Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:6]=[C:7]([C:14]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)=[O:15])[C:8]2[S:13][CH:12]=[CH:11][C:9]=2[N:10]=1.C([NH+](CC)CC)C.[C:28](Cl)(=[O:33])[CH2:29][CH:30]([CH3:32])[CH3:31]>C(Cl)Cl>[CH3:31][CH:30]([CH3:32])[CH2:29][C:28]([NH:1][CH2:2][CH2:3][NH:4][C:5]1[N:6]=[C:7]([C:14]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)=[O:15])[C:8]2[S:13][CH:12]=[CH:11][C:9]=2[N:10]=1)=[O:33]
Reactant: CC(C)CC(=O)Cl
Reactant: NCCNc1nc(C(=O)c2cccs2)c2sccc2n1
Agent: CC[NH+](CC)CC
Solvent: ClCCl
Product: CC(C)CC(=O)NCCNc1nc(C(=O)c2cccs2)c2sccc2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.3 %

Procedure:
A solution of 2-(2-aminoethylamino)thieno[3,2-d]pyrimidin-4-yl 2-thienylmethanone (50 mg, 0.16 mmol) in CH2Cl2 (2 mL) was treated with triethylammonium methylpolystyrene carbonate (80 mg, 0.25 mmol) then isovaleryl chloride (30 mg, 0.25 mmol) and shaken at room temperature for 6 h. The reaction mixture was treated with tris-(2-aminoethyl)amine polystyrene (0.20 g, 0.75 mmol), shaken at room temperature for 16 h, treated with polystyrene methylisocyanate (0.18 g, 0.25 mmol) and CH2Cl2 (2 mL), shaken for a further 6 h then filtered and concentrated in vacuo to give the title compound (35 mg, 55%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[C:8](Br)[CH:7]=[C:6]([CH3:11])[C:5]=1[N:12]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.[Cl:32][C:33]1[S:37][C:36](B(O)O)=[CH:35][CH:34]=1>>[CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[C:8]([C:36]2[S:37][C:33]([Cl:32])=[CH:34][CH:35]=2)[CH:7]=[C:6]([CH3:11])[C:5]=1[N:12]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: OB(O)c1ccc(Cl)s1
Reactant: COC(=O)c1cc(Br)cc(C)c1N(Cc1cccnc1)S(=O)(=O)c1ccc(OC)cc1
Product: COC(=O)c1cc(-c2ccc(Cl)s2)cc(C)c1N(Cc1cccnc1)S(=O)(=O)c1ccc(OC)cc1
Yield: 61.1 %

Procedure:
In the same manner as described in Example 241, 505 mg (1.0 mmol) of the product of Example 89 and 357 mg (2.2 mmol) of 5-chlorothiophene-2-boronic acid provided 332 mg (61%) of the desired product as an yellow solid. Electrospray Mass Spec 543 (M+H).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].Cl.[CH3:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[CH2:23][CH2:24][NH:25]2.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[CH3:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[CH2:23][CH2:24][N:25]2[C:15](=[O:17])[CH2:14][C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:8]=1
Reactant: Cc1cccc2c1CCN2
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cc1cccc2c1CCN2C(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Yield: 6.2 %

Procedure:
The product is prepared according to the procedure described in example 5, using 261 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 339 mg of 4-methylindoline hydrochloride, and 254 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 241 μl of pyridine and 4.0 ml of N,N-dimethylformamide. 22 mg of 2-[2-(4-methyl-2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a fuchsia crystalline powder, the characteristics of which are the following:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=[O:7])[C:5]2=[CH:11][CH:12]=1.[CH3:13][N:14]([CH3:24])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH3:23])[CH3:22])[CH:16]=1>>[CH3:22][N:21]([CH3:23])[C:17]1[CH:16]=[C:15]([N:14]([CH3:24])[CH3:13])[CH:20]=[CH:19][C:18]=1[C:6]([C:5]1[CH:11]=[CH:12][C:2]([NH2:1])=[CH:3][C:4]=1[C:9]([OH:8])=[O:10])=[O:7]
Reactant: Nc1ccc2c(c1)C(=O)OC2=O
Reactant: CN(C)c1cccc(N(C)C)c1
Product: CN(C)c1ccc(C(=O)c2ccc(N)cc2C(=O)O)c(N(C)C)c1

Procedure:
Condensation of 4-aminophthalic anhydride and N,N,N',N'-tetramethyl-m-phenylenediamine by the method of part A of Example 3 affords 2-(2,4-bis(dimethylamino)benzoyl)-5-aminobenzoic acid.
Reaction SMILES: Br[C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[SH:21])=[O:12].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[F:20][C:17]1[CH:18]=[CH:19][C:14]2[NH:13][C:11](=[O:12])[C:3]3[C:4]4[CH2:10][CH2:9][CH2:8][CH2:7][C:5]=4[S:6][C:2]=3[S:21][C:15]=2[CH:16]=1
Reactant: O=C(Nc1ccc(F)cc1S)c1c(Br)sc2c1CCCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=C1Nc2ccc(F)cc2Sc2sc3c(c21)CCCC3

Procedure:
In the same manner as in Example 74 and using 2-bromo-4,5,6,7-tetrahydro-N-(4-fluoro-2-mercaptophenyl)-benzo[b]thiophene-3-carboxamide, dimethyl sulfoxide and potassium carbonate, 8-fluoro-1,2,3,4-tetrahydro-[1]benzothieno[2,3-b][1,5]benzothiazepin-12(11H)-one is obtained.
Reaction SMILES: [CH:1]1([N:4]([CH:32]2[CH2:34][CH2:33]2)[C:5]([C:7]2[N:29]([CH2:30][CH3:31])[C:10]3=[N:11][C:12]([NH:19][C:20]4[CH:24]=[C:23]([CH:25]=[O:26])[N:22]([CH2:27][CH3:28])[N:21]=4)=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.[OH:35]OS([O-])=O.[K+].O>CN(C=O)C>[CH:32]1([N:4]([CH:1]2[CH2:2][CH2:3]2)[C:5]([C:7]2[N:29]([CH2:30][CH3:31])[C:10]3=[N:11][C:12]([NH:19][C:20]4[CH:24]=[C:23]([C:25]([OH:35])=[O:26])[N:22]([CH2:27][CH3:28])[N:21]=4)=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:33][CH2:34]1
Reactant: O=S([O-])OO
Reactant: CCn1nc(Nc2nc3c(cc(C(=O)N(C4CC4)C4CC4)n3CC)c3c2ncn3C)cc1C=O
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1nc(Nc2nc3c(cc(C(=O)N(C4CC4)C4CC4)n3CC)c3c2ncn3C)cc1C(=O)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 71.1 %

Procedure:
A mixture of N,N-dicyclopropyl-6-ethyl-4-(1-ethyl-5-formyl-1H-pyrazol-3-ylamino)-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (example 101C, 27 mg, 0.059 mmol) and OXONE (79 mg, 0.129 mmol) in DMF was stirred at room temperature for 20 hrs. Water was added and the mixture was extracted with dichloromethane 3 times. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified with preparative HPLC to give 3-(7-(dicyclopropylcarbamoyl)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-ylamino)-1-ethyl-1H-pyrazole-5-carboxylic acid (20 mg, 98% yield)
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[NH:13][C:14](=[O:41])[N:15]([C:17]1[N:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[CH:26][C:25]=2[NH:36][C:37](=[O:40])[CH:38]=[CH2:39])[CH:18]=1)[CH3:16].CCN(C(C)C)C(C)C.[C:51](Cl)(=[O:53])[CH3:52]>C(Cl)Cl>[C:51]([N:33]1[CH2:32][CH2:31][N:30]([C:27]2[CH:28]=[CH:29][C:24]([NH:23][C:19]3[CH:18]=[C:17]([N:15]([CH3:16])[C:14]([NH:13][C:3]4[C:2]([Cl:1])=[C:7]([O:8][CH3:9])[CH:6]=[C:5]([O:10][CH3:11])[C:4]=4[Cl:12])=[O:41])[N:22]=[CH:21][N:20]=3)=[C:25]([NH:36][C:37](=[O:40])[CH:38]=[CH2:39])[CH:26]=2)[CH2:35][CH2:34]1)(=[O:53])[CH3:52]
Reactant: CC(=O)Cl
Reactant: C=CC(=O)Nc1cc(N2CCNCC2)ccc1Nc1cc(N(C)C(=O)Nc2c(Cl)c(OC)cc(OC)c2Cl)ncn1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CC(=O)Nc1cc(N2CCN(C(C)=O)CC2)ccc1Nc1cc(N(C)C(=O)Nc2c(Cl)c(OC)cc(OC)c2Cl)ncn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 15.5 %

Procedure:
N-(2-((6-(3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methylureido)pyrimidin-4-yl)amino)-5-(piperazin-1-yl)phenyl)acrylamide (Procedure 2L, Example 157) (8.6 g, 0.014 mmol) and DIEA (7.5 μl, 0.043 mmol) were stirred in DCM (1.0 ml) at room temperature under nitrogen atmosphere. A solution of acetyl chloride (1.0 μl, 0.016 mmol) in DCM (11 ul) was added and the reaction mixture was stirred at room temperature for 2 hours. The solvent was evaporated and the resulting material was dissolved in 400 ul of DMSO. The DMSO solution was diluted with 1.0 ml of MeOH and purified by prep-HPLC (water/ACN in formic acid condition) to afford the title compound (1.4 mg, yield: 15%). 1H-NMR (400 MHz, MeOH-d4) δ 2.16 (s, 3H) 3.65-3.80 (m, 4H) 3.94 (s, 6H) 5.76 (dd, 1H) 6.15 (s, 1H) 6.28-6.49 (m, 2H) 6.78-6.82 (m, 1H) 6.95 (dd, 2.89 Hz, 1H) 7.28-7.38 (m, 2H) 8.31 (d, 1H) 8.58 (br. s., 1H); ESI-MS: 643 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][OH:6])[CH2:3][CH2:2]1.[H-].[Na+].[F:9][C:10]1[CH:22]=[C:21](F)[C:20]([F:24])=[CH:19][C:11]=1[C:12]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[O:13]>CN(C)C=O>[CH:1]1([CH2:4][CH2:5][O:6][C:21]2[C:20]([F:24])=[CH:19][C:11]([C:12]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[O:13])=[C:10]([F:9])[CH:22]=2)[CH2:3][CH2:2]1
Reactant: OCCC1CC1
Reactant: CS(=O)(=O)NC(=O)c1cc(F)c(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)NC(=O)c1cc(F)c(OCCC2CC2)cc1F
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 18.8 %

Procedure:
To a mixture of 2-cyclopropylethanol (0.172 g, 2.0 mmol) in anhydrous N,N-dimethylformamide (20 mL) was added sodium hydride (60% in mineral oil, 0.20 g, 5.0 mmol) at room temperature. The resulting mixture was stirred at 45° C. for 30 min and then cooled to room temperature. 2,4,5-Trifluoro-N-(methylsulfonyl)benzamide (WO 2012007883 A1) (0.51 g, 2.2 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. The mixture was cooled to 0° C. and quenched with hydrochloride acid (1N, 30 mL) followed by extraction with ethyl acetate (100 mL). The organic layer was washed with water (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo, the crude product was purified by silica gel column chromatography using 10-60% ethyl acetate (containing 2% acetic acid) in hexanes as an eluent to afford the title compound as a white solid (0.12 g, 19%): 1H NMR (300 MHz, DMSO-d6) δ 12.06 (brs, 1H), 7.58 (dd, J=6.9 Hz & 11.4 Hz, 1H), 7.30 (dd, J=6.9 Hz & 12.1 Hz, 1H), 4.19 (t, J=6.6 Hz, 2H), 3.35 (s, 3H), 1.69-1.62 (m, 2H), 0.88-0.74 (m, 1H), 0.47-0.41 (m, 2H), 0.16-0.11 (m, 2H); MS (ES−) m/z 318.1 (M−1).
Reaction SMILES: [CH3:1][N:2]=[C:3]([NH2:18])[NH:4][CH:5]([C:13]1[N:14]=[CH:15][S:16][CH:17]=1)[S:6][CH2:7][CH2:8][C:9](=[NH:12])OC.[N:19]#[C:20][NH2:21]>C(O)C>[C:20]([NH:21][C:9](=[NH:12])[CH2:8][CH2:7][S:6][CH:5]([NH:4][C:3]([NH2:18])=[N:2][CH3:1])[C:13]1[N:14]=[CH:15][S:16][CH:17]=1)#[N:19]
Reactant: CN=C(N)NC(SCCC(=N)OC)c1cscn1
Reactant: N#CN
Solvent: CCO
Product: CN=C(N)NC(SCCC(=N)NC#N)c1cscn1
Yield: 31.4 %

Procedure:
In 30 ml of ethanol was dissolved 6.4 g of methyl 3-(2-methylguanidinothiazol-4-ylmethylthio)propionimidate and after adding thereto 0.9 g of cyanamide and stirring the mixture for 2 hours at room temperature, the solvent was distilled off under reduced pressure. Then, the residue obtained was purified by column chromatography using a mixture of chloroform and methanol as the developing solvent and recrystallized from ethanol to provide 2.0 g of N-cyano-3-(2-methylguanidinothiazol-4-ylmethylthio)propionamidine showing a melting point of 144°-145° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15](Cl)[CH:14]=2)=[C:11]2[C:6]([N:7]([CH3:23])[C:8](=[O:22])[N:9]([CH3:21])[C:10]2=[O:20])=[CH:5]1.BrC1C=C(C=CC=1)[C:28]([O:30][CH3:31])=[O:29]>>[NH2:1][CH2:2][CH2:3][N:4]1[C:12]([C:13]2[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=2)[C:28]([O:30][CH3:31])=[O:29])=[C:11]2[C:6]([N:7]([CH3:23])[C:8](=[O:22])[N:9]([CH3:21])[C:10]2=[O:20])=[CH:5]1
Reactant: COC(=O)c1cccc(Br)c1
Reactant: Cn1c(=O)c2c(-c3cccc(Cl)c3)n(CCN)cc2n(C)c1=O
Product: COC(=O)c1cccc(-c2c3c(=O)n(C)c(=O)n(C)c3cn2CCN)c1

Procedure:
The title compound was prepared analogously to Intermediate B by replacing 1-bromo-3-chlorobenzene with methyl 3-bromobenzoate;
Reaction SMILES: O.[OH-].[Li+].O.[F:5][C:6]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH3:19])=[C:12]2[C:7]=1[C:8](=[O:37])[C:9]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)=[CH:10][N:11]2[CH2:20][CH2:21][S:22][CH2:23][CH2:24][C:25]([O:27]C)=[O:26]>C(#N)C>[F:5][C:6]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH3:19])=[C:12]2[C:7]=1[C:8](=[O:37])[C:9]([C:29]1[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=1)=[CH:10][N:11]2[CH2:20][CH2:21][S:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26]
Reactant: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OC)cc3)cn(CCSCCC(=O)OC)c12
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OC)cc3)cn(CCSCCC(=O)O)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.3 %

Procedure:
Lithium hydroxide mono-hydrate (31 mg, 0.74 mmol) and water (5 ml) were added to an acetonitrile solution (10 ml) of methyl 3-{2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]ethylsulfanyl}propionate (175 mg, 0.37 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was washed with ethyl acetate, and then 2N hydrochloric acid was added to the water layer to make the mixture acidic. The generated insoluble matter was separated, washed with water and then dried, giving a white powder of 3-{2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]ethylsulfanyl}propionic acid (140 mg, yield: 82%).
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]#[N:11])[C:4]=2[CH:3]=[N:2]1.[OH-].[K+].[I:14]I>CN(C=O)C>[I:14][C:3]1[C:4]2[C:5]([C:10]#[N:11])=[CH:6][CH:7]=[CH:8][C:9]=2[NH:1][N:2]=1
Reactant: II
Reactant: N#Cc1cccc2[nH]ncc12
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: N#Cc1cccc2[nH]nc(I)c12
Temperature: 25 °C
Reaction time: 5 h
Yield: 67.3 %

Procedure:
To a mixture of 1H-indazole-4-carbonitrile (1.65 g, 11.1 mmol) in DMF (30 mL) was added KOH (1.86 g 33.3 mmol) and I2 (5.6 g 22.2 mmol). The mixture was stirred at RT for 5 h. The reaction mixture was quenched with water (100 mL) and extracted with EtOAc (200 mL). The extract was concentrated in vacuo to afford 3-iodo-1H-indazole-4-carbonitrile as white solid (2.01 g, 64.7%). MS (ESI): m/z=270 [M+1]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:9])=[C:4]([F:21])[CH:3]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][N:25]=1>>[F:21][C:4]1[CH:3]=[C:2]([C:27]2[CH:26]=[N:25][C:24]([O:23][CH3:22])=[CH:29][CH:28]=2)[CH:7]=[CH:6][C:5]=1[C:8]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[CH2:15][N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:9]
Reactant: COc1ccc(B(O)O)cn1
Reactant: O=C(c1ccc(Br)cc1F)N1CCC[C@H]1CN1CCCC1
Product: COc1ccc(-c2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)c(F)c2)cn1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure SS starting from (4-bromo-2-fluoro-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone and 2-Methoxy-5-pyridine boronic acid. MS (M+H) 384.2
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([N:7]([CH3:15])[C:8](=[O:14])[CH:9]3[CH2:13][CH:10]32)=[CH:5][CH:4]=1.C1N2CN3CN(C2)CN1C3.FC(F)(F)[C:28](O)=[O:29]>>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([N:7]([CH3:15])[C:8](=[O:14])[CH:9]3[CH2:13][CH:10]32)=[CH:5][C:4]=1[CH:28]=[O:29]
Reactant: COc1ccc2c(c1)C1CC1C(=O)N2C
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Product: COc1cc2c(cc1C=O)N(C)C(=O)C1CC21
Temperature: 25 °C
Yield: 42 %

Procedure:
To a flame dried round bottom flask equipped with a nitrogen cap was added 972 mg (4.8 mmol) 6-Methoxy-3-methyl-1,1a,3,7b-tetrahydro-3-aza-cyclopropa[a]naphthalen-2-one, 40 ml of trifluoroacetic acid and 806 mg (5.7 mmol) of hexamethylene tetraamine. The mixture was stirred under reflux for 1.5 hours and then cooled to ambient temperature. The reaction mixture was quenched in 200 ml ice and then treated with solid sodium carbonate until pH 9 was reached. The aqueous phase was extracted with chloroform (3×30 ml). The combined organics were then washed with brine followed by drying over sodium sulfate and evaporation in vacuo. The crude residue was taken up in ethyl acetate whereupon crystals formed. Four crops totaling 373 mg were obtained. The mother liquors were purified by silica gel column chromatography eluting with 1/1 ethyl acetate/hexane to afford another 98 mg (total yield 42%) of a white solid which was used directly in the following step. Mass spectrum APCI m/e 232 (p+1).
Reaction SMILES: [P:1](=[O:5])([OH:4])([OH:3])[OH:2].[O-][P:7]([O-:10])([O-:9])=[O:8].[O-][P:12]([O-:15])([O-])=[O:13].[O-:16][P:17]([O-])([O-])=O.[F-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].S(=O)(=O)(O)O>>[O:5]=[P:1]12[O:4][P:7]3([O:10][P:12]([O:15][P:17]([O:9]3)([O:3]1)=[O:16])(=[O:13])[O:2]2)=[O:8]
Reactant: O=P([O-])([O-])[O-]
Reactant: O=P(O)(O)O
Agent: O=S(=O)(O)O
Agent: [Ca+2]
Agent: [F-]
Product: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Yield: 35 %

Procedure:
The conventional methods for the production of wet process phosphoric acid, finely ground phosphate rock is reacted with dilute phosphoric acid (10% P2O5 to 25% P2O5) and sulphuric acid which may or may not be diluted. The reaction product is leached (i.e., digested or reacted with the acid) to yield a crude aqueous phosphoric acid solution in which is suspended a substantial quantity of solid impurities. This slurry is filtered to separate most of the undissolved gypsum and other solid impurities to yield a crude (22% P2O5 to 35% P2O5) aqueous product sometimes known as the number one filtrate. This filtrate contains suspended, finely divided, impurities that were not removed during the solidliquid separation step plus solids that have crystallized after filtration. The solution also contains dissolved impurities. Reference is made to Chapter 16 of Volume II, Phosphorus and its Compounds, Van Wazer, Interscience Publishers (1961).
Reaction SMILES: [O:1]=[C:2]1[C:11]([C:12](O)=[O:13])=[C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[F:21][C:22]([F:36])([F:35])[C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:26][NH2:27]>>[F:21][C:22]([F:35])([F:36])[C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([C:31]([F:34])([F:32])[F:33])[CH:30]=1)[CH2:26][NH:27][C:12]([C:11]1[C:2](=[O:1])[NH:3][C:4]2[C:9]([C:10]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:13]
Reactant: NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C(O)c1c(-c2ccccc2)c2ccccc2[nH]c1=O
Product: O=C(NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1c(-c2ccccc2)c2ccccc2[nH]c1=O

Procedure:
1,2-Dihydro-2-oxo-4-phenyl-3-quinolinecarboxylic acid was reacted with 3,5-bis(trifluoromethyl)benzylamine by a method similar to Example 101 (amidation) to yield the title compound.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:20][NH:21][CH3:22]>C(Cl)Cl>[CH3:20][N:21]([CH3:22])[C:1](=[N:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNC
Reactant: O=C(Nc1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CN(C)C(=Nc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
Into a slurry of 19.7 g of benzanilide (m.p. 162°-164° C.) in 200 ml of methylene chloride was added a solution of 12.0 g of thionylchloride in 50 ml of methylene chloride. After the addition was completed and the reaction mixture was stirred for one hour at room temperature, gaseous dimethylamine was introduced until the solution became saturated. Workup by filtration, waterwash, removal of the solvent and distillation afforded N,N-dimethyl-N'-phenylbenzamidine in 18.6 g or 83% yield.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2[CH:33]=[CH:32][C:14]([O:15][C:16]3[CH:25]=[C:24]4[C:19]([CH:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:21][CH2:22][O:23]4)=[CH:18][C:17]=3[Cl:31])=[CH:13][CH:12]=2)=[O:10])[CH:5]=[CH:4][CH:3]=1.[Br-].[C:35]([Zn+])([CH3:38])([CH3:37])[CH3:36]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:35]([C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2[CH:12]=[CH:13][C:14]([O:15][C:16]3[CH:25]=[C:24]4[C:19]([CH:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:21][CH2:22][O:23]4)=[CH:18][C:17]=3[Cl:31])=[CH:32][CH:33]=2)=[O:10])[CH:5]=[CH:4][CH:3]=1)([CH3:38])([CH3:37])[CH3:36]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4cccc(Br)n4)cc3)c(Cl)cc21
Reactant: CC(C)(C)[Zn+]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Br-]
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4cccc(C(C)(C)C)n4)cc3)c(Cl)cc21
Reaction time: 1 h
Yield: 28.6 %

Procedure:
Ethyl 7-(4-(6-bromopyridin-2-ylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate (Example 52, Step A; 30 mg, 0.056 mmol) and bis(tri-t-butylphosphine)palladium (0) (14 mg, 0.028 mmol) were diluted with tert-butylzinc bromide (113 μl, 0.056 mmol) and stirred for 1 hour. The reaction was loaded onto silica gel and eluted with 5% ethyl acetate/hexanes to 70% ethyl acetate/hexanes to yield the desired compound (8 mg, 0.016 mmol, 56% yield).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[C:20]([C:24]([O:26][CH3:27])=[O:25])=[CH:19][CH:18]=[CH:17]3)=[CH:10][CH:9]=1.Cl[CH2:29][C:30]1[C:31]([C:38]2[C:43]([Cl:44])=[CH:42][CH:41]=[CH:40][C:39]=2[Cl:45])=[N:32][O:33][C:34]=1[CH:35]([CH3:37])[CH3:36]>CN(C)C=O>[Cl:44][C:43]1[CH:42]=[CH:41][CH:40]=[C:39]([Cl:45])[C:38]=1[C:31]1[C:30]([CH2:29][O:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20]([C:24]([O:26][CH3:27])=[O:25])=[CH:19][CH:18]=[CH:17]4)=[CH:12][CH:13]=2)=[C:34]([CH:35]([CH3:37])[CH3:36])[O:33][N:32]=1
Reactant: COC(=O)c1cccc2cc(-c3ccc(O)cc3)ccc12
Reactant: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2cc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C(C)C)cc3)ccc12
Temperature: 65 °C
Yield: 48.3 %

Procedure:
Cesium carbonate (352 g, 1.08 mol) was added to a mechanically stirred solution of methyl 6-(4-hydroxyphenyl)-1-naphthoate (199 g, 0.72 mol) in dimethylformamide (1 L) under N2. The resulting suspension was heated to 65° C. for 30 min followed by addition of 4-(chloromethyl)-3-(2,6-dichlorophenyl)-5-(1-methylethyl)isoxazole (280 g, 0.92 mol) in dimethylformamide (500 mL). The mixture was heated at 65° C. for 18 h, cooled to room temperature and partitioned between ethyl acetate (1 L) and water (1 L). The ethyl acetate layer was backwashed with water (2×1 L) and concentrated to a thick black syrup. This syrup was triturated with hexane (500 mL) and ethyl acetate (300 mL) for 2 h. Filtration gave 190 g of the product as beige crystals. 1H NMR (DMSO-d6); δ 8.77 (d, J=9 Hz, 1H), 8.23-8.20 (m, 2H), 8.09 (d, J=7 Hz, 1H), 7.92 (dd, J=2, 9 Hz, 1H), 7.69 (d, J=9 Hz, 2H), 7.63-7.51 (m, 4H), 6.91 (d, J=9 Hz, 2H), 4.86 (s, 2H), 3.92 (s, 3H), 3.45 (septet, J=7 Hz, 1H), 1.33 (d, J=7 Hz, 6H). ESI-LCMS m/z 546 (M+H)+.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[N:2]1.P(Cl)(Cl)([Cl:12])=O.P(Cl)(Cl)Cl>>[Cl:12][C:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1][N:2]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: c1ccc2sncc2c1
Solvent: ClP(Cl)Cl
Product: Clc1nsc2ccccc12

Procedure:
a method including reacting 1,2-benzisothiazole and phosphorus oxychloride or phosphorus trichloride in the absence of a solvent, to give 3-chloro-1,2-benzisothiazole (see, Patent Publication 1):