Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].S(Cl)(Cl)=O.[Cl:7][S:8]([OH:11])(=O)=[O:9].[CH2:12]([O:15][C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([OH:20])=[O:19])[CH2:13][CH3:14]>ClCCl>[Cl:7][S:8]([C:22]1[CH:23]=[CH:24][C:16]([O:15][CH2:12][CH2:13][CH3:14])=[C:17]([CH:21]=1)[C:18]([OH:20])=[O:19])(=[O:11])=[O:9]
Reactant: O=S(=O)(O)Cl
Reactant: CCCOc1ccccc1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCCOc1ccc(S(=O)(=O)Cl)cc1C(=O)O
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 79.7 %

Procedure:
A three-neck flask, equipped with a 5M aqueous sodium hydroxide scrub (550 ml), was charged with thionyl chloride (40 ml, 0.55 mol) and chlorosulphonic acid (150 ml, 2.26 mol) and the stirred mixture cooled to about −10° C. A solution of 2-n-propoxybenzoic acid (100 g, 0.55 mol) in dichloromethane (200 ml) was added over 20 minutes, ensuring that the reaction temperature was maintained below 5° C., then the reaction mixture was allowed to warm to room temperature. The resulting solution was added over 1 hour to stirred, ice-cold water, whilst maintaining the temperature at about 0° C., and stirring continued for a further 30 minutes. The mixture was filtered and the solid thus obtained was washed with cold water (100 ml) and dried under vacuum to give the title compound (122.2 g, 80%) as a white solid. δ (DMSOd6): 1.13 (3H, t), 2.00 (2H, m), 4.32 (2H, t), 7.23 (1H, d), 8.21 (1H m), 8.82 (1H, d).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[NH2:20][CH:21]([CH:23]1[CH2:28][CH2:27][CH2:26][N:25]([C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])[CH2:24]1)[CH3:22]>CN(C=O)C.C1(C)C=CC=CC=1.CCOC(C)=O>[CH2:32]([O:31][C:29]([N:25]1[CH2:26][CH2:27][CH2:28][CH:23]([CH:21]([NH:20][C:5]2[N:10]=[C:9]([N:11]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[N:13]=[CH:12]3)[CH:8]=[CH:7][N:6]=2)[CH3:22])[CH2:24]1)=[O:30])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CS(=O)(=O)c1nccc(-n2cnc3ccccc32)n1
Reactant: CC(N)C1CCCN(C(=O)OCc2ccccc2)C1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(Nc1nccc(-n2cnc3ccccc32)n1)C1CCCN(C(=O)OCc2ccccc2)C1
Yield: 54.8 %

Procedure:
2-Methanesulfonyl-4-[benzimidazol-1-yl]pyrimidine (EXAMPLE 1) (1.1 g, 4.0 mmol) was dissolved in DMF (10 mL), and to this was added 3-(1-aminoethyl)-1-(Benzyloxycarbonyl)piperidine (950 mg, 3.6 mmol) in toluene (10 mL). The mixture was placed in an oil bath at 100° C. and heated for 5 h. After cooling, the reaction mixture was diluted with EtOAc (80 mL) and was washed with H2O (4×40 mL) followed by brine. The organic extract was dried over Na2SO4 and purified by flash chromatography using 3:7 acetone:hexane as an eluent to obtain the title compound (900 mg). Partial 1H NMR (500 MHz, CDCl3): δ 8.6 (s, 1H); 8.36 (br s, 1H); 8.15 (d, J=8 Hz, 1H); 7.85 (d, J=8.5 Hz, 1H); 7.36 (m, 7H); 6.76 (d, J=5.4 Hz, 1H); 5.12 (s, 2H); 4.17 (m, 1H); 1.29 (br d, J=5 Hz, 3H). Mass spectrum 457.6 (ESI, M+1). The enantiomers of the title compound were separated on HPLC (Chiralcel OJ column; 85:15 hexane:EtOH system).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[CH2:14][O:13]C(=O)[N:11]2[C:16]2[CH:21]=[CH:20][N:19]3[N:22]=[CH:23][C:24]([C:25]([O:27]CC)=[O:26])=[C:18]3[N:17]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.CO.C1COCC1.O.[OH-].[Li+]>O>[F:1][C:2]1[CH:3]=[C:4]([C@H:10]([NH:11][C:16]2[CH:21]=[CH:20][N:19]3[N:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[C:18]3[N:17]=2)[CH2:14][OH:13])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: CCOC(=O)c1cnn2ccc(N3C(=O)OC[C@@H]3c3cc(F)cnc3OC)nc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1ncc(F)cc1[C@@H](CO)Nc1ccn2ncc(C(=O)O)c2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 45.2 %

Procedure:
To a solution of (S)-ethyl 5-(4-(5-fluoro-2-methoxypyridin-3-yl)-2-oxooxazolidin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (311 mg, 0.77 mmol) in a 1:1:1 mixture of MeOH:THF:H2O (15 mL) was added lithium hydroxide monohydrate (97.6 mg, 2.32 mmol). The mixture was stirred at ambient temperature for 16 hours and then at 50° C. for 19 hours, then concentrated to ⅓ volume, diluted with water (30 mL) and acidified to pH 4-5 with 1N HCl. The resulting precipitate was collected by filtration, washed with water and Et2O then dried under reduced pressure to afford (S)-5-(1-(5-fluoro-2-methoxypyridin-3-yl)-2-hydroxyethylamino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (121 mg, 45% yield) as a white powder. MS (apci) m/z=347.9 (M+H).
Reaction SMILES: [C:1](=[N:14][NH:15][C:16](=[O:29])[CH2:17][CH:18]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=1)[CH2:19][OH:20])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1.ClCCl>[C:1](=[N:14][NH:15][C:16]([CH2:17][CH:18]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=1)[CH2:19][O:20][S:31]([CH3:30])(=[O:33])=[O:32])=[O:29])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cccc(C(CO)CC(=O)NN=C(c2ccccc2)c2ccccc2)c1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cccc(C(COS(C)(=O)=O)CC(=O)NN=C(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 4-hydroxy-3-(3-methoxy-phenyl)-butyric acid benzhydrylidene-hydrazide and (1.7 g, 4.38 mmol) and 4-dimethylaminopyridine (26 mg, 0.22 mmol) in pyridine (15 mL) is cooled to 0° C. treated with methanesulfonyl chloride (0.4 mL, 5.25 mmol) and stirred 18 h at room temperature. The mixture is diluted with dichloromethane (30 mL) and washed with 1 N hydrochloric acid (30 mL), a saturated solution of sodium bicarbonate and brine. The mixture is dried over magnesium sulfate, filtered, concentrated in vacuo and chromatographed on SiO2 (2% methanol/dichloromethane) to yield the title compound, 1.64 g (80%), as yellow foam.
Reaction SMILES: [C:1]([C:5]1[CH:38]=[CH:37][C:8]([C:9]([NH:11][C:12]2[CH:36]=[CH:35][CH:34]=[CH:33][C:13]=2[C:14]([NH:16][C:17]2[CH:25]=[C:24]3[C:20]([CH:21]=[N:22][N:23]3C(OC(C)(C)C)=O)=[CH:19][CH:18]=2)=[O:15])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>C1(OC)C=CC=CC=1.ClCCl>[C:1]([C:5]1[CH:38]=[CH:37][C:8]([C:9]([NH:11][C:12]2[CH:36]=[CH:35][CH:34]=[CH:33][C:13]=2[C:14]([NH:16][C:17]2[CH:25]=[C:24]3[C:20]([CH:21]=[N:22][NH:23]3)=[CH:19][CH:18]=2)=[O:15])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1ncc2ccc(NC(=O)c3ccccc3NC(=O)c3ccc(C(C)(C)C)cc3)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CC(C)(C)c1ccc(C(=O)Nc2ccccc2C(=O)Nc2ccc3cn[nH]c3c2)cc1
Reaction time: 0.5 h
Yield: 77.1 %

Procedure:
To a stirring solution of 2-[(4-t-butylbenzoyl)amino]-N-(1-Boc-6-indazolyl)benzamide (200 mg, 0.39 mmol) in anisole (1 mL) and dichloromethane (10 mL) was added TFA (10 mL). After stirring for 30 min, the solvents were removed by rotary evaporation and the residue was partitioned between ethyl acetate and satd aq NaHCO3. The aqueous phase was removed and the organic phase was washed again with NaHCO3, followed by brine. The organic phase was then dried with MgSO4, filtered and concentrated in vacuo to a very small volume, then diluted with ether and sonicated. The white precipitate was then filtered and dried in vacuo to give 124 mg (77%) of white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:16]=[C:15]([Sn](CCCC)(CCCC)CCCC)[CH:14]=[C:6]([C:7]([N:9]([CH3:13])[CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=1.Cl.[C:32](Cl)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[N:35][CH:34]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(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.[Pd].C1COCC1>[CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:16]=[C:15]([C:32]([C:33]2[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=2)=[O:39])[CH:14]=[C:6]([C:7]([N:9]([CH3:13])[CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(C(=O)OC)cc(C(=O)N(C)CCC)c1
Reactant: O=C(Cl)c1cccnc1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CCCN(C)C(=O)c1cc(C(=O)OC)cc(C(=O)c2cccnc2)c1
Temperature: 50 °C
Yield: 20.6 %

Procedure:
Add THF (3 mL), N-methyl-N-propyl-5-tributylstannanyl-isophthalamic acid methyl ester (0.524 g, 1.00 mmol), nicotinoyl chloride hydrochloride (0.232 g, 1.30 mmol), 2-(di-tert-butylphosphino)biphenyl (0.045 g, 0.151 mmol), bis(dibenzylidene-acetone)palladium (0) (029 g, 0.05 mmol) to a sealed tube flushed with nitrogen. Heat the mixture at 50° C. for 16 h and cool to room temperature. Filter the mixture though a filtering agent, concentrate and purify (silica gel chromatography, eluting with 50:50 to 100:0 ethyl acetate:hexanes) to give the title compound (0.070 g, 21%).
Reaction SMILES: [C:1]([N:20]1[CH:24]=[CH:23][N:22]=[C:21]1[CH2:25][CH:26]=[O:27])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO.C1COCC1.O>[C:1]([N:20]1[CH:24]=[CH:23][N:22]=[C:21]1[CH2:25][CH2:26][OH:27])([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CCc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: OCCc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 18 h

Procedure:
Crude 2-(1-trityl-1H-imidazol-2-yl)acetaldehyde (2.025 g (5.75 mmol) was dissolved in MeOH/THF (1:1, 40 ml) and NaBH4 (0.435 g, 11.5 mmol) was added portionwise to the above mixture. The mixture was stirred for 18 hours, diluted with 100 ml of water and extracted with 2×DCM. The combined organic extracts were washed with water, brine, dried over Na2SO4 and concentrated in vacuum. Weight of the residue 1.915 g (94%). 1H NMR (500 MHz, CDCl3) δ 7.35-7.31 (m, 9H), 7.12 (dd, J=6.7, 2.7, 6H), 6.93 (d, J=1.0, 1H), 6.74 (d, J=1.0, 1H), 5.04 (br, 1H), 3.46 (t, J=5.4, 2H), 2.00 (t, J=5.4, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:7](=[O:8])[CH:6]([OH:9])[CH2:5][C:4]([CH3:11])([CH3:10])[C:3]=1[CH:12]=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=[O:17].N1C=CC=CC=1.[O:25]([CH2:32][C:33](Cl)=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>C(OCC)C>[CH3:1][C:2]1[C:7](=[O:8])[C@@H:6]([O:9][C:33](=[O:34])[CH2:32][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:5][C:4]([CH3:10])([CH3:11])[C:3]=1[CH:12]=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=[O:17]
Reactant: CC(C=CC1=C(C)C(=O)C(O)CC1(C)C)=CC=O
Reactant: O=C(Cl)COc1ccccc1
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: O
Product: CC(C=CC1=C(C)C(=O)[C@@H](OC(=O)COc2ccccc2)CC1(C)C)=CC=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
14 g of the hydroxyketoaldehyde of formula XIII obtained in Example 26 are dissolved in 200 ml of diethyl ether. 20 ml of pyridine are added to the solution at 0° C. and 12 g of phenoxyacetic acid chloride are then added dropwise. The mixture is stirred for 2 hours at 0° C. and then poured into water and extracted with diethyl ether. The 5-[2,6,6-trimethyl-3-oxo-4(S)-(phenoxyacetoxy)-cyclohex-1-en-1-yl]-3-methyl-penta-2,4-dien-1-al (IIA) is isolated from the ether extract.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:9]=[C:10]([CH:15]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:28]=[N:29][NH:30][CH:31]=3)=[CH:23][CH:22]=2)[CH2:16][C:17]([NH:19][CH3:20])=O)[CH:11]=[CH:12][C:13]=1[F:14].[Cl-].[Al+3].[Cl-].[Cl-].C1(C)C=CC=CC=1>C(OCC)C>[F:7][C:8]1[CH:9]=[C:10]([CH:15]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:31]=[N:30][NH:29][CH:28]=3)=[CH:23][CH:22]=2)[CH2:16][CH2:17][NH:19][CH3:20])[CH:11]=[CH:12][C:13]=1[F:14]
Reactant: CNC(=O)CC(c1ccc(-c2cn[nH]c2)cc1)c1ccc(F)c(F)c1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CNCCC(c1ccc(-c2cn[nH]c2)cc1)c1ccc(F)c(F)c1
Temperature: 70 °C

Procedure:
Lithium aluminium hydride was added to a suspension of 3-(3,4-Difluoro-phenyl)-N-methyl-3-[4-(1H-pyrazol-4-yl)-phenyl]-propionamide in diethyl ether, followed by a solution of aluminium chloride in diethyl ether at 0° C., under a nitrogen atmosphere. Toluene was added and the reaction mixture was heated at 70° C. for 18 hours. Upon cooling the reaction was quenched with addition of water, basified (2N NaOH) and extracted with ethyl acetate. The organic layer was separated, dried (MgSO4), filtered and concentrated to afford the desired compound. LC/MS: (PS-A2) Rt 2.15 [M+H]+ 328.06. 1H NMR (Me-d3-OD) δ 2.19-2.29 (2H, m), 2.35 (3H, s), 2.51 (2H, t), 4.00 (1H, t), 7.06-7.24 (3H, m), 7.27 (2H, d), 7.52 (2H, d), 7.92 (2H, s).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[OH:11].C(=O)(O)[O-].[Na+].Br[CH2:18][C:19](Br)=[O:20].FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl.O.CC#N.O>[CH3:10][O:9][C:6]1[CH:7]=[CH:8][C:3]2[NH:2][C:19](=[O:20])[CH2:18][O:11][C:4]=2[CH:5]=1
Reactant: O=C(Br)CBr
Reactant: COc1ccc(N)c(O)c1
Agent: Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1)OCC(=O)N2
Temperature: 0 °C
Reaction time: 2 h
Yield: 34.6 %

Procedure:
2-amino-5-methoxy-phenol hydrochloride (4.0 g, 22.8 mmol) was dissolved in 100 mL of chloroform in a 500 mL round-bottom flask and treated with 80 mL of saturated sodium bicarbonate solution. This mixture was stirred rapidly and was cooled to 0° C. in an ice bath. A solution of bromoacetyl bromide (2.98 mL, 34.2 mmol) in 20 mL of chloroform was added slowly. After 2 hours, HPLC (Eclipse XDB-C18, 4.6×250 mm, 5 micron, 1-99% CH3CN/H2O with 0.1% trifluoroacetic acid) showed that all of the starting material (Rt=2.4 min) was consumed and that a major product peak had formed (Rt=4.5 min). The reaction was diluted with 200 mL of chloroform and 200 mL of water. The layers were separated and the aqueous layer was extracted with chloroform (3×150 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated to a red-brown solid. This solid was dissolved in 200 mL of anhydrous DMF, treated with potassium carbonate (3.2 g, 22.8 mmol) and heated to 85° C. After two hours, HPLC showed that all of the material had converted to a new product (Rt=4.4 min), so the reaction mixture was allowed to cool to room temperature and was poured into 700 mL of water. The aqueous phase was extracted with ethyl acetate (3×200 mL) and the combined organic layers were washed with water (3×500 mL) and saturated NaCl (1×200 mL), dried over magnesium sulfate, filtered, and concentrated to give 7-(methyloxy)-2H-1,4-benzoxazin-3(4H)-one (1.42 g, 7.9 mmol, 34%) as a red-orange solid. MS (ES) m/e 180 [M+H]+.
Reaction SMILES: [Br:1]C1(Br)NC(=O)NC1=O.[Cl:10][C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[C:13]([Cl:20])[C:12]=1[CH3:21].CC(N=NC(C#N)(C)C)(C#N)C.CC(=O)OCC>ClC1C=CC=CC=1>[Cl:10][C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[C:13]([Cl:20])[C:12]=1[CH2:21][Br:1]
Reactant: O=C1NC(=O)C(Br)(Br)N1
Reactant: Cc1c(Cl)ccc([N+](=O)[O-])c1Cl
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: Clc1ccccc1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(Cl)c(CBr)c1Cl
Reaction time: 1 h

Procedure:
A mixture of dibromohydantoin (70 g, 0.24 mol) and AlBN (5 g) was added in portions at 150° C. to 2,6-dichloro-3-nitrotoluene (100 g, 0.48 mol) in chlorobenzene (400 ml). After 1 h, a mixture of dibromohydantoin (35 g, 0.12 mol) and AIBN (2.5 g) was again added. After a further 1.5 h, the mixture was allowed to cool and EA (500 ml) was added. This mixture was washed once each with saturated Na2SO3, Na2CO3 and NaCl solution, dried (MgSO4) and concentrated, the title compound being obtained as an amorphous powder.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([C:18]([N:20]([O:22][CH3:23])[CH3:21])=[O:19])=[CH:9][C:10]([Cl:17])=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[CH:12]2)(=O)=O.[NH:26]1[CH2:30][CH2:29][C@@H:28]([OH:31])[CH2:27]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1.ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:17][C:10]1[CH:9]=[C:8]([C:18]([N:20]([O:22][CH3:23])[CH3:21])=[O:19])[C:7]([N:26]2[CH2:30][CH2:29][C@@H:28]([OH:31])[CH2:27]2)=[C:16]2[C:11]=1[CH:12]=[CH:13][CH:14]=[N:15]2
Reactant: CON(C)C(=O)c1cc(Cl)c2cccnc2c1OS(=O)(=O)C(F)(F)F
Reactant: O[C@@H]1CCNC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CON(C)C(=O)c1cc(Cl)c2cccnc2c1N1CC[C@@H](O)C1
Temperature: 65 °C
Yield: 91.1 %

Procedure:
A stirred mixture of 5-chloro-7-{[methoxy(methyl)amino]carbonyl}quinolin-8-yl trifluoromethanesulfonate (0.150 g, 0.376 mmol), (3R)-pyrrolidin-3-ol (0.0394 g, 0.452 mmol, Aldrich), palladium acetate (2 mg, 0.008 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (7 mg, 0.01 mmol), and cesium carbonate (0.343 g, 1.05 mmol) in tetrahydrofuran (4 mL) was heated at 65° C. overnight. The mixture was cooled, diluted with dichloromethane, washed with brine, dried over sodium sulfate, and evaporated to dryness. The resultant residue was purified on silica gel, eluting with 0 to 10% MeOH in dichloromethane, to give the desired product (115 mg, 91%). LCMS calculated for C16H19ClN3O3(M+H)+: m/z=336.1; found: 336.1.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH3:16])[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.CS(C)=O.CCN(CC)CC>C(Cl)Cl.CCOCC>[CH:2]([C:3]1([CH3:16])[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1)=[O:1]
Reactant: CC1(CO)CCCN(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC1(C=O)CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
To an ice water cooled solution of tert-butyl 3-(hydroxymethyl)-3-methyl-1-piperidinecarboxylate (1.5 g, 6.6 mmol) in CH2Cl2 were added DMSO (7.1 g, 91.6 mmol), Et3N (5.5 mL, 39.8 mmol), and sulfur trioxide-Pyridine complex (3.1 g, 19.9 mmol) successively. The mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with ether, purified by column chromatography on silica gel (hexane:ethyl acetate, 5:1-4:1) to give tert-butyl 3-formyl-3-methyl-1-piperidinecarboxylate as a colorless oil form (1.3 g, yield; 86%).
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:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH:14]=3)[CH:10]=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.Br[C:39]1[S:40][C:41]([S:44][CH3:45])=[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>[CH3:45][S:44][C:41]1[S:40][C:39]([C:19]2[CH:20]=[C:21]3[C:16](=[CH:17][CH:18]=2)[N:15]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH:14]=[C:13]3[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([N:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)[N:12]=2)=[N:43][N:42]=1
Reactant: CC(C)(C)OC(=O)n1cc(-c2cccc(N3CCOCC3)n2)c2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: CSc1nnc(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: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: CSc1nnc(-c2ccc3c(c2)c(-c2cccc(N4CCOCC4)n2)cn3C(=O)OC(C)(C)C)s1
Temperature: 100 °C
Yield: 47.1 %

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 (1.20 g, 2.374 mmol) and 2-bromo-5-(methylthio)-1,3,4-thiadiazole (1.002 g, 4.75 mmol) in p-dioxane/H2O (4:1, 15 mL) followed by potassium carbonate (0.984 g, 7.12 mmol, Aldrich) and Pd(PPh3)4 (0.137 g, 0.119 mmol, Strem). The reaction was stirred and heated in an Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 100° C. for 2 h. The mixture was diluted with DCM (150 mL) and washed with H2O. The organic layer was dried, filtered and concentrated. The residue was purified with silica gel chromatography (eluting with 0-18% EtOAc in DCM) to give tert-butyl 5-(5-(methylthio)-1,3,4-thiadiazol-2-yl)-3-(6-morpholinopyridin-2-yl)-1H-indole-1-carboxylate (570 mg, 1.118 mmol, 47.1%) as a yellow solid. MS (ESI, pos. ion) m/z: 510 (M+1); 1H NMR (400 MHz, CDCl3) δ ppm 8.91 (1H, s), 8.17-8.32 (2H, m), 7.98 (1H, dd, J=8.7, 1.7 Hz), 7.65 (1H, t, J=8.0 Hz), 7.18 (1H, d, J=7.4 Hz), 6.70 (1H, d, J=8.4 Hz), 3.92-4.01 (4H, m), 3.68-3.77 (4H, m), 2.84 (3H, s), 1.72 (9H, s).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5].C(N(C(C)C)CC)(C)C.[CH3:21][O:22][CH2:23]Cl.O>C(Cl)Cl>[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:2]([O:1][CH2:21][O:22][CH3:23])=[C:3]([CH:6]=1)[CH:4]=[O:5]
Reactant: COc1ccc(O)c(C=O)c1
Reactant: COCCl
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1ccc(OC)cc1C=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 88.8 %

Procedure:
To a solution of 2-hydroxy-5-methoxybenzaldehyde (10 g, 67.5 mmol) and diisopropylethylamine (14 mL, 80 mmol) in CH2Cl2 (100 mL) was added chloromethyl methyl ether (6.1 mL, 80 mmol) at 0° C., and the mixture was stirred for 15 hours at room temperature. Then, water was added to the solution, the aqueous layer was extracted with CH2Cl2 (100 mL×3). The combined organic layer was washed with saturated aqueous NaCl (100 mL×2), water (100 mL×1), dried over MgSO4, and evaporated to afford the objective compound as a brown oil (11.76 g, 91%), which was used for next reaction without further purification: 1H-NMR (400 MHz, CDCl3) δ3.52 (s, 3H), 3.81 (s, 3H), 5.24 (s, 2H), 7.12 (dd, 1H, J=9.6, 3.2 Hz), 7.18 (d, 1H, J=9.6 Hz), 7.32 (d, 1H, J=3.2 Hz), 10.47 (s, 1H).
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)=[O:10].Cl[C:23]1[C:24]([CH3:30])=[N:25][CH:26]=[C:27]([CH3:29])[N:28]=1>>[CH3:29][C:27]1[C:26]([N:7]2[CH2:8][CH:4]3[CH:5]([CH2:1][N:2]([C:9]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[C:17]4[S:18][CH:19]=[CH:20][CH:21]=4)=[O:10])[CH2:3]3)[CH2:6]2)=[N:25][C:24]([CH3:30])=[CH:23][N:28]=1
Reactant: O=C(c1ccccc1-c1cccs1)N1CC2CNCC2C1
Reactant: Cc1cnc(C)c(Cl)n1
Product: Cc1cnc(C)c(N2CC3CN(C(=O)c4ccccc4-c4cccs4)CC3C2)n1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 37 and 3-chloro-2,5-dimethyl-pyrazine. MS (ESI) mass calcd. for C23H24N4OS, 404.54; m/z found, 405.2 [M+H]+.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25][CH3:26])=[O:24])=[C:19]([NH:27][CH:28]([CH3:30])[CH3:29])[CH:18]=2)=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:31]1[O:39][C@@H:32]1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(O)C>[CH2:1]([N:8]([CH2:31][C@H:32]([OH:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25][CH3:26])=[O:24])=[C:19]([NH:27][CH:28]([CH3:30])[CH3:29])[CH:18]=2)=[CH:13][CH:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc([C@@H]2CO2)cc1
Reactant: COC(=O)c1ccc(-c2ccc(CCNCc3ccccc3)cc2)cc1NC(C)C
Solvent: CCO
Product: COC(=O)c1ccc(-c2ccc(CCN(Cc3ccccc3)C[C@H](O)c3ccccc3)cc2)cc1NC(C)C

Procedure:
To a solution of methyl 4′-[2-(benzylamino)ethyl]-3-(isopropylamino)-4-biphenylcarboxylate (250 mg) in ethanol (15 ml) was added (R)-(+)-styreneoxide (142 μl) at room temperature, and the mixture was stirred under reflux for 48 hours. The mixture was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=3/1) to give methyl 4′-[2-[benzyl[(2R)-2-hydroxy-2-phenylethyl]amino]ethyl]-3-(isopropylamino)-4-biphenylcarboxylate (251 mg).