Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1/[CH:6]=[C:7]1\[C:8](=[O:16])[NH:9][C:10]2[C:15]\1=[CH:14][CH:13]=[CH:12][CH:11]=2.[CH2:17]=O.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>O1CCOCC1.CCO>[N:19]1([CH2:17][N:9]2[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:7](=[CH:6][C:2]3[NH:1][CH:5]=[CH:4][CH:3]=3)[C:8]2=[O:16])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1
Reactant: C=O
Reactant: O=C1Nc2ccccc2/C1=C/c1ccc[nH]1
Reactant: C1COCCN1
Solvent: CCO
Solvent: C1COCCO1
Product: O=C1C(=Cc2ccc[nH]2)c2ccccc2N1CN1CCOCC1
Temperature: 25 °C
Yield: 49.9 %

Procedure:
A mixture of Z-(1H-Pyrrol-2-ylmethylene)-1,3-dihydro-indol-2-one (120 mg, 0.57 mmol), paraformaldehyde (32 mg, 1.1 mmol), and morpholine (62.2 μL, 0.71 mmol) in 8.0 mL of 20% dioxane in EtOH was heated at reflux for 19.5 h. The reaction mixture was concentrated and paraformaldehyde (10.0 mg, 0.33 mmol), morpholine (15 μL, 0.17 mmol) and EtOH (7 mL) was added. The reaction mixture refluxed for 24 h. The reaction mixture was cooled to room temperature and concentrated. The residue was dissolved in 15 mL of CHCl3 and treated with activated charcoal. The resulting suspension was filtered and the filtrate concentrated. The residue was crystallization from ethyl acetate/hexane to give the title compound (88.0 mg, 50%) as a bright yellow solid.
Reaction SMILES: [OH:1][C:2]([CH3:12])([CH3:11])[CH2:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.[Br:13]N1C(=O)CCC1=O.O>CN(C=O)C>[Br:13][C:9]1[CH:8]=[CH:7][C:6]([OH:10])=[CH:5][C:4]=1[CH2:3][C:2]([OH:1])([CH3:12])[CH3:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(O)Cc1cccc(O)c1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(O)Cc1cc(O)ccc1Br
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Alcohol 29 (12.3 g, 74.2 mmol) is dissolved in dry DMF and cooled to 0° C. under N2. Solid N-bromosuccinimide (NBS, 14.77 g, 83.0 mmol) is added in small portions (the yellow color is allowed to dissipate between additions) over 1.5 h. After the addition is complete, stirring at 0° C. is continued for 30 min. The mixture is then poured into water and extracted with EtOAc (3×). The organic phase is washed with water (1×) and brine (1×), dried (MgSO4), filtered, and evaporated. The residue is dissolved in EtOAc/CH2Cl2 and diluted with hexane to afford 30 as white crystals, mp 139-141° C. (12.7 g, 70%). Concentration of the mother liquor gives two more crops (1.2 and 1.0 g) of crystals, bringing the total to 14.9 g (82%). 1H NMR (acetone-d6, 2.05 ppm) 8.43 (S,1), 7.34 (d, 1, J=8.7), 7.01 (d, 1, J=2.7), 6.64 (dd, 1, J=8.7, 2.8), 2.89 (s,2), 1.21 (s,6); 13C NMR (acetone-d6, 20.83 ppm) 147.90, 130.98, 124.56, 111.34, 107.05, 106.19, 62.35, 39.59, 20.76; MS (EI, eE=70 eV) m/z 246/244 (M+), 231/229, 201, 188/186, 163, 150, 131, 108, 107, 91, 77, 63, 59 (base peak), 51, 43; Anal. Calcd for C10H13BrO2 (MW=245.1) : C,49.00 H,5.35. Found: C,49.03 H,5.20.
Reaction SMILES: [CH:1]1[C:6]2[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH2:9][CH2:10][CH2:11][C:5]=2[C:4]([CH2:16][NH2:17])=[CH:3][CH:2]=1.[Cl:18][C:19]([C:29]([F:32])([F:31])[F:30])=[CH:20][C@@H:21]1[C@H:23]([C:24](Cl)=[O:25])[C:22]1([CH3:28])[CH3:27].N1C=CC=CC=1.O>C1C=CC=CC=1>[CH:1]1[C:6]2[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH2:9][CH2:10][CH2:11][C:5]=2[C:4]([CH2:16][NH:17][C:24]([C@H:23]2[C@@H:21]([CH:20]=[C:19]([Cl:18])[C:29]([F:32])([F:30])[F:31])[C:22]2([CH3:28])[CH3:27])=[O:25])=[CH:3][CH:2]=1
Reactant: NCc1cccc2c1CCCc1ccccc1-2
Reactant: CC1(C)[C@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)Cl
Solvent: O
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CC1(C)[C@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)NCc1cccc2c1CCCc1ccccc1-2
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.3 %

Procedure:
A solution containing 6,7-dihydro-5H-dibenzo[a,c]cyclohepten-4-methanamine (0.5 gram, 0.0022 mole) and benzene (40 ml) was added dropwise to a stirred solution of cis-3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarboxylic acid chloride (0.75 gram, 0.0029 mole) and pyridine (1.0 gram, 0.013 mole) in benzene (20 ml). The resulting mixture was stirred at room temperature for approximately 16 hours, poured into water and the total extracted with three 100 ml portions of diethyl ether. The combined extracts were washed with a 10% aqueous sodium carbonate solution (100 ml) followed by two 50 ml portions of water. The washed extracts were dried over anhydrous magnesium sulfate, and filtered. The solvent was evaporated from the filtrate under reduced pressure leaving a yellow residue. This residue was purified by column chromatography on silica gel, elution with benzene:diethyl ether (3:1), to yield N-(6,7-dihydro-5H-dibenzo[a,c]cyclohepten-4-yl)methyl cis-3-(2-chloro-3,3,3-trifluoropropenyl)-2,2-dimethylcyclopropanecarboxamide as a colorless solid (0.85 gram, mp 65°-70°).
Reaction SMILES: [CH2:1]([CH:3]([CH2:13][CH3:14])[CH2:4][C:5]1([C:11]#N)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[CH3:2].[OH-:15].[Na+].C([OH:21])(C)(C)C>>[CH2:1]([CH:3]([CH2:13][CH3:14])[CH2:4][C:5]1([C:11]([OH:21])=[O:15])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[CH3:2]
Reactant: CC(C)(C)O
Reactant: [OH-]
Reactant: CCC(CC)CC1(C#N)CCCCC1
Agent: [Na+]
Product: CCC(CC)CC1(C(=O)O)CCCCC1
Temperature: 280 °C

Procedure:
A stream of 1-(2-ethyl-butyl)-cyclohexanecarbonitrile (0.5 g, 2.59 mmol) in tert-butanol (12.5 mL, 0.2 M, flow=0.18 mL/min; Knauer WellChrom HPLC K-501 pump) was combined with a second stream containing aqueous sodium hydroxide solution (2.0 M, 50 mL, flow=0.70 mL/min; Knauer WellChrom HPLC K-501 pump) using a custom made static micromixer (internal volume ca. 0.1 mL). The resulting mixture was directed through a stainless steel coil reactor (volume=53 mL, ID=2.1 mm; Supelco 304 stainless steel; nominal residence time of 1 h, which doesn't take the volume expansion of the solvent mixture into account) equipped with a total back pressure valve of 2500 psi and heated to 280° C. by means of a HP 6890 Series GC Oven System.
Reaction SMILES: [O-:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].C1(O)C=CC=CC=1.[H-].[Na+].F[C:19]1[CH:26]=[CH:25][CH:24]=[C:23]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:20]=1[C:21]#[N:22]>O1CCCC1.CS(C)=O>[O:1]([C:19]1[CH:26]=[CH:25][CH:24]=[C:23]([NH:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:20]=1[C:21]#[N:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1c(F)cccc1Nc1ccccc1
Reactant: [O-]c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: Oc1ccccc1
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: N#Cc1c(Nc2ccccc2)cccc1Oc1ccccc1
Temperature: 110 °C
Reaction time: 4 h

Procedure:
Sodium phenoxide was generated by dissolving phenol (0.36 g, 3.83 mmol) in dry tetrahydrofuran (5 mL), and adding sodium hydride (0.087 g, 3.6 mmol). After gas evolution ceased, the solvent was evaporated and 2-fluoro-6-(phenylamino)benzonitrile (0.6 g, 2.83 mmol) dissolved in dimethyl sulfoxide (10 mL) was added. The mixture was heated to 110° C. while stirring under argon for 4 hours. The solvent was evaporated in vacuo, and the residue was partitioned between ethyl acetate and water. The organic phase was washed with water (5×), brine (1×) dried over anhydrous Na2SO4 filtered, and evaporated to give the crude product which was then chromatographed on silica gel eluted with 10–40% CH2Cl2 in hexane to give the title compound as a white amorphous solid. mp 146–147° C.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:18]=[CH:17][C:16]2[NH:15][C:14](=[O:19])[C:13]3[NH:20][CH:21]=[CH:22][C:12]=3[C:11]=2[CH:10]=1.Cl.[CH2:24]([C:26]([OH:28])=[O:27])[CH3:25].[F:29][C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1>CN(C)C=O>[F:29][C:30]1[CH:35]=[CH:34][C:33]([S:36]([NH:8][C:9]2[CH:18]=[CH:17][C:16]3[NH:15][C:14](=[O:19])[C:13]4[NH:20][CH:21]=[CH:22][C:12]=4[C:11]=3[CH:10]=2)(=[O:38])=[O:37])=[CH:32][CH:31]=1.[CH2:24]([C:26]([O-:28])=[O:27])[CH3:25]
Reactant: Nc1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: CCC(=O)O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC(=O)[O-]
Product: O=c1[nH]c2ccc(NS(=O)(=O)c3ccc(F)cc3)cc2c2cc[nH]c12
Temperature: 0 °C
Reaction time: 1 h
Yield: 37.2 %

Procedure:
82 μL (0.59 mmol) of triethylamine is added to 60 mg (0.20 mmol) of 8-amino-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate hydrochloride (synthesis 64) suspended in anhydrous dimethylformamide (1 mL). The mixture is cooled to 0° C., then 42 mg (0.21 mmol) of 4-fluoro-benzenesulfonyl chloride is added. The solution is stirred for 1 h at 0° C. The solvent is evaporated and the raw product obtained is purified by recrystallization from methanol to give 32 mg (38%) of 8-(4-fluoro-benzenesulfonylamino)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in the form of a light brown solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(=O)CC>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Reactant: CCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCCCCCCCOc1ccc(-c2ccc(C#N)cc2)cc1

Procedure:
A mixture of 4-cyano-4'-hydroxybiphenyl (56) (10.10 g, 0.052 mol), 1-bromodecane (14.38 g, 0.065 mol), anhydrous potassium carbonate (37.32 g, 0.27 mol), butanone (300 ml) and a trace of potassium iodide was heated under reflux overnight. The cooled solution was filtered to remove inorganic salts and the solvent was removed in vacuo. The residual oil was distilled (to remove excess bromide) and finally purified by column chromatography (dichloromethane) to yield a colourless, low melting solid.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[CH2:38]([O:40][C:41]([N:43]1[CH2:48][CH2:47][CH:46]([NH2:49])[CH2:45][CH2:44]1)=[O:42])[CH3:39]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:38]([O:40][C:41]([N:43]1[CH2:44][CH2:45][CH:46]([NH:49][C:7](=[O:9])[C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[O:4][C:3]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:2]=2[Cl:1])[CH2:47][CH2:48]1)=[O:42])[CH3:39]
Reactant: O=C(O)c1ccccc1Oc1ccc(Cl)cc1Cl
Reactant: CCOC(=O)N1CCC(N)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)N1CCC(NC(=O)c2ccccc2Oc2ccc(Cl)cc2Cl)CC1
Reaction time: 0.5 h
Yield: 45.3 %

Procedure:
AMR01059 A solution of 2-(2,4-dichlorophenoxy)benzoic acid (AMR01057, 200 mg, 0.706 mmol) in dry DCM (10 mL) was stirred under nitrogen, and 4-dimethylaminopyridine (DMPA, 40 mg, 0.327 mmol), (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 406 mg, 2.12 mmol) and triethylamine (0.15 mL) were added. The resulting mixture was stirred for 30 min under nitrogen and ethyl-4-amino-1-piperidine carboxylate (122 mg, 0.706 mmol) in dry DCM (4 mL) was added. After stirring at room temperature for 12 h, the mixture was diluted with DCM, washed with HCl 1M (3×25 mL), water, saturated NaHCO3 (2×25 mL) and brine. The organic layer was dried (MgSO4), filtered and evaporated. Flash chromatography on silica gel using DCM to DCM/MeOH 9:1 gradient as eluent gave 4-[2-(2,4-dichlorophenoxy)benzoylamino]piperidine-1-carboxylic acid ethyl ester (140 mg, 45%) as a white solid. Rf: 0.62 (DCM/MeOH 9:1) 1H NMR (300 MHz, CDCl3) 11.26 (3H, t, J=7.1 Hz, CH3), 1.40 (2H, m, CH2), 1.97 (2H, m, CH2), 3.00 (2H, m, CH2), 4.03 (2H, m, CH2), 4.13 (2H, q, J=7.1 Hz, CH3CH2O), 4.19 (1H, m, CH), 6.80 (1H, dd, J=8.2, 0.9 Hz, ArH), 6.90 (1H, d, J=8.8 Hz, ArH), 7.24 (1H, dd, J=8.8, 2.5 Hz, ArH), 7.27 (1H, m, ArH), 7.36 (1H, br s, NH), 7.42 (1H, m, ArH), 7.53 (1H, d, J=2.5 Hz, ArH) and 8.19 (1H, dd, J=7.8, 1.8 Hz, ArH).
Reaction SMILES: [CH:1]1([CH:6]=[CH:7][C:8]#[N:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1CCN2C(=NCCC2)CC1.[C:21]([O:27][CH2:28][N:29]1[C:33]2[N:34]=[CH:35][N:36]=[C:37]([C:38]3[CH:39]=[N:40][NH:41][CH:42]=3)[C:32]=2[CH:31]=[CH:30]1)(=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23]>C(#N)C>[C:21]([O:27][CH2:28][N:29]1[C:33]2[N:34]=[CH:35][N:36]=[C:37]([C:38]3[CH:39]=[N:40][N:41]([CH:6]([CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[CH2:7][C:8]#[N:9])[CH:42]=3)[C:32]=2[CH:31]=[CH:30]1)(=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23]
Reactant: N#CC=CC1CCCC1
Reactant: CC(C)(C)C(=O)OCn1ccc2c(-c3cn[nH]c3)ncnc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC(C)(C)C(=O)OCn1ccc2c(-c3cnn(C(CC#N)C4CCCC4)c3)ncnc21
Temperature: 55 °C
Yield: 30.9 %

Procedure:
Method A. 3-Cyclopentylacrylonitrile (8, 14.6 g, 0.12 mol, 1.20 equiv) and DBU (18.2 mL, 0.12 mol, 1.2 equiv) was added to a suspension of 4-(1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7yl]methyl pivalate (19, 30.0 g, 0.1 mol) in acetonitrile (45 mL) at room temperature. The resulting reaction mixture was heated to 50-60° C. for 17 hours (a clear solution developed midway through heating) then to room temperature for 8 hours. When LCMS analysis showed the reaction was deemed complete, the reaction mixture was concentrated under reduced pressure and the residue was dissolved in 2 L of ethyl acetate. The resulting solution was washed with water (3×200 mL), dried over sodium sulfate (Na2SO4) and concentrated under reduced pressure to give the crude product (20) as a thick oil. The crude product was then purified by flash chromatography (SiO2, 0-50% EtOAc/hexanes gradient elution) to afford racemic (4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (20, 13.0 g, 42.14 g theoretical, 30.8% yield) as a white solid. For 20: 1H NMR (DMSO-d6, 400 MHz) δ ppm 8.84 (s, 1H), 8.78 (s, 1H), 8.39 (s, 1H), 7.74 (d, 1H, J=3.7 Hz,), 7.11 (d, 1H, J=3.8 Hz), 6.23 (s, 2H), 4.53 (ddd, 1H, J=9.9, 9.6, 4.2 Hz), 3.26 (dd, 1H, J=17.4, 9.9 Hz), 3.19 (dd, 1H, J=17.2, 4.3 Hz), 2.41 (m, 1H), 1.87-1.13 (m, 8H), 1.07 (s, 9H); C23H28N6O2 (MW, 420.51), LCMS (EI) m/e 421.4 (M++H).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([NH:21][C:22]2[CH:27]=[C:26]([CH3:28])[C:25]([N+:29]([O-:31])=[O:30])=[CH:24][N:23]=2)[CH2:17][CH2:16]1)=O)(C)(C)C.[ClH:32]>ClCCl.O1CCOCC1>[ClH:32].[CH3:28][C:26]1[C:25]([N+:29]([O-:31])=[O:30])=[CH:24][N:23]=[C:22]([NH:21][CH:18]2[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]2)[CH:27]=1.[ClH:32]
Reactant: Cc1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)ncc1[N+](=O)[O-]
Agent: Cl
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(NC2CCNCC2)ncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Trifluoroacetic acid (1 mL) is added to a solution of 4-(4-methyl-5-nitro-pyridin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (170 mg; 0.51 mmol, prepared in accordance with Example 69) in dichloromethane (5 mL) under stiffing and the resulting mixture is stirred for 30 minutes at room temperature. The mixture is then concentrated under reduced pressure and co-evaporated with dichloromethane (2×10 mL). The residue obtained is diluted in dioxane (3 mL) and a 4N solution of hydrochloric acid in dioxane (3 mL) is added. The precipitate formed is filtered and is triturated with a small volume of acetone and dried under high vacuum to afford the desired product as hydrochloride (120 mg; 0.44 mmol).
Reaction SMILES: [CH2:1]([N:7]1[C:15]2[C:14](=[O:16])[NH:13][C:12](=[O:17])[N:11]([CH3:18])[C:10]=2[N:9]=[CH:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Cl:19][C:20]1[CH:33]=[CH:32][C:23]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]Br)=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:33]=[CH:32][C:23]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][N:13]2[C:14](=[O:16])[C:15]3[N:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH:8]=[N:9][C:10]=3[N:11]([CH3:18])[C:12]2=[O:17])=[CH:22][CH:21]=1
Reactant: Clc1ccc(OCCCCCCBr)cc1
Reactant: CCCCCCn1cnc2c1c(=O)[nH]c(=O)n2C
Product: CCCCCCn1cnc2c1c(=O)n(CCCCCCOc1ccc(Cl)cc1)c(=O)n2C
Yield: 84 %

Procedure:
7-Hexyl-3-methylxanthine and 6-(4-chlorophenoxy)hexyl bromide were reacted and treated in substantially the same manner as described in Example 9(a) to give 1-[6-(4-chlorophenoxy)hexyl]-7-hexyl-3-methylxanthine (84%) as an oil.
Reaction SMILES: COC[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:17]([O:18][C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][N:27]=4)=[CH:21][CH:20]=3)=[N:16][CH:15]=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5].C(N(C(C)C)CC)(C)C.Cl[C:43](OC)=[O:44]>C(Cl)Cl>[CH3:32][C:29]1[CH:30]=[CH:31][C:26]([NH:25][C:22]2[CH:23]=[CH:24][C:19]([O:18][C:17]3[C:12]([CH:9]4[CH2:10][CH2:11][N:6]([C:4]([O:44][CH3:43])=[O:5])[CH2:7][CH2:8]4)=[N:13][CH:14]=[CH:15][N:16]=3)=[CH:20][CH:21]=2)=[N:27][CH:28]=1
Reactant: COCC(=O)N1CCC(c2nccnc2Oc2ccc(Nc3ccc(C)cn3)cc2)CC1
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N1CCC(c2nccnc2Oc2ccc(Nc3ccc(C)cn3)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred mixture of 5-methyl-N-(4-(3-(piperidin-4-yl)pyrazin-2-yloxy)phenyl)pyridin-2-amine (0.278 g, 0.548 mmol) (See step 3, Example 282), and diisopropylethylamine (0.502 mL, 2.88 mmol) in DCM (5 mL) was added methyl chloroformate (0.051 mL, 0.658 mmol). The reaction mixture was stirred at RT for 2 h. The reaction mixture was purified by ISCO column (40% EtOAc/Hexanes) to give the title compound. MS (ESI, pos. ion) m/z: 420.2 (M+1). IC50 (uM) 0.000107.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:12][CH3:13])=[C:9]([NH2:11])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C[O:15][C:16](=O)[C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([N:24]2[CH:28]=[C:27]([C:29]3[CH:30]=[N:31][N:32]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:33]=3[CH2:34][CH3:35])[N:26]=[CH:25]2)[CH:18]=1>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:12][CH3:13])=[C:9]([NH:11][C:16](=[O:15])[C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([N:24]3[CH:28]=[C:27]([C:29]4[CH:30]=[N:31][N:32]([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)[C:33]=4[CH2:34][CH3:35])[N:26]=[CH:25]3)[CH:18]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCc1c(-c2cn(-c3cc(C(=O)OC)ccc3C)cn2)cnn1-c1ccccc1
Reactant: COc1ccc(C(C)(C)C)cc1N
Product: CCc1c(-c2cn(-c3cc(C(=O)Nc4cc(C(C)(C)C)ccc4OC)ccc3C)cn2)cnn1-c1ccccc1

Procedure:
Example 153 was prepared from 5-tert-butyl-2-methoxy-phenylamine and 3-[4-(5-ethyl-1-phenyl-1H-pyrazol-4-yl)-imidazol-1-yl]-4-methyl-benzoic acid methyl ester (Example 151) in the same manner as Example 151. ESI MS m/z 534 [C33H35N5O2+H]+.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)C.C(O)C.O.[NH2:17][NH2:18]>O>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([C:4]([NH:17][NH2:18])=[O:3])=[CH:6][CH:7]=1
Reactant: NN
Reactant: CCOC(=O)c1ccc(Br)cc1
Solvent: O
Solvent: CCO
Product: NNC(=O)c1ccc(Br)cc1
Temperature: 78 °C
Yield: 96 %

Procedure:
Into a 200 mL three-neck flask was put 25 g (0.19 mol) of ethyl-4-bromobenzoate, 50 mL of ethanol was added thereto, and the mixture was stirred. After that, 20 mL of hydrazine monohydrate was added to the mixture, and then the mixture was stirred while being heated at 78° C. for 5 hours to be reacted. After the reaction, water was added to the reaction mixture, and a precipitated solid was collected by suction filtration. The obtained solid was washed with water and collected by suction filtration, whereby 24 g of a white solid of 4-bromobenzoylhydrazine, which was the object of the synthesis, was obtained in a yield of 96% (synthesis scheme (a-1)).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]([CH2:54][C:55](=[O:63])[NH:56][CH2:57][C:58](=[O:62])[O:59]CC)[CH2:12][CH2:13][NH:14][C:15](=[O:53])[CH2:16][N:17]2[CH2:28][CH2:27][N:26]([CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25][CH2:24][N:23]([CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:22][CH2:21][N:20]([CH2:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:19][CH2:18]2)=[O:10])=[CH:4][CH:3]=1.O[Li].O.CCO>O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([N:11]([CH2:54][C:55]([NH:56][CH2:57][C:58]([OH:62])=[O:59])=[O:63])[CH2:12][CH2:13][NH:14][C:15](=[O:53])[CH2:16][N:17]2[CH2:28][CH2:27][N:26]([CH2:29][C:30](=[O:31])[O:32][C:33]([CH3:35])([CH3:36])[CH3:34])[CH2:25][CH2:24][N:23]([CH2:37][C:38](=[O:39])[O:40][C:41]([CH3:42])([CH3:43])[CH3:44])[CH2:22][CH2:21][N:20]([CH2:45][C:46]([O:48][C:49]([CH3:50])([CH3:51])[CH3:52])=[O:47])[CH2:19][CH2:18]2)=[O:10])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CNC(=O)CN(CCNC(=O)CN1CCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CC1)C(=O)Cc1ccc(O)cc1
Agent: [Li]O
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)CN1CCN(CC(=O)NCCN(CC(=O)NCC(=O)O)C(=O)Cc2ccc(O)cc2)CCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a 50-mL round bottom flask loaded with tri-tert-butyl 2,2′,2″-(10-(6-(2-(4-hydroxyphenyl)acetyl)-2,8,11-trioxo-12-oxa-3,6,9-triazatetradecyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate 2 (0.260 g, 0.291 mmol) was added LiOH.H2O (0.018 g, 0.437 mmol, 1.5 eq.), 6 mL of EtOH, and 2 mL of H2O. The reaction was stirred at room temperature for 12 hours. After solvent removal in vacuo, purification was achieved by preparative reverse-phase HPLC (gradient from 100% 0.1% formic acid in water to 50% 0.1% formic acid in water/50% CH3CN) to give 3. 65.5% 1H-NMR (300 MHz, CDCl3) δ 8.66 (m, 1H), 8.07 (m, 1H), 7.02 (m, 2H), 6.29 (m, 2H), 6.34 (br s, 1H), 4.20-2.80 (m, 34H), 1.44 (s, 27H); 13C-NMR (75 MHz, CDCl3) δ 174.51, 174.14, 173.70, 173.45, 172.43, 169.80, 167.18, 156.59, 156.45, 130.43, 130.02, 125.93, 116.08, 115.89, 81.89, 81.85, 81.75, 56.42, 55.62, 52.76, 52.32, 51.61, 50.52, 49.67, 49.31, 49.25, 49.12, 47.69, 47.52, 43.54, 43.21, 40.37, 39.38, 38.07, 28.14.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[NH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH:33]1[C:38]([NH2:40])=[O:39]>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:35]5[CH2:36][CH2:37][NH:32][CH:33]([C:38]([NH2:40])=[O:39])[CH2:34]5)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1
Reactant: NC(=O)C1CNCCN1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: NC(=O)C1CN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)CCN1

Procedure:
4-[5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]piperazine-2-carboxamide was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and piperazine-2-carboxylic acid amide following General Procedure C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=O)[O:10]C)=[CH:4][CH:3]=1.[Cl:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[Cl:21])[NH2:17].CN(CCCCCCCCCCCC)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:17][C:16]2[CH:18]=[CH:19][C:20]([Cl:21])=[C:14]([Cl:13])[CH:15]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: COC(=O)Nc1ccc(Cl)cc1
Reactant: Nc1ccc(Cl)c(Cl)c1
Agent: CCCCCCCCCCCCN(C)C
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(Cl)cc1)Nc1ccc(Cl)c(Cl)c1

Procedure:
A mixture of 4.61 g (25 mmoles) of methyl N-(4-chlorophenyl)-carbamate, 4.07 g (25 mmoles) of 3,4-dichloroaniline, 100 ml of toluene and 4.7 g (25 mmoles) of N,N-dimethyl-dodecylamine is reacted for 20 hours as described in Example 8, and then the mixture is allowed to cool. 4.60 g (58.4%) of N-(4-chlorophenyl)-N'-(3,4-dichlorophenyl)-urea separate from the mixture as a crystalline substance.