Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH:10]1[CH2:15][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH2:13][N:12]([C:26]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[O:27])[CH2:11]1.[C:34](Cl)(=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36]>CN(C1C=CN=CC=1)C.ClCCl>[CH3:36][C:35]([CH3:38])([CH3:37])[C:34]([NH:9][CH:10]1[CH2:15][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:18][CH:17]=2)[CH2:13][N:12]([C:26]([N:28]2[CH2:29][CH2:30][O:31][CH2:32][CH2:33]2)=[O:27])[CH2:11]1)=[O:39]
Reactant: NC1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Reactant: CC(C)(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)NC1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
212 μl of triethylamine (1.52 mmol) and 18.6 mg of DMAP (0.152 mmol) were added to a solution of the compound from Example 57A (200 mg, 0.508 mmol) in dichloromethane (12 ml), and 94 μl of pivaloyl chloride (0.76 mmol) were then added at 0° C. The reaction mixture was warmed to RT and stirred overnight. The reaction solution was washed with aqueous 1 N hydrochloric acid and the organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC (RP18 column; acetonitrile/water gradient). Yield: 154 mg (68% of theory)
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:6][N:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:9][N:8]=2)[C:4](=[O:21])[NH:3]1.[H-].[Na+].IC.[C:27]([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:27][N:3]1[C:2]([CH3:22])([CH3:1])[CH2:6][N:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:9][N:8]=2)[C:4]1=[O:21]
Reactant: O=C([O-])O
Reactant: CC1(C)CN(c2ccc(C#Cc3ccccc3)cn2)C(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN1C(=O)N(c2ccc(C#Cc3ccccc3)cn2)CC1(C)C
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
(110 mg, 378 μmol) 4,4-Dimethyl-1-(5-(phenylethynyl)pyridin-2-yl)imidazolidin-2-one (Example 15, step 3) was dissolved in DMF (0.5 ml) and cooled to 0-5° C. NaH (55%) (19.8 mg, 453 μmol, 1.2 equiv.) was added and the mixture was stirred for 30 min at 0-5° C. Iodomethane (35.3 μl, 566 μmol, 1.5 equiv.) was added and the mixture was stirred for 30 min at 0-5° C. The reaction mixture was treated with sat. NaHCO3 solution and extracted twice with a small volume of CH2Cl2. The organic layers were loaded directly to silica gel column and the crude material was purified by flash chromatography on silica gel (20 gr, ethyl acetate/heptane gradient, 0:100 to 100:0). The desired 3,4,4-trimethyl-1-(5-phenylethynyl-pyridin-2-yl)-imidazolidin-2-one (93 mg, 81% yield) was obtained as a yellow solid, MS: m/e=306.2 (M+H+).
Reaction SMILES: [N+:1](=[CH2:3])=[N-].[O:4]=[S:5]1(=[O:17])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]([CH2:15][Cl:16])N1>>[O:17]=[S:5]1(=[O:4])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]([CH2:15][Cl:16])[N:1]1[CH3:3]
Reactant: O=S1(=O)NC(CCl)=Nc2ccccc21
Reactant: C=[N+]=[N-]
Product: CN1C(CCl)=Nc2ccccc2S1(=O)=O

Procedure:
The title compound is prepared by diazomethane methylation of 1,1-dioxo-3-(chloromethyl)-2H-benzo[e][1,2,4]thiadiazine (CAS#37162-65-5, Enamine #EN300-62803) by the method published in Farmaco, Edicione Scientifica 1966, 21, 430-442 (see compound XVI).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[N:7]2[CH:8]=[CH:9][N:10]=[CH:11][C:6]2=[N:5][N:4]=1.[OH:14]O>C(O)(=O)C>[F:13][C:2]([F:12])([F:1])[C:3]1[N:7]2[CH:8]=[CH:9][N+:10]([O-:14])=[CH:11][C:6]2=[N:5][N:4]=1
Reactant: OO
Reactant: FC(F)(F)c1nnc2cnccn12
Solvent: CC(=O)O
Product: [O-][n+]1ccn2c(C(F)(F)F)nnc2c1
Temperature: 95 °C
Reaction time: 8 h

Procedure:
A mixture of 250 mg (1.33 mmol) of 3-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyrazine (Intermediate 6, Step A), 0.479 mL (4.66 mmol) of 30% hydrogen peroxide aqueous solution, and 2 mL of glacial acetic acid was stirred at 95° C. After 8 h, the solution was cooled and concentrated. The residue was partitioned between dichloromethane and saturated sodium bicarbonate aqueous solution. Thin-layer chromatography on silica gel (90:10:1 dichloromethane:methanol:concentrated ammonium hydroxide solution) revealed that the product was in the aqueous phase. Therefore, the aqueous solution was concentrated to dryness, and the residue was purified by preparative HPLC (C18 reverse phase column, 0-50% acetonitrile in water containing 0.05% trifluoroacetic acid) to provide the title compound as a white solid. LC-MS 205 (M+1).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH:22]=2)[C:17]([OH:32])=[C:16]([C:33](OCC)=[O:34])[C:15]1=[O:38].[NH2:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][OH:45]>CCO>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[CH:22]=2)[C:17]([OH:32])=[C:16]([C:33]([NH:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][OH:45])=[O:34])[C:15]1=[O:38]
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2C(=O)c3ccccc3C2=O)c1=O
Reactant: NCCOCCO
Solvent: CCO
Product: O=C(NCCOCCO)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2C(=O)c3ccccc3C2=O)c1=O
Temperature: 25 °C

Procedure:
A solution of ethyl 1-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (0.025 g, 0.049 mmol) in EtOH (1 mL) under nitrogen was treated with 2-[(2-aminoethyl)oxy]ethanol (0.0042 mL, 0.058 mmol) for 10 min.@150° C. in a microwave vessel. An additional 0.001 mL of the amine was added to the reaction and it was further microwaved for 20 min.@150° C. The reaction was then cooled to ambient temperature and the resulting suspension was filtered, washed with 1:1 water:EtOH and then thoroughly dried under high vacuum to provide the title compound as a white solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 3.35-3.44 (m, 6 H), 3.44-3.51 (m, 2 H), 3.90 (t, J=5.05 Hz, 2 H), 4.11 (s, 2 H), 4.50-4.62 (m, 3 H), 7.08-7.17 (m, 2 H), 7.30-7.38 (m, 2 H), 7.82 (s, 4 H), 8.14 (s, 1 H), 8.52 (s, 1 H), 10.02 (m, 1 H), 17.11 (s, 1 H); ES+ MS: 575 (M+H+).
Reaction SMILES: C([O:5][C:6](=[O:42])[C@@H:7]([NH:31][C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])[CH2:8][CH2:9][C:10]([N:12]1[CH2:17][CH2:16][CH:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:25]3[NH:26][CH2:27][CH2:28][CH2:29][N:30]=3)[CH:19]=2)[CH2:14][CH2:13]1)=[O:11])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:35]([O:34][C:32]([NH:31][C@@H:7]([CH2:8][CH2:9][C:10]([N:12]1[CH2:13][CH2:14][CH:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:25]3[NH:26][CH2:27][CH2:28][CH2:29][N:30]=3)[CH:19]=2)[CH2:16][CH2:17]1)=[O:11])[C:6]([OH:42])=[O:5])=[O:33])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CC(C)(C)OC(=O)[C@H](CCC(=O)N1CCC(c2cccc(NC3=NCCCN3)c2)CC1)NC(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(N[C@@H](CCC(=O)N1CCC(c2cccc(NC3=NCCCN3)c2)CC1)C(=O)O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the compound of Example 147 in dichloromethane (10 ml) is added trifluoroacetic acid (10 ml), and the mixture is stirred at 25° C. overnight. The solvent is evaporated under reduced pressure, and the residue is purified by CHP-20 (eluent: gradient, 35% to 100% methanol/0.05% aqueous trifluoroacetic acid solution) to give the title compound (200 mg).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([NH:10][C:11]2[CH:21]=[CH:20][C:14]([C:15]([O:17]CC)=[O:16])=[CH:13][CH:12]=2)=[O:9])[CH2:4][CH2:3]1.O[Li].O.C1COCC1.Cl>O>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([NH:10][C:11]2[CH:21]=[CH:20][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=2)=[O:9])[CH2:4][CH2:3]1
Reactant: CCOC(=O)c1ccc(NC(=O)N2CCN(C)CC2)cc1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CN1CCN(C(=O)Nc2ccc(C(=O)O)cc2)CC1
Yield: 78 %

Procedure:
A solution of 162 (1.39 g, 4.77 mmol) and LiOH.H2O (300 mg, 7.16 mmol) in 1:1 THF:water (8 ml) was stirred at room temperature for 24 h. 1 M HCl was added to reach pH=5 and the solvent was evaporated. The title compound was purified by preparative HPLC (Aquasil C18, reverse phase, eluent: MeOH/water) to give 979 mg (78%) of the title compound 163 as a white powder. 1H NMR: (400 MHz, DMSO) δ (ppm): 8.81 (s, 1H), 7.78 (dt, J=8.6, 1.8 Hz, 2H), 7.53 (dt, J=8.8, 2.0 Hz, 2H), 3.44 (t, J=4.9 Hz, 4H), 2.31 (t, J=5.0 Hz, 4H), 2.19 (s, 3H).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([N:7]=[N:8][C:9]2[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=2)=[CH:5][CH:6]=1.C(N(CC)CC)C.[C:23](Cl)(=[O:26])[CH2:24][CH3:25]>CCOCC>[C:4]1([N:7]=[N:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][C:23](=[O:26])[CH2:24][CH3:25])=[CH:13][CH:14]=2)[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1
Reactant: Oc1ccc(N=Nc2ccccc2)cc1
Reactant: CCC(=O)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCC(=O)Oc1ccc(N=Nc2ccccc2)cc1
Yield: 71.8 %

Procedure:
4-Phenylazophenol (0.25 g, 1.26 mmoles) was dissolved in ether (5-10 mL) and triethylamine (0.26 mL) was added. Then propanoyl chloride (0.14 g 1.5 mmoles) in ether (1 mL) was added dropwise at room temperature. The mixture was stirred and reaction was rapidly completed. The reaction mixture was washed with water, dilute acid and brine and dried with magnesium sulfate. The solvent was evaporated to give 0.23 g (72%) of product. 1H NMR (CDCl3) δ=1.16 (3H, t, J=7.7), 2.40 (2H, q J=7.7), 7.25 (2H, m), 7.40-7.58 (3H, m), 7.88-8.0 (4H, m) ppm.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([NH2:12])=[C:5]([C:7]([CH2:9][CH2:10][NH2:11])=[O:8])[CH:6]=1.[N+:13]([C:16]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:17]=1F)([O-:15])=[O:14].C([O-])(O)=O.[Na+]>C(O)C>[NH2:12][C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][C:5]=1[C:7]([CH:9]([C:17]1[CH:18]=[CH:19][C:20]([N+:22]([O-:24])=[O:23])=[CH:21][C:16]=1[N+:13]([O-:15])=[O:14])[CH2:10][NH2:11])=[O:8]
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Reactant: NCCC(=O)c1ccccc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: NCC(C(=O)c1ccccc1N)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reaction time: 0.08 h
Yield: 63 %

Procedure:
Kynuramine 2HBr (125 mg) is dissolved in 5 cc of absolute ethanol in a 50 cc flask. A solution of 2,4-dinitrofluorobenzene, 71 mg in EtOH 5 cc is then added (a clear yellow solution is formed). After five minutes, 2 cc of a 10% NaHCO3 solution are introduced drop-wise in the flask. The reaction is left at room temperature overnight. The following morning the formed light yellow precipitate is filtered, washed with water and ethanol and dried in UHV obtaining 80 mg of product (approx. yield 63%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:24])[C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[CH:17]=[N:18][C:19]([F:23])=[CH:20][C:21]=3[CH3:22])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[CH:25]1(B(O)O)[CH2:27][CH2:26]1>>[CH:25]1([C:2]2[CH:3]=[C:4]([CH3:24])[C:5]([N:8]3[CH2:13][CH2:12][N:11]([C:14]([C:16]4[CH:17]=[N:18][C:19]([F:23])=[CH:20][C:21]=4[CH3:22])=[O:15])[CH2:10][CH2:9]3)=[N:6][CH:7]=2)[CH2:27][CH2:26]1
Reactant: OB(O)C1CC1
Reactant: Cc1cc(F)ncc1C(=O)N1CCN(c2ncc(Br)cc2C)CC1
Product: Cc1cc(F)ncc1C(=O)N1CCN(c2ncc(C3CC3)cc2C)CC1
Yield: 120.5 %

Procedure:
Using [4-(5-bromo-3-methylpyridin-2-yl)piperazin-1-yl](6-fluoro-4-methylpyridin-3-yl)methanone (2.2 g) described in Preparation Example 139 and cyclopropylboronic acid (721 mg) and by the reaction and treatment in the same manner as in Preparation Example 100, the title compound (2.39 g) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([F:10])=[C:6]([CH2:8]O)[CH:7]=1.S(Cl)([Cl:14])=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl.CN1C(=O)CCC1>[Cl:14][CH2:8][C:6]1[CH:7]=[C:2]([CH:3]=[C:4]([F:11])[C:5]=1[F:10])[NH2:1]
Reactant: Nc1cc(F)c(F)c(CO)c1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: Nc1cc(F)c(F)c(CCl)c1
Reaction time: 2 h

Procedure:
To a stirring solution of (5-amino-2,3-difluorophenyl)methanol (4.13 g; 25.9 mmol) in DCM (78 mL) and NMP (11 mL) at RT was added dropwise thionylchloride (4.7 mL; 64.9 mmol). The mixture was allowed to react at RT overnight. Then, the mixture was poured into aqueous sodium bicarbonate solution/saturated aqueous sodium chloride solution/ice. The batch was stirred for 2 hours before it was extracted with ethyl acetate (2×). The combined organic phases were filtered using a Whatman filter and concentrated to give crude 3-(chloromethyl)-4,5-difluoroaniline.
Reaction SMILES: [Li]CCCC.[CH:6]1([S:9]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:11])=[O:10])[CH2:8][CH2:7]1.[CH3:20][O:21][CH2:22][CH2:23][O:24][CH2:25]Cl>C1COCC1>[CH3:20][O:21][CH2:22][CH2:23][O:24][CH2:25][C:6]1([S:9]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])(=[O:11])=[O:10])[CH2:7][CH2:8]1
Reactant: COCCOCCl
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)C1CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCCOCC1(S(=O)(=O)NC(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
BuLi 2.5 M in hexanes (7.53 ml) was added dropwise to the solution of tert-butyl (cyclopropylsulfonyl)carbamate (1.81 g) in THF (40 ml) at −78° C. This solution was stirred at −78° C. for 1 hour then 2-methoxyethoxymethyl chloride (1.85 ml) was added dropwise. The reaction was allowed to warm to room temperature and was stirred for 3 days. The solvent was evaporated under reduced pressure and the residue was diluted with ethyl acetate. At this point, HCl (1 M) was added and the mixture was extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography (ISCO, 0 to 100% ethyl acetate in hexanes) to give the desired product (0.630 g) as a clear oil. LRMS (ES+) m/z 332.2 (M+Na)+.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([F:13])=[CH:5][C:3]=1[NH2:4].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[C:36]([O:40][CH2:41][CH3:42])(=[O:39])[CH:37]=[CH2:38]>C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:4][C:3]1[CH:5]=[C:6]([F:13])[C:7]([C:9]([F:12])([F:11])[F:10])=[CH:8][C:2]=1/[CH:38]=[CH:37]/[C:36]([O:40][CH2:41][CH3:42])=[O:39]
Reactant: C=CC(=O)OCC
Reactant: Nc1cc(F)c(C(F)(F)F)cc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/c1cc(C(F)(F)F)c(F)cc1N
Temperature: 85 °C

Procedure:
2-Bromo-5-fluoro-4-(trifluoromethyl)aniline (0.97 mmol) and P(o-tol)3 (0.40 mmol) were dissolved in triethylamine (2.0 mL) in a glass pressure tube and nitrogen gas was bubbled through the solution via a gas dispersion tube for 10 minutes. Ethyl acrylate (1.0 mmol) and palladium acetate (0.20 mmol) were added to the reaction mixture and the tube was sealed and placed into an oil bath pre-heated to 85° C. for 18 h. The resulting solution was concentrated under vacuum and purified via an isco column. Retention time (min)=2.504, method [1], MS(ESI) 278.0 (M+H).
Reaction SMILES: [O:1]=[C:2]1[C:15]2[CH:14]=[C:13]([C:16]([OH:18])=[O:17])[CH:12]=[CH:11][C:10]=2[O:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[CH2:19](O)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].S(=O)(=O)(O)O>S(=O)(=O)(O)O.C([O-])(=O)C.[Na+]>[O:1]=[C:2]1[C:15]2[CH:14]=[C:13]([C:16]([O:18][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH3:19])=[O:17])[CH:12]=[CH:11][C:10]=2[O:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2
Reactant: O=C(O)c1ccc2oc3ccccc3c(=O)c2c1
Reactant: CCCCCCCCCCCCO
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCCCCCCCCCCCOC(=O)c1ccc2oc3ccccc3c(=O)c2c1
Reaction time: 6 h
Yield: 81.8 %

Procedure:
A mixture of 12.01 g (50 mmol) of the above 9-oxo-9H-xanthene-2-carboxylic acid, 77.4 g (420 mmol) of n-dodecanol and 0.2 g (2 mmol) of concentrated sulfuric acid is kept at 140° C. for 6 hours. The sulfuric acid is neutralized with 0.33 g (4 mmol) of sodium acetate and the excess n-dodecancl is removed by distillation (98° C./0.1 mbar). The brown residue is taken up in isopropanol and the product which has precipitated is filtered off and dried under a high vacuum. 16.7 g(82%) of n-dodecyl 9-oxo-9H-xanthene-2-carboxylate, melting point 79°-81° C., result s a beige powder.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[CH2:10]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([N:19]([CH2:34][CH3:35])[CH2:20][CH2:21][NH:22][C:23]([C:25]1[C:29]([CH3:30])=[C:28]([CH:31]=O)[NH:27][C:26]=1[CH3:33])=[O:24])[CH3:18]>>[CH2:34]([N:19]([CH2:17][CH3:18])[CH2:20][CH2:21][NH:22][C:23]([C:25]1[C:29]([CH3:30])=[C:28]([CH:31]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:8]=3)[NH:12][C:11]2=[O:16])[NH:27][C:26]=1[CH3:33])=[O:24])[CH3:35]
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Reactant: O=C1Cc2cc(-c3ccccc3)ccc2N1
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3ccc(-c4ccccc4)cc32)c1C
Yield: 45.9 %

Procedure:
5-Phenyl-1,3-dihydroindol-2-one (80 mg, 0.4 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide (0.1 g) using method B to give 79 mg (46%) of the title compound.
Reaction SMILES: [OH-].[Na+].Cl.[C:4]([NH2:12])(=[NH:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Br[CH:14]1[CH2:29][CH2:28][C:17]2=[C:18]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[S:19][C:20]([S:21][CH3:22])=[C:16]2[C:15]1=O>O.C(Cl)(Cl)Cl>[CH3:22][S:21][C:20]1[S:19][C:18]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:17]2[CH2:28][CH2:29][C:14]3[N:11]=[C:4]([C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)[NH:12][C:15]=3[C:16]=12
Reactant: CCOC(=O)c1sc(SC)c2c1CCC(Br)C2=O
Reactant: N=C(N)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1sc(SC)c2c1CCc1nc(-c3ccccc3)[nH]c1-2
Yield: 13.2 %

Procedure:
A solution of sodium hydroxide (1.65 g) in water (3 ml) was added to a solution of benzamidine hydrochloride (5.38 g) in water (2 ml) at room temperature; a solution of ethyl 5-bromo-4,5,6,7-tetrahydro-3-methylthio-4-oxobenzo[c]thiophene-1-carboxylate (2.00 g) in chloroform (30 ml) was further added. The reaction mixture was refluxed under heating for 3 days, after which it was poured over water and extracted with ethyl acetate. The organic layer was washed with water and dried (MgSO4), after which the solvent was distilled off. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:2, v/v) to yield ethyl 4,5-dihydro-8-methylthio-2-phenylthieno[3,4-e]benzimidazole-6-carboxylate (0.28 g, 13.2%), which was then recrystallized from ethyl acetate-ethanol. Brown prisms. Melting point 218-219° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11](=[O:19])OC2C=CC=CC=2)[CH:5]=[CH:6][C:7]=1[CH2:8][OH:9].Cl.[Cl:21][C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=1[N:29]1[C:33]([CH2:34][NH2:35])=[CH:32][C:31]([C:36]([F:39])([F:38])[F:37])=[N:30]1>C(Cl)Cl.O>[Cl:21][C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=1[N:29]1[C:33]([CH2:34][NH:35][C:11]([NH:10][C:4]2[CH:5]=[CH:6][C:7]([CH2:8][OH:9])=[C:2]([F:1])[CH:3]=2)=[O:19])=[CH:32][C:31]([C:36]([F:38])([F:39])[F:37])=[N:30]1
Reactant: O=C(Nc1ccc(CO)c(F)c1)Oc1ccccc1
Reactant: NCc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1Cl
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: O=C(NCc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1Cl)Nc1ccc(CO)c(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 23.3 %

Procedure:
To a stirred solution of phenyl 3-fluoro-4-(hydroxymethyl)phenylcarbamate (0.175 g, 0.63 mmol, 1.0 eq) in DCM (5 mL) was added TEA (0.25 mL, 1.9 mmol, 3.0 eq.) followed by compound (1-(2,3-dichlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanamine hydrochloride (0.218 mg, 0.63 mmol, 1.0 eq.) at RT and stirred for 16 h at RT. The reaction mixture was diluted with water (10 mL) and extracted into DCM (25 mL). The organic layer was washed with brine (10 mL), dried over (Na2SO4) and the solvent evaporated under vacuum. The resulting residue was purified by CC using EtOAc/PE (1:1) as eluent to get 1-((1-(2,3-dichlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(3-fluoro-4-(hydroxymethyl)phenyl)urea (70 mg; 23%) as white solid (TLC system: EtOAc, Rf: 0.55).
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[C:19](=[O:23])[N:18]([C:24]1[CH:25]=[N:26][CH:27]=[C:28]([S:30][CH3:31])[CH:29]=1)[CH2:17][CH2:16]2.[OH-].[Na+]>C(Cl)Cl>[Cl:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[C:19](=[O:23])[N:18]([C:24]1[CH:25]=[N:26][CH:27]=[C:28]([S:30]([CH3:31])=[O:9])[CH:29]=1)[CH2:17][CH2:16]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1cncc(N2CCc3cc(Cl)ccc3C2=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CS(=O)c1cncc(N2CCc3cc(Cl)ccc3C2=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 18.7 %

Procedure:
MCPBA (17.3 mg, 0.1 mmol) was added into a solution of 6-chloro-2-(5-methylsulfanyl-pyridin-3-yl)-3,4-dihydro-2H-isoquinolin-1-one (example 59) (30.5 mg, 0.1 mmol) in DCM (2 mL). The reaction mixture was stirred at RT for 2 hours before it was neutralized with 5% aq. NaOH and extracted with DCM (5 mL, 2×). The organic layers were washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product which was then purified by prep-HPLC to give title compound (6 mg, 19%) as a white solid. MS: 321.1 (M+H+).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:6]([CH3:17])=[N:7][O:8][C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=1)=[O:4].[CH2:18]([SH:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:18]([S:25][CH2:2][C:3]([C:5]1[C:6]([CH3:17])=[N:7][O:8][C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=1)=[O:4])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(=O)CBr
Reactant: SCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1noc(-c2ccc(Br)cc2)c1C(=O)CSCc1ccccc1
Reaction time: 8 h

Procedure:
2-bromo-1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-ethanone and benzyl mercaptan were dissolved in DMF. Cesium carbonate was added and the reaction stirred overnight. Standard aqueous workup afforded provided the product.
Reaction SMILES: C([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])=[CH:8][N:7]=1)C.O1CCCC1.[OH-].[Na+:30]>CC(O)C>[CH2:16]([O:15][C:13]([NH:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][C:4]([O-:23])=[O:3])=[N:7][CH:8]=1)=[O:14])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Na+:30]
Reactant: CCOC(=O)Cc1ccc(NC(=O)OCc2ccccc2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(C)O
Product: O=C([O-])Cc1ccc(NC(=O)OCc2ccccc2)cn1
Reaction time: 3 h

Procedure:
To a solution of ethyl(5-(((benzyloxy)carbonyl)amino)pyridin-2-yl)acetate (1.0 g) obtained in Step A of Example 363 in a mixed solvent of tetrahydrofuran (20 mL) and 2-propanol (5.0 mL) was added 2 M aqueous sodium hydroxide solution (6.4 mL) in an ice bath, and the mixture was stirred at the same temperature for 3 hr. The reaction mixture was collected by filtration to give the title compound (2.6 g).