Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:6])[CH3:5])[CH3:2].Br[C:8]1[CH:9]=[C:10]([S:15][C:16]2[CH:26]=[CH:25][C:19]([O:20]CC(O)=O)=[C:18]([CH3:27])[CH:17]=2)[CH:11]=[C:12]([OH:14])[CH:13]=1.[CH2:28]([N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)[C:29]#[CH:30]>C(N(CC)CC)C.CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu](I)I>[CH2:1]([O:3][C:4](=[O:6])[CH2:5][O:20][C:19]1[CH:25]=[CH:26][C:16]([S:15][C:10]2[CH:9]=[C:8]([C:30]#[C:29][CH2:28][N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[CH:13]=[C:12]([OH:14])[CH:11]=2)=[CH:17][C:18]=1[CH3:27])[CH3:2]
Reactant: Cc1cc(Sc2cc(O)cc(Br)c2)ccc1OCC(=O)O
Reactant: CCOC(C)=O
Reactant: C#CCN1CCOCC1
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)COc1ccc(Sc2cc(O)cc(C#CCN3CCOCC3)c2)cc1C

Procedure:
[4-(3-Bromo-5-hydroxy-phenylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl acetate (3 g; 7.55 mmol), 4-prop-2-ynyl-morpholine (2.8 g; 22.65 mmol), bis(triphenylphosphine)-palladium (II) chloride (0.42 g; 0.60 mmol) and copper iodide (0.09 g; 0.45 mmol) were dissolved in a mixture of triethylamine (7 mL) and DMF (8 mL) under an atmosphere of nitrogen. The reaction mixture was reacted in a microwave oven at 100° C. for 1.5 h. The reaction mixture was purified by preparative HPLC (method A). Yield: 1.4 g. HPLC-MS: m/z: 442.4 (M+); Rt: 1.54 min.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH2:23])=[CH:20][CH:19]=1>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:23][CH2:22][C:21]2[CH:24]=[CH:25][C:18]([Cl:17])=[CH:19][CH:20]=2)[N:3]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Solvent: CCN(CC)CC
Product: Clc1ccc(CNc2nc(Cl)nc3c2ncn3C2CCCC2)cc1

Procedure:
2-Chloro-6-[(4-chlorobenzyl)amino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 4-chlorobenzylamine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:13]2[CH:12]=[C:11]([C:14]([NH:16][NH:17][C:18](=[O:20])[CH3:19])=O)[S:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.N(C(OCC)=O)=NC(OCC)=O>ClCCCl>[CH3:1][O:2][CH2:3][O:4][C:5]1[C:13]2[CH:12]=[C:11]([C:14]3[O:20][C:18]([CH3:19])=[N:17][N:16]=3)[S:10][C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: COCOc1cccc2sc(C(=O)NNC(C)=O)cc12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: COCOc1cccc2sc(-c3nnc(C)o3)cc12
Temperature: 0 °C
Yield: 62.1 %

Procedure:
N′-(4-(Methoxymethyloxy)benzo(b)thiophen-2-ylcarbonyl)acetohydrazide (2.4 g) was dissolved in 1,2-dichloroethane (50 ml) and triphenylphosphine (3.2 g) and triethylamine (2 ml) were added. The mixture was stirred under ice-cooling. Diethyl azodicarboxylate (40% toluene solution) (5.2 g) was added and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into ice water and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title product (1.4 g) as pale-yellow crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[CH:17]=[C:16](Br)[CH:15]=2)=[CH:9][C:8]=1[CH3:32])[CH3:2].[CH2:34]([N:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1)[C:35]#[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:33])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[CH:17]=[C:16]([C:36]#[C:35][CH2:34][N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)[CH:15]=2)=[CH:9][C:8]=1[CH3:32])[CH3:2]
Reactant: CCOC(=O)COc1ccc(Sc2cc(Br)cc(Oc3cccc(C(F)(F)F)c3)c2)cc1C
Reactant: C#CCN1CCOCC1
Agent: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccc(CO)cc3)cc(OCCc3ccc(Cl)cc3)c2)cc1C
Product: CCOC(=O)COc1ccc(Sc2cc(C#CCN3CCOCC3)cc(Oc3cccc(C(F)(F)F)c3)c2)cc1C

Procedure:
The title product was prepared from {4-[3-Bromo-5-(3-trifluoromethyl-phenoxy)phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (230 mg; 0.43 mmol) and 4-prop-2-ynyl-morpholine (159.5 mg; 1.28 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 A). Yield: 160 mg. HPLC-MS: m/z: 586.5 (M+H)+; Rt: 2.18 min
Reaction SMILES: Br[CH2:2][CH:3]=[O:4].[CH3:5][CH:6]([NH2:12])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[OH-].[Na+]>O>[CH3:5][CH:6]([NH:12][CH2:2][CH:3]=[O:4])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCC(C)N
Reactant: O=CCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCC(C)NCC=O
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
The diethylacetal of 2-bromoacetaldehyde (40 grams) and 1-methylhexylamine (50 grams) were charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture was heated at a temperature of about 100° C. for a period of about 3 hours. After this time sodium hydroxide (10 grams) dissolved in water (100 ml) was added and the resulting mixture stirred for about 30 minutes. The reaction mixture was then extracted with ether. The ether extract was separated, dried over magnesium sulfate, filtered and stripped of solvent under reduced pressure to yield the desired product the diethylacetal of 2-(1-methylhexylamino)acetaldehyde having a boiling point of 110° C. at 1 mm of Hg pressure.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Br:20]Br.CCN(C(C)C)C(C)C.O[CH2:32][C:33]1[CH:34]=[C:35]([CH:63]=[CH:64][CH:65]=1)[O:36][C:37]([O:39][CH2:40]/[C:41](/[C:53]1[CH:58]=[CH:57][C:56]([S:59]([CH3:62])(=[O:61])=[O:60])=[CH:55][CH:54]=1)=[C:42](/[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)\[C:43]([O:45][CH3:46])=[O:44])=[O:38]>C(Cl)Cl>[Br:20][CH2:32][C:33]1[CH:34]=[C:35]([CH:63]=[CH:64][CH:65]=1)[O:36][C:37]([O:39][CH2:40]/[C:41](/[C:53]1[CH:58]=[CH:57][C:56]([S:59]([CH3:62])(=[O:61])=[O:60])=[CH:55][CH:54]=1)=[C:42](/[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)\[C:43]([O:45][CH3:46])=[O:44])=[O:38]
Reactant: BrBr
Reactant: COC(=O)/C(=C(\COC(=O)Oc1cccc(CO)c1)c1ccc(S(C)(=O)=O)cc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)/C(=C(\COC(=O)Oc1cccc(CBr)c1)c1ccc(S(C)(=O)=O)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 470 mg of Ph3P in 15 mL of CH2Cl2 cooled at 0° C. was added 1.75 mL of a 1.0M Br2 solution in CH2Cl2. After 10 min, 340 μL of Hunig's base was added followed by 798 mg of methyl (2Z)-4-({[3-(hydroxymethyl)phenoxy]carbonyl}oxy)-3-[4-(methylsulfonyl)phenyl]-2-phenylbut-2-enoate dissolved in 20 mL of CH2Cl2. After 15 min at 0° C., the reaction mixture was warmed to rt for 1 h. The reaction was quenched with H2O, extracted twice with EtOAc and washed with brine, dried over sodium sulfate, evaporated, and purified by flash chromatography (10–50% EtOAc/hexane) to afford 786 mg of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][C:10]23[CH2:17][CH2:16][C:13]([C:18]4[O:19][C:20]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[C:29]([F:32])([F:31])[F:30])=[N:21][N:22]=4)([CH2:14][CH2:15]2)[CH2:12][CH2:11]3)OCC[O:3]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[F:32][C:29]([F:30])([F:31])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:20]1[O:19][C:18]([C:13]23[CH2:14][CH2:15][C:10]([CH2:9][CH2:8][CH2:7][C:2](=[O:3])[CH3:1])([CH2:11][CH2:12]2)[CH2:17][CH2:16]3)=[N:22][N:21]=1
Reactant: CC1(CCCC23CCC(c4nnc(-c5ccccc5C(F)(F)F)o4)(CC2)CC3)OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: CC(=O)CCCC12CCC(c3nnc(-c4ccccc4C(F)(F)F)o3)(CC1)CC2

Procedure:
2-{4-[3-(2-Methyl-1,3-dioxolan-2-yl)propyl]bicyclo[2.2.2]oct-1-yl }-5-[2-(trifluoromethyl)phenyl]-1,3,4-oxadiazole (4-G) (0.158 g) was stirred in a mixure of 90% acetone/10% water (20 mL). p-Toluenesulfonic acid (10 mg) was added to the solution. The reaction was heated to reflux for 1 h. The volume was reduced by evaporation of acetone in vacuo. The mixture was then layered with ethyl acetate (25 mL) and saturated sodium bicarbonate solution (25 mL). The ethyl acetate layer was extracted and dried (MgSO4). Solvent was removed in vacuo to afford pure 5-(4-{5-[2-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}bicyclo[2.2.2]oct-1-yl)pentan-2-one (4-H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][OH:8])=[CH:3][CH:2]=1.F[C:10]1[CH:15]=[CH:14][C:13]([S:16]([N:19]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[N:21]=2)(=[O:18])=[O:17])=[CH:12][CH:11]=1.[H-].[Na+]>CN(C)C=O>[CH2:28]([N:19]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[N:21]=1)[S:16]([C:13]1[CH:14]=[CH:15][C:10]([O:8][CH2:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[CH:11][CH:12]=1)(=[O:18])=[O:17])[CH:29]([CH3:31])[CH3:30]
Reactant: COc1cccc(N(CC(C)C)S(=O)(=O)c2ccc(F)cc2)n1
Reactant: OCc1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(N(CC(C)C)S(=O)(=O)c2ccc(OCc3ccncc3)cc2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 26.8 %

Procedure:
Pyridin-4-ylmethanol (20.22 mg, 0.185 mmol) and 4-fluoro-N-isobutyl-N-(6-methoxypyridin-2-yl)benzenesulfonamide (62.7 mg, 0.185 mmol) were dissolved in N,N-dimethylformamide (DMF) (3 mL) and sodium hydride (7.41 mg, 0.185 mmol, 60% wt in mineral oil) added. Reaction left to stir at room temperature, under nitrogen, for 3 hours. The reaction was then quenched by adding water (2 mL). The mixture was concentrated in vacuo and the product extracted to the organic phase of an aqueous work up between ethyl acetate and water. The organic phase was dried by passing it through a hydrophobic frit, concentrated and then purified by mass directed autoprep (formic acid modifier), to give the title compound (21.2 mg). LCMS (2 min, formic) Rt 1.05 min, m/z (ES+) 428 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][CH2:11][CH2:10][CH2:9]2)=[O:7])=[C:4]([Cl:21])[CH:3]=1.Cl[C:23](Cl)([O:25][C:26](=[O:32])OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[N:41]1[CH:46]=[CH:45][C:44](CO)=[CH:43][CH:42]=1>ClC1C=CC=CC=1Cl.C(OCC)(=O)C>[N:41]1[CH:46]=[CH:45][C:44]([CH2:23][O:25][C:26]([NH:1][C:2]2[CH:20]=[CH:19][C:5]([C:6]([N:8]3[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=4[CH2:12][CH2:11][CH2:10][CH2:9]3)=[O:7])=[C:4]([Cl:21])[CH:3]=2)=[O:32])=[CH:43][CH:42]=1
Reactant: OCc1ccncc1
Reactant: Nc1ccc(C(=O)N2CCCCc3ccccc32)c(Cl)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: Clc1ccccc1Cl
Product: O=C(Nc1ccc(C(=O)N2CCCCc3ccccc32)c(Cl)c1)OCc1ccncc1
Temperature: 120 °C
Reaction time: 3 h
Yield: 117.8 %

Procedure:
To a solution of 1-(4-amino-2-chlorobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine (0.8 g) in o-dichlorobenzene (5 ml) is added triphosgen (0.26 g), and the mixture is stirred at 120° C. for three hours. To the mixture is added triethylamine (0.27 g), and the mixture is stirred at 120° C. for two hours. To the mixture is added (4-pyridyl)methanol (0.29 g), and the mixture is stirred at 120° C. for two hours. To the reaction solution is added ethyl acetate, and the mixture is washed with water, and the organic layer is dried over magnesium sulfate, filtered, and evaporated to remove the solvent. The resulting residue is purified by silica gel column chromatography (solvent; ethyl acetate:n-hexane=1:5→dichloromethane:methanol=25:1), and the residue is washed with methanol/diethyl ether to give 1-{4-[(4-pyridyl)methoxycarbonylamino]-2-chlorobenzoyl}-2,3,4,5-tetrahydro-1H-benzazepine (0.45 g) as white powder.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:15]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)#[N:16]>C1C(O)=CC=CC=1C>[C:4]1([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[NH:2][C:15]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[NH:16]
Reactant: Nc1ccccc1-c1ccccc1
Reactant: N#CN1CCOCC1
Agent: Cl
Solvent: Cc1cccc(O)c1
Product: N=C(Nc1ccccc1-c1ccccc1)N1CCOCC1

Procedure:
A mixture of 2-aminobiphenyl hydrochloride (6.17 g) and 4-cyanomorpholine (5.05 g) in m-cresol (25 ml) was heated at 90°-95° C. for 15 hours to yield N-(2-biphenylyl)-4-morpholine carboxamidine (m.p. 153°-154° C.) which was recrystallised from ethylacetate. N-(2-Biphenylyl)morpholine-4-carboxamidine (3.5 g) was dissolved in methanol (15 ml) and treated with fumaric acid (1.45 g) to give N-(2-biphenylyl)morpholine-4-carboxamidine fumarate (m.p. 222°-223° C.) which was recrystallised from a 1:1 mixture of methanol and ether.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[C:9]3[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=3[CH:15]=[CH:16][C:6]=2[N:5]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][S:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[N+:33]([O-:35])=[O:34])(=[O:26])=[O:25])=[CH:19][CH:18]=2)[C:4](=[O:36])[CH2:3]1.CI.[C:39](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:1]=[C:2]1[NH:8][C:7]2[C:9]3[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=3[CH:15]=[CH:16][C:6]=2[N:5]([C:17]2[CH:18]=[CH:19][C:20]([N:23]([CH3:39])[S:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[N+:33]([O-:35])=[O:34])(=[O:26])=[O:25])=[CH:21][CH:22]=2)[C:4](=[O:36])[CH2:3]1
Reactant: O=C([O-])[O-]
Reactant: O=C1CC(=O)N(c2ccc(NS(=O)(=O)c3ccccc3[N+](=O)[O-])cc2)c2ccc3c(c2N1)CCCC3
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN(c1ccc(N2C(=O)CC(=O)Nc3c2ccc2c3CCCC2)cc1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.7 %

Procedure:
N-[4-(2,4-Dioxo-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diazepine-5-yl)phenyl]-2-nitrobenzenesulfonamide (150 mg, 0.3 mmol), methyl iodide (22 μL, 0.36 mmol), potassium carbonate (45 mg, 0.33 mmol), and dry dimethylformamide (3 mL) were mixed. The mixture was stirred at room temperature for 16 hours. The solvent was removed by evaporation under reduced pressure. To the residue was added water. The mixture was stirred at room temperature. Insoluble was obtained by filtration, washed with water, and air-dried overnight to give the titled compound as off-white crystal (112 mg, yield 73%).
Reaction SMILES: [O:1]=[O+][O-].[C:4]([O:8][C:9](=[O:28])[CH2:10][N:11]([S:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH2:12][CH:13]=C(C)C)([CH3:7])([CH3:6])[CH3:5].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl.CO>[C:4]([O:8][C:9](=[O:28])[CH2:10][N:11]([S:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)(=[O:18])=[O:19])[CH2:12][CH:13]=[O:1])([CH3:5])([CH3:6])[CH3:7]
Reactant: COc1ccc(S(=O)(=O)N(CC=C(C)C)CC(=O)OC(C)(C)C)cc1
Reactant: O=[O+][O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(S(=O)(=O)N(CC=O)CC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Ozone is passed through a solution of [(4-methoxybenzenesulfonyl)-(3-methyl-but-2-enyl)-amino]-acetic acid t-butyl ester (2.0 grams, 5.4 mmol) in methylene chloride-methanol (50 mL, ca. 1:1) at -78° C. until a blue color persisted. Triphenylphosphine (4.24 grams, 16.2 mmol) is added and the resulting solution is stirred at room temperature for 3 hours. Concentration provided the crude product which is purified by silica gel chromatography (elution with 1:1 ethyl acetate-hexanes) to provide [(4-methoxybenzenesulfonyl)-(2-oxo-ethyl)-amino]-acetic acid t-butyl ester.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][N:5]=[C:6]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=1)[C:7]([O:9]C)=[O:8]>CO>[CH3:3][O:4][N:5]=[C:6]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=1)[C:7]([OH:9])=[O:8]
Reactant: CON=C(C(=O)OC)c1ccc(O)c([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CON=C(C(=O)O)c1ccc(O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 60 h
Yield: 96.8 %

Procedure:
A 2 N aqueous solution of sodium hydroxide (14 ml.) was added with stirring at ambient temperature to a solution of methyl 2-methoxyimino-2-(3-nitro-4-hydroxyphenyl)acetate (syn isomer) (3.5 g.) in methanol (70 ml.) and the mixture was stirred for 60 hours at ambient temperature. The reaction mixture was concentrated to dryness at 40° C. under reduced pressure and the residue was dissolved in water. The solution was washed with ethyl acetate, adjusted to pH 1 with 10% hydrochloric acid under ice-cooling and extracted with ethyl acetate. The extract was back-extracted with a saturated sodium bicarbonate aqueous solution. The aqueous extract was adjusted to pH 1 with conc. hydrochloric acid under ice-cooling and extracted with ethyl acetate. The extract was washed with ice-water and dried over magnesium sulfate. The solvent was concentrated to dryness at 40° C. under reduced pressure to give yellow crystals of 2-met hoxyimino-2-(3-nitro-4-hydroxyphenyl)acetic acid (syn isomer) (3.2 g.), mp 142° to 143° C. (dec.).
Reaction SMILES: [OH:1][C:2]1[CH2:7][CH:6]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([CH3:15])=[C:10]([CH2:16][C:17]#[N:18])[C:9]=2[CH3:19])[CH2:5][C:4](=[O:20])[C:3]=1[C:21](=[O:24])[CH2:22][CH3:23].C(N)(=[S:27])C.Cl>>[OH:1][C:2]1[CH2:7][CH:6]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([CH3:15])=[C:10]([CH2:16][C:17](=[S:27])[NH2:18])[C:9]=2[CH3:19])[CH2:5][C:4](=[O:20])[C:3]=1[C:21](=[O:24])[CH2:22][CH3:23]
Reactant: CCC(=O)C1=C(O)CC(c2c(C)cc(C)c(CC#N)c2C)CC1=O
Reactant: CC(N)=S
Agent: Cl
Product: CCC(=O)C1=C(O)CC(c2c(C)cc(C)c(CC(N)=S)c2C)CC1=O

Procedure:
A solution of 3-hydroxy-2-propionyl-5-(3-cyanomethyl-2,4,6-trimethylphenyl)cyclohex-2-en-1-one (0.77 g, 2.37 mmol) and thioacetamide (0.36 g, 4.74 mmol) in dmf (10 ml) was saturated with anhydrous hydrogen chloride. The solutuion was then heated under a distillation head at 110° for 45 m. Most of the dmf was then distilled off under reduced pressure. The dark red residue was cooled, saturated sodium bicarbonate solution was added, and the aqueous layer extracted with ethylacetate. The organic layer was washed extensively with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield an orange solid. The crude material was purified by chromatography on silica gel (elution with an increasing gradient of ethylacetate in methylene chloride) to give 3-hydroxy-2-propionyl-5-(3-thiocarbamoylmethyl-2,4,6-trimethylphenyl)cyclohex-2-en-1-one as a colourless solid (0.40, 47%). Proton magnetic resonance spectrum (CDCl3 ; δ in ppm); 1.15 (3H, t); 2.22 (3H,s); 2.28 (3H,s); 2.36 (3H,s); 2.4-4.2 (9H,m); 6.70 (1H,brs); 6.90 (1H,s); 8.25 (1H,brs); 18.20 (1H,s).
Reaction SMILES: [Cl-].[CH:2]1([CH2:7][NH2+:8][CH2:9][CH2:10]Cl)[CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:12][C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=1[N:22]=[C:23]=[S:24]>>[CH3:12][C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=1[N:22]=[C:23]1[N:8]([CH2:7][CH:2]2[CH2:6][CH2:5][CH2:4][CH2:3]2)[CH2:9][CH2:10][S:24]1
Reactant: ClCC[NH2+]CC1CCCC1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Agent: [Cl-]
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SCCN1CC1CCCC1

Procedure:
2-Hydroxyethylamine was reacted with cyclopentylmethyl bromide according to Method B2a to give N-cyclopentylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-cyclopentylmethyl-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2-methyl-4-nitrophenyl isothiocyanate to give 2-(2-methyl-4-nitrophenylimino)-3-(cyclopentylmethyl)-1,3-thiazolidine.
Reaction SMILES: [CH2:1]([N:8]([CH2:13]OC)[Si](C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][O:17][C:18](=[O:28])/[CH:19]=[CH:20]/[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Br:27])[CH:22]=1.F[C:30](F)(F)C(O)=O>C(Cl)Cl.O>[CH3:16][O:17][C:18]([C@H:19]1[C@H:20]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Br:27])[CH:22]=2)[CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:30]1)=[O:28]
Reactant: O=C(O)C(F)(F)F
Reactant: COCN(Cc1ccccc1)[Si](C)(C)C
Reactant: COC(=O)/C=C/c1cccc(Br)c1
Solvent: O
Solvent: ClCCl
Product: COC(=O)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1cccc(Br)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 1457.4 %

Procedure:
Add benzyl-methoxymethyl-trimethylsilanyl-amine (14.7 g, 2.20 mmol) to a solution of trans-3-(3-bromo-phenyl)-acrylic acid methyl ester (10.0 g, 41.4 mmol) in methylene chloride (80 mL). Cool the mixture to 0° C. and stir for 10 min then add trifluoroacetic acid (0.92 mL, 12.4 mmol) and stir the mixture at 0° C. for an additional 4 h. Dilute the reaction mixture with water and extract with methylene chloride. Dry the combined organic phase over anhydrous sodium sulfate and concentrate under reduced pressure. Purify the residue by silica gel chromatography to provide 12 g (77%) of trans-1-benzyl-4-(3-bromo-phenyl)-pyrrolidine-3-carboxylic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5](O)=[O:6].[NH2:27][C:28]1[O:29][CH2:30][CH2:31][N:32]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH:27][C:28]2[O:29][CH2:30][CH2:31][N:32]=2)=[O:6])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: NC1=NCCO1
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Product: O=C(NC1=NCCO1)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 2-amino-4,5-dihydrooxazole via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-(4,5-dihydrooxazol-2-yl)terephthalamide.
Reaction SMILES: [CH:1]1([C:6]2[C:7]([O:22]S(C3C=CC(C)=CC=3)(=O)=O)=[N:8][N:9]3[C:14]=2[C:13]([CH3:15])=[N:12][N:11]=[C:10]3[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:33]([N:35]1[C:39]([CH2:40]O)=[N:38][CH:37]=[N:36]1)[CH3:34].[H-].[Na+].O>CN(C=O)C>[CH:1]1([C:6]2[C:7]([O:22][CH2:40][C:39]3[N:35]([CH2:33][CH3:34])[N:36]=[CH:37][N:38]=3)=[N:8][N:9]3[C:14]=2[C:13]([CH3:15])=[N:12][N:11]=[C:10]3[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1ccc(S(=O)(=O)Oc2nn3c(-c4ccccc4)nnc(C)c3c2C2CCCC2)cc1
Reactant: CCn1ncnc1CO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1ncnc1COc1nn2c(-c3ccccc3)nnc(C)c2c1C1CCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To toluene-4-sulfonic acid 3-cyclopentyl-4-methyl-7-phenylpyrazolo[1,5-d][1,2,4]triazin-2-yl ester (300 mg, 0.67 mmol) and (2-ethyl-2H-[1,2,4]triazol-3-yl)methanol (102 mg, 1.2 molar eq; prepared as described in EP-A-170073) in DMF (10 ml) was added sodium hydride (29.5 mg of a 60% dispersion in mineral oil; 1.2 molar eq) and the mixture was stirred at room temperature for 1 h. Water (90 ml) was added then the solution was extracted with diethyl ether (4×60 ml). The combined ether layers were washed with brine (1×100 ml), dried (Na2SO4), the solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel eluting with 0 to 50% ethyl acetate in dichloromethane. 3-Cyclopentyl-2-(2-ethyl-2H-[1,2,4]triazol-3-ylmethoxy)-4-methyl-7-phenylpyrazolo[1,5-d][1,2,4]triazine was isolated as a gum, which solidified upon trituration under diethyl ether/isohexane (144 mg, mp=112° C.). 1H NMR (360 MHz, CDCl3) δ 1.42 (3H, t, J=7.3 Hz), 1.66-1.95 (8H, m), 2.87 (3H, s), 3.43 (1H, m), 4.20 (2H, q, J=7.3 Hz), 5.55 (2H, s), 7.51-7.61 (3H, m), 7.93 (1H, s), 8.28-8.31 (2H, m); MS (ES+) m/e 403 [MH]+. Anal. Found C, 65.10; H, 6.06; N, 24.19%. C22H25N7O requires C, 65.49; H, 6.25; N, 24.06%.