Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([CH:10]([OH:17])[C:11]2[N:12]([CH3:16])[CH:13]=[N:14][CH:15]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[OH:28].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[CH3:16][N:12]1[C:11]([C:10]([C:8]2[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([O:28][C:19]3[CH:20]=[CH:21][C:22]4[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:18]=3)[CH:9]=2)=[O:17])=[CH:15][N:14]=[CH:13]1
Reactant: Cn1cncc1C(O)c1ccc(C#N)c(F)c1
Reactant: Oc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1cncc1C(=O)c1ccc(C#N)c(Oc2ccc3ccccc3c2)c1
Temperature: 60 °C

Procedure:
2-Fluoro-4-[hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-benzonitrile (as described in Example 22, Step E) (0.172 g, 0.743 mmol), 2-naphthol (0.107 g, 0.743 mmol) and Cs2CO3 (0.727 g, 2.23 mmol) were dissolved in anhydrous DMF (5 mL) and heated at 60° C. under Ar for 2 days. The reaction was diluted with EtOAc, washed with satd. NaHCO3 solution, water, and brine. The organic layer was dried (MgSO4), concentrated and purified using SiO2 chromatography (1-2% MeOH/CH2Cl2) to give the title compound.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][C@:8]12[CH2:25][CH2:24][C@H:23]3[C@@H:13]([CH2:14][CH2:15][C:16]4[C@:21]3([CH3:22])[CH:20]=[CH:19][C:18](=[O:26])[CH:17]=4)[C@@H:12]1[CH2:11][CH2:10][C:9]2=[O:27].[Cl-].[NH4+]>CS(C)=O>[CH3:7][C@:8]12[CH2:25][CH2:24][C@H:23]3[C@@H:13]([CH2:14][CH:15]=[C:16]4[C@:21]3([CH3:22])[CH:20]=[CH:19][C:18](=[O:26])[CH2:17]4)[C@@H:12]1[CH2:11][CH2:10][C:9]2=[O:27]
Reactant: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CS(C)=O
Product: C[C@]12C=CC(=O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12

Procedure:
To a solution of potassium t-butoxide in dimethyl-sulfoxide at 25° C. under nitrogen is added 1,4-androstadiene-3,17-dione in dimethylsulfoxide with stirring. After fifteen minutes the mixture is poured onto cold aqueous ammonium chloride. The solid is rapidly filtered, washed well with water and dissolved in ether. The ether solution is washed again with water, dried over sodium sulfate and evaporated at room temperature to yield 1,5-androstadiene-3,17-dione.
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][CH2:5][CH2:6]Cl.Cl.[NH2:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]=1[CH3:20]>ClC1C=CC=CC=1>[CH3:20][C:11]1[CH:12]=[CH:13][C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]=1[N:9]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: ClCCNCCCl
Reactant: Cc1ccc2ccccc2c1N
Agent: Cl
Solvent: Clc1ccccc1
Product: Cc1ccc2ccccc2c1N1CCNCC1
Yield: 62 %

Procedure:
14.7 g (82.7 mmol) of bis(2-chloroethyl)amine×HCl were added to 13.0 g (82.7 mmol) of 1-amino-2-methylnaphthalene in 100 ml of chlorobenzene, and the mixture was boiled under nitrogen and at reflux for 90 h. The mixture was then evaporated and the residue was partitioned between methylene chloride and water at pH=9; the organic phase was then evaporated after having been dried. The crude product was purified by column chromatography (silica gel, eluent THF/methanol/ammonia 85/13/2). 11.6 g (62%) of product were isolated.
Reaction SMILES: [NH2:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[O:7])=[C:4]([O:19][CH2:20][C:21]#[N:22])[CH:3]=1>[Ni]>[NH2:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:12][CH3:13])[CH2:14][CH3:15])=[O:7])=[C:4]([O:19][CH2:20][CH2:21][NH2:22])[CH:3]=1
Reactant: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1OCC#N
Agent: [Ni]
Product: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1OCCN
Reaction time: 5 h
Yield: 45.6 %

Procedure:
To a suspension of one teaspoonful of Raney nickel (well washed with methanol) in methanol (130 ml) was added 4-amino-5-chloro-2-cyanomethyl-N-[2-(diethylamino)ethyl]benzamide (12.05 g, 37.1 mmoles) (prepared in Example 13), and the mixture hydrogenated at 40 psi for 5 hours. The catalyst was removed by filtration under nitrogen and the filtrate concentrated in vacuo. This was dissolved in methylene chloride and washed with 1N sodium hydroxide (4×25 ml). The washings were back extracted with methylene chloride and the organic phases combined, dried and concentrated in vacuo to give 5.56 g of the title product as a semi-solid. This was recrystallized from methanol-ether in the cold to give a sample, mp. 97°-99° C.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[C:6]([NH:8][CH2:9][C:10]([NH:12][C@H:13]1[CH2:17][CH2:16][NH:15][CH2:14]1)=[O:11])=[O:7].C1CCNCC1.[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C1(N=C=O)C=CC=CC=1>C(#N)C>[CH2:29]([N:15]1[CH2:16][CH2:17][C@H:13]([NH:12][C:10](=[O:11])[CH2:9][NH:8][C:6](=[O:7])[C:5]2[CH:18]=[CH:19][CH:20]=[C:3]([C:2]([F:1])([F:21])[F:22])[CH:4]=2)[CH2:14]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@H]1CCNC1
Reactant: BrCc1ccccc1
Solvent: O=C=Nc1ccccc1
Solvent: C1CCNCC1
Solvent: CC#N
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@H]1CCN(Cc2ccccc2)C1
Temperature: 45 °C
Reaction time: 5 h

Procedure:
An acetonitrile (1.1 mL) solution of (S)-3-[N-[3-(trifluoromethyl)benzoyl]glycyl]aminopyrrolidine (0.06 mmol) and a (piperidinomethyl)polystyrene (2.6 to 2.8 mmol/g, 30 mg) were added to an acetonitrile (0.4 mL) solution of benzyl bromide (0.050 mmol). The resulting reaction mixture was stirred at 45° C. for 5 hours. The mixture solution was cooled to room temperature, and the resin was then removed by filtration to concentrate the filtrate. The resulting residue was dissolved in acetonitrile (1.0 mL), and phenyl isocyanate (0.008 mL, 0.05 mmol) was then added to the obtained solution. The mixture solution was stirred at room temperature for 1 hour, loaded onto a Varian™ SCX column and washed with methanol (15 mL). The obtained crude product was eluted with a solution of 2 M NH3 in methanol (6 mL) and concentrated to thereby provide (S)-1-benzyl-3-[N-[3-(trifluoromethyl)benzoyl]glycyl]aminopyrrolidine (Compd. No. 239) (9.0 mg, 44%). The purity was determined by RPLC/MS (99%). ESI/MS m/e 406.0 (M++H, C21H22F3N3O2).
Reaction SMILES: ClCC(O)CSCC(O)CCl.[OH-].[Na+].NC(N)=S.C(OC(=O)C)(=O)C.O1CC1C[CH:28]1[S:40][CH:29]1[CH2:30][S:31][CH2:32][CH:33]1[S:39][CH:34]1CC1OC1>C1(C)C=CC=CC=1.CO>[S:39]1[CH2:34][CH:33]1[CH2:32][S:31][CH2:30][CH:29]1[S:40][CH2:28]1
Reactant: C1OC1CC1SC1CSCC1SC1CC1CO1
Agent: NC(N)=S
Agent: OC(CCl)CSCC(O)CCl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: CC(=O)OC(C)=O
Product: C(SCC1CS1)C1CS1
Temperature: 36 °C
Reaction time: 0.5 h

Procedure:
1072.48 g (8.47 mol) of bis(3-chloro-2-hydroxypropyl)sulfide, 1300 g of toluene, and 800 g of methanol were put into a 10-liter reactor. The reaction temperature was adjusted to 30° C. with stirring. When the reaction temperature reached 25° C., NaOH (50% aq., 783.08 g, 9.78 mol) was added dropwise within 1 h. The reaction was carried out while maintaining a temperature of 35-37° C. After standing at 37° C. for about 30 min, 2000 g of toluene was added to the reaction mixture, followed by stirring for about 10 min. The resulting mixture was left standing for layer separation. The upper organic layer was washed twice with water, and then the water was removed as much as possible. To the organic layer was added 400 g of methanol. After stirring, thiourea (1117.65 g, 14.30 mol) and acetic anhydride (70 g) were added at a temperature of 8° C. The reaction was continued at 18° C. for 18 h. The reaction was stopped when almost all the starting materials disappeared, which was confirmed by HPLC, and the content of 2,3-epoxypropyl(2,3-epithiopropyl)sulfide reached 3.5%, which was confirmed by GC analysis. After completion of the reaction, stirring was stopped for layer separation. The obtained organic layer was washed three times with water and the organic solvent was removed, affording bis(2,3-epithiopropyl)sulfide. The product had a refractive index (nD, 20° C.) of 1.623.
Reaction SMILES: [CH2:1]([O:5][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7])[CH2:2][CH:3]=[CH2:4].B1C2CCCC1CCC2.FC(F)(F)S(O[C:28]1[CH:40]=[CH:39][C:31]2[C:32]([C:35]([F:38])([F:37])[F:36])=[N:33][O:34][C:30]=2[C:29]=1[CH2:41][CH2:42][CH3:43])(=O)=O.C([O-])([O-])=O.[K+].[K+]>C1COCC1.CN(C=O)C.[Pd]>[Si:6]([O:5][CH2:1][CH2:2][CH2:3][CH2:4][C:28]1[CH:40]=[CH:39][C:31]2[C:32]([C:35]([F:37])([F:38])[F:36])=[N:33][O:34][C:30]=2[C:29]=1[CH2:41][CH2:42][CH3:43])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:7])[CH3:8]
Reactant: CCCc1c(OS(=O)(=O)C(F)(F)F)ccc2c(C(F)(F)F)noc12
Reactant: C=CCCO[Si](C)(C)C(C)(C)C
Agent: [Pd]
Agent: B1C2CCCC1CCC2
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCCc1c(CCCCO[Si](C)(C)C(C)(C)C)ccc2c(C(F)(F)F)noc12
Reaction time: 5 h

Procedure:
To a solution of (but-3-enyloxy)(tert-butyl)dimethylsilane, from this Example step 2, (148 mg, 0.79 mmol) in dry THF (0.25 mL) was added 9-BBN (0.5M 1.75 mL, 0.88 mmol) at 0° C. under N2. The mixture was stirred for 5 hours, then added to a mixture of 7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl trifluoromethanesulfonate, as prepared in this Example step 1, (300 mg, 0.79 mmol), K2CO3 (220 mg, 1.59 mmol), and dichlorobis(triphenylphosphene) palladium (32.5 mg, 0.039 mmol) in DMF (3 mL) under N2 in a sealed tube. The mixture was stirred overnight at 55° C. The reaction mixture was partitioned between ethyl acetate and water. Combined organic extracts were washed with water twice and brine and then dried over Na2SO4. The solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel using ethyl acetate and hexane (1:30) to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][NH2:11].[C:12](OC(=O)C)(=[O:14])[CH3:13]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][NH:11][C:12](=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccccc1CCN
Product: COc1ccccc1CCNC(C)=O

Procedure:
In close analogy to the procedure described above, 2-(2-methoxy-phenyl)-ethylamine is reacted with acetic anhydride to provide the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=3)[CH:11]=[C:10]([CH3:22])[N:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:23][C:24]1[CH:29]=[CH:28][C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][N:25]=1>>[Cl:21][C:16]1[CH:15]=[C:14]([C:12]2[CH:11]=[C:10]([CH3:22])[N:9]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:27]4[CH:26]=[N:25][C:24]([NH2:23])=[CH:29][CH:28]=4)[CH:7]=3)[N:13]=2)[CH:19]=[CH:18][C:17]=1[Cl:20]
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(-c2ccnc(Cl)c2)n1
Product: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(-c2ccnc(-c3ccc(N)nc3)c2)n1

Procedure:
The title compound was prepared from 2-(2-chloro-pyridin-4-yl)-4-(3,4-dichloro-phenyl)-6-methyl-pyrimidine (example E.63) (0.15 g, 0.43 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.12 g, 0.54 mmol) according to the general procedure VI. Obtained as a yellow solid (0.11 g, 63%). MS (ISP) 408.4 [(M+H)+]; mp 205° C.
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[OH:3][CH2:4][CH2:6][CH2:7][N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:12][CH2:13]1
Reactant: CCOC(=O)CCN1CCN(c2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCCN1CCN(c2ccccc2)CC1
Reaction time: 2 h
Yield: 94.2 %

Procedure:
6.75 g of 1-(2-ethoxycarbonylethyl)-4-phenylpiperazine are dissolved in 100 ml of anhydrous tetrahydrofuran, and the solution is added dropwise at a temperature below 5° C. to a suspension of 1.96 g of lithium aluminum hydride in 200 ml of anhydrous tetrahydrofuran. The mixture is stirred at the same temperature for 2 hours. After decomposing an excess of lithium aluminum hydride, insoluble materials are removed by filtration. The filtrate is concentrated under reduced pressure to dryness, and the residue is recrystallized from isopropyl ether. 5.34 g of 1-(3-hydroxy-n-propyl)-4-phenyl-piperazine are thereby obtained as colorless granules. Yield: 94%
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].Cl[C:17]1[CH:18]=[N:19][CH:20]=[C:21]([CH:27]=1)[C:22]([O:24][CH2:25][CH3:26])=[O:23]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:17]2[CH:18]=[N:19][CH:20]=[C:21]([CH:27]=2)[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: CCOC(=O)c1cncc(Cl)c1
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Product: CCOC(=O)c1cncc(-c2cc(OC)c(OC)c(OC)c2)c1

Procedure:
3,4,5-Trimethoxyphenylboronic acid (6.36 g) and ethyl 5-chloronicotinate (6.90 g) were reacted in the same manner as in Preparation Example 1 to obtain the title compound.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:7]=[C:8]([C:23]([OH:25])=[O:24])[CH:9]=[C:10]([S:19]([NH2:22])(=[O:21])=[O:20])[C:11]=1[O:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1.[C:26]([O:32][CH2:33]Cl)(=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28].C(N(CC)CC)C.[I-].[Na+]>CN(C)C=O>[NH2:22][S:19]([C:10]1[CH:9]=[C:8]([CH:7]=[C:6]([NH:5][CH2:4][CH2:3][CH2:2][CH3:1])[C:11]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:23]([O:25][CH2:33][O:32][C:26]([C:27]([CH3:30])([CH3:29])[CH3:28])=[O:31])=[O:24])(=[O:21])=[O:20]
Reactant: CCCCNc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccccc1
Reactant: CC(C)(C)C(=O)OCCl
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCNc1cc(C(=O)OCOC(=O)C(C)(C)C)cc(S(N)(=O)=O)c1Oc1ccccc1
Temperature: 50 °C
Yield: 41.5 %

Procedure:
Bumetanide (1.2 g, 3.29 mmol) was dissolved in dimethylformamide (DMF, 10 mL) and chloromethyl pivalate (575 uL, 3.9 mmol) was added followed by triethylamine (0.70 mL) and sodium iodide (545 mg, 3.6 mmol). The reaction was heated to 50° C. for 10 hours, at which time TLC and LC/MS indicated the reaction was complete. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate, water and brine, and dried over anhydrous magnesium sulfate. The ethyl acetate was removed under reduced pressure and the product was purified via flash chromatography to yield 653 mg (60%) of pure t-butylcarbonyloxymethyl 3-aminosulfonyl-5-butylamino-4-phenoxybenzoate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C@@H:18]3[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH3:25])[CH2:19]3)=[CH:14][CH:13]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1.C([O-])(C)(C)C.[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+].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>O1CCCC1>[CH2:23]([N:20]1[CH2:21][CH2:22][C@@H:18]([C:15]2[CH:16]=[CH:17][C:12]([NH:11][S:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([N:26]4[CH2:30][CH2:29][CH2:28][CH2:27]4)[CH:3]=3)(=[O:10])=[O:9])=[CH:13][CH:14]=2)[CH2:19]1)[CH2:24][CH3:25]
Reactant: C1CCNC1
Reactant: CCCN1CC[C@@H](c2ccc(NS(=O)(=O)c3cccc(Br)c3)cc2)C1
Agent: CC(C)(C)[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCN1CC[C@@H](c2ccc(NS(=O)(=O)c3cccc(N4CCCC4)c3)cc2)C1
Temperature: 50 °C
Reaction time: 4 h
Yield: 79.5 %

Procedure:
0.4 g of 3-Bromo-N-[4-((S)-1-propyl-pyrrolidin-3-yl)-phenyl]-benzenesulfonamide (0.94 mmol), 0.156 ml pyrrolidin (1.89 mmol), 160 mg sodium tert-butanolate ((1.66 mmol) and 540 mg sodium sulfate were dissolved in 15 ml of tetrahydrofuran and heated to 50° C. 120 mg of 2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (0.19 mmol) and 85 mg tri(dibenzylidenacetone)dipalladium(0) (0.09 mmol) were added and the reaction stirred for 4 h under reflux. After workup, the partially converted starting material was reacted again under the same reaction conditions until completion. The solvents were evaporated under reduced pressure, the residue was treated with dichloromethane and water, the organic layer was dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The crude product was purified with silica gel chromatography with dichloromethane/methanol (0-20%) as eluent using a semi-automated ISCO companion instrument, yielding 0.309 g of the purified product.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH2:12]([O:16][C:17]([N:19]([C:39]1[C:44]([O:45][CH3:46])=[N:43][C:42]([CH3:47])=[CH:41][N:40]=1)[S:20]([C:23]1[C:24]([C:29]2[CH:34]=[CH:33][C:32]([CH2:35][C:36]([CH3:38])=[CH2:37])=[CH:31][CH:30]=2)=[N:25][CH:26]=[CH:27][CH:28]=1)(=[O:22])=[O:21])=[O:18])[CH:13]([CH3:15])[CH3:14]>ClCCl>[O:6]1[CH2:37][C:36]1([CH3:38])[CH2:35][C:32]1[CH:33]=[CH:34][C:29]([C:24]2[C:23]([S:20]([N:19]([C:17]([O:16][CH2:12][CH:13]([CH3:14])[CH3:15])=[O:18])[C:39]3[C:44]([O:45][CH3:46])=[N:43][C:42]([CH3:47])=[CH:41][N:40]=3)(=[O:22])=[O:21])=[CH:28][CH:27]=[CH:26][N:25]=2)=[CH:30][CH:31]=1
Reactant: C=C(C)Cc1ccc(-c2ncccc2S(=O)(=O)N(C(=O)OCC(C)C)c2ncc(C)nc2OC)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1nc(C)cnc1N(C(=O)OCC(C)C)S(=O)(=O)c1cccnc1-c1ccc(CC2(C)CO2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 8.6 %

Procedure:
3-Chloroperoxybenzoic acid (50%, 2.4 g) was added over 5 minutes to a solution of N-(isobutoxycarbonyl)-N-(3-methoxy-5-methylpyrazin-2-yl)-2-[4-(2-methylprop-2-enyl)phenyl]pyridine-3-sulphonamide (1.8 g) in dichloromethane (75 ml) at 0° C. The reaction mixture was allowed to warm to ambient temperature and stirred a further 1 hour. The mixture was washed with saturated aqueous sodium hydrogen carbonate solution (20 ml), water and saturated sodium chloride solution then dried (MgSO4). Volatile material was removed by evaporation and the residue was purified by suction flash chromatography followed by gradient elution with 0-40% ethyl acetate/hexane through a silica gel Mega Bond Elut column to give 2-[4-(2,3-epoxy-2-methylpropyl)phenyl]-N-(isobutoxycarbonyl)-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (0.16 g) as a solid, 1H NMR (CDCl3): 0.65 (d, 6H), 1.3 (s, 3H), 1.7 (m, 1H), 2.5 (s, 3H), 2.65 (dd, 2H), 2.9 (q, 2H), 3.85 (d, 2H), 4.0 (s, 3H), 7.3 (d, 2H), 7.5 (dd, 1H), 7.6 (d, 2H), 7.95 (s, 1H), 8.85 (dd, 1H), 8.95 (dd, 1H); mass spectrum (+ve ESP): 527 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:4][C:5]#[N:6])[CH2:3][CH2:2]1.[CH3:7][N:8]([CH:10](N(C)C)OC(C)(C)C)[CH3:9]>>[CH:1]1([C:4](=[CH:7][N:8]([CH3:10])[CH3:9])[C:5]#[N:6])[CH2:3][CH2:2]1
Reactant: N#CCC1CC1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Product: CN(C)C=C(C#N)C1CC1

Procedure:
At 100° C., 25 g (292.8 mmol) of cyclopropylacetonitrile (obtainable by the process described in U.S. Pat. No. 3,454,575) and 25.5 g (30.2 ml, 146.4 mmol) of bis(dimethylamino)-tert-butyloxymethane are stirred under a riser pipe for 46 hours. Volatile components are evaporated under reduced pressure and the residue is subsequently distilled at 0.1 Torr and 60-65° C.
Reaction SMILES: [C:1]1([CH2:7][C:8](=[O:35])[CH2:9][NH:10][C:11]2[N:16]([CH3:17])[C:15](=[O:18])[C:14]([C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=3)=[C:13]([C:29]3[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=3)[N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].CC([N-]C(C)C)C.[Cl-].[Li+].CC1(C)[C@@]23C4(ON4S(=O)(=O)C2)C[C@@H]1CC3>C1COCC1>[C:1]1([CH2:7][CH:8]([OH:35])[CH2:9][NH:10][C:11]2[N:16]([CH3:17])[C:15](=[O:18])[C:14]([C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=3)=[C:13]([C:29]3[CH:30]=[CH:31][N:32]=[CH:33][CH:34]=3)[N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cn1c(NCC(=O)Cc2ccccc2)nc(-c2ccncc2)c(-c2ccc3ccccc3c2)c1=O
Agent: CC(C)[N-]C(C)C
Agent: CC1(C)[C@H]2CC[C@]13CS(=O)(=O)N1OC13C2
Agent: [Cl-]
Solvent: C1CCOC1
Product: Cn1c(NCC(O)Cc2ccccc2)nc(-c2ccncc2)c(-c2ccc3ccccc3c2)c1=O
Reaction time: 1 h

Procedure:
To a solution of 2-[3-phenyl-2-oxo-propylamino]-3-methyl-5-naphthalen-2-yl-6-pyridin-4-yl-3H-pyrimidin-4-one (123 mg, 0.27 mmol) in THF (5 mL) at −78° C. was added LDA (Aldrich, 2.0 M in THF, 0.4 mL). The mixture was stirred for 1 h. Lithium chloride (30 mg) was added. After 5 minutes, (1S)-(+)-(10-camphorsulfonyl)oxaziridine (200 mg, 0.87 mmol) was added. The mixture was stirred at −78 for 2 hours, and quenched with water (5 mL) and ethyl acetate (80 mL). The solution was washed with brine (3×50 mL), dried, and evaporated. The crude product was purified by preparative TLC (6% MeOH/CH2Cl2). 8 mg (7%) solids. M+1=477.2.
Reaction SMILES: [C:1]1([C:7]2[S:8][CH:9]=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:15]1([C:21]2[N:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=2)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>>[N:15]1([C:21]2[N:26]=[CH:25][C:24]([NH:27][C:12]([C:10]3[N:11]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[S:8][CH:9]=3)=[O:14])=[CH:23][CH:22]=2)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: O=C(O)c1csc(-c2ccccc2)n1
Reactant: Nc1ccc(N2CCOCC2)nc1
Product: O=C(Nc1ccc(N2CCOCC2)nc1)c1csc(-c2ccccc2)n1

Procedure:
With a procedure similar to example 1 above, 2-phenyl-thiazole-4-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide was prepared from 2-phenyl-thiazole-4-carboxylic acid and 6-morpholin-4-yl-pyridin-3-ylamine. LCMS calcd for C19H18N4O2S (m/e) 366, obsd 367 (M+H).
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6]/[C:7](=[CH:9]/[CH2:10][OH:11])/[CH3:8])[CH3:3].N1C=CC=CC=1.[Cl:18][CH2:19][C:20](Cl)=[O:21].O>ClCCl>[Cl:18][CH2:19][C:20]([O:11][CH2:10]/[CH:9]=[C:7](\[CH3:8])/[CH2:6][CH2:5][CH:4]=[C:2]([CH3:1])[CH3:3])=[O:21]
Reactant: O=C(Cl)CCl
Reactant: CC(C)=CCC/C(C)=C/CO
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: CC(C)=CCC/C(C)=C/COC(=O)CCl
Temperature: 0 °C
Reaction time: 24 h

Procedure:
Geraniol [1] (7.711 g, 50 mmol) and pyridine (3.955 g, 50 mmol) were suspended in anhydrous dichloromethane (200 ml) and chilled to 0° C. under an atmosphere of dry nitrogen. Chloroacetylchloride (5.647 g, 50 mmol) was added dropwise (violent reaction) and the resulting solution was stirred for 24 hrs at room temperature. Water (100 ml) was added, the organic layer was separated and the aqueous layer extracted with dichloromethane. The combined organic layers were successively washed with 2N HCl, saturated NaHCO3 solution and brine, dried over MgSO4 and the solvent was evaporated. Remaining volatile material was removed under reduced pressure (0.01 mbar) to yield product [2] as yellow liquid. The product was pure according to 1H NMR and directly subjected to the next step without further purification.
Reaction SMILES: [C:1]1([C:11](Cl)=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:14]([NH:21][C:22]([C:24]1[S:28][C:27]([NH2:29])=[N:26][C:25]=1[CH3:30])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([NH:21][C:22]([C:24]1[S:28][C:27]([NH:29][C:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)=[O:12])=[N:26][C:25]=1[CH3:30])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1cccc2ccccc12
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Product: Cc1nc(NC(=O)c2cccc3ccccc23)sc1C(=O)NCc1ccccc1
Yield: 12 %

Procedure:
Following the procedure as described in Example 2, making variations only as required to use naphthalene-1-carbonyl chloride in place of benzoyl chloride to react with 2-amino-4-methylthiazole-5-carboxylic acid benzylamide, the title compound was obtained as a white solid in 12% yield; m.p. 99-101° C.; 1H NMR (CDCl3, 300 MHz) δ 8.40 (d, J=7.5 Hz, 1H), 7.99 (d, J=8.3 Hz, 1H), 7.87 (d, J=7.5 Hz, 1H), 7.85 (d, J=7.5 Hz, 1H), 7.79-7.76 (m, 8H), 5.93 (t, J=5.6 Hz, 1H), 4.57 (d, J=5.6 Hz, 2H), 2.09 (s, 3H); MS (ES+) m/z 402.2 (M+1).