Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]([OH:12])=[O:11])=[N:8][CH:9]=1)([O-:3])=[O:2].OS(O)(=O)=O.[CH3:18][CH2:19]O>CCOC(C)=O.C([O-])(O)=O.[Na+]>[CH2:18]([O:11][C:10]([C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=1)=[O:12])[CH3:19]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cn1
Reactant: CCO
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc([N+](=O)[O-])cn1
Reaction time: 1.5 h

Procedure:
A mixture of 5-nitro-pyridine-2-carboxylic acid (Step 39.5) (5.74 g, 34.2 mmol), H2SO4 (1 mL) and EtOH (50 mL) was stirred for 1.5 h at reflux. The residue was diluted with EtOAc and saturated solution of NaHCO3. The aqueous layer was separated and extracted with EtOAc. The organic phase was washed with H2O and brine, dried (Na2SO4), filtered and concentrated to afford 6.1 g of the title compound as a white solid: ES-MS: 197.1 [M+H]+; tR=3.22 min (System 1).
Reaction SMILES: ClCC=CC=C.[CH2:7]([C:10]([CH2:12][CH2:13][CH3:14])=[O:11])[CH2:8][CH3:9].[OH-].[K+].[C:17]1([CH3:23])[CH:22]=[CH:21]C=[CH:19][CH:18]=1>>[CH2:8]([CH:7]([CH2:21][CH:22]=[C:17]([CH3:23])[CH:18]=[CH2:19])[C:10](=[O:11])[CH2:12][CH2:13][CH3:14])[CH3:9]
Reactant: CCCC(=O)CCC
Reactant: Cc1ccccc1
Agent: C=CC=CCCl
Agent: [K+]
Agent: [OH-]
Product: C=CC(C)=CCC(CC)C(=O)CCC

Procedure:
According to the procedure described in Example 1, from 116.6 g of 1-chloro-2,4-pentadiene and 114.2 g of dipropyl ketone (heptan-4-one) in the presence of 200 g of powdered potassium hydroxide in 600 ml of toluene there are obtained 91.9 g of crude 5-ethyl-8-methyl-7,9-decadien-4-one which are subjected to a fractional distillation.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[CH3:13][N:14]([CH3:19])[CH2:15][C:16](O)=[O:17].[NH:20]1[CH2:25][CH2:24][CH:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22][CH2:21]1.C(N(CC)CC)C>ClCCl.O.OC1C2N=NNC=2C=CC=1>[CH3:13][N:14]([CH2:15][C:16]([N:20]1[CH2:25][CH2:24][CH:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22][CH2:21]1)=[O:17])[CH3:19]
Reactant: CCOC(=O)C1CCNCC1
Reactant: CN(C)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCN(C(=O)CN(C)C)CC1
Reaction time: 18 h

Procedure:
4.6 g of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride are added, at 20° C., under an argon atmosphere, to a solution of 2.3 g of N,N-dimethylglycine, 3.2 cm3 of ethyl 4-piperidinecarboxylate, 3.4 cm3 of triethylamine and 0.27 g of hydroxybenzotriazol hydrate in 100 cm3 of dichloromethane. After stirring for 18 hours, the reaction mixture is washed with twice 100 cm3 of distilled water. The organic phase is dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa). 4.6 g of ethyl 1-(dimethylaminoacetyl)piperidine-4-carboxylate are obtained in the form of a yellow oil.
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:14][C:15]1[N:20]=[C:19]([N:21]2[CH2:30][CH2:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22]2)[C:18]([CH3:31])=[C:17]([CH3:32])[N:16]=1>CN(C)C=O>[ClH:14].[CH3:31][C:18]1[C:19]([N:21]2[CH2:30][CH2:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22]2)=[N:20][C:15]([NH:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:16][C:17]=1[CH3:32]
Reactant: NC1CCCC1
Reactant: Cc1nc(Cl)nc(N2CCc3ccccc3C2)c1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(NC2CCCC2)nc(N2CCc3ccccc3C2)c1C
Product: Cl
Yield: 41.8 %

Procedure:
After cyclopentylamine(0.27 ml, 2.7 mmol) and triethylamine(0.38 ml, 2.7 mmol) were added to a solution of 2-chloro-5,6-dimethyl-4-(1,2,3,4-tetrahydroisoquinolin-2-yl) pyrimidine(0.5 g, 1.8 mmol) in dimethylformamide, 270 mg of the titled compound was obtained in accordance with the same procedure as in Example 1.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][S:5][CH:6]=1.[N:11]([O-])=O.[Na+].[CH3:15][NH:16][CH3:17]>>[CH3:15][N:16]([N:11]=[N:1][C:2]1[C:3]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][S:5][CH:6]=1)[CH3:17]
Reactant: O=N[O-]
Reactant: COC(=O)c1cscc1N
Reactant: CNC
Agent: [Na+]
Product: COC(=O)c1cscc1N=NN(C)C

Procedure:
Diazotization of methyl 4-aminothiophene-3-carboxylate with sodium nitrite followed by treatment with dimethylamine provides methyl 4-[(dimethylamino)diazenyl]thiophene-3-carboxylate. Treatment of the ester with ammonia gave the required 4-[dimethylamino)diazenyl]thiophene-3-carboxamide (compd. No. 13). The methyl 4-aminothiophene-3-carboxylate is produced using known procedures in the prior art (33, 34, 35). Thus addition of methyl acrylate to methyl thioglycolate provided methyl 3-[(methoxycarbonyl)methylthio]propanoate in quantitative yield, which on cyclization in presence of sodium methoxide gave methyl 4-oxo-2,3,5-trihydrothiophene-3-carboxylate. Treatment of methyl 4-oxo-2,3,5-trihydrothiophene-3-carboxylate with hydroxylamine followed by basification with ammonia gave methyl 4-aminothiophene-3-carboxylate.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][CH3:10])[C:3]1=O.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.P(Cl)(Cl)(Cl)=O.[C:30]([OH:37])(=[O:36])/[CH:31]=[CH:32]/[C:33]([OH:35])=[O:34]>C1C=CC=CC=1.CO>[C:30]([OH:37])(=[O:36])/[CH:31]=[CH:32]/[C:33]([OH:35])=[O:34].[CH3:1][N:2]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][CH3:10])[C:3]1=[N:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1
Reactant: Nc1ccccc1N1CCOCC1
Reactant: COCCN1CCN(C)C1=O
Agent: O=C(O)/C=C/C(=O)O
Solvent: CO
Solvent: c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: COCCN1CCN(C)C1=Nc1ccccc1N1CCOCC1

Procedure:
Reaction of 1-methyl-3-(2-methoxyethyl)-2-imidazolidinone (11.4 g) in benzene (60 ml) with 4-(2-aminophenyl)morpholine (8.9 g) in benzene (80 ml) in the presence of phosphorus oxychloride (7.2 ml) for 30 hours at 80°-85° C. gave an oil a portion of which (1.8 g) was dissolved in methanol (10 ml) and treated with fumaric acid (0.9 g) to give 4-((2-[1-methyl-3-(2-methoxyethyl)-2-imidazolidinylideneamino]phenyl))morpholine monofumarate (m.p. 127√-129° C.) which was recrystallised from propan-2-ol.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][N:5]([C:7]2[CH:8]=[N:9][C:10]([Cl:14])=[C:11]([Cl:13])[CH:12]=2)[CH2:4][C@@H:3]1[CH2:15]O.S(Cl)(Cl)=O.O>COCCOC>[Cl:13][C:11]1[CH:12]=[C:7]([N:5]2[CH2:6][C@@H:2]3[C@@H:3]([CH2:15][NH:1]3)[CH2:4]2)[CH:8]=[N:9][C:10]=1[Cl:14]
Reactant: N[C@@H]1CN(c2cnc(Cl)c(Cl)c2)C[C@@H]1CO
Solvent: O=S(Cl)Cl
Solvent: COCCOC
Solvent: O
Product: Clc1cc(N2C[C@@H]3CN[C@@H]3C2)cnc1Cl
Temperature: 50 °C
Reaction time: 3 h

Procedure:
(3S,4S)-[4-Amino-1-(5,6-dichloro-pyridin-3-yl)-pyrrolidin-3-yl]-methanol (10 g) was suspended in 1,2-dimethoxyethane (100 mL) and N-methylpyyrolidinone (15 mL). The mixture was heated to 50° C. and then a solution of thionyl chloride (7.9 g) in 1,2-dimethoxyethane (35 mL) was slowly added, while maintaining the temperature below 60° C. The reaction mixture was stirred at 50° C. for about 3 hours and then cooled to room temperature. After adding water (100 mL), the 1,1-dimethoxyethane was removed by distillation. Ethanol (100 mL) and water (100 mL) were added and the pH adjusted to 11-12 with 50% aqueous sodium hydroxide. The resulting mixture was heated at 60° C. for at least 12 hours and then cooled to room temperature. After filtering through a bed of Hy-Flo, the ethanol was removed by vacuum distillation. The pH was adjusted to >12 with 50% aqueous sodium hydroxide and then extracted with isopropyl acetate (2×80 mL). The combined organic extracts were concentrated, and then suspended in isopropyl acetate (˜50 mL). After heating to 80° C., the solution was cooled to room temperature while stirring rapidly. The suspension was cooled to 0° C., filtered, washed with isopropyl acetate and dried in the vacuum oven. 1H NMR (MeOH-d4, 300 MHz) δ 3.04 (dd, J=10.9, 4.8 Hz, 1H), 3.11 (dd, J=10.2, 6.8 Hz, 1H), 3.26 (dd, J=8.8, 4.4 Hz, 1H), 3.38 (m, 1H), 3.73 (t, J=11.2 Hz, 2H), 3.84 (t, J=8.1 Hz, 1H), 4.55 (dd, J=6.8, 4.8 Hz, 1H), 7.37 (d, J=3.1 Hz, 1H), 7.84 (d, J=2.7 Hz, 1H); MS (DCI/NH3) m/z 244/246/248 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:12]([CH3:21])=[N:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=2)=[O:10])=[CH:4][C:3]=1I.[Br-].C[C:25]1[N:30]=[C:29]([Zn+])[CH:28]=[CH:27][CH:26]=1.[CH2:32]1COCC1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:12]([CH3:21])=[N:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=2)=[O:10])=[CH:4][C:3]=1[C:25]1[C:26]([CH3:32])=[CH:27][CH:28]=[CH:29][N:30]=1
Reactant: Cc1nc(C(F)(F)F)ccc1C(=O)Nc1ccc(Cl)c(I)c1
Reactant: C1CCOC1
Reactant: Cc1cccc([Zn+])n1
Agent: [Br-]
Product: Cc1cccnc1-c1cc(NC(=O)c2ccc(C(F)(F)F)nc2C)ccc1Cl

Procedure:
N-(4-Chloro-3-iodophenyl)-6-(trifluoromethyl)-2-methylpyridine-3-carboxamide (142 mg, 0.32 mmol) was used in Procedure B with 6-methyl-2-pyridylzinc bromide (1.75 mL, of a 0.5 M in THF). Purified by silica gel chromatography (5-100% Ethyl acetate/Hexanes) to yield N-(4-chloro-3-(3-methylpyridin-2-yl)phenyl)-6-(trifluoromethyl)-2-methylpyridine-3-carboxamide as a white solid: TLC Rf=0.23 (30% ethyl acetate/hexanes); 1H NMR (CDCl3, 400 MHz) δ 8.81 (bs, 1H), 7.95 (dd, 1H), 7.67 (m, 3H), 7.53 (t, 2H), 7.38 (d, 1H), 7.07 (d, 1H), 2.71 (s, 3H), 2.43 (s, 3H); MS (Q1) 406.1 (M)+.
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]([CH2:11][CH2:12][C:13]([CH3:42])([CH3:41])[CH2:14][CH:15]1[NH:19][CH:18]([C:20]([OH:22])=O)[CH:17]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=2[F:30])[C:16]1([C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:34]=1[F:40])[C:31]#[N:32])=[N+:9]=[N-:10].[CH3:43][C:44]1([CH3:52])[O:48][C@@H:47]([CH2:49][CH2:50][NH2:51])[CH2:46][O:45]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:43][C:44]1([CH3:52])[O:48][C@@H:47]([CH2:49][CH2:50][NH:51][C:20]([CH:18]2[CH:17]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=3[F:30])[C:16]([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:34]=3[F:40])([C:31]#[N:32])[CH:15]([CH2:14][C:13]([CH3:42])([CH3:41])[CH2:12][CH2:11][N:8]=[N+:9]=[N-:10])[NH:19]2)=[O:22])[CH2:46][O:45]1
Reactant: CC(C)(CCN=[N+]=[N-])CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: CC1(C)OC[C@H](CCN)O1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(CCN=[N+]=[N-])CC1NC(C(=O)NCC[C@H]2COC(C)(C)O2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 90.6 %

Procedure:
In a manner similar to the method described in Examples 42c, rac-(2R,3S,4R,5S)-5-(4-azido-2,2-dimethyl-butyl)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 120c (0.54 g, 0.85 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine (0.37 g, 2.54 mmol), HATU (0.58 g, 1.5 mmol) and iPr2NEt (0.74 mL, 4.2 mmol) in CH2Cl2 at room temperature for 20 h, to give rac-(2R,3S,4R,5S)-5-(4-azido-2,2-dimethyl-butyl)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethyl]-amide as a light yellow solid (0.5 g, 91%).
Reaction SMILES: C([N:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][C:13]([Cl:20])=[C:14]([Cl:19])[CH:15]=2)[C:10]1([CH2:23][C:24]1[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32][CH3:33])=[C:26]([O:34][CH3:35])[CH:25]=1)C#N)(=O)C1C=CC=CC=1>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C1(C)C=CC=CC=1>[ClH:19].[Cl:19][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][C:13]=1[Cl:20])[C:10]([CH2:23][C:24]1[CH:25]=[C:26]([O:34][CH3:35])[C:27]([O:32][CH3:33])=[C:28]([O:30][CH3:31])[CH:29]=1)=[N:9][CH:18]=[CH:17]2
Reactant: COc1cc(CC2(C#N)c3cc(Cl)c(Cl)cc3C=CN2C(=O)c2ccccc2)cc(OC)c1OC
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: COc1cc(Cc2nccc3cc(Cl)c(Cl)cc23)cc(OC)c1OC
Product: Cl

Procedure:
Benzyltriethylammonium chloride (0.118 g, 0.517 mmole) was added to a solution of 2.3 g (4.5 mmole) of 2-benzoyl-1-(3,4,5-trimethoxybenzyl)-6,7-dichloro-1-cyano-1, 2-dihydroisoquinoline in 40 ml of toluene. The stirred solution was flushed with nitrogen and then 19 ml of 50% sodium hydroxide solution was added in one portion. The reaction mixture was stirred and refluxed under nitrogen for 1.5 hours; it was then cooled and 25 ml of water and 25 ml of ethyl acetate were added. The organic layer was separated, washed (water, brine), dried (magnesium sulfate) and concentrated. The residue in a small volume of methanol was acidified with hydrogen chloride and ether was added to give 6,7-dichloro-1-(3,4,5-trimethyoxybenzyl)isoquinoline hydrochloride as white crystals, melting at 211°-212° C., after recrystallization from methanol-ether.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([C:8](=O)[CH3:9])[CH:7]=1.[O:14]1[CH2:19][CH2:18][N:17]([S:20]([C:23]2[CH:24]=[C:25]([CH:30]=[CH:31][CH:32]=2)[C:26]([NH:28][NH2:29])=[O:27])(=[O:22])=[O:21])[CH2:16][CH2:15]1>CO.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6](/[C:8](=[N:29]/[NH:28][C:26](=[O:27])[C:25]2[CH:30]=[CH:31][CH:32]=[C:23]([S:20]([N:17]3[CH2:18][CH2:19][O:14][CH2:15][CH2:16]3)(=[O:21])=[O:22])[CH:24]=2)/[CH3:9])[CH:7]=1
Reactant: NNC(=O)c1cccc(S(=O)(=O)N2CCOCC2)c1
Reactant: CC(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Solvent: CC(=O)O
Solvent: CO
Product: C/C(=N\NC(=O)c1cccc(S(=O)(=O)N2CCOCC2)c1)c1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 120 °C
Yield: 20 %

Procedure:
1-(5-chloro-2-nitrophenyl)ethanone (30 mg, 0.150 mmol) and 3-(morpholinosulfonyl)benzohydrazide (42.9 mg, 0.150 mmol) was dissolved in Methanol (Volume: 4 ml) in the presence of acetic acid as a catalyst and then the reaction mixture was heated via microwave irradiation to 120° C. for 30 min. Reaction was monitored by TLC. After completion of the reaction, following cooling, the solvent was removed by vacuum and the resulting crude material was purified by flash column chromatography (2% CH3OH/CH2Cl2), afforded the product (E)-N′-(1-(5-chloro-2-nitrophenyl)ethylidene)-3-(morpholinosulfonyl)benzohydrazide (15 mg, 0.030 mmol, 20.09% yield) as a solid. 1H NMR (CDCl3, 400 MHz): δ 8.20 (m, 1H), 8.07 (m, 1H), 7.88 (m, 1H), 7.66 (m, 1H), 7.51 (m, 2H), 7.39 (m, 1H), 3.69 (m, 4H), 2.99 (m, 4H), 2.29 (s, 3H). Mass [M+H]+:468.0
Reaction SMILES: [C:1]([Si:5]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].C([Li])(CC)C.CN(C)CCN(C)CCN(C)C.CN([CH:39]=[O:40])C>C1COCC1>[Si:5]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[C:13]([F:18])=[C:14]([CH:15]=[CH:16][CH:17]=1)[CH:39]=[O:40])([C:1]([CH3:4])([CH3:2])[CH3:3])([CH3:7])[CH3:6]
Reactant: CN(C)C=O
Reactant: CC(C)(C)[Si](C)(C)OCCCc1ccccc1F
Agent: CN(C)CCN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCCc1cccc(C=O)c1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl(3-(2-fluorophenyl)propoxy)dimethylsilane (example 88, step b) (4.4 g) was added dropwise over 5 min to a solution of sec-butyllithium (1.4M in cyclohexane, 11.7 mL) and 1,1,4,7,7-pentamethyldiethylenetriamine (3.4 mL) in THF (25 mL) at −78° C. The resulting mixture was stirred for 2 h, then DMF (6.4 mL) was cautiously added and the resulting mixture allowed to warm to RT and stirred overnight. The reaction was quenched with water (100 mL) and then ethyl acetate (250 mL) was added. The phases were separated and the organic phase washed with water (2×100 mL), 2M HCl solution (2×50 mL), and brine (100 mL), then dried over magnesium sulphate, filtered and evaporated. Purification was by silica gel chromatography eluting with isohexane to 10% ether in isohexane gradient. The product containing fractions were combined and evaporated to give the subtitled compound as a clear oil. Yield 1 g.
Reaction SMILES: CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[NH2:14][N+:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=1[NH2:22].[F:23][C:24]1[N:29]=[C:28]([C:30](Cl)=O)[CH:27]=[CH:26][CH:25]=1>>[Br:21][C:18]1[CH:19]=[CH:20][N:15]2[N:14]=[C:30]([C:28]3[CH:27]=[CH:26][CH:25]=[C:24]([F:23])[N:29]=3)[N:22]=[C:16]2[CH:17]=1
Reactant: O=C(Cl)c1cccc(F)n1
Reactant: Nc1cc(Br)cc[n+]1N
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Product: Fc1cccc(-c2nc3cc(Br)ccn3n2)n1
Yield: 85.1 %

Procedure:
The product was prepared in the same manner as described in example 1b using 1,2-diamino-4-bromopyridinium 2,4,6-trimethylbenzenesulfonate (2.24 g, 5.77 mmol) and 6-fluoropicolinoyl chloride (1.84 g, 11.5 mmol) as starting materials. The reaction affords 7-bromo-2-(6-fluoro-pyridin-2-yl)-[1,2,4]triazolo[1,5-a]pyridine (1.44 g, 85.4%) as brown solid. MS: m/z=294.9 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:12][CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[C:10]=2[N:11]=1.[Cl:26][C:27]1[C:32]([NH:33][S:34]([C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:38]=2[F:44])(=[O:36])=[O:35])=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][N:28]=1.C(=O)(O)[O-].[Na+]>O1CCOCC1>[Cl:26][C:27]1[N:28]=[CH:29][C:30]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]=[CH:7][N:8]=[C:9]([NH:12][CH:13]4[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:24])([CH3:25])[CH3:23])=[O:20])[CH2:15][CH2:14]4)[C:10]=3[N:11]=2)=[CH:31][C:32]=1[NH:33][S:34]([C:37]1[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:38]=1[F:44])(=[O:36])=[O:35]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ncnc3ccc(Cl)nc23)CC1
Reactant: CC1(C)OB(c2cnc(Cl)c(NS(=O)(=O)c3ccc(F)cc3F)c2)OC1(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(Nc2ncnc3ccc(-c4cnc(Cl)c(NS(=O)(=O)c5ccc(F)cc5F)c4)nc23)CC1
Temperature: 25 °C
Yield: 4.5 %

Procedure:
A mixture of tert-butyl 4-(6-chloropyrido[3,2-d]pyrimidin-4-ylamino)piperidine-1-carboxylate (Intermediate 24) (0.050 g, 0.137 mmol), N-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-yl)-2,4-difluorobenzenesulfonamide (Intermediate 3) (0.065 g, 0.151 mmol), PdCl2(dppf)-CH2Cl2Adduct (5.61 mg, 6.87 μmol) and 1 N aq. sodium bicarbonate (0.275 ml, 0.275 mmol) in dioxane (1.40 ml) subjected to microwave irradiation for 1 hour at 110° C. After cooling to room temperature, the reaction mixture was filtered through Celite and washed with CH2Cl2. The filtrate was concentrated in vacuo. The residue was purified by prep TLC (Hex:EtOAc=1:2) to give tert-butyl 4-(6-(6-chloro-5-(2,4-difluorophenylsulfonamido)pyridin-3-yl)pyrido[3,2-d]pyrimidin-4-ylamino)piperidine-1-carboxylate (3.90 mg, 4.5%) as a yellow solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 1.48 (9H, s), 1.55-1.72 (2H, m), 2.05-2.22 (2H, m), 2.92-3.12 (2H, m), 4.02-4.25 (2H, m), 4.30-4.48 (1H, m), 6.90-7.04 (2H, m), 7.14 (1H, J=8.0 Hz), 7.80-7.92 (1H, m), 8.07 (1H, d, J=8.8 Hz), 8.22 (1H, d, J=8.8 Hz), 8.69 (1H, s), 8.70 (1H, br s), 8.79 (1H, br s). m/z=632.2 [M+1]+1.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[C:17]3[C:12](=[CH:13][C:14]4CC=[C:22]([C:25]([O:27]CC)=[O:26])[O:21][C:15]=4[C:16]=3[CH2:18][CH2:19][CH3:20])[CH2:11][CH:10]=[CH:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:30]([OH:32])[CH3:31].[OH-:33].[Na+]>>[O:32]=[C:30]1[C:14]2[CH:13]=[C:12]3[C:17](=[C:16]([CH2:18][CH2:19][CH3:20])[C:15]=2[O:21][C:22]([C:25]([OH:27])=[O:26])=[CH:31]1)[N:8]([CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH:9]=[CH:10][C:11]3=[O:33]
Reactant: [OH-]
Reactant: CCO
Reactant: CCCc1c2c(cc3c1N(Cc1ccccc1)C=CC3)CC=C(C(=O)OCC)O2
Agent: [Na+]
Product: CCCc1c2oc(C(=O)O)cc(=O)c2cc2c(=O)ccn(Cc3ccccc3)c12
Yield: 32 %

Procedure:
A suspension of ethyl 6,9-dihydro-9-phenylmethyl-10-propyl-4H-pyrano[3,2-g]quinoline-2-carboxylate (1.8 g, 4.6 mmol) in 0.1 N aqueous sodium hydroxide solution (46.9 ml) containing ethanol (10 ml) was heated at reflux for 6 hours. The mixture was cooled, filtered and the filtrate was acidified and filtered. The solid obtained was dried (in vacuo) at 80° to give the required acid as a yellow powder 0.6 g (32%) mp>250°.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([C:12]1[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=1)[CH2:7]2.[CH:22]([C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1)=[CH2:23].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CCN(CC)CC>CC([O-])=O.CC([O-])=O.[Pd+2].C(Cl)(Cl)Cl.O>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([N:8]2[CH2:7][C:6]3[C:10](=[C:2]([CH:23]=[CH:22][C:24]4[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=4)[CH:3]=[CH:4][CH:5]=3)[C:9]2=[O:11])=[CH:13][CH:14]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: C=Cc1ccncc1
Reactant: CC(C)(C)c1ccc(N2Cc3cccc(Br)c3C2=O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1ccc(N2Cc3cccc(C=Cc4ccncc4)c3C2=O)cc1
Reaction time: 0.17 h

Procedure:
7-Bromo-2-(4-t-butyl-phenyl)-2,3-dihydro-isoindol-1-one (0.14 g), 4-vinylpyridine (0.55 mL), Pd(OAc)2 (1.2 mg), tri-o-tolylphosphine (27.3 mg), and 2 mL of Et3N were added into a microwave reaction tube and subjected to 120° C., 10 min of microwave (2×). H2O and CHCl3 were added and the layers were separated. The aqueous phase was extracted with CHCl3 (3×). The combined organic phases were washed with H2O, dried over Na2SO4, filtered, then evaporated in vacuo to yield a light brown residue as crude product. The crude was purified by silica gel chromatography (25 g, 10-50% EtOAc/hexanes) to afford 2-(4-t-butylphenyl)-7-(2-pyridin-4-yl-vinyl)-2,3-dihydro-isoindol-1-one as an off-white solid:
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[CH2:15][O:14][NH:13][C:12]2=[O:16])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[C:20]1([C:26]([O:28][CH3:29])=[O:27])[CH:24]=[CH:23][C:22](=[O:25])[O:21]1>CN(C)C=O.C(OCC)(=O)C.O>[C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[CH2:15][O:14][N:13]([C:20]3([C:26]([O:28][CH3:29])=[O:27])[CH:24]=[CH:23][C:22](=[O:25])[O:21]3)[C:12]2=[O:16])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cc1ccccc1)N[C@@H]1CONC1=O
Reactant: COC(=O)C1(Br)C=CC(=O)O1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C1(N2OC[C@@H](NC(=O)Cc3ccccc3)C2=O)C=CC(=O)O1
Yield: 8.9 %

Procedure:
In 3 ml of anhydrous N,N-dimethylformamide was dissolved 220 mg of (4R)-4-phenylacetamido-3-isoxazolidinone. To the solution were added, under ice-cooling and stirring, 60 mg of sodium hydride (50% mineral oil) and 0.5 ml of anhydrous N,N-dimethylformamide solution dissolving 220 mg of the Compound (26) obtained in Example 26. The reaction solution was stirred for 69 minutes under ice-cooling, which was then poured into a mixture of ethyl acetate and water. The ethyl acetate layer was taken, washed with water and dried (Na2SO4). The solvent was evaporated off, and the residue was subjected to a silica gel column chromatography, followed by elution with hexane-ethyl acetate (2:1→2:3) to give 32 mg of the subject Compound (30) as colorless oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[C:19]3[C:14](=[CH:15][C:16]([F:20])=[CH:17][CH:18]=3)[NH:13][N:12]=2)[CH2:7][CH2:6]1.[CH2:21]1[O:29][C:28]2[CH:27]=[CH:26][C:25]([N:30]=[C:31]=[O:32])=[CH:24][C:23]=2[O:22]1.O.CCOCC>CN(C=O)C>[CH2:21]1[O:29][C:28]2[CH:27]=[CH:26][C:25]([NH:30][C:31]([O:1][CH2:2][CH2:3][CH2:4][N:5]3[CH2:10][CH2:9][CH:8]([C:11]4[C:19]5[C:14](=[CH:15][C:16]([F:20])=[CH:17][CH:18]=5)[NH:13][N:12]=4)[CH2:7][CH2:6]3)=[O:32])=[CH:24][C:23]=2[O:22]1
Reactant: OCCCN1CCC(c2n[nH]c3cc(F)ccc23)CC1
Reactant: O=C=Nc1ccc2c(c1)OCO2
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1ccc2c(c1)OCO2)OCCCN1CCC(c2n[nH]c3cc(F)ccc23)CC1
Temperature: 80 °C
Yield: 13.7 %

Procedure:
A solution of 3-[1-(1-hydroxyprop-3-yl)-4-piperidinyl]-6-fluoro-1H-indazole (230 mg, 0.83 mmol) in 5 ml dry DMF was added 3,4-methylenedioxyphenylisocyanate (291 mg, 1.65 mmol) in 3 ml dry DMF. The reaction was heated to 100° C. for 2 h and 16 h at 80° C. The reaction was cooled to room temperature and added a mixture of 50 ml water and 200 ml ether, filtered and separated. The ether phase was washed with water, brine and dried with sodium sulphate and concentrated in vacuo. The crude product was purified by chromatography on silica gel 60 eluting with ethyl acetate:methanol (9:1, v/v). Concentration of the appropriate fractions afforded 50 mg (11%) of the title compound as an amorphous solid.