Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[S:13]([OH:16])(=O)=[O:14].C(OCC)(=O)C.[CH2:23]([NH2:25])[CH3:24]>C1COCC1>[CH2:23]([NH:25][S:13]([C:8]1[C:9]([F:11])=[CH:10][C:2]([F:1])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5])(=[O:16])=[O:14])[CH3:24]
Reactant: O=C(O)c1ccc(F)cc1F
Reactant: O=S(=O)(O)Cl
Reactant: CCN
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCNS(=O)(=O)c1cc(C(=O)O)c(F)cc1F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2,4-difluorobenzoic acid (200 mg, 0.765 mmol) in chlorosulfonic acid (1.535 ml, 22.92 mmol) was stirred at room temperature for 30 seconds, then microwave 200 degree for 10 mins. The reaction mixture was cooled to room temperature and dumped on ice (10 g) slowly. Ethyl acetate (25 ml) was added and extracted twice with ethyl acetate (10 mL X2). The combined organic phase was dried over MgSO4. Ethylamine (1833 μl, 3.67 mmol) in THF (2.0 M) was added, stirred at room temperature for 10 mins and washed with 1 N HCl (10 ml). The organic phase was dried over MgSO4 and concentrated to give 5-[(ethylamino)sulfonyl]-2,4-difluorobenzoic acid, which was purified by HPLC 5%-60% CH3CN/H2O TFA (0.1%) to give 60 mg. To 5-[(ethylamino)sulfonyl]-2,4-difluorobenzoic acid in N,N-dimethylformamide (3 ml) and dichloromethane (3 ml) was added to EDC (32.5 mg, 0.170 mmol) and HOBt (26.0 mg, 0.170 mmol). After 10 mins, 5-cyclopentyl-1,3,4-thiadiazol-2-amine was added. The reaction mixture was stirred at rt overnight, concentrated and purifed by HPLC. The solvents were removed and purified by HPLC (30-70% with TFA 0.1% CNCH3 and H2O, 18 mins) to give the title compound (5 mg).
Reaction SMILES: [C:1]([O:14]CCCC1C=C([Si](C)(C)C)OC=1)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C1C(I)=C(O)C(I)=C2OC3C([C:43]4([O:56][C:54](=[O:55])[C:45]5[C:46](Cl)=[C:47](Cl)[C:48](Cl)=C(Cl)[C:44]4=5)C=12)=CC(I)=C(O)C=3I.[O:60]=O>O1CCCC1>[C:1]([O:14][CH2:48][CH2:47][CH2:46][C:45]1[CH:54]([OH:55])[O:56][C:43](=[O:60])[CH:44]=1)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCC(=O)OCCCc1coc([Si](C)(C)C)c1
Reactant: O=O
Reactant: O=C1OC2(c3cc(I)c(O)c(I)c3Oc3c2cc(I)c(O)c3I)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Solvent: C1CCOC1
Product: CCCCCCCCCCCC(=O)OCCCC1=CC(=O)OC1O

Procedure:
A mixture of 3-(5-trimethylsilyl-3-furyl)propyl dodecanoate (105 mg, 0.27 mmol) and Rose Bengal (5 mg) in tetrahydrofuran (6 ml) was exposed to singlet oxygen for 2.5 hours at -78°. The residue, after solvent removal, was purified by preparative thin layer chromatography (TLC) (20×20 cm, 500μ silica plate; developed with 60% ethyl ether/petroleum ether). The title ester was obtained as an off-white solid.
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[N-:15]=[N+:16]=[N-:17].[Na+].O.C(=O)(O)[O-].[Na+]>CN(C=O)C.[I-].[Na+]>[N:15]([CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1)=[N+:16]=[N-:17]
Reactant: CC(C)(C)OC(=O)N1CCC(Br)CC1
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(N=[N+]=[N-])CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 100.2 %

Procedure:
To a solution of 45.3 g (172 mmol) of 4-bromo-1-(tert-butoxycarbonyl)piperidine in 750 mL of DMF was added 22.3 g (343 mmol) of sodium azide and 2.5 g (17 mmol) of sodium iodide. The reaction was stirred at RT for 24 h and then at 60° C. for 4 h. The mixture was poured into water containing 20 mL of sodium bicarbonate and extracted twice with 1:1 ether/hexane. The organic layers were each washed with a portion of water and brine, dried over sodium sulfate, combined and concentrated. The residue was purified by flash column chromatography, eluting with 5-10% ethyl acetate in hexane, to afford 39 g of title compound having a trace of elimination byproduct. 1H NMR (400 MHz, CDCl3): δ3.78 (m, 2H), 3.55 (m, 1H), 3.07 (m, 2H), 1.85 (m, 2H), 1.52 (m, 2H), 1.43 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:12])=[C:6]2[C:13]1[CH:14]=[C:15](Br)[CH:16]=[CH:17][CH:18]=1.[Li]CCCC.[C:25](=[O:27])=[O:26].Cl.[N+](=[CH2:31])=[N-]>C1COCC1.CCOCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:12])=[C:6]2[C:13]1[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=1)[C:25]([O:27][CH3:31])=[O:26]
Reactant: COc1ccc2[nH]c(C)c(-c3cccc(Br)c3)c2c1
Reactant: C=[N+]=[N-]
Reactant: O=C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)c1cccc(-c2c(C)[nH]c3ccc(OC)cc23)c1
Temperature: 25 °C

Procedure:
To a -78° C. solution of the bromide (539 mg, 1.7 mmol) from Step 2 in THF (10 mL) was added dropwise n-BuLi (1 .4M, 2.67 mL). After 15 min the mixture was poured over crushed CO2 and allowed to warm up to room temperature. Dilute HCl (25 mL) was added and the product was extracted in ethyl acetate. The organic layer was washed with brine, dried with MgSO4 and the solvents removed to leave a residue which was treated with a slight excess of diazomethane in ether. Removal of the solvent yielded the product (351 mg).
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[NH2:17].Cl>CO.[OH-].[Na+]>[NH2:17][CH:12]1[CH2:13][CH2:14][N:9]([C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:10][CH2:11]1
Reactant: O=C1CCN(C(=O)c2ccccc2)CC1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: NC1CCN(C(=O)c2ccccc2)CC1
Reaction time: 8 h
Yield: 39.3 %

Procedure:
N-Benzoyl-4-piperidone (45.92 g, 226 mmol) was converted to the oxime by treatment with HONH2.HCl (237 mmol, 16.49 g) in 90 ml of methanol and 90.4 ml of 2.5N NaOH. After stirring overnight, the reaction was concentrated under reduced pressure and three times treated with toluene and reconcentrated to remove the last traces of water. The resulting oxime (57 g) was dissolved in 1L of methanol, treated with 226 ml of 1N HCl and 4 g of PtO2. The mixture was then hydrogenated in a Paar apparatus at 50 psi. After 16.75 h, the catalyst was filtered and the methanol was concentrated in vacuo. Water (100 ml) was then added to the aqueous phase that was then extracted with 7×700 ml of CH2Cl2. The aqueous phase was made basic with 2.5N NaOH and extracted with 5×100 ml of CH2Cl2. The pooled extracts were concentrated in vacuo affording 18.17 g (88.9 mmol, 39% overall yield) of 4-amino-1-benzoylpiperidine as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17]C2CCCCO2)=[CH:13][CH:12]=1)=O.[CH:24]1([Mg]Br)[CH2:28][CH2:27][CH2:26][CH2:25]1>>[C:24]1(=[C:9]([C:3]2[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[C:11]2[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=2)[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: Br[Mg]C1CCCC1
Reactant: O=C(c1ccc(OC2CCCCO2)cc1)c1c(F)cccc1F
Product: Oc1ccc(C(=C2CCCC2)c2c(F)cccc2F)cc1

Procedure:
Compound 12 was synthesized from ketone 5 (1 mmol) and cyclopentyl magnesium bromide (2 mmol) using procedure B described for synthesis of 6. The THP protection group was cleaved under the acidic conditions used. Yield: 18 mg (16%). 1H-NMR (400 MHz, CDCl3): δ ppm 7.26-7.14 (m, 1H), 7.13-7.12 (m, 2H), 6.89-6.85 (m, 2H), 6.76-6.73 (m, 2H), 4.75 (s, 1H), 2.50 (broad t, J=6.4 Hz, 2H), 2.13 (broad t, J=6.4 Hz, 2H), 1.75-1.58 (m, 4H).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:5][N:6]2[CH:11]=[C:10]([CH3:12])[CH:9]=[N:8][C:7]=12.[F:19][C:20]([F:28])=[CH:21][CH:22]1[CH2:26][NH:25][C:24](=[O:27])[CH2:23]1.CN(C=O)C.[H-].[Na+]>O>[F:19][C:20]([F:28])=[CH:21][CH:22]1[CH2:26][N:25]([CH2:2][C:3]2[C:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:5][N:6]3[CH:11]=[C:10]([CH3:12])[CH:9]=[N:8][C:7]=23)[C:24](=[O:27])[CH2:23]1
Reactant: Cc1cnc2c(CCl)c(-c3ccccc3)nn2c1
Reactant: O=C1CC(C=C(F)F)CN1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cnc2c(CN3CC(C=C(F)F)CC3=O)c(-c3ccccc3)nn2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
The above mentioned solution of intermediate x146 is added to a solution containing 4-(2,2-difluorovinyl)pyrrolidin-2-one x98 (2.64 mmol, 1.1 eq, 0.356 g), 6 ml of dry DMF and sodium hydride (60% dispersion in oil, 2.64 mmol, 1.1 eq, 0.1 g) that have been stirred at room temperature for 0.5 hour. The resulting mixture is heated up at 80° C. for 1 hour. The mixture is poured in water and extracted with AcOEt. The cumulated organic layers are washed with brine, dried over MgSO4, filtered and evaporated under reduced pressure. The residue is crystallized in AcOEt to afford 0.443 g of 4-(2,2-difluorovinyl)-1-[(6-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]pyrrolidin-2-one 211.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[N:4][N:3]=1.[CH2:7]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[N:14][C:13]([C:19](Cl)=[O:20])=[CH:12]2)[CH3:8].O>N1C=CC=CC=1>[CH2:7]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[N:14][C:13]([C:19]([NH:1][C:2]1[NH:6][N:5]=[N:4][N:3]=1)=[O:20])=[CH:12]2)[CH3:8]
Reactant: Nc1nnn[nH]1
Reactant: CCc1ccc2nnc(C(=O)Cl)cc2c1
Solvent: O
Solvent: c1ccncc1
Product: CCc1ccc2nnc(C(=O)Nc3nnn[nH]3)cc2c1
Reaction time: 8 h

Procedure:
A solution of 5-amino-1,2,3,4-tetrazole (0.425 g.) in dry pyridine (10 ml.) was added to 6-ethylcinnolin-3-yl carbonyl chloride (1.1 g.). The resulting solution was kept at room temperature overnight, and water (50 ml.) and N-hydrochloric acid (50 ml.) were then added. The mixture was filtered, and the solid residue washed with water and crystallised from aqueous dimethylformamide to give 6-ethyl-N-(1,2,3,4-tetrazol-5-yl)cinnolin-3-yl carboxamide, m.p. over 250° C.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:48][O:49][CH3:50])[C:27]([NH:29][CH:30]2[C:37](=[O:38])[N:36]3[CH:31]2[CH2:32][S:33][C:34]([CH2:46]O)=[C:35]3[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:51]>ClCCl.S(Cl)(C1C=CC(C)=CC=1)(=O)=O.CN(C)C1C=CN=CC=1>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:48][O:49][CH3:50])[C:27]([NH:29][CH:30]2[C:37](=[O:38])[N:36]3[CH:31]2[CH2:32][S:33][C:34]([CH2:46][Cl:51])=[C:35]3[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(C)(C)C)=C(CO)SCC12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: Cl
Agent: CN(C)c1ccncc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(C)(C)C)=C(CCl)SCC12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 0.33 h

Procedure:
623 mg of the alcohol of Step F were dissolved in 8 ml of dichloromethane with 834 ml of tosyl chloride, and over 20 minutes, a solution of 534 mg of 4-dimethylamino-pyridine and 5 ml of dichloromethane was added. After stirring for one hour, 2.2 ml of N hydrochloric acid were added with stirring, and after decanting, the organic phase was dried and distilled under reduced pressure. The residue was chromatographed over silica and eluted with dichloromethane-ethyl acetate (9-1) to obtain 245 mg of 1,1-dimethylethyl 7-[2-(2-tritylaminothiazol-4-yl)-2-methoxyimino-acetamido]-8-oxo-3-chloromethyl-4-thia-1-azabicyclo[4,2,0]oct-2-ene-2-carboxylate crystallizing from ether.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10]Cl)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:12][NH2:13].F[C:15]1[C:28]2[C:27](=O)[C:26]3[CH:25]=[N:24][CH:23]=[CH:22][C:21]=3[C:20](=[O:30])[C:19]=2[C:18]([O:31][S:32]([C:35]2[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=2)(=[O:34])=[O:33])=[CH:17][CH:16]=1.ClC1C2C(=O)C3C=NC=CC=3C(=O)C=2C(OS(C2C=CC(C)=CC=2)(=O)=O)=CC=1.C(N(CC)C(C)C)(C)C>C1COCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][N:12]1[C:15]2[CH:16]=[CH:17][C:18]([O:31][S:32]([C:35]3[CH:36]=[CH:37][C:38]([CH3:41])=[CH:39][CH:40]=3)(=[O:33])=[O:34])=[C:19]3[C:20](=[O:30])[C:21]4[CH:22]=[CH:23][N:24]=[CH:25][C:26]=4[C:27]([C:28]=23)=[N:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NN
Reactant: CC(C)(C)OC(=O)NCCCl
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc(F)c3c2C(=O)c2ccncc2C3=O)cc1
Agent: Cc1ccc(S(=O)(=O)Oc2ccc(Cl)c3c2C(=O)c2ccncc2C3=O)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)Oc2ccc3c4c(nn3CCNC(=O)OC(C)(C)C)-c3cnccc3C(=O)c24)cc1

Procedure:
(2-N-tert-butoxycarbonylaminoethyl)hydrazine is prepared by reaction of N-t-butoxycarbonyl-2-chloroethylamine with hydrazine following a procedure adapted from J. Med. Chem. 7, 493, (1964). Under a nitrogen atmosphere a solution of (2-N-tert-butoxycarbonylaminoethyl)hydrazine (9.2 g) in anhydrous THF (10 mL) is added during 30' to the stirred 9:1 mixture of 9-fluoro-6-(p-toluenesulfonyloxy)benzo[g]isoquinoline-5,10-dione and 9-chloro-6-(p-toluenesulfonyloxy)benzo [g]isoquinoline-5,10-dione of Preparative Example 10b (3.0 g) in THF (25 mL) containing N,N-diisopropylethylamine (1.38 mL). A slightly exothermic reaction ensues, and the reaction temperature increases from 21° C. to 24° C. After stirring for one hour at room temperature the obtained precipitate is recovered by suction, washed with THF/n-hexane 1/1 (15 mL) and dried at 40° C. under vacuum, to give 2-[2-(N-tert-butoxycarbonylamino)ethyl]-5-(p-toluenesulfonyloxy)isoquino[8,7,6-cd]indazole-6(2H)-one (1.33 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].Cl[C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=[CH:16][C:15]=1[N+:23]([O-:25])=[O:24].C(N(CC)CC)C>O1CCCC1.C(OCC)(=O)C>[N+:20]([C:19]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:23]([O-:25])=[O:24])[C:14]=1[NH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:9])([CH3:11])[CH3:10])([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1Cl
Reactant: CC(C)(C)OC(=O)NCCCN
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCCNc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.5 %

Procedure:
A mixture of tert-butyl (3-aminopropyl)carbamate (4.20 g, 24.1 mmol), 2-chloro-1,3-dinitrobenzene (4.07 g, 20.1 mmol) and triethylamine (5.60 mL, 40.2 mmol) in tetrahydrofuran (200 mL) was stirred at room temperature for 3 h. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with a 30% ethyl acetate/n-hexane mixture to give a yellow solid (6.79 g, 20.0 mmol, 99.5%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:10]2[N:19]=[C:18]([NH:20][C:21]3[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=3)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)=O)=[N:6][CH:7]=1.[CH:27]1([NH2:30])[CH2:29][CH2:28]1.[BH4-].[Na+].CO>CC(O)C.CC(O)=O>[CH:27]1([NH:30][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=2)[C:10]2[N:19]=[C:18]([NH:20][C:21]3[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=3)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[CH2:29][CH2:28]1
Reactant: Cc1cc(Nc2nc(C(=O)c3ccc(F)cn3)nc3ccccc23)n[nH]1
Reactant: NC1CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: CC(C)O
Product: Cc1cc(Nc2nc(C(NC3CC3)c3ccc(F)cn3)nc3ccccc23)n[nH]1
Temperature: 140 °C

Procedure:
To (5-fluoropyridin-2-yl)(4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)methanone from Example 1 (1 equiv) in 2-propanol are added cyclopropylamine (5 equiv) and 3 Å(8-12 mesh) molecular sieves, and the mixture is heated at 140° C. in a microwave reactor. Additional cyclopropylamine is added and microwave or conventional heating is continued until the reaction is substantially complete according to NMR. Then a suspension of sodium borohydride (10 equiv) in 2-propanol is added and the mixture is stirred at rt. Methanol, additional sodium borohydride, and traces of HOAc are added as necessary until the reaction is substantially complete, then the mixture is filtered and the filtrate is concentrated. DMSO is added and the mixture is purified by preparative HPLC to afford 2-((cyclopropylamino)(5-fluoropyridin-2-yl)methyl)-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7]([O:16][CH3:17])[C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([Cl:18])[N:3]=1.[NH:19]1[CH2:24][CH2:23][CH:22]([N:25]2[C:34](=[O:35])[CH2:33][C:28]3([CH2:32][CH2:31][CH2:30][CH2:29]3)[CH2:27][C:26]2=[O:36])[CH2:21][CH2:20]1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[ClH:18].[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([O:16][CH3:17])[C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([N:19]2[CH2:24][CH2:23][CH:22]([N:25]3[C:26](=[O:36])[CH2:27][C:28]4([CH2:32][CH2:31][CH2:30][CH2:29]4)[CH2:33][C:34]3=[O:35])[CH2:21][CH2:20]2)[N:3]=1
Reactant: O=C1CC2(CCCC2)CC(=O)N1C1CCNCC1
Reactant: COc1cc2c(N)nc(Cl)nc2c(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(N)nc(N3CCC(N4C(=O)CC5(CCCC5)CC4=O)CC3)nc2c(OC)c1OC
Product: Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The mixture of 5.39 g of 4-amino-2-chloro-6,7,8-trimethoxyquinazoline, 5.25 g of 8-(4-piperidinyl)-8-azaspiro-[4,5]decan-7,9-dione, 4.24 g of anhydrous sodium carbonate and 75 ml of dimethylformamide is stirred at 1502° for 8 hours. After cooling to room temperature it is filtered, the filtrate evaporated, the residue dissolved in ethyl acetate and the solution washed with aqueous sodium bicarbonate and water. It is dried, evaporated, the residue dissolved in 75 ml of ethyl acetate and allowed to crystallize. The crystals are dissolved in 50 ml of hot isopropanol and the solution acidified with hydrogen chloride to pH=1 and the precipitate filtered off, to yield the 8-[1-(4-amino-6,7,8-trimethoxy-2-quinazolinyl)-4-piperidinyl]-8-azaspiro[4,5]decan-7,9-dione monohydrochloride melting at 225°-227°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:11]=[CH:10][C:9](=[O:12])[NH:8][C:7]=2[N:13]=1.[H-].[Na+].CS(O[CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25][CH2:24]1)(=O)=O.COC1C=C2C(C=CC(=O)N2CCN2CCC(NC(=O)OC(C)(C)C)CC2)=CC=1>ClCCl.CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:11]=[CH:10][C:9](=[O:12])[N:8]([CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH:26]([NH:29][C:30](=[O:31])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:25][CH2:24]3)[C:7]=2[N:13]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCOS(C)(=O)=O)CC1
Reactant: COc1ccc2ncc(=O)[nH]c2n1
Agent: COc1ccc2ccc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)=O
Product: COc1ccc2ncc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2n1
Yield: 67.1 %

Procedure:
6-Methoxypyrido[2,3-b]pyrazin-3(4H)-one (Intermediate 204, 0.085 g, 0.48 mmol) was deprotonated with sodium hydride (0.030 g, 60% in oil, 0.7.5 mmol) and alkylated with 2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethyl methanesulfonate (Intermediate 6) (1.05 mmol) as described for Intermediate 2. Chromatography on silica gel with 0-25% acetone in dichloromethane gave 0.13 g of the title compound.
Reaction SMILES: [NH2-].[Na+].[CH3:3][N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7](=[O:15])[CH2:6][C:5]1=[O:16].[CH3:17]OS([O-])(=O)=O>C1(C)C(C)=CC=CC=1>[CH3:3][N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([CH3:17])[C:7](=[O:15])[CH2:6][C:5]1=[O:16]
Reactant: CN1C(=O)CC(=O)Nc2ccccc21
Reactant: COS(=O)(=O)[O-]
Agent: [NH2-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: CN1C(=O)CC(=O)N(C)c2ccccc21
Reaction time: 3 h

Procedure:
2 g of sodium amide are added to a suspension of 9.5 g of 1-methyl 1,2,4,5-tetrahydro 2,4-diketo 3-H-1,5-benzodiazepine, obtained in the example XIV, in 30 c.c. of xylene, and the whole is heated for about thirty minutes, while agitating, treated with 20 c.c. of methyl-sulfate and as soon as the exothermic reaction has ceased, this is heated and boiled for three hours. The solvent is evaporated under reduced pressure, the residue is taken up in 200 c.c. of a 10% solution of caustic soda, and after agitation, suction filtered, and purified upon crystallisation in 90% ethanol. Yield 4.5 g; melting point : 240°-242° C. Analysis: C11H12N2O2Calculated: C % 64.69 H % 5.92; N % 13.72; Found: 64.67; 6.12; 13.95.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:22]3[CH:23]=[N:24][N:25]([CH2:27][C:28]([OH:30])=O)[CH:26]=3)=[N:20][NH:21][C:15]=2[CH:14]=1.[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[Cl:12][C:4]1[C:5]([O:10][CH3:11])=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Cl:1])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:22]3[CH:23]=[N:24][N:25]([CH2:27][C:28]([N:35]4[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]4)=[O:30])[CH:26]=3)=[N:20][NH:21][C:15]=2[CH:14]=1
Reactant: COc1cc(OC)c(Cl)c(-c2cc3[nH]nc(-c4cnn(CC(=O)O)c4)c3cn2)c1Cl
Reactant: CN1CCNCC1
Product: COc1cc(OC)c(Cl)c(-c2cc3[nH]nc(-c4cnn(CC(=O)N5CCN(C)CC5)c4)c3cn2)c1Cl

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 36, Step 2, starting from {4-[6-(2,6-dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-1H-pyrazol-1-yl}acetic acid and 1-methyl piperazine. LCMS (M+H)+=530.1/532.1.
Reaction SMILES: [N:1]([O-])=O.[Na+].[Br:5][C:6]1[C:12]([F:13])=[CH:11][C:9]([NH2:10])=[C:8]([F:14])[CH:7]=1.Cl.[CH3:16][O:17][CH2:18][C:19](=[O:25])[CH2:20][C:21]([O:23][CH3:24])=[O:22].CC([O-])=O.[Na+]>O.CO>[Br:5][C:6]1[C:12]([F:13])=[CH:11][C:9]([NH:10][N:1]=[C:20]([C:19](=[O:25])[CH2:18][O:17][CH3:16])[C:21]([O:23][CH3:24])=[O:22])=[C:8]([F:14])[CH:7]=1
Reactant: Nc1cc(F)c(Br)cc1F
Reactant: O=N[O-]
Reactant: COCC(=O)CC(=O)OC
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COCC(=O)C(=NNc1cc(F)c(Br)cc1F)C(=O)OC
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 105.6 %

Procedure:
A solution of NaNO2 (7.9 g, 115 mmol) in H2O (20 mL) was added dropwise at 0° C. to a mixture of 4-bromo-2,5-difluoroaniline (20 g, 96 mmol) and 6 M HCl aqueous solution (96 mL, 576 mmol). After stirring for 15 min, the resulting aqueous solution was added to a suspension of methyl 4-methoxyacetoacetate (12.4 mL, 96 mmol) and NaOAc (34 g, 576 mmol) in MeOH (165 mL) pre-cooled at 0° C. The precipitate was collected by filtration, washed with water and dried at room temperature to give the title compound (37 g, 100% yield) as a red solid: 1H NMR (300 MHz, DMSO-d6): δ ppm 3.34 (3H, s), 3.83 (3H, s), 4.68 (2H, s), 7.70 (1H, dd, J=9.7, 7.0 Hz), 7.89 (1H, dd, J=10.6, 6.1 Hz), 12.16 (1H, s).
Reaction SMILES: [CH:1]#[C:2][CH:3]([OH:6])[CH2:4][CH3:5].I[C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1/[C:10](=[CH:18]/[C:19]1[NH:20][CH:21]=[CH:22][C:23]=1[O:24][CH3:25])/[C:11](=[O:17])[NH:12]2>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C=O)C.CCN(CC)CC>[OH:6][CH:3]([CH2:4][CH3:5])[C:2]#[C:1][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1/[C:10](=[CH:18]/[C:19]1[NH:20][CH:21]=[CH:22][C:23]=1[O:24][CH3:25])/[C:11](=[O:17])[NH:12]2
Reactant: C#CC(O)CC
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(I)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC(O)C#Cc1cccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2

Procedure:
Using Method C above, 1-pentyn-3-ol (40 mg, 0.48 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (146 mg, 0.4 mmol) (Starting Material 2 supra) using (Ph3P)2PdCl2 (20 mg) and CuI (10 mg) as catalyst in DMF (2 mL) and Et3N (2 mL) as solvent at 70° C. for 15 h to yield rac-(Z)-1,3-dihydro-4-(3-hydroxy-1-pentynyl)-3-[(3methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 78 mg, 60%).