Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[CH:3]1[CH2:8][CH2:7][CH:6]([O:9][C:10](=[O:26])[N:11]([C@H:13]2[C@H:17]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=3)[CH2:16][NH:15][CH2:14]2)[CH3:12])[CH2:5][CH2:4]1.[O:29]1[CH2:34][CH2:33][CH:32]([C:35](O)=[O:36])[CH2:31][CH2:30]1>>[F:28][C:2]([F:1])([F:27])[CH:3]1[CH2:8][CH2:7][CH:6]([O:9][C:10](=[O:26])[N:11]([C@H:13]2[C@H:17]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=3)[CH2:16][N:15]([C:35]([CH:32]3[CH2:33][CH2:34][O:29][CH2:30][CH2:31]3)=[O:36])[CH2:14]2)[CH3:12])[CH2:5][CH2:4]1
Reactant: O=C(O)C1CCOCC1
Reactant: CN(C(=O)OC1CCC(C(F)(F)F)CC1)[C@@H]1CNC[C@H]1c1ccc(Cl)c(Cl)c1
Product: CN(C(=O)OC1CCC(C(F)(F)F)CC1)[C@@H]1CN(C(=O)C2CCOCC2)C[C@H]1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of example 44 (step c), the title compound [(3S,4R)-4-(3,4-dichloro-phenyl)-1-(tetrahydro-pyran-4-carbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-trifluoromethyl-cyclohexyl ester was prepared from [(3S,4R)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-trifluoromethyl-cyclohexyl ester instead of [(3S,4R)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester using tetrahydropyran-4-yl-carboxylic acid instead of 1-methylcyclopropane-1-carboxylic acid and was obtained as an off-white foam. MS m/e: 551.4 [M]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][O:17][C:18]([CH:20]=[CH2:21])=[CH2:19]>C1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:12](=[CH:13][CH:14]=1)[O:15][C:18]([O:17][CH3:16])([CH3:19])[CH2:20][CH2:21]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CC(=C)OC
Reactant: Oc1ccc(OCc2ccccc2)cc1
Solvent: c1ccccc1
Product: COC1(C)CCc2cc(OCc3ccccc3)ccc2O1

Procedure:
A mixture of 40g. of p-(benzyloxy)phenol, 33.6 g. of 2-methoxybutadiene, and 30 ml. of benzene was sealed in a glass tube under N2. The tube was heated at 160°-165° for 20 hours, cooled and opened. The yellow solution was chromatographed on silica gel with 97.5:2.5 benzene-ethyl acetate to give (±)-6-benzyloxy-2-methoxy-2-methylchroman, identical with the material prepared as described in Example 44, as 34.5 g. of pale yellow oil.
Reaction SMILES: [CH2:1]1[NH:6][C@@H:5]([CH2:7][OH:8])[CH2:4][N:3]2[CH2:9][CH2:10][NH:11][CH2:12][CH:2]12.CCN(CC)CC.[CH3:20][C:21]([Si:24]([CH3:40])([CH3:39])OCC1CN2C(CS(=O)(=O)CC2)CN1)([CH3:23])[CH3:22]>ClCCl>[CH3:20][C:21]([Si:24]([CH3:40])([CH3:39])[O:8][CH2:7][C@H:5]1[CH2:4][N:3]2[CH2:9][CH2:10][NH:11][CH2:12][CH:2]2[CH2:1][NH:6]1)([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)OCC1CN2CCS(=O)(=O)CC2CN1
Reactant: OC[C@H]1CN2CCNCC2CN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC[C@H]1CN2CCNCC2CN1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The starting (3R)-octahydro-2H-pyrazino[1,2-a]pyrazin-3-ylmethanol (D89, 528 mg, 3.08 mmol) was dissolved in 20 mL of dichloromethane and treated with Et3N (1.29 mL, 9.25 mmol) and TDBMSCl (929.5 mg, 6.17 mmol). The reaction was stirred at room temperature overnight and then for additional 24 h. It was checked by UPLC/MS, which showed conversion to product: peak at 0.47 min, m/z=286 (M+1), 172 (M-TBDMS+1). The crude was purified by flash chromatography (silica, CH2Cl2: (0.5 M NH3 in MeOH) 98:2 to 85:15). The residue obtained evaporating the fractions containing the product was dissolved in dichloromethane:MeOH 90:10 and the insoluble material was filtered away. The solution was evaporated to give 638 mg of the target product.
Reaction SMILES: [C:1]([OH:14])(=[O:13])/[CH:2]=[CH:3]/[C:4]1[CH:12]=[CH:11][C:9]([OH:10])=[C:6]([O:7][CH3:8])[CH:5]=1.Cl.[CH3:16]O>>[OH:10][C:9]1[CH:11]=[CH:12][C:4]([CH2:3][CH2:2][C:1]([O:14][CH3:16])=[O:13])=[CH:5][C:6]=1[O:7][CH3:8]
Reactant: COc1cc(/C=C/C(=O)O)ccc1O
Reactant: CO
Agent: Cl
Product: COC(=O)CCc1ccc(O)c(OC)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
20 ml of 10% hydrogen chloride-methanol was added to 1.94 g (10 mmol) of ferulic acid and the mixture was stirred at room temperature for one day. After the reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, washed twice with water, and dried (MgSO4). The solvent was distilled off. The resulting residue was dissolved in 25 ml of methanol. 0.5 g of 10% palladium-carbon was added thereto and the solution was stirred overnight under hydrogen atmosphere. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1 (v/v)) to obtain 1.86 g (8.85 mmol) of methyl 3-(4-hydroxy-3-methoxyphenyl)propionate as a colorless oily substance. Its spectroscopic data are as follows:
Reaction SMILES: C[O:2][C:3](=[O:38])[CH:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[N:14][C:15]([NH:18][C:19]3[N:20]=[CH:21][C:22]4[CH:27]=[C:26]([C:28](=[O:32])[N:29]([CH3:31])[CH3:30])[N:25]([CH:33]5[CH2:37][CH2:36][CH2:35][CH2:34]5)[C:23]=4[N:24]=3)=[CH:16][CH:17]=2)[CH2:8][CH2:7]1)[CH3:5].[Li+].[OH-]>C1COCC1.O>[CH:33]1([N:25]2[C:23]3[N:24]=[C:19]([NH:18][C:15]4[N:14]=[CH:13][C:12]([N:9]5[CH2:8][CH2:7][N:6]([CH:4]([CH3:5])[C:3]([OH:38])=[O:2])[CH2:11][CH2:10]5)=[CH:17][CH:16]=4)[N:20]=[CH:21][C:22]=3[CH:27]=[C:26]2[C:28](=[O:32])[N:29]([CH3:31])[CH3:30])[CH2:34][CH2:35][CH2:36][CH2:37]1
Reactant: COC(=O)C(C)N1CCN(c2ccc(Nc3ncc4cc(C(=O)N(C)C)n(C5CCCC5)c4n3)nc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C(=O)O)N1CCN(c2ccc(Nc3ncc4cc(C(=O)N(C)C)n(C5CCCC5)c4n3)nc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.5 %

Procedure:
To a solution of 2-{4-[6-(7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazin-1-yl}-propionic acid methyl ester (250 mg, 0.48 mmol) in 10 mL of THF is added a solution of LiOH (19 mg, 48 mmol) in 10 mL of H2O. After 18 h stirring at room temperature, the resulting mixture is concentrated and diluted with H2O and adjusted to pH=6 with 1 N HCl. Ished with dichloromethane then solids precipitated and collected to give 2-{4-[6-(7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazin-1-yl}-propionic acid (225 mg, 94%). MS (ESI) m/z 507.3 (M+H)+
Reaction SMILES: N[C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH2:12]([O:15][C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1C(Cl)=O)[CH2:13][CH3:14]>>[CH3:11][C:10]1[C:2]([C:17]2[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=2[O:15][CH2:12][CH2:13][CH3:14])=[C:3]([CH:7]=[CH:8][CH:9]=1)[C:4]([NH2:6])=[O:5]
Reactant: Cc1cccc(C(N)=O)c1N
Reactant: CCCOc1ccccc1C(=O)Cl
Product: CCCOc1ccccc1-c1c(C)cccc1C(N)=O

Procedure:
The title compound was prepared from 2-amino-3-methylbenzamide and 2-n-propoxybenzoyl chloride following the procedure of Preparation 5 and was obtained as a colorless solid (71%), m.p. 140°-142° C. Found: C,69.39; H,6.58; N,8.98. C18H20N2O3 requires C,69.21; H,6.45; N,8.97%.
Reaction SMILES: [Cl:1][C:2]([F:20])([F:19])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([OH:18])[CH:4]=1.[C:21]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[Cl:1][C:2]([F:19])([F:20])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:10])[F:11])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([O:18][CH3:21])[CH:4]=1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1c(O)cc(C(F)(F)Cl)nc1C(F)(F)F
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CCOC(=O)c1c(OC)cc(C(F)(F)Cl)nc1C(F)(F)F
Yield: 88.4 %

Procedure:
This compound was prepared using the procedure of Example 8, 12.0 g (0.038 mol) of product of Example 5, 5.8 g (0.042 mol) of K2CO3, 12 ml (0.190 mol) of methyl iodide in 200 ml of acetone were reacted affording 11.21 g of solid which was purified by HPLC using 25% ethyl acetate/cyclohexane as eluting solvent to give 9.33 g (73.6%) of product as a white solid; mp 62°-64° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([NH2:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.C([O:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][N:31]2[C:39]3[C:34](=[CH:35][C:36]([C:40](O)=[O:41])=[CH:37][CH:38]=3)[C:33]([CH3:43])=[C:32]2[CH3:44])=[CH:26][CH:25]=1)=[O:17])(C)(C)C>>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([NH:10][C:40]([C:36]2[CH:35]=[C:34]3[C:39](=[CH:38][CH:37]=2)[N:31]([CH2:30][C:27]2[CH:26]=[CH:25][C:24]([C:19]4[C:18]([C:16]([OH:17])=[O:15])=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:29][CH:28]=2)[C:32]([CH3:44])=[C:33]3[CH3:43])=[O:41])[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: C[C@H](N)c1cccc(Cl)c1
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@@H](C)c3cccc(Cl)c3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the (S)-1-(3-chlorophenyl)ethanamine and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 537/538/539 [M+H]+.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[C:12]2[C:13]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20][C:14]=3[NH:15][C:16]=2[CH:17]=[CH:18][CH:19]=1)[CH2:2][CH3:3].I[CH2:26]CC>>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[C:12]2[C:13]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20][C:14]=3[NH:15][C:16]=2[CH:17]=[CH:18][CH:19]=1)[CH2:2][CH2:3][CH3:26]
Reactant: CCCI
Reactant: CCCOc1ccccc1-c1cccc2[nH]c3c(c12)CCNCC3
Product: CCCCOc1ccccc1-c1cccc2[nH]c3c(c12)CCNCC3

Procedure:
Following the procedure for 10-(2-propoxyphenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole and substituting 1-iodobutane for 1-iodopropane while making non-critical variations the title compound was obtained as 128 mg (50%) of a brown oil: 1H NMR (400 MHz, CDCl3) δ 7.94 (br s, 1 H), 7.37-7.30 (m, 2 H), 7.25 (dd, J=8.0 Hz, 0.9 Hz, 1 H), 7.17-7.13 (m, 1 H), 7.05-7.04 (m, 1 H), 6.99 (d, J=8.2 Hz, 1 H), 6.95-6.93 (m, 1 H), 3.96-3.87 (m, 2 H), 3.11-3.00 (m, 2 H), 2.96-2.81 (m, 4 H), 2.44-2.39 (m, 2 H), 1.59-1.51 (m, 2 H), 1.27-1.17 (m, 2 H), 0.80 (t, J=7.4 Hz, 3 H); HRMS (FAB) calcd for C22H26N2O+H1: 335.2123 found 335.2137.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C@H:9]([OH:17])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH3:20]I>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C@H:9]([O:17][CH3:20])[CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:3]=1
Reactant: CI
Reactant: O[C@H](Cc1ccccc1)Cc1cccc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CO[C@H](Cc1ccccc1)Cc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.8 %

Procedure:
To a solution of 1-(3-bromophenyl)-3-phenyl-2(R)-propanol (437 mg, 1.50 mmol) in 20 mL of anhydrous THF was added NaH (70% dispersion in mineral oil, 64 mg, 1.87 mmol, 1.24 equiv.) at 0° C. under N2. The mixture was warmed to room temperature and stirred for 30 min, then CH3I (2.1 g, 15 mmol, 10 equiv.) was added at room temperature. The mixture was stirred for 3 h at room temperature. The reaction was quenched with saturated aqueous NH4Cl solution, and the mixture was extracted with EtOAc (3×50 mL). The combined organic phases were washed with brine and dried over Na2SO4. After filtration and concentration, the residue was purified by CC on silica gel with EtOAc/petroleum ether 1:20 to provide the methyl ether (347 mg, 76%) as a colorless oil. 1H NMR (CDCl3, 300 MHz) δ 7.36-7.12 (m, 9H), 3.61 (quintet, 1H, J=6.3 Hz), 3.27 (s, 3H), 2.85 (dd, 1H, J=13.8, 6.6 Hz), 2.75 (dd, 3H, J=12.9, 6.6 Hz).
Reaction SMILES: Br[C:2]1[CH:19]=[C:18]2[C:5]([CH2:6][C:7]3([C:11]42[N:15]=[C:14]([NH2:16])[C:13]([CH3:17])=[N:12]4)[CH2:10][CH2:9][CH2:8]3)=[CH:4][CH:3]=1.[C:20]([CH:22]1[CH2:24][CH2:23]1)#[CH:21].C(N(CC)CC)C>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:22]1([C:20]#[C:21][C:2]2[CH:19]=[C:18]3[C:5]([CH2:6][C:7]4([C:11]53[N:15]=[C:14]([NH2:16])[C:13]([CH3:17])=[N:12]5)[CH2:8][CH2:9][CH2:10]4)=[CH:4][CH:3]=2)[CH2:24][CH2:23]1
Reactant: CC1=NC2(N=C1N)c1cc(Br)ccc1CC21CCC1
Reactant: C#CC1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1=NC2(N=C1N)c1cc(C#CC3CC3)ccc1CC21CCC1
Temperature: 65 °C
Reaction time: 8 h
Yield: 48.9 %

Procedure:
To a solution of 6′-bromo-5″-methyl-3′H-dispiro[cyclobutane-1,2′-indene-1′,2″-imidazol]-4″-amine (Example 54, 0.10 g, 0.31 mmol) in DMF (10 mL) under argon was added ethynylcyclo-propane (0.031 g, 0.47 mmol), tetrakis(triphenylphosphine)palladium(0) (0.036 g, 0.03 mmol) and triethylamine (1.31 mL, 9.43 mmol). The reaction mixture was stirred at r.t. for 5 min before addition of cuprous iodide (8.98 mg, 0.05 mmol). The reaction mixture was stirred overnight at 65° C. The reaction mixture was partitioned between sat aq. NaHCO3 and EtOAc. The organic phase was dried over MgSO4 and concentrated to give a crude product which was purified by preparative chromatography to afford the title compound (0.046 g, 48% yield): 1 H NMR (500 MHz, DMSO-d6) δ ppm 0.60-0.73 (m, 2 H), 0.77-0.89 (m, 2 H), 1.46 (tt, 1 H), 1.50-1.65 (m, 4 H), 1.72-1.85 (m, 1 H), 2.08-2.16 (m, 1 H), 2.18 (s, 3 H), 3.07-3.23 (m, 2 H), 6.54 (d, 1 H), 6.60 (s, 2 H), 7.16 (dd, 1 H), 7.20-7.27 (m, 1 H); MS (ES+) m/z 304 [M+H]+.
Reaction SMILES: CO.[Na].[SH:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1.Cl[C:12]1[C:13]([C:22]#[N:23])=[N:14][C:15]([C:20]#[N:21])=[C:16](Cl)[C:17]=1Cl>CC(C)=O>[N:8]1[CH:9]=[CH:10][C:5]([S:4][C:12]2[C:13]([C:22]#[N:23])=[N:14][C:15]([C:20]#[N:21])=[C:16]([S:4][C:5]3[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=3)[C:17]=2[S:4][C:5]2[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=2)=[CH:6][CH:7]=1
Reactant: Sc1ccncc1
Reactant: N#Cc1nc(C#N)c(Cl)c(Cl)c1Cl
Agent: [Na]
Solvent: CO
Solvent: CC(C)=O
Product: N#Cc1nc(C#N)c(Sc2ccncc2)c(Sc2ccncc2)c1Sc1ccncc1
Reaction time: 0.08 h
Yield: 45.7 %

Procedure:
In a 500 ml single-neck flask equipped with a magnetic stirrer and a reflux condenser fitted with a calcium chloride drying tube were placed 250 ml of methanol and 2.30 g (0.10 mol) of sodium metal. After all of the sodium had reacted, 11.11 g (0.10 mol) of 4-mercaptopyridine was added and the solution was allowed to stir for five minutes. To the resulting thiolate solution, 7.65 g (0.033 mol) of 3,4,5-trichloro-2,6-pyridinedicarbonitrile was added. The reaction mixture immediately became cloudy and orange in color. The reaction mixture was heated to reflux and then cooled. The methanol was removed in vacuo leaving a red-orange gum. Mixing of the gum with acetone, filtering off the solid and drying the latter afforded 6.89 g of the title compound as a yellow to orange powder, m.p. 186°-189° C (dec.). A 1.00 g sample was recrystallized from absolute ethanol to give a 0.25 g analytical sample as small, yellow-orange crystals, m.p. 186°-189° C (dec.). Anal. % Calcd. for C22H12N6S3 : C, 57.87; H, 2.65; N, 18.41. Found: C, 57.64; H, 2.59; N, 18.22.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([S:12][Si](C(C)C)(C(C)C)C(C)C)[CH:6]=1)[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-].C(N(CC)CC)C.Cl[CH2:50][C:51](=[O:53])[CH3:52]>C1COCC1>[CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([S:12][CH2:50][C:51](=[O:53])[CH3:52])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(C)c(S[Si](C(C)C)(C(C)C)C(C)C)c1
Reactant: CC(=O)CCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C)c(SCC(C)=O)c1
Reaction time: 0.42 h

Procedure:
To a stirred solution of 4-Methyl-3-triisopropylsilanylsulfanyl-benzoic acid ethyl ester (crude from step 1) in THF (50 mL) at 0° C. was added TBAF (13.9 mmol, 13.9 mL of a 1.0 M solution in THF). After 25 minutes, triethylamine (34.7 mmol, 4.74 mL) was added, followed by chloroacetone (16.7 mmol, 1.33 mL). The reaction was stirred for an additional 5 minutes, then subjected to standard aqueous workup. The crude material was purified by silica gel chromatography (0-50% EtOAc in hexanes) to afford the title compound.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[CH:12]=[N:11][NH:10][C:7]2=[N:8][CH:9]=1.[CH3:13][Si:14]([CH3:21])([CH3:20])[CH2:15][CH2:16][O:17][CH2:18]Cl>C1COCC1.C(OCC)(=O)C>[Br:3][C:4]1[CH:5]=[C:6]2[CH:12]=[N:11][N:10]([CH2:18][O:17][CH2:16][CH2:15][Si:14]([CH3:21])([CH3:20])[CH3:13])[C:7]2=[N:8][CH:9]=1
Reactant: Brc1cnc2[nH]ncc2c1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1ncc2cc(Br)cnc21
Reaction time: 8 h
Yield: 152.3 %

Procedure:
NaH (0.082 g, 2.06 mmol, 60% suspension in mineral oil) was added portionwise to a cold (0° C.) solution of 5-bromo-1H-pyrazolo[3,4-b]pyridine (0.204 g, 1.03 mmol) in dry THF (10 mL). The reaction mixture was stirred at 0° C. for 10 minutes before 2-(trimethylsilyl)ethoxymethyl chloride (0.31 mL, 0.292 mmol) was added dropwise via a syringe. The reaction mixture was left at room temperature overnight. The reaction mixture was diluted with ethyl acetate (50 mL) and carefully quenched with water (10 mL). The aqueous layer was separated and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried, filtered and concentrated. The crude product was purified by column chromatography, eluting with hexanes/ethyl acetate (50:1) to give 5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridine (0.146 g, 43%) as an oil.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[C:7]1([CH:13]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][OH:22])[CH2:16][CH2:15]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C1(C)C=CC=CC=1>[C:4]([O:22][CH2:21][CH2:20][N:17]1[CH2:16][CH2:15][CH:14]([CH:13]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:19][CH2:18]1)(=[O:5])[CH2:3][C:2]([CH3:1])=[O:6]
Reactant: OCCN1CCC(C(c2ccccc2)c2ccccc2)CC1
Reactant: C=C1CC(=O)O1
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)OCCN1CCC(C(c2ccccc2)c2ccccc2)CC1
Temperature: 70 °C

Procedure:
Diketene (0.33 ml) was added to a solution of 4-diphenylmethyl-1-piperidineethanol (1.04 g) in toluene (2 ml) at 70° C. and the mixture was stirred at 70° C. for an hour. The solvent was distilled off under reduced pressure and the residue was purified by silica gel chromatography [hexane-ethyl acetate (2:3, v/v)] to give 2-(4-diphenylmethylpiperidino)ethyl acetoacetate as an oil. Yield 1.23 g (92.1%).
Reaction SMILES: [NH2:1]CCC1N=CN(CCCNC(C)(C)COC2C=CC=CC=2)C=1.[C:24]1([S:30](Cl)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:24]1([S:30]([NH2:1])(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)(COc1ccccc1)NCCCn1cnc(CCN)c1
Product: NS(=O)(=O)c1ccccc1

Procedure:
3-[4-(2-Aminoethyl)imidazol-1-yl]-N-(1,1-dimethyl-2-phenoxyethyl)propylamine (2.05 g) was reacted with benzenesulphonyl chloride (1.15 g) in a similar manner to Example 55 to give N-(2-{1-3-(1,1-dimethyl-2-phenoxyethylamino)propyl]imidazol-4-yl}ethyl]benzenesulphonamide, as an oil. The compound contained 7% of N-(2-{1-[3-(1,1-dimethyl-2-phenoxyethylamino)propyl]imidazol-5-yl}ethyl]benzenesulphonamide, by 1H nmr and 13C nmr. These compounds may be separated by HPLC.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[C:9]([Cl:15])[CH:8]=1)[OH:6])[CH3:2].[C:17](OC(=O)C)(=[O:19])[CH3:18]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:16])[CH:5]([O:6][C:17](=[O:19])[CH3:18])[C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[C:9]([Cl:15])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(O)c1ccc(SC)c(Cl)c1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)C(OC(C)=O)c1ccc(SC)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91 %

Procedure:
A solution of (3-chloro-4-methylsulfanyl-phenyl)-hydroxy-acetic acid ethyl ester (1.43 g, 5.49 mmol) in pyridine (2 mL) was treated with acetic anhydride (2 mL) and 4-dimethylaminopyridine (50 mg, 0.41 mmol). The reaction mixture was stirred at 25° C. for 16 h. The reaction mixture was then diluted with methylene chloride (100 mL). The organic layer was washed with a 1N aqueous hydrochloric acid solution (2×30 mL), washed with a saturated aqueous sodium chloride solution (1×30 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 4/1 hexanes/ethyl acetate) afforded acetoxy-(3-chloro-4-methylsulfanyl-phenyl)-acetic acid ethyl ester (1.51 g, 91%) as a light yellow oil: EI-HRMS m/e calcd for C13H15ClO4S (M+) 302.0379, found 302.0387.
Reaction SMILES: [O:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH:5]=[CH:4][CH2:3][CH2:2]1.C(=O)([O-])[OH:13].[Na+].OOS([O-])=O.[K+]>C(OCC)(=O)C.O.O>[O:13]1[CH:5]2[CH:4]1[CH2:3][CH2:2][O:1][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=12
Reactant: C1=Cc2ccccc2OCC1
Reactant: O=C([O-])O
Agent: O=S([O-])OO
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: c1ccc2c(c1)OCCC1OC21
Reaction time: 1 h

Procedure:
To 0.5 g of 2,3-dihydro-1-benzoxepin (3.42 mmol), prepared according to the method described in J. Org. Chem., 1969, 34 (1), 207, dissolved in 30 ml of a mixture of ethyl acetate/water 50/50, there are added 1.44 g of sodium hydrogen carbonate (17.1 mmol) and then, over 1 hour, a solution of 2.1 g of Oxone® (3.42 mmol) in 15 ml of water. After the end of the addition, stirring is carried out for a further hour and then the organic phase is separated off. The aqueous phase is again extracted with 10 ml of ethyl acetate, and the combined organic phases are washed with water, dried, filtered and evaporated to dryness to yield the expected product in the form of an oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][C:15]=1[CH3:23])[O:9][CH2:8][CH2:7][CH:6]2[C:24]([O:26][CH3:27])=[O:25])#[N:2].C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:61][C:62]1[CH:67]=[CH:66][C:65]([CH2:68][CH2:69][NH2:70])=[CH:64][CH:63]=1.Cl>CN(C=O)C>[Cl:61][C:62]1[CH:67]=[CH:66][C:65]([CH2:68][CH2:69][NH:70][C:18]([C:17]2[CH:21]=[CH:22][C:14]([O:13][C:12]3[CH:11]=[C:10]4[C:5]([CH:6]([C:24]([O:26][CH3:27])=[O:25])[CH2:7][CH2:8][O:9]4)=[CH:4][C:3]=3[C:1]#[N:2])=[C:15]([CH3:23])[CH:16]=2)=[O:20])=[CH:64][CH:63]=1
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3C)c(C#N)cc21
Reactant: NCCc1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccc(Cl)cc4)cc3C)c(C#N)cc21
Reaction time: 48 h
Yield: 33.6 %

Procedure:
4-(6-Cyano-4-(methoxycarbonyl)-3,4-dihydro-2H-chromen-7-yloxy)-3-methylbenzoic acid (0.013 g, 0.03539 mmol) in 1 ml dry DMF was treated with N-ethyl-N-isopropylpropan-2-amine (0.01233 ml, 0.07078 mmol), HBTU (0.01610 g, 0.04247 mmol) and 2-(4-chlorophenyl)ethanamine (0.009843 ml, 0.07078 mmol) at ambient temperature. After 48 h, the reaction was poured into 10% aqueous HCl, extracted with ethyl acetate, dried over sodium sulfate, filtered, and concentrated to provide the crude material as a yellow film. Purification of the crude material on silica gel, eluting with 1% MeOH/DCM, provided the title compound (6 mg, 34%)