Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:8]([C:22]([O:24]CC1C=CC=CC=1)=O)[CH2:9][CH2:10][CH2:11][NH:12][CH:13]([CH2:18][CH2:19][CH2:20][CH3:21])[C:14]([O:16][CH3:17])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.CCN=C=NCCCN(C)C.C([O-])(O)=O.[Na+].N>CO.CN(C=O)C.[Pd].CCOC(C)=O>[CH2:1]([CH:8]1[CH2:9][CH2:10][CH2:11][N:12]([CH:13]([CH2:18][CH2:19][CH2:20][CH3:21])[C:14]([O:16][CH3:17])=[O:15])[C:22]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCC(NCCCC(Cc1ccccc1)C(=O)OCc1ccccc1)C(=O)OC
Agent: [Pd]
Agent: CCN=C=NCCCN(C)C
Agent: N
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCC(C(=O)OC)N1CCCC(Cc2ccccc2)C1=O
Reaction time: 0.08 h

Procedure:
The benzyl ester from Example 54 was dissolved in 10 ml of MeOH and hydrogenolyzed (H2 in balloon in the presence of 10% Pd/C, 0.3 g) at room temperature for 3 h. At the end, the catalyst was removed by filtration and the crude product, after removal of MeOH under reduced pressure, was added to a flask containing HOBT (967 mg, 7.16 mmol), Et3N (0.33 ml, 2.4 mmol) in 10 ml of DMF at 0° C. After 5 min, EDAC (458 mg, 2.38 mmol) was added and the reaction was slowly brought to room temperature. At the end of 13 h at room temperature, the contents was poured onto a slurry of aqueous NaHCO3 and AcOEt. The product was extracted and purified by Column chromatography (silica gel, Hexane-AcOEt, 4:1) which gave a mixture of two diastereomers (340 mg, 45%, 1:1 ratio, dl mixture at the benzyl centre): DCI-NH3 -MS, m/z 318 (MH+, 100%).
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([C:9](Cl)=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:12]([C:14]1[S:15][C:16]2[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:17]=2[N:18]=1)[NH2:13]>>[CH3:23][C:21]1[CH:20]=[CH:19][C:17]2[N:18]=[C:14]([NH:12][NH:13][C:9]([C:7]3[O:8][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)=[O:10])[S:15][C:16]=2[CH:22]=1
Reactant: Cc1ccc2nc(NN)sc2c1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])o1
Product: Cc1ccc2nc(NNC(=O)c3ccc([N+](=O)[O-])o3)sc2c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The compound 4b was prepared according to above described method by using 5-nitro-2-furancarboxylic acid chloride (300 mg, 1 mmol) and 2-hydrazino-6-methylbenzothiazole (179 mg, 1 mmol) which stirred for 1 h at 0° C. and stirring continued at 25° C. for 11 h (yield 216 mg, 85%).
Reaction SMILES: [CH2:1]([O:17][CH2:18][CH:19]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:20]=[CH2:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].B.[O:31]1CCCC1>>[CH2:1]([O:17][CH2:18][CH:19]([O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[CH2:20][CH2:21][OH:31])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: C=CC(COCCCCCCCCCCCCCCCC)OCc1ccccc1
Reactant: C1CCOC1
Agent: B
Product: CCCCCCCCCCCCCCCCOCC(CCO)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 11.5 g of [[[1-[(hexadecyloxy)-methyl]-2-propenyl]oxy]methyl]benzene in 50 ml of tetrahydrofuran was added dropwise, at 0° C.,57.12 ml of 1 M borane in tetrahydrofuran. After stirring at room temperature for 3 hours the excess borane was destroyed by the addition of water. The mixture was cooled in an ice bath, 100 ml of 3N sodium hydroxide was added followed by 100 ml of 30% hydrogen peroxide and after 10 minutes the mixture was stirred for 1/2 hour at room temperature and then diluted with ether. The ether layer was separated, washed with brine, then saturated sodium bisulfite, dried over magnesium sulfate and the solvent removed. The residue was purified by HPLC [hexane: ethyl acetate (9:1)] giving 7.8 g of the desired compound as an oil.
Reaction SMILES: C(OC(N1CCC([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)CC1)=O)(C)(C)C.Br[CH2:24][C:25]1[CH:29]=[CH:28][S:27][CH:26]=1>C(OCC)C>[N:18]1([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH2:24][C:25]3[CH:29]=[CH:28][S:27][CH:26]=3)[CH:15]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2c[nH]c3ncccc23)CC1
Reactant: BrCc1ccsc1
Solvent: CCOCC
Product: c1cnc2c(c1)c(N1CCCCC1)cn2Cc1ccsc1

Procedure:
This compound was prepared following the procedure described in example 7, parts E and F, starting with 0.3 g (1 mmol) of 4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidine-1-carboxylic acid tert-butyl ester and 2.12 ml of a freshly prepared 0.61 M solution of 3-bromomethylthiophene in ethyl ether. After standard work-up, 0.39 g (100% of yield) of the expected product were isolated.
Reaction SMILES: [CH2:1]([N:8]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([BH2:22])[CH:17]=1)[CH2:9][CH2:10][CH2:11]N(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23]([NH:30][CH2:31]CCN(C)C)C1C=CC=CC=1>>[CH2:1]([N:8]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([BH2:22])[CH:17]=1)[CH2:9][CH:10]([N:30]([CH3:31])[CH3:23])[CH3:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)CCCNCc1ccccc1
Reactant: Bc1cccc(CN(CCCN(C)C)Cc2ccccc2)c1
Product: Bc1cccc(CN(Cc2ccccc2)CC(C)N(C)C)c1

Procedure:
Following the procedures as set forth above, N-benzyl-N-(3-boranyl-benzyl)-N′,N′-dimethyl-propane-1,3-diamine was prepared starting from N′-benzyl-N,N-dimethyl-propane-1,3-diamine.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([N:10]([CH3:12])[CH3:11])[CH2:7][NH:6]1)=O.[NH3:13]>CO>[CH3:11][N:10]([CH3:12])[C@H:8]1[CH2:7][NH:6][C@H:5]([C:3]([NH2:13])=[O:2])[CH2:9]1
Reactant: COC(=O)[C@@H]1C[C@@H](N(C)C)CN1
Reactant: N
Solvent: CO
Product: CN(C)[C@H]1CN[C@H](C(N)=O)C1

Procedure:
A solution of (2S,4R)-4-Dimethylamino-pyrrolidine-2-carboxylic acid methyl ester (225 mg) and 7M ammonia in methanol (7 ml) is stood for 18 hours at room temperature in a sealed vessel. Evaporation and trituration with diethyl ether gives the title compound as a white solid.
Reaction SMILES: Cl[CH:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[F:16][C:17]([F:22])([F:21])[C:18]([NH2:20])=[S:19].C([O-])([O-])=O.[Na+].[Na+]>CC#N>[C:10]1([C:2]2[S:19][C:18]([C:17]([F:22])([F:21])[F:16])=[N:20][C:3]=2[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NC(=S)C(F)(F)F
Reactant: CCOC(=O)C(=O)C(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)c1nc(C(F)(F)F)sc1-c1ccccc1

Procedure:
A solution of ethyl 3-chloro-2-oxo-3-phenylpropanoate and trifluorothioacetamide in MeCN was heated under reflux. To the reaction mixture was added an aqueous Na2CO3 solution, followed by extraction with EtOAc. The organic layer was washed with water and brine in this order, dried, and then concentrated under reduced pressure. The residue was purified by medium-pressure preparative liquid chromatography (silica gel, YAMAZEN YFLC WPrep2XY, hexane: EtOAc) to obtain ethyl 5-phenyl-2-(trifluoromethyl)-1,3-thiazole-4-carboxylate as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([N:13](CC3C=CC=CC=3)[CH3:14])[CH:8]=2)=[C:4]([F:24])[CH:3]=1>CO.[Pd]>[NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH3:14])[CH:8]=2)=[C:4]([F:24])[CH:3]=1
Reactant: CN(Cc1ccccc1)c1cc(Oc2ccc(N)cc2F)ccn1
Agent: [Pd]
Solvent: CO
Product: CNc1cc(Oc2ccc(N)cc2F)ccn1
Temperature: 75 °C
Reaction time: 12 h
Yield: 77.4 %

Procedure:
To a solution of 4-(4-amino-2-fluorophenoxy)-N-benzyl-N-methylpyridin-2-amine (1.0 g, 3.1 mmol) in MeOH (10 mL) was added 10% Pd/C (0.25 g, 0.23 mmol). The reaction was stirred under a H2 atmosphere (50 psi) at 75° C. for 12 h. The reaction mixture was filtered, concentrated under reduced pressure and purified by reverse phase prep-HPLC to provide 4-(4-amino-2-fluorophenoxy)-N-methylpyridin-2-amine (560 mg, 78% yield). 1H NMR (400 MHz, DMSO-d6) δ 7.80 (d, J=5.6 Hz, 1H), 6.90 (t, J=9.0 Hz, 1H), 6.40-6.45 (m, 3H), 6.06 (dd, J=8.0, 2.8 Hz, 1H), 5.73 (d, J=2.8 Hz, 1H), 5.37 (s, 2H), 2.68 (d, J=4.8 Hz, 3H); MS (ESI) m/z: (M+H+): 234.2.
Reaction SMILES: [C:1]1([C:7]2[C:11](=[O:12])[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:8]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:31]([C:33]1[CH:38]=[CH:37][C:36]([Mg]Br)=[CH:35][CH:34]=1)=[CH2:32]>CCOCC>[C:13]1([C:10]2[C:11]([C:36]3[CH:37]=[CH:38][C:33]([CH:31]=[CH2:32])=[CH:34][CH:35]=3)([OH:12])[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[C:8]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:9]=2[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C=Cc1ccc([Mg]Br)cc1
Reactant: O=C1C(c2ccccc2)=C(c2ccccc2)C(c2ccccc2)=C1c1ccccc1
Solvent: CCOCC
Product: C=Cc1ccc(C2(O)C(c3ccccc3)=C(c3ccccc3)C(c3ccccc3)=C2c2ccccc2)cc1

Procedure:
46.2 g (0.12 mol) of tetraphenylcyclopentadienone were reacted with 0.61 mol of p-vinylphenylmagnesium bromide in 400 ml of ether and then hydrolysis to yield 1,2,3,4-tetraphenyl-5-p-vinylphenylcyclopenta-1,3-dien-5-ol. (Elemental analysis for C37H28O: found: C, 90.91%, H, 5.75%. calculated: C, 90.85%, H, 5.78%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[C:4]=1[F:25])#[N:2].[NH:26]1[CH2:29][CH:28]([N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[CH2:27]1>>[F:25][C:4]1[C:5]([CH3:24])=[C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([N:26]4[CH2:29][CH:28]([N:30]5[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]5)[CH2:27]4)=[O:21])=[CH:17][N:16]=3)[C:13]=2[OH:14])[CH:7]=[CH:8][C:3]=1[C:1]#[N:2]
Reactant: Cc1c(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccc(C#N)c1F
Reactant: C1CCN(C2CNC2)CC1
Product: Cc1c(-c2cnn(-c3ccc(C(=O)N4CC(N5CCCCC5)C4)cn3)c2O)ccc(C#N)c1F

Procedure:
The title compound was prepared in a manner similar to Example 303 using 6-(4-(4-cyano-3-fluoro-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 1-(azetidin-3-yl)piperidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.22-2.00 (m, 6H) 2.33 (d, J=2.27 Hz, 3H) 2.84 (br. s., 2H) 3.23-3.70 (m, 2H) 4.06-4.19 (m, 1H) 4.33 (br. s., 2H) 4.61 (br. s., 1H) 4.66-4.77 (m, 1H) 7.63 (d, J=7.07 Hz, 1H) 7.75 (t, J=7.45 Hz, 1H) 7.98-8.89 (m, 4H). ESI-MS m/z [M+H]+ 461.3.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18]([NH:20][C@@H:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C@H:24]([O:31][C:32]3[CH:33]=[CH:34][C:35]4[N:36]([C:38]([N:41]5[CH2:46][CH2:45][N:44]([CH2:47][CH2:48][O:49][Si](C(C)C)(C(C)C)C(C)C)[CH2:43][CH2:42]5)=[N:39][N:40]=4)[CH:37]=3)[CH2:23][CH2:22]2)=[O:19])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.O>[C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18]([NH:20][C@@H:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C@H:24]([O:31][C:32]3[CH:33]=[CH:34][C:35]4[N:36]([C:38]([N:41]5[CH2:42][CH2:43][N:44]([CH2:47][CH2:48][OH:49])[CH2:45][CH2:46]5)=[N:39][N:40]=4)[CH:37]=3)[CH2:23][CH2:22]2)=[O:19])[N:8]([C:10]2[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCN(CCO[Si](C(C)C)(C(C)C)C(C)C)CC5)n4c3)c3ccccc32)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCN(CCO)CC5)n4c3)c3ccccc32)cc1

Procedure:
A solution of Intermediate 94d (243 mg, 0.29 mmol) and TBAF (1M in THF, 0.53 mL, 0.53 mmol) in THF (3.5 mL) was stirred at RT for 45 min, then diluted with water and extracted with DCM (3×20 mL). The combined organics were dried and concentrated in vacuo. The residue was purified by FCC, using 0-7.5% (2M NH3 in MeOH) in DCM, to give the title compound as a white powder after freeze-drying (135 mg, 58%). LCMS (Method 5): Rt 3.52 min, m/z 664 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.27 (9H, s), 1.86-1.92 (2H, m), 2.04-2.11 (2H, m), 2.36 (3H, s), 2.48 (2H, q, J 5.8), 2.66 (4H, t, J 4.8), 3.19 (4H, t, J 4.5), 3.55 (2H, q, J 5.8), 4.44 (1H, t, J 5.4), 4.79-4.82 (1H, m), 5.57 (1H, t, J 4.4), 6.32 (1H, s), 7.07 (1H, d, J 8.5), 7.15 (1H, dd, J 9.9, 2.1), 7.32-7.44 (8H, m), 7.60-7.63 (1H, m), 7.68 (1H, d, J 2.0), 8.04 (1H, s).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][C:14]([C:16]([C:18]3OC(C4C=CC(S(C)(=O)=O)=CC=4)=CC=3)=[O:17])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[BH4-].[Na+]>O1CCOCC1.O>[CH3:18][CH:16]([OH:17])[C:14]1[O:15][C:11]([C:8]2[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=2)=[CH:12][CH:13]=1
Reactant: CS(=O)(=O)c1ccc(-c2ccc(C(=O)c3ccc(-c4ccc(S(C)(=O)=O)cc4)o3)o2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(O)c1ccc(-c2ccc(S(C)(=O)=O)cc2)o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2.0 g (0.0076 mole) of 5-(p-methylsulfonylphenyl)-2-furyl ketone and 40 ml of 95% of dioxane/H2O was treated portionwise with 0.29 g (0.0076 mole) of NaBH4 while maintaining the temperature at 15°-20° by means of an ice bath. The resulting solution was stirred at room temperature for 2 hours, added to ice/H2O and the resulting precipitate filtered and dried in the vacuum pistol at room temperature to yield 1.3 g (64%), m.p. 118°-120°, of title compound.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][C@H:11]([O:15][C:16]2[C:21]([F:22])=[CH:20][C:19]([S:23]([N:26](CC3C=CC(OC)=CC=3OC)[C:27]3[CH:32]=[CH:31][N:30]=[CH:29][N:28]=3)(=[O:25])=[O:24])=[C:18]([F:44])[CH:17]=2)[C@H:10]1[C:45]1[N:49]([CH3:50])[N:48]=[CH:47][CH:46]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][C@H:11]([O:15][C:16]2[C:21]([F:22])=[CH:20][C:19]([S:23]([NH:26][C:27]3[CH:32]=[CH:31][N:30]=[CH:29][N:28]=3)(=[O:24])=[O:25])=[C:18]([F:44])[CH:17]=2)[C@H:10]1[C:45]1[N:49]([CH3:50])[N:48]=[CH:47][CH:46]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(F)c(O[C@H]3CCC[C@@H](OCc4ccccc4)[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nccc1[C@@H]1[C@@H](Oc2cc(F)c(S(=O)(=O)Nc3ccncn3)cc2F)CCC[C@H]1OCc1ccccc1
Yield: 96.9 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 4-{[(1S*,2S*,3R*)-3-(benzyloxy)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide (185 mg, 0.262 mmol) prepared in Example 100d, triethylsilane (0.30 mL), trifluoroacetic acid (3.0 mL) and dichloromethane (3.0 mL), to yield the title compound (141 mg, 97%) as a colorless solid.
Reaction SMILES: [C:1]1([CH2:11][CH2:12][OH:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br>>[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:13][CH2:12][CH2:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: OCCc1cccc2ccccc12
Reactant: BrCCCCCCBr
Product: BrCCCCCCOCCc1cccc2ccccc12
Yield: 74 %

Procedure:
1-Naphthaleneethanol (3.00 g) and 1,6-dibromohexane (12.73 g) were treated according to the method of Intermediate 1. FCC eluting with cyclohexane followed by ethyl acetate-cyclohexane (1:20, then 1:4) gave the title compound (4.32 g) as a colourless oil.
Reaction SMILES: [CH2:1]([Si:4]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:9][CH2:8][CH:7]([CH:10]2[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[F:23][C:24]1[CH:29]=[CH:28][C:27]([Mg]Cl)=[CH:26][CH:25]=1>>[CH2:1]([Si:4]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:9][CH2:8][CH:7]([CH:10]2[CH2:15][CH2:14][C:13]([C:27]3[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=3)=[CH:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: CCC[Si]1(c2ccccc2)CCC(C2CCC(=O)CC2)CC1
Reactant: Fc1ccc([Mg]Cl)cc1
Product: CCC[Si]1(c2ccccc2)CCC(C2CC=C(c3ccc(F)cc3)CC2)CC1
Yield: 82 %

Procedure:
In the same manner as in Example 1, 35.0 g of 4-(4-n-propyl-4-phenyl-4-silacyclohexyl)cyclohexanone were subjected to coupling reaction with 4-fluorophenylmagnesium chloride, followed by dehydration reaction in the presence of an acid catalyst to obtain 35.9 g of 4-(4-n-propyl-4-phenyl-4-silacyclohexyl)-1-(4-fluorophenyl)-1-cyclohexene (yield: 82%). The results of 1H-NMR analysis are shown below. 1H-NMR (CDCl3) δ:0.50-2.55 (23H, m), 5.90-6.14 (1H, m), 6.80-7.65 (9H, ppm
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:11][CH2:12][CH3:13])=[N:4][C:5]([S:9][CH3:10])=[N:6][C:7]=1[NH2:8].ClC1C=CC=C(C(OO)=[O:22])C=1>C(Cl)Cl>[Br:1][C:2]1[C:3]([NH:11][CH2:12][CH3:13])=[N:4][C:5]([S:9]([CH3:10])=[O:22])=[N:6][C:7]=1[NH2:8]
Reactant: CCNc1nc(SC)nc(N)c1Br
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCNc1nc(S(C)=O)nc(N)c1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.7 %

Procedure:
To a stirring solution of 5-bromo-N4-ethyl-2-(methylthio)pyrimidine-4,6-diamine (intermediate 19) (4.2 mmol) in 10 ml of DCM, 1.04 g (4.6 mmol) of m-chloroperbenzoic acid (77%) (Aldrich) in 3 ml of DCM were added dropwise. The reaction mixture was stirred at room temperature for 1 hour. After evaporation of the solvent under reduced pressure, the remaining solid was first washed with cold DCM and then several times with cold water, filtered and dried. 1.11 g (95%) of 5-bromo-N4-ethyl-2-(methylsulfinyl)pyrimidine-4,6-diamine were obtained.
Reaction SMILES: [C:1]1([C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(O)[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C)C.S(=O)(=O)(O)O.C(CC(C)(C)C)(C)C>O>[C:1]1([C:7]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCC(O)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: CC(C)CC(C)(C)C
Solvent: CC(C)O
Solvent: O
Product: CC=C(c1ccccc1)c1ccccc1
Yield: 49.4 %

Procedure:
A mixture of 1,1-diphenyl-1-propanol (64 g, 0.30 mol), isopropanol (300 ml) and a 5 N solution of sulphuric acid (150 ml) was heated at reflux temperature for 18 h. The reaction mixture was cooled, diluted with water (600 ml) and extracted with toluene (3×150 ml). The combined organic phases was dried over sodium sulphate and the solvent was evaporated in vacuo to give a solid residue which was trituated with iso-octane. The solid was collected by filtration to give 28.8 g (49%) of 1,1-diphenyl-1-propene.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([NH:9][C:10]2[C:11](=[O:23])[N:12]([CH2:17][C:18]([O:20]CC)=[O:19])[C:13]([CH3:16])=[CH:14][N:15]=2)=[CH:7][CH:6]=[CH:5][N:4]=1)[CH3:2].CO.[OH-].[Na+].Cl>O>[CH2:1]([C:3]1[C:8]([NH:9][C:10]2[C:11](=[O:23])[N:12]([CH2:17][C:18]([OH:20])=[O:19])[C:13]([CH3:16])=[CH:14][N:15]=2)=[CH:7][CH:6]=[CH:5][N:4]=1)[CH3:2]
Reactant: CCOC(=O)Cn1c(C)cnc(Nc2cccnc2CC)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCc1ncccc1Nc1ncc(C)n(CC(=O)O)c1=O
Yield: 73.9 %

Procedure:
To a solution of 3-(2-Ethylpyrid-3-ylamino)-6-methyl-1-(ethoxycarbonylmethyl)pyrazinone (0.058 g, 0.183 mMol) from step 3 above in 6 mL of 1:1:1-tetrahydrofuran:methanol:water was added 183 μL (0.183 mMol) of 1N sodium hydroxide solution. The solution was stirred at ambient temperature for 18 h at which time 183 μL (0.183 mMol) of 1N hydrochloric acid solution was added. The solution was concentrated in vacuo several times from methanol and the residue was triturated with diethyl ether. The resulting precipitate was filtered off to afford the title compound as a beige powder (0.039 g; HPLC RT=3.13 min, method A).
Reaction SMILES: COC1C(OC)=NS(=O)(=O)N=1.CN(CC1OC(CSCCN)=CC=1)C.[CH3:26][N:27]([CH2:29][C:30]1[O:34][C:33]([CH2:35][S:36][CH2:37][CH2:38][NH:39][C:40]2[C:44](OC)=[N:43][S:42](=[O:48])(=[O:47])[N:41]=2)=[CH:32][CH:31]=1)[CH3:28].[S:49]1[CH:53]=[CH:52][C:51]([CH2:54][S:55][CH2:56][CH2:57][NH2:58])=[N:50]1>CO>[CH3:26][N:27]([CH2:29][C:30]1[O:34][C:33]([CH2:35][S:36][CH2:37][CH2:38][NH:39][C:40]2[C:44]([NH:58][CH2:57][CH2:56][S:55][CH2:54][C:51]3[CH:52]=[CH:53][S:49][N:50]=3)=[N:43][S:42](=[O:48])(=[O:47])[N:41]=2)=[CH:32][CH:31]=1)[CH3:28]
Reactant: COC1=NS(=O)(=O)N=C1NCCSCc1ccc(CN(C)C)o1
Reactant: NCCSCc1ccsn1
Agent: CN(C)Cc1ccc(CSCCN)o1
Agent: COC1=NS(=O)(=O)N=C1OC
Solvent: CO
Product: CN(C)Cc1ccc(CSCCNC2=NS(=O)(=O)N=C2NCCSCc2ccsn2)o1

Procedure:
When a methanol suspension of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide is reacted with one equivalent of 2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamine according to the procedure described in Example 17, Step A, and the resultant 3-{2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino}-4-methoxy-1,2,5-thiadiazole 1,1-dioxide is treated with one equivalent of 2-[3-isothiazolylmethylthio]ethylamine, the title compound is produced.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[N:5]=[CH:6][C:7]=1Cl.[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>C(O)C>[Cl:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[N:5]=[CH:6][C:7]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1
Reactant: Cn1ncc(Cl)c(Cl)c1=O
Reactant: C1CNCCN1
Solvent: CCO
Product: Cn1ncc(N2CCNCC2)c(Cl)c1=O
Yield: 60.2 %

Procedure:
A solution of 4.48 g (25 mmoles) of 4,5-dichloro-2-methyl-3(2H)-pyridazinone and 17.2 g (200 mmoles) of piperazine in 45 ml of anhydrous ethanol is boiled for 4 hours under stirring and reflux cooling. The solvent is evaporated in vacuo and the residue is dissolved in a mixture of water and dichloromethane. The organic phase is washed with water, dried and evaporated. The residue is triturated with ether. Thus 3.44 g (60%) of the desired compound are obtained. M.p.: 83°-87° C.
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[C:10]3[N:11]([C:15]([C:19]([NH:21][C@H:22]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[F:32])[CH2:23][CH2:24][OH:25])=[O:20])=[C:16]([CH3:18])[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=[O:35].C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl.C(OCC)(=O)C>[CH:1]1([CH2:7][O:8][C:9]2[C:10]3[N:11]([C:15]([C:19]([NH:21][C@H:22]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[F:32])[CH2:23][C:24]([OH:35])=[O:25])=[O:20])=[C:16]([CH3:18])[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Reactant: Cc1nc2c(OCC3CCCCC3)cccn2c1C(=O)N[C@@H](CCO)c1ccccc1F
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1nc2c(OCC3CCCCC3)cccn2c1C(=O)N[C@@H](CC(=O)O)c1ccccc1F
Reaction time: 8 h
Yield: 26.7 %

Procedure:
To a solution of 290 mg of 8-(cyclohexylmethoxy)-N-[(1S)-1-(2-fluorophenyl)-3-hydroxypropyl]-2-methylimidazo[1,2-a]pyridine-3-carboxamide in dichloromethane was added 300 mg of 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one, followed by stirring overnight. To the reaction mixture were added saturated aqueous sodium bicarbonate, an aqueous sodium thiosulfate solution, and ethyl acetate to carry out a layer separation operation. The organic layer was washed with saturated aqueous sodium bicarbonate and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. To a solution of the obtained residue and 230 μl of 2-methyl-2-butene in 6.5 ml of dioxane was added 1.7 ml of an aqueous solution of 93 mg of sodium chlorite and 315 mg of sodium dihydrogen phosphate in a water bath, followed by stirring for 30 minutes in a water bath. To the reaction mixture were added water, 1 M hydrochloric acid, and chloroform to carry out a layer separation operation. The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography. To the obtained purified product was added diisopropyl ether, and the resulting solid was filtered and dried to obtain 80 mg of (3S)-3-({[8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridin-3-yl]carbonyl}amino)-3-(2-fluorophenyl)propanoic acid.