Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]3[N:13]=[C:14]([CH2:16][C:17]([O:19]CC)=O)[NH:15][C:10]3=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]#[N:30]>>[NH2:30][C:29]1[C:24]2[C:23](=[CH:28][CH:27]=[CH:26][CH:25]=2)[NH:22][C:17](=[O:19])[C:16]=1[C:14]1[NH:13][C:11]2=[N:12][C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)=[CH:8][CH:9]=[C:10]2[N:15]=1
Reactant: N#Cc1ccccc1N
Reactant: CCOC(=O)Cc1nc2nc(N3CCOCC3)ccc2[nH]1
Product: Nc1c(-c2nc3ccc(N4CCOCC4)nc3[nH]2)c(=O)[nH]c2ccccc12

Procedure:
The title compound was synthesized as described in Example 45, Method E using ethyl 2-(5-morpholin-4-ylimidazolo[5,4-b]pyridin-2-yl)acetate and 2-aminobenzenecarbonitrile, with a modified workup procedure. After quenching with a saturated aqueous ammonium chloride solution, the two phases were separated and the aqueous phase extracted with EtOAc. Upon standing, a solid formed and precipitated out of the organic extracts. The precipitate, a dark brown solid, was filtered off and dried. Purification by reverse phase chromatography afforded the desired product as a reddish solid. LC/MS m/z 363.2 (MH+), Rf 2.20 minutes.
Reaction SMILES: CS(O)(=O)=O.OCCC[N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][C:11]1=[O:19].FC1C=CC(C(C2C=CC(F)=CC=2)N2CCNCC2)=CC=1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C>O>[NH:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][C:11]1=[O:19]
Reactant: O=c1[nH]c2ccccc2n1CCCO
Agent: CS(=O)(=O)O
Agent: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: O=c1[nH]c2ccccc2[nH]1

Procedure:
A mixture of 2.7 parts of 1,3-dihydro-1-(3-hydroxypropyl)-2H-benzimidazol-2-one methanesulfonate, 2.88 parts of 1-[bis(p-fluorophenyl)methyl]piperazine, 2.66 parts of sodium carbonate and 100 parts of 4-methyl-2-pentanone is stirred and refluxed overnight. After cooling, water is added and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 5% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 2-propanol, yielding 1-[3-{4-bis(4-fluorophenyl)methyl]-1-piperazinyl}propyl]-1,3-dihydro-2H-benzimidazol-2-one; mp. 197.3° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1.C(O)(=O)/C=C\C(O)=O.[CH2:21]([N:23]([CH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)[C:24]1[S:25][C:26]2[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=2[N:28]=1)[CH3:22].C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>CN(C)C=O>[CH2:21]([N:23]([CH:33]1[CH2:38][CH2:37][N:36]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=2)[CH2:35][CH2:34]1)[C:24]1[S:25][C:26]2[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=2[N:28]=1)[CH3:22]
Reactant: CCN(c1nc2ccccc2s1)C1CCNCC1
Reactant: Cc1ccc(OCCCBr)cc1
Agent: O=C(O)/C=C\C(=O)O
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CCN(c1nc2ccccc2s1)C1CCN(CCCOc2ccc(C)cc2)CC1
Temperature: 60 °C
Yield: 75 %

Procedure:
A mixture of 5.04 parts of 1-(3-bromopropoxy)-4-methylbenzene, 7.54 parts of N-ethyl-N-(4-piperidinyl)-2-benzothiazolamine (Z)-2-butenedioate (1:1), 5.3 parts of sodium carbonate, 0.1 parts of potassium iodide and 180 parts of N,N-dimethylformamide was stirred and heated overnight at 60° C. The reaction mixture was poured onto water and the product was extracted with methylbenzene. The extract was washed three times with water, dried, filtered and evaporated. The residue was crystallized from 2-propanol, yielding 6 parts (75%) of N-ethyl-N-[1-[3-(4-methylphenoxy)propyl]-4-piperidinyl]-2-benzothiazolamine; mp. 101.0° C. (123).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:13](=[O:17])[CH:14]([CH3:16])[CH3:15].[CH3:18][N:19]([CH2:21][C@H:22]1[CH2:27][CH2:26][C@H:25]([NH2:28])[CH2:24][CH2:23]1)[CH3:20]>>[Cl:12][C:9]1[N:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([C:13](=[O:17])[CH:14]([CH3:16])[CH3:15])=[C:2]2[NH:28][CH:25]1[CH2:26][CH2:27][CH:22]([CH2:21][N:19]([CH3:20])[CH3:18])[CH2:23][CH2:24]1
Reactant: CC(C)C(=O)c1cnc2ccc(Cl)nc2c1Cl
Reactant: CN(C)C[C@H]1CC[C@H](N)CC1
Product: CC(C)C(=O)c1cnc2ccc(Cl)nc2c1NC1CCC(CN(C)C)CC1
Yield: 88.9 %

Procedure:
Following general procedure I, 1-(4,6-dichloro-1,5-naphthyridin-3-yl)-2-methylpropan-1-one (500 mg, 1.85 mmol) was reacted with trans-4-((dimethylamino)methyl)cyclohexanamine (436 mg, 2.78 mmol) to afford the product (640 mg, 89%) as a white solid: ESI MS m/z 389 [M+H]+.
Reaction SMILES: [S].[N+:2]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH3:15])=[CH:7][CH:6]=1)([O-])=O.[OH-:16].[Na+]>C(O)C.C(OCC)(=O)C>[NH2:2][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH:15]=[O:16])=[CH:7][CH:6]=1
Reactant: [OH-]
Reactant: Cc1ccc([N+](=O)[O-])c2ccccc12
Agent: [Na+]
Agent: [S]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1ccc(C=O)c2ccccc12

Procedure:
To a stirring boiling solution of sulfur (3.7 g) in 12% aqueous NaOH (50 mL) was added a solution of 4-nitro-1-methylnaphthalene (8 g) in ethanol (50 mL). After refluxing the solution for one hour, the reaction was diluted with 500 mL of ethyl acetate and washed with water and brine, dried over MgSO4, and concentrated. The product was purified via silica gel column chromatography using ethyl acetate:hexane (5:95 to 10:90). The product (2.54 g, 34%) was stored at −78° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>CCO>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[CH:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Reactant: C1CNCCN1
Solvent: CCO
Product: Clc1ccc2c(N3CCNCC3)ccnc2c1
Yield: 65.4 %

Procedure:
4,7-Dichloroquinoline (9.9 g, 50 mmol) and piperazine (43.1 g, 500 mmol) in EtOH (200 mL) are reacted according to method B yielding 8.10 g of the product.
Reaction SMILES: N1N=C(C2C=CC=CC=2C([N:14]2[CH2:18][CH:17]3[CH2:19][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH:16]3[CH2:15]2)=O)NC=1.[N:29]1[N:30]([C:34]2[C:35]([C:40]([OH:42])=O)=[N:36][CH:37]=[CH:38][CH:39]=2)[N:31]=[CH:32][CH:33]=1.N1N=C(C2C=CC=CC=2C(O)=O)NC=1>>[N:31]1[N:30]([C:34]2[C:35]([C:40]([N:14]3[CH2:18][CH:17]4[CH2:19][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH:16]4[CH2:15]3)=[O:42])=[N:36][CH:37]=[CH:38][CH:39]=2)[N:29]=[CH:33][CH:32]=1
Reactant: O=C(O)c1ncccc1-n1nccn1
Reactant: CC(C)(C)OC(=O)N1CC2CN(C(=O)c3ccccc3-c3nnc[nH]3)CC2C1
Agent: O=C(O)c1ccccc1-c1nnc[nH]1
Product: CC(C)(C)OC(=O)N1CC2CN(C(=O)c3ncccc3-n3nccn3)CC2C1

Procedure:
tert-Butyl 5-(3-(2H-1,2,3-triazol-2-yl)picolinoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate was prepared in a manner analogous to Intermediate 59 substituting 3-[1,2,3]triazol-2-yl-pyridine-2-carboxylic acid (Intermediate 72) for 2-(4H-[1,2,4]triazol-3-yl)benzoic acid. MS (ESI) mass calculated for C19H24N6O3, 384.19; m/z found, 385.1.
Reaction SMILES: [CH3:1][N:2]([CH3:9])[CH2:3][CH2:4][CH2:5][C:6](O)=[O:7].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:39][O:40][C:41]1[CH:61]=[CH:60][C:44]([O:45][C:46]2[CH:59]=[CH:58][C:49]([CH2:50][NH:51][C:52]([C:54]3([NH2:57])[CH2:56][CH2:55]3)=[O:53])=[CH:48][CH:47]=2)=[C:43]([C:62]([F:65])([F:64])[F:63])[CH:42]=1>CN(C=O)C>[CH3:39][O:40][C:41]1[CH:61]=[CH:60][C:44]([O:45][C:46]2[CH:59]=[CH:58][C:49]([CH2:50][NH:51][C:52]([C:54]3([NH:57][C:6](=[O:7])[CH2:5][CH2:4][CH2:3][N:2]([CH3:9])[CH3:1])[CH2:55][CH2:56]3)=[O:53])=[CH:48][CH:47]=2)=[C:43]([C:62]([F:63])([F:64])[F:65])[CH:42]=1
Reactant: CN(C)CCCC(=O)O
Reactant: COc1ccc(Oc2ccc(CNC(=O)C3(N)CC3)cc2)c(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(Oc2ccc(CNC(=O)C3(NC(=O)CCCN(C)C)CC3)cc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1.44 mg (11 μMol) 4-dimethylamino-butyric acid was dissolved in 100 μL DMF, 3.5 μL (24.95 μMol) triethylamine and 3.37 mg (10.5 μMol) TBTU in 100 μL DMF were added and the mixture was stirred for 10 min at RT. Then 3.80 mg (10 μMol) 1-amino-cyclopropanecarboxylic acid 4-(4-methoxy-2-trifluoromethyl-phenoxy)-benzylamide in 100 μL DMF was added and the mixture was shaken for 3 days at ambient temperature. Filtered through Alox B, washed with DMF/MeOH=9/1 and the filtrate was evaporated down.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:4][C:3]=1[CH3:22].[CH3:23][O:24][C:25]1[CH:30]=[C:29](B(O)O)[CH:28]=[CH:27][N:26]=1.C(=O)([O-])[O-].[Na+].[Na+].B(O)O>COCCOC.[Pd].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>[CH3:23][O:24][C:25]1[CH:30]=[C:29]([C:2]2[C:3]([CH3:22])=[CH:4][CH:5]=[C:6]([NH:8][C:9]([C:11]3([C:14]4[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=4)[CH2:13][CH2:12]3)=[O:10])[N:7]=2)[CH:28]=[CH:27][N:26]=1
Reactant: COc1cc(B(O)O)ccn1
Reactant: COc1ccc(C2(C(=O)Nc3ccc(C)c(Cl)n3)CC2)cc1
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: COc1ccc(C2(C(=O)Nc3ccc(C)c(-c4ccnc(OC)c4)n3)CC2)cc1
Temperature: 80 °C

Procedure:
N-(6-Chloro-5-methylpyridin-2-yl)-1-(4-methoxyphenyl)cyclopropane carboxamide (63 mg, 0.20 mmol) was dissolved in 1,2-dimethoxyethane (2.0 mL) in a reaction tube. 2-Methoxypyridin-4-ylboronic acid (46 mg, 0.30 mmol), aqueous 2 M sodium carbonate (0.20 mL), and (Ph3P)4Pd (12 mg, 0.010 mmol) were added and the reaction mixture was heated at 80° C. under N2 atmosphere for 18 hours. Since the reaction was incomplete, it was re-treated with same amount of boronic acid, base and Pd catalyst and heated at 80° C. for 18 hours. The resulting material was cooled to room temperature, filtered, and evaporated under reduced pressure. The crude product was dissolved in DMSO (2 mL), filtered, and purified by reverse phase preparative HPLC to yield N-(2′-methoxy-3-methyl-2,4′-bipyridin-6-yl)-1-(4-methoxyphenyl)cyclopropane carboxamide. ESI-MS m/z calc. 389.2. found 390.5 (M+1)+. Retention time 1.84 minutes.
Reaction SMILES: C1C=[N+]([C@@H]2O[C@H](COP(OP(OC[C@H]3O[C@@H](N4C5N=CN=C(N)C=5N=C4)[C@H](OP(O)(O)=O)[C@@H]3O)(O)=O)(O)=O)[C@@H](O)[C@H]2O)C=C(C(N)=O)C=1.P(OC[C@H]1O[C@@H](N2C3N=CN=C(N)C=3N=C2)[C@H](O)[C@@H]1O)(OP(OP(O)(O)=O)(O)=O)(=O)O.[C:80](O)(=[O:90])[C:81]1[CH:89]=[CH:88][C:86]([OH:87])=[C:83]([O:84]C)[CH:82]=1.O=CC1C=CC(O)=C(OC)C=1.C(O)(=O)C1C=CC(O)=C(O)C=1>>[CH:80](=[O:90])[C:81]1[CH:89]=[CH:88][C:86]([OH:87])=[C:83]([OH:84])[CH:82]=1
Reactant: COc1cc(C(=O)O)ccc1O
Agent: COc1cc(C=O)ccc1O
Agent: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Agent: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]1O
Product: O=Cc1ccc(O)c(O)c1
Yield: 33 %

Procedure:
Aryl-aldehyde dehydrogenase (Gross, G. G. et al., Biochem. Biophy. Res. Commun. 32:173 (1968); Gross, G. G. et al., Eur. J. Biochem. 8:413 (1969); Gross, G. G., Eur. J. Biochem. 31:585 (1972); Zenk, M. H. et al., Recent Adv. Phytochem. 4:87 (1972)) in Neurospora crassa mycelial extract was purified away from an unwanted dehydrogenase which reduced vanillin to vanillyl alcohol. Vanillic, protocatechuic, and isovanillic acids were extracted into EtOAc after acidification of fermentor broth. A subsequent reprecipitation step increased the vanillic acid/protocatechuic acid ratio from 1:2 to 2.5:1 (mol/mol). The resulting aromatic mixture was incubated with glucose 6-phosphate dehydrogenase (to recycle NADP+) 25 and aryl-aldehyde dehydrogenase at 30° C. and pH 8.0 using 0.07 equiv of NADP+ and 2 equiv of ATP relative to vanillic acid. Reduction of vanillic acid to vanillin (FIG. 2) proceeded in 92% yield in 7 h. Reduction of protocatechuic acid was slower with a 33% yield of protocatechualdehyde obtained after 7 h. Vanillin was extracted from the enzymatic reduction with CH2Cl2 leaving protocatechualdehyde and protocatechuic acid in the aqueous phase. Isovanillin at 10 mol % remained as the only contaminant. Extraction of the fermentor broth, selective precipitation to remove excess protocatechuic acid, aryl-aldehyde dehydrogenase reduction, and the final CH2Cl2 extraction led to a 66% overall yield (mol/mol) for conversion of vanillic acid into vanillin.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:18]=[CH:17][S:16][CH:15]=2)=[CH:10][C:9]=1[NH:19][C:20](=[O:32])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]#[N:31])[CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:32]=[C:20]1[CH2:21][C:22]([C:24]2[CH:25]=[C:26]([CH:27]=[CH:28][CH:29]=2)[C:30]#[N:31])=[N:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:18]=[CH:17][S:16][CH:15]=3)=[CH:10][C:9]=2[NH:19]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccsc2)cc1NC(=O)CC(=O)c1cccc(C#N)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cccc(C2=Nc3ccc(-c4ccsc4)cc3NC(=O)C2)c1

Procedure:
Prepared from {2-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-4-thiophen-3-yl-phenyl}-carbamic acid tert.-butyl ester (Example K4) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a beige solid (54 mg).
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:8][CH2:7][N:6]([C:9]([C:11]2[S:19][C:18]3[C:13](=[N:14][CH:15]=[CH:16][C:17]=3[Cl:20])[CH:12]=2)=[O:10])[CH2:5]1.[CH3:21]N(C=O)C>>[CH3:21][O:3][CH:4]1[CH2:8][CH2:7][N:6]([C:9]([C:11]2[S:19][C:18]3[C:13](=[N:14][CH:15]=[CH:16][C:17]=3[Cl:20])[CH:12]=2)=[O:10])[CH2:5]1
Reactant: CN(C)C=O
Reactant: O=C(c1cc2nccc(Cl)c2s1)N1CCC(O)C1
Agent: [H-]
Agent: [Na+]
Product: COC1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1
Reaction time: 0.33 h
Yield: 50 %

Procedure:
NaH (0.07 g, 1.3 mmol) was added to a solution of (+/−)-(3-hydroxy-pyrrolidin-1-yl)-[7-chloro-thieno[3,2-b]pyridin-2-yl]-methanone (0.25 g, 0.88 mmol) in DMF (10 mL), at 0° C. The reaction mixture was allowed to stir for 20 min, and Mel (0.188 g, 1.33 mmol) was added dropwise. After 3 h the reaction was quenched with saturated aqueous KCN (10 mL). The aqueous layer was extracted with CH2Cl2 (3×10 mL). The combined organic extracts were dried (Na2SO4), and the solvent was removed. Purification by flash chromatography on silica gel (CH2Cl2/MeOH 94:6) afforded the title compound as a white solid (0.13 g, 50%). MS: 297/299 (MH+); HPLC Rf: 4.11 min; HPLC purity: 93%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17](N)=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].Cl.CC1C(C(O)=O)=C(C)C=CN=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C.O>[CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7]
Reactant: COC(=O)[C@H](Cc1ccc(N)cc1)NC(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cc1ccnc(C)c1C(=O)O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Reaction time: 15 h
Yield: 16.9 %

Procedure:
To a solution of 4-amino-N-[(1,1-dimethylethoxyl)carbonyl]-L-phenylalanine methyl ester (1.4 g, 4.8 mmol) in DMF (12 mL) were added 2,4-dimethyl-3-pyridinecarboxylic acid hydrocloride (919 mg, 4.9 mmol), HBTU (1900 mg, 5 mmol) and diisopropylethylamine (2.7 mL, 15 mmol) at room temperature. The mixture was stirred for 15 hr and was diluted with 10 mL of ethyl acetate and 10 mL of water. The layers were separated and the aqueous layer was extracted with ethyl acetate (2×20 mL). The combined extracts were washed with brine and dried over anhydrous magnesium sulfate. Filtration and concentration of the solvent gave a crude product which was purified on silica gel eluting with ethyl acetate:hexane (2:1 to 4:1) to give of 4-[(2,4-dimethyl-3-pyridyl)carbonyl)amino]-N-[(1,1-dimethylethoxyl)carbonyl]-L-phenylalanine methyl ester (226 mg). This compound (220 mg) was treated with 6 mL of 4 N hydrochloric acid in dioxane at room temperature. After 5 minutes, the solid went into solution and the mixture was stirred for 18 hr and was concentrated to give white solid (210 mg). This intermediate was used in the next step synthesis without further purification.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:7](I)=[N:8][C:9]([S:12]([CH2:15][CH3:16])(=[O:14])=[O:13])=[CH:10][CH:11]=2)[CH2:3][CH2:2]1.[CH3:18][N:19]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]1=[O:38].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:1]1([CH2:4][O:5][C:6]2[C:7]([C:27]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20](=[O:38])[N:19]([CH3:18])[CH:28]=3)=[N:8][C:9]([S:12]([CH2:15][CH3:16])(=[O:14])=[O:13])=[CH:10][CH:11]=2)[CH2:3][CH2:2]1
Reactant: CCS(=O)(=O)c1ccc(OCC2CC2)c(I)n1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)c2ccccc2c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CCS(=O)(=O)c1ccc(OCC2CC2)c(-c2cn(C)c(=O)c3ccccc23)n1
Temperature: 90 °C
Reaction time: 12 h
Yield: 33.5 %

Procedure:
To a solution of the title compound from Step 6 (45 mg, 0.12 mmol) and 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-one (50 mg, 0.16 mmol) in dioxane (2.5 mL) and H2O (0.5 mL) was added Pd(dppf)Cl2 (9 mg, 0.013 mmol) and K3PO4 (86 mg, 0.4 mmol) in one portion at r.t. under N2. The mixture was stirred for 12 hours at 90° C. under N2. Water (15 mL) was added and the mixture was extracted with DCM (30 mL×3). The combined organic phases were dried over Na2SO4, filtered, concentrated under reduced pressure. The residue was purified by prep-HPLC to give the title compound (16 mg, yield: 32%) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 8.52 (d, J=7.6 Hz, 1H), 8.11 (d, J=8.8 Hz 1H), 7.61-7.56 (m, 1H), 7.53-7.49 (m, 1H), 7.42 (d, J=8.8 Hz 1H), 7.38 (s, 1H), 7.34 (d, J=7.6 Hz 1H), 3.92 (d, J=7.2 Hz 2H), 3.68 (s, 3H), 3.41 (q, J=6.8 Hz, 2H), 1.33 (t, 3H), 1.08-1.02 (m, 1H), 0.54-0.48 (m, 2H), 0.22-0.21 (m, 2H). LCMS: 399.1 (M+1)+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:27])[C:7]3[C:15](=[O:16])[N:14]([C:17]4[CH:22]=[CH:21][C:20]([O:23]C)=[CH:19][C:18]=4[CH3:25])[N:13]=[C:12]([OH:26])[C:8]=3[NH:9][C:10]=2[CH:11]=1.O.[OH-].OCC[N+](C)(C)C.Cl>CS(O)(=O)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:27])[C:7]3[C:15](=[O:16])[N:14]([C:17]4[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:18]=4[CH3:25])[N:13]=[C:12]([OH:26])[C:8]=3[NH:9][C:10]=2[CH:11]=1
Reactant: COc1ccc(-n2nc(O)c3[nH]c4cc(Cl)ccc4c(=O)c3c2=O)c(C)c1
Agent: CS(=O)(=O)O
Agent: C[N+](C)(C)CCO
Agent: Cl
Solvent: O
Product: Cc1cc(O)ccc1-n1nc(O)c2[nH]c3cc(Cl)ccc3c(=O)c2c1=O
Temperature: 150 °C
Yield: 36.3 %

Procedure:
7-Chloro-4-hydroxy-2-(4-methoxy-2-methylphenyl)-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione (1.00 g, 2.61 mM) was stirred in methanesulfonic acid (10 mL) to give a brown solution. This solution was heated to 150° C. for 3 hours and cooled to room temperature. The cooled solution was added dropwise to water (50 mL) with stirring to give a grey suspension which was stirred for 20 hours and filtered. The collected solids were washed with water and then suspended in water (50 mL). To this suspension was added choline hydroxide solution (2 mL, 45 wt % in methanol) which dissolved the solids to give a brown solution. This solution was heated to reflux for 1 hour, additional choline hydroxide solution (2 mL) was added and the solution was heated to reflux for 3 hours. The solution was cooled to room temperature and acidified to pH=1 with 1N HCl to give a brown suspension. The suspension was filtered and the collected solids were washed with water to give a brown solid. Several recrystallizations from hot methanol gave the title compound as an off-white powder (0.35 g, 36%), mp 287° C. (decomp.); MS(CI): 370.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([CH2:8][CH2:9][O:10][C:11]1[C:24]2[C:23](=[O:25])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[S:16][C:15]=2[C:14]([OH:26])=[CH:13][CH:12]=1)[CH2:5][CH2:6][Cl:7].[Si:27](Cl)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28].N1C=CN=C1.CN(C1C=CC=CN=1)C>CN(C)C=O.O>[Cl:1][CH2:2][CH2:3][N:4]([CH2:8][CH2:9][O:10][C:11]1[C:24]2[C:23](=[O:25])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[S:16][C:15]=2[C:14]([O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])=[CH:13][CH:12]=1)[CH2:5][CH2:6][Cl:7]
Reactant: O=c1c2ccccc2sc2c(O)ccc(OCCN(CCCl)CCCl)c12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccccn1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(OCCN(CCCl)CCCl)c2c(=O)c3ccccc3sc12

Procedure:
A solution of 0.50 g of 1-(N,N-bischloroethylaminoethoxy)-4-hydroxythioxanthone in 10 ml of dimethylformamide is mixed with 0.22 g of tert-butyldimethylsilyl chloride, 0.20 g of imidazole and a catalytic amount of dimethylaminopyridine, and stirred at room temperature for 12 h. The solution is then added over water and extracted with ethyl acetate. The ethyl acetate extract is washed sequentially with saturated sodium bicarbonate and water, dried over sodium sulfate, concentrated and dissolved in a mixture of ethyl acetate: hexanes (1:4) and passed through a plug of alumina. The solid obtained after concentration is pure and weighed 0.48 g (70%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]1[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]1)[CH:5]=O.[Cl:16][CH2:17][CH2:18][CH2:19][CH:20](P(OCC)(OCC)=O)[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].O.[OH-].[Li+].O.C(=O)(O)[O-].[Na+]>C1COCC1.C(O)C>[Cl:16][CH2:17][CH2:18][CH2:19]/[C:20](=[CH:5]\[C:4]1[CH:7]=[CH:8][C:9]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]2)=[C:2]([F:1])[CH:3]=1)/[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]
Reactant: CCOP(=O)(OCC)C(CCCCl)C(=O)OC(C)(C)C
Reactant: Cc1cn(-c2ccc(C=O)cc2F)cn1
Agent: O=C([O-])O
Agent: [Li+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cn(-c2ccc(/C=C(\CCCCl)C(=O)OC(C)(C)C)cc2F)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 46.2 %

Procedure:
3-Fluoro-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (2.29 g) and tert-butyl 5-chloro-2-(diethoxyphosphoryl)valerate (3.68 g) were dissolved in a mixed solvent of THF (30 mL) and ethanol (10 mL). Lithium hydroxide monohydrate (1.41 g) was added to the reaction solution at room temperature, and the reaction solution was stirred at room temperature for 18 hours. Saturated sodium bicarbonate water was added to the reaction solution, followed by extraction with ethyl acetate. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system), solidified with tert-butyl methyl ether and heptane, and separated by filtration to obtain 1.96 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(N(CCCCCCCC)CCCCCCCC)CCCCCCC.[Sn](Cl)(Cl)(Cl)Cl.[CH2:39]=[O:40].Cl>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[CH:7]=[C:6]([CH:39]=[O:40])[C:5]([OH:8])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: C=O
Agent: CCCCCCCCN(CCCCCCCC)CCCCCCCC
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Solvent: Cc1ccccc1
Product: O=Cc1cc(Cl)ccc1O
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 30.7 %

Procedure:
64.25 g (0.5 mole) of p-chlorophenol and 55 g (0.2 mole) of trioctylamine are dissolved in 100 ml of toluene. Under N2, 13 g of tin tetrachloride are added dropwise at 0° C. After 20 min at room temperature, 33 g of dried paraformaldehyde are added, and the mixture is heated at 100° C. for 5 hours. After cooling, the mixture is poured onto 2.5 l of H2O, and the mixture is acidified to pH 2 with 2N HCl and extracted with diethyl ether. The ether phase is washed with saturated NaCl solution and dried with Na2SO4 and concentrated. Chromatography on silica gel using ethyl acetate/cyclohexane (1:6) provides 24 g of the title compound, melting point 99° C.