Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[C:11]([C:13]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19](B5OC(C)(C)C(C)(C)O5)[CH:20]=4)[N:15](C(OC(C)(C)C)=O)[CH:14]=3)[CH:10]=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[Br:38][C:39]1[S:40][C:41](Br)=[N:42][N:43]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C(Cl)Cl.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>[Br:38][C:39]1[S:40][C:41]([C:19]2[CH:20]=[C:21]3[C:16](=[CH:17][CH:18]=2)[NH:15][CH:14]=[C:13]3[C:11]2[N:12]=[C:7]([N:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)[CH:8]=[CH:9][CH:10]=2)=[N:42][N:43]=1
Reactant: CC(C)(C)OC(=O)n1cc(-c2cccc(N3CCOCC3)n2)c2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: Brc1nnc(Br)s1
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: [K+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: Brc1nnc(-c2ccc3[nH]cc(-c4cccc(N5CCOCC5)n4)c3c2)s1
Temperature: 100 °C
Yield: 16.4 %

Procedure:
A glass microwave reaction vessel was charged with tert-butyl 3-(6-morpholinopyridin-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylate (250 mg, 0.495 mmol) and 2,5-dibromo-1,3,4-thiadiazole (133 mg, 0.544 mmol) in p-dioxane/H2O (4:1, 4.5 mL) followed by potassium carbonate (205 mg, 1.484 mmol) and Pd(PPh3)4 (28.6 mg, 0.025 mmol). The reaction was stirred and heated in a Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 100° C. for 75 min. The mixture was diluted with DCM, washed with H2O, dried, filtered and concentrated. The residue was purified with silica gel chromatography (eluting with 2-10% EtOAc in DCM) to give 4-(6-(5-(5-bromo-1,3,4-thiadiazol-2-yl)-1H-indol-3-yl)pyridin-2-yl)morpholine (36.0 mg, 0.081 mmol, 16.45%) as a yellow solid. MS (ESI, pos. ion) 442 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.85 (1H, br. s.), 9.11 (1H, d, J=1.6 Hz), 8.19 (1H, d, J=2.5 Hz), 7.80 (1H, dd, J=8.6, 1.8 Hz), 7.56-7.64 (2H, m), 7.24 (1H, d, J=7.4 Hz), 6.67 (1H, d, J=8.4 Hz), 3.79-3.86 (4H, m), 3.58-3.65 (4H, m).
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH3:17])=[C:13]([CH3:16])[CH2:14]Br)=[CH:8][CH:7]=1)([CH2:4][CH3:5])([CH3:3])[CH3:2].[CH3:18][CH:19]1[CH2:24][CH:23]([CH3:25])[CH2:22][NH:21][CH2:20]1>CCOCC>[C:1]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH3:17])=[C:13]([CH3:16])[CH2:14][N:21]2[CH2:22][CH:23]([CH3:25])[CH2:24][CH:19]([CH3:18])[CH2:20]2)=[CH:8][CH:7]=1)([CH2:4][CH3:5])([CH3:3])[CH3:2]
Reactant: CCC(C)(C)c1ccc(C(C)=C(C)CBr)cc1
Reactant: CC1CNCC(C)C1
Solvent: CCOCC
Product: CCC(C)(C)c1ccc(C(C)=C(C)CN2CC(C)CC(C)C2)cc1

Procedure:
62 G. of 3-(p-tert.-amyl-phenyl)-2,3-dimethyl-allyl bromide in 150 ml. of ether are added dropwise to a solution of 45.2 g. of 3,5-dimethylpiperidine in 200 ml. of absolute ether and the mixture is heated at reflux for 16 hours. The 3,5-dimethylpiperidine hydrobromide is removed by filtration and back-washed with ether. The ether solution is extracted with 2 N hydrochloric acid and made alkaline with 50% sodium hydroxide. The alkaline-aqueous solution is again extracted with ether, washed with water, dried over sodium sulfate and evaporated. By distillation, there is obtained pure 1-[3-(p-tert.-amylphenyl)-2,3-dimethyl-2-propenyl]-3,5-dimethylpiperidine having a boiling point of 155° C./0.04 Torr.
Reaction SMILES: CO[C:3](=[O:16])[CH:4]=[CH:5][C:6]1[C:11]([O:12]C)=[CH:10][CH:9]=[CH:8][C:7]=1[O:14]C.B(Br)(Br)Br.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(Cl)Cl.C(OCC)(=O)C>[OH:12][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:6]=1[CH:5]=[CH:4][C:3](=[O:16])[O:14]2
Reactant: COC(=O)C=Cc1c(OC)cccc1OC
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=c1ccc2c(O)cccc2o1
Yield: 89.6 %

Procedure:
To a cold (-30° C.) solution of 2,6-dimethoxycinnamic acid methyl ester (5.2 g, 23.4 mmol, prepared as described above), in chloroform (250 ml), was added boron tribromide (80 ml of a 1M solution in methylene chloride). The mixture was allowed to stir under anhydrous conditions was poured into saturated aqueous sodium hydrogen carbonate solution (400 ml). [Caution Frothing] The organic phase was diluted with ethyl acetate (250 ml), the mixture was transferred to a separating funnel and extracted thoroughly. The organic phase was isolated, dried (MgSO4) and evaporated in vacuo to give a dark red oil which did not crystallize. The oil was purified further by chromatography on silica gel to give 5-hydroxycoumarin (3.4 g, 89%), as a pale-yellow crystalline powder. M.p. 226°-229 ° C. (Das Gupta et al. J. Chem. Soc. (C), 29, 1969 give m.p. 224-225° C.) 1H NMR (DMSO-d6): 8.11 (dd, J=9,6,0.6 Hz, 1H), 7.40 (t, J=8.4 Hz, 1H), 6.78 (m, 2H), 6.34 (d, J=9.6 Hz, 1H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:10]=[CH:9][NH:8][N:7]=1.C1C(=O)N([Cl:18])C(=O)C1>CN(C=O)C>[Cl:18][C:10]1[C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[N:7][NH:8][CH:9]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: c1csc(-c2cc[nH]n2)c1
Solvent: CN(C)C=O
Product: Clc1c[nH]nc1-c1cccs1

Procedure:
Following protocol L, 3-thiophen-2-yl-1H-pyrazole was treated with NCS in DMF., to yield title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:20])[N:10]([CH3:19])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:12][C:13]=2Cl)=[CH:4][CH:3]=1.[F-:21].[K+]>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:20])[N:10]([CH3:19])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:12][C:13]=2[F:21])=[CH:4][CH:3]=1
Reactant: Cn1c(C(F)(F)F)cc(Cl)c(-c2ccc(Cl)cc2)c1=O
Reactant: [F-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cn1c(C(F)(F)F)cc(F)c(-c2ccc(Cl)cc2)c1=O
Temperature: 120 °C
Reaction time: 2 h
Yield: 45.7 %

Procedure:
To 10 ml of dimethylsulfoxide, 0.33 g (1.09 mmol) of 3-(4-chlorophenyl)-4-chloro-1-methyl-6-trifluoromethyl-2(1H)-pyridone and 0.05 g (0.86 mmol) of potassium fluoride were dissolved, followed by heating and stirring at 120° C. for 2 hours. After completion of the reaction, the reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. The organic layer was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain 0.12 g (yield: 38%) of the desired product. Melting point: 120-122° C.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[N:13]1([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][CH2:14]1.[Cl:30][CH2:31]I>C1COCC1>[Cl:30][CH2:31][C:16]1([C:19]([O:21][CH3:22])=[O:20])[CH2:15][CH2:14][N:13]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18][CH2:17]1
Reactant: ClCI
Reactant: COC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)C1(CCl)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.75 h
Yield: 51.4 %

Procedure:
To a solution of diisopropylamine (22.6 mL, 159 mmol) in anhydrous THF (140 mL) in an oven-dried round-bottomed flask was added n-BuLi (65.4 mL, 163 mmol, 2.50 M in hexanes) dropwise at 0° C. The solution was stirred for 45 minutes and 1-tert-butyl 4-methyl piperidine-1,4-dicarboxylate (20 g, 80 mmol) in THF (60 mL) was added dropwise at 0° C. and the mixture was stirred at 0° C. for 1 hour. Chloroiodomethane (17.9 mL, 239 mmol) was added dropwise and the mixture was stirred for 1 h. The mixture was quenched with 250 mL of saturated aqueous NaHCO3 followed by extraction with ethyl acetate (3×250 mL). The combined organic layers were washed (brine, 250 mL), dried (Na2SO4) and concentrated under reduced pressure to give a yellow oil that was purified by silica chromatography using a Combiflash ISCO purification system (Teledyne Isco Inc., Lincoln, Nebr.) system to give 1-tert-butyl 4-methyl 4-(chloromethyl)piperidine-1,4-dicarboxylate (12 g, 52%). 1H NMR (CDCl3) δ 1.43 (s, 9H), 2.10-2.17 (m, 4H), 2.97 (br s, 2H), 3.56 (s, 2H), 3.74 (s, 3H), 3.83 (br s, 2H).
Reaction SMILES: Cl[C:2](=[O:20])[CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:6][CH2:5]1.S1C=CC=C1.O(C(C)C)C(C)C.[H][H]>[Pd].CN(C)C(=O)C>[O:20]=[CH:2][CH2:3][CH:4]1[CH2:5][CH2:6][N:7]([C:10]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:11])[CH2:8][CH2:9]1
Reactant: O=C(Cl)CC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(C)OC(C)C
Solvent: CC(=O)N(C)C
Solvent: c1ccsc1
Product: O=CCC1CCN(C(=O)OCc2ccccc2)CC1
Yield: 95.7 %

Procedure:
A mixture of 90 parts of (phenylmethyl) 4-(2- chloro-2-oxoethyl)-1-piperidinecarboxylate, 90 parts of N,N-dimethylacetamide 6 parts of a thiophene solution and 438 parts of 2,2'-oxybispropane was hydrogenated at normal pressure and at room temperature in the presence of 5 parts of palladium-on-charcoal 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was taken up in water. The separated organic layer was dried, filtered and evaporated, yielding 75 parts (95.7%) of (phenylmethyl) 4-(2-oxoethyl)-1-piperidinecarboxylate as a residue (interm. 7).
Reaction SMILES: Br.Br[CH:3]([C:10]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([O-])(=[O:20])C.[K+].O>C(OC(=O)C)(=O)C>[OH:20][CH:3]([C:10]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(c1cccnc1)C(Br)c1ccccc1
Reactant: CC(=O)[O-]
Agent: Br
Agent: [K+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: O=C(c1cccnc1)C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.3 %

Procedure:
Alternatively, a mixture of 20.0 g (56.0 mmoles) of 3-pyridyl α-bromobenzyl ketone hydrobromide and 24.0 g (0.24 mole) of potassium acetate in 100 ml of acetic anhydride was stirred overnight at room temperature. The reaction mixture was poured into water and the product extracted into ether. The combined ether layers were washed with water and then 10% aqueous sodium bicarbonate solution. The ether layer was dried over potassium carbonate and evaporated. A solution of the residue in 140 ml of 1 N aqueous hydrochloric acid was heated at reflux for 30 minutes and after cooling made basic with solid sodium carbonate. The product was extracted into ether and the combined ether extracts evaporated, after drying over anhydrous potassium carbonate, to give 8.15 g of 3-pyridyl α-hydroxybenzyl ketone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21](O)=[O:22])[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.[CH:25]1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH3:46][C:47]1([CH3:56])[CH2:52][CH:51]([NH2:53])[CH2:50][C:49]([CH3:55])([CH3:54])[NH:48]1>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21]([NH:53][CH:51]3[CH2:50][C:49]([CH3:55])([CH3:54])[N:48]([CH3:25])[C:47]([CH3:56])([CH3:46])[CH2:52]3)=[O:22])[CH:17]=2)[CH3:14])(=[O:11])=[O:12])=[C:5]([CH3:24])[CH:4]=1
Reactant: CC1(C)CC(N)CC(C)(C)N1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)c1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)NC3CC(C)(C)N(C)C(C)(C)C3)co2)c(C)c1
Reaction time: 1 h

Procedure:
5-({[(4-Methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (53 mg, 0.15 mmol) was dissolved in DMF (1 mL) and HOBt (23 mg, 0.15 mmol) and EDCI (29 mg, 0.15 mmol) were added. The reaction was stirred for 1 h prior to addition of 2,2,6,6-tetramethylpiperidin-4-amine (21 mg, 0.135 mmol). The reaction was stirred for 16 h and then absorbed directly on to Isolute SCX-2 cartridge, washed with MeOH (5 mL) and then eluted with 7 N NH3 in MeOH (5 mL). The solvent was removed under a stream of N2 and the resulting crude product purified using prep method A.
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.CC1C([C:26]([OH:28])=O)=CC=CC=1.[NH3:29]>>[NH2:29][C:2]1[C:11]2[N:12]=[C:13]([CH2:26][OH:28])[N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: Cc1ccccc1C(=O)O
Reactant: CC(C)Cn1cnc2c(Cl)nc3ccccc3c21
Reactant: N
Product: CC(C)Cn1c(CO)nc2c(N)nc3ccccc3c21
Temperature: 175 °C

Procedure:
4-Chloro-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline-2-methyl benzoate (5.0 g; 0.13 mol, Example 7) was added to 15% methanolic ammonia (50 mL). The mixture was heated in a Parr bomb for 7 hr at 175° C. The resulting solution was evaporated to reduce the volume. A sticky solid crystallized from the solution. The solid was filtered from the mixture and slurried in aqueous sodium bicarbonate solution. The resulting solid was filtered from the mixture, washed with water, and dried to yield 2.1 g (61.7%) of crude product which was recrystallized from ethanol several times to yield pure product m.p. 226°-231° C. Analysis: Calculated: C, 66.6: H, 6.7; N, 20.7. Found: C, 66.4; H, 6.5; N, 20.4.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH2:10][CH:11]([CH2:15][OH:16])[CH:12]([CH3:14])[CH3:13].[C:17]1([CH3:26])[CH:22]=[CH:21][C:20]([C:23](Cl)=[O:24])=[CH:19][CH:18]=1.[OH-].[Na+]>C(Cl)Cl>[C:17]1([CH3:26])[CH:22]=[CH:21][C:20]([C:23]([NH:10][C@H:11]([CH2:15][OH:16])[CH:12]([CH3:14])[CH3:13])=[O:24])=[CH:19][CH:18]=1
Reactant: CC(C)C(N)CO
Reactant: Cc1ccc(C(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(C(=O)N[C@H](CO)C(C)C)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 89.6 %

Procedure:
Diisopropylethyl amine (17.4 ml, 134 mmol) was added a solution of (DL)-valinol (9.85 g, 95 mmol) in methylene chloride (100 ml). The reaction mixture was cooled to 0° C., treated with a solution of p-toluoyl chloride (12.8 ml, 91 mmol ) in methylene chloride (50 ml) and then allowed to warm to room temperature. After stirring for 3 hours, excess aqueous sodium hydroxide solution was added and the reaction was transferred to a separatory funnel. The organic layer was separated and the aqueous layer washed with one portion of methylene chloride. The combined organic layers were washed with water and brine, dried over magnesium sulfate and concentrated in vacuo. Chromatography eluting with 25% ethyl acetate in hexanes, followed by 50% ethyl acetate in hexanes gave N-p-toluoyl valinol (18.04 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.C(O)(=O)C.[CH3:14][C:15]([CH3:17])=O.C([BH3-])#N.[Na+].C1COCC1.Cl>CO>[CH:15]([NH:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)([CH3:17])[CH3:14]
Reactant: COc1ccc(N)cc1
Reactant: CC(C)=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1ccc(NC(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To a stirred solution of 4-methoxyphenylamine (1.24 g, 6.22 mmol) in methanol (15 mL) at ambient temperature was added successively, glacial acetic acid (415 mg, 6.91 mmol), acetone (669 mg, 11.5 mmol), and 1M sodium cyanoborohydride in THF (12.7 mL, 12.6 mmol). The reaction mixture was stirred overnight at room temperature. The pH was adjusted to 2 with 6N HCl and stirred for 30 minutes to quench excess sodium cyanoborohydride. The pH was then adjusted to 8.5 with 1N NaOH and the resultant solution extracted with diethyl ether (2×50 mL) and ethyl acetate (50 mL). The organic extracts were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (1.42 g, 5.91 mmol) as a yellow oil. 1H NMR (300 MHz, CDCl3): δ 6.78(d, J=8.8 Hz, 2H), 6.57(d, J=9.1 Hz, 2H), 3.75(s, 3H), 3.55(m, 1H), 2.92(br s, 1H), 1.18(d, J=6.1 Hz, 6H); TLC (EtOAc/Hex (2:3)): Rf =0.72
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.[CH3:11][C:12]1[C:16](C(B(O)O)=O)=[C:15]([CH3:22])[O:14][N:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.C(O)C>[S:9]1[CH:8]=[CH:7][C:6]2[CH:10]=[C:2]([C:16]3[C:12]([CH3:11])=[N:13][O:14][C:15]=3[CH3:22])[CH:3]=[CH:4][C:5]1=2
Reactant: Cc1noc(C)c1C(=O)B(O)O
Reactant: Brc1ccc2sccc2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: Cc1noc(C)c1-c1ccc2sccc2c1
Temperature: 80 °C
Reaction time: 6 h
Yield: 60.2 %

Procedure:
To a solution of 5-bromo-1-benzothiophene (ABCR, CAS: 133150-64-8, 1.0 6 g, 5.0 mmol) in dimethoxyethane (60 mL) and ethanol (6.0 mL) was added 3,5-dimethyl-4-isoxazoylboronic acid (1.0 g, 7.5 mmol), and 2 m sodium carbonate (2.0 mL). The reaction mixture was degassed 2-3 times, tetrakis-(triphenylphosphine)palladium (0.813 g, 0.7 mmol) was added, and the mixture was stirred for 6 h at 80° C. and concentrated. The residue was taken up in water and extracted with ethyl acetate. The organics were washed, dried and concentrated. The crude product was chromatographed on silica gel using heptane/ethyl acetate as eluent to obtain 4-benzo[b]thiophen-5-yl-3,5-dimethyl-isoxazole (0.69 g) as a light yellow solid. MS (ISP): m/e 230.1 (M+H)+
Reaction SMILES: Br[C:2]1([CH:9]=[CH:8][CH:7]=[CH:6][CH:5]1Br)[CH:3]=[CH2:4].[N-:11]=[N+:12]=[N-:13].[Na+].[OH-].[Na+].C(=O)([O-])O.[Na+]>CS(C)=O.C(Cl)Cl>[N:11]([C:2]1([CH:9]=[CH:8][CH:7]=[CH:6][CH2:5]1)[CH:3]=[CH2:4])=[N+:12]=[N-:13]
Reactant: [N-]=[N+]=[N-]
Reactant: C=CC1(Br)C=CC=CC1Br
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CS(C)=O
Product: C=CC1(N=[N+]=[N-])C=CC=CC1
Temperature: 25 °C
Reaction time: 10 h
Yield: 97.8 %

Procedure:
26.4 g of 1,2-dibromostyrene was dissolved in 150 ml of dimethylsulfoxide, then 9.8 g of sodium azide was added little by little at 15° to 18° C. in an atmosphere of nitrogen, and the mixture was stirred at room temperature for 10 hours. Then the reaction mixture was cooled to 10° C. and 10 g of a 50% aqueous sodium hydroxide solution was added dropwise thereto. After the addition the reaction mixture was stirred for 24 hours at room temperature, then 400 ml of a 2% aqueous sodium hydrogencarbonate solution was poured to it, and extraction with 150 ml of methylene chloride was carried out. After drying the extract liquid the solvent was distilled off under reduced pressure. 50 ml of n-hexane was added to the residue and the solution was treated by simple column chromatography, wherein the column was filled with 50 g of alumina (eluent: n-hexane). The solvent was removed from the elutant by distillation under reduced pressure, to obtain 14.4 g of 1-azidostyrene (B).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N:9]2[C:13]3[N:14]=[C:15]([CH3:26])[N:16]=[C:17]([N:18]4[CH2:23][CH2:22][CH:21]([CH2:24][OH:25])[CH2:20][CH2:19]4)[C:12]=3[C:11]([CH3:27])=[CH:10]2)=[C:4]([CH3:28])[CH:3]=1.[H-].[Na+].Cl[C:32]([O:34][CH2:35][CH3:36])=[O:33]>O1CCCC1>[CH2:35]([O:34][C:32](=[O:33])[O:25][CH2:24][CH:21]1[CH2:22][CH2:23][N:18]([C:17]2[C:12]3[C:11]([CH3:27])=[CH:10][N:9]([C:5]4[C:6]([CH3:8])=[CH:7][C:2]([Br:1])=[CH:3][C:4]=4[CH3:28])[C:13]=3[N:14]=[C:15]([CH3:26])[N:16]=2)[CH2:19][CH2:20]1)[CH3:36]
Reactant: Cc1nc(N2CCC(CO)CC2)c2c(C)cn(-c3c(C)cc(Br)cc3C)c2n1
Reactant: CCOC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)OCC1CCN(c2nc(C)nc3c2c(C)cn3-c2c(C)cc(Br)cc2C)CC1
Temperature: 0 °C
Yield: 27.5 %

Procedure:
{1-[7-(4-Bromo-2,6-dimethylphenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]piperidin-4-yl}methanol (1.15 g) synthesized in the similar manner as example 1 in tetrahydrofuran (25 mL) was stirred, then NaH (60% in paraffin, 0.10 g) was added and the mixture was heated at reflux for 3 hours. After cooling to 0° C., ethyl chloroformate (0.28 g) in a small amount of tetrahydrofuran was added and the reaction mixture was allowed to reach room temperature and evaporated. The residue was purified over a silica gel on a glass filter (eluent: CH2Cl2/CH3CN=95:5 then 90:10) to give the title product (366 mg).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:11]([O:24][CH3:25])=[CH:12][C:13]2[O:18][C:17](=[O:19])[C:16]3[CH2:20][CH2:21][CH2:22][C:15]=3[C:14]=2[CH:23]=1)(=O)=O.[F:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[CH:29][CH:28]=1.C([O-])(=O)/C=C/C([O-])=O>C(O)C>[F:26][C:27]1[CH:28]=[CH:29][C:30]([N:33]2[CH2:38][CH2:37][N:36]([CH2:6][CH2:7][CH2:8][O:9][C:10]3[C:11]([O:24][CH3:25])=[CH:12][C:13]4[O:18][C:17](=[O:19])[C:16]5[CH2:20][CH2:21][CH2:22][C:15]=5[C:14]=4[CH:23]=3)[CH2:35][CH2:34]2)=[CH:31][CH:32]=1
Reactant: COc1cc2oc(=O)c3c(c2cc1OCCCOS(C)(=O)=O)CCC3
Reactant: Fc1ccc(N2CCNCC2)cc1
Agent: O=C([O-])/C=C/C(=O)[O-]
Solvent: CCO
Product: COc1cc2oc(=O)c3c(c2cc1OCCCN1CCN(c2ccc(F)cc2)CC1)CCC3
Yield: 84 %

Procedure:
Method B (12 h at 55° C.); starting materials: 2,3-dihydro-8-[3-(methanesulfonyloxy)propoxy]-7-methoxy-cyclopenta[c][1]-benzopyran-4(1H)-one (example 82) and 1-(4-fluorophenyl)piperazine; yield 84%; fusion point 139°-141° C. (from ethanol). Fumarate: method E; yield 90%; fusion point 195°-200° C. (from ethanol).
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3].[CH:14]([NH2:18])([CH2:16][CH3:17])[CH3:15]>>[CH:14]([NH:18][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3])([CH2:16][CH3:17])[CH3:15]
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Reactant: CCC(C)N
Product: CCC(C)NS(=O)(=O)c1cccc(C(=O)O)c1

Procedure:
Procedure H was performed to couple 3-(chlorosulfonyl)benzoic acid with sec-butyl amine to produce 3-(sec-butylsulfamoyl)benzoic acid which was purified by reverse phase HPLC.
Reaction SMILES: [CH3:1][C:2]([CH3:36])([CH2:5][C@@:6]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:11][C:10](=[O:12])[N:9]([C@H:13]([C:15]2[CH:20]=[CH:19][C:18](B3OC(C)(C)C(C)(C)O3)=[CH:17][CH:16]=2)[CH3:14])[CH2:8][CH2:7]1)[C:3]#[N:4].I[C:38]1[CH:43]=[CH:42][NH:41][C:40](=[O:44])[CH:39]=1>>[CH3:36][C:2]([CH3:1])([CH2:5][C@@:6]1([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[O:11][C:10](=[O:12])[N:9]([C@H:13]([C:15]2[CH:20]=[CH:19][C:18]([C:38]3[CH:43]=[CH:42][NH:41][C:40](=[O:44])[CH:39]=3)=[CH:17][CH:16]=2)[CH3:14])[CH2:8][CH2:7]1)[C:3]#[N:4]
Reactant: O=c1cc(I)cc[nH]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)C#N)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2cc[nH]c(=O)c2)cc1)N1CC[C@](CC(C)(C)C#N)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from 2,2-dimethyl-3-((R)-2-oxo-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-6-yl)propanenitrile and 4-iodopyridin-2(1H)-one following a procedure analogous to that described in Example 4. LC-MS Method 1 tR=1.36 min, m/z=456 (M+1); 1H NMR (CDCl3) 7.77 (d, 1H), 7.43-7.32 (m, 7H), 7.01 (t, 4H), 5.67 (q, 1H), 2.99 (dd, 1H), 2.57-2.43 (m, 2H), 2.32 (m, 1H), 2.17 (s, 2H), 1.57 (d, 3H), 1.40 (s, 3H), 1.33 (s, 3H).