Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C@@H:18]([NH2:20])[CH3:19])[C:8]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)=[N:9]2)=[CH:4][CH:3]=1.Cl[C:22]1[N:30]=[CH:29][N:28]=[C:27]2[C:23]=1[NH:24][CH:25]=[N:26]2.CCN(C(C)C)C(C)C>C(O)CCC>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C@@H:18]([NH:20][C:22]3[N:30]=[CH:29][N:28]=[C:27]4[C:23]=3[N:24]=[CH:25][NH:26]4)[CH3:19])[C:8]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: C[C@H](N)c1cc2ccc(F)cc2nc1-c1cccnc1
Reactant: Clc1ncnc2nc[nH]c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1cc2ccc(F)cc2nc1-c1cccnc1

Procedure:
Prepared according to Procedure H using (1S)-1-(7-fluoro-2-(pyridin-3-yl)-quinolin-3-yl)ethanamine (0.067 g, 0.236 mmol), 6-chloropurine (0.044 g, 0.283 mmol, 1.2 eq) and DIEA (0.48 mmol, 2.0 eq) in n-butanol (3 mL). N-((S)-1-(7-fluoro-2-(pyridin-3-yl)quinolin-3-yl)ethyl)-9H-purin-6-amine [PI3Kδ IC50=23 nM] was obtained after purification as a white solid. 1H-NMR (MeOD) δ ppm 8.99 (s, 1 H), 8.57-8.65 (m, 2 H), 8.33 (d, J=7.83 Hz, 1 H), 8.16 (s, 1 H), 8.08 (s, 1 H), 7.85-7.96 (m, 2 H), 1.62 (d, 3 H), Mass Spectrum (ESI) m/e=402 (M+1).
Reaction SMILES: B.CSC.C(O[C:13]1[CH:30]=[CH:29][C:16]2[CH:17]=[C:18](C3C=CC(OC)=CC=3)[CH2:19][O:20][C:15]=2[CH:14]=1)C1C=CC=CC=1.C1C[O:34]CC1>>[O:20]1[C:15]2[C:16](=[CH:29][CH:30]=[CH:13][CH:14]=2)[CH:17]([OH:34])[CH2:18][CH2:19]1
Reactant: C1CCOC1
Reactant: COc1ccc(C2=Cc3ccc(OCc4ccccc4)cc3OC2)cc1
Agent: B
Solvent: CSC
Product: OC1CCOc2ccccc21
Reaction time: 0.08 h
Yield: 60 %

Procedure:
Borane-dimethylsulfide complex (BH3—SMe2) (10 M, 1.14 mL, 11.4 mmol) in THF was added dropwise at 0° C. to a solution of compound 1 (1 g, 2.9 mmol) in THF (12 mL), and the resultant mixture was stirred at 0° C. for 4 hrs. After completion of the reaction, the mixture was quenched with H2O (7 mL), and then continually stirred for 5 min, followed by addition of 10% NaOH (2 mL) and 37% H2O2 (0.36 mL). After stirring for 30 min, the mixture was extracted with CH2Cl2 (30 mL×5). The organic layers were combined and dried with anhydrous MgSO4. After filtration, the filtrate was concentrated in vacuo, followed by purification via silica gel column chromatography (ethyl acetate/n-hexane=1:4), thus giving the title compound 4 as a colorless crystal (0.63 g, 60% yield).
Reaction SMILES: Br[CH:2]([C:4]1[N:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[C:8](=[O:17])[CH:7]=[CH:6][N:5]=1)[CH3:3].[CH3:18][NH2:19]>C(O)C>[F:16][C:13]1[CH:14]=[CH:15][C:10]([N:9]2[C:8](=[O:17])[CH:7]=[CH:6][N:5]=[C:4]2[CH:2]([NH:19][CH3:18])[CH3:3])=[CH:11][CH:12]=1
Reactant: CN
Reactant: CC(Br)c1nccc(=O)n1-c1ccc(F)cc1
Solvent: CCO
Product: CNC(C)c1nccc(=O)n1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 76 %

Procedure:
The bromide (25) (190 mg, 0.64 mmol) was dissolved in a 33% solution of methylamine in ethanol (5 mL) and stirred at ambient temperature. After 3.5 h, the solvent and excess methylamine were evaporated under reduced pressure and residue was partitioned between water (10 mL) and dichloromethane (10 mL). The organic layer was washed again with water (10 mL), dried (MgSO4), and concentrated to give the title amine (26) (120 mg, 76%) as a yellow oil:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=2[O:15][CH3:16])[C:5]([F:17])=[CH:4][N:3]=1.[CH:18]1([S:21][CH2:22][C:23]2[CH:24]=[C:25]([CH:27]=[C:28]([F:30])[CH:29]=2)[NH2:26])[CH2:20][CH2:19]1>>[CH:18]1([S:21][CH2:22][C:23]2[CH:24]=[C:25]([NH:26][C:2]3[N:7]=[C:6]([C:8]4[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=4[O:15][CH3:16])[C:5]([F:17])=[CH:4][N:3]=3)[CH:27]=[C:28]([F:30])[CH:29]=2)[CH2:19][CH2:20]1
Reactant: COc1cc(F)ccc1-c1nc(Cl)ncc1F
Reactant: Nc1cc(F)cc(CSC2CC2)c1
Product: COc1cc(F)ccc1-c1nc(Nc2cc(F)cc(CSC3CC3)c2)ncc1F

Procedure:
Intermediate 50.3 was prepared under similar conditions as described in the preparation of Intermediate 20.1 using 2-chloro-5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyrimidine and 3-[(cyclopropylsulfanyl)-methyl]-5-fluoroaniline. The batch was purified by chromatography (hexane to hexane/ethyl acetate 50%) to give the desired product.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1.[CH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]=1[O:30][C:31](Cl)=[O:32]>>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:31](=[O:32])[O:30][C:21]3[CH:22]=[CH:23][C:24]4[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:20]=3)[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: O=C(Cl)Oc1ccc2ccccc2c1
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Product: Nc1nc2ccccc2c2c1ncn2CCCCNC(=O)Oc1ccc2ccccc2c1

Procedure:
According to the general method of Example 7, 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine and chloroformic acid 2-naphthyl ester were combined to provide 2-naphthyl N-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]carbamate as a white powder, m.p. 154.0-155.0° C. 1H NMR (300 MHz, DMSO-d6) δ 8.23 (s, 1H), 8.08 (d, J=7.4 Hz, 1H), 7.94-7.86 (m, 4H), 7.64 (dd, J=8.3, 1.0 Hz, 1H), 7.56-7.43 (m, 4H), 7.30 (m, 1H), 7.20 (dd, J=8.8, 2.3 Hz, 1H), 6.61 (broad s, 2H), 4.65 (t, J=6.9 Hz, 2H), 3.14 (q, J=6.4 Hz, 2H), 1.94 (m, 2H), 1.56 (m, 2H), MS (EI) m/e 426.1927 (426.1930 calcd for C25H23N5O2).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](O)=[N:6][CH:7]=1.P(Br)(Br)[Br:13]>>[Br:13][C:5]1[C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]([Br:1])=[CH:7][N:6]=1
Reactant: BrP(Br)Br
Reactant: O=[N+]([O-])c1cc(Br)cnc1O
Product: O=[N+]([O-])c1cc(Br)cnc1Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 43.1 %

Procedure:
77.11 g (354.4 mmol) of 5-bromo-2-hydroxy-3-nitropyridine are heated at 120° C. for 3 hours together with 101.61 g (354.4 mmol) of phosphorus oxytribromide and 33.7 ml (354.4 mmol) of phosphorus tribromide. The reaction mixture is subsequently poured carefully, in small portions, into ice water, stirred for 1 hour and extracted three times with dichloromethane. The organic phase is washed twice with water, dried over sodium sulfate, filtered and freed from the solvent. Chromatographic purification (silica gel/dichloromethane) gives 43.05 g of 2,5-dibromo-3-nitropyridine. ##STR11##
Reaction SMILES: S(O)([O-])(=O)=O.[NH2:6][C:7]1[S:11][N:10]=[C:9]([C:12](=[N:35][O:36][CH3:37])[C:13]([NH:15][CH:16]2[C:33](=[O:34])[N:18]3[C:19]([C:30]([OH:32])=[O:31])=[C:20]([CH2:23][N+:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:21][S:22][C@H:17]23)=[O:14])[N:8]=1.[C:38](=O)([O-:40])[OH:39].[Na+:42]>>[C:38]([NH:6][C:7]1[S:11][N:10]=[C:9]([C:12](=[N:35][O:36][CH3:37])[C:13]([NH:15][CH:16]2[C:33](=[O:34])[N:18]3[C:19]([C:30]([O-:32])=[O:31])=[C:20]([CH2:23][N+:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:21][S:22][C@H:17]23)=[O:14])[N:8]=1)([O-:40])=[O:39].[Na+:42]
Reactant: O=C([O-])O
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C[n+]3ccccc3)CS[C@H]12)c1nsc(N)n1
Agent: O=S(=O)([O-])O
Agent: [Na+]
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccccc3)CS[C@H]12)c1nsc(NC(=O)[O-])n1

Procedure:
Sodium 7-[2-(5-carboxylatoamino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-(1-pyridinio)methyl-3-cephem-4-carboxylate (syn isomer) was prepared by reacting 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-(1-pyridinio)methyl-3-cephem-4-carboxylate sulfate (syn isomer) (50 mg) and sodium hydrogencarbonate (22 mg) and detected according to a similar manner to that of Example 17.
Reaction SMILES: [C:1]([CH2:3][C@H:4]1[CH2:15][CH2:14][C:13]2[S:12][C:11]3[N:10]=[CH:9][N:8]=[C:7]([O:16][CH:17]4[CH2:22][CH2:21][CH:20]([N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:19][CH2:18]4)[C:6]=3[C:5]1=2)#[N:2].[OH:32][Li].O.OO>CO>[C:1]([CH2:3][C@H:4]1[CH2:15][CH2:14][C:13]2[S:12][C:11]3[N:10]=[CH:9][N:8]=[C:7]([O:16][CH:17]4[CH2:18][CH2:19][CH:20]([N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[CH2:21][CH2:22]4)[C:6]=3[C:5]1=2)(=[O:32])[NH2:2]
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CC#N)CC4)CC1
Reactant: [Li]O
Agent: OO
Solvent: O
Solvent: CO
Product: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CC(N)=O)CC4)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.1 %

Procedure:
A solution of tert-butyl N-(4-[[(3R)-3-(cyanomethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (709 mg, 1.60 mmol, 1.00 equiv) in 6 mL of MeOH was added LiOH.H2O (135 mg, 3.21 mmol, 2.01 equiv) and H2O2 (30%, 1 mL) at 0° C. The resulting solution was stirred for 2 h at room temperature and quenched with saturated aqueous NaHSO3 solution and extracted with 3×50 mL of ethyl acetate. The combined extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:4) to give tert-butyl N-(4-[[(3R)-3-(carbamoylmethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (524 mg, 71%) as a white solid. MS: m/z 461 [M+H]+.
Reaction SMILES: S(O[CH:12]([CH2:21][CH3:22])[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])(C1C=CC(C)=CC=1)(=O)=O.[N-:23]=[N+:24]=[N-:25].[Na+]>CS(C)=O>[N:23]([CH:12]([CH2:21][CH3:22])[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[N+:24]=[N-:25]
Reactant: [N-]=[N+]=[N-]
Reactant: CCC(CC(=O)OC(C)(C)C)OS(=O)(=O)c1ccc(C)cc1
Agent: [Na+]
Solvent: CS(C)=O
Product: CCC(CC(=O)OC(C)(C)C)N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 66 h
Yield: 88.9 %

Procedure:
t-Butyl 3-tosyloxypentanoate (7.75 g, 23.6 mmol) was added to a suspension of sodium azide (3.07 g, 47.2 mmol) in dry DMSO (135 ml) and stirred at room temperature for 66 h. The reaction mixture was poured into ice-water (200 ml) and extracted with CH2Cl2 (2×150 ml). The organic extracts were combined, washed with water (4×150 ml) and dried over anhydrous MgSO4. Evaporation of CH2Cl2 under reduced pressure gave an oil (4.18 g, 89.4%). ir (neat) νmax : 2096 (N3) and 1720 cm-1 (C=O of ester); 1Hmr (CDCl3) δ: 1.0 (3H, t), 1.27-1.85 (2H, m) 1.48 (9H, s) 2.40 (2H, d) and 3.68 ppm (H, m).
Reaction SMILES: [CH3:1][C:2]1[CH:23]=[CH:22][C:5]([NH:6][CH2:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17](=[O:20])(=[O:19])[NH2:18])=[CH:13][C:12]=2[Cl:21])=[O:9])=[CH:4][CH:3]=1.[CH2:24]=O>C(O)C.O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:6]2[CH2:7][C:8](=[O:9])[N:10]([C:11]3[CH:16]=[CH:15][C:14]([S:17](=[O:19])(=[O:20])[NH2:18])=[CH:13][C:12]=3[Cl:21])[CH2:24]2)=[CH:22][CH:23]=1
Reactant: C=O
Reactant: Cc1ccc(NCC(=O)Nc2ccc(S(N)(=O)=O)cc2Cl)cc1
Solvent: O
Solvent: CCO
Product: Cc1ccc(N2CC(=O)N(c3ccc(S(N)(=O)=O)cc3Cl)C2)cc1
Temperature: 0 °C

Procedure:
2-(p-Methylanilino)-N-(2-chloro-4-sulphamoylphenyl)-acetamide (15g) was dissolved in ethanol (200 ml) and paraformaldehyde (2.5 g) in water (400ml) added thereto. The mixture was refluxed for 3 hours, cooled in ice/water and filtered to yield the title compound (6.45g), m.p. 223°-226° (ethanol).
Reaction SMILES: [OH:1][C:2]1[C:12]([O:13][C:14](=[O:16])[CH3:15])=[CH:11][C:5]2[C:6](=[O:10])[N:7]([CH3:9])[S:8][C:4]=2[CH:3]=1.[N+:17]([O-])([OH:19])=[O:18]>C(O)(=O)C>[OH:1][C:2]1[C:12]([O:13][C:14](=[O:16])[CH3:15])=[CH:11][C:5]2[C:6](=[O:10])[N:7]([CH3:9])[S:8][C:4]=2[C:3]=1[N+:17]([O-:19])=[O:18]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Oc1cc2c(=O)n(C)sc2cc1O
Solvent: CC(=O)O
Product: CC(=O)Oc1cc2c(=O)n(C)sc2c([N+](=O)[O-])c1O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of acetic acid 6-hydroxy-2-methyl-3-oxo-2,3-dihydro-benzo[d]isothiazol-5-yl ester (0.055 g) in acetic acid at 10° C. nitric acid (100% 0.015 g) was added and stirring was continued at room temperature for 15 minutes. The mixture was poured into ice water and extracted with ethyl acetate. Ethyl acetate was dried and evaporated to dryness.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([C:13]([NH:15][CH2:16][C:17]([OH:19])=[O:18])=[O:14])[N:3]=1.[C:20]1([SH:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[OH:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([S:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:3][C:4]=1[C:13]([NH:15][CH2:16][C:17]([OH:19])=[O:18])=[O:14]
Reactant: Sc1ccccc1
Reactant: O=C(O)CNC(=O)c1nc(Cl)c2ccccc2c1O
Product: O=C(O)CNC(=O)c1nc(Sc2ccccc2)c2ccccc2c1O
Temperature: 140 °C

Procedure:
The title compound was prepared as follows: To a solution of 250 mg of [(1-chloro-4-hydroxy-isoquinoline-3-carbonyl)-amino]-acetic acid, (U.S. Pat. No. 6,093,730, disclosed as N-((1-chloro-4-hydroxyisoquinoline-3-yl)carbonyl)glycine), in 1 ml 1-methyl-2-pryrrolidinone was added 1.2 ml of benzenethiol. The solution was heated at 130 to 150° C. in a sealed tube for 16 h. The solution was concentrated under vacuum. The resultant residue was crystallized from methanol to yield 91 mg of a tan solid; MS (−) m/z 353.07 (M−1)
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[C:15]([F:21])[CH:16]=[C:17]([F:20])[CH:18]=3)[CH:13]=[CH:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[O:23]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[O:26][CH2:25][CH:24]1[C:33](O)=[O:34].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[C:19]2[C:14]=1[CH:13]=[CH:12][C:11](=[O:22])[N:10]2[CH2:9][CH2:8][N:5]1[CH2:4][CH2:3][CH:2]([NH:1][C:33]([CH:24]2[O:23][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[O:26][CH2:25]2)=[O:34])[CH2:7][CH2:6]1
Reactant: NC1CCN(CCn2c(=O)ccc3c(F)cc(F)cc32)CC1
Reactant: O=C(O)C1COc2ccccc2O1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Product: O=C(NC1CCN(CCn2c(=O)ccc3c(F)cc(F)cc32)CC1)C1COc2ccccc2O1
Yield: 48.3 %

Procedure:
1-[2-(4-Aminopiperidin-1-yl)ethyl]-5,7-difluoroquinolin-2(1H)-one (Intermediate 23, 100 mg, 0.326 mmol) was reacted as described for Example 99 with 2,3-dihydro-1,4-benzodioxine-2-carboxylic acid (71 mg, 0.391 mmol), EDC (94 mg, 0.489 mmol) and HOBT (66 mg, 0.489 mmol) to give title compound (73.9 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[CH:38][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([C@H:16]3[C@@H:20]4[O:21][C:22]([CH3:25])([CH3:24])[O:23][C@@H:19]4[C@@H:18]([CH2:26][N:27]([CH3:37])[CH:28]4[CH2:31][CH:30]([CH2:32][C:33]([O:35]C)=[O:34])[CH2:29]4)[O:17]3)[C:9]=2[N:10]=[CH:11][N:12]=1.[OH-].[Na+].O.Cl>CO>[CH3:1][O:2][C:3]1[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[CH:38][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([C@H:16]3[C@@H:20]4[O:21][C:22]([CH3:24])([CH3:25])[O:23][C@@H:19]4[C@@H:18]([CH2:26][N:27]([CH3:37])[CH:28]4[CH2:29][CH:30]([CH2:32][C:33]([OH:35])=[O:34])[CH2:31]4)[O:17]3)[C:9]=2[N:10]=[CH:11][N:12]=1
Reactant: COC(=O)CC1CC(N(C)C[C@H]2O[C@@H](n3ccc4c(NCc5ccc(OC)cc5OC)ncnc43)[C@@H]3OC(C)(C)O[C@@H]32)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2O[C@H](CN(C)C3CC(CC(=O)O)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Temperature: 50 °C
Reaction time: 17 h

Procedure:
A solution of methyl 2-(3-((((3aR,4R,6R,6aR)-6-(4-((2,4-dimethoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)(methyl)amino)cyclobutyl)acetate (270 mg, 0.453 mmol) in methanol (8.6 mL) was treated dropwise with a solution of sodium hydroxide (36 mg, 0.91 mmol) in water (0.9 mL, 50 mmol) and the mixture was heated at 50° C. After 17 h, HPLC indicated the reaction was complete. The reaction mixture was cooled to room temperature and treated with 0.91 mL 1.0N HCl to adjust the pH to ˜7. The solution was concentrated to remove the methanol and the resulting aqueous suspension was lyophilized to yield a white solid. The material was used as is in the next step, assuming a quantitative recovery: MS (ESI+) for C30H39N5O7 m/z 582.4 (M+H)+; MS (ESI−) for C30H39N5O7 m/z 580.4 (M−H)−; HPLC purity >95% (ret. time, 2.72 min).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:18]3[C@H:19]([CH2:24][C:25]4[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=4)[C:28]([OH:30])=O)[CH2:20][CH2:21][CH2:22][CH:23]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1CCCC1.ClC(OCC(C)C)=O.[NH3:47]>C(N(CC)CC)C>[C:1]1([C:7]2[N:8]=[C:9]([C:18]3[C@H:19]([CH2:24][C:25]4[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=4)[C:28]([NH2:47])=[O:30])[CH2:20][CH2:21][CH2:22][CH:23]=3)[O:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N
Reactant: O=C(O)c1cccc(C[C@@H]2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: NC(=O)c1cccc(C[C@@H]2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Reaction time: 0.5 h

Procedure:
To a solution of (S)-3-{[2-(4,5-diphenyloxazol-2-yl)-2- cyclohexen-1-yl]methyl}benzoic acid (0.3 g) in a tetrahydrofuran (10 ml) were added isobutyl chloroformate (0.15 ml) and triethylamine (0.2 ml) at 0° C. under N2. After being stirred for 30 minutes, NH3 (5 ml, 4M solution in methanol) was added to the mixture. After being stirred for 30 minutes, the solvent was removed in vacuo. The residue was partitioned between ethyl acetate and lN-NaOH and the organic layer was washed with brine. The dried solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel to give and the obtained residue was purified by chromatography on silica gel to give (S)-3-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl]methyl}- benzamide (0.03 g).
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:49]1[C:50]([C:58]2[CH:59]=[C:60]([NH2:64])[CH:61]=[CH:62][CH:63]=2)=[CH:51][N:52]2[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=12>CN(C)C=O>[N:49]1[C:50]([C:58]2[CH:59]=[C:60]([NH:64][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[OH:10])=[O:24])[CH:61]=[CH:62][CH:63]=2)=[CH:51][N:52]2[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=12
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Reactant: Nc1cccc(-c2cn3ccccc3n2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc(-c2cn3ccccc3n2)c1)c1cc2cccc(O)c2oc1=O
Temperature: 25 °C
Yield: 22 %

Procedure:
DIEA (0.046 mL, 0.27 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.050 g, 0.24 mmol) and HATU (0.101 g, 0.27 mmol) in 1 mL of dimethylformamide (DMF) with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-imidazo[1,2-a]pyridin-2-yl-phenylamine (0.051 g, 0.24 mmol) was added and allowed to react overnight, when a yellow solid precipitated out of solution. The precipitate was filtered and dried under suction and then in vacuo to give 0.021 g of 1541A in a 22% yield: LCMS (ESI) m/z 398 (MH+).
Reaction SMILES: N1C=CC=CC=1.Cl[C:8]([O:10][CH2:11][Cl:12])=[O:9].[CH3:13][C:14]([OH:17])([CH3:16])[CH3:15]>C(Cl)Cl>[C:8](=[O:9])([O:10][CH2:11][Cl:12])[O:17][C:14]([CH3:16])([CH3:15])[CH3:13]
Reactant: CC(C)(C)O
Reactant: O=C(Cl)OCCl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)OCCl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
0.62 mL pyridine was added dropwise to a solution of 0.77 g chloromethyl chloroformate and 1.32 mL t-BuOH in 60 mL CH2Cl2 cooled in an ice bath under an Ar atmosphere. The reaction was stirred 2 hours at 0° C. then transferred to a separatory funnel. The reaction was washed twice with H2O, once with 10% CuSO4, once with brine and dried with MgSO4. Suction filtration and evaporation provided 0.55 g of desired product which was used without purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[C:7](=[O:12])[N:6]([CH:13]([CH3:15])[CH3:14])[CH2:5]2.CC1(C)C(C)(C)[O:20][B:19](B2OC(C)(C)C(C)(C)O2)[O:18]1>>[F:11][C:10]1[CH:9]=[C:8]2[C:4]([CH2:5][N:6]([CH:13]([CH3:15])[CH3:14])[C:7]2=[O:12])=[CH:3][C:2]=1[B:19]([OH:20])[OH:18]
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: CC(C)N1Cc2cc(Br)c(F)cc2C1=O
Product: CC(C)N1Cc2cc(B(O)O)c(F)cc2C1=O

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 52, Step 7 starting from 5-bromo-6-fluoro-2-isopropylisoindolin-1-one and 4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl]. LCMS: (M+H)+=238.1.
Reaction SMILES: Br[C:2]1[S:22][C:5]2=[N:6][C:7]([CH3:21])=[CH:8][C:9]([NH:10][S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)(=[O:13])=[O:12])=[C:4]2[C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=1.[CH3:31][N:32]([CH3:36])[CH2:33][C:34]#[CH:35].C(N(CC)CC)C>C1COCC1.[Cu]I.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>[Cl:20][C:16]1[CH:15]=[C:14]([S:11]([NH:10][C:9]2[CH:8]=[C:7]([CH3:21])[N:6]=[C:5]3[S:22][C:2]([C:35]#[C:34][CH2:33][N:32]([CH3:36])[CH3:31])=[C:3]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=4)[C:4]=23)(=[O:13])=[O:12])[CH:19]=[CH:18][CH:17]=1
Reactant: COc1cccc(-c2c(Br)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Reactant: C#CCN(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cccc(-c2c(C#CCN(C)C)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Temperature: 70 °C
Reaction time: 3 h
Yield: 4 %

Procedure:
A mixture of N-{2-bromo-6-methyl-3-[3-(methyloxy)phenyl]thieno[2,3-b]pyridin-4-yl}-3-chlorobenzenesulfonamide (Example 33) (122 mg, 0.233 mmol), N,N-dimethyl-2-propyn-1-amine (0.037 mL, 0.349 mmol), copper(I) iodide (4.44 mg, 0.023 mmol), bis(triphenylphosphine)palladium(II) chloride (6.54 mg, 9.32 μmol) and triethylamine (0.097 mL, 0.699 mmol) in THF (1.0 mL) was stirred under an atmosphere of nitrogen at 70° C. for 3 h. The mixture was allowed to cool to RT and was then partitioned between saturated aqueous NaHCO3 (25 mL) and ethyl acetate (75 mL). The aqueous phase was separated and extracted with additional ethyl acetate (25 mL). The organic extracts were combined, washed with brine (25 mL), dried with anhydrous MgSO4, filtered and evaporated to dryness. The residue was purified on silica, eluting with a gradient of 0-10% MeOH in DCM, and then further purified on silica, eluting with a gradient of 0-10% 2M NH3 in MeOH in DCM to afford the title compound (4.9 mg). 1H NMR (MeOD, 400 MHz) δ ppm: 2.42 (6H, s), 2.55 (3H, s), 3.80 (5H, s), 6.89 (2H, m), 7.01 (1H, d, J=7.7 Hz), 7.26 (1H, s), 7.32-7.48 (3H, m), 7.49-7.60 (2H, m).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[NH:34]1[CH2:38][CH2:37][CH2:36][CH:35]1[CH2:39][N:40]1[CH2:44][CH2:43][CH2:42][CH2:41]1>>[NH:2]=[C:1]([N:34]1[CH2:38][CH2:37][CH2:36][CH:35]1[CH2:39][N:40]1[CH2:44][CH2:43][CH2:42][CH2:41]1)[C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1
Reactant: C1CNC(CN2CCCC2)C1
Product: N=C(c1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1)N1CCCC1CN1CCCC1
Yield: 12 %

Procedure:
The title compound was prepared from 4-(3-(3-cyanophenyl)ureido)-N-(4-sulfamoylbenzyl)benzenesulfonamide following procedure C and using 2 equivalents of 1-(pyrrolidin-2-ylmethyl)pyrrolidine as secondary amine. The product was purified by preparative HPLC.