Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH:9](C(OCC)=O)[C:10]([O:12]CC)=[O:11])=[C:4]([F:20])[CH:3]=1.[OH-].[Na+].Cl>CCO.O>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH2:9][C:10]([OH:12])=[O:11])=[C:4]([F:20])[CH:3]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1cc(F)c(Cl)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)Cc1cc(F)c(Cl)cc1F
Temperature: 60 °C
Reaction time: 12 h

Procedure:
Diethyl 2-(4-chloro-2,5-difluorophenyl)malonate (330 mg, 1.08 mmol) was dissolved in EtOH (1 mL), and then NaOH (0.6 mL, 5N) was added. The resulting solution was stirred at ambient for 12 hours. At this time, the reaction mixture was heated to 60° C. for 3 hours, after which it was acidified to a pH of 1 with HCl (1N). The reaction was diluted with water (1 mL) and then extracted twice with diethyl ether. The combined organics were dried over magnesium sulfate, filtered and concentrated to give 2-(4-chloro-2,5-difluorophenyl)acetic acid which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([OH:13])=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[K+].[CH3:15][O:16][C:17](=[O:22])[CH2:18]C([O-])=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:11](=[O:13])[CH2:18][C:17]([O:16][CH3:15])=[O:22])[CH2:9][CH2:10]2)=[CH:6][CH:7]=1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CC1
Reactant: COC(=O)CC(=O)[O-]
Agent: [K+]
Product: COC(=O)CC(=O)C1(c2ccc(Cl)cc2)CC1
Yield: 78 %

Procedure:
The title compound was prepared in 78% yield from 1-(4-chlorophenyl)cyclopropane-1-carboxylic acid and 3-methoxy-3-oxopropanoic acid potassium salt according to the procedure for the preparation of Example 170, part A. 1H NMR (300 MHz, CDCl3): δ 1.22-1.26 (2H, m), 1.70-1.74 (2H, m), 3.35 (2H, s), 3.67 (3H, s), 7.29-7.34 (4H, m).
Reaction SMILES: S(=O)(=O)(O)O.C([O:8][C:9]([CH:11]1[CH2:15][CH2:14][CH2:13][C:12]1=O)=O)C.[CH3:17][NH:18][C:19]([NH2:21])=[S:20]>>[SH:20][C:19]1[N:18]([CH3:17])[C:9](=[O:8])[C:11]2[CH2:15][CH2:14][CH2:13][C:12]=2[N:21]=1
Reactant: CCOC(=O)C1CCCC1=O
Reactant: CNC(N)=S
Agent: O=S(=O)(O)O
Product: Cn1c(S)nc2c(c1=O)CCC2
Temperature: 100 °C
Yield: 28 %

Procedure:
Five (5) drops of concentrated sulfuric acid were added to a mixture of 2-ethoxycarbonylcyclopentanone (31.2 g) and methylthiourea (18.0 g) and the mixture was heated at 100° C. for 2 days. The resulting precipitate was collected by filtration, rinsed with ethanol, and dried to provide the title compound as colorless powder (10.2 g).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[C:15]([N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:25]=[C:26]([CH:28]=[CH:29][CH:30]=2)[NH2:27])[CH2:20][CH2:19]1)(=[O:17])[CH3:16].C(N(CC)CC)C>CN1C(=O)CCC1>[C:15]([N:18]1[CH2:19][CH2:20][N:21]([C:24]2[CH:25]=[C:26]([CH:28]=[CH:29][CH:30]=2)[NH:27][C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=2[N+:12]([O-:14])=[O:13])[CH2:22][CH2:23]1)(=[O:17])[CH3:16]
Reactant: COC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CC(=O)N1CCN(c2cccc(N)c2)CC1
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(Nc2cccc(N3CCN(C(C)=O)CC3)c2)c([N+](=O)[O-])c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 84.9 %

Procedure:
To a solution of methyl 4-chloro-3-nitrobenzoate (2.0 g, 9.28 mmol) in anhydrous NMP (5 ml) was added 2d (2.03 g, 9.28 mmol) and triethylamine (1.3 ml, 9.28 mmol). The mixture was heated with stirring to 80° C. overnight. The cooled solution was poured into ice-water (50 ml) and the resulting mixture was extracted with ethyl acetate (3×10 ml). The combined organic extracts were washed with water, dried over sodium sulfate and evaporated to dryness. The residue was triturated with petroleum ether to yield methyl 4-(3-(1-acetylpiperazin-4-yl)anilino)-3-nitrobenzoate (3.14 g, 85%) as red crystals.
Reaction SMILES: [N+](C1C=C(C=CC=1)C(NC1C=CC=CC=1OC1C=C([P:19](=[O:22])([OH:21])[OH:20])C=CC=1)=O)([O-])=O.C(OP([C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([O:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=2[NH:51][C:52](=[O:62])[C:53]2[CH:58]=[CH:57][CH:56]=[C:55]([N+:59]([O-:61])=[O:60])[CH:54]=2)[CH:39]=1)(=O)OCC)C>>[N+:59]([C:55]1[CH:54]=[C:53]([CH:58]=[CH:57][CH:56]=1)[C:52]([NH:51][C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=1[O:44][C:40]1[CH:39]=[CH:38][C:43]([P:19](=[O:20])([OH:22])[OH:21])=[CH:42][CH:41]=1)=[O:62])([O-:61])=[O:60]
Reactant: O=C(Nc1ccccc1Oc1cccc(P(=O)(O)O)c1)c1cccc([N+](=O)[O-])c1
Reactant: CCOP(=O)(OCC)c1cccc(Oc2ccccc2NC(=O)c2cccc([N+](=O)[O-])c2)c1
Product: O=C(Nc1ccccc1Oc1ccc(P(=O)(O)O)cc1)c1cccc([N+](=O)[O-])c1

Procedure:
{3-[2-(3-Nitrobenzoylamino)phenoxyl]phenyl}phosphonic acid (Compound 145) from {3-[2-(3-nitrobenzoylamino)phenoxy]phenyl}phosphonic acid diethyl ester (110 mg, 0.234 mmol) (yield: 64 mg white crystals (66%)). Mp: 120.4-122.4° C. LC/MS: m/e 415 (M+1).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[C:5]2[N:6]([CH:11]=[C:12]([CH3:14])[N:13]=2)[N:7]=[C:8]([CH3:10])[CH:9]=1)[CH3:3].[CH2:15]([CH:17]([C:20]1[C:21]2[N:22]([C:27](I)=[C:28]([CH3:30])[N:29]=2)[N:23]=[C:24]([CH3:26])[CH:25]=1)[CH2:18][CH3:19])[CH3:16]>>[CH2:15]([CH:17]([C:20]1[C:21]2[N:22]([C:27]([C:11]3[N:6]4[N:7]=[C:8]([CH3:10])[CH:9]=[C:4]([CH:2]([CH3:1])[CH3:3])[C:5]4=[N:13][C:12]=3[CH3:14])=[C:28]([CH3:30])[N:29]=2)[N:23]=[C:24]([CH3:26])[CH:25]=1)[CH2:18][CH3:19])[CH3:16]
Reactant: CCC(CC)c1cc(C)nn2c(I)c(C)nc12
Reactant: Cc1cn2nc(C)cc(C(C)C)c2n1
Product: CCC(CC)c1cc(C)nn2c(-c3c(C)nc4c(C(C)C)cc(C)nn34)c(C)nc12
Yield: 31.7 %

Procedure:
Using a procedure analogous to Example 16B, 8-(1-methylethyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.19 g, 1.01 mmol) and 8-(1-ethyl-propyl)-3-iodo-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.40 g, 1.16 mmol) give the title compound (0.13 g, 0.32 mmol, 32%). 1H NMR (CDCl3): δ 0.92 (t, J=7.5 Hz, 6H), 1.43 (d, J=1.4 Hz, 3H), 1.45 (d, J=1.4 Hz, 3H), 1.80-1.93 (m, 4H), 2.43 (s, 3H), 2.44 (s, 3H), 2.47 (s, 3H), 2.48 (s, 3H), 3.36-3.44 (m, 1H), 3.74-3.82 (m, 1H), 6.69 (s, 1H), 6.75 (s, 1H) ppm. ES-MS (m/z): calcd for C24H32N6 (M+H)+: 405.6. found: 405.3.
Reaction SMILES: [Cl-].[C:2]([C:4]1[C:16]([N+:17]([O-])=O)=[CH:15][CH:14]=[CH:13][C:5]=1[O:6][CH2:7][C@@H:8]1[CH2:12][CH2:11][CH2:10][NH2+:9]1)#[N:3].[CH2:20]([N:23]=[C:24]=[O:25])[CH2:21][CH3:22]>>[NH2:17][C:16]1[C:4]([C:2]#[N:3])=[C:5]([CH:13]=[CH:14][CH:15]=1)[O:6][CH2:7][C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:24]([NH:23][CH2:20][CH2:21][CH3:22])=[O:25]
Reactant: N#Cc1c(OC[C@@H]2CCC[NH2+]2)cccc1[N+](=O)[O-]
Reactant: CCCN=C=O
Agent: [Cl-]
Product: CCCNC(=O)N1CCC[C@H]1COc1cccc(N)c1C#N
Yield: 100 %

Procedure:
Prepared as in Example 209a from (5)-2-((2-cyano-3-nitrophenoxy)methyl)pyrrolidinium chloride (Example 209b) and propyl isocyanate in 100% yield as a white solid. MS 303 (MH+).
Reaction SMILES: [CH3:1][N:2]([CH2:9][C:10]([F:13])([F:12])[F:11])[C:3](=[O:8])[C:4]([O:6]C)=[O:5].[Li+].[OH-].Cl>CO.O>[CH3:1][N:2]([CH2:9][C:10]([F:11])([F:12])[F:13])[C:3](=[O:8])[C:4]([OH:6])=[O:5]
Reactant: COC(=O)C(=O)N(C)CC(F)(F)F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN(CC(F)(F)F)C(=O)C(=O)O
Reaction time: 2 h
Yield: 53.8 %

Procedure:
To a solution of methyl 2-(methyl(2,2,2-trifluoroethyl)amino)-2-oxoacetate (1.2 g, 6.03 mmol) in methanol (15 mL) and water (15.00 mL) was added LiOH (0.506 g, 12.05 mmol) and the mixture stirred for 2 h. The solution was then acidified with conc. HCl and concentrated. The solid was washed with CH2Cl2 (2×100 mL), filtered and the filtrate concentrated to afford the title compound (600 mg, 53.8% yield) (mixture of rotational isomers at room temperature) as an off-white solid. 1H NMR (500 MHz, DMSO-d6) δ: 4.32 (1 H, q, J=9.36 Hz), 4.23 (1 H, q, J=9.46 Hz), 3.07 (2 H, s), 2.97 (1 H, s).
Reaction SMILES: C(N(CC)CC)C.[OH:8][CH:9]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1[O:25][CH3:26])[C:10](=[NH:14])[O:11]CC.[O:27]1CCC[CH2:28]1>>[CH3:26][O:25][C:16]1[CH:17]=[CH:18][C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:15]=1[CH:9]1[O:8][C:28](=[O:27])[NH:11][C:10]1=[O:14]
Reactant: C1CCOC1
Reactant: CCOC(=N)C(O)c1c(OC)ccc2ccccc12
Solvent: CCN(CC)CC
Product: COc1ccc2ccccc2c1C1OC(=O)NC1=O

Procedure:
By the procedure of Example 12, except that 2.3 rather than 2.0 equivalents of triethylamine were used, ethyl 1-hydroxy-1-(2-methoxy-1-naphthyl)methanecarboximidate (16.5 g., 0.063 mole) in 500 ml. of tetrahydrofuran was converted to crude product. Recrystallization from ethyl acetate/toluene gave purified 5-(2-methoxy-1-naphthyl)oxazolidine-2,4-dione in two crops [7.7 g.; m.p. 199°201° C.; ir (KBr) 1820, 1740 cm-1 ].
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[S:7][C:8]([C:11]#[C:12][C:13]2[S:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=2)=[CH:9][CH:10]=1)CCC.Br[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:31]1([C:6]2[S:7][C:8]([C:11]#[C:12][C:13]3[S:14][C:15]4[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=4[CH:17]=3)=[CH:9][CH:10]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C#Cc2cc3ccccc3s2)s1
Reactant: Brc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: C(#Cc1cc2ccccc2s1)c1ccc(-c2ccccc2)s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 46.6 %

Procedure:
To a stirred solution of 1.0 gram (0.0019 mole) of tributyl 5-(benzothien-2-ylethynyl)thien-2-yltin and 0.33 gram (0.0021 mole) of bromobenzene in 10 ml of tetrahydrofuran was added a catalytic amount of bis(triphenylphosphine)palladium(II) chloride. Upon completion of addition, the reaction mixture was warmed to reflux where it was stirred for 18 hours. After this time the reaction mixture was cooled to ambient temperature, and then it was subjected to column chromatography on silica gel. Elution was accomplished with hexane. The appropriate fractions were combined and concentrated under reduced pressure, yielding 0.28 gram of 2-(5-phenylthien-2-ylethynyl)benzothiophene; m.p. 185°-186.5° C. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([CH2:15][CH2:16][CH2:17][C:18]2[CH:30]=[CH:29][C:21]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:20][CH:19]=2)=[CH:13][N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:8][C:9]1[C:14]([CH2:15][CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:22]([OH:24])=[O:23])=[CH:29][CH:30]=2)=[CH:13][N:12]=[CH:11][N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(CCCc2cncnc2OCc2ccccc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(CCCc2cncnc2OCc2ccccc2)cc1
Reaction time: 2 h

Procedure:
tert-Butyl 4-[3-(4-(benzyloxy)pyrimid-5-yl)propyl]benzoate (0.36 g, 0.92 mmol) was dissolved in dichloromethane (0.7 ml) and treated with trifluoro-acetic acid (1.05 g, 9.2 mmol). The reaction was stirred at amibent temperature for 2 hours. The mixture was partitioned between EtOAc/water and the aqueous layer extracted with EtOAc. The organic layers were combined, dried (MgSO4) and evaporated and the solid was triturated with hexane and recrystallised from isopropanol/water. The cream coloured solid was taken up in THF, filtered through Celite and evaporated to give the title product.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:8](=[O:9])[CH2:7][S:6][C:5]1=[O:10].[CH3:11][NH:12][CH3:13].O>CN(C=O)C>[CH3:11][N:12]([CH3:13])[CH2:2][CH2:3][N:4]1[C:8](=[O:9])[CH2:7][S:6][C:5]1=[O:10]
Reactant: CNC
Reactant: O=C1CSC(=O)N1CCBr
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CCN1C(=O)CSC1=O
Temperature: 50 °C
Yield: 23.8 %

Procedure:
To a 35 ml seal tube, 3-(2-bromoethyl)thiazolidine-2,4-dione (1.5 g, 0.6.69 mmole) was taken in DMF (1 mL) under N2 atmosphere and dimethyl amine (2M solution in THF) (11 mL, 20.0 mmole) was added. The reaction mixture was heated to 50° C. for 16 hrs. After completion of the reaction, water was added to the reaction mixture and product was extracted with ethyl acetate. The combined organic layer was dried over Na2SO4 and evaporated to get the crude product which was purified using column purification using 60-120 mesh size neutral silica by eluting the compound with 2% MeOH in CH2Cl2 to yield 0.3 g of 3-(2-(dimethylamino)ethyl)thiazolidine-2,4-dione which was converted to 3-(2-(dimethylamino)-ethyl)-5-(4-(7-pivaloyl-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)benzylidene)-thiazolidine-2,4-dione as described in Example 6 above.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Cl)=[CH:13][CH:12]=1.[H-].[Na+]>>[Br:1][C:2]1[N:7]=[C:6]([N:8]([CH2:15][C:14]2[CH:17]=[CH:18][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)[CH2:15][C:14]2[CH:17]=[CH:18][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc(Br)n1
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2cccc(Br)n2)cc1
Reaction time: 2 h
Yield: 106.7 %

Procedure:
To a solution of 6-bromo-pyridin-2-ylamine (1.00 g, 5.78 mmol) under a nitrogen atmosphere at room temperature was added 4-methoxybenzyl chloride (1.96 mL, 14.5 mmol) in one portion. To this mixture was added NaH (60% suspension in mineral oil, 694 mg, 17.3 mmol) in one portion. The reaction was stirred for 2 h then partitioned between aqueous NaHCO3 and CH2Cl2. The layers were separated and the aqueous layer was further extracted with CH2Cl2. The combined organic layers were dried with MgSO4 and concentrated in vacuo to give a light yellow oil. This oil was purified by flash chromatography on silica gel (1→15% EtOAc/hexanes) to give 2.55 g of the title compound as a colorless oil, m/z 413.9 [M−H]+.
Reaction SMILES: C(=O)(O)[O-].[Na+].Cl[C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[C:9]([Cl:16])[N:8]=1.[NH2:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[C:21]#[N:22]>C(#N)C>[Cl:16][C:9]1[N:8]=[C:7]([NH:17][C:18]2[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=2)[C:21]#[N:22])[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: N#Cc1cccc(N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: N#Cc1cccc(Nc2nc(Cl)ccc2[N+](=O)[O-])c1
Temperature: 60 °C

Procedure:
In step 1-1, sodium bicarbonate (1.68 g, 20 mmol) was added into a solution of 2,6-dichloro-3-nitropyridine (1.93 g, 10 mmol) and 3-amino benzonitrile (1.18 g, 10 mmol) in acetonitrile and the suspension was heated for 24 hours at 60° C. The mixture was filtered and washed twice with water to give 3-(6-chloro-3-nitropyridin-2-ylamino)benzonitrile (1-1) as a pale yellow solid. 1H NMR DMSO-d6 δ (ppm) 10.24 (s, 1H), 8.57 (d, 1H), 8.09 (m, 1H), 7.93 (m, 1H), 7.62 (m, 2H), 7.08 (d, 1H); m/z 357 M+1.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:5][CH2:4]1.C(N(CC)CC)C.[Cl:21][C:22]1[N:31]=[C:30](Cl)[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([CH3:33])[CH:28]=2)[N:23]=1>O1CCCC1>[Cl:21][C:22]1[N:31]=[C:30]([NH:1][CH2:2][C:3]2([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH2:4][CH2:5]2)[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([CH3:33])[CH:28]=2)[N:23]=1
Reactant: CC(C)(C)OC(=O)NC1(CN)CC1
Reactant: Cc1ccc2nc(Cl)nc(Cl)c2c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc2nc(Cl)nc(NCC3(NC(=O)OC(C)(C)C)CC3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a solution of tert-butyl [1-(aminomethyl)cyclopropyl]carbamate (0.92 g, 4.9 mmol) in tetrahydrofuran (50 mL) was added triethylamine (1.3 mL, 9.4 mmol) followed by 2,4-dichloro-6-methylquinazoline (1.0 g, 4.7 mmol) in portions at room temperature. After being stirred at room temperature overnight, the resultant mixture was concentrated in vacuo to remove 20 mL of solvent and then stirred vigorously with water (200 mL). The formed solid was collected by filtration and washed with water and ether, then dried in vacuo to afford 1.5 g of the product as a white powder.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][S:10](Cl)(=[O:12])=[O:11])=[CH:5][CH:4]=1.[CH2:16]([NH2:18])[CH3:17]>C1COCC1>[CH2:16]([NH:18][S:10]([CH2:9][C:6]1[CH:7]=[CH:8][C:3]([C:2]([F:15])([F:14])[F:1])=[CH:4][CH:5]=1)(=[O:12])=[O:11])[CH3:17]
Reactant: O=S(=O)(Cl)Cc1ccc(C(F)(F)F)cc1
Reactant: CCN
Solvent: C1CCOC1
Product: CCNS(=O)(=O)Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
[[4-(Trifluoromethyl)phenyl]methyl]sulfonyl chloride (0.60 g, 2.32 mmol) was added dropwise to a saturated solution of ethylamine in THF (10 mL). The mixture was stirred at room temperature for 1 h. It was evaporated and the residue was dissolved in DCM and the resulting mixture was washed with 5% HCl, dried and evaporated to give the title compound (0.49 g, 79%) as a solid; 1H NMR (500 MHz, CDCl3): δ 7.68 (d, 2H), 7.55 (d, 2H), 4.32 (s, 2H), 4.01 (bs, 1H), 3.08-3.14 (m, 2H), 1.19 (t, 3H); Mass Spectrum: M−H+ 265.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[O:8])=[CH:5][CH:4]=1)#[N:2].C(O[CH:15](OCC)[N:16]([CH3:18])[CH3:17])C>>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](/[N:9]=[CH:15]/[N:16]([CH3:18])[CH3:17])=[O:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C(N)=O)cc1
Reactant: CCOC(OCC)N(C)C
Product: CN(C)/C=N/C(=O)c1ccc(C#N)cc1
Temperature: 120 °C
Reaction time: 1.17 h
Yield: 96.1 %

Procedure:
4-cyanobenzamide (327.0 mg, 2.237 mmol) and N,N-dimethylformamide diethyl acetal (0.53 ml, 3.09 mmol) were combined and heated to 120° C. A short path distillation apparatus was used to collect the ethanol that was liberated during the reaction. The reaction mixture was a dark purple solution that slowly turned lighter until it had become an amber solution. After 70 minutes, the reaction mixture solidified. The reaction mixture was cooled to room temperature and was placed under high vacuum overnight to give the title compound (432.7 mg, 2.150 mmol) as a yellow solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[CH:20]=3)[CH:15]=[CH:14][C:13]=2[O:24][S:25]([C:28]([F:31])([F:30])[F:29])(=[O:27])=[O:26])=[N:4][N:3]=1.[C:32]1([C@H:38]([NH2:40])[CH3:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH3:23][O:22][C:19]1[CH:20]=[C:21]2[C:16]([CH:15]=[CH:14][C:13]([O:24][S:25]([C:28]([F:31])([F:30])[F:29])(=[O:27])=[O:26])=[C:12]2[C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]([NH:40][C@@H:38]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH3:39])=[N:3][N:4]=2)=[CH:17][CH:18]=1
Reactant: COc1ccc2ccc(OS(=O)(=O)C(F)(F)F)c(-c3nnc(Cl)c4ccccc34)c2c1
Reactant: C[C@@H](N)c1ccccc1
Product: COc1ccc2ccc(OS(=O)(=O)C(F)(F)F)c(-c3nnc(N[C@H](C)c4ccccc4)c4ccccc34)c2c1
Temperature: 23 °C
Yield: 80.9 %

Procedure:
A solution of trifluoromethanesulfonic acid 1-(4-chlorophthalazin-1-yl)-7-methoxynaphthalen-2-yl ester (2.2 g, 4.7 mmol) in (R)-1-phenylethylamine (3.5 ml, 27 mmol) was stirred for 8 hrs at 130° C., then cooled to 23° C. The resulting viscous mixture was purified by flash chromatography on silica gel (toluene/EtOAc 5:1 to 3:1) to give 2.1 g (3.8 mmol) of the title compound as a 1:1 mixture of diastereomers as a light brown foam.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]=[CH:9][NH:10][C:6]=2[CH:5]=[CH:4][N:3]=1.Br[CH2:12][C:13]#[C:14][CH3:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH2:12]([N:8]1[C:7]2[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][C:6]=2[N:10]=[CH:9]1)[C:13]#[C:14][CH3:15]
Reactant: Clc1nccc2[nH]cnc12
Reactant: CC#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC#CCn1cnc2ccnc(Cl)c21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2.0 μg of 4-chloro-1H-imidazo[4,5-c]pyridine, 1.37 ml of 1-bromo-2-butyne, and 1.98 g of potassium carbonate were suspended in 15 ml of N,N-dimethylformamide, and the suspension was stirred at room temperature for 18 hours. The reaction solution was diluted with ethyl acetate, and washed with water. The organic layer was dried over anhydrous magnesium sulfate, then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 1.79 g of a 1:1 mixture consisting of the title compound and the compound alkylated at the 1-position was obtained from the fraction eluted with hexane-ethyl acetate (1:2).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][N:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:23])[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][C:15]=2[C:24](=[O:26])[NH2:25].Br[CH2:28][C:29]([O:31][CH3:32])=[O:30]>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][N:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([O:23][CH2:28][C:29]([O:31][CH3:32])=[O:30])[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][C:15]=2[C:24](=[O:26])[NH2:25]
Reactant: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cccc(F)c1F
Reactant: COC(=O)CBr
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1cccc(F)c1F
Reaction time: 0.25 h
Yield: 80.8 %

Procedure:
40% Methanolic Triton B (0.51 mL, 1.12 mM) was added to a solution of the 9-[(2,3-difluorophenyl)methyl]-4-hydroxy-5-carbamoyl carbazole (303 mg, 0.86 mM) in 5 mL DMF at room temperature. After 15 minutes, methyl bromoacetate (270 mg, 1.72 mM) was added and the resultant mixture stirred at room temperature for 18 hours. The mixture was diluted with ethyl acetate, washed with H2O, 1 N HCl, H2O, and saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with ethyl acetate) to afford 295 mg (80%) of the {9-[(2,3-difluorophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester as a white solid. 1H NMR (CDCl3) δ7.5-7.3 (m, 5H), 7.05 (d, 1H, J=8 Hz), 6.8 (m, 1H), 6.6 (d, 1H, J=8 Hz), 6.4 (t, 1H, J=8 Hz), 6.2 (br s, 1H), 6.0 (br s, 1H), 5.6 (s, 2H), 4.9 (s, 2H), and 3.8 (s, 3H). IR (KBr, cm−1) 3432, 3180, 1774, 1766, and 1674. MS (ES) m/e 425.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[OH:39])[C:5]([N:7]([CH:33]([CH3:35])[CH3:34])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[CH:16]1[CH2:25][CH2:24][C:23]2[CH:22]=[C:21]([O:26]C(=O)C(C)(C)C)[CH:20]=[CH:19][C:18]=2[CH2:17]1)=O.[CH:40]12[CH2:48][CH2:47][CH:44]([CH2:45][CH2:46]1)[CH2:43][N:42]([C:49](=O)[CH2:50]Cl)[CH2:41]2>>[CH:40]12[CH2:48][CH2:47][CH:44]([CH2:45][CH2:46]1)[CH2:43][N:42]([CH2:49][CH2:50][O:39][C:38]1[CH:37]=[CH:36][C:4]([CH2:5][N:7]([CH:33]([CH3:35])[CH3:34])[C:8]3[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=3[CH:16]3[CH2:25][CH2:24][C:23]4[CH:22]=[C:21]([OH:26])[CH:20]=[CH:19][C:18]=4[CH2:17]3)=[CH:3][C:2]=1[F:1])[CH2:41]2
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(N(C(=O)c2ccc(O)c(F)c2)C(C)C)c1
Reactant: O=C(CCl)N1CC2CCC(CC2)C1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(N(Cc2ccc(OCCN3CC4CCC(CC4)C3)c(F)c2)C(C)C)c1
Yield: 12 %

Procedure:
Synthesized from pivalic acid 6-{2-[(3-fluoro-4-hydroxybenzoyl)isopropylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (25 mg) and 1-(3-azabicyclo[3.2.2]non-3-yl)-2-chloroethanone (19 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (3.3 mg) was obtained.