Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:4]([NH2:7])(=[O:6])=[O:5])[CH2:2][CH3:3].[OH-].[Na+].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]=[C:18]=[O:19])=[CH:13][CH:12]=1>CC(C)=O>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:7][S:4]([CH2:1][CH2:2][CH3:3])(=[O:6])=[O:5])=[O:19])=[CH:13][CH:12]=1
Reactant: CCCS(N)(=O)=O
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CCCS(=O)(=O)NC(=O)Nc1ccc(Cl)cc1
Yield: 64.1 %

Procedure:
Procedure A was followed with 1-propanesulfonamide (5.0 g, 40.6 mmole), in acetone (40 ml), and 1.0N sodium hydroxide (40.6 ml). After ten minutes of stirring, 4-chlorophenyl isocyanate (6.2 g, 40.6 mmole) dissolved in about 40 ml of acetone was added over a five minute period. The mixture was allowed to stir for about two hours and filtered. The filtered solid was washed with water which dissolved most of it. 1N HCl (40 ml) was added to the combined filtrates and the resulting precipitate was filtered off and dried at about 65° C. under vacuum to provide 7.2 g of product.
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.C(Cl)CCl.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[N:38]=[C:37]([NH:39][C:40]3[CH:45]=[C:44]([O:46][CH3:47])[C:43]([O:48][CH3:49])=[C:42]([O:50][CH3:51])[CH:41]=3)[C:36]3=[C:52]([CH3:56])[N:53]=[C:54]([CH3:55])[N:35]3[N:34]=2)=[CH:29][CH:28]=1>>[CH3:56][C:52]1[N:53]=[C:54]([CH3:55])[N:35]2[C:36]=1[C:37]([NH:39][C:40]1[CH:41]=[C:42]([O:50][CH3:51])[C:43]([O:48][CH3:49])=[C:44]([O:46][CH3:47])[CH:45]=1)=[N:38][C:33]([C:30]1[CH:29]=[CH:28][C:27]([NH:26][C:1](=[O:4])[CH3:2])=[CH:32][CH:31]=1)=[N:34]2
Reactant: COc1cc(Nc2nc(-c3ccc(N)cc3)nn3c(C)nc(C)c23)cc(OC)c1OC
Reactant: CC(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: COc1cc(Nc2nc(-c3ccc(NC(C)=O)cc3)nn3c(C)nc(C)c23)cc(OC)c1OC

Procedure:
14.28 mg (0.24 mmol) of acetic acid, 32.14 mg (0.24 mmol) of HOBt, 72.17 mg (0.71 mmol) of 4-methylmorpholine, 45.6 mg (0.24 mmol) of EDC and 100 mg (0.24 mmol) of N-[2-(4-aminophenyl)-5,7-dimethylimidazo[5,1-f][1,2,4]triazin-4-yl]-N-(3,4,5-trimethoxyphenyl)amine from example 3 are reacted analogously to example 2. The work-up is carried out by HPLC separation.
Reaction SMILES: [C:1]([NH:4][C@H:5]([CH2:16][OH:17])[C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])(=[O:3])[CH3:2].[OH-].[Na+].S(OC)(O[CH3:24])(=O)=O>C(#N)C.CC(C)=O>[CH3:2][C:1]([NH:4][C@@H:5]([C:6]([NH:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:7])[CH2:16][O:17][CH3:24])=[O:3]
Reactant: CC(=O)N[C@H](CO)C(=O)NCc1ccccc1
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CC#N
Product: COC[C@@H](NC(C)=O)C(=O)NCc1ccccc1
Reaction time: 1 h
Yield: 70 %

Procedure:
(R)-2-Acetamido-N-benzyl-3-hydroxypropionamide (25 g, 0.1059 mole) was suspended in 125 ml of acetonitrile at room temperature. To this was added aqueous sodium hydroxide solution (6.3 g in 15 ml, 0.158 mol) drop wise, followed by dimethyl sulfate (26.7 g, 0.211 mole) drop wise. The reaction mixture was stirred for one hour and concentrated under reduced pressure. The resulting residue was dissolved in 200 ml dichloromethane and the solution washed with water (100 ml×3). The organic layer was treated with 1 g charcoal and stirred for one hour. It was filtered and the filtrate was concentrated under reduced pressure. The solid residue obtained was dissolved in acetone and precipitated by adding diisopropyl ether to obtain Lacosamide. (18.5 g, Yield: 70%; chiral HPLC: 99.8% and chemical HPLC: 99.7%)
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl.[CH2:23]([O:30][C:31](=[O:39])[CH2:32][C@@H:33]([NH2:38])[CH2:34][N:35]([CH3:37])[CH3:36])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([O:30][C:31](=[O:39])[CH2:32][C@@H:33]([NH:38][C:18](=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:34][N:35]([CH3:36])[CH3:37])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CN(C)C[C@H](N)CC(=O)OCc1ccccc1
Reactant: O=C(O)CCCCCCCCCCCc1ccccc1
Agent: Cl
Product: CN(C)C[C@@H](CC(=O)OCc1ccccc1)NC(=O)CCCCCCCCCCCc1ccccc1

Procedure:
The title compound, m/e=403.6 ([M−H]−), was produced in analogy with example 1, steps 3 and 4. Thus, commercially available 12-phenyldodecanoic acid was coupled in step 3 with (R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride to produce (R)-4-dimethylamino-3-(12-phenyl-dodecanoylamino)-butyric acid benzyl ester, which was hydrogenated in step 4.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([C:9]3[N:14]=[C:13]([NH:15][C:16]4[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=4)[C:12]([O:22][CH3:23])=[CH:11][N:10]=3)[C:5]=2[CH3:24])[CH2:3][CH2:2]1.Br[CH2:26][C:27]1[C:28]([Cl:38])=[C:29]([CH:34]=[CH:35][C:36]=1[Cl:37])[C:30]([O:32]C)=[O:31].[H-].[Na+]>C1COCC1>[Cl:38][C:28]1[C:27]([CH2:26][N:8]2[C:4]([CH:1]3[CH2:3][CH2:2]3)=[C:5]([CH3:24])[C:6]([C:9]3[N:14]=[C:13]([NH:15][C:16]4[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=4)[C:12]([O:22][CH3:23])=[CH:11][N:10]=3)=[N:7]2)=[C:36]([Cl:37])[CH:35]=[CH:34][C:29]=1[C:30]([OH:32])=[O:31]
Reactant: COC(=O)c1ccc(Cl)c(CBr)c1Cl
Reactant: COc1cnc(-c2n[nH]c(C3CC3)c2C)nc1Nc1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cnc(-c2nn(Cc3c(Cl)ccc(C(=O)O)c3Cl)c(C3CC3)c2C)nc1Nc1ccncc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
200 mg of 2-(5-cyclopropyl-4-methyl-1H-pyrazol-3-yl)-5-methoxy-N-(pyridin-4-yl)pyrimidin-4-amine 1-16-1 (0.62 mmol, 1.0 eq.), 184.86 mg of methyl 3-(bromomethyl)-2,4-dichlorobenzoate (0.62 mmol, 1.0 eq.) and 31.0 mg of 60% sodium hydride in paraffin oil were suspended in 6.3 mL of dry THF and stirred for 20 hours at rt. The reaction mixture was partitioned between water and DCM/propan-2-ol 4:1. The separated aqueous layer was extracted three times with DCM/propan-2-ol 4:1. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The purification by flash chromatography and preparative HPLC of the residue provided 37.5 mg (0.07 mmol, 11%) of analytically pure target compound.
Reaction SMILES: [C:1]([Si:5]([CH3:26])([CH3:25])[O:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[C:14](OS(C(F)(F)F)(=O)=O)[CH:13]=[CH:12]2)([CH3:4])([CH3:3])[CH3:2].[CH3:27][O:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[C:31]([N+:36]([O-:38])=[O:37])[CH:30]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([Si:5]([CH3:26])([CH3:25])[O:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[C:14]([NH:33][C:32]1[CH:34]=[CH:35][C:29]([O:28][CH3:27])=[CH:30][C:31]=1[N+:36]([O-:38])=[O:37])[CH:13]=[CH:12]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc2ccc(OS(=O)(=O)C(F)(F)F)nc12
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1ccc(Nc2ccc3cccc(O[Si](C)(C)C(C)(C)C)c3n2)c([N+](=O)[O-])c1
Temperature: 100 °C

Procedure:
Trifluoro-methanesulfonic acid 8-(tert-butyl-dimethyl-silanyloxy)-quinolin-2-yl ester B (9.81 g, 24.1 mmol) and 4-methoxy-2-nitroaniline (4.86 g, 28.9 mmol) were dissolved in 100 mL of dioxane under an atmosphere of dry N2. To this solution was added (11.0 g, 33.7 mmol) cesium carbonate (Cs2CO3), (900 mg, 1.45 mmol) racemic-2,2′-bis(diphenylposphino)-1,1′-binapthyl (BINAP) and tris(dibenzylideneacetone)dipalladium (0) (883 mg, 0.964 mmol) and the reaction mixture was heated to 100° C. and reacted at this temperature for 4 hours. The mixture was then cooled to ambient temperature, concentrated under vacuum, treated with DCM, filtered and concentrated under vacuum to give a red solid. The solid was chromatographed on flash silica gel eluting with hexanes/DCM (3:1) to give 7.25 g of C as a red solid.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].[Cl:18][C:19]1[CH:33]=[CH:32][C:22]2[N:23]=[C:24]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[S:25][C:21]=2[CH:20]=1>>[Cl:18][C:19]1[CH:33]=[CH:32][C:22]2[N:23]=[C:24]([N:26]3[CH2:31][CH2:30][N:29]([C:7]([C:6]4[CH:10]=[C:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:12]=[CH:13][C:5]=4[O:4][CH:1]([CH3:2])[CH3:3])=[O:9])[CH2:28][CH2:27]3)[S:25][C:21]=2[CH:20]=1
Reactant: Clc1ccc2nc(N3CCNCC3)sc2c1
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2nc3ccc(Cl)cc3s2)CC1

Procedure:
Prepared in analogy to example 1.1 b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example 2.2) and 6-chloro-2-piperazin-1-yl-benzothiazole. The crude material was purified by chromatography (SiO2, CH2Cl2/MeOH=95/5) to yield the title compound as a yellowish solid. MS (m/e): 552.3 (M+CH3COOH+)
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][CH:2]1[C:7]([OH:9])=[O:8].[CH3:10]O>C(Cl)(Cl)Cl.C[Si](C=[N+]=[N-])(C)C>[NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([O:9][CH3:10])=[O:8]
Reactant: CO
Reactant: O=C1CCC(C(=O)O)N1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@@H]1CCC(=O)N1
Reaction time: 0.33 h

Procedure:
1 g of dl-pyroglutamic acid was dissolved in a mixed solvent of 25 ml of methanol and 15 ml of chloroform, and 7.7 ml of trimethylsilyldiazomethane (2 M hexane solution) was added to it at room temperature, and then stirred for 20 minutes as it was. The solvent was evaporated away under reduced pressure, the residue was dissolved in chloroform, and washed with saturated saline water. After dried, the solvent was removed to obtain 1.03 g of the entitled compound as a pale yellow oil.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.C(O)(=O)C.[Br:15]Br>O>[Br:15][CH2:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1)=[O:10]
Reactant: CC(=O)c1ccc(I)cc1
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: O=C(CBr)c1ccc(I)cc1
Temperature: 15 °C
Reaction time: 3 h
Yield: 102.6 %

Procedure:
Dissolving 20 g (81 mmol) of 4′-iodo acetophenone into 200 milliliter of acetic acid, and adding 12.8 g (81 mmol) of bromine while cooling with ice, stirred at the temperature of 15° C. for 3 hours. After the color of bromine disappeared, adding water and separating the precipitated solids by filtration, thereby obtained 27 g of crude 2-bromo-4′-iodo acetophenone.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-])=O)[CH:11]=2)=[O:8])=[CH:5][C:4]([CH3:19])=[N:3]1.O.NN>C(O)C.[Pd]>[NH2:16][C:12]1[CH:11]=[C:10]([NH:9][C:7]([C:6]2[N:2]([CH3:1])[N:3]=[C:4]([CH3:19])[CH:5]=2)=[O:8])[CH:15]=[CH:14][CH:13]=1
Reactant: Cc1cc(C(=O)Nc2cccc([N+](=O)[O-])c2)n(C)n1
Agent: [Pd]
Agent: NN
Solvent: CCO
Solvent: O
Product: Cc1cc(C(=O)Nc2cccc(N)c2)n(C)n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 100.9 %

Procedure:
To a solution of 3-nitroaniline (1.0 g, 7.2 mmol) in N,N-dimethylacetamide (6 mL) was added a solution of 1,3-dimethyl-1H-pyrazole-5-carbonylchloride (1260 mg, 8.0 mmol) in N,N-dimethylacetamide (2 mL), and the mixture was stirred at room temperature for 30 min. Water (200 mL) was added to the mixture under ice-cooling, and the mixture was filtrated. The obtained solid was washed with water and diethyl ether to give 1,3-dimethyl-N-(3-nitrophenyl)-1H-pyrazole-5-carboxamide (1850 mg, 7.1 mmol). To a solution of the obtained 1,3-dimethyl-N-(3-nitrophenyl)-1H-pyrazole-5-carboxamide (1850 mg, 7.1 mmol) in ethanol (50 mL) was added 10% palladium/carbon (190 mg). Hydrazine monohydrate (1090 mg, 22 mmol) was slowly added to the mixture at room temperature and the mixture was stirred at 60° C. for 1 hr. The reaction mixture was filtrated, and the filtrate was evaporated under reduced pressure. To the residue were added ethyl acetate and water, and the aqueous layer was extracted with ethyl acetate (×4). Combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The filtrate was concentrated under reduced pressure, and the residue was washed with ethyl acetate/hexane to give the title compound (1650 mg, 99%) as a pale-yellow solid.
Reaction SMILES: CC(C[AlH]CC(C)C)C.[CH3:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[CH:22]=[CH:21][C:20](/[C:23](/[CH3:30])=[CH:24]/[C:25](OCC)=[O:26])=[CH:19][CH:18]=1>>[CH3:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[CH:18]=[CH:19][C:20](/[C:23](/[CH3:30])=[CH:24]/[CH2:25][OH:26])=[CH:21][CH:22]=1
Reactant: CCOC(=O)/C=C(\C)c1ccc(-c2ccccc2C)cc1
Agent: CC(C)C[AlH]CC(C)C
Product: C/C(=C\CO)c1ccc(-c2ccccc2C)cc1

Procedure:
The colourless oil (E)-3-(2′-methyl-biphenyl-4-yl)-but-2-en-1-ol was prepared by DIBAL-H reduction of (E)-ethyl 3-(2′-methyl-biphenyl-4-yl)-but-2-enoate by a procedure analogous to that described in example 50b.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:22]2[C:27](=[O:28])[NH:26][C:25](=[O:29])[C:24]([C:30]#[N:31])=[N:23]2)[CH:5]=[C:6]([Cl:21])[C:7]=1[O:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12](=[O:18])[N:11]([CH2:19][OH:20])[N:10]=1.C(N(CC)C(C)C)(C)C.Cl[C:42]([O:44][CH2:45][CH3:46])=[O:43]>C(Cl)Cl>[CH2:45]([O:44][C:42](=[O:43])[O:20][CH2:19][N:11]1[C:12](=[O:18])[C:13]([CH:15]([CH3:17])[CH3:16])=[CH:14][C:9]([O:8][C:7]2[C:6]([Cl:21])=[CH:5][C:4]([N:22]3[C:27](=[O:28])[NH:26][C:25](=[O:29])[C:24]([C:30]#[N:31])=[N:23]3)=[CH:3][C:2]=2[Cl:1])=[N:10]1)[CH3:46]
Reactant: CCOC(=O)Cl
Reactant: CC(C)c1cc(Oc2c(Cl)cc(-n3nc(C#N)c(=O)[nH]c3=O)cc2Cl)nn(CO)c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)OCn1nc(Oc2c(Cl)cc(-n3nc(C#N)c(=O)[nH]c3=O)cc2Cl)cc(C(C)C)c1=O
Temperature: 25 °C
Yield: 38.9 %

Procedure:
A solution of 2-[3,5-dichloro-4-(1-hydroxymethyl-5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)-phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carbonitrile (200 mg, 0.43 mmol), 4-N,N-dimethyaminopyridine (25.3 mg, 0.21 mmol), N,N-diisopropylethylamine (0.23 mL, 1.29 mmol), in methylene chloride (3 mL) at 0° C. was treated with ethyl chloroformate (45 μL, 0.47 mmol). The reaction was stirred at allowed to gradually warm to 25° C. and was stirred at 25° C. for 48 h. At this time, the reaction mixture was diluted with methylene chloride (100 mL) and was washed with water (3×100 mL). The combined organics were washed with a saturated aqueous sodium chloride solution (1×100 mL), dried over magnesium sulfate, filtered, rinsed and concentrated in vacuo. ISCO CombiFlash chromatography (40 g, 1-10% methanol/methylene chloride) followed by reverse phase chromatography (Pursuit C-18 column, acetonitrile gradient with ammonium acetate) afforded carbonic acid 3-[2,6-dichloro-4-(6-cyano-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-phenoxy]-5-isopropyl-6-oxo-6H-pyridazin-1-ylmethyl ester ethyl ester (89.9 mg, 39%) as a white solid. ES+-HRMS m/e calcd for C21H18N6O7Cl2 (M+H+) 537.0687, found 537.0686.
Reaction SMILES: [CH:1]1([C:5](=O)[CH2:6][C:7]#[N:8])[CH2:4][CH2:3][CH2:2]1.[NH2:10][NH2:11]>CCO>[CH:1]1([C:5]2[NH:11][N:10]=[C:7]([NH2:8])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: N#CCC(=O)C1CCC1
Reactant: NN
Solvent: CCO
Product: Nc1cc(C2CCC2)[nH]n1
Temperature: 75 °C
Reaction time: 14 h
Yield: 91 %

Procedure:
To an aliquot of the crude 3-cyclobutyl-3-oxo-propionitrile (10.0 g, 81.3 mmol) prepared above in EtOH (300 mL) was added hydrazine. The resulting mixture was heated to 75° C. (oil bath). After 14 hr, the reaction was cooled to room temperature and concentrated under reduced pressure. The resulting oil was taken up in EtOAc and washed with saturated aqueous NaHCO3 solution. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered through a pad of diatomaceous earth, and concentrated under reduced pressure. Purification of this material was accomplished by flash column chromatography on a Biotage® 75S MPLC system (A Dynax Corp., Charlottesville, Va.), eluting with 100 EtOAc (2 L) and 10% MeOH/CH2Cl2 (2 L). The product-containing fractions were collected and concentrated to give the title compound (10.0 g, 91% yield) as a brown oil. 400 MHz 1H NMR (CDCl3) d 5.47 (s, 1H), 5.25 (bs, 3H), 3.40 (dddd, J=8.3, 8.3, 8.3, 8.3 Hz, 1H), 2.34-2.27 (m, 2H), 2.16-1.88 (m, 4H). LRMS m/z (APCI+) 138 (M+1).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH:8]=[C:7]([C:10]2[C:18]3[S:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)=[N:15][C:14]=3[C:13]([O:29][CH3:30])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]>CO.[Pd]>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:18]3[S:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=4)=[N:15][C:14]=3[C:13]([O:29][CH3:30])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: COc1ccc(C2=CCN(C(C)=O)CC2)c2sc(NC(=O)c3ccc(F)cc3)nc12
Agent: [Pd]
Solvent: CO
Product: COc1ccc(C2CCN(C(C)=O)CC2)c2sc(NC(=O)c3ccc(F)cc3)nc12
Reaction time: 6 h
Yield: 5.2 %

Procedure:
To a solution of 0.04 g (0.94 mMol) of N-[7-(1-acetyl-1,2,3,6-tetrahydro-pyridin-4-yl)-4-methoxy-benzothiazol-2-yl]-4-fluoro-benzamide in 2.0 ml of methanol 10.0 mg of Pd/C (10%) were added. This reaction mixture was hydrogenated at 60° C. for 6 h, then filtered and evaporated to dryness in vacuo to yield 0.021 g (52%) N-[7-(1-acetyl-piperidin-4-yl)-4-methoxy-benzothiazol-2-yl]-4-fluoro-benzamide as a white solid. F.p.: 225-233° C.
Reaction SMILES: [H-].[Na+].[NH2:3]/[C:4](/[C:11]([F:14])([F:13])[F:12])=[CH:5]\[C:6]([O:8]CC)=O.[CH2:15]([O:17][N:18]=[CH:19][C:20]1[CH:25]=[C:24]([N:26]=[C:27]=[O:28])[C:23]([Cl:29])=[CH:22][C:21]=1[Cl:30])[CH3:16]>>[CH2:15]([O:17][N:18]=[CH:19][C:20]1[CH:25]=[C:24]([N:26]2[C:6](=[O:8])[CH:5]=[C:4]([C:11]([F:12])([F:13])[F:14])[NH:3][C:27]2=[O:28])[C:23]([Cl:29])=[CH:22][C:21]=1[Cl:30])[CH3:16]
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Reactant: CCON=Cc1cc(N=C=O)c(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Product: CCON=Cc1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(Cl)cc1Cl

Procedure:
9.2 g (0.31 mol) of sodium hydride, 51.3 g (0.28 mol) of ethyl 3-amino-4,4,4-trifluorocrotonate and 72.6 g (0.28 mol) of 2,4-dichloro-5-isocyanatobenzaldehyde (O-ethyl)oxime were reacted in the manner described for precursor 3.2. Yield: 72.0 g; m.p.: 205-209° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]([NH2:13])=[S:12])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Br[CH2:15][C:16](=O)[C:17]([O:19]CC)=[O:18]>C(O)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[S:12][CH:15]=[C:16]([C:17]([OH:19])=[O:18])[N:13]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CCOC(=O)C(=O)CBr
Reactant: NC(=S)Nc1ccc2[nH]ccc2c1
Solvent: CCO
Product: O=C(O)c1csc(Nc2ccc3[nH]ccc3c2)n1

Procedure:
A solution of 5-aminoindole (8 g, 60.6 mmol) in acetone (150 mL) was reacted with benzoylisothiocyanate (9.88 g, 60. mmol) at RT for about 4 h. The resulting solid was filtered and treated with 2 N NaOH in THF (120 mL). The mixture was refluxed for about 6 h and allowed to warm to RT. The solvent was evaporated off under vacuum. The residue was diluted with water (20 mL) and neutralized to pH 7 with 1 N HCl. The resulting solid was filtered and dried under vacuum to afford 5-indolylthiourea (55-2). 5-Indolyl thiourea (0.01 mol) and ethyl bromopyruvate (0.011 mol) were dissolved in 3 mL ethanol and held at reflux for 2 h. The reaction was cooled, the crystalline ethyl 2-(1H-indol-5-ylamino)thiazole-4-carboxylate (55-3) was collected by filtration and washed with ethanol. Refluxing the mixture of ethyl esters with the NaOH-ethanol solution gave 2-(1H-indol-5-ylamino)thiazole-4-carboxylic acid (55-4) which was used directly in next steps. To a mixture of the crude acid (2.5 mmol), EDCI (2.9 mmol), HOBt (2.6 mmol) and NMM (5.3 mmol) in CH2Cl2 (30 mL) was added HNCH3OCH3HCl salt (2.6 mmol) and stirring continued at RT for overnight. The reaction mixture was diluted with CH2Cl2 (20 mL) and sequentially washed with water, satd. NaHCO3, brine and dried over MgSO4. The solvent was removed under reduced pressure to yield a crude product, which was purified by column chromatography to obtain pure compound 2-(1H-indol-5-ylamino)-N-methoxy-N-methylthiazole-4-carboxamide (55-5) (45.6% yield for overall 5 steps). At −78° C., to a solution of 5-bromo-1,2,3-trimethoxybenzene (1.235 g, 5.0 mmol) in 30 mL THF was charged n-BuLi in hexane (2.5 N, 2.4 mL, 6 mmol) under Ar2 protection and stirred for 10 min Weinreb amide (1 mmol) in 10 mL THF was added to lithium reagent and allowed to stir at RT for 2 h. The reaction mixture was quenched with satd. NH4Cl, extracted with ethyl ether, dried with MgSO4. The solvent was removed under reduced pressure to yield a crude product, which was purified by column chromatography to obtain pure compound 55 (51.7% yield). 1H NMR (300 MHz, CDCl3) δ 8.29 (br, 1H), 7.68 (d, 1H), 7.46 (s, 2H), 7.39 (s, 1H), 7.36 (s, 1H), 7.28-7.26 (m, 1H), 7.15-7.12 (m, 1H), 6.55 (m, 1H), 3.93 (s, 3H), 3.89 (s, 6H). MS (ESI) m/z 432.1 (M+Na)+, 408.0 (M−H)−.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])[CH2:10][CH:9]1[CH2:22][OH:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])[CH2:10][CH:9]1[CH2:22][O:23][C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CC(Oc2ccc(F)cc2F)CC1CO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCC2CC(Oc3ccc(F)cc3F)CN2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Yield: 75.1 %

Procedure:
To a stirred solution of 1-(tert-butoxycarbonyl)-4-(2,4-difluorophenoxy)-2-pyrrolidinylmethanol (500 mg, 1.52 mmol), methyl 4-hydroxybenzoate (277 mg, 1.82 mmol), and Ph3P (477 mg, 1.82 mmol) in THF (10 ml) was added DIAD (358 ul, 1.82 mmol), and the mixture was heated at reflux for 5 h. After cooling to room temperature, the mixture was concentrated in vacuo and the residue was chromatographed on silica gel with CHCl3-EtOAc (20:1) as eluent to give methyl 4-[1-(tert-butoxycarbonyl)-4-(2,4-difluorophenoxy)-2-pyrrolidinylmethoxy]benzoate (529 mg, 75%) as a colorless oil. 1H-NMR (CDCl3) δ1.46 (s, 9 H), 2.20-2.47 (m, 2 H), 3.64 (m, 2 H), 3.86 (s, 3 H), 4.07-4.43 (m, 3 H), 4.86 (m, 1 H), 6.74-6.87 (m, 3 H), 6.94 (d, 2 H, J=8.5 Hz), 7.95 (d, 2 H, J=8.5 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:18])[N:9]([CH3:17])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3I)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:19]1([C:25]#[CH:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(NCC)C.C(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[C:7]2[C:8](=[O:18])[N:9]([CH3:17])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:26]#[C:25][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CN1Cc2c(I)ncn2-c2cccc(Cl)c2C1=O
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: ClCCl
Solvent: CCNCC
Product: CN1Cc2c(C#Cc3ccccc3)ncn2-c2cccc(Cl)c2C1=O

Procedure:
3.73 g (10 mmol) of 7-chloro-4,5-dihydro-3-iodo-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one was stirred at room temperature for 20 hours with 1.12 g (11 mmol) of phenylacetylene, 70 mg of bis-(triphenylphosphine)-palladium(II) dichloride and 10 mg of copper(I) iodide in 20 ml of diethylamine. The reaction mixture was diluted with methylene chloride and washed twice with water. The organic phase was dried over magnesium sulphate and evaporated. After recrystallization of the residue from ethyl acetate there was obtained 7-chloro-4,5-dihydro-5-methyl-3-(phenylethynyl)-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 205°-206°.