Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:14])[CH:5]([CH3:13])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)C.O.[OH-].[Li+]>O1CCOCC1.O>[CH3:13][CH:5]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[C:4]([OH:14])=[O:3]
Reactant: CCOC(=O)C(C)Cc1ccccn1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(Cc1ccccn1)C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (±)-2-methyl-3-pyridin-2-yl-propionic acid ethyl ester (250 mg, 1.29 mmol, 1.0 eq.) in dioxane (8 mL), lithium hydroxide monohydrate (67 mg, 1.55 mmol, 1.2 eq.) in water (5 mL) was added in portions keeping the temperature below 30° C. The resulting solution was stirred at r.t. for 18 hours. The mixture was concentrated in vacuo The residue was dissolved in water (3 mL), MeCN (1 mL) and formic acid (0.5 mL). The solution was directly purified by prep. HPLC (column: Atlantis, 30×75 mm, 10 um, UV/MS, acidic conditions, extremely polar method) and concentrated in vacuo to give the title compound as a white solid.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][C:7]([C:10]3[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=3)[C:13]([NH:15][CH3:16])=[O:14])=[CH:6][C:5]=12.C1C(=O)N([Br:27])C(=O)C1>CN(C=O)C.CCOC(C)=O>[Br:27][C:3]1[N:4]2[CH:9]=[CH:8][C:7]([C:10]3[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=3)[C:13]([NH:15][CH3:16])=[O:14])=[CH:6][C:5]2=[N:1][CH:2]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CNC(=O)c1cccc(-c2ccn3ccnc3c2)c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CNC(=O)c1cccc(-c2ccn3c(Br)cnc3c2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3-Imidazo[1,2-a]pyridine-7-yl-N-methyl-benzamide (1 eq, 0.398 mmol, 100 mg) is dissolved in DMF (4 ml) at 0° C. and NBS (1.1 eq, 0.438 mmol, 77.9 mg) is added. The reaction mixture is stirred for 1 h at 0° C. and then is diluted with EtOAc. The reaction mixture is washed with NaHCO3 and brine, dried over MgSO4, filtered and evaporated. The product is purified by flash column chromatography eluting with 8:2 DCM/MeOH to afford 3-(3-bromo-imidazo[1,2-a]pyridin-7-yl)-N-methyl-benzamide as a brown solid; [M+H]+=331
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH3:23])[C:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:11](=[O:22])[C:10]=3[C:5]2=[CH:4][CH:3]=1.[CH2:24]([O:31][C:32]1[CH:37]=[CH:36][NH:35][C:34](=[O:38])[CH:33]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C([O-])([O-])=O.[Cs+].[Cs+].N#N.CN[C@@H]1CCCC[C@H]1NC>C1(C)C=CC=CC=1.C(Cl)Cl.CO.[Cu](I)I>[CH2:24]([O:31][C:32]1[CH:37]=[CH:36][N:35]([C:2]2[N:7]=[C:6]3[N:8]([CH3:23])[C:9]4[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:11](=[O:22])[C:10]=4[C:5]3=[CH:4][CH:3]=2)[C:34](=[O:38])[CH:33]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Reactant: Cn1c2c(c3ccc(Br)nc31)C(=O)N(C(=O)OC(C)(C)C)CC2
Agent: I[Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: N#N
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CO
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)nc31)C(=O)N(C(=O)OC(C)(C)C)CC2
Temperature: 105 °C

Procedure:
tert-Butyl 2-bromo-9-methyl-5-oxo-5,7,8,9-tetrahydro-6H-pyrido[3′,4′:4,5]pyrrolo[2,3-b]pyridine-6-carboxylate (140 mg, 0.37 mmol), 4-benzyloxy pyridinone (74 mg, 0.37 mmol), and Cs2CO3 (132 mg, 0.41 mmol) were suspended in toluene (2 mL), and the air was removed under vacuum at −70° C. for 15 min. The system was flushed with N2, and trans-N,N′-dimethylcyclohexane-1,2-diamine (0.12 mL, 0.74 mmol) and copper iodide (140 mg, 0.74 mmol) were added to the suspension. The evacuation/N2 flushing process was repeated twice more, and the reaction mixture was heated at 105° C. for 18 h under N2. The mixture was cooled, diluted with 95:5 CH2Cl2/MeOH (12 mL), and washed with 2:1 brine/NH4OH (3×12 mL). The resulting organic solution was dried over Na2SO4, filtered, and concentrated to dryness under reduced pressure. The crude title compound was used in the next step without purification.
Reaction SMILES: C(OC([NH:11][N:12]([C:19](=[O:28])[C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[CH:21]=1)[C:13]([CH3:18])([CH3:17])[CH2:14][O:15][CH3:16])=O)C1C=CC=CC=1.COC.C(Cl)Cl.[SiH](CC)(CC)CC.CCN(CC)CC>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CCCCCC.C(OCC)(=O)C>[CH3:16][O:15][CH2:14][C:13]([N:12]([C:19](=[O:28])[C:20]1[CH:21]=[C:22]([CH3:27])[CH:23]=[C:24]([CH3:26])[CH:25]=1)[NH2:11])([CH3:18])[CH3:17]
Reactant: COCC(C)(C)N(NC(=O)OCc1ccccc1)C(=O)c1cc(C)cc(C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COCC(C)(C)N(N)C(=O)c1cc(C)cc(C)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 80.1 %

Procedure:
To a flask containing 0.94 g (0.002 mol) of methyl ether N′-(3,5-dimethyl-benzoyl)-N′-(2-methoxy-1,1-dimethyl-ethyl)-hydrazinecarboxylic acid benzyl ester, was added 10 mL of CH2Cl2, 0.87 g of Et3SiH, 0.10 g of palladium acetate, and 1 g of Et3N. The reaction mixture was stirred at room temperature for over 10 hours. More CH2Cl2 (10-20 mL) was added, and the mixture was filtered to remove the palladium. The brown CH2Cl2 solution was treated with MgSO4 and charcoal, then filtered and evaporated. The evaporation yielded 0.87 g of a red, oily solid. TLC indicated the presence of the product; Rf=0.44 in 1:1 ethyl acetate:hexane. The product was purified by chromatography, eluted with 19-20% ethyl acetate/hexane to yield 401 mg (80%) of 3,5-dimethyl-benzoic acid N-(2-methoxy-1,1-dimethyl-ethyl)-hydrazide product. 1H NMR (CDCl3, 300 MHz) δ (ppm): 7.1 (s, 2H), 7.0 (s, 1H), 3.682 (s, 2H), 3.377 (s, 3H), 2.319 (s, 6H), 1.495 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:22]=[C:21]([F:23])[C:5]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[F:20])[N:8]=2)=[C:4]([F:24])[CH:3]=1.[CH3:25][N:26](C=O)C>O.[C-]#N.[C-]#N.[Zn+2].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].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[F:20][C:14]1[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]=1[C:9]1[N:8]=[C:7]([CH2:6][C:5]2[C:21]([F:23])=[CH:22][C:2]([C:25]#[N:26])=[CH:3][C:4]=2[F:24])[CH:12]=[CH:11][CH:10]=1
Reactant: Fc1ccc(-c2cccc(Cc3c(F)cc(Br)cc3F)n2)c(F)c1
Reactant: CN(C)C=O
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: N#Cc1cc(F)c(Cc2cccc(-c3ccc(F)cc3F)n2)c(F)c1
Temperature: 120 °C

Procedure:
To a solution of 2-(4-bromo-2,6-difluorobenzyl)-6-(2,4-difluorophenyl)pyridine (from Step D above, 7.32 g, 18.5 mmol) in wet DMF (200 mL of DMF and 2 mL water) was added Zn(CN)2 (1.74 g, 14.8 mmol), tris(dibenzylideneacetone)dipalladium (842 mg, 0.92 mmol), and 1,1′-bis(diphenylphosphino)ferrocene (1.23 g, 2.22 mmol) and heated to 120° C. for 1 hr (monitored via LCMS). After the reaction cooled to ambient temperature, the mixture was diluted with H2O and extracted with EtOAc (3×). The combined organic layers were washed with water (4×), brine (3×), dried over MgSO4, and condensed in vacuo. The crude material was purified via silica gel chromatography (hexanes/ethyl acetate) to give the title compound (6.1 g).
Reaction SMILES: C([O:5][C:6](=[O:28])[CH2:7][N:8]([S:10]([C:13]1[CH:22]=[C:21]2[C:16]([C:17]([Cl:27])=[CH:18][N:19]=[C:20]2[NH:23][C:24]([NH2:26])=[NH:25])=[CH:15][CH:14]=1)(=[O:12])=[O:11])[CH3:9])(C)(C)C.[C:29]([C:33]([OH:35])=[O:34])([F:32])([F:31])[F:30]>C(Cl)Cl.C1(C)C=CC=CC=1>[F:30][C:29]([F:32])([F:31])[C:33]([OH:35])=[O:34].[F:30][C:29]([F:32])([F:31])[C:33]([OH:35])=[O:34].[Cl:27][C:17]1[C:16]2[C:21](=[CH:22][C:13]([S:10]([N:8]([CH3:9])[CH2:7][C:6]([OH:28])=[O:5])(=[O:11])=[O:12])=[CH:14][CH:15]=2)[C:20]([NH:23][C:24]([NH2:26])=[NH:25])=[N:19][CH:18]=1
Reactant: CN(CC(=O)OC(C)(C)C)S(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CN(CC(=O)O)S(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1

Procedure:
N-[(4-Chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-N-methylglycine t-butyl ester (255 mg, 5.96 mmol) was dissolved in CF3CO2H (4.0 mL) and CH2Cl2 (2.0 mL), and the mixture stirred at room temperature for 1 h. The mixture was diluted with PhMe and the solvents were evaporated in vacuo to give N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-N-methylglycine bis(trifluoroacetate) (349 mg, 0.56 mmol) as a white powder.
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[C:7]1[CH:19]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30](=[O:38])[NH:31][CH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])[CH:17]=[C:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[B-](F)(F)(F)F.CN(C(O[N:62]1[C:67](=[O:68])[CH2:66][CH2:65][C:63]1=[O:64])=[N+](C)C)C>C1COCC1>[C:1]([O:5][C:6](=[O:39])[C:7]1[CH:19]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30](=[O:38])[NH:31][CH2:32][CH2:33][CH2:34][C:35]([O:37][N:62]2[C:67](=[O:68])[CH2:66][CH2:65][C:63]2=[O:64])=[O:36])[CH:17]=[C:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:8]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Reactant: CC(C)(C)OC(=O)c1cc(OCCCCCCCCCC(=O)NCCCC(=O)O)cc(C(=O)OC(C)(C)C)c1
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)c1cc(OCCCCCCCCCC(=O)NCCCC(=O)ON2C(=O)CCC2=O)cc(C(=O)OC(C)(C)C)c1
Temperature: 25 °C

Procedure:
To a solution of 5-[9-(3-Carboxy-propylcarbamoyl)-nonyloxy]-isophthalic acid di-tert-butyl ester (62 mg, 0.11 mmol) in dry THF (2 ml) was added DIPEA (0.05 ml) and TSTU (41 mg, 0.14 mmol). The mixture was stirred at room temperature under nitrogen over night. The mixture was concentrated and EtOAc was added to the residue. The precipitate was removed by filtration. The filtrate was washed with 0.1 N HCl (2×) and brine (1×), dried (Na2SO4) and concentrated to give a clear syrup.
Reaction SMILES: [C:1]([OH:14])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C1CCC(N=C=NC2CCCCC2)CC1.CS(O[C:35]1[CH:44]=[CH:43][C:42]2[C:37](=[CH:38][CH:39]=[C:40]([C:45](=[NH:47])[NH2:46])[CH:41]=2)[CH:36]=1)(=O)=O>N1C=CC=CC=1>[C:1]([O:14][C:35]1[CH:44]=[CH:43][C:42]2[C:37](=[CH:38][CH:39]=[C:40]([C:45](=[NH:46])[NH2:47])[CH:41]=2)[CH:36]=1)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CS(=O)(=O)Oc1ccc2cc(C(=N)N)ccc2c1
Reactant: CCCCCCCCCCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Product: CCCCCCCCCCCC(=O)Oc1ccc2cc(C(=N)N)ccc2c1
Reaction time: 0.5 h
Yield: 18.1 %

Procedure:
To a solution of 3.6 g of lauric acid in 50 ml of anhydrous pyridine, while being cooled in ice, was added 4.4 g of DCC. After stirring for 30 minutes, 5.0 g of 6-amidino-2-naphthol methanesulfonate was added to the mixture and further stirred overnight at room temperature. The precipitate was collected by filtration, washed with ether, then with acetone, dissolved in methanol, freed from the insolubles by filtration, concentrated under reduced pressure, and recrystallized from ethanol to yield 1.2 g of white crystals of 6-amidino-2-naphthyl laurate methanesulfonate.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]=[C:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)[CH3:2]>C(O)C>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)[CH3:2]
Reactant: CCOC(=O)C=C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: CCO
Product: CCOC(=O)CC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 12 h
Yield: 89 %

Procedure:
tert-Butyl 4-(2-ethoxy-2-oxoethylidene)piperidine-1-carboxylate (5.0 g, 18.58 mmol, 1 eq) was dissolved in ethanol (20 ml) and degassed for 30 min with argon. Pd—C (500 mg, 10%) was added and hydrogenation was carried out for 12 h at RT under balloon pressure (H2). After monitoring by thin-layer chromatography, the reaction mixture was filtered off over Celite and washed with ethanol (200 ml), and the filtrate was concentrated under reduced pressure. Yield: 89% (4.5 g, 16.6 mmol).
Reaction SMILES: [Br:1][C:2]1[C:11]([O:12][CH2:13][C:14]#[N:15])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:16][NH:17][C:18]([C:20]1[O:21][C:22]3[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=3[C:24]=1[CH3:25])=[O:19])=[CH:7]2.[N-:30]=[N+:31]=[N-:32].[Na+].[Cl-].[NH4+].[OH-].[Na+]>CN(C=O)C.O>[Br:1][C:2]1[C:11]([O:12][CH2:13][C:14]2[NH:32][N:31]=[N:30][N:15]=2)=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:16][NH:17][C:18]([C:20]1[O:21][C:22]3[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=3[C:24]=1[CH3:25])=[O:19])=[CH:7]2
Reactant: Cc1c(C(=O)NCc2ccc3c(Br)c(OCC#N)ccc3c2)oc2ccccc12
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(C(=O)NCc2ccc3c(Br)c(OCc4nnn[nH]4)ccc3c2)oc2ccccc12
Temperature: 100 °C
Reaction time: 5 h
Yield: 78.9 %

Procedure:
A mixture of 3-methyl-benzofuran-2-carboxylic acid (5-bromo-6-cyanomethoxy-naphthalen-2-ylmethyl)-amide (1.14 g, 2.54 mmol), prepared in the previous step, sodium azide (492 mg, 7.57 mmol) and ammonium chloride (406 mg, 7.59 mmol) in 50 mL of DMF was stirred under nitrogen at 100° C. for 5 h. By TLC starting material remained. An additional 494 mg (7.60 mmol) of sodium azide was added and the stirring continued at 100° C. for 2 h. The reaction was diluted with water, made basic by the addition of 1 N NaOH and extracted three times with ethyl acetate. The aqueous layer was acidified with 1 N HCl and the solid that precipitated was collected by filtration and dried under reduced pressure to give the title compound (987 mg, 79%) as a light brown solid, mp 212-215° C.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[C:19](=O)[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1.O.[NH2:33][NH2:34]>CN(C=O)C>[N+:28]([C:25]1[CH:26]=[CH:27][C:22]([CH2:21][CH2:20][C:19]2[C:3]3[C:4](=[O:18])[N:5]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:6]4[N:7]=[CH:8][CH:9]=[CH:10][C:11]=4[C:2]=3[NH:34][N:33]=2)=[CH:23][CH:24]=1)([O-:30])=[O:29]
Reactant: NN
Reactant: O=C(CCc1ccc([N+](=O)[O-])cc1)c1c(O)c2cccnc2n(-c2ccccc2)c1=O
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2c(CCc3ccc([N+](=O)[O-])cc3)n[nH]c2c2cccnc2n1-c1ccccc1
Yield: 97.2 %

Procedure:
To a suspension of 4-hydroxy-3-[1-oxo-3-(4-nitrophenyl)propyl]-1-phenyl-1,8-naphthyridin-2 (1H)-one (104 mg, 0.25 mmol, prepared in Synthetic Example 7) in DMF (2 ml) was added hydrazine monohydrate (80%, 40 μl, 11.0 mmol, 4.0 eq.), and the mixture was treated in the same manner as in Example 9 to give 3-[2-(4-nitrophenyl)ethyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (100 mg, 97%).
Reaction SMILES: [C:1]([OH:13])(=[O:12])/[CH:2]=[CH:3]/[C:4]1[CH:11]=[CH:10][C:8]([OH:9])=[C:6]([OH:7])[CH:5]=1.C(=O)(O)[O-].[K+].[CH2:19](Br)[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CS(C)=O.[Cl-].C([N+](CCCC)(CCCC)CCCC)C1C=CC=CC=1>[CH2:19]([O:12][C:1](=[O:13])/[CH:2]=[CH:3]/[C:4]1[CH:11]=[CH:10][C:8]([OH:9])=[C:6]([OH:7])[CH:5]=1)[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCCc1ccccc1
Reactant: O=C(O)/C=C/c1ccc(O)c(O)c1
Agent: CCCC[N+](CCCC)(CCCC)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CS(C)=O
Solvent: O
Product: O=C(/C=C/c1ccc(O)c(O)c1)OCCc1ccccc1
Reaction time: 90 h

Procedure:
1.0 g of caffeic acid was dissolved in 5 mL of dimethylsulfoxide and 0.55 g potassium bicarbonate were added and the mixture was allowed to react for 2 hours at room temperature. 0.75 mL of phenethyl bromide and 0.07 g of benzyl tributyl ammonium chloride were added and the reaction mixture was stirred for 90 hours. The reaction mixture was slowly added to 50 mL of water under agitation to precipitate the product, which was recovered by filtration. The crude product was then recrystallized from 17.5 mL boiling toluene to obtain caffeic acid phenethyl ester The yield was 830 mg and the purity was 97%.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].C(OP(Cl)(OCC)=O)C.[CH3:23][N:24]1[C:30](=[O:31])[C:29]2[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=2[NH:27][C:26](=O)[CH2:25]1>O1CCCC1.O.C(O)(=O)C>[CH3:23][N:24]1[C:30](=[O:31])[C:29]2[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=2[NH:27][C:26](=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])[CH2:25]1
Reactant: CN1CC(=O)Nc2ccccc2C1=O
Reactant: CCOC(=O)CC(=O)OCC
Agent: CCOP(=O)(Cl)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(C(=O)OCC)=C1CN(C)C(=O)c2ccccc2N1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A mixture of 910 ml of diethyl malonate and 3.0 liters of tetrahydrofuran is cooled to 0° C. while stirring under argon and treated portionwise with 350 g of sodium hydride (55 percent oil dispersion) in such a manner that the temperature does not exceed 15° C. Thereafter, the mixture is stirred at room temperature overnight, cooled to 0°-5° C. and 290 ml of diethylchlorophosphate are added dropwise over a period of 15 minutes. After a further 2 hours at room temperature, the mixture is treated slowly with a suspension, warmed to ca 45° C., of 190 g of 4-methyl-3H-1,4-benzodiazepine-2,5(1H,4H)-dione in 2 liters of tetrahydrofuran, the addition taking ca 1 hour. The mixture is stirred at room temperature overnight, cooled to 5° C. and treated dropwise with 350 ml of glacial acetic acid. There is thus obtained a thick slurry which is again made well stirrable by the addition of 500 ml of water. The tetrahydrofuran is distilled off from the mixture and the partially crystalline residue is partitioned between ether and water. The organic phase is washed with water, dried and concentrated. The red-brown coloured residue is dissolved in 2 liters of boiling n-hexane and then cooled. The mixture is left to stand at 2° C. overnight and the resulting crystallisate is filtered off under suction. The light yellow crystals are subsequently dissolved in 800 ml of hot toluene and crystallised by the addition of 600 ml of n-hexane and scratching. After standing in the cold overnight, the crystals are filtered off under suction and dried at 50° C. in vacuo. There is obtained diethyl (1,3,4,5-tetrahydro-4-methyl-5-oxo-2H-1,4-benzodiazepin-2-ylidene)malonate in the form of white crystals of melting point 139° C.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:16]([O:18]CC)=[O:17])=[C:5]([C:7]2[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=2[O:14][CH3:15])[N:6]=1.[OH-].[K+].Cl.C(Cl)Cl>C1COCC1.O>[Br:1][C:2]1[S:3][C:4]([C:16]([OH:18])=[O:17])=[C:5]([C:7]2[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=2[O:14][CH3:15])[N:6]=1
Reactant: CCOC(=O)c1sc(Br)nc1-c1cc(Cl)ccc1OC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc(Cl)cc1-c1nc(Br)sc1C(=O)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 94.8 %

Procedure:
A mixture of ethyl 2-bromo-4-(5-chloro-2-methoxyphenyl)thiazole-5-carboxylate (1.40 g, 3.72 mmol), potassium hydroxide (278 mg) in THF (40 mL) and water (10 mL) was stirred for 20 hours at ambient temperature. The mixture was treated with 1M HCl aq. (ca. 8 mL, 2 eq.), DCM was added, and the organics separated and evaporated to dryness to give 1.23 g (95%) of 2-bromo-4-(5-chloro-2-methoxyphenyl)thiazole-5-carboxylic acid as a yellow solid. LCMS (ESI) m+H=350.1. 1H NMR (400 MHz, DMSO-d6): δ 7.47 (dd, 1H); 7.39 (d, 1H); 7.13 (d, 1H); 3.73 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[C:9]([CH3:24])[N:8]([CH2:25][C@@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31](=[O:35])[CH2:32][C:33]#[N:34])[C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:36][N:37]([CH3:43])[C:38]([CH3:42])([CH3:41])[CH:39]=O.C(O)(=O)C.N1CCCCC1>CCO>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][CH:12]=3)=[C:9]([CH3:24])[N:8]([CH2:25][C@@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31]([C:32](=[CH:39][C:38]([N:37]([CH3:43])[CH3:36])([CH3:42])[CH3:41])[C:33]#[N:34])=[O:35])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Cc1c(-c2ccc(Oc3ccccc3)cc2)c2c(N)ncnc2n1C[C@@H]1CCCN1C(=O)CC#N
Reactant: CN(C)C(C)(C)C=O
Solvent: CCO
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: Cc1c(-c2ccc(Oc3ccccc3)cc2)c2c(N)ncnc2n1C[C@@H]1CCCN1C(=O)C(C#N)=CC(C)(C)N(C)C
Temperature: 70 °C
Reaction time: 12 h
Yield: 4.2 %

Procedure:
To a solution of (S)-3-(2-((4-amino-6-methyl-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrrolidin-1-yl)-3-oxopropanenitrile (0.1 g, 0.21 mmol, 1.0 eq) in EtOH (2 mL) was added 2-(dimethylamino)-2-methylpropanal (0.06 g, 0.53 mmol, 2.5 eq) and piperidine acetate (5 mg). The resulted solution was stirred at 70° C. for 12 h, concentrated and purified by pre-HPLC to afford the title compound as a white solid (5 mg, 4% in yield). LCMS m/z 564.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:4][CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([O:14][CH3:15])=[CH:10][CH:11]=2)[CH:6]1[N:16]=[N+]=[N-])[CH:2]=[CH2:3].[H-].[H-].[H-].[H-].[Li+].[Al+3].S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[CH2:1]([O:4][C@@H:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([O:14][CH3:15])=[CH:10][CH:11]=2)[C@H:6]1[NH2:16])[CH:2]=[CH2:3]
Reactant: C=CCOC1Cc2ccc(OC)cc2C1N=[N+]=[N-]
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: C=CCO[C@@H]1Cc2ccc(OC)cc2[C@H]1N
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Step AA (6): To a solution of (1RS,2RS)-2-(allyloxy)-1-azido-6-methoxy-2,3-dihydro-1H-indene from Step AA (5) (71 mg) in THF (4 mL) at rt was added LiAlH4 (33 mg), and the resulting suspension was stirred at rt for 10 min. Five crystals of Na2SO4.10H2O was added followed by anhydrous sodium sulfate, and the reaction mixture was stirred at rt for 30 min and filtered through a pad of Celite. The filtrate was evaporated in vacuo to give the title compound as a slightly yellowish oil (53 mg). retention time: 1.31 min (method A). MS (ESI) (M+H)+ 220.15.
Reaction SMILES: [P:1]([O:10][CH2:11][CH2:12][Cl:13])([O:6][CH2:7][CH2:8][Cl:9])[O:2][CH2:3][CH2:4][Cl:5].C1[O:16]C1>>[P:1]([O:10][CH2:11][CH2:12][Cl:13])([O:6][CH2:7][CH2:8][Cl:9])([O:2][CH2:3][CH2:4][Cl:5])=[O:16]
Reactant: C1CO1
Reactant: ClCCOP(OCCCl)OCCCl
Product: O=P(OCCCl)(OCCCl)OCCCl

Procedure:
However, phosphorus trichloride can easily be oxidized by oxygen or oxygen-containing gases to phosphorus oxychloride. A slow, steady increase in the phosphorus oxychloride content can be observed during storage, transport and use of phosphorus trichloride. The phosphorus oxychloride lowers the quality of the phosphorus trichloride and necessarily leads to undesirable by-products during chemical processing, so that the desired end product is of lower quality and is obtained in a lesser yield. For example, in further processing to phosphorus pentachloride or phosphorus sulfochloride, all the phosphorus oxychloride reaches the end product. Because of the physical properties, subsequent separation is much more difficult than separation from phosphorus trichloride. During further processing to phosphorous acid, phosphoric acid is formed from the phosphorus oxychloride and phosphates are formed as by-products during the reaction with alcohols to phosphites. During the synthesis of tri-(2-chloroethyl) phosphite by reaction with ethylene oxide, tri-(2-chloroethyl) phosphate is formed as an interfering by-product.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])[C:5]([NH2:18])=[CH:4][CH:3]=1.[Br:19][C:20]1[CH:24]=[C:23]([Cl:25])[S:22][C:21]=1[S:26](Cl)(=[O:28])=[O:27]>>[Br:19][C:20]1[CH:24]=[C:23]([Cl:25])[S:22][C:21]=1[S:26]([NH:18][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[C:7]([F:8])[C:6]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=1[F:17])(=[O:28])=[O:27]
Reactant: Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F
Reactant: O=S(=O)(Cl)c1sc(Cl)cc1Br
Product: O=S(=O)(Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F)c1sc(Cl)cc1Br

Procedure:
According to the general procedure B, 5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene1,2-diamine was reacted with 3-bromo-5-chlorothiophene-2-sulfonyl chloride to obtain the title compound. 1H NMR (300 MHz, CDCl3): δ 7.41 (dd, J=2.1 & 10.5 Hz, 1H), 7.35 (br m, 2H), 7.31 (dd, J=2.1 & 4.2 Hz, 1H), 7.19 (d, J=8.7 Hz, 1H), 7.08 (dd, J=9.0 & 17.4 Hz, 1H), 6.02 (dt, J=2.1, 8.4 & 17.1 Hz, 1H), 5.59 (br s, 1H).