Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH2:4].N1C=CC=CC=1.[I:16]Cl.O>C(O)(=O)C>[I:16][C:7]1[CH:8]=[C:2]([F:1])[C:3]([NH2:4])=[C:5]([F:9])[CH:6]=1
Reactant: ClI
Reactant: Nc1c(F)cccc1F
Solvent: c1ccncc1
Solvent: CC(=O)O
Solvent: O
Product: Nc1c(F)cc(I)cc1F
Yield: 58.6 %

Procedure:
2,6-Difluoroaniline (38 g) was dissolved in acetic acid (120 ml), and then pyridine (25 g) was added thereto, followed by stirring. Then, a mixture of iodine monochloride (50 g) with acetic acid (30 ml) was added dropwise thereto. After stirring at room temperature for 1 hour, the reaction solution was further stirred at 70° to 80° C. for 2 hours. Then, the reaction solution was poured into water, and the precipitated crystals were filtered, followed by washing with water. The resulting crystals were dissolved in chloroform, and then washed with water twice, further with 10% potassium hydroxide aqueous solution twice, and furthermore with water twice, followed by distilling off chloroform. The residue was distilled under reduced pressure (b.p. 120° to 130° C./20 mmHg), and then recrystallized from methanol to give 4-iodo-2,6-difluoroaniline (44 g).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:20]=[CH:19][C:7]([CH2:8][CH:9]2[CH2:14][CH:13]([C:15]([O:17][CH3:18])=[O:16])[CH2:12][CH2:11][NH:10]2)=[CH:6][CH:5]=1.CCN(C(C)C)C(C)C.[C:32](Cl)(=[O:35])[O:33][CH3:34]>C(Cl)Cl>[F:22][C:2]([F:21])([F:1])[O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][CH:9]2[CH2:14][CH:13]([C:15]([O:17][CH3:18])=[O:16])[CH2:12][CH2:11][N:10]2[C:32]([O:33][CH3:34])=[O:35])=[CH:19][CH:20]=1
Reactant: COC(=O)C1CCNC(Cc2ccc(OC(F)(F)F)cc2)C1
Reactant: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1CCN(C(=O)OC)C(Cc2ccc(OC(F)(F)F)cc2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.3 %

Procedure:
To a solution of methyl 2-(4-(trifluoromethoxy)benzyl)piperidine-4-carboxylate (8.19 g, 25.81 mmol) in DCM (100 mL) was added DIPEA (5.40 mL, 30.97 mmol) followed by methyl carbonochloridate (2.236 mL, 28.39 mmol). The reaction mixture was stirred at room temperature for 30 min. The solvents were evaporated and the residue partitioned between ethyl acetate and 3.8 M HCl. After phase separation the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over MgSO4 and evaporated to give a yellow oil. Dimethyl 2-(4-(trifluoromethoxy)benzyl)piperidine-1,4-dicarboxylate (9.72 g, 100%) was isolated. MS m/z 376 (M+H)+
Reaction SMILES: C([Sn](CCCC)(CCCC)/[CH:6]=[CH:7]\[CH2:8][NH2:9])CCC.Br[C:19]1[N:20]=[C:21]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[S:22][C:23]=1[C:24]([O-:26])=O>C1(C)C=CC=CC=1.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>[N:27]1([C:21]2[S:22][C:23]3[C:24](=[O:26])[NH:9][CH2:8][CH:7]=[CH:6][C:19]=3[N:20]=2)[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1
Reactant: O=C([O-])c1sc(N2CCOCC2)nc1Br
Reactant: CCCC[Sn](/C=C\CN)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: O=C1NCC=Cc2nc(N3CCOCC3)sc21
Temperature: 120 °C
Reaction time: 120 h
Yield: 15.8 %

Procedure:
A solution of Z-3-(tributylstannyl)-2-propen-1-amine (30.0 g, 86.7 mmol) and 4-bromo-2-morpholin-4-yl-1,3-thiazole-5-carboxylate (27.8 g, 86.7 mmol) in toluene (136 mL) was purged with argon, and then tetrakis(triphenylphosphinepalladium(0) (5.01 g, 4.33 mmol) was added. The reaction mixture was stirred at 120° C. under an atmosphere of argon for 5 days. The solvent was evaporated, then the residue was adsorbed onto silica gel then purified using column chromatography on silica gel (600 gr Analogix column, gradient DCM to 5% MeOH in DCM over 40 minutes) to give the product (3.44 g, 16%). LCMS: (AA) ES+ 252. 1H NMR (400 MHz, d6-DMSO) δ: 7.73 (s, 1H), 6.63 (d, J=10.3 Hz, 1H), 6.24 (dt, J=10.3, 6.6 Hz, 1H), 3.74-3.63 (m, 4H), 3.54-3.47 (m, 2H), 3.47-3.40 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11]([N:14]3[CH2:19][CH2:18][CH:17]([NH:20][CH3:21])[CH2:16][CH2:15]3)=[C:10]([CH3:22])[C:9]=2[CH3:23])=[CH:4][CH:3]=1.[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH2:34][CH2:33][C@H:32]1[C:37]([OH:39])=O)=[O:30])([CH3:27])([CH3:26])[CH3:25].C(N(CC)CC)C.CCN=C=NCCCN(C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11]([N:14]3[CH2:19][CH2:18][CH:17]([N:20]([CH3:21])[C:37]([C@@H:32]4[CH2:33][CH2:34][CH2:35][CH2:36][N:31]4[C:29]([O:28][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:30])=[O:39])[CH2:16][CH2:15]3)=[C:10]([CH3:22])[C:9]=2[CH3:23])=[CH:4][CH:3]=1
Reactant: CNC1CCN(c2nnc(-c3ccc(F)cc3)c(C)c2C)CC1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(-c2ccc(F)cc2)nnc(N2CCC(N(C)C(=O)[C@@H]3CCCCN3C(=O)OC(C)(C)C)CC2)c1C
Temperature: 25 °C
Reaction time: 48 h
Yield: 49.1 %

Procedure:
Sequentially treat a solution of 1-(6-(4-fluorophenyl)-4,5-dimethylpyridazin-3-yl)-N-methylpiperidin-4-amine (100 mg, 0.318 mmol) in CH2Cl2 (3.2 mL) with (S)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (109 mg, 0.477 mmol), triethylamine (0.067 mL, 0.477 mmol) and EDCI (92 mg, 0.477 mmol). Stir the resulting mixture at ambient temperature for 2 d. Pour the reaction mixture into H2O containing NaHCO3. Separate the layers, and extract the aqueous layer with CH2Cl2. Combine the organic layers, dry over Na2SO4, filter, and concentrate under reduced pressure. Purify the residue by flash silica gel chromatography (gradient of 0 to 2% 2 M NH3/MeOH in CH2Cl2) to afford the title compound as a white solid (82 mg, 49%). ES/MS m/z 526.2 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:13])[C:11]#[N:12])=[CH:6][CH:5]=1)([O-])=O>N.CO.[Ni]>[NH2:12][CH2:11][CH:10]([C:7]1[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=1)[CH3:13]
Reactant: CC(C#N)c1ccc([N+](=O)[O-])cc1
Agent: [Ni]
Agent: N
Solvent: CO
Product: CC(CN)c1ccc(N)cc1
Reaction time: 4 h
Yield: 99.9 %

Procedure:
2-(4-Nitrophenyl)propionitrile (5.0 g, 28.38 mmoL) was dissolved in a 20% NH3/methanol mixture (100 mL) and treated with Raney Nickel (24.79 g). It was then hydrogenated at 60 psi at room temperature for 4 hr. The reaction was then filtered through a nylon membrane. The filtrate was then concentrated in vacuo to give 4.26 g (100%) of the title compound. It was used without further purification. 1H NMR (300 MHz, CDCl3) δ ppm 7.00 (d, J=8.46 Hz, 2H) 6.66 (d, J=8.09 Hz, 2H) 3.58 (s, 2H) 2.71-2.85 (m, 2H) 2.56-2.70 (m, 1H) 1.20 (d, J=6.62 Hz, 3H). MS m/z (DCI) 151.0 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]([C:11]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)=O)[C:6]([CH:8]1[CH2:10][CH2:9]1)=O)[CH3:2].Cl.[NH2:21][NH2:22].O.O1CCOCC1.Cl>C(O)C>[CH2:1]([O:3][C:4]([C:5]1[C:11]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:21][NH:22][C:6]=1[CH:8]1[CH2:10][CH2:9]1)=[O:19])[CH3:2]
Reactant: NN
Reactant: CCOC(=O)C(C(=O)c1ccncc1)C(=O)C1CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1c(-c2ccncc2)n[nH]c1C1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
220 mg (0.84 mmol) of 3-cyclopropyl-3-oxo-2-(pyridine-4-carbonyl)-propionic acid ethyl ester and 57 mg (0.84 mmol) hydrazine.hydrochloride were dissolved in 3 ml ethanol, 1.5 ml water and 0.2 ml 4M HCl dioxane. The yellow solution was stirred 1 h at room temperature. The reaction mixture was evaporated, the residue taken in EtOAc and washed with brine, the aqueous layers were extracted with EtOAc. The combined organic phases were dried over magnesium sulfate and evaporated. The title compound was received as yellow gum (148 mg, 68%). MS: 258.0 (MH+).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH2:14])=[O:13])=[C:6]2[S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=O.Cl.[CH2:23]([NH2:26])[CH2:24][CH3:25]>CO.C(Cl)Cl>[C:16]1([S:15][C:6]2[C:5]3[C:9](=[CH:10][CH:11]=[C:3]([CH2:1][NH:26][CH2:23][CH2:24][CH3:25])[CH:4]=3)[NH:8][C:7]=2[C:12]([NH2:14])=[O:13])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCCN
Reactant: NC(=O)c1[nH]c2ccc(C=O)cc2c1Sc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CCCNCc1ccc2[nH]c(C(N)=O)c(Sc3ccccc3)c2c1

Procedure:
Treat 5-formyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide 13 (m=0, R3=Ph) (80 mg, 0.27 mmol) with propylamine hydrochloride (28 mg, 0.30 mmol) as described in General Procedure X to afford Iae (41.0 mg, 44.8%) as an ivory colored solid, tlc Rf=0.1 (10% MeOH/CH2Cl2-0.2% Et3N), m/z obs=340 (M+1).
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].Cl[C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9].C(N(CC)CC)C>ClCCl>[CH3:5][O:4][N:3]([CH3:2])[C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C(=O)Cl
Reactant: CNOC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=O)N(C)OC
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of N,O-dimethylhydroxylamine hydrochloride (10 g, 102.52 mmol) and ethyl chlorooxoacetate (13.77 ml, 123.02 mmol) in dichloromethane (163 ml) at 0° C. was added triethylamine (28.6 ml, 205.04 mmol) drop wise. The reaction was stirred at room temperature for 1.5 hrs. The reaction was quenched with 20 ml of methanol, and then concentrated. The resulting solid was triturated with THF and filtered away. The filtrate was concentrated. The residue was vacuum distilled bulb to bulb. At approximately 85° C. impurities were collected and then discarded. The title compound was collected at approximately 120° C. as a neat oil (11.6 g, 72.0 mmol, 70.2%).
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=O.N1CCCCC1.C(O)(=O)C.[NH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][C:19]1=[O:27]>C1(C)C=CC=CC=1.C(O)C>[C:1]([O:5][CH2:6][CH:7]=[C:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[NH:18][C:19]1=[O:27])(=[O:4])[CH3:2]
Reactant: O=C1Cc2ccccc2N1
Reactant: CCOC(=O)C=O
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: CC(=O)O
Product: CC(=O)OCC=C1C(=O)Nc2ccccc21
Temperature: 70 °C
Reaction time: 20 h
Yield: 47 %

Procedure:
73.5 mL (360 mmol) of a 50% solution of ethyl glyoxalate in toluene then 3.6 ml, (36 mmol) of piperidine and 4.2 mL (72 mmol) of acetic acid are added to a solution of 24 g (180 mmol) of 1,3-dihydro-indol-2-one dissolved in 350 mL of ethanol. The reaction mixture is stirred at 70° C. for 20 hours then concentrated to a quarter by evaporation of the solvents under vacuum. The solid is filtered to give 18.3 g (47%) of (2-oxo-1,2-dihydro-indol-3-ylidene)-ethyl ethanoate in the form of an orange solid. The filtrate is evaporated, then recrystallized from ethanol to give an additional 2.7 g (7%) of (2-oxo-1,2-dihydro-indol-3-ylidene)-ethyl ethanoate in the form of an orange solid.
Reaction SMILES: [F:1][C:2]([C:5]1[N:6]=[C:7]([CH2:10][N:11]2[N:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)[S:8][CH:9]=1)([F:4])[CH3:3].[CH3:17][N:18]([CH3:33])[C:19]1[CH:20]=[C:21]([C:25]2[O:29][CH:28]=[N:27][C:26]=2[C:30](O)=[O:31])[CH:22]=[CH:23][CH:24]=1>>[F:1][C:2]([C:5]1[N:6]=[C:7]([CH2:10][N:11]2[N:15]=[C:14]([NH:16][C:30]([C:26]3[N:27]=[CH:28][O:29][C:25]=3[C:21]3[CH:22]=[CH:23][CH:24]=[C:19]([N:18]([CH3:33])[CH3:17])[CH:20]=3)=[O:31])[CH:13]=[N:12]2)[S:8][CH:9]=1)([F:4])[CH3:3]
Reactant: CN(C)c1cccc(-c2ocnc2C(=O)O)c1
Reactant: CC(F)(F)c1csc(Cn2ncc(N)n2)n1
Product: CN(C)c1cccc(-c2ocnc2C(=O)Nc2cnn(Cc3nc(C(C)(F)F)cs3)n2)c1

Procedure:
Following general procedure Z2, starting from 2-[4-(1,1-difluoro-ethyl)-thiazol-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-(3-dimethylamino-phenyl)-oxazole-4-carboxylic acid.
Reaction SMILES: [CH:1]1([C:7]([NH:9][C:10]2[S:11][C:12]3[CH2:23][CH2:22][CH2:21][CH2:20][C:13]=3[C:14]=2[C:15]([O:17]CC)=O)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([NH:31][C:15]([C:14]1[C:13]2[CH2:20][CH2:21][CH2:22][CH2:23][C:12]=2[S:11][C:10]=1[NH:9][C:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:8])=[O:17])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NCc1ccccc1
Reactant: CCOC(=O)c1c(NC(=O)C2CCCCC2)sc2c1CCCC2
Product: O=C(NCc1ccccc1)c1c(NC(=O)C2CCCCC2)sc2c1CCCC2

Procedure:
The product of Example 13 and benzylamine were processed as in Examples 29A and 29B to afford the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.19-1.41 (m, 3H), 1.45-1.62 (m, 2H), 1.64-1.73 (m, 1H), 1.76-1.88 (m, 6H), 1.96-2.06 (m, 2H), 2.38 (tt, J=11.5, 3.6 Hz, 1H), 2.61-2.72 (m, 4H), 4.63 (d, J=5.4 Hz, 2H), 6.18-6.26 (m, 1H), 7.27-7.42 (m, 5H), 12.15 (s, 1H); MS (DCI/NH3) m/z 397 (M+H)+; anal. calculated for C23H28N2O2S: C, 69.66; H, 7.12; N, 7.06. Found: C, 69.62; H, 7.07; N, 6.88.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:10]([C:11](OCC)=[O:12])=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:1][C:2]1[O:3][C:4]2[C:10]([CH2:11][OH:12])=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: CCOC(=O)c1cccc2nc(C)oc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nc2cccc(CO)c2o1
Temperature: 0 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
To a solution of ethyl 2-methylbenzo[d]oxazole-7-carboxylate (743) (1.27 g, 6.19 mmol) in tetrahydrofuran (61 mL) at 0° C. was added lithium aluminum hydride (7.43 mL, 7.43 mmol, 1M in tetrahydrofuran). The reaction was stirred at 0° C. for 1 hour and quenched with 0.6 mL of water, 0.6 mL of 15% NaOH and 1.8 mL of water. The reaction was warmed to room temperature and diluted with diethyl ether. Magnesium sulfate was added and the solution was filtered, washed with diethyl ether, and the solvent was removed in vacuo to provide (2-methylbenzo[d]oxazol-7-yl)methanol (744) (0.687 g, 68%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@:9]1([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:11][C@H:10]1[CH2:12][CH:13]([OH:18])[CH2:14][CH2:15][CH:16]=[CH2:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[C:1]([O:5][C:6]([N:8]([C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[C@:9]1([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:11][C@H:10]1[CH2:12][C:13](=[O:18])[CH2:14][CH2:15][CH:16]=[CH2:17])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CCCC(O)C[C@@H]1C[C@@]1(C(=O)OCC)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: C=CCCC(=O)C[C@@H]1C[C@@]1(C(=O)OCC)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 89.3 %

Procedure:
To a solution of (1R,2S)-ethyl 1-(bis(tert-butoxycarbonyl)amino)-2-(2-hydroxyhex-5-enyl)cyclopropanecarboxylate (4.3 g, 10 mmol) in dichloromethane (50 ml) at 25° C. was added Dess-Martin Periodinane (5.97 g, 14.1 mmol). The reaction mixture was stirred for 3 h and quenched with 1 N aqueous sodium thiosulfate solution (50 mL) and saturated aqueous sodium bicarbonate solution (15 mL), and the reaction mixture stirred for 1 h. The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced. The crude product was purified by flash chromatography on silica gel (15% ethyl acetate/hexane) to provide (1R,2S)-ethyl 1-(bis(tert-butoxycarbonyl)amino)-2-(2-oxohex-5-enyl)cyclopropane carboxylate (3.8 g, 88% yield) as an oil. MS (ESI): m/z=448.1 [M+Na].
Reaction SMILES: C([O:5][C:6](=[O:39])[CH:7]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[N:18][C:19]3[N:20]([C:22]([C:25]4([C:28]5[CH:29]=[C:30]6[C:35](=[CH:36][CH:37]=5)[N:34]=[CH:33][CH:32]=[CH:31]6)[CH2:27][CH2:26]4)=[CH:23][N:24]=3)[CH:21]=2)=[CH:12][C:11]=1[F:38])[CH3:8])(C)(C)C>C(Cl)Cl.FC(F)(F)C(O)=O>[F:38][C:11]1[CH:12]=[C:13]([C:16]2[CH:17]=[N:18][C:19]3[N:20]([C:22]([C:25]4([C:28]5[CH:29]=[C:30]6[C:35](=[CH:36][CH:37]=5)[N:34]=[CH:33][CH:32]=[CH:31]6)[CH2:27][CH2:26]4)=[CH:23][N:24]=3)[CH:21]=2)[CH:14]=[CH:15][C:10]=1[O:9][CH:7]([CH3:8])[C:6]([OH:39])=[O:5]
Reactant: CC(Oc1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)cc1F)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(Oc1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)cc1F)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl-2-{2-fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]phenoxy}propanoate (100 mg, 0.2 mmol) was dissolved in a mixed solvent of methylene chloride (5.0 mL) and trifluoroacetic acid (5.0 mL). The solution was stirred at RT for 2 h. The volatiles were evaporated under reduced pressure. The residue was co-evaporated with toluene three times, and was directly used in next step. LCMS: (M+H)=469. 1.
Reaction SMILES: [CH:1]1([N:4]([S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)(=[O:21])=[O:20])[CH:5]2[CH2:10][CH2:9][CH2:8][N:7]([CH2:11][C:12]([NH:14][CH2:15][CH:16](C)[CH3:17])=[O:13])[CH2:6]2)[CH2:3][CH2:2]1.Cl.C1(N(C2CCCNC2)S(C2C=CC=[C:42]([C:46](F)(F)[F:47])[CH:41]=2)(=O)=O)CC1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH:1]1([N:4]([S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:29])[F:30])[CH:23]=2)(=[O:20])=[O:21])[CH:5]2[CH2:10][CH2:9][CH2:8][N:7]([CH2:11][C:12]([NH:14][C:15]3[CH:41]=[CH:42][C:46]([F:47])=[CH:17][CH:16]=3)=[O:13])[CH2:6]2)[CH2:2][CH2:3]1
Reactant: CC(C)CNC(=O)CN1CCCC(N(C2CC2)S(=O)(=O)c2cccc(C(F)(F)F)c2)C1
Reactant: O=S(=O)(c1cccc(C(F)(F)F)c1)N(C1CC1)C1CCCNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(CN1CCCC(N(C2CC2)S(=O)(=O)c2cccc(C(F)(F)F)c2)C1)Nc1ccc(F)cc1
Temperature: 40 °C
Reaction time: 16 h

Procedure:
General procedure for preparing compounds 42 and 43: A mixture of compound 6 (100 mg, 0.26 mmol), compound La or Lb (0.3 mmol) and K2CO3 (200 mg) in DMF (1 mL) was shaken at 40° C. for 16 hours. After cooling to room temperature, the reaction mixture was quenched with water, extracted with CHCl3, concentrated and purified by column (silica gel, EtOAc/hexanes 1/1) to give the desired product as a free base. The free base was converted to its HCl-salt by treating with HCl (1 N aqueous) and drying under vacuum.
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:23]=[CH:22][S:21][C:5]=3[C:6](=[O:20])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][Si](C(C)(C)C)(C)C.CC1(C)C(C)(C)OB([C:32]2[CH2:37][CH2:36][CH:35]([NH:38][C:39](=O)OC(C)(C)C)CC=2)O1>>[OH:12][C:11]1[CH:10]=[CH:9][C:8]2[NH:7][C:6](=[O:20])[C:5]3[S:21][CH:22]=[CH:23][C:4]=3[C:3]=2[C:2]=1[C:37]1[CH2:32][CH2:39][NH:38][CH2:35][CH:36]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2[nH]c(=O)c3sccc3c2c1Br
Reactant: CC(C)(C)OC(=O)NC1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Product: O=c1[nH]c2ccc(O)c(C3=CCNCC3)c2c2ccsc12
Yield: 234.6 %

Procedure:
Following General Procedure B, 9-bromo-8-(tert-butyldimethylsilyloxy)thieno[2,3-c]quinolin-4(5H)-one (80 mg, 0.20 mmol) was reacted with tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-enylcarbamate (90 mg, 0.29 mmol) to afford the desired product (140 mg, 23%) as an off-white solid: 1H NMR (500 MHz, CD3OD) δ 8.01-7.98 (m, 2H), 7.35 (d, J=8.9 Hz, 1H), 7.12 (d, J=8.9 Hz, 1H), 5.80 (s, 1H), 4.01-3.91 (m, 2H), 3.63-3.60 (m, 2H), 2.88-2.84 (m, 1H), 2.57-2.53 (m, 1H); ESI MS m/z 299 [C16H14N2O2S+H]+; HPLC >99% (AUC), tR=6.70 min.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])[CH:4]=[N:3]1.S(=O)(=O)(O)O.[OH-].[Na+].[CH3:19]O>>[CH3:1][N:2]1[CH:6]=[C:5]([CH:7]=[CH:8][C:9]([O:11][CH3:19])=[O:10])[CH:4]=[N:3]1
Reactant: CO
Reactant: Cn1cc(C=CC(=O)O)cn1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)C=Cc1cnn(C)c1

Procedure:
3-(1-Methylpyrazol-4-yl)acrylic acid (86.8 g) was added to a solution of sulphuric acid (20 ml) in methanol (690 ml), and the mixture refluxed for 2.5 hours, cooled, then poured onto ice. The acid was neutralised with aqueous sodium hydroxide and the product extracted into dichloromethane, which was dried and evaporated. Crystallisation from ether/petrol gave methyl 3-(1-methylpyrazol-4-yl)acrylate (89.0 g). 1H-NMR (d6-DMSO) δ 3.77 (3H,s), 3.91 (3H,s), 6.16 (1H,d), 7.54 (1H,s), 7.56 (1H,d), 7.69 (1H,s). (APCI) found (M+H)=167. C8H10N2O2 requires 166.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([N+:9]([O-])=O)=[CH:7][C:6]([CH3:12])=[C:5]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][C:14]=2[O:24][CH3:25])[N:4]=1)[CH3:2]>C(O)C.[Pd]>[CH2:1]([C:3]1[C:8]([NH2:9])=[CH:7][C:6]([CH3:12])=[C:5]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]([F:22])([F:23])[F:21])=[CH:15][C:14]=2[O:24][CH3:25])[N:4]=1)[CH3:2]
Reactant: CCc1nc(-c2ccc(OC(F)(F)F)cc2OC)c(C)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CCc1nc(-c2ccc(OC(F)(F)F)cc2OC)c(C)cc1N
Reaction time: 4 h

Procedure:
10% Pd/C (0.1 g) is added to a solution of 2-ethyl-6-(2-methoxy-4-trifluoromethoxy-phenyl)-5-methyl-3-nitro-pyridine (0.3 g, 0.84 mmol) in ethanol (10 mL). The mixture is hydrogenated at a pressure of 50 psi for 4 hours. The mixture is filtered through celite and evaporated to dryness under reduced pressure to give 2-ethyl-6-(2-methoxy-4-trifluoromethoxy-phenyl)-5-methyl-pyridin-3-ylamine as a yellow solid which is used without further purification TLC Rf 0.30 (elution with 5% methanol-methylene chloride).
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH3:9][O:10][CH2:11][CH2:12][NH2:13].I[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(O)CO>[Cu]I.CCCCCC.C(OCC)(=O)C.CC(O)C>[CH3:9][O:10][CH2:11][CH2:12][NH:13][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Ic1ccccc1
Reactant: COCCN
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CC(C)O
Solvent: OCCO
Product: COCCNc1ccccc1
Yield: 91.3 %

Procedure:
The general procedure under argon or air was followed using copper(I) iodide (10 mg, 0.05 mmol or 2.0 mg, 0.01 mmol), K3PO4 (425 mg, 2.00 mmol), 2-methoxyethylamine (104 μL, 1.20 mmol), iodobenzene (112 μL, 1.00 mmol), ethylene glycol (111 μL, 2.00 mmol) and 2-propanol (1.0 mL). Column chromatography using a solvent mixture (hexane/ethyl acetate=10/1, Rf=0.2) afforded N-(2-methoxyethyl)aniline (138 mg, 91% isolated yield) as colorless liquid. The spectral data (1H NMR) matched with the literature references and GC analysis indicated >95% purity. See Fancher, L. W.; Gless, R. D., Jr.; Wong, R. Y. Tetrahedron Lett. 1988, 29, 5095–5098.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][C:14]([CH3:17])([CH3:16])[C:13](=[O:18])[C:12]=2I)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH2:20]1[O:28][C:27]2[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][C:22]=2[O:21]1>>[NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][C:14]([CH3:17])([CH3:16])[C:13](=[O:18])[C:12]=2[C:25]2[CH:24]=[CH:23][C:22]3[O:21][CH2:20][O:28][C:27]=3[CH:26]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: OB(O)c1ccc2c(c1)OCO2
Reactant: CC1(C)OC(c2ccc(S(N)(=O)=O)cc2)=C(I)C1=O
Product: CC1(C)OC(c2ccc(S(N)(=O)=O)cc2)=C(c2ccc3c(c2)OCO3)C1=O
Yield: 33.8 %

Procedure:
120 mg of 5-{4-(aminosulfonyl)phenyl}-2,2-dimethyl-4-iodo-3(2H)-furanone was reacted with 100 mg of 3,4-(methylenedioxy)benzeneboronic acid by following a procedure similar to Step 4 of Example 22 to yield 40 mg of 5-{4-(aminosulfonyl)phenyl}-2,2-dimethyl-4-{3,4-(methylenedioxy)phenyl}-3(2H)-furanone as a solid. mp: 178-179° C. NMR: δ1.56 (s, 6H), 4.89 (br s, 2H), 5.99 (s, 2H), 6.74 (m, 2H), 6.83 (m, 1H), 7.82 (d, J=9.0 Hz, 2H), 7.92 (d, J=9.0 Hz, 2H). IR (cm−1): 3237, 1682, 1338, 1245, 1164.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])[N:5]=[C:4]([N:13]2C(C)=CC=C2C)[CH:3]=1.Cl.NO.[OH-].[K+]>C(O)C.O>[NH2:13][C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])[N:5]=1
Reactant: Cc1cc(CCC(C)C)nc(-n2c(C)ccc2C)c1
Agent: Cl
Agent: NO
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Cc1cc(N)nc(CCC(C)C)c1

Procedure:
By analogy to Example 56, Step B, 4-methyl-6-(3-methylbutyl)-2-(2,5-dimethylpyrrol-1-yl)pyridine was treated with 4.6 equivalents of hydroxylamine hydrochloride and 2.8 equivalents of potassium hydroxide in refluxing ethanol/water to yield 2-amino-4-methyl-6-(3-methylbutyl)pyridine as an amber oil.