-H) reported for 18-[2-[4-(isopropyl)thiazol-2-yl]-7-methoxyquinolin-4-yloxy]-2,15-dioxo-3,16-diazatricyclo[14.3.0.04,6]nonadec-7-ene-4-carboxylic acid 10: m/z=648 (M+H)+. 1H NMR (CDCl3): 1.01-1.41 (m, 12H), 1.81-1.95 (m, 3H), 2.11-2.30 (m, 3H), 2.43 (m, 1H), 2.55 (m, 1H), 2.91 (m, 1H), 3.47 (m, 2H), 3.60 (m, 1H), 3.94 (s, 3H), 4.27 (M, 1H), 4.78 (d, J=8.0 Hz, 1H), 5.52-5.70 (m, 3H), 7.10 (d, 1H, J=8.6 Hz), 7.32 (s, 1H), 7.45-7.52 (m, 2H), 7.96 (d, 1H, J=8.6 Hz), 9.5 (s, 1H).
Reaction SMILES: [C:1]([O-:8])(=[O:7])/[CH:2]=[CH:3]\[C:4]([O-:6])=[O:5].[Ca].[OH-:10].[Na+].[OH-]>>[C:1]([OH:8])(=[O:7])[CH:2]([CH2:3][C:4]([OH:6])=[O:5])[OH:10]
Reactant: O=C([O-])/C=C\C(=O)[O-]
Reactant: [OH-]
Agent: [Ca]
Agent: [Na+]
Product: O=C(O)CC(O)C(=O)O

Procedure:
A preferred procedure to be followed when using calcium carbonate as a calcium source, i.e., as a calcium starting-material, in the instant process is as follows; preformed malic acid, sodium hydroxide, a maleate reactant selected from maleic anhydride, maleic acid and mixtures thereof, and a calcium reactant selected from calcium carbonate and mixtures thereof with calcium hydroxide are reacted according to the immediately consecutive steps: (i) mixing calcium carbonate, water, malic acid and a proportion of said maleate reactant, allowing complete evolution of carbon dioxide and forming an acidic mixture; (ii) adding sodium hydroxide or a mixture thereof with calcium hydroxide, to the acidic mixture of step (i), forming a sodium cation-containing alkaline mixture; (iii) in a period of duration about 1 hour or less, adding the remainder of said maleate reactant to the stirred sodium cation-containing alkaline mixture of step (ii), at temperatures in the range from about 75° C. to about 110° C., having at the end of the step (iii) addition a net hydroxide excess MOH ; (iv) in a period of duration about 1 hour or less, cooling the mixture formed in step (iii) to a temperature in the range from about 35° C. to about 45° C.; (v) at said temperature in the range from about 35° C. to about 45° C., continuing to react the mixture of step (iv); the duration of step (v) being from about 48 hours to about 240 hours, whereby a crude product having a HPLC yield of at least 80% 2,2'-oxodisuccinate is secured; and (vi) diluting the product of step (v) with water and precipitating calcium carbonate therefrom; thereby arresting the step (iv) reaction and depleting the level of calcium; provided that in step (iii) and (iv) together; the total time at any temperature above about 100° C. does not exceed about 15 minutes; the total time at any temperature above about 90° C. does not exceed about 30 minutes; the total time at any temperature above about 80° C. does not exceed about 2 hours; the total time at any temperature above about 70° C. does not exceed about 6 hours; and the total time at any temperature above about 65° C. does not exceed about 12 hours; and provided that for each mole of preformed malic acid reacted, the total molar amount of maleate reactant is about 1.1 to about 1.6 moles; the total molar amount of calcium reactant, is from about 0.9 to about 1.65 moles; the total molar amount of sodium hydroxide, is from about 0.92 to about 3.7 moles; the net hydroxide excess in step (iii), MOH, is from about 0.02 to about 0.3 moles; and further provided that for each mole of preformed malic acid reacted (i.e., charged in the reactor), the total net amount of water added in steps (i), (ii) and (iii) together, allowing for evaporation losses, is no less than about 189 grams and no more than about 282 grams.
Reaction SMILES: [CH:1]12[CH:8]([N:9]([CH3:17])[C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:5]([CH2:6][CH2:7]1)[CH2:4][NH:3][CH2:2]2.CS(O[CH2:23][CH2:24][CH2:25][CH:26]([C:38]1[CH:43]=[CH:42][C:41]([C:44]#[N:45])=[CH:40][CH:39]=1)[O:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([O:36][CH3:37])[CH:29]=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:44]([C:41]1[CH:40]=[CH:39][C:38]([CH:26]([O:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([O:36][CH3:37])[CH:29]=2)[CH2:25][CH2:24][CH2:23][N:3]2[CH2:4][CH:5]3[CH:8]([N:9]([CH3:17])[C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:14])[CH3:15])[CH:1]([CH2:7][CH2:6]3)[CH2:2]2)=[CH:43][CH:42]=1)#[N:45]
Reactant: CN(C(=O)OC(C)(C)C)C1C2CCC1CNC2
Reactant: COc1ccc(OC(CCCOS(C)(=O)=O)c2ccc(C#N)cc2)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(OC(CCCN2CC3CCC(C2)C3N(C)C(=O)OC(C)(C)C)c2ccc(C#N)cc2)cc1OC
Temperature: 90 °C
Yield: 60.1 %

Procedure:
A mixture of tert-butyl 3-azabicyclo[3.2.1]oct-8-yl(methyl)carbamate (Preparation D; 2.60 g, 10.9 mmol), 4-(4-cyanophenyl)-4-(3,4-dimethoxyphenoxy)butyl methanesulfonate (see step (iii) above; 4.40 g, 10.9 mmol), and potassium carbonate (1.50 g, 10.9 mmol) in DMF (50 mL) was heated at 90° C. under nitrogen for 4 h. The mixture was partitioned with water (50 mL) and diethyl ether (50 mL). The aqueous layer was extracted with diethyl ether (2×50 mL). The combined organic extracts were washed with brine (2×30 mL), dried (Na2SO4), filtered and then concentrated in vacuo. The residue was chromatographed on silica gel, eluting with dichloromethane:methanol (98:2), to afford 3.60 g (60%) of the sub-title compound as an amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[C:11]1([CH2:17][C:18](Cl)=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C(=S)=S>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:18](=[O:19])[CH2:17][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: COc1cccc(Cl)c1Cl
Reactant: O=C(Cl)Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: COc1cc(C(=O)Cc2ccccc2)cc(Cl)c1Cl
Reaction time: 17 h

Procedure:
To a stirred mixture of 2,3-dichloroanisole (62 g., 0.35 mole), phenylacetyl chloride (54 g., 0.35 mole) and carbon disulfide (250 ml.) is added portionwise aluminum chloride (47 g., 0.35 mole) with cooling at 0°-5° C. The reaction mixture is left at 25° C. for 17 hours, the carbon disulfide removed, and the residue treated with ice-water and concentrated hydrochloric acid (50 ml.) to give 68.8 g. of 2,3-dichloro-5-phenylacetylanisole which melts at 126°-129° C. on crystallization from benzene:cyclohexane, 2:1.
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:8][N:7]([CH:9]([CH3:11])[CH3:10])[C:6]2[N:12]=[C:13]([NH:16][C:17]3[CH:25]=[CH:24][C:20]([C:21]([OH:23])=O)=[CH:19][C:18]=3[O:26][CH3:27])[N:14]=[CH:15][C:5]=2[N:4]([CH3:28])[C:3]1=[O:29].C([N:33](C(C)C)C(C)C)C.[Cl-].[NH4+]>CN(C)C=O>[F:30][C:2]1([F:1])[CH2:8][N:7]([CH:9]([CH3:11])[CH3:10])[C:6]2[N:12]=[C:13]([NH:16][C:17]3[CH:25]=[CH:24][C:20]([C:21]([NH2:33])=[O:23])=[CH:19][C:18]=3[O:26][CH3:27])[N:14]=[CH:15][C:5]=2[N:4]([CH3:28])[C:3]1=[O:29]
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C(C)C)CC(F)(F)C(=O)N2C
Reactant: CCN(C(C)C)C(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COc1cc(C(N)=O)ccc1Nc1ncc2c(n1)N(C(C)C)CC(F)(F)C(=O)N2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
To a mixture of 0.08 g (0.19 mmole) of 4-(7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-292), 0.13 mL (0.76 mmole) of ethyldiisopropyl amine and 0.020 g (0.38 mmole) of ammonium chloride in 2.0 mL of dimethylformamide was added 0.082 g (0.21 mmole) of 1-(di-1-pyrrolidinylmethylene)-1H-benzotriazolium 3-oxide hexafluorophosphate. The mixture was stirred at room temperature for 1 hour, then diluted with 10 mL of ice water. The mixture was extracted three times with dichloromethane. The combined organic layers were washed three times with sodium carbonate, three times with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-90:10) gave 0.074 g of 4-(7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzamide (I-294) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][CH:12]=[C:13]2[C:18](=[O:19])OC(C)(C)OC2=O)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.CCCCCC>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[C:5]2[C:6]=1[C:18](=[O:19])[CH:13]=[CH:12][NH:11]2
Reactant: COc1cc(NC=C2C(=O)OC(C)(C)OC2=O)cc(OC)c1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCCCCC
Product: COc1cc(OC)c2c(=O)cc[nH]c2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5-[(3,5-Dimethoxyphenylamino)-methylene]-2,2-dimethyl[1,3]dioxane-4,6-dione (400 mg, 1.30 mmol) in diphenyl ether (5 mL) and heated at 200° C. for 30 min. The reaction mixture was cooled to rt and hexane was added and stirred for 30 min. The brown solid was filtered and dried to yield 5,7-dimethoxy-1H-quinolin-4-one LCMS m/z=206 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:22])[N:13]([C:15]3[CH:20]=[CH:19][NH:18][C:17](=[O:21])[CH:16]=3)[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.I[CH2:24][CH2:25][OH:26]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:22])[N:13]([C:15]3[CH:20]=[CH:19][N:18]([CH2:24][CH2:25][OH:26])[C:17](=[O:21])[CH:16]=3)[CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc(C#Cc2cccc(Cl)c2)cn1-c1cc[nH]c(=O)c1
Reactant: OCCI
Product: Cc1nc(C#Cc2cccc(Cl)c2)cn1-c1ccn(CCO)c(=O)c1

Procedure:
The title compound, orange gum, MS: m/e=354.2, 356.2 (M+H+), was prepared in accordance with the general method of example 3 from 4-[4-(3-chloro-phenylethynyl)-2-methyl-imidazol-1-yl]-1H-pyridin-2-one and 2-iodoethanol.