Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O.C([O-])([O-])=O.[K+].[K+].[NH:21]1[CH2:25][CH2:24][N:23]=[C:22]1S(O)(=O)=O>CO>[NH:23]1[CH2:24][CH2:25][N:21]=[C:22]1[N:11]1[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=S(=O)(O)C1=NCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(C2=NCCN2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
1.86 of Boc-piperazine were combined with 25 ml of water, 25 ml of methanol, 2.77 g of K2CO3 and 1.5 g of imidazoline-2-sulphonic acid and stirred for 2 days at RT. After dilution with water the mixture was extracted with EE and chromatographed over silica gel. 0.8 g of 1-(imidazolin-2-yl)-4-Boc-piperazine were obtained. This substance was combined with 6.2 ml of DMF and 136 mg of NaH dispersion (60%). After one hour, 0.214 ml of methyl iodide was added dropwise and the reaction mixture was left for three days at RT. It was combined with water, extracted with EE and chromatographed over silica gel. In this way, 0.47 g of 1-(1-methylimidazolin-2-yl)-4-Boc-piperazine was obtained, which was treated with 5 ml of 4N HCl in dioxane at RT. After one hour, the mixture was concentrated by evaporation, stirred with ether and evaporated to dryness in vacuo. 0.38 g of 1-(1-methyl-imidazolin-2-yl)-piperazine dihydrochloride was thus obtained as a solid substance (yield 15%)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([S:14][CH2:15][C:16](=O)[CH3:17])[CH:7]=1)[CH3:2].Cl.[Cl:21][C:22]1[CH:23]=[C:24]([NH:28]N)[CH:25]=[CH:26][CH:27]=1>>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([S:14][C:15]2[C:25]3[C:24](=[CH:23][C:22]([Cl:21])=[CH:27][CH:26]=3)[NH:28][C:16]=2[CH3:17])[CH:7]=1)[CH3:2]
Reactant: NNc1cccc(Cl)c1
Reactant: CCOC(=O)Cc1ccc(OC)c(SCC(C)=O)c1
Agent: Cl
Product: CCOC(=O)Cc1ccc(OC)c(Sc2c(C)[nH]c3cc(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 10, Step 2, using the following starting materials: [4-methoxy-3-(2-oxo-propylsulfanyl)-phenyl]-acetic acid ethyl ester and 3-chlorophenylhydrazine hydrochloride.
Reaction SMILES: S(O[C:6]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:7]=1[CH:8]([CH3:12])[C:9]([OH:11])=[O:10])(C)(=O)=O.CO.[H][H]>[Pd].C(N(CC)CC)C>[CH3:17][C:14]1[CH:13]=[C:7]([CH:6]=[CH:16][CH:15]=1)[CH:8]([CH3:12])[C:9]([OH:11])=[O:10]
Reactant: Cc1ccc(OS(C)(=O)=O)c(C(C)C(=O)O)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: Cc1cccc(C(C)C(=O)O)c1

Procedure:
To a solution of 1.29 g. of 2-mesyloxy-5-methyl-hydratropic acid in 25 ml. of methanol 1.4 ml. of triethylamine and 0.2 g. of a 5% palladium-on-charcoal catalyst are added. The mixture is hydrogenated at 25° C., under atmospheric pressure until the calculated amount of hydrogen is used up. The catalyst is filtered off and the solution is evaporated. The evaporation residue is taken up in water, acidified with a 20% aqueous hydrochloric acid solution and shaken with ether. Ether is distilled off to give 3-methyl-hydratropic acid as an oily residue. The corresponding cyclohexylamine salt melts at 168° C. to 169° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:12][CH2:13][CH:14]2[CH2:16][CH2:15]2)=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].CCN(C(C)C)C(C)C.[CH2:26]([O:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:36](O)=O)=[CH:31][CH:30]=1)[CH3:27].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:14]1([CH2:13][N:12]2[C:3]3=[N:4][CH:5]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:11]=[C:2]3[N:1]=[C:36]2[CH2:35][C:32]2[CH:33]=[CH:34][C:29]([O:28][CH2:26][CH3:27])=[CH:30][CH:31]=2)[CH2:16][CH2:15]1
Reactant: COC(=O)c1cnc(NCC2CC2)c(N)c1
Reactant: CCOc1ccc(CC(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOc1ccc(Cc2nc3cc(C(=O)OC)cnc3n2CC2CC2)cc1
Yield: 33.7 %

Procedure:
Following general procedure 13B: Combined methyl 5-amino-6-[(cyclopropylmethyl)amino]nicotinate (950 mg, 4.3 mmol), DIPEA (1.1 ml), 4-ethoxyphenylacetic acid (850 mg, 4.72 mmol) and HATU (1.80, 4.74 mmol) in DMF (15 mL). The crude product was purified by flash chromatography on silica gel (EtOAc) to produce the desired product (530 mg, 34%).
Reaction SMILES: Cl.[NH2:2][CH:3]([C:9](=[O:13])[CH:10]([CH3:12])[CH3:11])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1.C(N(CC)CC)C>ClCCl>[CH3:11][CH:10]([CH3:12])[C:9](=[O:13])[CH:3]([NH:2][C:19](=[O:20])[C:18]1[CH:22]=[CH:23][C:15]([CH3:14])=[CH:16][CH:17]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(N)C(=O)C(C)C
Reactant: Cc1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(NC(=O)c1ccc(C)cc1)C(=O)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
10 g of ethyl 2-amino-4-methyl-3-oxopentanoate hydrochloride and 7.4 g of 4-methylbenzoyl chloride are dissolved in 250 ml of dichloromethane, and 13.3 ml of triethylamine are slowly added dropwise at 0° C. The mixture is stirred at room temperature for one hour and then washed with water, the organic phase is separated off and dried over MgSO4 and the solvent is then removed under reduced pressure. This gives 13 g of ethyl 4-methyl-2-(4-methylbenzoylamino)-3-oxopentanoate as an oil. C16H21NO4 (291.35), MS (ESI)=292 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:11]([C:17]([O:19][CH3:20])=[O:18])#[C:12][C:13]([O:15][CH3:16])=[O:14].C(O)C>CO>[CH3:16][O:15][C:13](=[O:14])[C:12]([NH:4][C:3]1[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:2]=1[Br:1])=[CH:11][C:17]([O:19][CH3:20])=[O:18]
Reactant: COc1ccc(N)c(Br)c1
Reactant: COC(=O)C#CC(=O)OC
Solvent: CCO
Solvent: CO
Product: COC(=O)C=C(Nc1ccc(OC)cc1Br)C(=O)OC
Yield: 93 %

Procedure:
A solution of 2-bromo-4-methoxy aniline (6.02 g, 29.8 mmol) in 125 mL anhydrous methanol was treated with dimethyl acetylenedicarboxylate (3.70 mL, 30.2 mmol) and the solution was heated at reflux under nitrogen for 8 hours. The reaction mixture was cooled, concentrated, and redissolved in hot methanol. Yellow crystals were obtained by filtration (6.93 g, 68%). A second crop of crystals was obtained from ethanol (0.942 g, 9%). The filtrates were combined and purified by flash chromatography on silica gel using 4:1 hexanes:ethyl acetate to afford an additional 1.63 g (16%) for a total yield of 93%. 1H NMR (300 MHz, DMSO, d6) δ 9.60 (s, 1 H, NH), 7.26 (d, 1 H, Jm=2.7 Hz, ArH3), 6.93 (dd, 1 H, Jo=8.7, Jm=2.7 Hz, ArH5), 6.87 (d, 1 H, Jo=8.7 Hz, ArH6), 5.34 (s, 1 H, C═CH), 3.76 (s, 3H, OCH3), 3.68 (s, 3 H, CHCO2CH3), 3.66 (s, 3 H, CNCO2CH3); Mass Spec.: calc. for [C13H14BrNO5+H]+ Theor. m/z=344, 346; Obs. 344, 346.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[F:25][C:26]([F:36])([F:35])[C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29]Br.C(OC(N1CCC2C(=C(C3C=CC(Cl)=CC=3)N(CC3C=CC=CC=3C(F)(F)F)N=2)CC1)=O)(C)(C)C>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:29][C:28]3[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=3[C:26]([F:25])([F:35])[F:36])[N:13]=2)=[CH:23][CH:22]=1
Reactant: FC(F)(F)c1ccccc1CBr
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Agent: CC(C)(C)OC(=O)N1CCc2nn(Cc3ccccc3C(F)(F)F)c(-c3ccc(Cl)cc3)c2CC1
Product: FC(F)(F)c1ccccc1Cn1nc(-c2ccc(Cl)cc2)c2c1CCNCC2
Yield: 49.3 %

Procedure:
The title compound (0.04 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 0.2 mmol) using 2-trifluoromethylbenzyl bromide (0.3 mmol) in place of 2-chloromethyl-thiophene. The reaction sequence also yielded 3-(4-chloro-phenyl)-2-(2-trifluoromethyl-benzyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester in the alkylation step. MS (ESI): exact mass calculated for C21H19ClF3N3, 405.12; found, m/z 406.1 [M+H]+. 1H NMR (400 MHz, CD3OD): 7.45 (d, J=7.7 Hz, 2H), 7.25-7.24 (br m, 3H), 7.18-7.16 (br m, 3H), 6.46-6.44 (br m, 1H), 5.43-5.41 (s, 2H), 3.14-3.11 (br m, 4H), 2.89-2.87 (br m, 4H).
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:49]([C:56]1[CH:61]=[CH:60][C:59]([C:62]2[CH:67]=[CH:66][CH:65]=[C:64]([NH2:68])[CH:63]=2)=[CH:58][CH:57]=1)[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>CN(C=O)C>[O:49]([C:56]1[CH:61]=[CH:60][C:59]([C:62]2[CH:67]=[CH:66][CH:65]=[C:64]([NH:68][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[OH:10])=[O:24])[CH:63]=2)=[CH:58][CH:57]=1)[C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1
Reactant: Nc1cccc(-c2ccc(Oc3ccccc3)cc2)c1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc(-c2ccc(Oc3ccccc3)cc2)c1)c1cc2cccc(O)c2oc1=O
Temperature: 25 °C
Yield: 35.1 %

Procedure:
DIEA (0.011 mL, 0.063 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.012 g, 0.057 mmol) and HATU (0.024 g, 0.063 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 4′-phenoxy-biphenyl-3-ylamine (0.015 g, 0.057 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and the solvent removed under vacuum to give 0.009 g of product in 34% yield: LCMS (ESI) m/z 450 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=3)[CH:17]=[C:16](Br)[CH:15]=2)=[CH:9][C:8]=1[CH3:33])[CH3:2].[C:35]([C:37]1[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=1)#[CH:36].C(OC(=O)COC1C=CC(SC2C=C(C#CC3C=CC(CO)=CC=3)C=C(OCCC3C=CC(Cl)=CC=3)C=2)=CC=1C)C>>[CH2:1]([O:3][C:4](=[O:34])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=3)[CH:17]=[C:16]([C:36]#[C:35][C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)[CH:15]=2)=[CH:9][C:8]=1[CH3:33])[CH3:2]
Reactant: CCOC(=O)COc1ccc(Sc2cc(Br)cc(OCc3ccc(S(C)(=O)=O)cc3)c2)cc1C
Reactant: C#Cc1ccc(F)cc1
Agent: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccc(CO)cc3)cc(OCCc3ccc(Cl)cc3)c2)cc1C
Product: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccc(F)cc3)cc(OCc3ccc(S(C)(=O)=O)cc3)c2)cc1C

Procedure:
The title product was prepared from {4-[3-Bromo-5-(4-methanesulfonyl-benzyloxy)phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (335 mg; 0.59 mmol), 1-ethynyl-4-fluorobenzene (142.3 mg; 1.19 mmol) applying the procedure described for {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methylphenoxy}-acetic acid ethyl ester. The crude product was purified by preparative HPLC (method B). Yield: 140 mg (39%). HPLC-MS: m/z: 605.5 (M+H)+; Rt: 2.80 min.
Reaction SMILES: [CH:1]1([C@:7]([OH:17])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:18][N:19]([CH3:25])[CH2:20][C:21]#[C:22][CH2:23][NH2:24].O>C(Cl)(Cl)Cl>[CH3:18][N:19]([CH3:25])[CH2:20][C:21]#[C:22][CH2:23][NH:24][C:8](=[O:10])[C:7]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)([OH:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(O)[C@@](O)(c1ccccc1)C1CCCCC1
Reactant: CN(C)CC#CCN
Solvent: ClC(Cl)Cl
Solvent: O
Product: CN(C)CC#CCNC(=O)C(O)(c1ccccc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.9 %

Procedure:
A mixture of (S)-(+)-2-cyclohexyl-2-hydroxy-2-phenylacetic acid (1.13 g, 80% ee) and N,N'-carbonyldiimidazole (0.77 g) in chloroform (5 ml) was stirred at room temperature for 2 hours. After an addition of 4-dimethylamino-2-butynylamine (0.54 g), the mixture was stirred at the same temperature for an additional hour, then the mixture was poured into water, and extracted with ethyl acetate. The extract was washed with water and the organic layer was extracted with 1N-hydrochloric acid. The acidic solution was adjusted to pH 13 with aqueous solution of sodium hydroxide and extracted with ethyl acetate. The extract was washed with sodium chloride aqueous solution, dried over sodium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel with a mixture of chloroform and methanol (10:1) as an eluent to give (-)-N-(4-dimethylamino-2-butynyl)-2-cyclohexyl-2-hydroxy-2-phenylacetamide (0.60 g, 88% ee).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][C:18]([F:21])([F:20])[F:19])[CH2:13][CH2:12]3)[N:9]=[CH:10][C:5]2=[C:4]([N:22]2[CH2:28][CH:27]3[O:29][CH:24]([CH2:25][CH2:26]3)[CH2:23]2)[N:3]=1.[NH2:30][C:31]1[CH:36]=[CH:35][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][CH:32]=1>C1(C)C=CC=CC=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].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:27]12[O:29][CH:24]([CH2:25][CH2:26]1)[CH2:23][N:22]([C:4]1[N:3]=[C:2]([C:34]3[CH:35]=[CH:36][C:31]([NH2:30])=[CH:32][CH:33]=3)[N:7]=[C:6]3[N:8]([CH:11]4[CH2:12][CH2:13][N:14]([CH2:17][C:18]([F:19])([F:20])[F:21])[CH2:15][CH2:16]4)[N:9]=[CH:10][C:5]=13)[CH2:28]2
Reactant: FC(F)(F)CN1CCC(n2ncc3c(N4CC5CCC(C4)O5)nc(Cl)nc32)CC1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
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: CCO
Solvent: Cc1ccccc1
Product: Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(CC(F)(F)F)CC4)c3n2)cc1
Temperature: 120 °C

Procedure:
A mixture of 3-(6-chloro-1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (0.55 g, 1.3 mmol), 4-aminophenylboronic acid pinacol ester (0.42 g, 1.9 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.15 g, 10 mol %) in toluene/ethanol (1:1, 10 mL) and 2 M aqueous sodium carbonate solution (2 mL) was heated in a 10-20 mL Smith process vial in the microwave reactor for one hour at 120° C. The cooled mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted three times with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude residue was purified via reverse-phase high performance liquid chromatography using a Phenomenex Prodigy 21 mm×250 mm column, running a gradient elution of 10% acetonitrile/90% of 0.1% aqueous trifluoroacetic acid to 95% acetonitrile over 30 minutes. After the concentration of fractions under reduced pressure, 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)aniline was obtained as a maroon oil that solidified upon standing. MS (ES+): 488.4 (M+H)+
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C@@H:5]([CH2:7][C:8]([OH:10])=[O:9])[C:4](=[O:11])[O:3]1.C(O)(=O)[C@H](CC(O)=O)O.N1C=CN=C1.[Si:27](Cl)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]>CN(C)C=O.C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:12])[O:6][CH:5]([CH2:7][C:8]([O:10][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])=[O:9])[C:4](=[O:11])[O:3]1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC1(C)OC(=O)[C@H](CC(=O)O)O1
Agent: O=C(O)C[C@H](O)C(=O)O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC1(C)OC(=O)C(CC(=O)O[Si](C)(C)C(C)(C)C)O1
Temperature: 22 °C
Reaction time: 18 h
Yield: 95.6 %

Procedure:
A solution of (S)-(+)-2,2-dimethyl-5-oxo-1,3-dioxolane-4-acetic acid (13.20 g, 75.8 mmol), which was derived from L-malic acid by means known in the art, in N,N-dimethylformamide (25 ml) was treated at 22° C. with imidazole (10.56 g, 0.155 mmol) followed by tert-butyldimethylsilyl chloride (12.0 g, 79.6 mmol) and the resulting mixture was stirred at 22° C. for 18 h. The reaction mixture was then diluted with toluene (500 ml), washed with water (×3), saturated sodium bicarbonate and brine. After drying (magnesium sulfate), the solvent was evaporated under reduced pressure to give an oil. Distillation under vacuum gave 20.9 g (96%) of the title material as a clear oil: Bp 80-90° C./0.1 torr (bulb to bulb distillation, air bath temperature). 1H NMR (400 MHz, CDCl3) δ: 0.33 (s, 3), 0.36 (s, 3), 1.00 (s, 9), 1.11 (s, 3), 1.37 (s, 3), 2.72 (m, 2), 4.35 (dd, 1, J=4, 6).
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[S:10][CH:11]=[C:12]([CH2:14][OH:15])[N:13]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:17]1[N:22]=[CH:21][C:20]([C:23](OC)=[O:24])=[CH:19][CH:18]=1.O>CN(C)C=O>[C:3]1([C:9]2[S:10][CH:11]=[C:12]([CH2:14][O:15][C:17]3[N:22]=[CH:21][C:20]([CH2:23][OH:24])=[CH:19][CH:18]=3)[N:13]=2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: OCc1csc(-c2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: OCc1ccc(OCc2csc(-c3ccccc3)n2)nc1
Reaction time: 0.5 h
Yield: 55.7 %

Procedure:
Sodium hydride (60%, oily, 1.40 g) was added to a solution of 2-phenyl-4-thiazolylmethanol (6.69 g) and methyl 6-chloro-3-pyridinecarboxylate (6.01 g) in N,N-dimethylformamide (100 ml) at 0° C., and the mixture was stirred for 30 minutes. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. Lithium aluminium hydride (1.33 g) was added to a solution of the residue in tetrahydrofuran (150 ml) at 0° C., which was stirred at room temperature for 10 minutes. Sodium sulfate decahydrate (11.3 g) was added to the reaction mixture, which was stirred for 30 minutes at room temperature. The precipitate was removed by filtration, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography to obtain 6-(2-phenyl-4-thiazolylmethoxy)-3-pyridylmethanol (5.81 g, yield 56%) as colorless crystals from the fraction eluted with tetrahydrofuran. This was recrystallized from tetrahydrofuran-hexane. Melting point: 134–135° C.
Reaction SMILES: C(OC(N1CCC(N)CC1)=O)(C)(C)C.[CH2:15]([N:22]1[CH2:27][CH2:26][CH:25]([NH:28][S:29]([C:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:35]([C:42]#[N:43])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-:44].[K+].[OH2:46]>>[CH2:15]([N:22]1[CH2:27][CH2:26][CH:25]([NH:28][S:29]([C:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:35]([C:42]#[N:43])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH2:15]([N:22]1[CH2:27][CH2:26][CH:25]([NH:28][S:29]([C:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:35]([C:42]([OH:46])=[O:44])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O
Reactant: [OH-]
Agent: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: N#Cc1ccc(S(=O)(=O)NC2CCN(Cc3ccccc3)CC2)c2ccccc12
Agent: [K+]
Product: O=C(O)c1ccc(S(=O)(=O)NC2CCN(Cc3ccccc3)CC2)c2ccccc12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
4-Cyano-naphthalene-1-sulfonic acid (1-benzyl-piperidin-4-yl)-amide (33) was prepared according to the general procedure in Scheme 11, substituting 1-benzyl-piperidin-4-ylamine for 4-amino-piperidine-1-carboxylic acid tert-butyl ester. To a solution of 4-cyano-naphthalene-1-sulfonic acid (1-benzyl-piperidin-4-yl)-amide 33 (3.0 g, 7.43 mmol) in H2O (70 mL) was added KOH (4.2 g, 75 mmol). After stirring at 100° C. overnight, the resultant mixture became a clear solution. The aqueous layer was washed with CH2Cl2 twice and acidified to pH 4 by adding hydrochloric acid. After filtration, the resultant solid was dried to give 1.8 g of crude 4-(1-benzyl-piperidin-4-ylsulfamoyl)-naphthalene-1-carboxylic acid 34 in 57% yield. LCMS showed m/z: 425 (M+H)+. This material was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([C:6](SC3C(F)=C(C=CC=3)C(OCC)=O)=[CH:7][N:8]2[C:12]2[CH:13]=[N:14][N:15]([CH2:17][CH3:18])[CH:16]=2)=[CH:4][CH:3]=1.[CH2:32]1[C:37](=O)N(Cl)C(=O)[CH2:33]1>C(Cl)Cl.O>[Cl:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([CH:6]=[C:7]([CH:33]3[CH2:32][CH2:37]3)[N:8]2[C:12]2[CH:13]=[N:14][N:15]([CH2:17][CH3:18])[CH:16]=2)=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)c1cccc(Sc2cn(-c3cnn(CC)c3)c3c(F)c(Cl)ccc23)c1F
Solvent: O
Solvent: ClCCl
Product: CCn1cc(-n2c(C3CC3)cc3ccc(Cl)c(F)c32)cn1
Reaction time: 16 h
Yield: 54.9 %

Procedure:
To a solution of compound 3 (100 mg, 0.21 mmol) in CH2Cl2 (3 mL) under inert atmosphere was added NCS (58 mg, 0.43 mmol) at RT and stirred for 16 h. The reaction mixture was diluted with water (10 mL) and extracted with CH2Cl2 (2×15 mL). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure to obtain the crude. The crude was purified (silica gel; 14-17% EtOAc/Hexanes) to afford 5 (35 mg, 33%) as an off-white solid. 1H NMR (400 MHz, CDCl3): δ 7.71-7.66 (m, 3H), 7.30 (d, J=7.6 Hz, 1H), 7.19 (dd, J=8.8, 6.4 Hz, 1H), 7.04-6.97 (m, 2H), 4.40 (q, J=7.2 Hz, 2H), 4.27 (q, J=7.6 Hz, 2H), 1.58 (t, J=7.6 Hz, 3H), 1.49 (t, J=7.2 Hz, 3H); LC-MS (ESI): m/z 496.7 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](Cl)=[CH:4][CH:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.N(P(Cl)Cl)(C1CCCCC1)C1CCCCC1>O1CCOCC1.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]>[C:9]1([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Cc1ccc(Cl)cc1
Reactant: OB(O)c1ccccc1
Agent: [Pd]
Agent: ClP(Cl)N(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1ccc(-c2ccccc2)cc1
Reaction time: 24 h
Yield: 62.9 %

Procedure:
The general procedure from Example 8 was followed using 4-methylchlorobenzene (152 mg, 1.2 mmol) and PhB(OH)2 (1.2 mmol) with Pd2(dba)3 (20 mg, 0.0218 mmol) and (Me3C)2PH(O) from Experiment 2 (14.5 mg, 0.0878 mmol) and CsCO3 (651 mg, 2.0 mmol) in 4.0 mL of 1,4-dioxane. After 24 h, the reaction mixture was chromatographed with 5% ethyl acetate/hexane to give 127 mg (63% yield) of 4-phenyltoluene. It was >95% pure by 1H NMR and GC/MS. 1H NMR (500 MHz, CDCl3): δ7.74 (d, J=7.50 Hz, 2H), 7.65 (d, J=8.05 Hz, 2H), 7.57 (m, 2H), 7.47 (m, 1H), 7.40 (m, 2H), 2.54 (s, 3H) ppm. 13C NMR (125 MHz, CDCl3): δ141.1, 138.3, 136.9, 129.4, 128.6, 126.9, 126.8, 21.0 ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:9]=1[NH:10][CH3:11])[C:7]#[N:8].[H-].[Na+].Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].C(OCC)C>CN(C=O)C>[CH2:19]([O:18][C:16]([C:15]1[N:10]([CH3:11])[C:9]2[C:2]([Cl:1])=[CH:3][N:4]=[CH:5][C:6]=2[C:7]=1[NH2:8])=[O:17])[CH3:20]
Reactant: CNc1c(Cl)cncc1C#N
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)c1c(N)c2cncc(Cl)c2n1C
Reaction time: 0.25 h
Yield: 60.1 %

Procedure:
5-Chloro-4-methylamino-nicotinonitrile (340 mg, 2.02 mmol) was dissolved in DMF (5 mL) and the solution cooled in an ice-bath. This solution was treated portionwise with sodium hydride (120 mg, 60% in oil, 3.03 mmol). The ice-bath was removed and stirring continued for 15 minutes at room temperature before treating the mixture with ethyl bromoacetate (508 mg, 3.03 mmol). The reaction mixture was then partitioned between ethyl acetate and water. The organic layer was isolated, washed with water followed by brine then dried (MgSO4) and evaporated to give a solid. Trituration of the resultant solid with diethyl ether gave the title compound (308 mg, 60%) as a cream solid. 1H NMR (CDCl3) 8.90 (1H, s), 8.26 (1H, s), 8.26 (1H, s, br), 4.43 (2H, q, J=7.0 Hz), 4.28 (3H, s), 1.44 (3H, t, J=7.0 Hz)