Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[C@H]1([CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[C:39]([Cl:43])=[CH:40][CH:41]=[CH:42][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:16][CH2:15]2)[C@@H]2N(CCCC2)CCC1.Cl.Cl.Cl.NC1CCN([CH2:54][C@@H:55]([N:57]2[CH2:62][CH2:61][CH:60]([OH:63])[CH2:59][CH2:58]2)C)CC1>>[OH:63][CH:60]1[CH2:61][CH2:62][N:57]([C@@H:55]([CH3:54])[CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[C:39]([Cl:43])=[CH:40][CH:41]=[CH:42][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:16][CH2:15]2)[CH2:58][CH2:59]1
Reactant: O=C(NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1)c1cc2c(OCc3coc4cccc(Cl)c34)cccc2[nH]1
Reactant: C[C@@H](CN1CCC(N)CC1)N1CCC(O)CC1
Agent: Cl
Product: C[C@@H](CN1CCC(NC(=O)c2cc3c(OCc4coc5cccc(Cl)c45)cccc3[nH]2)CC1)N1CCC(O)CC1

Procedure:
This compound is synthesized from 4-(4-chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (118, see example 76) and amine 50 analogously to the method described in example 1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[N:8]([CH2:17][C:18]#[N:19])[N:7]=1)[CH3:2].Cl.N[C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[C:25]([F:30])[C:24]=1[SH:31]>C(O)C>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[N:8]([CH2:17][C:18]2[S:31][C:24]3[C:25]([F:30])=[CH:26][C:27]([F:29])=[CH:28][C:23]=3[N:19]=2)[N:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1nn(CC#N)c(=O)c2ccccc12
Reactant: Nc1cc(F)cc(F)c1S
Agent: Cl
Solvent: CCO
Product: CCOC(=O)Cc1nn(Cc2nc3cc(F)cc(F)c3s2)c(=O)c2ccccc12

Procedure:
A mixture of ethyl-3-cyanomethyl-4-oxo-phthalazin-1-ylacetate (1.29 g), 2-amino-4,6-difluoro-thiophenol hydrochloride (0.98 g) and ethanol (20 ml) was refluxed for 6 hours. Upon cooling, the title compound precipitated out as a pale yellow solid (yield: 1.62 g; m.p. 115°-117° C.).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[Br:6][C:7]1[CH:15]=[C:11]([C:12]([OH:14])=O)[C:10]([OH:16])=[CH:9][CH:8]=1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C>[Br:6][C:7]1[CH:8]=[CH:9][C:10]([OH:16])=[C:11]([CH:15]=1)[C:12]([N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[O:14]
Reactant: CCNCC
Reactant: O=C(O)c1cc(Br)ccc1O
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCN(CC)C(=O)c1cc(Br)ccc1O
Temperature: 50 °C
Reaction time: 12 h

Procedure:
Diethylamine (2.39 mL, 23.0 mmol) was added to a solution of 5-bromosalicylic acid (1.000 g, 4.61 mmol), EDC (1.33 g, 6.91 mmol), HOAt (0.627 g, 4.61 mmol) and DMF (20.0 mL) and the system was flushed with argon. The tube was sealed and the mixture stirred at 50° C. for 12 h. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was separated and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford a brown oil. This oil was purified via column chromatography on silica gel (RediSep 40 g column, gradient elution with 0-50% ethyl acetate-hexane) to afford 5-bromo-N,N-diethyl-2-hydroxybenzamide as an off-white solid. MS m/z=272.1, 274.1 [M+H]+. Calcd for C11H14BrNO2: 272.1.
Reaction SMILES: C(O[C:4](=[O:9])[C:5](Br)([CH3:7])[CH3:6])C.[CH:10]1([NH:18][C:19]([NH2:21])=[S:20])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>>[CH:10]1([NH:18][C:19]2[S:20][C:5]([CH3:6])([CH3:7])[C:4](=[O:9])[N:21]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: NC(=S)NC1CCCCCCC1
Reactant: CCOC(=O)C(C)(C)Br
Product: CC1(C)SC(NC2CCCCCCC2)=NC1=O

Procedure:
Synthesis was performed from ethyl-2-bromo-2-methylpropanoate and N-cyclooctylthiourea according to Method C1.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:27]/[O:28][CH3:29])/[C:8]([NH:10][CH:11]2[C:25](=[O:26])[N:13]3[C:14]([C:22]([OH:24])=[O:23])=[C:15](/[CH:18]=[CH:19]\[CH2:20][CH3:21])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.C([O-])([O-])=O.[K+].[K+].[C:36]([O:39][CH:40](Br)[CH3:41])(=[O:38])[CH3:37]>CN(C=O)C.C(OCC)(=O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:27]/[O:28][CH3:29])/[C:8]([NH:10][CH:11]2[C:25](=[O:26])[N:13]3[C:14]([C:22]([O:24][CH:40]([O:39][C:36](=[O:38])[CH3:37])[CH3:41])=[O:23])=[C:15](/[CH:18]=[CH:19]\[CH2:20][CH3:21])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CC/C=C\C1=C(C(=O)O)N2C(=O)C(NC(=O)/C(=N\OC)c3csc(N)n3)[C@H]2SC1
Reactant: CC(=O)OC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC/C=C\C1=C(C(=O)OC(C)OC(C)=O)N2C(=O)C(NC(=O)/C(=N\OC)c3csc(N)n3)[C@H]2SC1
Temperature: 5 °C
Reaction time: 1 h
Yield: 69.6 %

Procedure:
To a mixture of 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(Z)-1-butenyl]-3-cephem-4-carboxylic acid (1.55 g, 3.54 mmoles) and K2CO3 (636 mg, 4.6 mmoles) in DMF (4 ml) was added at 5° C. 1-bromoethyl acetate (769 mg, 4.6 mmoles). The mixture was stirred at 5° C. for 1 hour, diluted with ethyl acetate (300 ml), washed with water, dried over anhydrous MgSO4 and concentrated in vacuo. The residue was dissolved in chloroform and chromatographed on a silica gel column (50 g) with 1% methanol in CHCl3. The desired fractions were combined and concentrated to a small volume. The resdiue was triturated with isopropyl ether to give 1.29 g (70%) of the title compound as the isopropyl ether solvate. Estimated purity 90% (by HPLC). Mp. 103°-110° C. (dec.).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH:8][C:9]([C:11]2[CH:15]=[C:14](Br)[N:13]([CH3:17])[N:12]=2)=[O:10])=[CH:3][CH:2]=1.C(OC([N:25]1[C:33]2[C:28](=[CH:29][C:30](B3OC(C)(C)C(C)(C)O3)=[CH:31][CH:32]=2)[CH:27]=[C:26]1[C:43]1[O:47][N:46]=[C:45]([CH3:48])[N:44]=1)=O)(C)(C)C.C([O-])([O-])=O.[Na+].[Na+]>CN(C)C=O.C(OCC)(=O)C>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH:8][C:9]([C:11]2[CH:15]=[C:14]([C:30]3[CH:29]=[C:28]4[C:33](=[CH:32][CH:31]=3)[NH:25][C:26]([C:43]3[O:47][N:46]=[C:45]([CH3:48])[N:44]=3)=[CH:27]4)[N:13]([CH3:17])[N:12]=2)=[O:10])=[CH:3][CH:2]=1
Reactant: Cc1noc(-c2cc3cc(B4OC(C)(C)C(C)(C)O4)ccc3n2C(=O)OC(C)(C)C)n1
Reactant: Cn1nc(C(=O)NCc2ccncc2)cc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1noc(-c2cc3cc(-c4cc(C(=O)NCc5ccncc5)nn4C)ccc3[nH]2)n1
Temperature: 100 °C
Yield: 16.1 %

Procedure:
To a solution of 5-Bromo-l-methyl-1H-pyrazole-3-carboxylic acid(pyridin-4-ylmethyl)-amide (90 mg, 0.3 mmol), and 2-(3-Methyl-1,2,4-oxadiazol-5-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-indole-1-carboxylic acid tert-butyl ester (142 mg, 0.33 mmol) in N,N dimethylformamide (1.5 ml) is added aqueous Na2CO3 (0.4 ml, 0.77 mmol). The mixture is purged with argon for 10 minutes. (Bis(di-t-butyl(4-dimethylaminutesophenyl)phosphine)dichloropalladium(II) (40 mg, 0.06 mmol), is then added and the reaction mixture is sealed in a seal tube and heated to 100° C. in a microwave reactor for 30 minutes. The reaction mixture is diluted with ethyl acetate (70 ml), washed with water (20 ml), brine (2×25 ml), dried over Na2SO4, filtered, and concentrated in vacuo. Purified by reverse phase LC/MS to provide the title compound 20 mg, (16%), LC/MS ESI m/z (M+H)+=414.9.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH:11][C:12](=[O:38])[O:13][CH2:14][C@@H:15]([N:24]([CH3:37])[C:25]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:30]=2[F:36])=[O:26])[CH2:16][CH2:17][CH2:18][O:19][P:20]([OH:23])([OH:22])=[O:21])[N:2]=1.[OH-].[Na+:40]>CO>[P:20]([O-:22])([O-:23])([O:19][CH2:18][CH2:17][CH2:16][C@H:15]([N:24]([CH3:37])[C:25]([NH:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:30]=1[F:36])=[O:26])[CH2:14][O:13][C:12](=[O:38])[NH:11][C:3]1[N:2]=[CH:1][C:10]2[C:5]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2)=[O:21].[Na+:40].[Na+:40]
Reactant: CN(C(=O)NCc1cccc(F)c1F)[C@@H](CCCOP(=O)(O)O)COC(=O)Nc1cc2ccccc2cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(C(=O)NCc1cccc(F)c1F)[C@@H](CCCOP(=O)([O-])[O-])COC(=O)Nc1cc2ccccc2cn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.8 %

Procedure:
(S)-2-(3-(2,3-difluorobenzyl)-1-methylureido)-5-(phosphonooxy)pentyl isoquinolin-3-ylcarbamate (261 mg, 0.472 mmol) in MeOH (10 mL) was added NaOH (0.1 N, 9.2 mL, 0.92 mmol) at 0° C. After stirred at 0° C. for 1 h, the mixture was concentrated to give sodium (S)-4-(3-(2,3-difluorobenzyl)-1-methylureido)-5-(isoquinolin-3-ylcarbamoyloxy)pentyl phosphate (260 mg, 88%) as a white solid. LRMS (M+H+) m/z 585.5.
Reaction SMILES: [F:1][C:2]1[C:8]([F:9])=[C:7](Br)[C:6]([F:11])=[C:5]([F:12])[C:3]=1[NH2:4].[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC=CC=1.C(O)C>[F:1][C:2]1[C:8]([F:9])=[C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:6]([F:11])=[C:5]([F:12])[C:3]=1[NH2:4]
Reactant: Nc1c(F)c(F)c(Br)c(F)c1F
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCO
Product: Nc1c(F)c(F)c(-c2ccccc2)c(F)c1F
Temperature: 25 °C

Procedure:
2,3,5,6-Tetrafluoro-4-bromoaniline (13.8 g, 56.7 mmol) is dissolved in benzene (200 mL) and treated with 1.5 equivalents of phenylboronic acid (10.4 g, 85.1 mmol) and a catalytic amount of tetrakistriphenylphosphine palladium(0) (4.2 g, 3.6 mmol) as a solution in ethanol (30 mL). Sodium carbonate (60 mL of 2 M aqueous solution) is added and the reaction mixture stirred and heated to reflux temperature for 24 hours. After cooling to room temperature the mixture is partitioned between Et2O (500 mL) and water (250 mL). The organic layer is washed with brine, dried (MgSO4) and concentrated by rotary evaporator. The residual oil is purified by flash chromatography (9:1 hexanes/EtOAc) to give 2,3,5,6-tetrafluoro-4-phenylaniline as an oil.
Reaction SMILES: C[O:2][C:3](=[O:38])[CH:4]([O:35][CH2:36][CH3:37])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2([CH2:15][N:16]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C:17]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=3[F:27])=[O:18])[CH2:14][CH2:13]2)=[CH:8][CH:7]=1.[Li+].[OH-]>O1CCCC1>[F:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[NH:19][C:17](=[O:18])[N:16]([CH2:15][C:12]1([C:9]2[CH:8]=[CH:7][C:6]([CH2:5][CH:4]([O:35][CH2:36][CH3:37])[C:3]([OH:38])=[O:2])=[CH:11][CH:10]=2)[CH2:13][CH2:14]1)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCCN(CC1(c2ccc(CC(OCC)C(=O)OC)cc2)CC1)C(=O)Nc1ccc(F)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCCCCN(CC1(c2ccc(CC(OCC)C(=O)O)cc2)CC1)C(=O)Nc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 61.8 %

Procedure:
A solution of 3-(4-{1-[3-(2,4-difluoro-phenyl)-1-heptyl-ureidomethyl]-cyclopropyl}-phenyl)-2-ethoxy-propionic acid methyl ester (50 mg, 0.094 mmol) and 1 M LiOH (0.283 mmol, 0.283 mL) in tetrahydrofuran (1 mL) was allowed to stir at room temperature for 18 hours. 2 N HCL was then added until the solution had a pH<2. After dilution with twice its volume in water, the aqueous layer was extracted with diethyl ether (2×). The organic layers were combined, washed with 2 M HCl (2×), dried over anhydrous sodium sulfate, and concentrated to give 3-(4-{1-[3-(2,4-difluoro-phenyl)-1-heptyl-ureidomethyl]-cyclopropyl}-phenyl)-2-ethoxy-propionic acid as a clear oil (30 mg, 61%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[CH2:13][CH2:14][NH:15][C:16](=[O:19])[CH2:17]Br)=[CH:5][CH:4]=1.[I-:20].[K+]>>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[CH2:13][CH2:14][NH:15][C:16](=[O:19])[CH2:17][I:20])=[CH:5][CH:4]=1
Reactant: COc1ccc2cccc(CCNC(=O)CBr)c2c1
Reactant: [I-]
Agent: [K+]
Product: COc1ccc2cccc(CCNC(=O)CI)c2c1

Procedure:
The product of the title is obtained by treating the N-[2-(7-methoxynaphth-1-yl)ethyl]-2-bromoacetamide obtained in Example 9 with potassium iodide.
Reaction SMILES: [CH:1]([S:4][C:5]1[S:9][C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:7]2[CH2:15][CH2:16][CH2:17][C:18](=[O:19])[C:6]=12)([CH3:3])[CH3:2].[Br:20]Br.O>CO>[Br:20][CH:17]1[CH2:16][CH2:15][C:7]2=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[S:9][C:5]([S:4][CH:1]([CH3:2])[CH3:3])=[C:6]2[C:18]1=[O:19]
Reactant: CCOC(=O)c1sc(SC(C)C)c2c1CCCC2=O
Reactant: BrBr
Solvent: O
Solvent: CO
Product: CCOC(=O)c1sc(SC(C)C)c2c1CCC(Br)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.8 %

Procedure:
Ethyl 4,5,6,7-tetrahydro-3-isopropylthio-4-oxobenzo[c]thiophene-1-carboxylate (2.50 g) was dissolved in methanol (80 ml); a solution of bromine (1.34 g) in methanol (8.6 ml) was added dropwise at room temperature. After the reaction mixture was stirred at room temperature for 2 hours, it was poured over water and extracted with ethyl acetate. The organic layer was washed with an aqueous solution of sodium thiosulfate, a saturated aqueous solution of sodium hydrogen carbonate and water in that order, 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 (1:5, v/v) to yield ethyl 5-bromo-4,5,6,7-tetrahydro-3-isopropylthio-4-oxobenzo[c]thiophene-1-carboxylate (2.65 g, 83.9%), which was then recrystallized from ethyl acetate-hexane. Colorless prisms. Melting point 107-108° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].CO[C:10]([NH:12][C@H:13]([C:23]1[NH2+:24][C:25]([C:28]2[CH:37]=[CH:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=2)=[CH:26][N:27]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19](=[O:22])[CH2:20][CH3:21])=[O:11].O[Li].[OH2:40]>C1COCC1.O>[F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[C:3]([C:10]([NH:12][C@H:13]([C:23]1[NH2+:24][C:25]([C:28]2[CH:37]=[CH:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=2)=[CH:26][N:27]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19](=[O:22])[CH2:20][CH3:21])=[O:11])([OH:4])=[O:40]
Reactant: O
Reactant: CCC(=O)CCCCC[C@H](NC(=O)OC)C1=NC=C(c2ccc3ccccc3c2)[NH2+]1
Agent: O=C([O-])C(F)(F)F
Agent: [Li]O
Solvent: C1CCOC1
Product: CCC(=O)CCCCC[C@H](NC(=O)C(=O)O)C1=NC=C(c2ccc3ccccc3c2)[NH2+]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl ({(1S)-1-[5-(2-naphthyl)-1H-imidazol-2-yl]-7-oxononyl}amino)(oxo)acetate (Prepared as in example 147) was dissolved in THF and a solution of LiOH.H2O (1.05 eq.) in H2O was added and the mixture was then stirred for 1 hr at RT. The reaction was quenched with 1M HCl until pH 5 was reached and then the THF was removed under reduced pressure. The aqueous phase was extracted with DCM (3×); the combined organic phases were washed with brine and then dried (Na2SO4) and concentrated under reduced pressure. The resulting crude was purified by preparative RP-HPLC, using H2O (0.1% TFA) and MeCN (+0.1% TFA) as eluents (column: C18). The desired fractions were lyophilized to afford the titled compound as colorless oil. 1H NMR (300 MHz, DMSO-d6) δ: 9.39 (1H, d, J=8.2 Hz), 8.30 (1H, s), 8.11-7.85 (6H, m), 7.58-7.47 (2H, m), 6.88-6.18 (1H, bs), 5.15-5.02 (1H, m), 2.45-2.36 (4H, m), 2.13-1.87 (2H, m), 1.55-1.41 (2H, m), 1.40-1.20 (4H, m), 0.90 (3H, t, J=7.3 Hz). MS (ES) C24H27N3O4 requires: 421, found: 422 (M+H)+.
Reaction SMILES: C(Cl)Cl.[Cl-].[Al+3].[Cl-].[Cl-].[C:8](Cl)(=[O:10])[CH3:9].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:24](=[O:25])[CH:23]=[C:22]3[CH2:26][CH2:27][S:28][C:29]4[S:33][CH:32]=[CH:31][C:30]=4[C:21]3=[N:20]2)=[CH:15][CH:14]=1>O>[C:8]([C:32]1[S:33][C:29]2[S:28][CH2:27][CH2:26][C:22]3[C:21](=[N:20][N:19]([C:16]4[CH:17]=[CH:18][C:13]([Cl:12])=[CH:14][CH:15]=4)[C:24](=[O:25])[CH:23]=3)[C:30]=2[CH:31]=1)(=[O:10])[CH3:9]
Reactant: O=c1cc2c(nn1-c1ccc(Cl)cc1)-c1ccsc1SCC2
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CC(=O)c1cc2c(s1)SCCc1cc(=O)n(-c3ccc(Cl)cc3)nc1-2

Procedure:
To a mixture of 50 ml of methylene chloride and 1.9 g of aluminum chloride is added 1.0 ml of acetyl chloride with stirring under ice-cooling and then the mixture is stirred at room temperature for 10 minutes. To the mixture is further added 2.0 g of 2-(4-chlorophenyl)-5,6-dihydrothieno[2',3':2,3]thiepino[4,5-c]pyridazin-3(2H)-one under ice-cooling and the mixture is stirred for 3 hours at room temperature. To the mixture is added water and the solution is extracted with chloroform. The extract is washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The resulting crystals are recrystallized from a mixed solvent of chloroform and ethanol to give 2.0 g of 9-acetyl-2-(4-chlorophenyl)-5,6-dihydrothieno[2',3':2,3]thiepino[4,5-c]pyridazin-3(2H)-one, as white crystals, melting at 248°-250° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[CH3:17].[NH2:18][C:19]1[CH:23]=[CH:22][NH:21][N:20]=1>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[N:20]3[N:21]=[CH:22][CH:23]=[C:19]3[N:18]=2)=[CH:4][C:3]=1[CH3:17]
Reactant: Cc1cc(C(=O)CC(=O)C(F)(F)F)ccc1Cl
Reactant: Nc1cc[nH]n1
Solvent: CC(=O)O
Product: Cc1cc(-c2cc(C(F)(F)F)n3nccc3n2)ccc1Cl
Yield: 98.4 %

Procedure:
A mixture of 1-(4-chloro-3-methyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (3.95 g, 14.9 mmol) and commercially available 3-aminopyrazole (1.24 g, 14.9 mmol) in acetic acid (40 mL) was refluxed for 5.5 h and evaporated. The crude product was further purified by crystallization (ethyl acetate/hexane) to yield 5-(4-chloro-3-methyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine (4.57 g, 98%) as ayellow solid. MS (EI) 311.2 [(M)+]; mp 114° C.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][O:5][C:4](=[O:7])[N:3]1[C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1.[ClH:17].[CH3:18][C:19]1[CH:20]=[C:21]([C:31]([F:34])([F:33])[F:32])[C:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[N:23][CH:24]=1>>[ClH:17].[CH3:1][C@@H:2]1[CH2:6][O:5][C:4](=[O:7])[N:3]1[C:8]1[CH:9]=[CH:10][C:11]([C:12]([N:28]2[CH2:29][CH2:30][N:25]([C:22]3[C:21]([C:31]([F:34])([F:32])[F:33])=[CH:20][C:19]([CH3:18])=[CH:24][N:23]=3)[CH2:26][CH2:27]2)=[O:14])=[CH:15][CH:16]=1
Reactant: Cc1cnc(N2CCNCC2)c(C(F)(F)F)c1
Reactant: C[C@@H]1COC(=O)N1c1ccc(C(=O)O)cc1
Agent: Cl
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4C)cc3)CC2)c(C(F)(F)F)c1
Yield: 10.5 %

Procedure:
By reaction and treatment in the same manner as in Example 87 and using (R)-4-(4-methyl-2-oxooxazolidin-3-yl)benzoic acid (422 mg) described in Preparation Example 37 and 1-(5-methyl-3-trifluoromethylpyridin-2-yl)piperazine hydrochloride (282 mg) described in Preparation Example 55, the title compound (51 mg) was obtained.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)[CH2:7][O:8][CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])#[N:2]>N.[Ni]>[NH3:2].[NH2:2][CH2:1][CH2:3][C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)[CH2:7][O:8][CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)NCCOCc1cccc(CC#N)c1
Agent: [Ni]
Agent: N
Product: CC(C)(C)OC(=O)NCCOCc1cccc(CCN)c1
Reaction time: 24 h
Yield: 161.1 %

Procedure:
Raney® nickel (170 mg) was added to a solution of tert-butyl 2-{[3-(cyanomethyl)benzyl]oxy}ethylcarbamate (preparation 104) (654 mg, 2.26 mmol) in ethanolic ammonia solution (15 ml), and the mixture hydrogenated at 60 psi and room temperature for 24 hrs. The reaction mixture was filtered through Arbocel®, and the filtrate evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using dichloromethane:methanol:0.88 ammonia (90:10:1) to afford the title compound, (536 mg, 80%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[NH:16][C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1.Br[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[C:22]([F:31])[CH:21]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[N:16]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]([F:28])([F:29])[F:30])=[C:22]([F:31])[CH:21]=2)[C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1
Reactant: Fc1cc(CBr)ccc1OC(F)(F)F
Reactant: COc1cccc(OC)c1C1CCCC(=O)N1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccc(OC(F)(F)F)c(F)c1

Procedure:
Prepared according to the described general procedure 4 (GP4) by reaction of 6-(2,6-dimethoxyphenyl)piperidin-2-one with commercially available 4-(bromomethyl)-2-fluoro-1-(trifluoromethoxy)benzene. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions E): tR=0.81 min.; [M+H]+: 428.21 g/mol.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:15]=[C:14]([O:16][CH2:17][CH:18]([OH:21])[CH2:19][OH:20])[CH:13]=[C:12]([C:22](O)=[O:23])[CH:11]=1)#[N:2].Cl.Cl.[CH3:27][C:28]1[N:33]=[CH:32][C:31]([C@H:34]([NH2:36])[CH3:35])=[CH:30][CH:29]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:15]=[C:14]([O:16][CH2:17][CH:18]([OH:21])[CH2:19][OH:20])[CH:13]=[C:12]([C:22]([NH:36][C@@H:34]([C:31]2[CH:32]=[N:33][C:28]([CH3:27])=[CH:29][CH:30]=2)[CH3:35])=[O:23])[CH:11]=1)#[N:2]
Reactant: Cc1ccc([C@@H](C)N)cn1
Reactant: Cc1ccc(-c2cc(OCC(O)CO)cc(C(=O)O)c2)c(C#N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(OCC(O)CO)cc(C(=O)N[C@H](C)c3ccc(C)nc3)c2)c(C#N)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2′-cyano-5-(2,3-dihydroxypropoxy)-4′-methylbiphenyl-3-carboxylic acid (30 mg, 0.092 mmol) in N,N-dimethylformamide (1 mL) were added (R)-1-(6-methylpyridin-3-yl)ethanamine dihydrochloride (60 mg, 0.29 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (100 mg, 0.26 mmol), and N,N-diisopropylethylamine (400 μL, 2.3 mmol). The reaction mixture was stirred for 16 hours at 25° C., and then purified by preparative HPLC to afford the final product as a light color solid.
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]2[NH:6][C:7]([CH2:9][N:10]([CH3:18])[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[N:8][C:4]=2[CH:3]=1.CN(C=O)C.C([O-])([O-])=O.[K+].[K+].Cl[CH2:33][O:34][CH3:35]>CCOC(C)=O>[Br:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]([CH2:33][O:34][CH3:35])[C:7]([CH2:9][N:10]([CH3:18])[C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[N:8][C:4]=2[CH:3]=1
Reactant: CN(Cc1nc2cc(Br)ccc2[nH]1)C(=O)OC(C)(C)C
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCn1c(CN(C)C(=O)OC(C)(C)C)nc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of tert-butyl [(5-bromo-1H-benzimidazol-2-yl)methyl]methylcarbamate (1.54 g) and DMF (20 mL) were added K2CO3 (1.88 g) and chloromethylmethyl ether (516 μL) under ice-cooling, followed by stirring at room temperature overnight. The reaction mixture was diluted with EtOAc, and washed with water and brine in this order. The organic layer was dried over Na2SO4 and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: Hex/EtOAc=80/20-55/45) to obtain a mixture (1.25 g) of tert-butyl {[5-bromo-1-(methoxymethyl)-1H-benzimidazol-2-yl]methyl}methylcarbamate and tert-butyl {[6-bromo-1-(methoxymethyl)-1H-benzimidazol-2-yl]methyl}methylcarbamate.
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][CH:6]([C:24]1[CH:25]=[N:26][C:27]([CH3:30])=[N:28][CH:29]=1)[CH2:7][CH2:8][CH2:9][C:10](=[O:23])[CH2:11][CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[CH2:19][CH2:18][CH2:17][NH:16][C:15]=2[N:14]=1)C.[OH-].[Na+]>CCO>[CH3:30][C:27]1[N:28]=[CH:29][C:24]([CH:6]([CH2:7][CH2:8][CH2:9][C:10](=[O:23])[CH2:11][CH2:12][C:13]2[CH:22]=[CH:21][C:20]3[CH2:19][CH2:18][CH2:17][NH:16][C:15]=3[N:14]=2)[CH2:5][C:4]([OH:31])=[O:3])=[CH:25][N:26]=1
Reactant: CCOC(=O)CC(CCCC(=O)CCc1ccc2c(n1)NCCC2)c1cnc(C)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ncc(C(CCCC(=O)CCc2ccc3c(n2)NCCC3)CC(=O)O)cn1
Reaction time: 2 h

Procedure:
To a solution of 2-12 (77 mg, 0.18 mmol) in EtOH (2 mL) was added 1N NaOH (272 μl, 0.27 mmol). After stirring for 2 h, the solvents were evaporated and the residue was chromatographed (silica gel, 25:10:1:1 to 15:10:1:1 EtOAc/EtOH/H2O/NH4OH) to give 2-13 as a white solid.