Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Cl:4][C:5]1[CH:6]=[CH:7][C:8]([N:13]2[C:17]3=[N:18][C:19]4[C:24]([Cl:25])=[CH:23][CH:22]=[C:21]([CH:26]([CH2:29][CH3:30])[CH2:27][CH3:28])[C:20]=4[N:16]3[CH2:15][CH2:14]2)=[C:9]([CH:12]=1)[CH:10]=O.C(O)(=O)C.C([BH3-])#N.[Na+]>CO.O1CCCC1.O>[Cl:4][C:5]1[CH:6]=[CH:7][C:8]([N:13]2[C:17]3=[N:18][C:19]4[C:24]([Cl:25])=[CH:23][CH:22]=[C:21]([CH:26]([CH2:29][CH3:30])[CH2:27][CH3:28])[C:20]=4[N:16]3[CH2:15][CH2:14]2)=[C:9]([CH2:10][N:2]([CH3:3])[CH3:1])[CH:12]=1
Reactant: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCN3c1ccc(Cl)cc1C=O
Reactant: CNC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CO
Product: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCN3c1ccc(Cl)cc1CN(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37 %

Procedure:
Dimethylamine (2.0 M solution in tetrahydrofuran, 0.096 mL, 0.194 mmol) was added to a solution of 5-chloro-2-[8-chloro-5-(1-ethylpropyl)-2,3-dihydro-1H-imidazo[1,2-a]benzimidazol-1-yl]benzaldehyde (26 mg, 0.0646 mmol) in a mixture of methanol (0.5 mL) and tetrahydrofuran (0.5 mL). After the mixture was stirred for 30 min at room temperature, acetic acid (0.037 mL, 0.0646 mmol) and sodium cyanoborohydride (12 mg, 0.194 mmol) were added. The mixture was stirred at room temperature for 18 hr. The mixture was diluted with water and extracted with ethyl acetate. The extracts were washed with saturated aqueous sodium hydrogen carbonate and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by NH-silica gel column chromatography eluting with a 3-30% ethyl acetate/n-hexane gradient mixture. The desired fractions were concentrated in vacuo, and the resulting solid was triturated with n-hexane to give the title compound (10.3 mg, 0.0239 mmol, 37%) as an amorphous.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([CH3:13])[C:10]([NH2:12])=[O:11])#[CH:2].[Cl:14][C:15]1[N:20]=[C:19](Cl)[C:18]([Cl:22])=[CH:17][N:16]=1.CCN(CC)CC>O1CCOCC1.[Cu]I.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>[Cl:14][C:15]1[N:20]=[C:19]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[CH:9]([CH3:13])[C:10]([NH2:12])=[O:11])[C:18]([Cl:22])=[CH:17][N:16]=1
Reactant: C#Cc1ccccc1C(C)C(N)=O
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(C(N)=O)c1ccccc1C#Cc1nc(Cl)ncc1Cl
Temperature: 60 °C

Procedure:
To a solution of 2-(2-ethynylphenyl)propanamide K7 (2.5 g, 14 mmol) and 2,4,5-trichloropyrimidine (2.2 mL, 19 mmol) in 1,4-dioxane (27 mL) and Et3N (8.1 mL, 58 mmol) containing CuI (0.055 g, 0.29 mmol) was added PdCl2(PPh3)2 (0.10 g, 0.14 mmol). The reaction mixture was heated at 60° C. for 2.5 hours under a nitrogen atmosphere. The solvent was removed in vacuo and the residue was diluted with 20% Et2O in cyclohexane. The precipitate was filtered, washed with water and dried in vacuo to give the title compound A29 as a light brown solid (4.52 g, 98%). LCMS-C: rt 5.10 min; m/z 320 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[NH:12][CH:13]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pd].CCO>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11]2[NH:12][CH:13]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=2)=[CH:8][CH:9]=1
Reactant: COC(=O)c1c[nH]c(Cc2ccc([N+](=O)[O-])cc2)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1c[nH]c(Cc2ccc(N)cc2)n1
Yield: 91.1 %

Procedure:
A 100-mL round bottomed flask was charged with methyl 2-[(4-nitrophenyl)methyl]-1H-imidazole-4-carboxylate (220 mg, 0.84 mmol), Pd/C (270 mg, 10 wt %, 0.255 mmol, 0.3 eq.) and EtOH (24 ml). The mixture was stirred under 1 atmosphere of hydrogen overnight. The insoluble material was removed by filtration and the organics was evaporated under reduced pressure to dryness to afford the title compound (177 mg, 91% yield). The product thus obtained was forwarded to the next step without any further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][NH:18][C:19]2[CH:24]=[C:23]([CH3:25])[N:22]=[C:21](Cl)[N:20]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][O:28][C:29]1[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:30]=1[CH2:31][NH2:32]>>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][NH:18][C:19]2[CH:24]=[C:23]([CH3:25])[N:22]=[C:21]([NH:32][CH2:31][C:30]3[CH:33]=[CH:34][C:35]([O:37][CH3:38])=[CH:36][C:29]=3[O:28][CH3:27])[N:20]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: Cc1cc(NCC2CCN(C(=O)OCc3ccccc3)CC2)nc(Cl)n1
Product: COc1ccc(CNc2nc(C)cc(NCC3CCN(C(=O)OCc4ccccc4)CC3)n2)c(OC)c1
Temperature: 25 °C

Procedure:
A stirred solution of 4-[(2-chloro-6-methyl-pyrimidin-4-ylamino)-methyl]-piperidine-1-carboxylic acid benzyl ester (EXAMPLE 57, 0.5 g, 1.33 mmol) in 2,4-dimethoxybenzylamine (1.00 mL, 6.67 mmol) was heated at 100° C. for 6 h, then cooled to rt and purified by silica gel chromatography [1-10 (10% NH4OH in MeOH)/99-90 CH2Cl2)] to give 4-{[2-(2,4-dimethoxy-benzylamino)-6-methyl-pyrimidin-4-ylamino]-methyl}-piperidine-1-carboxylic acid benzyl ester. M.S.(M+1):506.46
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([C:19]2[N:23]3[N:24]=[C:25]([C:28]4[CH:29]=[N:30][N:31]([CH3:33])[CH:32]=4)[CH:26]=[CH:27][C:22]3=[N:21][CH:20]=2)=O)=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O.C([SiH](CC)CC)C>C(O)C>[CH2:3]([O:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:17][C:19]2[N:23]3[N:24]=[C:25]([C:28]4[CH:29]=[N:30][N:31]([CH3:33])[CH:32]=4)[CH:26]=[CH:27][C:22]3=[N:21][CH:20]=2)=[CH:15][CH:16]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Cn1cc(-c2ccc3ncc(C(=O)c4ccc(OCc5ccccc5)cc4)n3n2)cn1
Agent: CC[SiH](CC)CC
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cn1cc(-c2ccc3ncc(Cc4ccc(OCc5ccccc5)cc4)n3n2)cn1
Reaction time: 16 h

Procedure:
Sodium borohydride was added to a solution of (4-benzyloxy-phenyl)-[6-(1-methyl-1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazin-3-yl]-methanone (Stage 5.2, 190 mg, 0.46 mmol) in ethanol (1.5 mL) and the reaction stirred for 16 h. Water was added to the reaction and the resulting solid was filtered off and dried under vacuum. The solid was dissolved in TFA (2 mL) and to this solution was added triethylsilane (0.18 mL, 1.16 mmol) and the mixture was stirred at rt for 30 min. Water was added and the mixture extracted with EtOAc. The EtOAc extract was dried, filtered and concentrated to give the title compound as red solid (tR 1.3 min (conditions 2), MH+=396).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.[CH3:11][C:12]([CH3:19])([CH3:18])[C:13](=O)[CH2:14][C:15]#[N:16]>>[C:12]([C:13]1[CH:14]=[C:15]([NH2:16])[N:9]([C:6]2[CH:7]=[CH:8][C:3]([Cl:2])=[CH:4][CH:5]=2)[N:10]=1)([CH3:19])([CH3:18])[CH3:11]
Reactant: NNc1ccc(Cl)cc1
Reactant: CC(C)(C)C(=O)CC#N
Agent: Cl
Product: CC(C)(C)c1cc(N)n(-c2ccc(Cl)cc2)n1
Yield: 32.7 %

Procedure:
Following the procedure in Example 161A Step 3, 4-chlorophenylhydrazine hydrochloride (1.43 g, 8.0 mol) and 4,4-dimethyl-3-oxopentanenitrile (1.0 g, 8.0 mmol) were reacted to give 3-tert-butyl-1-(4-chlorophenyl)-1H-pyrazol-5-amine (653 mg, 2.62 mmol, 33%). 1H NMR (300 MHz, DMSO-d6) δ 7.61 (d, 1H), 7.49 (d, 2H), 5.39 (s, 1H), 5.28 (s, 1H), 1.09 (s, 9H); LC-MS (ESI) m/z 250 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][C:6]([C:12]3([CH3:24])[CH2:16][CH2:15][CH2:14][N:13]3[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[N:5][C:4]=2[CH:3]=1>CCCCCC.C(O)C>[Br:1][C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][C:6]([C@@:12]3([CH3:24])[CH2:16][CH2:15][CH2:14][N:13]3[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[N:5][C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCCC1(C)c1nc2cc(Br)sc2c(=O)[nH]1
Solvent: CCCCCC
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC[C@]1(C)c1nc2cc(Br)sc2c(=O)[nH]1
Yield: 48.9 %

Procedure:
tert-Butyl 2-(6-bromo-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-2-methylpyrrolidine-1-carboxylate (180 mg) was fractionated by high performance liquid chromatography (column: CHIRALPAK AD (50 mm i.d.×500 mm L, manufactured by DAICEL CHEMICAL INDUSTRIES, LTD.), mobile phase: hexane/ethanol (900/100), flow rate: 80 mL/min, column temperature: 30° C.). Under the above-mentioned high performance liquid chromatography conditions, the fraction solution containing an optically active form having a shorter retention time was concentrated to give tert-butyl (2R)-2-(6-bromo-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-2-methylpyrrolidine-1-carboxylate (88 mg, 9.25 min, >99.9% ee). In addition, the fraction solution containing an optically active form having a longer retention time was concentrated to give tert-butyl (2S)-2-(6-bromo-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-2-methylpyrrolidine-1-carboxylate (85 mg, 19.3 min, >99.9% ee). The analysis was performed by high performance liquid chromatography (column: CHIRALPAK AD (4.6 mm i.d.×250 mm L, manufactured by DAICEL CHEMICAL INDUSTRIES, LTD.), mobile phase: hexane/ethanol (900/100), flow rate: 1.0 mL/min, column temperature: 30° C., detection 220 nm). The absolute configuration was determined by comparison to tert-butyl (2S)-2-(6-bromo-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-2-methylpyrrolidine-1-carboxylate produced in Example 103, step A.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:17]=[CH:18][CH:19]=2)[CH2:11]OS(C)(=O)=O)[CH:5]=[CH:4][N:3]=1.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][C@H:28]1[CH3:33])=[O:26])([CH3:23])([CH3:22])[CH3:21].C(N(C(C)C)CC)(C)C>COCCOC>[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][N:30]([CH2:11][C:10]2[CH:17]=[CH:18][CH:19]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)[CH:9]=2)[CH2:29][C@H:28]1[CH3:33])=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: C[C@@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)OCc1cccc(-c2ccnc(Cl)n2)c1
Solvent: COCCOC
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CN(Cc2cccc(-c3ccnc(Cl)n3)c2)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 53 %

Procedure:
Intermediate 125 Methanesulfonic acid 3-(2-chloro-pyrimidin-4-yl)-benzyl ester (0.70 g) and Intermediate 127 2-(R)-Methyl-piperazine-1-carboxylic acid tert-butyl ester (0.61 g) with diisopropylethylamine (0.70 mL) in ethylene glycol dimethyl ether (20 mL) was refluxed for 3 hours, cooled to room temperature, evaporated under reduced pressure and the residue was dissolved in dichloromethane, washed with water (3×), brine, dried over dried over Na2SO4, chromatographed on silica gel (dichloromethane:methanol=98:2) to give 0.50 g of oily product with yield 53%. LC-MS showed the product had the expected M+H+ of 403. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 8.6 (s, 1H) 8.0 (s, 1H) 7.9 (d, 1H) 7.6 (d, 1H) 7.5 (m, 2H) 4.2 (S, 1 h) 3.8 (d, 1H) 3.4 (m, 2H) 3.0 (m, 1H) 2.7 (d, 1H), 2.6 (d, 1H) 2.1 (m, 2H) 1.4 (s, 9H) 1.2 (d, 3H).
Reaction SMILES: [C:1]([C:3]1[C:8]([NH:9][C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:11]=2)=[CH:7][C:6]([NH:21][C@H:22]([CH2:26][CH:27]2[CH2:29][CH2:28]2)[C:23]([NH2:25])=[O:24])=[C:5]([F:30])[CH:4]=1)#[N:2].[OH-].[Na+].OO.CC(O)=[O:37]>CCO.CS(C)=O>[NH2:25][C:23](=[O:24])[C@H:22]([NH:21][C:6]1[C:5]([F:30])=[CH:4][C:3]([C:1]([NH2:2])=[O:37])=[C:8]([NH:9][C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:11]=2)[CH:7]=1)[CH2:26][CH:27]1[CH2:28][CH2:29]1
Reactant: CC(=O)O
Reactant: N#Cc1cc(F)c(N[C@H](CC2CC2)C(N)=O)cc1Nc1cc(-c2ccccc2)no1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Product: NC(=O)c1cc(F)c(N[C@H](CC2CC2)C(N)=O)cc1Nc1cc(-c2ccccc2)no1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of (R)-2-(4-cyano-2-fluoro-5-(3-phenylisoxazol-5-ylamino)phenylamino)-3-cyclopropylpropanamide (75 mg) in EtOH (1 mL) and DMSO (0.5 mL) at room temperature, aq. 1N NaOH (0.5 mL) and aq. H2O2 (50%, 0.5 mL) were added. The mixture was stirred at room temperature for 15 min. HOAc (0.5 mL) was added. After being concentrated in vacuo, the residue was purified by HPLC to give the titled compound (13 mg). MS 424.4 (M+H); UV 201.0, 244.9, 289.1 nm; t 0.668 min.
Reaction SMILES: [CH2:1]([Mg]Br)[CH:2]([CH3:4])[CH3:3].[CH3:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([O:17][CH2:18][C@H:19]2[O:21][CH2:20]2)(=[O:16])=[O:15])=[CH:10][CH:9]=1>O1CCCC1>[OH:21][C@@H:19]([CH2:20][CH2:1][CH:2]([CH3:4])[CH3:3])[CH2:18][O:17][S:14]([C:11]1[CH:12]=[CH:13][C:8]([CH3:7])=[CH:9][CH:10]=1)(=[O:16])=[O:15]
Reactant: CC(C)C[Mg]Br
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)OC[C@@H](O)CCC(C)C)cc1
Temperature: 2.5 °C
Yield: 75.5 %

Procedure:
Add dropwise over 5 minutes isobutylmagnesium bromide (4.4 mL, 8.8 mmol, 2 M in diethyl ether) to a solution of lithium tetrachlorocuprate (4.4 mL, 0.44 mmol, 0.1 M in tetrahydrofuran) cooled to −35-40° C. Dissolve (2S)-(+)-glycidyl tosylate (1.674 g, 7.73 mmol) in tetrahydrofuran (8 mL), cool to −40° C. and cannulate into the stirring Grignard reaction flask. Quench with saturated aqueous ammonium chloride (25 mL), pour supernate into saturated aqueous ammonium chloride (25 mL) and water and shake well. Wash with saturated aqueous sodium chloride, dry (magnesium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 10:90 to 25:75 ethyl acetate:hexanes) to give the desired compound (1.6711 g, 75%).
Reaction SMILES: [OH:1][PH:2]([CH:4]([CH:21]([C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:14](=[O:15])[C:13]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]2[C:11]1=[O:20])=[O:3].[CH2:42](I)[CH:43]([CH3:45])[CH3:44]>CS(C)=O>[OH:3][PH:2]([CH:4]([C:21]([CH2:42][CH:43]([CH3:45])[CH3:44])([C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])[C:22]([O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:23])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:14](=[O:15])[C:13]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]2[C:11]1=[O:20])=[O:1]
Reactant: CC(C)CI
Reactant: O=C(OCc1ccccc1)C(C(=O)OCc1ccccc1)C(CCCCCN1C(=O)c2ccccc2C1=O)[PH](=O)O
Solvent: CS(C)=O
Product: CC(C)CC(C(=O)OCc1ccccc1)(C(=O)OCc1ccccc1)C(CCCCCN1C(=O)c2ccccc2C1=O)[PH](=O)O

Procedure:
3.6 g of dibenzyl 2-(6-phthalimidohexylidene)malonate were added to a solution of 0.88 g of crystalline hypophosphorus acid in 10 ml of dry dichloromethane, the solution was cooled to 0° and then 2.8 g of triethylamine and 2.8 g of trimethylsilyl chloride were added. After stirring at room temperature for 3 hours, the mixture was poured into 60 ml of 1M hydrochloric acid and the resulting solution was extracted four times with dichloromethane. The combined extracts were dried and evaporated to give 3.9 g of a colorless gum containing crude dibenzyl 2-[1(RS)-(hydroxyphosphinyl)-6-phthalimidohexyl]malonate which was dissolved in 40 ml of dry dimethyl sulphoxide and reacted with isobutyl iodide in a manner analogous to that described in Example 10(ii). After purification of the crude product by chromatography on silica gel using dichloromethane/methanol/acetic acid/water (240:24:3:2) for the elution, there was obtained 2.0 g of dibenzyl 2-[1(RS)-(hydroxyphosphinyl)-6phthalimidohexyl]-2-isobutylmalonate as a colorless gum.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[F:15][C:16]1[CH:21]=[CH:20][C:19]([C@@H:22]([OH:30])[CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:18][CH:17]=1.[CH2:31]([O:33][CH2:34]OCC)[CH3:32]>ClCCl.C(OCC)C>[CH2:31]([O:33][CH2:34][O:30][C@H:22]([C:19]1[CH:18]=[CH:17][C:16]([F:15])=[CH:21][CH:20]=1)[CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH3:32]
Reactant: CCOCOCC
Reactant: COC(=O)CCC[C@H](O)c1ccc(F)cc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CCOCC
Solvent: ClCCl
Product: CCOCO[C@@H](CCCC(=O)OC)c1ccc(F)cc1
Temperature: 29 °C
Yield: 113.9 %

Procedure:
40.6 g of phosphorus pentoxide are added to a vigorously stirred solution of 10.5 g (42.7 mmol) of methyl 5-(4-fluorophenyl)-5-(S)-hydroxypentanoate with a purity of 92% area % (Example 1) in 220 ml of dichloromethane and 152 ml (1200 mmol) of 99% pure diethoxymethane in a 4-neck flask with mechanical stirrer, the internal temperature rising from initially 23° C. to 30° C. There is initial formation of a white suspension whose particles quickly agglomerate and form a viscous mass which partly adheres to the bottom of the flask and changes color via yellow to brown. HPLC analysis (system as in Example 5) shows complete conversion of the precursor (tret9.8 min.) into the product (tret 13.4 min.) after only 5 min. The reaction mixture is stirred at 29° C. without external heating (i.e. continuing exothermic reaction) for 0.5 h, but the only effect of this was to increase an impurity (tret 13.2 min.). The reaction mixture is cooled to +10° C. in an ice bath, and 100 g of ice are added to the mixture. The viscous solid mass dissolves only slowly even with vigorous stirring. The mixture is transferred into a separating funnel and diluted with 200 ml of diethyl ether. The organic phase is separated off, and the aqueous phase is extracted again with 100 ml of diethyl ether. The combined extracts are washed with 100 ml of saturated aqueous sodium bicarbonate solution and with 100 ml of saturated aqueous sodium chloride solution, and then concentrated in vacuo, and the residue is dried under HV. 13.83 g of brown oil are obtained. The crude product has a GC purity of 84 area %. It is distilled through a silvered 15 cm vacuum-jacketed Vigreux column under HV (0.005 mbar). After a fore-run (1 g, b.p. 33-88° C., colorless mobile oil), the product distills (9.5 g, b.p. 102-103° C., colorless oil) at a bath temperature of 160-170° C., and 3 g of higher-boiling impurity remain as bottom product. Yield: 9.5 g (33.4 mmol), 78% of theory.
Reaction SMILES: [C:1]([C:4]1[C:9]2[CH2:10][C:11](=O)[C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[S:14][C:8]=2[CH:7]=[CH:6][CH:5]=1)([OH:3])=[O:2].O.NN>C(O)C>[C:1]([C:4]1[C:9]2[CH2:10][CH2:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[S:14][C:8]=2[CH:7]=[CH:6][CH:5]=1)([OH:3])=[O:2]
Reactant: O=C1Cc2c(cccc2C(=O)O)Sc2ccccc21
Agent: NN
Solvent: CCO
Solvent: O
Product: O=C(O)c1cccc2c1CCc1ccccc1S2
Reaction time: 2 h
Yield: 42.2 %

Procedure:
The mixture of 1.0 g of 9-carboxy-10,11-dihydro-11-oxo-dibenzo[b,f]thiepin, 1.0 g of hydrazine hydrate and 30 ml of ethanol was heated under reflux on water bath for 4 hours. The reaction mixture was concentrated to about 15 ml to separate crystals on cooling, which were collected by filtration. They were added to the mixture of 1.0 g of sodium hydroxide and 20 ml of diethylene glycal and the resulting mixture was heated with stirring at 190°-200° C. for 2 hours. After cooling, 300 ml of water was added to the mixture, which was extracted with diethyl ether. The aqueous layer was acidified with conc. hydrochloric acid and extracted with chloroform, and the solvent was evaporated therefrom. The thus obtained residue was chromatographed over silica gel and eluted with benzene-ethyl acetate (1:1), and there was obtained 0.4 g of 9-carboxy-10,11-dihydrodibenzo[b,f]thiepin as yellow prismatic crystals having a melting point of 186°-187° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][N:21]4C(=O)C5C(=CC=CC=5)C4=O)=[CH:15][CH:14]=3)=[CH:11][C:10]([C:32]([F:35])([F:34])[F:33])=[N:9]2)=[CH:4][CH:3]=1.NN>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][NH2:21])=[CH:15][CH:14]=3)=[CH:11][C:10]([C:32]([F:34])([F:33])[F:35])=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1CCc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(Cl)cc2)cc1
Agent: NN
Solvent: CC#N
Product: NCCc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(Cl)cc2)cc1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
A mixture of 2-(2-{4-[1-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}ethyl)-1H-isoindole-1,3(2H)-dione obtained by Example 52 (1.5 g) and hydrazine (2.93 ml) in acetonitrile (30 ml) was stirred at 60° C. for 5 hrs.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([NH:11][CH:12]([C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[OH:32])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[OH-].[Na+].[CH3:36][N:37](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)[CH3:38].[B-](F)(F)(F)F.CNC>C(O)C>[CH3:24][O:23][C:17]1[CH:16]=[C:15]([CH2:14][CH2:13][CH:12]([NH:11][CH:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:3]([N:37]([CH3:38])[CH3:36])=[O:2])[C:25]2[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=2[OH:32])[CH:20]=[CH:19][C:18]=1[O:21][CH3:22]
Reactant: COC(=O)C(NC(CCc1ccc(OC)c(OC)c1)c1cc(F)ccc1O)c1ccccc1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CNC
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(CCC(NC(C(=O)N(C)C)c2ccccc2)c2cc(F)ccc2O)cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 8.8 %

Procedure:
A mixture of 36.2 mg (0.8 mmol) [3-(3,4-dimethoxy-phenyl)-1-(5-fluoro-2-hydroxy-phenyl)-propylamino]-phenyl-acetic acid methyl ester and 0.32 mmol NaOH aq. in ethanol was evaporated to dryness and dissolved in DMF. TBTU (0.24 mmol) and dimethylamine (0.24 mmol) was added and the mixture was stirred for 1 h at room temperature. The mixtures was evaporated and purified by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and formic acid. The product containing fractions were evaporated to yield 9.8 mg (26%) of the title compound. MS (m/e): 467.2 (MH+).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:9]2[N:10]=[C:11]([SH:13])[S:12][C:8]=2[C:7]([F:14])=[CH:6][C:5]=1[F:15].Br[CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].Cl>CN(C=O)C.O>[CH2:24]([O:23][C:21](=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17][S:13][C:11]1[S:12][C:8]2[C:7]([F:14])=[CH:6][C:5]([F:15])=[C:4]([F:3])[C:9]=2[N:10]=1)[CH3:25]
Reactant: CCOC(=O)CCCCBr
Reactant: Fc1cc(F)c2sc(S)nc2c1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCSc1nc2c(F)c(F)cc(F)c2s1
Yield: 63 %

Procedure:
Sodium hydride (60% in oil, 220 mg, 5.5 mmol) was suspended in DMF (2 ml) and the suspension was stirred on a water bath. To the suspension was added dropwise a solution of 4,5,7-trifluoro-2-mercaptobenzothiazole (1.1 g, 5 mmol) in DMF (5 ml) under ice cooling and the mixture was stirred for 30 min. at room temperature and then cooled on a water bath. To the cooled mixture was added dropwise a solution of ethyl 5-bromopentanoate (1.05 g, 5 mmol) in DMF (3 ml) and the mixture was stirred for 2 hours at room temperature. The resultant mixture was diluted with water, then acidified with 7% hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with an aqueous saturated saline solution, dried and then evaporated. The resulting residue was purified on a silica gel column to give 5-(4,5,7-trifluorobenzothiazol-2-ylthio)pentanoic acid ethyl ester (1.1 g, 64%) as an oil.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][N:3]=1.C1N2CCN(CC2)C1.[C:18]([O:22][CH3:23])(=[O:21])[CH:19]=[CH2:20]>O1CCOCC1.O.[Cl-].[Na+].O>[CH3:23][O:22][C:18](=[O:21])[C:19]([CH:8]([OH:9])[C:5]1[CH:4]=[N:3][C:2]([CH3:1])=[N:7][CH:6]=1)=[CH2:20]
Reactant: C=CC(=O)OC
Reactant: Cc1ncc(C=O)cn1
Agent: C1CN2CCN1CC2
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: C=C(C(=O)OC)C(O)c1cnc(C)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.4 %

Procedure:
A mixture of 2-methylpyrimidine-5-carbaldehyde (1 g, 8.18 mmol, 1 eq), DABCO (1 eq, 935 mg) and methyl acrylate (5 eq, 3.68 ml) dissolved in a 1,4-dioxane (40 ml/H2O (40 ml) mixture was stirred at room temperature for 2 hours. The mixture was then poured into 300 ml of brine and the organic substances were extracted with DCM (3 times, 300 ml was used in total). The gathered DCM layers were dried, the solvent was evaporated and the obtained crude oil was triturated with diethyl ether to afford 2-[hydroxy-(2-methyl-pyrimidin-5-yl)-methyl]acrylic acid methyl ester (1.58 g, yield=83.40%, purity=90%) in form of white powder. MS: [M+H]+=209.18 1H NMR (300 MHz; CDCl3) δ/ppm 2.72 (s, 3H), 3.61 (br.s., 1H), 3.75 (s, 3H), 5.58 (s, 1H), 5.97 (s, 1H), 6.43 (s, 1H) 8.64 (s, 2H)