Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:30])=[C:7]2[C:12](=[C:13](Br)[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:8]2)=[O:4].C([Sn](CCCC)(CCCC)[C:36]1[S:40][CH:39]=[N:38][CH:37]=1)CCC.CCOC(C)=O.Cl>CN(C=O)C.[Cl-].[Na+].O.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>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:30])=[C:7]2[C:12](=[C:13]([C:36]3[S:40][CH:39]=[N:38][CH:37]=3)[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:8]2)=[O:4]
Reactant: COC(=O)c1nc(Br)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1nc(-c2cncs2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 120 °C
Yield: 59.1 %

Procedure:
A mixture of 1-benzyl-8-bromo-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (100 mg, 0.22 mmol), 5-tributylstannanyl-thiazole (121 mg, 0.32 mmol) and PdCl2(PPh3)2 (30 mg, 0.043 mmol) in 5 mL of DMF was heated at 120° C. for 2 h under nitrogen atmosphere. After the mixture was cooled to r.t., EtOAc and brine were added. 1 M HCl was added with stirring until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the combined organic layer was washed with water and brine, and dried over MgSO4. After evaporating the solvent in vacuo, the crude product was purified twice by silica gel chromatography (0-50% EtOAc/CH2Cl2, then 5-60% EtOAc/hexanes+1% AcOH) to give 61 mg of the title compound. MS: (+) m/z 470.39 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1.[CH:28]([C@@H:31]1[C:35]([CH3:37])([CH3:36])[O:34][C:33](=[O:38])[NH:32]1)([CH3:30])[CH3:29]>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:32]4[C@H:31]([CH:28]([CH3:29])[CH3:30])[C:35]([CH3:36])([CH3:37])[O:34][C:33]4=[O:38])=[CH:3][C:4]=3[S:24]([CH3:27])(=[O:26])=[O:25])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Reactant: CC(C)[C@H]1NC(=O)OC1(C)C
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)OC(C)(C)[C@H]4C(C)C)cc3S(C)(=O)=O)CC2)c(C)c1
Yield: 4.9 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (4-bromo-2-methanesulfonylphenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (890 mg) described in Preparation Example 61 and (R)-(+)-4-isopropyl-5,5-dimethyloxazolidin-2-one (409 mg), the title compound (51 mg) was obtained.
Reaction SMILES: Cl.[NH2:2][C:3]1[S:4][C:5]([Cl:8])=[CH:6][N:7]=1.[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([O:19][CH3:20])=[C:14]([CH:18]=1)[C:15](O)=[O:16].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([O:19][CH3:20])=[C:14]([CH:18]=1)[C:15]([NH:2][C:3]1[S:4][C:5]([Cl:8])=[CH:6][N:7]=1)=[O:16]
Reactant: Nc1ncc(Cl)s1
Reactant: COc1ccc(Cl)cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(Cl)cc1C(=O)Nc1ncc(Cl)s1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 2-amino-5-chlorothiazole hydrochloric acid (1.0 g, 5.9 mmol), 5-chloro-2-methoxybenzoic acid (1.3 g, 7.0 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (Chem-Impex International, 2.2 g, 12 mmol), 1-hydroxybenzotriazole (0.95 g, 7.0 mmol) and 4-dimethylaminopyridine (0.14 g, 1.2 mmol) in 6 mL of pyridine was allowed to stir at ambient temperature for 72 hours. The reaction mixture was concentrated under reduced pressure and 10 mL of H2O was added. The resulting solids were isolated by filtration, washed with 5 mL of H2O and twice with 5 mL of ethyl acetate, and dried to afford the title compound. MS (DCI/NH3) m/Z 303 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[S:13][C:12]([NH:14][C:15](=[O:17])[CH3:16])=[N:11][C:10]=2[CH3:18])[CH:5]=[N:6][C:7]=1[Cl:8].[CH:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([BH3-])#N.[Na+].Cl[Si](C)(C)C>CN1C(=O)CCC1.C(O)(=O)C>[CH2:19]([NH:1][C:2]1[CH:3]=[C:4]([C:9]2[S:13][C:12]([NH:14][C:15](=[O:17])[CH3:16])=[N:11][C:10]=2[CH3:18])[CH:5]=[N:6][C:7]=1[Cl:8])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=Cc1ccccc1
Reactant: CC(=O)Nc1nc(C)c(-c2cnc(Cl)c(N)c2)s1
Agent: C[Si](C)(C)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CC(=O)O
Product: CC(=O)Nc1nc(C)c(-c2cnc(Cl)c(NCc3ccccc3)c2)s1
Reaction time: 8 h
Yield: 46.3 %

Procedure:
N-[5-(5-amino-6-chloropyridin-3-yl)-4-methyl-1,3-thiazol-2-yl]acetamide (30 mg, 0.11 mmol), benzaldehyde (0.016 mL, 0.16 mmol) and sodium cyanoborohydride (13 mg, 0.21 mmol) were mixed in NMP (0.9 mL) and acetic acid (0.1 mL). Chlorotrimethylsilane (0.04 mL, 0.32 mmol) was added and the mixture was stirred overnight. The reaction product was purified by preparative HPLC (Method A) to give the title product (retention time 9.73 minutes; 19 mg); 1H NMR Spectrum: (DMSOd6) 12.13 (1H, s); 7.60 (1H, d); 7.38-7.30 (4H, m); 7.22 (1H, t); 6.80 (1H, d); 6.67 (1H, s); 4.47 (2H, s); 2.12 (3H, s); 2.03 (3H, s); Mass Spectrum: M+H+ 373 and 375.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.C[CH2:13][O:14][C:15](C)=[O:16].O.C([O-])(O)=O.[Na+].ClC(OC)=O>CCOC(C)=O>[CH3:13][O:14][C:15](=[O:16])[NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2
Reactant: CCOC(C)=O
Reactant: Nc1ccc2c(c1)CCC2=O
Agent: COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: COC(=O)Nc1ccc2c(c1)CCC2=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 89 %

Procedure:
To a suspension of 5-Amino-indan-1-one (commercially available, 100 mg, 0.679 mmol, 1 eq.) in a 2:1 v/v mixture of EtOAc/H2O (6 mL) is added NaHCO3 (114 mg, 1.36 mmol, 2 eq.). The resulting mixture is cooled to 0° C. followed by the addition of methyl chloroformate (0.052 mL, 0.679 mmol, 1 eq.). After stirring at 0° C. for 15 min., the reaction is warmed to 25° C. and stirred for 12 h. The reaction is diluted with EtOAc and sequentially washed with 1 N HCl (aq) and saturated aqueous NaCl. The resulting organic solution is dried over Na2SO4 and concentrated to give (1-Oxo-indan-5-yl)-carbamic acid methyl ester as a tan solid (124 mg, 89% yield). [MS: (ES+) 206.1 (M+1)+].
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([C:8]2[C:13]([F:14])=[CH:12][C:11]([F:15])=[CH:10][N:9]=2)[CH:7]=1.[B:17]1(B2OCC(C)(C)CO2)[O:22]CC(C)(C)C[O:18]1.O1CCOCC1.C([O-])(=O)C.[K+]>C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe].CS(C)=O>[F:16][C:5]1[CH:4]=[CH:3][C:2]([B:17]([OH:22])[OH:18])=[CH:7][C:6]=1[C:8]1[C:13]([F:14])=[CH:12][C:11]([F:15])=[CH:10][N:9]=1
Reactant: Fc1cnc(-c2cc(Br)ccc2F)c(F)c1
Reactant: CC1(C)COB(B2OCC(C)(C)CO2)OC1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CS(C)=O
Product: OB(O)c1ccc(F)c(-c2ncc(F)cc2F)c1
Temperature: 85 °C
Reaction time: 24 h
Yield: 94.3 %

Procedure:
To 2-(5-bromo-2-fluorophenyl)-3,5-difluoropyridine (0.746 g, 2.59 mmol) and bis(neopentyl glycolato)diboron (0.704 g) was added dry 1,4-dioxane (9 ml) and dry dimethylsulfoxide (1.1 ml), followed by dry potassium acetate (0.542 g) and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (0.080 g). The mixture was thoroughly degassed with nitrogen, and then stirred at 85° C. for 24 h. On cooling to room temperature, 1 N aqueous sodium hydroxide (24 ml) was added, and the mixture stirred for 0.5 h. Diethyl ether was added and the aqueous phase was separated and washed with diethyl ether. The organic extracts were washed with water, and the combined aqueous phases were filtered, then acidified to pH 5 by addition of 2 N aqueous hydrochloric acid (12 ml). The resulting solid was collected by filtration, washed with water, and dried in vacuo at 60° C. to afford 0.618 g of 4-fluoro-3-(3,5-difluoropyridin-2-yl)phenylboronic acid as a colourless solid: 1H NMR (400 MHz, DMSO-d6) δ 8.69 (1H, d, J 2.3 Hz), 8.21 (2H, s), 7.94-8.14 (3H, m), 7.34 (1H, dd, J 8.2, 10.6 Hz).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:17]3[S:18][C:19]([Cl:22])=[CH:20][CH:21]=3)=[N:10][N:11]([CH:13]([CH2:15][CH3:16])[CH3:14])[CH:12]=2)[CH:5]=[CH:4][N:3]=1.[CH3:23][N:24](C)C=O>[C-]#N.[Zn+2].[C-]#N>[C:23]([C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:17]3[S:18][C:19]([Cl:22])=[CH:20][CH:21]=3)=[N:10][N:11]([CH:13]([CH2:15][CH3:16])[CH3:14])[CH:12]=2)[CH:5]=[CH:4][N:3]=1)#[N:24]
Reactant: CN(C)C=O
Reactant: CCC(C)n1cc(-c2ccnc(Cl)c2)c(-c2ccc(Cl)s2)n1
Agent: [C-]#N
Agent: [Zn+2]
Product: CCC(C)n1cc(-c2ccnc(C#N)c2)c(-c2ccc(Cl)s2)n1
Temperature: 120 °C
Reaction time: 0.17 h
Yield: 55 %

Procedure:
To a solution of 2-chloro-4-[1-sec-butyl-3-(5-chloro-2-thienyl)-1H-pyrazol-4-yl]pyridine (0.28 mmol) in 1 mL of N,N-dimethylformamide was added zinc cyanide (0.14 mmol) and tetrakistriphenylphosphine palladium (O) (0.057 mmol). The resulting mixture was stirred in the microwave for 10 min at 120° C. After cooling to room temperature, the mixture was filtered and purified by preparative HPLC (column: Waters Sunfire C18, eluent:water/methanol/0.1% formic acid) to afford 56.7 mg of 2-cyano-4-[1-sec-butyl-3-(5-chloro-2-thienyl)-1H-pyrazol-4-yl]pyridine (55% yield).
Reaction SMILES: COC1C=C(C(C2N3C(C=CC=C3)=C(OC)C=2C)=O)C=CC=1NCC(O)=O.[CH3:28][O:29][C:30]1[CH:42]=[C:41]([C:43]([C:45]2[N:53]3[C:48]([CH:49]=[CH:50][CH:51]=[CH:52]3)=[C:47]([O:54][CH3:55])[C:46]=2[C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)=[O:44])[CH:40]=[CH:39][C:31]=1[NH:32][CH2:33][C:34]([O:36]CC)=[O:35].[OH-].[Na+]>>[CH3:28][O:29][C:30]1[CH:42]=[C:41]([C:43]([C:45]2[N:53]3[C:48]([CH:49]=[CH:50][CH:51]=[CH:52]3)=[C:47]([O:54][CH3:55])[C:46]=2[C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)=[O:44])[CH:40]=[CH:39][C:31]=1[NH:32][CH2:33][C:34]([OH:36])=[O:35]
Reactant: CCOC(=O)CNc1ccc(C(=O)c2c(-c3ccccc3)c(OC)c3ccccn23)cc1OC
Agent: COc1cc(C(=O)c2c(C)c(OC)c3ccccn23)ccc1NCC(=O)O
Agent: [Na+]
Agent: [OH-]
Product: COc1cc(C(=O)c2c(-c3ccccc3)c(OC)c3ccccn23)ccc1NCC(=O)O

Procedure:
Obtained according to the same procedure as the compound of Example 196, by saponification of ethyl 2-{2-methoxy-4-[(1-methoxy-2-phenylindolizin-3-yl)carbonyl]anilino}acetate, a compound of Example 197, with 1 N sodium hydroxide. A yellow powder is obtained.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:11][CH:10]=[C:9]1[C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([O:29]C)[CH:25]=2)[CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.N1C=CC=CC=1>>[CH2:1]([N:8]1[C:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:11][CH:10]=[C:9]1[C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[CH:25]=[C:24]([OH:29])[CH:23]=[CH:22]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2cc(-c3ccc(-c4ccccc4)n3Cc3ccccc3)ccc2c1
Agent: Cl
Solvent: c1ccncc1
Product: Oc1ccc2cc(-c3ccc(-c4ccccc4)n3Cc3ccccc3)ccc2c1
Temperature: 180 °C

Procedure:
In a similar manner as described in step 5 of Example 1, the title compound was prepared from 1-benzyl-2-(6-methoxy-2-naphthyl)-5-phenyl-1H-pyrrole (0.22 g, 0.56 mmol), prepared in the previous step, and pyridine hydrochloride (15 g) heated to 180° C. under nitrogen for 3 hours. Purification on a Biotage FlashElute™ system with a KP-Sil Flash 40+M column (90 g Silica Gel, 60 Å) using methylene chloride as the eluent gave 6-(1-benzyl-5-phenyl-1H-pyrrol-2-yl)-2-naphthol a grayish solid (0.155 g, 73%), mp 153–154° C. Elemental Analysis for C27H21NO Calc'd: C, 86.37; H, 5.64; N, 3.73. Found: C, 85.95; H, 5.86; N, 3.59.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([N+:37]([O-:39])=[O:38])[CH:32]=2)[C:7]([C:13]([O:15][CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]([NH2:30])([CH3:29])[CH3:28])=[CH:21][CH:20]=2)=[O:14])=[C:8]([CH3:12])[NH:9][C:10]=1[CH3:11])=[O:4].[O:40]1[CH2:52][CH:41]1[CH2:42][O:43][C:44]1[CH:51]=[CH:50][CH:49]=[CH:48][C:45]=1[C:46]#[N:47]>C(O)(C)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([N+:37]([O-:39])=[O:38])[CH:32]=2)[C:7]([C:13]([O:15][CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]([NH:30][CH2:52][CH:41]([OH:40])[CH2:42][O:43][C:44]3[CH:51]=[CH:50][CH:49]=[CH:48][C:45]=3[C:46]#[N:47])([CH3:29])[CH3:28])=[CH:21][CH:20]=2)=[O:14])=[C:8]([CH3:12])[NH:9][C:10]=1[CH3:11])=[O:4]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCOc2ccc(OCC(C)(C)N)cc2)C1c1cccc([N+](=O)[O-])c1
Reactant: N#Cc1ccccc1OCC1CO1
Solvent: CC(C)O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCOc2ccc(OCC(C)(C)NCC(O)COc3ccccc3C#N)cc2)C1c1cccc([N+](=O)[O-])c1

Procedure:
A solution of 5.4 g (10 mmol) of 1,4-dihydro-2,6-dimethyl-4-(m-nitrophenyl)-pyridine-3,5-dicarboxylic acid 3-{2-[p-(2-amino-2-methylpropoxy)-phenoxy]-ethyl}-ester 5-methyl ester and 2.3 g (13 mmol) of 2-(2,3-epoxypropoxy)-benzonitrile in 30 ml of isopropanol is heated under reflux for 18 hours. After working up and chromatography analogously to Example 1, 1,4-dihydro-2,6-dimethyl-4-(m-nitrophenyl)-pyridine-3,5-dicarboxylic acid 3-{{{2-{{p-{2-[3-(o-cyanophenoxy)-2-hydroxypropylamino]-2-methylpropoxy}-phenoxy}}-ethyl}}}-ester 5-methyl ester is obtained in the form of an amorphous solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[C:4]([CH3:15])[CH:3]=1.[Cl:16][C:17]1[CH:32]=[CH:31][C:20]([O:21][C:22]2[N:26]([CH3:27])[N:25]=[C:24]([CH3:28])[C:23]=2[CH:29]=O)=[CH:19][CH:18]=1.C([BH3-])#N.[Na+].C(O)(=O)C>C(#N)C.CO>[Cl:16][C:17]1[CH:32]=[CH:31][C:20]([O:21][C:22]2[N:26]([CH3:27])[N:25]=[C:24]([CH3:28])[C:23]=2[CH2:29][NH:1][C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:11])([CH3:12])[CH3:13])=[C:4]([CH3:15])[CH:3]=2)=[CH:19][CH:18]=1
Reactant: Cc1nn(C)c(Oc2ccc(Cl)cc2)c1C=O
Reactant: Cc1cc(N)ccc1NC(=O)C(C)(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Solvent: CC(=O)O
Product: Cc1cc(NCc2c(C)nn(C)c2Oc2ccc(Cl)cc2)ccc1NC(=O)C(C)(C)C
Temperature: 170 °C
Reaction time: 0.33 h

Procedure:
A mixture of N-(4-Amino-2-methylphenyl)-2,2-dimethylpropionamide (300 mg, 1.45 mmol) and 5-(4-Chlorophenoxy)-1,3-dimethyl-1H-pyrazole-4-carbaldehyde (360 mg, 1.45 mmol) in acetonitrile (4 mL) was heated and stirred at 170° C. under microwave irradiation for 20 minutes. The obtained reaction mixture was added carefully into solution of sodium cyanoborohydride (0.36 g) in methanol followed by acetic acid (1 mL). After 60 minutes it was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution and the organic layer was evaporated. The title compound was separated by flash chromatography on SiO2 with gradient heptane-ethyl acetate and then precipitated from ethyl acetate with heptane. Yield 112 mg, 18%. LC/MS-TOF (m/z) 441; RT=2.34, (UV, ELSD) 98%, 100%. 1H NMR (DMSO-d6): 1.18 (s, 9H), 1.96 (s, 3H), 2.15 (s, 3H), 3.47 (s, 3H), 3.75 (d, 2H), 5.4 (t, 1H, NH), 6.29 (dd, 1H), 6.33 (d, 1H), 6.24 (d, 1H), 6.99 (d, 2H), 7.41 (d, 2H), 8.58 (s, 1H, NH).
Reaction SMILES: [CH2:1]([O:8][N:9]1[CH2:13][CH2:12][NH:11][C:10]1=[N:14][C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:25]I>CN(C)C=O.C1(C)C=CC=CC=1>[CH2:1]([O:8][N:9]1[CH2:13][CH2:12][N:11]([CH3:25])[C:10]1=[N:14][C:15]1[C:16]([Cl:22])=[CH:17][CH:18]=[CH:19][C:20]=1[Cl:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: Clc1cccc(Cl)c1N=C1NCCN1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CN1CCN(OCc2ccccc2)C1=Nc1c(Cl)cccc1Cl
Reaction time: 1 h

Procedure:
16.8 g of 1-(benzyloxy)-2-[(2,6-dichlorophenyl)imino]-imidazolidine are dissolved in 80 ml of dimethylformamide and treated while stirring at room temperature with 1.44 g of sodium hydride. After 1 hour, there is added dropwise thereto a solution of 4 ml of methyl iodide in 20 ml of toluene. The temperature rises to 48°. After 16 hours, the mixture is poured into ice and extracted with ether. The organic phase is washed successively with water, 15 percent tartaric acid solution and water, dried over magnesium sulfate and evaporated in vacuo. The 1-(benzyloxy)-2-[(2,6-dichlorophenyl)imino]-3-methylimidazolidine obtained is used in the next step without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[N:14]3[N:15]=[N:16][N:17]=[C:13]3[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:11]([CH3:28])=[C:10]2[C:29]([NH2:31])=O)=[CH:5][CH:4]=1)#[N:2].[OH-].COC(NS([N+](CC)(CC)CC)(=O)=O)=O>C1COCC1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[N:14]3[N:15]=[N:16][N:17]=[C:13]3[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:11]([CH3:28])=[C:10]2[C:29]#[N:31])=[CH:5][CH:4]=1)#[N:2]
Reactant: CC1=C(C(N)=O)[C@@H](c2ccc(C#N)cc2)n2nnnc2N1c1cccc(C(F)(F)F)c1
Agent: CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC
Agent: [OH-]
Solvent: C1CCOC1
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nnnc2N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The reaction was carried out under argon. (7R)-7-(4-Cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxamide (34 mg, 80 μmol) was initially charged in dry THF (1.9 ml), methoxycarbonylsulfamoyltriethylammonium hydroxide (Burgess reagent; 76 mg, 320 μmol, 4 eq.) was added and the mixture was stirred at RT for 1 h. HPLC showed complete conversion. The reaction mixture was then concentrated and the residue was purified by preparative HPLC (Gromsil C18 column, 10 μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). The title compound was obtained as a solid (29 mg, 89% of theory).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:26][CH3:27])=[C:4]([C:17]([CH3:25])=[C:18]([F:24])[C:19](OCC)=[O:20])[CH:5]=[C:6]2[C:11]=1[O:10][C:9]([CH3:13])([CH3:12])[CH:8]=[C:7]2[CH:14]([CH3:16])[CH3:15].ClC1C(OC)=C(/C(/C)=C(/F)\C(OCC)=O)C=C2C=1OC(C)(C)C=C2C(C)C.[H-].C([Al+]CC(C)C)C(C)C>>[Cl:1][C:2]1[C:3]([O:26][CH3:27])=[C:4](/[C:17](/[CH3:25])=[C:18](/[F:24])\[CH2:19][OH:20])[CH:5]=[C:6]2[C:11]=1[O:10][C:9]([CH3:12])([CH3:13])[CH:8]=[C:7]2[CH:14]([CH3:16])[CH3:15]
Reactant: CCOC(=O)C(F)=C(C)c1cc2c(c(Cl)c1OC)OC(C)(C)C=C2C(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: CCOC(=O)/C(F)=C(/C)c1cc2c(c(Cl)c1OC)OC(C)(C)C=C2C(C)C
Agent: [H-]
Product: COc1c(/C(C)=C(/F)CO)cc2c(c1Cl)OC(C)(C)C=C2C(C)C

Procedure:
Following General Procedure L, ethyl 3-(8-chloro-4-isopropyl-7-methoxy-2,2-dimethyl-2H-chromen-6-yl)-2-fluoro-but-2-enoate (Compound 146, 110 mg, 0.28 mmol) and diisobutylaluminum hydride (1 M in hexanes, 1.1 mL, 1.1 mmol) were reacted to give the title compound as a colorless oil after purification by flash chromatography (silica gel, 1:9 to 1:4 ethyl acetate/hexane).
Reaction SMILES: [CH2:1]([SH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=2F)=[O:17])=[CH:12][CH:11]=1.[Cl-].[NH4+].C(=O)([O-])O.[Na+]>C1COCC1>[CH2:1]([S:8][C:19]1[CH:20]=[C:21]([O:24][CH3:25])[CH:22]=[CH:23][C:18]=1[C:16]([C:13]1[CH:14]=[CH:15][C:10]([Br:9])=[CH:11][CH:12]=1)=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)c2ccc(Br)cc2)c(F)c1
Reactant: SCc1ccccc1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)c2ccc(Br)cc2)c(SCc2ccccc2)c1
Temperature: 25 °C

Procedure:
4.3 g of potassium tert. butylate are dissolved in 160 ml of THF and treated slowly with 4.5 ml of benzyl mercaptan. The suspension is stirred at RT and then treated with 10 g of (4-bromophenyl)-(2-fluoro-4-methoxy-phenyl)-methanone in 200 ml of THF. The solution is stirred at RT and treated with 100 ml of ammonium chloride solution as well as 200 ml of sodium hydrogen carbonate solution. The phases are separated, the inorganic phase is extracted with ethyl acetate and the organic phases are washed with sat. sodium hydrogen carbonate solution and sodium chloride solution and dried. There are obtained 15.8 g of (2-benzylsulphanyl-4-methoxyphenyl)-(4-bromo-phenyl)-methanone which are taken up in 160 ml of methylene chloride, treated with 3.4 ml of sulphuryl chloride and stirred at RT. After distillation of the sulphuryl chloride the residue is taken up in 160 ml of THF, treated with 120 ml of a saturated ammonia solution in ethanol and stirred. 100 ml of sodium hydrogen carbonate solution are added. The solvent is removed and the residue is again taken up in sodium hydrogen carbonate solution and ethyl acetate. The phases are separated and the inorganic phase is extracted with ethyl acetate and ether. The organic phases are washed with sodium chloride solution and dried. Recrystallization from ethyl acetate/ethanol yields 7.52 g of 3-(4-bromo-phenyl)-6-methoxy-[d]-benzisothiazole, MS: m/e 318 (M, 1 Br).
Reaction SMILES: [CH2:1]([O:3][O:4][P:5]([CH2:11][CH2:12][N:13]1[C:17](=[O:18])[C:16]([CH3:20])([CH3:19])[NH:15][C:14]1=[O:21])([O:7][O:8][CH2:9][CH3:10])=[O:6])[CH3:2].[CH2:22]([CH:24]1[O:26][CH2:25]1)Cl.[OH-].[Na+]>[Cl-].C[N+](C)(C)C>[CH2:22]([N:15]1[C:16]([CH3:19])([CH3:20])[C:17](=[O:18])[N:13]([CH2:12][CH2:11][P:5]([O:7][O:8][CH2:9][CH3:10])([O:4][O:3][CH2:1][CH3:2])=[O:6])[C:14]1=[O:21])[CH:24]1[O:26][CH2:25]1
Reactant: ClCC1CO1
Reactant: CCOOP(=O)(CCN1C(=O)NC(C)(C)C1=O)OOCC
Agent: C[N+](C)(C)C
Agent: [Cl-]
Agent: [Na+]
Product: CCOOP(=O)(CCN1C(=O)N(CC2CO2)C(C)(C)C1=O)OOCC
Temperature: 105 °C
Reaction time: 1.75 h

Procedure:
A mixture of 146.1 g of 3-(diethoxyphosphonoethyl)-5,5-dimethyl-hydantoin (0.5 mol), 694 g of epichlorohydrin (7.5 mols) and 0.5 g of tetramethylammonium chloride is stirred for 105 minutes at 105° C. 44 g of 50% strength aqueous sodium hydroxide solution are added dropwise over the course of 3 hours at 60° C, analogously to Example 1 (c). The mixture is worked up analogously to Example 1 (c) and 157 g of a yellow, clear resin (90.2% of theory) with 2.74 epoxide equivalents/kg (95.5% of theory) and a phosphorus content of 6.13% are obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH:5]1[CH2:10][N:9]([CH3:11])[CH2:8][C:7]([NH2:18])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6]1.[CH3:19][O:20][C:21]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([S:34][CH3:35])[C:22]=1[C:23](Cl)=[O:24]>>[CH3:19][O:20][C:21]1[CH:29]=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:27]=[C:26]([S:34][CH3:35])[C:22]=1[C:23]([NH:18][C:7]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6][CH:5]([O:4][CH2:3][O:2][CH3:1])[CH2:10][N:9]([CH3:11])[CH2:8]1)=[O:24]
Reactant: COCOC1CN(C)CC(N)(c2ccccc2)C1
Reactant: COc1cc(C(F)(F)F)cc(SC)c1C(=O)Cl
Product: COCOC1CN(C)CC(NC(=O)c2c(OC)cc(C(F)(F)F)cc2SC)(c2ccccc2)C1

Procedure:
In analogy to the procedure described for the synthesis of example 16, the title compound was prepared from rac-5-methoxymethoxy-1-methyl-3-phenyl-piperidin-3-ylamine (Example A.10) and 2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzoyl chloride (Example B.6).