Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][CH2:2][CH:3]([CH2:5][OH:6])[OH:4].[C:7]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:11])/[CH:8]=[CH:9]/[CH3:10].C(N(CC)CC)C>O>[C:13]([O:12][C:7](=[O:11])[CH2:8][CH:9]([CH3:10])[S:1][CH2:2][CH:3]([OH:4])[CH2:5][OH:6])([CH3:16])([CH3:15])[CH3:14]
Reactant: OCC(O)CS
Reactant: C/C=C/C(=O)OC(C)(C)C
Solvent: O
Solvent: CCN(CC)CC
Product: CC(CC(=O)OC(C)(C)C)SCC(O)CO
Temperature: 60 °C
Reaction time: 48 h
Yield: 73 %

Procedure:
To thioglycerol (0.835 ml), t-butyl crotonate (10 ml) and triethylamine (1 ml) were added, followed by stirring at 60° C. for 48 hours. After cooling and addition of water, the reaction mixture was extracted with ethyl acetate. The extract was washed with a 5% aqueous solution of citric acid, a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, and dried over anhydrous sodium sulfate, and the solvent was distilled off, to yield the title compound (1.82 g, yield 73%) as a colorless oily substance.
Reaction SMILES: [N:1]1([CH:7]([CH3:10])[CH2:8][NH2:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:11]([O:13][C:14]([C:16]1[C:17](=[O:39])[C:18]2[CH:23]=[N:22][C:21](S(C)(=O)=O)=[N:20][C:19]=2[N:28]([C:30]2[CH:31]=[C:32]3[C:36](=[CH:37][CH:38]=2)[CH2:35][CH2:34][CH2:33]3)[CH:29]=1)=[O:15])[CH3:12]>>[CH2:11]([O:13][C:14]([C:16]1[C:17](=[O:39])[C:18]2[CH:23]=[N:22][C:21]([NH:9][CH2:8][CH:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[CH3:10])=[N:20][C:19]=2[N:28]([C:30]2[CH:31]=[C:32]3[C:36](=[CH:37][CH:38]=2)[CH2:35][CH2:34][CH2:33]3)[CH:29]=1)=[O:15])[CH3:12]
Reactant: CC(CN)N1CCOCC1
Reactant: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(S(C)(=O)=O)ncc2c1=O
Product: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(NCC(C)N3CCOCC3)ncc2c1=O

Procedure:
Using the procedure outlined in Example 1(Step F) the title compound was prepared from 2-morpholin-4-yl-propylamine (5.3 μL, 0.036 mmol) and 8-indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 1(Step E), 15 mg, 0.036 mmol). 17.2 mg of 8-indan-5-yl-2-(2-morpholin-4-yl-propylamino)-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester was obtained as a white solid. 1H NMR (400 MHz, CDCl3) δ (ppm): 9.26 (s, 1H), 8.46 (s, 1H), 7.02-7.40 (m, 3H), 6.64 (br, 1H), 4.35 (q, 2H), 3.71 (m, 4H), 3.22 (m, 2H), 2.98 (m, 4H), 2.38 (m, 6H), 2.17 (m, 2H), 1.67 (m, 2H), 1.37 (t, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C26H31N5O4: 478.24 (M+H). Found: 478.4.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][CH3:11])[C:5](=[O:9])[NH:6][C:7]=1[CH3:8].IC.Cl[CH2:15]Cl>[Al].C(=O)([O-])[O-].[Ag+2]>[Br:1][C:2]1[C:7]([CH3:8])=[N:6][C:5]([O:9][CH3:15])=[C:4]([CH2:10][CH3:11])[CH:3]=1
Reactant: CCc1cc(Br)c(C)[nH]c1=O
Reactant: ClCCl
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Agent: [Al]
Solvent: CI
Product: CCc1cc(Br)c(C)nc1OC
Temperature: 25 °C
Reaction time: 17 h
Yield: 99.9 %

Procedure:
A mixture of 5-bromo-3-ethyl-6-methyl-1H-pyridin-2-one (41.8 g, 0.193 mol) obtained from Step 2 as described above, iodomethane (70 mL, 1.12 mol), silver carbonate (72 g, 0.261 mol) and dichloromethane is mechanically stirred at ambient temperature for 17 hr (The reaction vessel is wrapped in aluminum foil). An additional portion of iodomethane (70 mL, 1.12 mol) is added and stirring continued for an additional 20 hr. The reaction mixture is filtered through a pad of Celite and the filter cake is washed with dichloromethane. The combined filtrate and wash is concentrated to afford the title compound (44.35 g, 99.9% yield) as a yellow oil.
Reaction SMILES: Cl.[CH3:2][O:3][NH:4][CH3:5].[CH:6]1([S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]([CH2:22][CH:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:19](O)=[O:20])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH2:8][CH2:7]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C.C(N(CC)CC)C>[CH:6]1([S:9]([C:12]2[CH:13]=[CH:14][C:15]([CH:18]([CH2:22][CH:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[C:19]([N:4]([O:3][CH3:2])[CH3:5])=[O:20])=[CH:16][CH:17]=2)(=[O:10])=[O:11])[CH2:8][CH2:7]1
Reactant: O=C(O)C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CON(C)C(=O)C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.6 %

Procedure:
To a solution of N-methoxymethanamine hydrochloride (3.90 g) in N,N-dimethylformamide (100 mL) was added triethylamine (5.60 mL) for neutralization, and a solution of 2-[4-(cyclopropylsulfonyl)phenyl]-3-(tetrahydro-2H-pyran-4-yl)propanoic acid (11.23 g) in N,N-dimethylformamide (50 mL), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (9.60 g) and 1-hydroxybenzotriazole (6.80 g) were added under ice-cooling. The reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was diluted with ethyl acetate, and washed with water, 1N aqueous hydrochloric acid solution and saturated aqueous sodium hydrogen carbonate. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (10.2 g, yield 81%) was obtained as colorless amorphous crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). MS: 382 (MH+).
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][CH:8]([CH2:11][OH:12])[CH2:7][C:6]=2[C:5]([F:13])=[CH:4][CH:3]=1.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>N1C=CC=CC=1>[CH3:24][C:14]1[CH:19]=[CH:18][C:17]([S:20]([O:12][CH2:11][CH:8]2[CH2:7][C:6]3[C:5]([F:13])=[CH:4][CH:3]=[C:2]([Br:1])[C:10]=3[O:9]2)(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: OCC1Cc2c(F)ccc(Br)c2O1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2Cc3c(F)ccc(Br)c3O2)cc1
Yield: 88.2 %

Procedure:
Treatment of (±)-(7-bromo-4-fluoro-2,3-dihydro-1-benzofuran-2-yl)methanol (6.21 g, 0.025 mol) with p-toluenesulfonyl chloride (5.26 g, 0.028 mol) in pyridine (120 mL) generally according to the procedure described for Intermediate 10 afforded 8.85 g (88%) of (±)-(7-bromo-4-fluoro-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a white solid. Rf=0.60 (silica, ethyl acetate:hexanes 1:1); mp 100-103° C.; Anal. calcd. for C16H14BrFO4S: C, 47.89; H, 3.52. Found: C, 47.89; H, 3.68.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8][CH3:9])=[O:7].[H-].[Na+].F[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1.O>CN(C=O)C>[N+:19]([C:16]1[CH:17]=[CH:18][C:13]([N:1]2[CH:5]=[CH:4][CH:3]=[C:2]2[C:6]([O:8][CH3:9])=[O:7])=[CH:14][CH:15]=1)([O-:21])=[O:20]
Reactant: COC(=O)c1ccc[nH]1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccn1-c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 664.9 %

Procedure:
Methyl 1H-pyrrole-2-carboxylate (1 g, 8.0 mmol) was dissolved in DMF (14 mL). The mixture was cooled down at 0° C. and sodium hydride (350 mg, 8.8 mmol) was added. After 5 min 1-fluoro-4-nitro-benzene (1.13 mmol, 7.99 mmol) was added and the mixture stirred at 80° C. for 3 hours. Water was added, the solid collected by filtration and washed with water to give (i) (1.85 g). 1H NMR (400 MHz, DMSO) δ 8.30 (d, J=9.0 Hz, 2H), 7.87-7.49 (m, 2H), 7.38 (dd, J=2.7, 1.8 Hz, 1H), 7.13 (dd, J=3.9, 1.7 Hz, 1H), 6.41 (dd, J=3.8, 2.8 Hz, 1H), 3.66 (s, 3H).
Reaction SMILES: [H-].[Na+].[S:3]([N:13]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[C:17](=[O:24])[CH2:16][CH2:15][CH2:14]1)([C:6]1[CH:12]=[CH:11][C:9]([CH3:10])=[CH:8][CH:7]=1)(=[O:5])=[O:4].S(OC)(O[CH3:29])(=O)=O.[Cl-].[NH4+]>CN(C)C=O>[CH3:29][O:24][C:17]1[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N:13]([S:3]([C:6]2[CH:7]=[CH:8][C:9]([CH3:10])=[CH:11][CH:12]=2)(=[O:4])=[O:5])[CH2:14][CH2:15][CH:16]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCCC(=O)c3ccccc32)cc1
Reactant: COS(=O)(=O)OC
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COC1=CCCN(S(=O)(=O)c2ccc(C)cc2)c2ccccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In 10 ml of dimethylformamide was suspended 165 mg of 60% sodium hydride, and 1.0 g of 1-tosyl-2,3,4,5-tetrahydro-1-H-1 -benzazepin-5-one was added to the suspension under ice-cooling, followed by 1 hour of stirring in the ice bath. To this was added dropwise 0.90 ml of dimethyl sulfate, and the mixture was stirred for 30 minutes. After adding ammonium chloride aqueous solution to the reaction solution and subsequently evaporating the solvent, the thus obtained residue was treated with chloroform and water to effect phase separation, and the resulting organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated and the resulting residue was applied to column chromatography, which was eluted with hexane-ethyl acetate (4:1, v/v) to obtain 621 mg of 5-methoxy-1-tosyl-2,3-dihydro-1H-1-benzazepine.
Reaction SMILES: C(OC([NH:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([NH:17]/[C:18](=[C:25]2\[C:26](=[O:37])[NH:27][C:28]3[C:33]\2=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=3)/[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)[CH3:10])=O)(C)(C)C.C(OCC)(=O)C.[ClH:44]>>[ClH:44].[NH2:8][C@@H:9]([C:11]1[CH:12]=[CH:13][C:14]([NH:17]/[C:18](=[C:25]2\[C:26](=[O:37])[NH:27][C:28]3[C:33]\2=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=3)/[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:15][CH:16]=1)[CH3:10]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)c1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: C[C@@H](N)c1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 29a from (Z,R)-3-{1-[4-(1-tert.butoxycarbonylamino-ethyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone and ethyl acetate/hydrogen chloride.
Reaction SMILES: [I:1][C:2]1[C:3]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[C:10]([C:14]([NH:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=4)=[O:15])[CH:11]=3)[C:4]=2[NH:5][N:6]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32](Cl)[C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)=[CH:28][CH:27]=1.CCN(CC)CC>CN(C=O)C.[Cl-].[Na+].O>[CH3:40][O:39][C:36]1[CH:35]=[CH:34][C:33]([CH:32]([C:29]2[CH:30]=[CH:31][C:26]([O:25][CH3:24])=[CH:27][CH:28]=2)[N:5]2[C:4]3[C:7]4[C:12]([CH2:13][C:3]=3[C:2]([I:1])=[N:6]2)=[CH:11][C:10]([C:14]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[O:15])=[CH:9][CH:8]=4)=[CH:38][CH:37]=1
Reactant: COc1ccc(C(Cl)c2ccc(OC)cc2)cc1
Reactant: O=C(NCc1ccccn1)c1ccc2c(c1)Cc1c(I)n[nH]c1-2
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(C(c2ccc(OC)cc2)n2nc(I)c3c2-c2ccc(C(=O)NCc4ccccn4)cc2C3)cc1

Procedure:
A mixture of Example 124A (0.176 g, 0.423 mmol), bis-(4-methoxy-phenyl)-methyl chloride (0.122 g, 0.465 mmol), and Et3N (71 μL, 0.507 mmol) in DMF (2.0 mL) was stirred at room temperature for 4 hours. The reaction mixture was diluted with 50% brine and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered, concentrated, and purified by flash chromatography eluted with EtOAc to give 0.166 g (61%) of the desired as pale yellow solid. MS (ESI) m/z: 643.1 (M+H)+.
Reaction SMILES: N.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]([CH3:16])([CH3:15])[C:13]#[N:14])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]>[Ni]>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]([CH3:16])([CH3:15])[CH2:13][NH2:14])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C(C)(C)C#N)cc1OC
Agent: [Ni]
Agent: N
Product: COc1ccc(C(C)(C)CN)cc1OC
Yield: 89.1 %

Procedure:
A conventional alkylation reaction was carried out using a dimethylformamide solution (10 ml) of 1.77 g of 2-(3,4-dimethoxyphenyl)acetonitrile, 1.00 g of sodium hydride and 4.26 g of methyl iodide to give 1.78 g of 2-(3,4-dimethoxyphenyl)-2-methylpropionitrile. A conventional catalytic hydrogenation reaction was carried out using an ethanolic solution (30 ml) of 1.75 g of 2-(3,4-dimethoxyphenyl)-2-methylpropionitrile, 3.0 ml of an aqueous 28% ammonia solution and 4.3 g of Raney nickel to give 1.59 g of 2-(3,4-dimethoxyphenyl)-2-methylpropylamine. Then, a conventional cyclization reaction was carried out using a formic acid solution (8 ml) of 1.58 g of 2-(3,4-dimethoxyphenyl)-2-methylpropylamine and 0.252 g of paraformaldehyde to give 1.34 g of 6,7-dimethoxy-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline as a pale yellow oily substance. A conventional alkylation reaction was carried out using a solution (10 ml) of 1.77 g of 2-(3,4-dimethoxyphenyl)acetonitrile in dimethylformamide, 1.00 g of sodium hydride and 4.26 g of methyl iodide to give 1.78 g of 2-(3,4-dimethoxyphenyl)-2-methylpropionitrile.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][NH2:8])[CH2:4][O:3]1.C(N(CC)CC)C.[CH3:17][Si:18]([CH3:26])([CH3:25])[CH2:19][CH2:20][S:21](Cl)(=[O:23])=[O:22]>CN(C)C=O>[CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][NH:8][S:21]([CH2:20][CH2:19][Si:18]([CH3:26])([CH3:25])[CH3:17])(=[O:23])=[O:22])[CH2:4][O:3]1
Reactant: CC1(C)OCC(CN)O1
Reactant: C[Si](C)(C)CCS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1(C)OCC(CNS(=O)(=O)CC[Si](C)(C)C)O1
Reaction time: 15 h

Procedure:
A solution of 2,2-dimethyl-4-aminomethyl-1,3-dioxolane (10.0 g, 0.08 mol) and triethylamine (8.1 g, 11.1 mL, 0.08 mol) in 100 mL of N,N-dimethylformamide is cooled to 0 C. under argon atmosphere. Then β-trimethylsilylethanesulfonyl chloride (16.0 g, 0.08 mol) is added dropwise. The solution is allowed to reach 25 C. and is stirred for 15 hours. The solvents are removed under reduced pressure and the crude residue is partitioned between dichloromethane (100 mL) and 5% sodium bicarbonate solution (50 mL). The layers are separated and the organic layer is dried over anhydrous sodium sulfate and evaporated to give 2,2-dimethyl-4-[N-(β-trimethylsilylethanesulfonyl)-aminomethyl]-1,3-dioxolane.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([NH:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[C:15]([O:24][CH2:25][CH:26]2[CH2:28][CH2:27]2)[N:14]=1)=[O:12])[CH2:6][CH:7]([CH3:9])[CH3:8])=[N+]=[N-].C(N(CC)CC)C.C(S)CCS.[BH4-].[Na+]>CC(O)C>[NH2:1][CH2:4][C@@H:5]([NH:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:20][CH2:21][CH2:22][CH2:23]2)=[C:15]([O:24][CH2:25][CH:26]2[CH2:27][CH2:28]2)[N:14]=1)=[O:12])[CH2:6][CH:7]([CH3:8])[CH3:9]
Reactant: CC(C)C[C@@H](CN=[N+]=[N-])NC(=O)c1ccc(N2CCCC2)c(OCC2CC2)n1
Agent: SCCCS
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CC(C)C[C@@H](CN)NC(=O)c1ccc(N2CCCC2)c(OCC2CC2)n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 32 %

Procedure:
6-Cyclopropylmethoxy-5-pyrrolidin-1-yl-pyridine-2-carboxylic acid ((S)-1-azidomethyl-3-methyl-butyl)-amide (107 mg, 277 μmol) was combined with 2-propanol (725 μl) to give an off-white suspension. To this suspension was added triethylamine (56.0 mg, 77.2 μl, 554 μmol), 1,3-propanedithiol (3.00 mg, 2.8 μl, 27.7 μmol) and sodium borohydride (15.7 mg, 415 μmol). The resulting reaction mixture was stirred at room temperature for 20 hours. Volatiles were removed in vacuo and the residue was stirred with 10% citric acid solution (5 mL) and a mixture of ethyl acetate/heptane (5 mL, 1:1). The aqueous layer was brought with 2N NaOH to pH=12 and extracted twice with ethyl acetate. The organic phases were combined, dried with Na2SO4, and concentrated in vacuo to give the title compound (32 mg, 32%) as colorless, viscous oil that was used without further purification in the next step; MS (ESI) 361.3 (M+H)+.
Reaction SMILES: C([O:8][C:9](=[O:40])[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[N:18][CH:19]=[C:20]([CH2:22][C:23]([OH:25])=[O:24])[CH:21]=2)=[C:12]([CH2:26][N:27]([C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])[CH2:28][CH3:29])[CH:11]=1)C1C=CC=CC=1.[Li+].[OH-]>CO>[CH2:33]([O:32][C:30]([N:27]([CH2:26][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][C:13]=1[C:16]1[CH:17]=[N:18][CH:19]=[C:20]([CH2:22][C:23]([OH:25])=[O:24])[CH:21]=1)[C:9]([OH:40])=[O:8])[CH2:28][CH3:29])=[O:31])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: CCN(Cc1cc(C(=O)OCc2ccccc2)ccc1-c1cncc(CC(=O)O)c1)C(=O)OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CCN(Cc1cc(C(=O)O)ccc1-c1cncc(CC(=O)O)c1)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3-[(N-Benzyloxycarbonyl-N-ethyl-amino)-methyl]-4-(5-carboxymethyl-pyridin-3-yl)-benzoic acid benzyl ester (0.369 g, 0.68 mmol) was dissolved in MeOH (4 mL) and cooled to 0° C. 1N Aqueous LiOH (3 mL, 3 mmol) was added, and the reaction was stirred at room temperature for 1 hour. The mixture was quenched with 1N aqueous HCl (3 mL) and extracted with EtOAc. The combined organic layers were washed with H2O and concentrated, and the residue was purified by preparative HPLC to give Compound 1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5]2[CH:6]=[N:7][NH:8][C:9]=2[CH:10]=1.[H-].[Na+].[CH3:14]I>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5]2[CH:6]=[N:7][N:8]([CH3:14])[C:9]=2[CH:10]=1
Reactant: CI
Reactant: Nc1cc(Br)cc2[nH]ncc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1ncc2c(N)cc(Br)cc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 15 %

Procedure:
6-Bromo-1H-indazol-4-amine (available from Sinova, 300 mg, 1.42 mmol) was dissolved in THF (7.5 ml) and the mixture cooled to 0° C. Sodium hydride (62 mg, 1.56 mmol) was then slowly added. The mixture was stirred for 15 minutes, then methyl iodide (221 mg, 1.56 mmol) was added and stirring continued at 0° C. for 3 h. The reaction mixture was quenched by careful addition of methanol (2 ml), then water (10 ml), then extracted into ethyl acetate and the organic layer was concentrated in vacuo. The residue was purified by column chromatography on silica eluting with a gradient of 0-50% ethyl acetate in cyclohexane. Fractions containing desired product were combined and concentrated in vacuo to afford the title compound (48 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:14]=[CH:13][C:12]3[N:11]=[C:10]([NH:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])[NH:9][C:8](=[O:22])[C:7]=3[C:6]=2[CH:23]=1.[Br:24]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C1C=CC=CC=1>[Br:24][CH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:14]=[CH:13][C:12]3[N:11]=[C:10]([NH:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:18])[CH3:19])[NH:9][C:8](=[O:22])[C:7]=3[C:6]=2[CH:23]=1
Reactant: Cc1ccc2ccc3nc(NC(=O)C(C)(C)C)[nH]c(=O)c3c2c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: c1ccccc1
Product: CC(C)(C)C(=O)Nc1nc2ccc3ccc(CBr)cc3c2c(=O)[nH]1

Procedure:
To a hot solution of N-(1,2-dihydro-9-methyl-1-oxobenzo[f]quinazolin-3-yl)pivalamide (0.94 g, 3.0 mmol) in benzene (250 ml) under nitrogen were added N-bromosuccinimide (0.57 g, 3.2 mmol) (Kodak) and 2,2'-azobisisobutyronitrile (AIBN) (35 mg, 0.21 mmol) (Kodak). The solution was stirred at reflux for 1.5 hours and then concentrated in vacuo to give crude N-(9-bromomethyl-1,2-dihydro-1-oxobenzo[f]quinazolin-3-yl)pivalamide. The pivalamide and N-(4-aminobenzoyl)-L-glutamic acid diethyl ester (2.5 g, 7.8 mmol) (Aldrich) in DMF (10 ml) were stirred under nitrogen at 105-110° C. for 5 minutes and then allowed to cool. Triethylamine (0.5 ml, 3.6 mmol) was added and the solution was concentrated under high vacuum. The residue was purified by chromatography on silica gel (130 g) eluting with ethyl acetate:methylene chloride (1:19→2:3), followed by recrystallization of the solid from ethanol/diethyl ether. This was filtered and dried under high vacuum to give diethyl N-(4-(((1,2-dihydro-1-oxo-3-pivalamido-benzo [f]quinazolin-9-yl)methyl)amino)benzoyl)-L-glutamate (0.32 g) as a white solid. The filtrate was concentrated and the residue purified by chromatography and crystallization to give an additional 0.243 g. 1H NMR (DMSO-d6, 300 MHz) δ: 1.15 (t, J=7 Hz, 3H, ester CH3), 1.16 (t, J=7 Hz, 3H, ester CH3), 1.28 (s, 9H, t-butyl), 1.87-2.13 (m, 2H, glu CH2), 2.39 (t, J=7 Hz, 2H, glu CH2), 4.03 (q, J=7 Hz, 2H, ester CH2), 4.07 (q, J=7 Hz, 2H, ester CH2), 4.30-4.40 (m, 1H, glu CH), 4.57 (d, J=6 Hz, 2H, C9 --CH2) 6.63 (, J=9 Hz, 2H, Ar), 7.04 (t, J=6 Hz, 1H, ArNH), 7.53 (d, J=9 Hz, 1H, Ar), 7.61 (dd, J =8,2 Hz, 1H, Ar), 7.62 (d, J=9 Hz, 2H, Ar), 7.99 (d, J=8 Hz, 1H, Ar), 8.21 (d, J=8 Hz, 1H, glu NH), 8.22 (d, J=9 Hz, 1H, Ar), 9.75 (s, 1H, Ar), 11.25 (s, 1H, N2H), 12.30 (br s, 1H, NH). Mass spectrum (CI-CH4) 630 (M+1, 6.5%), 243 (100%). Anal. Calculated for C34H39N5O7 : C, 64.85; H, 6.24; N, 11.12. Found: C, 64.74; H, 6.25; N, 11.10.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].[NH2:12][C:13]1[C:14]2[C:21]([C:22]([C:24]3[CH:29]=[C:28](C)[N:27]=[C:26]([NH2:31])[CH:25]=3)=[O:23])=[CH:20][N:19]([CH:32]([CH3:34])[CH3:33])[C:15]=2[N:16]=[CH:17][N:18]=1>N1C=CC=CC=1>[NH2:12][C:13]1[C:14]2[C:21]([C:22]([C:24]3[CH:29]=[CH:28][N:27]=[C:26]([NH:31][S:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])(=[O:10])=[O:9])[CH:25]=3)=[O:23])=[CH:20][N:19]([CH:32]([CH3:34])[CH3:33])[C:15]=2[N:16]=[CH:17][N:18]=1
Reactant: Cc1cc(C(=O)c2cn(C(C)C)c3ncnc(N)c23)cc(N)n1
Reactant: O=S(=O)(Cl)c1ccccc1F
Solvent: c1ccncc1
Product: CC(C)n1cc(C(=O)c2ccnc(NS(=O)(=O)c3ccccc3F)c2)c2c(N)ncnc21
Temperature: 80 °C
Reaction time: 2 h
Yield: 29.9 %

Procedure:
2-Fluoro-benzenesulfonyl chloride (0.11 mL, 0.81 mmol) was added to a solution of (4-Amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(2-amino-6-methyl-pyridin4-yl)-methanone (200 mg, 0.67 mmol) in pyridine (2 mL). The mixture was stirred for 2 h at 80° C. The reaction mixture was quenched with H2O (10 mL) and extracted with hot EtOAC/MeOH (95:5, 3×10 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo. Purification by flash column chromatography (ethyl acetate/MeOH 99:1) afforded the title compound as a yellow solid (91 mg, 30%). MS: 455.8 (MH+); HPLC Rf: 5.98 min. (HPLC method 4); HPLC purity: 100%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:15]([OH:17])=O)[CH2:10][O:11][C:12]#[C:13][CH3:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:19][O:20][C:21](=[O:24])[CH2:22][NH2:23].C(N(CC)C(C)C)(C)C.C1C=C2N=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[CH3:19][O:20][C:21](=[O:24])[CH2:22][NH:23][C:15](=[O:17])[C@H:9]([CH2:10][O:11][C:12]#[C:13][CH3:14])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7]
Reactant: COC(=O)CN
Reactant: CC#COC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC#COC[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.7 %

Procedure:
N-tert-butoxycarbonyl O-propynyl L-serine (14.55 g, 59.82 mmol) was dissolved in DMF (60 mL) and the solution cooled to 0° C. (icebath). Glycine methyl ester hydrochloride (7.51 g, 59.8 mmol) was suspended in DMF (40 mL) and N,N-diisopropylethylamine (7.73 g, 59.8 mmol) added. The resulting suspension was added to the solution of N-tert-butoxycarbonyl O-propynyl L-serine in one portion. HOBt hydrate (9.16 g, 59.8 mmol) dissolved in DMF (20 mL) was added. Finally, EDC hydrochloride (12.61 g, 65.8 mmol) was added in small portions. The reaction mixture was stirred for 1 h at 0° C. after which the icebath was removed and stirring continued for 25 h at room temperature before the solvent was evaporated. The residue was taken up in EtOAc (400 mL) and the solution washed with 1 M aqueous H2SO4 (3×200 mL), 7.5% (w/w) K2CO3 solution (3×200 mL) and saturated brine (200 mL). The solution was dried with anhydrous MgSO4 and the solvent evaporated affording a yellow/orange oil (17.23 g, 92%); δH (300 MHz; d6-DMSO) 8.31 (1H, t, J 6, NH(Gly)), 6.85 (1H, d, J 8, NH(propSer)), 4.26-4.15 (1H, m, CαH(propSer)), 4.13 (2H, t, J 2, CH2CCH), 3.88 (1H, dd, J 17 and 6, CαHH(Gly)), 3.81 (1H, dd, J 17 and 6, CαHH(Gly)), 3.65 (1H, dd, J 10 and 5, CHH), 3.62 (3H, s, OCH3), 3.52 (1H, dd, J 10 and 8, CHH), 3.41 (1H, t, J 2, CCH), 1.39 (9H, s, (CH3)3); δC (75 MHz; d6-DMSO) 170.2, 170.0, 155.1, 79.9, 78.3, 77.2, 69.2, 59.7, 57.6, 54.0, 51.6, 40.6, 28.1, 20.7, 14.0