Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC[N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH:19]=[N:20][N:21]([C:23]4([CH2:32][C:33]#[N:34])[CH2:26][N:25]([S:27]([CH2:30][CH3:31])(=[O:29])=[O:28])[CH2:24]4)[CH:22]=3)[C:12]=2[CH:11]=[CH:10]1)(=O)C(C)(C)C.[OH-].[Na+]>CO.O1CCCC1>[N:14]1[C:13]2[NH:9][CH:10]=[CH:11][C:12]=2[C:17]([C:18]2[CH:19]=[N:20][N:21]([C:23]3([CH2:32][C:33]#[N:34])[CH2:24][N:25]([S:27]([CH2:30][CH3:31])(=[O:28])=[O:29])[CH2:26]3)[CH:22]=2)=[N:16][CH:15]=1
Reactant: CCS(=O)(=O)N1CC(CC#N)(n2cc(-c3ncnc4c3ccn4COC(=O)C(C)(C)C)cn2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCS(=O)(=O)N1CC(CC#N)(n2cc(-c3ncnc4[nH]ccc34)cn2)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 86 %

Procedure:
A suspension of (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (20, 1.0 g, 2.06 mmol) in methanol (MeOH, 5 mL) and tetrahydrofuran (THF, 20 mL) was treated with a 1 M aqueous sodium hydroxide solution (NaOH, 2.3 mL, 2.3 mmol, 1. 12 equiv) at room temperature, and the resulting reaction mixture was stirred at room temperature for 2-3 h. When HPLC showed that the reaction was deemed complete, the reaction mixture was quenched with water (10 mL) and a 1 N aqueous HCl solution (0.2 mL) to adjust pH to 7-7.5 at room temperature. The resulting mixture was stirred at room temperature for 30 min before the solids were collected by filtration. The solids were washed with a mixture of acetonitrile and water (2/3 by volume, 2×4 mL) and dried in vacuum at 40-45° for 24 h to afford crude 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(ethylsulfonyl)azetidin-3-yl)acetonitrile (14, 658 mg, 765 mg theoretical, 86% yield) as off-white solids, which was found to be identical to the material prepared by Method A. For crude 14: 1H NMR (DMSO-d6, 300 MHz) δ 12.15 (s, 1H), 8.94 (s, 1H), 8.72 (s, 1H), 8.49 (s, 1H), 7.63 (d, 1H), 7.09 (d, 1H), 4.62 (d, 2H), 4.25 (d, 2H), 3.71 (s, 2H), 3.24 (q, 2H), 1.26 (t, 3H) ppm; C16H17N7O2S (MW, 371.42), LCMS (EI) m/e 372 (M++H).
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[C:12]2[NH:20][CH:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][OH:29])[CH2:23][CH2:22]2)=[CH:6][CH:5]=1.[H-].[Na+].CN(C)C=O.CS([C:41]1[S:42][C:43]2[C:48]([N:49]=1)=[CH:47][CH:46]=[CH:45][N:44]=2)(=O)=O>O>[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[C:12]2[NH:20][CH:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][O:29][C:41]3[S:42][C:43]4[C:48]([N:49]=3)=[CH:47][CH:46]=[CH:45][N:44]=4)[CH2:23][CH2:22]2)=[CH:6][CH:5]=1
Reactant: CS(=O)(=O)c1nc2cccnc2s1
Reactant: OCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc(Cn2c(NC3CCN(CCOc4nc5cccnc5s4)CC3)nc3ccccc32)cc1
Reaction time: 2 h
Yield: 15 %

Procedure:
To a stirred mixture of 5.3 parts of 4-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-ylamino]-1-piperidineethanol dihydrochloride, 2.8 parts of a sodium hydride dispersion 50% and 90 parts of N,N-dimethylformamide were added 2.55 parts of 2-(methylsulfonyl)thiazolo[5,4-b]pyridine. The whole was stirred for 2 hours. The reaction mixture was poured into water. The product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane, hexane and methanol (45:45:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 0.9 parts (15%) of 1-[(4-fluorophenyl)methyl]-N-[1-[2-[(thiazolo[5,4-b]pyridin-2-yl)oxy]ethyl]-4-piperidinyl]-1H-benzimidazol-2-amine; mp. 151.0° C. (compound 107).
Reaction SMILES: CC#C.[Mg].C(Br)CBr.[O:9]([C:16]1[CH:23]=[CH:22][C:19](C=O)=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl.[O:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>>[C:27]([CH:26]([OH:25])[C:22]1[CH:19]=[CH:18][CH:17]=[C:16]([O:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:23]=1)#[C:28][CH3:29]
Reactant: C1CCOC1
Reactant: O=Cc1ccc(Oc2ccccc2)cc1
Agent: C#CC
Agent: Cl
Agent: [Mg]
Solvent: BrCCBr
Product: CC#CC(O)c1cccc(Oc2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 8 g of methyl acetylene in 100 ml of tetrahydrofurane is slowly added at 0° C. a Grignard solution freshly prepared from 4 gof magnesium and 20 g of ethylene bromide in 20 ml of tetrahydrofurane. Themixture is stirred for 15 minutes under argon and a solution of 27 g of p-phenoxybenzaldehyde in 100 ml of tetrahydrofurane is added dropwise at 0° to 5° C. After stirring for 14 hours at room temperature,the reaction mixture is cooled to 0° C. with 50 g of ice and, after the slow addition of 25 ml of conc. hydrochloric acid, extracted with ether. The ethereal extract is washed twice with water and twice with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The product is chromatographed over silica gel with ethyl acetate/hexane (1:4) as eluant, affording the compound of the formula ##STR4##with a refractive index of nD20° =1.5898.
Reaction SMILES: [CH3:1][C:2]([CH3:23])([CH2:16][C:17]1([CH3:22])[O:21][CH2:20][CH2:19][O:18]1)[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][C:6]=1[NH2:15].[CH:24](OC)(OC)OC>>[CH3:1][C:2]([CH3:23])([CH2:16][C:17]1([CH3:22])[O:21][CH2:20][CH2:19][O:18]1)[CH2:3][N:4]1[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:15]=[CH:24]1
Reactant: COC(OC)OC
Reactant: CC(C)(CNc1c(N)cnc2ccccc12)CC1(C)OCCO1
Product: CC(C)(Cn1cnc2cnc3ccccc3c21)CC1(C)OCCO1
Yield: 270.4 %

Procedure:
The general method described in Step 6 of Example 22 was used to cyclize N4-[2,2-dimethyl-3-(2-methyl-[1,3]dioxolan-2-yl)propyl]quinoline-3,4-diamine (8.1 g, 25.7 mmol) by reaction with trimethyl orthoformate (3.3 g, 10 mmol) to provide 1-[2,2-dimethyl-3-(2-methyl[1,3]dioxolan-2-yl)propyl]-1H-imidazo[4,5-c]quinoline (8.8 g) as an oil that was used directly in the next step without further purification.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.C(N(CC)CC)C.[C:29]([Si:35]([CH:40]([CH3:42])[CH3:41])([CH:37]([CH3:39])[CH3:38])Cl)([CH:32]([CH3:34])[CH3:33])([CH3:31])[CH3:30]>C1(C)C=CC=CC=1>[C:1]([O:5][Si:35]([C:29]([CH:32]([CH3:34])[CH3:33])([CH3:31])[CH3:30])([CH:40]([CH3:41])[CH3:42])[CH:37]([CH3:38])[CH3:39])(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)O
Reactant: CC(C)C(C)(C)[Si](Cl)(C(C)C)C(C)C
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C=CC(=O)O[Si](C(C)C)(C(C)C)C(C)(C)C(C)C
Temperature: 80 °C
Reaction time: 5 h

Procedure:
A flask equipped with a stirrer, reflux condenser, dropping funnel and thermometer was charged with 14.4 g (0.2 mol) of acrylic acid, 120 ml of toluene, and 0.06 g of 2,6-di-tert-butyl-4-methylphenol. At room temperature, 22.3 g (0.22 mol) of triethylamine was added dropwise over one hour. At the end of dropwise addition, the flask was heated at 80° C. After the internal temperature became constant, 47.0 g (0.20 mol) of thexyldiisopropylchlorosilane was added dropwise over two hours. After the completion of dropwise addition, the reaction solution was stirred for 5 hours at 80° C. The reaction solution was then cooled to room temperature, and the resulting hydrochloric acid salt removed by filtration. The filtrate was distilled, collecting 38.6 g of a fraction having a boiling point of 87-92° C./0.13 kPa.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[C:9](B3OC(C)(C)C(C)(C)O3)[CH:10]=2)[N:5]([CH3:21])[C:4](=[O:22])[C:3]=1[C:23]([NH:25][CH2:26][C:27]([O:29]C(C)(C)C)=[O:28])=[O:24].Cl[C:35]1[N:40]=[C:39]([CH3:41])[CH:38]=[CH:37][N:36]=1>>[OH:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[C:9]([C:35]3[N:40]=[C:39]([CH3:41])[CH:38]=[CH:37][N:36]=3)[CH:10]=2)[N:5]([CH3:21])[C:4](=[O:22])[C:3]=1[C:23]([NH:25][CH2:26][C:27]([OH:29])=[O:28])=[O:24]
Reactant: Cn1c(=O)c(C(=O)NCC(=O)OC(C)(C)C)c(O)c2cc(B3OC(C)(C)C(C)(C)O3)cnc21
Reactant: Cc1ccnc(Cl)n1
Product: Cc1ccnc(-c2cnc3c(c2)c(O)c(C(=O)NCC(=O)O)c(=O)n3C)n1

Procedure:
The title compound was prepared from tert-butyl 2-(4-hydroxy-1-methyl-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydro-1,8-naphthyridine-3-carboxamido)acetate (Example 26 (h)) and 2-chloro-4-methylpyrimidine analogously to the procedures described for the preparation of Example 26 (i) and Example 26 (k), or Example 21 (b). MS (ESI, pos. ion) m/z: 370 (M+1). 1NMR (400 MHz, DMSO-d6) δ ppm: 10.41 (s, 1 H), 9.65 (s, 1 H), 9.24 (s, 1 H), 8.80 (d, J=4.9 Hz, 1 H), 7.41 (d, J=4.9 Hz, 1 H), 4.13 (d, J=5.3 Hz, 2 H), 3.74 (s, 3 H), 2.59 (s, 3 H).
Reaction SMILES: [Si]([O:8][C@H:9]([CH2:22][CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[C@H:10]([CH3:21])[O:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1)(C(C)(C)C)(C)C.Br[C:31]1[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][C:32]=1[CH3:39].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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>[OH:8][C@H:9]([CH2:22][CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[C@H:10]([CH3:21])[O:11][C:12]1[CH:13]=[CH:14][C:15]([C:31]2[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][C:32]=2[CH3:39])=[CH:16][CH:17]=1
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@@H](CCc1cccnc1)O[Si](C)(C)C(C)(C)C
Reactant: Cc1cc(C#N)ccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1cc(C#N)ccc1-c1ccc(O[C@@H](C)[C@H](O)CCc2cccnc2)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 83.6 %

Procedure:
Prepared according to the method described in Example 12b) from (1S,2R)-4-[2-(tert-butyldimethylsilanyloxy)-1-methyl-4-pyridin-3-ylbutoxy]benzeneboronic acid (0.20 g, Example 11)), 4-bromo-3-methylbenzonitrile (0.20 g), 2M aqueous sodium carbonate solution (0.5 ml) and tetrakis(triphenylphosphine)palladium (0) (0.02 g) in toluene (5 ml) and ethanol (2 ml). The reaction mixture was heated at 100° C. under nitrogen for 4 hours. After cooling, the solution was concentrated under reduced pressure. Concentrated hydrochloric acid (1 ml) was added to a solution of the residue in methanol (5 ml) and the suspension stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure and the residue partitioned between diethyl ether and water. The aqueous layer was neutralised with a saturated solution of sodium bicarbonate in water and extracted with dichloromethane. The combined organics were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by normal-phase HPLC eluting with a gradient of 0-25% ethanol in dichloromethane to give an oil (0.15 g)
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[C-:10]#[N:11].[Na+]>CS(C)=O>[CH3:9][O:8][C:7]1[C:2]([C:10]#[N:11])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1cccnc1Br
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cccnc1C#N

Procedure:
A solution of 2-bromo-3-methoxy-pyridine from Example 13a in DMSO is treated with NaCN at 120° C. for 18 h. The reaction mixture is evaporated, the residue is taken into ethyl acetate, washed with 5% Na2CO3 (aqueous), dried over MgSO4 and evaporated to give 3-methoxy-pyridine-2-carbonitrile.
Reaction SMILES: Br[C:2]1[NH:22][C:5]2=[N:6][CH:7]=[C:8]([CH2:10][CH2:11][C:12]3[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[CH:13]=3)[N:9]=[C:4]2[CH:3]=1.[CH3:23][N:24]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30](B3OC(C)(C)C(C)(C)O3)[CH:31]=2)[CH:26]=[N:25]1>>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([CH:17]=[C:16]([O:18][CH3:19])[CH:15]=1)[CH2:11][CH2:10][C:8]1[N:9]=[C:4]2[CH:3]=[C:2]([C:30]3[CH:31]=[C:32]4[C:27]([CH:26]=[N:25][N:24]4[CH3:23])=[CH:28][CH:29]=3)[NH:22][C:5]2=[N:6][CH:7]=1
Reactant: Cn1ncc2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Reactant: COc1cc(CCc2cnc3[nH]c(Br)cc3n2)cc(OC)c1
Product: COc1cc(CCc2cnc3[nH]c(-c4ccc5cnn(C)c5c4)cc3n2)cc(OC)c1

Procedure:
The compound was prepared by using procedures analogous to those described for the synthesis of Example 53, Step 2 starting from 6-bromo-2-[2-(3,5-dimethoxyphenyl)ethyl]-5H-pyrrolo[2,3-b]pyrazine and 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (from Combi-Blocks). LCMS calculated for C24H24N5O2 (M+H)+: m/z=414.2. Found 414.2.
Reaction SMILES: [O:1]=[C:2]1[N:10]2[C@H:5]([CH2:6][CH2:7][C@@H:8]([NH:11][C:12]3[C:13]4[CH:20]=[CH:19][N:18]([S:21]([C:24]5[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=5)(=[O:23])=[O:22])[C:14]=4[N:15]=[CH:16][N:17]=3)[CH2:9]2)[CH2:4][C@@H:3]1[NH:31]C(=O)OC(C)(C)C.Cl>CO.O1CCOCC1>[NH2:31][C@@H:3]1[C:2](=[O:1])[N:10]2[C@H:5]([CH2:6][CH2:7][C@@H:8]([NH:11][C:12]3[C:13]4[CH:20]=[CH:19][N:18]([S:21]([C:24]5[CH:25]=[CH:26][C:27]([CH3:28])=[CH:29][CH:30]=5)(=[O:23])=[O:22])[C:14]=4[N:15]=[CH:16][N:17]=3)[CH2:9]2)[CH2:4]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(N[C@@H]4CC[C@@H]5C[C@H](NC(=O)OC(C)(C)C)C(=O)N5C4)ncnc32)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1ccc(S(=O)(=O)n2ccc3c(N[C@@H]4CC[C@@H]5C[C@H](N)C(=O)N5C4)ncnc32)cc1
Temperature: 25 °C
Reaction time: 23 h

Procedure:
A solution of tert-butyl (2S,6R,8aR)-3-oxo-6-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-octahydroindolizin-2-ylcarbamate 127.4 (550 mg (1.02 mmole) in MeOH (21 mL) was treated with of 4 M HCl in 1,4-dioxane (4.0 mL (20.3 mmol) and stirred at room temperature for 23 hr. The mixture was concentrated to dryness, and the residue was dissolved in MeOH (20 ml) and treated with polymer-supported carbonate resin (1.2 g, 3.5 mmol/g). The suspension was stirred at room temperature for 1 hour. The resin was removed by filtration through a celite plug, and the filtrate was concentrated in vacuo to yield 414 mg of (2S,6R,8aR)-2-amino-6-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)hexahydroindolizin-3(5H)-one 127.5 as pale yellow solid that was used without further purification. 1H NMR (400 MHz, CHLOROFORM-d) δ 8.42 (s, 1H), 8.04 (d, J=8.3 Hz, 2H), 7.43 (d, J=4.0 Hz, 1H), 7.28 (d, J=8.8 Hz, 2H), 6.49 (d, J=3.8 Hz, 1H), 5.64-5.46 (m, 1H), 4.41 (br. s., 1H), 4.22 (d, J=14.1 Hz, 1H), 3.72-3.54 (m, 2H), 3.08 (dd, J=3.1, 13.9 Hz, 1H), 2.38 (s, 3H), 2.10 (ddd, 0.1=4.3, 8.7, 13.3 Hz, 1H), 2.04-1.91 (m, 1H), 1.90-1.61 (m, 4H), 1.47 (dd, J=2.9, 11.9 Hz, 1H); LCMS (ESI) m/z: 441.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1.Cl[C:12]1[C:13]2[C:20]([C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:22])=[CH:19][NH:18][C:14]=2[N:15]=[CH:16][N:17]=1>>[OH:10][CH2:9][CH2:8][C:4]1[CH:3]=[C:2]([NH:1][C:12]2[C:13]3[C:20]([C:21]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)=[O:22])=[CH:19][NH:18][C:14]=3[N:15]=[CH:16][N:17]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: Nc1cccc(CCO)c1
Reactant: O=C(c1ccccc1)c1c[nH]c2ncnc(Cl)c12
Product: O=C(c1ccccc1)c1c[nH]c2ncnc(Nc3cccc(CCO)c3)c12

Procedure:
(4-((3-(2-Hydroxyethyl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(phenyl)methanone was synthesized using 2-(3-aminophenyl)ethanol and (4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(phenyl)methanone according to the general procedure A. A white solid was obtained. M.p.>300° C.; 400 MHz 1HNMR (DMSO-d6) δ 11.25 (s, 1H), 8.42 (s, 1H), 7.90-7.81 (m, 4H), 7.65-7.55 (m, 4H), 7.26 (m, 1H), 6.90 (d, J=7.2 Hz, 1H), 4.63 (s, 1H), 3.61-3.60 (m, 2H), 2.74-2.70 (m, 2H); LCMS [M+H] 359.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]2[S:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[C:9](=[O:11])[CH2:10][C:4]=2[CH:3]=1.[BH4-].[Na+].O>C(O)C>[F:1][C:2]1[CH:17]=[CH:16][C:5]2[S:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH:9]([OH:11])[CH2:10][C:4]=2[CH:3]=1
Reactant: O=C1Cc2cc(F)ccc2Sc2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: OC1Cc2cc(F)ccc2Sc2ccccc21

Procedure:
22 g of 2-fluoro-10,11-dihydro-dibenzo[b,f]thiepin-10-one are suspended in 110 ml of ethanol and treated with 6.1 g of sodium borohydride. The mixture is heated under reflux for 10-15 minutes, then treated with water and extracted with chloroform. The organic phase is washed with water, dried over sodium sulphate and evaporated. There is obtained 2-fluoro-10,11-dihydro-dibenzo[b,f]thiepin-10-ol which melts at 110°-113° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]=[C:12]=[O:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:16]=1[C:17](O)=[O:18]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[C:17](=[O:18])[C:16]3[C:15](=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:24])[NH:14][C:12]2=[O:13])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C=NS(=O)(=O)c1ccc(Cl)cc1
Reactant: Cc1cccc(N)c1C(=O)O
Product: Cc1cccc2[nH]c(=O)n(S(=O)(=O)c3ccc(Cl)cc3)c(=O)c12
Yield: 85.6 %

Procedure:
2.00 g (9.19 mmol) of 4-chlorobenzenesulfonylisocyanate and 1.26 g (8.33 mmol) of 2-amino-6-methylbenzoic acid were treated in the same way as in Example 1 to obtain 2.50 g of the above-identified compound (yield 85.6%). Properties: colorless crystal, Melting point: >250° C., PMR (δppm, DMSO-d6): 2.56 (3H,s), 6.99 (2H,t), 7.49 (1H,t), 7.77 (2H,d), 8.20 (2H,d), 11.54 (1H,br).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[C:4]([F:10])[CH:3]=1.[Li+].CC([N-]C(C)C)C.C1CCCCC1.Cl[C:26]([O:28][CH2:29][CH3:30])=[O:27]>C1COCC1>[CH2:29]([O:28][C:26](=[O:27])[C:9]#[C:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[F:10])[CH3:30]
Reactant: C#Cc1ccc(Br)cc1F
Reactant: CCOC(=O)Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: CCOC(=O)C#Cc1ccc(Br)cc1F
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 165.6 %

Procedure:
In a 100 mL round-bottomed flask, 4-bromo-1-ethynyl-2-fluorobenzene (2.0 g, 10.0 mmol) was combined with THF (28 ml) to give a brown solution. The solution was cooled to −78° C. and 1.5M LDA in cyclohexane (16.4 mL, 24.6 mmol, Eq: 2.45) was added via syringe. The reaction was stirred at −78° C. for 20 mins, ethyl chloroformate (5.42 g, 4.8 mL, 50.0 mmol, Eq: 4.97) was added at −78° C. and the reaction was stirred at room temp for 2 h under argon. The reaction was quenched with saturated NH4Cl and diluted with EtOAc. The aqueous layer was back-extracted with EtOAc. The organic layers were combined, washed with 1 M HCl (2×50 mL), H2O (1×50 mL), saturated NaHCO3 (1×50 mL) and brine (1×25 mL), dried over Na2SO4 and concentrated in vacuo to a dark red oil. The crude material was purified by flash chromatography (silica gel, 220 g, 0% to 20% EtOAc in heptane) to afford a pure fraction (4.49 g, 46%) of the desired product as an off white solid. The less pure fraction was stripped and the residue was recrystallized from EtOAc/hexane to afford an additional 1.64 g (17%) of the desired product as a pink powder. 1H NMR (CDCl3) δ ppm 7.40-7.53 (m, 1H), 7.28-7.39 (m, 2H), 4.28 (q, J=7.0 Hz, 2H), 1.32 (t, J=7.0 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]([OH:15])=O)[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][CH:23]([C:26]2[CH:27]=[C:28]([NH:32][C:33](=[O:35])[CH3:34])[CH:29]=[CH:30][CH:31]=2)[CH2:22][CH2:21]1>>[C:33]([NH:32][C:28]1[CH:27]=[C:26]([CH:23]2[CH2:24][CH2:25][N:20]([CH2:19][CH2:18][CH2:17][NH:16][C:13]([C:8]3([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[CH2:9][CH2:10][CH2:11][CH2:12]3)=[O:15])[CH2:21][CH2:22]2)[CH:31]=[CH:30][CH:29]=1)(=[O:35])[CH3:34]
Reactant: CC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CCCC1
Product: CC(=O)Nc1cccc(C2CCN(CCCNC(=O)C3(c4ccc(Cl)cc4)CCCC3)CC2)c1

Procedure:
Example 78 was prepared from 1-(4-chlorophenyl) cyclopentanecarboxylic acid and N-{3-[1-(3-amino propyl)-4-piperidinyl]phenyl}acetamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 7.44 (s, 1H), 7.34–7.26 (m, 7H), 6.97 (d, 1H, J=7.6 Hz), 6.54 (br s, 1H), 3.28 (dd, 2H, J=5.6, 12.0 Hz), 2.95 (d, 2H, J=12.0 Hz), 2.54–2.48 (m, 3H), 2.33 (t, 2H, J=6.8 Hz), 2.20 (s, 3H), 2.00–1.95 (m, 4H), 1.84–1.60 (m, 10H); ESMS m/e: 482.2 (M+H)+.
Reaction SMILES: CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.I[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=1.[SH:50][C:51]1[CH:52]=[C:53]([CH:57]=[CH:58][CH:59]=1)[C:54]([OH:56])=[O:55].C(N(CC)C(C)C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[N:45]1[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=1[S:50][C:51]1[CH:52]=[C:53]([CH:57]=[CH:58][CH:59]=1)[C:54]([OH:56])=[O:55]
Reactant: O=C(O)c1cccc(S)c1
Reactant: Ic1ccccn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)c1cccc(Sc2ccccn2)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
Xantphos (3.75 g) and Pd2(dba)3 (2.97 g) were added in that order to a dioxane (150 mL) solution of 2-iodopyridine (7.31 g), 3-mercaptobenzoic acid (5.0 g) and N,N-diisopropylethylamine (11.30 mL), and stirred overnight in a nitrogen atmosphere at 100° C. After left cooled, the reaction solution was evaporated under reduced pressure, then ethyl acetate was added to the residue, washed three times with aqueous saturated ammonium chloride solution, and dried with sodium sulfate. The drying agent was removed through filtration, and the solvent was evaporated off under reduced pressure. The residue was purified through silica gel column chromatography (methanol/chloroform=from 0% to 20%, gradient) to give the intended product (4.95 g, 66%) as a brown solid.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[OH:11])[CH:2]=[CH2:3].C1C=C(Cl)C=C(C(OO)=[O:20])C=1>C(Cl)(Cl)Cl>[F:10][C:8]1[CH:7]=[CH:6][C:5]2[O:11][CH:2]([CH2:3][OH:20])[CH2:1][C:4]=2[CH:9]=1
Reactant: C=CCc1cc(F)ccc1O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: OCC1Cc2cc(F)ccc2O1
Temperature: 60 °C
Yield: 79 %

Procedure:
Into a 500 ml round-bottomed flask that contained a solution of 2-allyl-4-fluoro-phenol (10.0 g, 65.7 mmol) in 300 ml of chloroform was added m-CPBA (11 g, 64 mmol, ˜0.96 eq). The mixture was heated at 60° C. (oil bath) for 6 hours. The contents were cooled to room temperature and the solids were filtered off and washed with 3×20 ml of chloroform The filtrate was washed with saturated aqueous NaHCO3 (2×100 mL) to remove traces of m-CPBA, dried over magnesium sulfate, filtered, and then concentrated under vacuum. The crude residue was then chromatographed on silica gel using petroleum ether/ethyl acetate to elute. The product-containing fractions were combined and concentrated under vacuum to afford 8.5 grams of the alcohol as a yellow oil (77%); 1H NMR (300 MHz, CDCl3): δ 6.91-6.88 (m, 1H), 6.84-6.78 (m, 1H), 6.72-6.68 (m, 1H), 4.99-4.90 (m, 1H), 3.90-3.85 (dd, J=3.3 Hz, 12 Hz, 1H), 3.78-3.70 (dd, J=3.3 Hz, 12 Hz, 1H), 3.29-3.21 (dd, J=9.3 Hz, 15.9 Hz, 1H), 3.01-3.08 (dd, J=7.5 Hz, 15.9 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.[CH2:10]([Mg]Cl)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1COCC1>[CH2:10]([C:4]1[CH:5]=[C:6]([Cl:8])[N:7]=[C:2]([Cl:1])[N:3]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: Clc1cc(Cl)nc(Cl)n1
Solvent: C1CCOC1
Product: Clc1cc(Cc2ccccc2)nc(Cl)n1
Temperature: -78 °C
Reaction time: 3 h
Yield: 46.6 %

Procedure:
1.78 g (9.70 mmoles) of 2,4,6-Trichloro-pyrimidine was dissolved in 10 mls of anhydrous THF and chilled to −78° C. 4.9 mls (9.8 mmoles) of benzyl magnesium chloride (2M in THF) was added dropwise and the solution allowed to warm to ambient temperature. The reaction was stirred for 3 hours, then quenched with 20 mls of water and extracted three times with ethyl acetate. The combined organic phases were washed with saturated NaCl solution, dried over NaSO4 and evaporated under reducd pressure. The crude residue was purified by flash chromatography, using EtOAc/Heptane as the eluent to yield 1.08 g (47%) of 4-benzyl-2,6-dichloro-pyrimidine as a light yellow oil. 1H NMR (CDCl3 03-499-77b)