Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:9][O:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13]Cl>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].[OH-].[Na+].C(Cl)Cl>[NH2:1][C:2]1[C:7]([O:8][CH2:13][C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[O:10][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: COc1ccccc1CCl
Reactant: Nc1ncccc1O
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccccc1COc1cccnc1N
Reaction time: 22 h
Yield: 38.1 %

Procedure:
To a mixture of 2-amino-3-hydroxypyridine (7.64 g) and Adogen 464 (Trademark: prepared by Aldrich Chemical Co.) (0.42 g) in 40% aqueous sodium hydroxide (35 ml) and methylene chloride (35 ml) was added 2-methoxybenzyl chloride (10.87 g) at ambient temperature. After being stirred for 22 hours, the organic layer was separated and the aqueous layer was extracted with methylene chloride. The combined extracts were washed with saturated sodium chloride aqueous solution, dried over magnesium sulfate, and evaporated in vacuo. The crystalline residue was recrystallized from ethyl acetate to give 2-amino-3-(2-methoxybenzyloxy)pyridine (6.09 g).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].Cl.[N:19]1([C:25]2[O:26][C:27]3[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=3[N:29]=2)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[O:26]1[C:27]2[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=2[N:29]=[C:25]1[N:19]1[CH2:20][CH2:21][N:22]([C:7]([C:6]2[CH:10]=[C:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:12]=[CH:13][C:5]=2[O:4][CH:1]([CH3:2])[CH3:3])=[O:9])[CH2:23][CH2:24]1
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: c1ccc2oc(N3CCNCC3)nc2c1
Agent: Cl
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2nc3ccccc3o2)CC1

Procedure:
Prepared in analogy to example 1.1 b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example 2.2) and 2-piperazin-1-yl-benzoxazole hydrochloride. The crude material was triturated with diethyl ether to yield the title compound as a colorless solid.
Reaction SMILES: [H-].[Na+].[C:3]([PH:7](=[O:15])[CH:8]([O:12][CH2:13][CH3:14])[O:9][CH2:10][CH3:11])([CH3:6])([CH3:5])[CH3:4].[CH2:16](Br)[CH:17]([CH3:19])[CH3:18]>O1CCCC1>[C:3]([P:7](=[O:15])([CH2:16][CH:17]([CH3:19])[CH3:18])[CH:8]([O:12][CH2:13][CH3:14])[O:9][CH2:10][CH3:11])([CH3:5])([CH3:4])[CH3:6]
Reactant: CCOC(OCC)[PH](=O)C(C)(C)C
Reactant: CC(C)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(OCC)P(=O)(CC(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Dry sodium hydride (0.42 g) is suspended in 50 ml of dry tetrahydrofuran under an argon atmosphere. To this stirred suspension is added 3.6 g (0.017 mol) of tertiary-butyl(diethoxymethyl)-phosphine oxide dissolved in 25 ml of dry tetrahydrofuran, at room temperature. Stirring is continued for 10 minutes at room temperature, during which time the solid dissolves and a gas is evolved. To the clear solution obtained is added a solution of 2.4 g (0.017 mol) of iso-butyl bromide in 25 ml of dry tetrahydrofuran. After the addition is complete, the reaction mixture is heated under reflux for 15 hours, then allowed to cool at room temperature and washed with 20 ml of water. The organic extracts are dried and evaporated under reduced pressure. The crude product is purified by chromatography on silica using ethyl acetate as eluent to give tertiary-butyl-(iso-butyl)(diethoxymethyl)phosphine oxide as a colourless oil.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:11][CH2:12][CH2:13][N:14]([CH3:57])[C:15](=[O:56])[C:16]1[CH:55]=[CH:54][CH:53]=[C:18]([C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:24][C:23]=2[C:34]2[CH:39]=[C:38]([C:40](=[O:52])[NH:41][C@@H:42]3[C:51]4[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=4)[CH2:45][CH2:44][CH2:43]3)[CH:37]=[CH:36][N:35]=2)=[O:20])[CH:17]=1.C(N(CC)CC)C>C(Cl)Cl.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH3:57][N:14]([CH2:13][CH:12]=[O:11])[C:15](=[O:56])[C:16]1[CH:55]=[CH:54][CH:53]=[C:18]([C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:24][C:23]=2[C:34]2[CH:39]=[C:38]([C:40](=[O:52])[NH:41][C@@H:42]3[C:51]4[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=4)[CH2:45][CH2:44][CH2:43]3)[CH:37]=[CH:36][N:35]=2)=[O:20])[CH:17]=1
Reactant: CN(CCO)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CN(CC=O)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of DMSO (2.07 mmol, 162 mg) in DCM (1.6 mL) at −78° C. was added a solution of oxalyl chloride (1.04 mmol, 131 mg) in DCM (0.2 mL). The mixture was stirred at −78° C. for 15 minutes. Then a solution of (S)—N1-(2-hydroxyethyl)-N1-methyl-N3-(4-(piperidin-1-yl)-2-(4-((1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyridin-2-yl)phenyl)isophthalamide Example 115 (0.69 mmol, 435 mg) in DCM (0.5 mL) was added. The mixture was stirred at −78° C. for 3 h. Triethylamine (0.5 mL) was added. The mixture was slowly warmed to room temperature. The mixture was diluted with aqueous 10% citric acid and extracted with DCM (3×). The combined organic layers was washed with water (1×), dried, concentrated to give a yellow solid which was used without purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3([O:23][CH3:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[C:3]=1[NH:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28]>C(O)C.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3([O:23][CH3:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[C:3]=1[NH:25][C:26](=[O:31])[C:27]([CH3:29])([CH3:28])[CH3:30]
Reactant: COC1(c2ccc(C=Cc3cc(F)cc(F)c3NC(=O)C(C)(C)C)cc2)CCOCC1
Agent: [Pd]
Solvent: CCO
Product: COC1(c2ccc(CCc3cc(F)cc(F)c3NC(=O)C(C)(C)C)cc2)CCOCC1

Procedure:
To a solution of the product from Example 6 (3.0 g) in ethanol, was added 10% palladium on charcoal (300 mg). The reaction mixture was treated with H2 at atmospheric pressure until uptake ceased. On completion, the reaction was filtered and the solvent was removed from the filtrate in vacuo to give a green oil. Traces of remaining catalyst were removed by filtration to give a yellow oil. The oil was precipitated from ethyl acetate/40°-60° petroleum ether to afford the title compound as a white solid, mp 147°-148°C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:11]([NH:13][C:14]1[CH:31]=[CH:30][C:17]([C:18]([N:20]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=2[OH:29])[CH3:21])=[O:19])=[CH:16][C:15]=1[O:32][CH3:33])=[O:12].Br[CH2:35][CH2:36][CH2:37][CH2:38][N:39]1[C:43](=[O:44])[C:42]2=[CH:45][CH:46]=[CH:47][CH:48]=[C:41]2[C:40]1=[O:49].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:11]([NH:13][C:14]1[CH:31]=[CH:30][C:17]([C:18]([N:20]([CH3:21])[C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=2[O:29][CH2:35][CH2:36][CH2:37][CH2:38][N:39]2[C:43](=[O:44])[C:42]3=[CH:45][CH:46]=[CH:47][CH:48]=[C:41]3[C:40]2=[O:49])=[O:19])=[CH:16][C:15]=1[O:32][CH3:33])=[O:12]
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2O)ccc1NC(=O)c1cccc([N+](=O)[O-])c1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCN2C(=O)c3ccccc3C2=O)ccc1NC(=O)c1cccc([N+](=O)[O-])c1N
Temperature: 60 °C
Yield: 89.1 %

Procedure:
A mixture of 4-(2-amino-3-nitrophenyl)carbonylamino-N-(2-hydroxy-4-methylphenyl)-3-methoxy-N-methylbenzamide (520 mg), N-(4-bromobutyl)phthalimide (326 mg) and potassium carbonate (160 mg) in N,N-dimethylformamide (10 ml) was heated at 60° C. for 8 hours. The mixture was diluted with ethyl acetate and the solution was washed with water and brine. The organic phase was dried over magnesium sulfate and the solvent was evaporated in vacuo. The crude oil was purified by silica gel column (1% methanol in chloroform) to give 4-(2-amino-3-nitrophenyl)carbonylamino-3-methoxy-N-methyl-N-[2-(4-phthalimidobut-1-yloxy)-4-methylphenyl]benzamide (670 mg).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH:5]([NH2:7])[CH3:6].C(N(CC)CC)C.[NH2:15][C:16]1[C:21]([Cl:22])=[C:20]([Cl:23])[N:19]=[C:18](Cl)[N:17]=1>C1(C)C=CC=CC=1>[NH2:15][C:16]1[C:21]([Cl:22])=[C:20]([Cl:23])[N:19]=[C:18]([NH:7][CH:5]([CH3:6])[CH2:4][CH2:3][O:2][CH3:1])[N:17]=1
Reactant: COCCC(C)N
Reactant: Nc1nc(Cl)nc(Cl)c1Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COCCC(C)Nc1nc(N)c(Cl)c(Cl)n1

Procedure:
3.4 g (0.033 mole) of 3-methoxy-1-methylpropylamine and 3.3 g (0.033 mole) of triethylamine are successively added dropwise to a solution of 6.5 g (0.033 mole) of 4-amino-2,5,6-trichloropyrimidine in 200 ml of toluene and the mixture is heated to the boil for five hours. When it has cooled, the reaction mixture is washed with water and the organic phase is dried over sodium sulphate and concentrated. The crude product thus obtained is purified by chromatography over silica gel (length of column: 80 cm, diameter: 5 cm), using ethyl acetate and petroleum ether (1:1). In addition to 4-amino-6-(3-methoxy-1-methylpropylamino)-2,5-dichloropyrimidine (1st fraction, melting point 62° C.), 1.5 g (17.2% of theory) (2nd fraction, melting point 96° C.) of the desired pyrimidine are obtained.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:11]([OH:13])=O)[N:10]=[C:6]2[CH:5]=[CH:4][NH:3]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.[NH2:58][C@@H:59]([CH3:76])[CH2:60][N:61]1[CH:65]=[CH:64][C:63]([C:66]2[CH:73]=[C:72]([F:74])[C:69]([C:70]#[N:71])=[C:68]([Cl:75])[CH:67]=2)=[N:62]1>CN(C=O)C.CCOC(C)=O>[Cl:75][C:68]1[CH:67]=[C:66]([C:63]2[CH:64]=[CH:65][N:61]([CH2:60][C@@H:59]([NH:58][C:11]([C:9]3[N:10]=[C:6]4[CH:5]=[CH:4][NH:3][C:2](=[O:1])[N:7]4[CH:8]=3)=[O:13])[CH3:76])[N:62]=2)[CH:73]=[C:72]([F:74])[C:69]=1[C:70]#[N:71]
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Reactant: O=C(O)c1cn2c(=O)[nH]ccc2n1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1cn2c(=O)[nH]ccc2n1
Temperature: 25 °C
Reaction time: 17 h
Yield: 5.1 %

Procedure:
5-Oxo-5,6-dihydroimidazo[1,2-c]pyrimidine-2-carboxylic acid (0.323 mmol, 0.058 g), HBTU (0.027 mmol, 10.21 mg), DIPEA (0.323 mmol, 0.042 g) and EDCI (0.323 mmol, 0.062 g) were suspended in DMF (2 ml) and the resulting mixture was stirred at RT for 10 min. (S)-4-(1-(2-Aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (0.269 mmol, 0.1 g) dissolved in DMF (2 ml) was added and the resulting mixture was stirred for 17 h at RT. At this point more starting materials were added so that the amount of every starting material was raised by half of the original amount. The amount of (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile was not changed. The reaction was continued for another 22 h after which the temperature was raised to 80° C. for 4.5 h. The reaction mixture was diluted with EtOAc and washed with 1M Na2CO3, brine and water. The organic phase was dried, filtered and evaporated. The crude product was purified by preparative HPLC. 0.006 g of the title compound was obtained. 1H-NMR (400 MHz, MeOH-d4): δ 1.25 (d, 3H), 4.30-4.37 (m, 1H), 4.42-4.49 (m, 1H), 4.54-4.65 (m, 1H), 6.61 (dd, 1H), 6.70 (d, 1H), 7.18 (d, 1H), 7.63 (d, 1H), 7.75-7.82 (m, 2H), 8.26 (s, 1H).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21]C4C=CC(C(O)=O)=CC=4OC)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1N=CC2N(C)C(=O)C(F)(F)CN(C3CCCC3)C=2N=1.[CH3:54][N:55]([CH3:66])[CH2:56][CH2:57][O:58][C:59]1[CH:65]=[CH:64][C:62](N)=[CH:61][CH:60]=1>>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:62]4[CH:64]=[CH:65][C:59]([O:58][CH2:57][CH2:56][N:55]([CH3:66])[CH3:54])=[CH:60][CH:61]=4)=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN(C)CCOc1ccc(N)cc1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Product: CN(C)CCOc1ccc(Nc2ncc3c(n2)N(C2CCCC2)CC(F)(F)C(=O)N3C)cc1

Procedure:
The title compound was synthesized using an analogous procedure to that described in connection with 4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid from 2-Chloro-9-cyclopentyl-7,7-difluoro-5-methyl-8,9-dihydro-5H-pyrimido[5,4-b][1,4]diazepin-6(7H)-one and 4-(2-(dimethylamino)ethoxy)aniline. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.44-1.79 (m, 6 H) 1.93 (br. s, 2 H) 2.20 (s, 6 H) 2.59 (t, J=5.81 Hz, 2 H) 3.32 (s, Hz, 3 H) 3.88-4.10 (m, 4 H) 4.68 (t, J=8.34 Hz, 1 H) 6.85 (d, J=8.84 Hz, 2 H) 7.55 (d, J=9.09 Hz, 2 H) 8.18 (s, 1 H) 9.20 (s, 1 H). [M+H] calc'd for C23H30F2N6O2, 461; found 461.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].CN1CCCC1=O.[Cl:23][C:24]1[C:29](F)=[C:28]([C:31]([F:34])([F:33])[F:32])[CH:27]=[CH:26][N:25]=1>O>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([Cl:8])[CH:7]=1)[O:9][C:29]1[C:24]([Cl:23])=[N:25][CH:26]=[CH:27][C:28]=1[C:31]([F:34])([F:33])[F:32]
Reactant: Oc1cc(Cl)cc(Br)c1
Reactant: Fc1c(C(F)(F)F)ccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: FC(F)(F)c1ccnc(Cl)c1Oc1cc(Cl)cc(Br)c1
Reaction time: 1 h

Procedure:
To a round bottom flask charged with 3-bromo-5-chlorophenol (5.20 g, 25.1 mmol) and potassium carbonate (3.46 g, 25.1 mmol) was added N-methylpyrrolidinone (25 mL). To this suspension under N2 was added 2-chloro-3-fluoro-4-(trifluoromethyl)pyridine (5.00 g, 25.1 mmol) and the reaction mixture was placed in an oil bath at 120° C. After 60 minutes, the reaction mixture was allowed to cool to room temperature at which point, water (100 mL) was added. The mixture was extracted with ethyl acetate (2×100 mL) and the combined organic fractions were washed with brine (3×100 mL), dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The resulting residue was adsorbed onto silica gel and purified by column chromatography on a pre-packed silica gel Redi Sep 330 gram column, eluting with 0-75% CH2Cl2 in hexanes to yield the title compound. 1H NMR (CDCl3) δ 8.53 (d, J=5.0 Hz, 1H), 7.62 (d, J=5.0 Hz, 1H), 7.29-7.27 (m, 1H), 6.87-6.84 (m, 1H), 6.76-6.73 (m, 1H). FIRMS (M+1)=385.8957.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[CH2:12][N:13]1[C:21]([C:22]2[N:26]([CH3:27])[CH:25]=[C:24]([C:28]([OH:30])=O)[CH:23]=2)=[C:20]2[C:15]([N:16]([CH2:34][CH:35]3[CH2:37][CH2:36]3)[C:17](=[O:33])[N:18]([CH3:32])[C:19]2=[O:31])=[N:14]1.[CH3:38][N:39]([CH3:43])[CH2:40][CH2:41][NH2:42].C(P(=O)(OCC)OCC)#N>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[CH2:12][N:13]1[C:21]([C:22]2[N:26]([CH3:27])[CH:25]=[C:24]([C:28]([NH:42][CH2:41][CH2:40][N:39]([CH3:43])[CH3:38])=[O:30])[CH:23]=2)=[C:20]2[C:15]([N:16]([CH2:34][CH:35]3[CH2:37][CH2:36]3)[C:17](=[O:33])[N:18]([CH3:32])[C:19]2=[O:31])=[N:14]1
Reactant: Cn1cc(C(=O)O)cc1-c1c2c(=O)n(C)c(=O)n(CC3CC3)c2nn1Cc1ccnc2ccc(Cl)cc12
Reactant: CN(C)CCN
Agent: CCOP(=O)(C#N)OCC
Product: CN(C)CCNC(=O)c1cc(-c2c3c(=O)n(C)c(=O)n(CC4CC4)c3nn2Cc2ccnc3ccc(Cl)cc23)n(C)c1

Procedure:
This compound was synthesized by the reaction of 5-[2-[(6-chloroquinolin-4-yl)methyl]-7-(cyclopropylmethyl)-5-methyl-4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl]-1-methyl-1H-pyrrole-3-carboxylic acid and N,N-dimethylethane-1,2-diamine using diethyl cyanophosphonate as a coupling reagent. Mass: 589.35 (M+H).
Reaction SMILES: O.[C@@H:2]1([N:11]2[C:21]3[N:20]=[C:18]([NH2:19])[NH:17][C:15](=O)[C:14]=3[N:13]=[CH:12]2)[O:10][C@H:7]([CH2:8][OH:9])[C@@H:5]([OH:6])[C@H:3]1[OH:4].[SiH3][NH:23][SiH3].C1(C)C=CC=CC=1.C(O)(C)C.[OH-].[NH4+].O>CS(C)=O.CO>[CH:12]1[N:11]([CH:2]2[O:10][CH:7]([CH2:8][OH:9])[CH:5]([OH:6])[CH:3]2[OH:4])[C:21]2[N:20]=[C:18]([NH2:19])[N:17]=[C:15]([NH2:23])[C:14]=2[N:13]=1
Reactant: [SiH3]N[SiH3]
Reactant: Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Agent: [NH4+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CO
Product: Nc1nc(N)c2ncn(C3OC(CO)C(O)C3O)c2n1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
To a 2 L stainless steel Parr bomb was added guanosine hydrate (100 g, 0.35 mol, Aldrich), hexamethyl) disilazane (320 mL, 1.52 mol, 4.4 eq.), trimethyl) silyl trifiouromethanesulfonate (8.2 mL), and toluene (350 mL). The bomb was sealed and partially submerged in an oil bath (170° C.; internal T 150° C., 150 psi) for 5 days. The bomb was cooled in a dry ice/acetone bath and opened. The contents were transferred with methanol (300 mL) to a flask and the solvent was evaporated under reduced pressure. Aqueous methanol (50%, 1.2 L) was added. The resulting brown suspension was heated to reflux for 5 h. The suspension was concentrated under reduced pressure to one half volume in order to remove most of the methanol. Water (600 mL) was added and the solution was heated to reflux, treated with charcoal (5 g) and hot filtered through Celite. The solution was allowed to cool to 25° C. The resulting precipitate was collected, washed with water (200 mL) and dried at 90° C./0.2 mmHg for 5 h to give a constant weight of 87.4 g (89%) of tan, crystalline solid; mp 247° C. (shrinks), 255° C. (dec, lit. (1) mp 250-252° C.); TLC homogenous (Rf 0.50, isopropanol-ammonium hydroxide-water 16:3:1 ); PMR (DMSO), δ 5.73 (d, 2, 2-NH2), 5.78 (s, 1, H-1), 6.83 (br s, 2, 6-NH2).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[CH:6][N:5]=[C:4]2[N:10]([Si](C(C)C)(C(C)C)C(C)C)[CH:11]=[CH:12][C:3]=12.[CH2:23]([NH2:25])[CH3:24]>COC(O)C>[CH2:23]([NH:25][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][N:5]=[C:4]2[NH:10][CH:11]=[CH:12][C:3]=12)[CH3:24]
Reactant: CCN
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(Cl)c(C=O)cnc21
Agent: COC(C)O
Product: CCNc1c(C=O)cnc2[nH]ccc12
Temperature: 120 °C
Reaction time: 8 h

Procedure:
A mixture of 4-chloro-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (1 g, 2.97 mmol), ethyl amine (70 wt. % solution in water, 8 mL, 100 mmol) in methoxyethanol (4 mL) is heated at 120° C. in a sealed tube. After overnight, the reaction mixture is cooled to room temperature and concentrated. The residue is dissolved in HCl solution (1N, 20 mL) and heated at 50° C. After stirring for 1.5 hours, the reaction mixture is basified with saturated sodium bicarbonate solution to pH=8. The solid is collected by filtration and washed with water, then hexanes, dried to afford the title compound as a solid. 1H NMR 600 MHz (DMSO-d6) δ 11.82 (s, 1H), 9.75 (s, 1H), 9.30 (t, 1H, J=4.8 Hz), 8.19 (s, 1H), 7.19 (t, 1H, J=3.6 Hz), 6.72 (m, 1H), 3.73-3.69 (m, 2H), 1.30 (t, 3H, J=7.2 Hz); MS m/z 190.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH2:22][NH:23][CH2:24][C:25]([F:28])([F:27])[F:26])[C:8]([F:11])=[CH:9][CH:10]=1.[C:30](Cl)(=[O:32])[CH3:31]>>[CH3:1][O:2][C:3](=[O:29])[CH2:4][C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][C:13]=2[CH2:22][N:23]([C:30](=[O:32])[CH3:31])[CH2:24][C:25]([F:28])([F:26])[F:27])[C:8]([F:11])=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(F)c(-c2ccc(C(F)(F)F)cc2CNCC(F)(F)F)c1
Reactant: CC(=O)Cl
Product: COC(=O)Cc1ccc(F)c(-c2ccc(C(F)(F)F)cc2CN(CC(F)(F)F)C(C)=O)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: {6-fluoro-2′-[(2,2,2-trifluoro-ethylamino)-methyl]-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid methyl ester and acetyl chloride.
Reaction SMILES: [C-]#N.[Na+].[N+:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])#[C-:5].C(O[C:15](=[S:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)C>C(O)C>[CH2:10]([O:9][C:7]([C:6]1[N:4]=[CH:5][S:22][C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:8])[CH3:11]
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: CCOC(=S)c1ccccc1
Agent: [C-]#N
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1ncsc1-c1ccccc1
Temperature: 50 °C
Reaction time: 96 h
Yield: 62 %

Procedure:
Prepare a suspension of NaCN (0.25 g, 5.2 mmol) in ethanol (50 mL). Add dropwise ethyl isocyanoacetate (5 mL, 45.6 mmol) and thiobenzoic acid O-ethyl ester (6.9 g, 41.5 mmol) in ethanol (25 mL). Stir the reaction mixture at 50° C. for 96 hours and then concentrate in vacuo to an oil. Chromatograph (silica gel, 3:7 hexane/ethyl acetate) to afford 5-phenylthiazole-4-carboxylic acid ethyl ester (6.0 g). MS: m/e=234 (MH+).
Reaction SMILES: [CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([Cl:19])=[CH:14][CH:15]=2)[N:10]=[C:9]1[CH:20]([N:24]1[C:30](=[O:31])[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[CH:21]([CH3:23])[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.CCN(CC)CC>C(Cl)Cl>[CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([Cl:19])=[CH:14][CH:15]=2)[N:10]=[C:9]1[CH:20]([N:24]1[C:30](=[O:31])[CH2:29][CH2:28][N:27]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:26][CH2:25]1)[CH:21]([CH3:23])[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C(c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1)N1CCNCCC1=O
Reactant: BrCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C(c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1)N1CCN(Cc2ccccc2)CCC1=O

Procedure:
3-Benzyl-7-chloro-2-[2-methyl-1-(7-oxo-[1 ,4]diazepan-1-yl)-propyl]-3H-quinazolin-4-one from Example 1e above, (133 mg, 0.30 mmol) was treated with benzyl bromide and Et3N in CH2Cl2 (10 mL) at room temperature overnight. The mixture was diluted with CH2Cl2 (10 mL), washed with H2, brine, dried and concentrated under vacuum. Purification by flash chromatography on silica gel (20% EtOAc/hexane) gave the title compound as a white solid: MS (ES) m/e 529.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:18])[C:15]([OH:17])=O.S(Cl)(Cl)=O.ClC1C=C2C(=CC=1)NC=C2CCNC(=O)C(Cl)=O.C(N(CC)CC)C.[C:48]1([CH2:54][C:55]([NH:57][NH2:58])=O)[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl.ClCCl>[CH2:54]([C:55]1[O:17][C:15]([C:14]([NH:13][CH2:12][CH2:11][C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=3)[NH:7][CH:6]=2)=[O:18])=[N:58][N:57]=1)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: NNC(=O)Cc1ccccc1
Reactant: O=C(O)C(=O)NCCc1c[nH]c2ccc(Cl)cc12
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(Cl)C(=O)NCCc1c[nH]c2ccc(Cl)cc12
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1nnc(Cc2ccccc2)o1
Temperature: 80 °C
Reaction time: 3 h
Yield: 2.6 %

Procedure:
To a suspension of 2-(2-(5-chloro-1H-indol-3-yl)ethylamino)-2-oxoacetic acid (0.350 mg; 1.31 mmol) in chloroform (20 mL) was added thionyl chloride (0.955 mL; 13.12 mmol) and the mixture was stirred at 80° C. for 3 h and was then evaporated to dryness. The resulting 2-(2-(5-chloro-1H-indol-3-yl)ethylamino)-2-oxoacetyl chloride (0.180 g, 0.631 mmol) was dissolved in dichloromethane (12 mL) and a mixture of triethylamine (0.355 mL; 2.53 mmol) and 2-phenylacetic acid hydrazide (0.092 g; 0.600 mmol) in dichloromethane (2 mL) was added at 0° C. The mixture was stirred at room temperature for 3 days and p-toluenesulfonyl chloride (0.122 g, 0.631 mmol) was added. The resulting mixture was stirred 18 h at room temperature, diluted with dichloromethane, washed with an aqueous solution of sodium carbonate, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluent 12 to 100% ethyl acetate in heptane) to give 0.006 g (2.5%) of 5-benzyl-N-(2-(5-chloro-1H-indol-3-yl)ethyl)-1,3,4-oxadiazole-2-carboxamide as a white solid.