Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C:9]1([C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:18][CH:17]=2)=[O:14])[CH2:12][CH2:11][CH2:10]1)=O)(C)(C)C.[ClH:29].C(OCC)(=O)C>C(Cl)(Cl)Cl>[ClH:29].[NH2:8][C:9]1([C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:18][CH:17]=2)=[O:14])[CH2:12][CH2:11][CH2:10]1
Reactant: CCOC(=O)/C=C/c1ccc(NC(=O)C2(NC(=O)OC(C)(C)C)CCC2)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)/C=C/c1ccc(NC(=O)C2(N)CCC2)cc1
Reaction time: 4 h
Yield: 91 %

Procedure:
To a solution of ethyl (E)-3-{4-[(1-tert-butoxycarbonylaminocyclobutanecarbonyl)amino]phenyl}acrylate (943 mg, 2.43 mmol) in chloroform (10 ml) was added 4N HCl-ethyl acetate solution (10 ml) under ice-cooling, and the mixture was stirred for 4 hr. The solvent was evaporated under reduced pressure and hexane:diethyl ether (1:1) solution was added to the obtained residue. The precipitated solid was collected by filtration and washed with hexane:diethyl ether (1:1) solution. The obtained solid was dried in vacuo to give ethyl (E)-3-{4-[(1-aminocyclobutanecarbonyl)amino]phenyl}acrylate hydrochloride (720 mg, yield 91%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[CH:27]=[CH:26][C:11]([NH:12][C:13]2[C:22]3[C:17](=[CH:18][C:19]([OH:25])=[C:20]([O:23][CH3:24])[CH:21]=3)[N:16]=[CH:15][N:14]=2)=[C:10]([F:28])[CH:9]=1.[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][CH:39]([CH2:42]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30].O>CN(C=O)C>[Br:7][C:8]1[CH:27]=[CH:26][C:11]([NH:12][C:13]2[C:22]3[C:17](=[CH:18][C:19]([O:25][CH2:42][CH:39]4[CH2:40][CH2:41][N:36]([C:34]([O:33][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:35])[CH2:37][CH2:38]4)=[C:20]([O:23][CH3:24])[CH:21]=3)[N:16]=[CH:15][N:14]=2)=[C:10]([F:28])[CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: COc1cc2c(Nc3ccc(Br)cc3F)ncnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3ccc(Br)cc3F)ncnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 79 %

Procedure:
Potassium carbonate (414 mg, 3 mmol) was added to a suspension of 4-(4-bromo-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (546 mg, 1.5 mmol) in DMF (5 ml). After stirring for 10 minutes at ambient temperature, 1-(tert-butoxycarbonyl)-4-(4-methylphenylsulphonyloxymethyl)piperidine (636 mg, 1.72 mmol) was added and the mixture was heated at 95° C. for 2 hours. After cooling, the mixture was poured onto cooled water (20 ml). The precipitate was collected by filtration, washed with water, and dried under vacuum to give 4-(4-bromo-2-fluoroanilino)-7-(1-(tert-butoxycarbonyl)piperidin-4-ylmethoxy)-6-methoxyquinazoline (665 mg, 79%).
Reaction SMILES: FC1C=CC=CC=1NC(=S)NC1C=CC(C2C=C3C(=CC=2)C(=O)N([C@@H](C(C)C)C(O)=O)C3)=CC=1.[CH3:35][CH:36]([CH3:69])[C@H:37]([N:42]1[CH2:50][C:49]2[C:44](=[CH:45][CH:46]=[C:47]([C:51]3[CH:56]=[CH:55][C:54]([NH:57][C:58]([NH:60][C:61]4[CH:66]=[CH:65][CH:64]=[CH:63][C:62]=4[CH3:67])=[S:59])=[CH:53][CH:52]=3)[CH:48]=2)[C:43]1=[O:68])[C:38]([O:40]C)=[O:39]>>[CH3:35][CH:36]([CH3:69])[C@H:37]([N:42]1[CH2:50][C:49]2[C:44](=[CH:45][CH:46]=[C:47]([C:51]3[CH:56]=[CH:55][C:54]([NH:57][C:58]([NH:60][C:61]4[CH:66]=[CH:65][CH:64]=[CH:63][C:62]=4[CH3:67])=[S:59])=[CH:53][CH:52]=3)[CH:48]=2)[C:43]1=[O:68])[C:38]([OH:40])=[O:39]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=S)Nc4ccccc4C)cc3)ccc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2cc(-c3ccc(NC(=S)Nc4ccccc4F)cc3)ccc2C1=O
Product: Cc1ccccc1NC(=S)Nc1ccc(-c2ccc3c(c2)CN([C@H](C(=O)O)C(C)C)C3=O)cc1
Yield: 88 %

Procedure:
The compound of example 273 was prepared analogous to compound of example 257 by hydrolysis of compound of example 272.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:16]([C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17].C(N(CC)CC)C.O>C1C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:1][N:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:24](=[O:25])[C:23]1[CH:27]=[CH:28][C:20]([C:16]([CH3:18])([CH3:17])[CH3:19])=[CH:21][CH:22]=1
Reactant: CC(C)(C)c1ccc(C(=O)O)cc1
Reactant: CNCc1ccccc1-c1ccccc1
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CN(Cc1ccccc1-c1ccccc1)C(=O)c1ccc(C(C)(C)C)cc1

Procedure:
Orthophenylbenzoic acid (10 g) and thionyl chloride (18.7 g) were mixed with 100 ml of chloroform, followed by heating for 4 hours under reflux. The reaction mixture was concentrated under reduced pressure, and the resulting concentrate was added dropwise to 40 ml of a 40% aqueous solution of methylamine under ice cooling. The temperature of the resulting mixture was allowed to rise to room temperature, at which a reaction was allowed to proceed under stirring for 4 days. 2 N hydrochloric acid was added to terminate the reaction, followed by the extraction of the resulting mixture with chloroform. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was collected, from which the solvent was distilled off so that N-methyl-2-phenylbenzoic acid amide was obtained. The acid amide was reduced with 0.54 g of lithium aluminum hydride in diethyl ether, whereby 1.46 g of N-methyl-2-phenylbenzylamine were obtained. The benzylamine was reacted with an acid chloride, which had been derived from 1.45 g of p-tert-butylbenzoic acid, in the presence of triethylamine in benzene. Water and chloroform were added to the reaction mixture for extraction. The organic layer was collected and was then washed successively with dilute hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate, water and a saturated aqueous solution of sodium chloride in the order that they are presented. The solvent was distilled off, whereby 2.42 g of N-methyl-N-(2-phenylbenzyl)-4-tert-butylbenzoic acid amide were obtained as yellow crystals. The acid amide was reduced with lithium aluminum hydride in tetrahydrofuran and the reduction product was extracted with diethyl ether, whereby 0.83 g of 4-tert-butyl-N-methyl-N-(2-phenylbenzyl)benzylamine (Compound 1) was obtained (yield: 35.7%). The following is its NMR spectrum data.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[Cl:22][C:23]1[N:28]=[CH:27][N:26]=[C:25]2[NH:29][N:30]=[CH:31][C:24]=12.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[Cl:22][C:23]1[N:28]=[CH:27][N:26]=[C:25]2[N:29]([CH:6]3[CH2:5][CH2:4][CH2:3][CH2:2][O:1]3)[N:30]=[CH:31][C:24]=12
Reactant: Clc1ncnc2[nH]ncc12
Reactant: C1=COCCC1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Clc1ncnc2c1cnn2C1CCCCO1
Temperature: 25 °C
Reaction time: 70 h
Yield: 80 %

Procedure:
3,4-Dihydro-2H-pyran (10 mL) and 10-camphorsulfonic acid (200 mg, 0.86 mmol) were added to a solution of 4-chloro-1H-pyrazolo[3,4-d]pyrimidine (Intermediate 30; 2.1 g, 13.6 mmol) in ethyl acetate (80 mL). The mixture was stirred at room temperature for 70 h, poured into saturated aqueous sodium bicarbonate, and extracted three times with ethyl acetate. The combined organic extracts were washed with brine, dried (magnesium sulfate), filtered, evaporated, and purified by column chromatography eluting with 20% ethyl acetate/hexanes to give 4-chloro-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (2.61 g, 80%) as a lavender-colored crystalline solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl>C(O)C>[CH2:11]([NH:18][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: NCc1ccccc1
Agent: Cl
Solvent: CCO
Product: O=[N+]([O-])c1ccc(NCc2ccccc2)nc1
Yield: 88.1 %

Procedure:
A solution of 2-chloro-5-nitropyridine (1.59 g, 10 mmol) and benzylamine (2.3 mL, 21 mmol) in ethanol (10 mL) was heated at reflux for 2 h. The reaction mixture was allowed to ambient temperature, 1.2 N HCl was added, the precipitate collected, rinsed with water, and dried to give 2.02 g of 2-benzylamino-5-nitropyridine as a yellow solid.
Reaction SMILES: C([Li])CCC.[O:6]1[CH:10]=[CH:9][C:8]([C:11]([OH:13])=[O:12])=[CH:7]1.[C:14](=[O:16])=[O:15]>C1COCC1>[O:6]1[CH:10]=[CH:9][C:8]([C:11]([OH:13])=[O:12])=[C:7]1[C:14]([OH:16])=[O:15]
Reactant: O=C(O)c1ccoc1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)c1ccoc1C(=O)O
Temperature: -78 °C

Procedure:
n-Butyllithium (2.5M in hexanes, 196 mL, 491 mmol) was introduced into a dry 3 L 3-necked flask fitted with an addition funnel, argon inlet, and mechanical stirrer. The mixture was diluted with dry THF (500 mL), and cooled to −78° C. 3-furoic acid (25 g, 223 mmol) was added as solution in THF (500 mL) dropwise. The mixture was stirred for 1.5 h, at which point dry carbon dioxide was bubbled through the reaction mixture for 1 h. After warming gradually to −10° C., the resultant thick white slurry was treated with aqueous HCl (2 N, 446 mL). The two layers were separated, and the aqueous layer was extracted with EtOAc (3×300 mL). The combined organics were dried (Na2SO4), filtered, and concentrated to afford crude furan-2,3-dicarboxylic acid as an orange solid (44 g) which was used without further purification. 1H NMR (300 MHz, d6-acetone) δ 7.06 (d, J=1.7, 1), 7.97 (d, J=1.7, 1), 10.7 (bs, 2H); TLC (CHCl3/MeOH/H2O 6:4:1) Rf=0.56.
Reaction SMILES: [CH:1]([C:3]1[C:4]([CH3:11])=[C:5]([C:9]#[N:10])[CH:6]=[N:7][CH:8]=1)=[CH2:2].C1C(=O)N(Br)C(=[O:15])C1.[OH-].[Na+]>O>[CH3:11][C:4]1[C:3]([CH:1]2[CH2:2][O:15]2)=[CH:8][N:7]=[CH:6][C:5]=1[C:9]#[N:10]
Reactant: C=Cc1cncc(C#N)c1C
Reactant: O=C1CCC(=O)N1Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1c(C#N)cncc1C1CO1
Temperature: 40 °C
Reaction time: 2.5 h

Procedure:
A suspension of 5-ethenyl-4-methylpyridine-3-carbonitrile (3.00 g, 20.8 mmol) in 30 mL of ButOH and 60 mL of water was added NBS (4.6 g, 26 mmol) portionwise. The mixture was stirred at 40° C. for 2.5 hour then cooled down to 10° C. NaOH solution (2.5 g in 70 mL of water, 62.4 mmol) was added dropwise and stirred for 15 minutes. The reaction mixture was extracted with EtOAc twice and condensed. The residue was purified by column chromatography (petrol ether: EtOAc=20:1) to afford 4-methyl-5-(oxiran-2-yl)pyridine-3-carbonitrile.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:17]2[O:18][CH2:19][C@H:20]3[CH2:24][CH2:23][CH2:22][N:21]3[C:16]2=[CH:15][CH:14]=1)(=[O:11])=[O:10].NC1C(C(OC)=O)=C2OC[C@@H]3CCCN3C2=CC=1.BrC1C=C(F)C=CC=1S(Cl)(=O)=O>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:17]2[O:18][CH2:19][C@@H:20]3[CH2:24][CH2:23][CH2:22][N:21]3[C:16]2=[CH:15][CH:14]=1)(=[O:11])=[O:10]
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1OC[C@H]1CCCN21
Agent: COC(=O)c1c(N)ccc2c1OC[C@@H]1CCCN21
Agent: O=S(=O)(Cl)c1ccc(F)cc1Br
Product: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1OC[C@@H]1CCCN21

Procedure:
Prepared by proceeding in a similar manner to Intermediate 2, starting from methyl (S)-7-amino-2,3,3a,4-tetrahydro-1H-benzo[b]pyrrolo[1,2-d][1,4]oxazine-6-carboxylate (Intermediate 13), and 2-bromo-4-fluorobenzenesulfonyl chloride.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[OH:29][C:30]1[CH:35]=[CH:34][C:33]([S:36]([NH:39][C:40]2[CH:45]=[CH:44][CH:43]=[C:42](B3OC(C)(C)C(C)(C)O3)[CH:41]=2)(=[O:38])=[O:37])=[CH:32][C:31]=1[CH3:55].C(=O)([O-])[O-].[Cs+].[Cs+]>>[NH2:1][C:2]1[C:3]([C:42]2[CH:41]=[C:40]([NH:39][S:36]([C:33]3[CH:34]=[CH:35][C:30]([OH:29])=[C:31]([CH3:55])[CH:32]=3)(=[O:38])=[O:37])[CH:45]=[CH:44][CH:43]=2)=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[N:5]=[CH:6][N:7]=1
Reactant: Cc1cc(S(=O)(=O)Nc2cccc(B3OC(C)(C)C(C)(C)O3)c2)ccc1O
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1cc(S(=O)(=O)Nc2cccc(-c3c(N)ncnc3N[C@@H](C)c3nn4ccc(C)c4c(=O)n3-c3ccccc3)c2)ccc1O
Yield: 53.1 %

Procedure:
(S)-2-(1-((6-Amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (100 mg, 0.23 mmol) was treated with 4-hydroxy-3-methyl-N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzenesulfonamide (133 mg, 0.34 mmol), 2M cesium carbonate (340 μl, 0.68 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (19 mg, 0.02 mmol) according to the method described in Example 3 to give 76 mg (53% yield) of the title compound. Purity 98%.
Reaction SMILES: [F:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N+:14]([O-])=O)[CH2:4][CH:3]1[N:17]1[C:25](=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]1=[O:27]>C(O)C.C(OCC)(=O)C>[NH2:14][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:8]=1[N:5]1[CH2:6][CH2:7][CH:2]([F:1])[CH:3]([N:17]2[C:18](=[O:27])[C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:25]2=[O:26])[CH2:4]1
Reactant: O=C1c2ccccc2C(=O)N1C1CN(c2ccncc2[N+](=O)[O-])CCC1F
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1cnccc1N1CCC(F)C(N2C(=O)c3ccccc3C2=O)C1
Yield: 87 %

Procedure:
Following Method 2 of Example 49, (+/−)-2-(4-fluoro-1-(3-nitropyridin-4-yl)piperidin-3-yl)isoindoline-1,3-dione in ethanol and ethyl acetate (1:1, 0.1 M solution) was reduced yielding (+/−)-2-(1-(3-aminopyridin-4-yl)-4-fluoropiperidin-3-yl)isoindoline-1,3-dione, (87%). LCMS (m/z): 341.1 (MH+); LC Rt=2.23 min.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:11][C:10]([C:20]([F:23])([F:22])[F:21])=[CH:9][CH:8]=2)([O-])=O.[OH-].[Na+]>Cl>[NH2:1][C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:11][C:10]([C:20]([F:23])([F:21])[F:22])=[CH:9][CH:8]=2
Reactant: O=[N+]([O-])c1cnc2ccc(C(F)(F)F)cc2c1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1cnc2ccc(C(F)(F)F)cc2c1-c1ccccc1
Reaction time: 1 h
Yield: 80.6 %

Procedure:
A mixture of 3-nitro-4-phenyl-6-trifluoromethylquinoline (2.0 g), stannous chloride dihydrate (5.0 g) and conc. hydrochloric acid (20 ml) was stirred for 1 hr. at 100° C. The mixture was neutralized with 6N-sodium hydroxide solution and extracted with chloroform. The chloroform layer was washed with water, dried over anhydrous magnesium sulfate, and then distilled to remove the solvent. The residue was recrystallized from a mixture of isopropyl ether and hexane to give 3-amino-4-phenyl-6-trifluoromethylquinoline (1.46 g, 80 %). m.p. 107°-108° C.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[S:11]([NH:14][C:15]1[C:24]([C:25]([O:27][CH3:28])=[O:26])=[C:23]2[C:18]([C:19]3[CH:31]=[CH:30][O:29][C:20]=3[CH2:21][O:22]2)=[CH:17][CH:16]=1)(=[O:13])=[O:12].Cl[C:33]([O:35][CH3:36])=[O:34].C(=O)(O)[O-].[Na+]>C1COCC1>[Br:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[S:11]([N:14]([C:15]1[C:24]([C:25]([O:27][CH3:28])=[O:26])=[C:23]2[C:18]([C:19]3[CH:31]=[CH:30][O:29][C:20]=3[CH2:21][O:22]2)=[CH:17][CH:16]=1)[C:33]([O:35][CH3:36])=[O:34])(=[O:12])=[O:13]
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1OCc1occc1-2
Reactant: COC(=O)Cl
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1c(N(C(=O)OC)S(=O)(=O)c2ccc(F)cc2Br)ccc2c1OCc1occc1-2

Procedure:
To a suspension of sodium hydride (60% dispersion in oil, 0.043 g) in THF (10 mL) was added methyl 7-(2-bromo-4-fluorobenzenesulfonylamino)-4H-furo[2,3-c]chromene-6-carboxylate (Intermediate 7, 0.40 g). Once gas evolution had ceased, methyl chloroformate (0.102 mL) was added and the resultant mixture was stirred at room temperature for 2.5 hours. Saturated aqueous sodium bicarbonate solution was added and the mixture was extracted with ethyl acetate. The combined organic layers were dried (MgSO4), filtered and the filtrate was concentrated in vacuo. The residue was triturated with ether to give methyl 7-{N[2-bromo-4-fluorobenzenesulfonyl]-N-(methoxycarbonyl)amino}-4H-furo[2,3-c]chromene-6-carboxylate (0.230 g) as a white powder.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:12]=[C:11]([N:13]([C:15]2[CH:20]=[CH:19][C:18]([N:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=2)[CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[C:40](OC(=O)C)(=[O:42])[CH3:41]>C(Cl)Cl.C(OCC)(=O)C>[CH3:1][N:2]([C:3]1[N:12]=[C:11]([N:13]([C:15]2[CH:16]=[CH:17][C:18]([N:21]([CH3:22])[CH3:23])=[CH:19][CH:20]=2)[CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[C:40](=[O:42])[CH3:41]
Reactant: CNc1nc(N(C)c2ccc(N(C)C)cc2)c2ccccc2n1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)N(C)c1nc(N(C)c2ccc(N(C)C)cc2)c2ccccc2n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.6 %

Procedure:
To a solution of (2-methylamino-quinazolin-4-yl)-(4-dimethylaminophenyl)-methylamine (40 mg, 0.13 mmol) in 4 mL of methylenechloride cooled at 0° C. was added triethylamine (50 uL, 0.36 mmol), few crystals of dimethylaminopyridine and acetic anhydride (50 uL, 0.53 mmol). The reaction mixture was stirred for 1 h at 0° C., warmed to room temperature, and stirred overnight. The reaction mixture was diluted with 25 mL of ethyl acetate and washed with 25 mL of saturated sodium bicarbonate. The organic layer was dried over anhydrous NaSO4, filtered and concentrated. The residue was purified by chromatography (40% ethyl acetate/hexane) to give the title compound (39 mg, 0.11 mmol, 85%). 1H NMR (CDCl3): 7.65-7.69 (m, 1H), 7.52 (ddd, J=8.4, 6.6, 1.8, 1H), 6.93-7.12 (m, 4H), 6.72 (m, 2H), 3.56 (s, 3H), 3.01 (s, 6H), 2.52 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([C:7]2[N:8]=[C:9]3[N:19]([CH:20]=2)[CH2:18][CH2:17][O:16][C:15]2[C:10]3=[CH:11][CH:12]=[C:13]([C:21]3[CH:22]=[N:23][N:24]([CH3:32])[C:25]=3[CH:26]3[CH2:31][CH2:30][CH2:29][NH:28][CH2:27]3)[CH:14]=2)[N:4]([CH:33]([CH3:35])[CH3:34])[N:3]=1.O1[CH2:41][CH2:40][C:39](=[O:42])CC1>CCO>[CH:33]([N:4]1[C:5]([C:7]2[N:8]=[C:9]3[C:10]4[CH:11]=[CH:12][C:13]([C:21]5[CH:22]=[N:23][N:24]([CH3:32])[C:25]=5[CH:26]5[CH2:31][CH2:30][CH2:29][N:28]([CH:40]6[CH2:39][O:42][CH2:41]6)[CH2:27]5)=[CH:14][C:15]=4[O:16][CH2:17][CH2:18][N:19]3[CH:20]=2)=[N:6][C:2]([CH3:1])=[N:3]1)([CH3:35])[CH3:34]
Reactant: O=C1CCOCC1
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(-c4cnn(C)c4C4CCCNC4)cc2OCC3)n(C(C)C)n1
Solvent: CCO
Product: Cc1nc(-c2cn3c(n2)-c2ccc(-c4cnn(C)c4C4CCCN(C5COC5)C4)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 17.8 %

Procedure:
A mixture of 4-[3-methyl-1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-12-[1-methyl-5-(piperidin-3-yl)-1H-pyrazol-4-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1 (14),2,4,10,12-pentaene (80 mg, 0.17 mmol), tetrahydropyran-4-one (25 mg, 0.25 mmol) and Ti(O-iPr)4 (2 drops) in EtOH (20 mL) was stirred at room temperature for 18 h. After concentration, the residue was purified by prep-HPLC (Gilson GX 281, Shim-pack PRC-ODS 250 mm×20 mm×2, gradient: CH3CN/10 mm/L NH4HCO3, 17 min) to give 213 (16 mg, 18% yield). LCMS (ESI): RT=4.75 min, m/z: 527.3 [M+H+]. 1H NMR (500 MHz, DMSO-d6) δ 8.42 (d, J=8.0 Hz, 1H), 7.91 (s, 1H), 7.43 (s, 1H), 7.08 (d, J=1.5 Hz, 1H), 6.94 (s, 1H), 7.39-7.36 (m, 1H), 5.87-5.84 (m, 1H), 4.54-4.40 (m, 8H), 3.90 (s, 3H), 3.18 (s, 1H), 2.74-2.69 (m, 2H), 2.24 (s, 3H), 2.11-2.06 (m, 1H), 1.78-1.71 (m, 5H), 1.47 (d, J=2.0 Hz, 6H)
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:6][C:5]([C:14]#[N:15])=[CH:4][C:3]=1[NH:16][C:17]1[N:22]=[C:21]([NH:23][CH:24]2[CH2:26][CH2:25]2)[C:20]2=[N:27][CH:28]=[C:29]([C:30]#[N:31])[N:19]2[N:18]=1.C[Si](C)(C)[O:34][C:35]1[CH2:38][CH2:37][C:36]=1O[Si](C)(C)C>CO>[Cl:1][C:2]1[C:7]([CH:8]2[CH2:9][CH2:10][N:11]([CH:36]3[CH2:37][CH2:38][C:35]3=[O:34])[CH2:12][CH2:13]2)=[CH:6][C:5]([C:14]#[N:15])=[CH:4][C:3]=1[NH:16][C:17]1[N:22]=[C:21]([NH:23][CH:24]2[CH2:25][CH2:26]2)[C:20]2=[N:27][CH:28]=[C:29]([C:30]#[N:31])[N:19]2[N:18]=1
Reactant: N#Cc1cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c(Cl)c(C2CCNCC2)c1
Reactant: C[Si](C)(C)OC1=C(O[Si](C)(C)C)CC1
Solvent: CO
Product: N#Cc1cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c(Cl)c(C2CCN(C3CCC3=O)CC2)c1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
To the stirred suspension of 2-((2-chloro-5-cyano-3-(piperidin-4-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile, (Example 208) (20 mg, 0.046 mmol) in TIIF (1 ml) was added drop wise a solution of 1,2-bis((trimethylsilyl)oxy)cyclobut-1-ene (12.75 mg, 0.055 mmol) in MeOH (0.4 ml) at 0° C. under nitrogen. The reaction mixture was allowed to warm to room temperature and stirred for 5 days (converted to clear solution). Solvent was removed. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 30-70% B over 18 minutes, then a 7-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to afford 2-((2-chloro-5-cyano-3-(1-(2-oxocyclobutyl)piperidin-4-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (6.6 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]([NH:5][C:6]1[S:10][N:9]=[C:8]([S:11][CH2:12][CH3:13])[C:7]=1[C:14]#[N:15])=[O:4].[OH:17]O>>[CH3:16][N:2]([CH3:1])[C:3]([NH:5][C:6]1[S:10][N:9]=[C:8]([S:11]([CH2:12][CH3:13])=[O:17])[C:7]=1[C:14]#[N:15])=[O:4]
Reactant: CCSc1nsc(NC(=O)N(C)C)c1C#N
Reactant: OO
Product: CCS(=O)c1nsc(NC(=O)N(C)C)c1C#N
Yield: 76.4 %

Procedure:
Seventeen grams of 1,1-dimethyl-3-(4-cyano-3-(ethylthio)5-isothiazolyl)urea was treated with 2.75 g of 30% hydrogen peroxide in the manner described in Example II. No solid separated on cooling the reaction mixture. The mixture was neutralized with saturated aqueous sodium bicarbonate solution, then concentrated to near dryness. The viscous residue was crystallized from ethanol to yield 13.8 g of 1,1-dimethyl-3-(4-cyano-3-(ethylsulfinyl)-5-isothiazolyl)urea, m.p. 162°-163°. The nmr spectrum was consistent with the assigned structure.