Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[Cl-].[F:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21][Zn+]>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.C1COCC1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[C:18]([F:17])[CH:19]=2)[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Reactant: Fc1cccc(C[Zn+])c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: Cc1c(Cc2cccc(F)c2)nc2cc(F)cc(F)c2c1Cl
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A screw cap vial was charged with 2,4-dichloro-5,7-difluoro-3-methylquinoline (500 mg, 2.016 mmol), tetrakis(triphenylphosphine)palladium(0) (233 mg, 0.202 mmol), and THF (5.04 mL). The mixture was sparged with N2, then 3-fluoro-benzylzinc chloride (0.5M in THF, 4.23 mL, 2.116 mmol) was added and the reaction stirred at 60° C. for 2 h. The reaction was then partitioned between EtOAc and water, and the organic layer washed with brine, dried (MgSO4), and concentrated. The crude material was purified by flash chromatography, eluting with a gradient of 0-15% EtOAc in hexane to give 4-chloro-5,7-difluoro-2-(3-fluorobenzyl)-3-methylquinoline. Mass Spectrum (ESI) m/e=322.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([OH:16])=O)=[CH:12][N:11]=[CH:10][CH:9]=2)=[C:4]([F:17])[CH:3]=1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.C(Cl)CCl.[F:41][C:42]([F:46])([F:45])[CH2:43][NH2:44]>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([NH:44][CH2:43][C:42]([F:46])([F:45])[F:41])=[O:16])=[CH:12][N:11]=[CH:10][CH:9]=2)=[C:4]([F:17])[CH:3]=1
Reactant: NCC(F)(F)F
Reactant: O=C(O)c1cnccc1-c1ccc(Cl)cc1F
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(F)(F)F)c1cnccc1-c1ccc(Cl)cc1F
Temperature: 0 °C
Reaction time: 12 h
Yield: 50.4 %

Procedure:
To stirred solution of 4-(4-chloro-2-fluorophenyl)nicotinic acid (300 mg, 1.192 mmol), prepared as described in Example 2, Part A, in anhydrous DMF (2 mL) under nitrogen was added HOBT (365 mg, 2.384 mmol), DIEA (0.927 mL, 4.77 mmol) and EDC (343 mg, 1.788 mmol). The reaction mixture was cooled to 0° C. and treated with 2,2,2-trifluoroethanamine (236 mg, 2.384 mmol) drop wise and warmed to RT and allowed to stir for 12 h. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layers were dried over sodium sulphate and concentrated under reduced pressure to afford 4-(4-chloro-2-fluorophenyl)-N-(2,2,2-trifluoroethyl)nicotinamide (200 mg, 0.601 mmol, 50% crude yield) as a yellow solid. LC/MS (ESI) m/e 333.2, [(M+H)+, calcd for C14H10ClF4N2O, 333.0]; LC/MS retention time (method A): tR=1.66 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:38])[C@H:4]([CH2:34][CH2:35][S:36][CH3:37])[NH:5][C:6](=[O:33])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH2:14][C@@H:15]2[CH2:19][S:18][CH2:17][N:16]2C(OC(C)(C)C)=O)=[CH:9][C:8]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.COC(=O)[C@H](CCSC)NC(=O)C1C=CC(NC([C@@H]2CSCN2C(OC(C)(C)C)=O)=O)=CC=1C1C=CC=CC=1>>[CH3:1][O:2][C:3](=[O:38])[C@H:4]([CH2:34][CH2:35][S:36][CH3:37])[NH:5][C:6](=[O:33])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH2:14][C@@H:15]2[CH2:19][S:18][CH2:17][NH:16]2)=[CH:9][C:8]=1[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(NC[C@@H]2CSCN2C(=O)OC(C)(C)C)cc1-c1ccccc1
Agent: COC(=O)[C@H](CCSC)NC(=O)c1ccc(NC(=O)[C@@H]2CSCN2C(=O)OC(C)(C)C)cc1-c1ccccc1
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(NC[C@@H]2CSCN2)cc1-c1ccccc1

Procedure:
The desired compound was prepared according to the method of Example 164C, except substituting [4-(N-tert-butoxycarbonyl-(R)-thiazolidin-4-ylmethyl)amino-2-phenylbenzoyl]methionine methyl ester, prepared as in Example 166B, for [4-(N-tert-butoxycarbonyl-(R)-thiazolidin-4-ylcarbonyl)amino-2-phenylbenzoyl]methionine methyl ester.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([O:18][CH:19]([CH3:21])[CH3:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C[N+]1([O-])CCOCC1>ClCCl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[CH:2]([C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([O:18][CH:19]([CH3:20])[CH3:21])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10])=[O:1]
Reactant: CCOC(=O)C(Cc1ccc(OC)c(CO)c1)OC(C)C
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: CCOC(=O)C(Cc1ccc(OC)c(C=O)c1)OC(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.3 %

Procedure:
826 mg of Ethyl 3-[3-(hydroxymethyl)-4-methoxyphenyl]-2-isopropoxypropanoate was dissolved in 20 ml of dichloromethane, and 390 mg of N-methylmorpholine N-oxide, 1.4 g of molecular sieve 4A and 49 mg of tetrapropylammonium perruthenate were added, and the mixture was stirred at room temperature overnight. The reaction mixture was filtered through Celite, the filtrate was concentrated, and the residue was purified by silica gel column chromatography, to give 782 mg of the title compound in the 5:1→2:1 hexane-ethyl acetate fraction.
Reaction SMILES: [N:1]1([C:10]2[N:18]=[C:17](Cl)[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[N:1]1([C:10]2[N:18]=[C:17]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: Nc1ccccc1
Reactant: Clc1nc(-n2cnc3ccccc32)c2nc[nH]c2n1
Solvent: ClCCl
Product: c1ccc(Nc2nc(-n3cnc4ccccc43)c3nc[nH]c3n2)cc1
Temperature: 140 °C
Reaction time: 48 h

Procedure:
300 mg of product obtained in stage 1 above are mixed with 0.52 ml of aniline and the mixture is then heated at 140° C. for approximately 72 hours. The mixture is allowed to return to ambient temperature for 48 hours. A paste is formed in methylene chloride and partial drying is carried out. 48 mg of expected product are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])[N:9]=[CH:8][N:7](COC(=O)C(C)(C)C)[C:6]2=[O:29].[OH-].[Na+].CC1C=CC(COC(NNC(C2C=NC=CN=2)=O)=O)=CC=1.Cl>CO.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])[N:9]=[CH:8][NH:7][C:6]2=[O:29]
Reactant: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCCCS(C)(=O)=O
Agent: Cc1ccc(COC(=O)NNC(=O)c2cnccn2)cc1
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cc2c(=O)[nH]cnc2cc1OCCCS(C)(=O)=O
Reaction time: 0.25 h
Yield: 94.2 %

Procedure:
6-Methoxy-7-(3-methylsulphonylpropoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (7 g, 17 mmol) was suspended in methanol and 2M sodium hydroxide (3.3 ml, 6.6 mmol) was added with continuous stirring. The reaction mixture became homogeneous after 15 minutes. After a further 45 minutes water was added (7 ml) and the reaction mixture was adjusted to pH10 with 2M hydrochloric acid. The precipitate (a white solid) was collected by filtration, washed with water and dried over phosphorus pentoxide under vacuum to give 6-methoxy-7-(3-methylsulphonylpropoxy)-3,4-dihydroquinazolin-4-one (5 g, 90%).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[C:7]3[N:8]([N:18]=[N:19][N:20]=3)[C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[NH:11][C:12]=2[N:13]=1.CC([O-])(C)C.[K+].[F:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=1[F:36])[CH2:31]Br>CN(C=O)C.CC(O)(C)C>[F:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=1[F:36])[CH2:31][N:11]1[C:12]2[N:13]=[C:3]([S:2][CH3:1])[N:4]=[CH:5][C:6]=2[C:7]2=[N:20][N:19]=[N:18][N:8]2[C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]1=2
Reactant: Fc1ccc(CBr)cc1F
Reactant: CSc1ncc2c(n1)Nc1ccccc1-n1nnnc1-2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CN(C)C=O
Product: CSc1ncc2c(n1)N(Cc1ccc(F)c(F)c1)c1ccccc1-n1nnnc1-2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
The 11-(methylthio)-9H-benzo[b]pyrimido[5,4-f]tetrazolo[1,5-d][1,4]diazepine (5) (1.03 g) in DMF (20 mL) was treated with 1.1 eq. of 1M t-BuOK in t-BuOH (4 mL). The mixture was stirred at R.T. for 10 minutes then the 3,4-difluorobenzyl bromide (0.6 mL) was added. The mixture was stirred at R.T. for one hour. The reaction mixture was quenched with the addition of saturated aqueous ammonium chloride solution (20 mL). The mixture was extracted with ethyl acetate (3×50 mL) and the combined organic extracts were dried over sodium sulfate. Concentration in vacuo provided the titled product as a yellow solid (6) (1.3 g). M.p.=281-283° C.; 400 MHz 1H NMR (DMSO-d6) δ: 8.91 (s, 1H), 7.79 (dd, J=8.4, 1.6 Hz, 1H), 7.61 (dd, J=8.4, 1.2 Hz, 1H), 7.54 (ddd, J=8.8, 7.2, 1.6 Hz, 1H), 7.45-7.34 (m, 2H), 7.32-7.25 (m, 1H), 7.17-7.13 (m, 1H), 5.24 (s, 2H), 2.56 (s, 3H); LCMS [M+H]: 410; Calc. for C19H13F2N7S: C, 55.74; H, 3.20; N, 23.95; found C, 55.65; H, 2.96; N, 23.67.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[N:4][N:3]=1.[OH-].[Na+].Cl.Cl[CH2:11][CH2:12][NH2:13]>C(#N)C.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.Br.C(O)C.O>[NH2:1][C:2]1([CH2:11][CH2:12][NH2:13])[NH:6][NH:5][N:4]=[N:3]1
Reactant: Nc1nnn[nH]1
Reactant: NCCCl
Agent: Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Solvent: O
Solvent: CCO
Solvent: CC#N
Product: NCCC1(N)N=NNN1
Reaction time: 0.5 h
Yield: 21.4 %

Procedure:
A mixture of 5-aminotetrazole (6.0 g, 58.2 mmol) and solid sodium hydroxide (8.36 g, 208 mmol) in acetonitrile (30 ml) was stirred for 0.5h. 2-Chloroethylamine hydrochloride (7.26 g, 62.4 mmol) and tetrabutylammonium hydrogen sulphate (0.788 g 2.32 mmol) were added and the reaction was heated at reflux for 18h. The mixture was filtered and the filtrate was evaporated to leave an oil which was taken up in 48% aqueous HBr. The solution was diluted with ethanol (150 ml) and then evaporated to leave an oil which soon solidified. The solid was leached with hot ethanol leaving a brown gum which was dissolved in water and the solution was evaporated to dryness to give a solid (1.62 g) after drying. The ethanol was reduced in volume and allowed to crystallise. The resulting solid (0.879 g) and the solid from the aqueous solution were combined and stirred in ethanol with a slight excess of sodium hydroxide until a clear solution was obtained. This solution was preabsorbed onto flash silica and purified by elution with dichloromethane:ethanol:0.88 ammonia (100:8:1) to (30:8:1). Fractions with product were evaporated to leave the title compound (0.217 g) as an oil. MH+ =129.
Reaction SMILES: C([O:4][C:5]1[C:10]([CH2:11][CH3:12])=[CH:9][C:8]([OH:13])=[C:7]([C:14](=[O:16])[CH3:15])[C:6]=1[CH2:17][CH3:18])(=O)C.[C:19]1(=O)[CH2:22][CH2:21][CH2:20]1.N1CCCC1>C1(C)C=CC=CC=1>[CH2:17]([C:6]1[C:5]([OH:4])=[C:10]([CH2:11][CH3:12])[CH:9]=[C:8]2[C:7]=1[C:14](=[O:16])[CH2:15][C:19]1([O:13]2)[CH2:22][CH2:21][CH2:20]1)[CH3:18]
Reactant: CCc1cc(O)c(C(C)=O)c(CC)c1OC(C)=O
Reactant: O=C1CCC1
Solvent: C1CCNC1
Solvent: Cc1ccccc1
Product: CCc1cc2c(c(CC)c1O)C(=O)CC1(CCC1)O2
Temperature: 25 °C
Reaction time: 16 h
Yield: 43.3 %

Procedure:
To a solution of 3-acetyl-2,6-diethyl-4-hydroxyphenyl acetate (4.0 g) and cyclobutanone (1.23 g) in toluene (150 mL) was added pyrrolidine (568 mg). The solution was left at room temperature for 16 hours, refluxed for two hours, and then a Dean-Stark was used to remove the water. After evaporation, the residue was dissolved in methanol and a lithium hydroxide solution (10%) was added until the solution reached a pH value greater than 9. The solution was stirred at room temperature for 2 hours and then neutralized to pH 7 using diluted hydrochloric acid. Work up and chromatography (silica gel, hexane-ethyl acetate 2% to 8%) gave 1.8 g of 5,7-diethyl-6-hydroxyspiro[chroman-2,1′-cyclobutan]-4-one. 1H-NMR (300 MHz, CDCl3) δ=6.67 (s, 1H), 5.14 (s, 1H), 4.01 (s, 3H), 3.11 (q, J=7.4 Hz, 2H), 2.84 (s, 2H), 2.65 (q, J=7.4 Hz, 2H), 2.30-1.65 (m, 6H), 1.30-1.10 (m, 6H) ppm. 13C-NMR (75 MHz, CDCl3) δ=194.3, 155.0, 146.0, 139.9, 130.6, 117.0, 115.8, 79.8, 47.7, 33.0, 23.8, 19.8, 13.9, 13.2, 12.1 ppm.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[C:19]2[N:23]([CH3:24])[C:22]([CH3:25])=[N:21][N:20]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[F:26].O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[NH:82]1[CH2:87][CH2:86][O:85][CH2:84][CH2:83]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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CN(C=O)C>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([NH:11][S:8]([C:5]2[CH:6]=[CH:7][C:2]([N:82]3[CH2:87][CH2:86][O:85][CH2:84][CH2:83]3)=[C:3]([F:26])[CH:4]=2)(=[O:10])=[O:9])=[C:13]([C:19]2[N:23]([CH3:24])[C:22]([CH3:25])=[N:21][N:20]=2)[CH:14]=1
Reactant: C1COCCN1
Reactant: Cc1nnc(-c2cc(Cl)ccc2NS(=O)(=O)c2ccc(Br)c(F)c2)n1C
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nnc(-c2cc(Cl)ccc2NS(=O)(=O)c2ccc(N3CCOCC3)c(F)c2)n1C
Temperature: 90 °C
Reaction time: 20 h

Procedure:
A 25 mL scintillation vial was charged with 4-bromo-N-[4-chloro-2-(4,5-dimethyl-4H-[1,2,4]triazol-3-yl)-phenyl]-3-fluoro-benzenesulfonamide (synthesized according to general procedure C, 92 mg, 0.2 mmol), potassium phosphate monohydrate (276 mg, 1.2 mmol), BINAP (30 mg, 0.048 mmol), morpholine (87 mg, 1.0 mmol), Pd2(dba)3 (10 mg, 0.011 mmol), and DMF (2 mL). The vial was sealed and stirred at 90° C. for 20 h. The crude product was purified by flash column chromatography (10-100% ethyl acetate and hexane) followed by preparative HPLC (10-90% gradient of MeCN-water) to afford the title compound as a white solid: 1H NMR (400 MHz, CDCl3/HCl) δ 2.4 (s, 3H), 2.7-3.7 (m, 8H), 3.8 (s, 3H), 6.7 (d, 1H), 7.1-7.3 (m, 3H), 7.4 (d, 1H), 7.5 (d, 1H), MS (ES) M+H expected 466.0, found 466.0.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1Br.[Li]CCCC.C(O[B:19]1[O:23][C:22]([CH3:25])([CH3:24])[C:21]([CH3:27])([CH3:26])[O:20]1)(C)C>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[B:19]1[O:23][C:22]([CH3:25])([CH3:24])[C:21]([CH3:27])([CH3:26])[O:20]1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: Cc1cccc(C)c1Br
Agent: [Li]CCCC
Product: Cc1cccc(C)c1B1OC(C)(C)C(C)(C)O1
Reaction time: 1 h

Procedure:
To a solution of 35.0 g (0.19 mol) of 2,6-dimethylbromobenzene cooled to −78° C., 76 ml (0.19 mol) of 2.5 M nBuLi in hexanes was added for 40 min. The resulting mixture was stirred at this temperature for 1 h, then 35.2 g (0.19 mol) of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was added. The resulting mixture was stirred overnight at room temperature and then evaporated to dryness. The residue was poured into 500 ml of water, crude product was extracted with 3×200 ml of ethyl acetate. The combined organic extract was dried over Na2SO4 and then evaporated to dryness. Yield 19.5 g (53%) of yellow crystalline solid. Anal. calc. for C14H21BO2: C, 72.44; H, 9.12. Found: C, 72.78; H, 9.45. 1H NMR (CDCl3): δ 7.12 (t, J=7.7 Hz, 1H, 4-H), 6.94 (d, J=7.7 Hz, 2H, 3, 5-H), 2.40 (s, 6H, 2, 6-Me), 1.38 (s, 12H, Bpin).
Reaction SMILES: Cl.[Cl:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[C:10](=[O:16])[NH:11][C:12](=[O:15])[NH:13][CH:14]=2)=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][CH:26]([O:29][CH3:30])[O:27][CH3:28]>CN(C=O)C>[Cl:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[C:10](=[O:16])[NH:11][C:12](=[O:15])[N:13]([CH2:24][CH2:25][CH:26]([O:29][CH3:30])[O:27][CH3:28])[CH:14]=2)=[CH:5][CH:4]=1
Reactant: COC(CCBr)OC
Reactant: O=c1[nH]cc(-c2ccc(Cl)nc2)c(=O)[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(CCn1cc(-c2ccc(Cl)nc2)c(=O)[nH]c1=O)OC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 40 %

Procedure:
A mixture of 5-(6-chloro-pyridin-3-yl)-1H-pyrimidine-2,4-dione hydrochloride (Prep91, 1.05 g, 4.10 mmol), and K2CO3 (565 mg, 4.10 mmol) in DMF (20 ml) was stirred 20 minutes at room temperature. 3-Bromo-1,1dimethoxy-propane (635 μl, 4.65 mmol) was added in three portions over 6 days. Solvent was then removed under vacuum at 40° C. and the residue washed once with petroleum ether and twice with ethyl acetate. Ethyl acetate phase was dried (Na2SO4), filtered and evaporated. The crude was purified by flash chromatography eluting with DCM-MeOH—NH4OH (98:2:0.2) to give 534 mg of the title compound as a white solid (40% yield).
Reaction SMILES: CC(C[AlH]CC(C)C)C.[C:10]1([C:16]2([C:19]3[N:24]=[C:23]4[S:25][C:26]([C:28]5[CH:35]=[CH:34][C:31]([C:32]#N)=[CH:30][CH:29]=5)=[N:27][C:22]4=[CH:21][CH:20]=3)[CH2:18][CH2:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(C(C(C([O-])=O)O)O)([O-])=[O:37]>C(Cl)Cl>[C:10]1([C:16]2([C:19]3[N:24]=[C:23]4[S:25][C:26]([C:28]5[CH:35]=[CH:34][C:31]([CH:32]=[O:37])=[CH:30][CH:29]=5)=[N:27][C:22]4=[CH:21][CH:20]=3)[CH2:18][CH2:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: N#Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)cc1
Reactant: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: O=Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
DIBAL-H (1.0M in hexanes) (185 μl, 0.185 mmol) was added to a solution of 4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzonitrile (59.6 mg, 0.169 mmol) in DCM (2.7 mL) at 25° C., and the resulting solution was stirred at 25° C. for 45 min. Sat. aq. Na/K tartrate solution (3.0 mL) was added, and the resulting mixture was vigorously stirred for 15 min, then partitioned between DCM (40 mL) and sat. aq. Na/K tartrate solution (10 mL). The organic layer was separated, and the aqueous layer was extracted with DCM. The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0-100% EtOAc/Hexanes) provided 4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzaldehyde as a light yellow solid. MS (ESI) m/z: Calculated: 356.1; Observed: 357.1 (M++1).
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([S:20][CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[N:15]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:21]([S:20][C:16]1[N:15]=[C:14]([C:12]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:10])[N:13]=2)[CH:19]=[CH:18][CH:17]=1)[CH2:22][CH:23]([CH3:25])[CH3:24]
Reactant: CC(C)CCSc1cccc(C#N)n1
Reactant: COC(=O)c1ccccc1S
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)CCSc1cccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 26 %

Procedure:
A mixture of methyl thiosalicylate (1.21 g, 7.2 mmol), 2-cyano-6-isopentylthiopyridine (1.48 g, 7.2 mmol), triethylamine (1.5 ml, 10.8 mmol) and toluene (30 ml) was refluxed for 48 hrs. The reaction mixture was concentrated under reduced pressure to give the precipitated crystals, which were recrystallized from ethyl acetate-hexane to give the titled compound (0.64 g, 26%).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([NH:10][C:11]([C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([NH:23][C:24]([C:26]1[C:27]([C:32]3[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=3)=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:25])[CH:17]=[CH:16]2)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:42](=O)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:42]([NH:1][CH2:2][C@@H:3]([NH:10][C:11]([C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([NH:23][C:24]([C:26]1[C:27]([C:32]3[CH:33]=[CH:34][C:35]([C:38]([F:41])([F:39])[F:40])=[CH:36][CH:37]=3)=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:25])[CH:17]=[CH:16]2)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: O=Cc1ccccc1
Reactant: NC[C@@H](NC(=O)c1ccc2nc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: O=C(N[C@H](CNCc1ccccc1)c1ccccc1)c1ccc2nc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(S)-2-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-6-carboxylic acid (2-amino-1-phenyl-ethyl)-amide (N, 30 mg, 0.05 mM) was dissolved in 1,2-dichloroethane. Benzaldehyde (0.15 mM) was added followed by sodium triacetoxy borohydride (110 mg, 0.51 mM). The mixture was stirred at room temperature for 16 h. The solution was concentrated, and the residue was purified by flash chromatography (silica gel) eluting with EtOAc/hexanes. HPLC retention time, 2.75 min; ESMS, 645; calc. Mw, 644
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]2=1.[CH3:15]I>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH3:15])[C:10]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: Brc1ccc2[nH]c3c(c2c1)CCCC3
Reactant: CI
Solvent: CN(C)C=O
Product: Cn1c2c(c3cc(Br)ccc31)CCCC2
Yield: 91.1 %

Procedure:
The desired product was prepared using a procedure similar to step 2 of example 3. Thus, 6-bromo-2,3,4,9-tetrahydro-1H-carbazole (1.501 g, 6 mmol) was reacted with k-t-butoxide (0.707 g, 6.3 mmol) and methyl iodide (0.894 g, 6.3 mmol) in DMF (15 ml) to give the desired product (1.443 g, 5.463 mmol, 91%) as an off-white solid, mp 70-73° C. 1H NMR (DMSO-d6) δ 1.73-1.77 (m, 2H), 1.82-1.87 (m, 2H), 2.58 (t, J=6.1 Hz, 2H), 2.70 (t, J=6.1 Hz, 2H), 3.58 (s, 3H), 7.13 (dd, J=1.7, 8.6 Hz, 1H), 7.32 (d, J=8.6 Hz, 1H), 7.55 (d, J=1.5 Hz, 1H); [EI], m/z 263/265 (M)+.
Reaction SMILES: [N:1]1([C:7](=[O:24])[CH2:8][CH:9]([CH2:13][S:14]([CH2:17][C:18]2[CH:23]=[CH:22]C=CC=2)(=[O:16])=[O:15])[C:10]([OH:12])=[O:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[OH-].[Na+].BrCC1CC1.OOS([O-])=O.[K+]>CCO.O>[CH:18]1([CH2:17][S:14]([CH2:13][CH:9]([CH2:8][C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)=[O:24])[C:10]([OH:12])=[O:11])(=[O:15])=[O:16])[CH2:23][CH2:22]1
Reactant: O=C(O)C(CC(=O)N1CCOCC1)CS(=O)(=O)Cc1ccccc1
Agent: BrCC1CC1
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CCO
Solvent: O
Product: O=C(O)C(CC(=O)N1CCOCC1)CS(=O)(=O)CC1CC1
Temperature: 25 °C

Procedure:
4-Morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyric acid (11.16 g, 40.74 mmol) was dissolved in 100 mL dry EtOH and set to stir at room temperature. NaOH pellets (4.81 g, 120.25 mmol) were added in one portion, and the reaction mixture was allowed to stir for 10 min. Bromomethylcyclopropane (5.0 g, 37.04 mmol) was then added, and the reaction mixture was allowed to stir at ambient temperature for 20 hours. Upon completion (LCMS), the reaction mixture was diluted with water and the pH was lowered to ˜pH2. The reaction mixture was then washed 3× with EtOAc. The organic phase was concentrated in vacuo and then diluted with 200 mL aqueous MeOH. Oxone (15.6 g, 24.0 mmol) was added in one portion and the reaction was stirred at room temperature for 4 h. Conversion of sulfide to sulfone was monitored via LCMS. Upon completion, reaction was quenched by the addition of sodium thiosulfate. Salts were filtered, and the reaction mixture was washed 3× with ethyl acetate and dried over sodium sulfate. The organics were evaporated by vacuum under reduced pressure. Product was purified via HPLC. Yield: 1.2 g, 15.1%. m/z (LCMS) M+ 320.1, Rf=1.84. δH 12.6 (1H, br s), 3.5 (4H, m), 3.5 (1H, m), 3.4 (4H, m), 3.25 (2H, d), 3.0 (2H, m), 2.9 (2H, d), 2.4 (1H, m), 1.1 (1H, m), 0.62 (2H, q), 0.38 (2H, q).