Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][NH:14][CH2:13][C@@H:12]1[C:17](=[O:29])[NH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH3:28])=[CH:22][CH:21]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C1C2C(COC([N:54]=[C:55]=[S:56])=O)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:55](=[S:56])[NH2:54])[CH2:13][C@@H:12]1[C:17](=[O:29])[NH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH3:28])=[CH:22][CH:21]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCc1ccc(CNC(=O)[C@H]2CNCCN2C(=O)OCc2ccccc2)cc1
Reactant: O=C(N=C=S)OCC1c2ccccc2-c2ccccc21
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCNCC1
Product: CCCc1ccc(CNC(=O)[C@H]2CN(C(N)=S)CCN2C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Yield: 88.7 %

Procedure:
To a solution of the compound (1.59 g) obtained in Step 3 in chloroform (16 ml) was added, with stirring at room temperature, triethylamine (840 μl), and 9-fluorenylmethoxycarbonyl isothiocyanate (1.13 g) was added. After stirring at room temperature for 4 hr, piperidine (805 μl) was added. After stirring overnight at room temperature, the reaction mixture was concentrated under reduced pressure. The residue was partitioned by adding ethyl acetate and water. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtrated, and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate:n-hexane=1:1-4:1) to give the title compound (1.62 g).
Reaction SMILES: C(P(CCCC)CCCC)CCC.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[Br:30][C:31]1[C:57]([CH3:58])=[CH:56][C:34]([O:35][C@@H:36]([CH2:53][CH2:54]O)[C:37]([NH:39][CH:40]2[CH2:45][CH2:44][N:43]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:42][CH2:41]2)=[O:38])=[C:33]([F:59])[CH:32]=1>C1COCC1>[Br:30][C:31]1[C:57]([CH3:58])=[CH:56][C:34]([O:35][C@H:36]2[CH2:53][CH2:54][N:39]([CH:40]3[CH2:45][CH2:44][N:43]([C:46]([O:48][C:49]([CH3:50])([CH3:52])[CH3:51])=[O:47])[CH2:42][CH2:41]3)[C:37]2=[O:38])=[C:33]([F:59])[CH:32]=1
Reactant: Cc1cc(O[C@@H](CCO)C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)c(F)cc1Br
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: Cc1cc(O[C@H]2CCN(C3CCN(C(=O)OC(C)(C)C)CC3)C2=O)c(F)cc1Br
Reaction time: 0.08 h
Yield: 75.4 %

Procedure:
Tributylphosphine (2.0 mL, 7.8 mmol) was added slowly to a degassed solution of di-tert-butyl diazene-1,2-dicarboxylate (1.8 g, 7.8 mmol) in dry THF (30 mL) at ambient temperature. The resulting mixture was stirred for 5 minutes, then added dropwise to a 0° C. solution of (S)-tert-butyl 4-(2-(4-bromo-2-fluoro-5-methylphenoxy)-4-hydroxybutanamido)piperidine-1-carboxylate (3.2 g, 6.5 mmol) in THF (30 mL). The reaction was allowed to stir at ambient temperature overnight. Another 1.2 equivalents of reagents (tributylphosphine, tert-butyl diazene-1,2-dicarboxylate, and THF, prepared in same fashion) was added to the reaction mixture, and the reaction was stirred overnight. The reaction was concentrated and purified over silica gel (35 to 50% EtOAc in hexanes) to afford (S)-tert-butyl 4-(3-(4-bromo-2-fluoro-5-methylphenoxy)-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (2.3 g, 4.9 mmol, 75% yield) as a white solid.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6](=[NH:25])[CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH:15]=[N:14][C:13]([NH:16][C:17]([NH2:24])=[N:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[N:12]1)(=O)[CH3:2]>CC(C)=O>[CH3:2][C:1]1[N:25]=[C:6]([CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[N:14][C:13]([NH:16][C:17]([NH2:24])=[N:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[N:12]2)[NH:5][N:4]=1
Reactant: CC(=O)NNC(=N)CCCCn1cnc(NC(N)=NCC(F)(F)F)n1
Solvent: CC(C)=O
Product: Cc1n[nH]c(CCCCn2cnc(NC(N)=NCC(F)(F)F)n2)n1

Procedure:
N-Acetylamino-5-[3-(2-[2,2,2-trifluoroethyl]guanidino)-1,2,4-triazol-1-yl]valeramidine (0.55 g.) was heated at 170° for 12 minutes. The resulting glass was boiled with acetone and the solid obtained crystallised from acetonitrile to give 3-methyl-5-(4-[3-(2-[2,2,2-trifluoroethyl]guanidino)-1,2,4-triazol-1-yl]butyl)-1,2,4-triazole as a white solid (0.34 g., 65%), m.p. 175°-176°.
Reaction SMILES: [C:1]([N:4]([C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)[C@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]([C:17]2[CH:22]=[CH:21][C:20](OS(C(F)(F)F)(=O)=O)=[CH:19][CH:18]=2)=[O:16])[C@@H:7]([CH3:31])[CH2:6]1)(=[O:3])[CH3:2].[CH2:39]([O:41][C:42]([CH:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1)=[O:43])[CH3:40].C([O-])([O-])=O.[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C1OCCOCCOCCOCCOCCOC1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:39]([O:41][C:42]([CH:44]1[CH2:49][CH2:48][N:47]([C:20]2[CH:19]=[CH:18][C:17]([C:15]([N:8]3[C:9]4[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=4)[C@H:5]([N:4]([C:1](=[O:3])[CH3:2])[C:32]4[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=4)[CH2:6][C@@H:7]3[CH3:31])=[O:16])=[CH:22][CH:21]=2)[CH2:46][CH2:45]1)=[O:43])[CH3:40]
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OS(=O)(=O)C(F)(F)F)cc2)c2ccccc21
Reactant: CCOC(=O)C1CCNCC1
Agent: [Pd]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCN(c2ccc(C(=O)N3c4ccccc4[C@H](N(C(C)=O)c4ccc(Cl)cc4)C[C@@H]3C)cc2)CC1

Procedure:
(2S,4R)-1-(4-{4-[Acetyl-(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenyl)-piperidine-4-carboxylic acid ethyl ester was prepared from (2S,4R)-trifluoro-methanesulfonic acid 4-{4-[acetyl(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenyl ester by adding piperidine-4-carboxylic acid ethyl ester (4 eq.), Cs2CO3 (3 eq.), 10% Pd2(dba)3, BINAP (0.20 equ), and 10% 18-Crown-6 (0.10 eq.) in toluene at 110° C. over night. The reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and water, then extracted three times with ethyl acetate, dried over MgSO4, filtered and concentrated down. The crude residue was purified by HPLC to afford the product.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([OH:18])=[O:17])[CH:11]=2)=[CH:6][CH:5]=1)([O-])=O>[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([OH:18])=[O:17])[CH:11]=2)=[CH:8][CH:9]=1
Reactant: O=C(O)c1cccc(-c2ccc([N+](=O)[O-])cc2)c1
Agent: [Pd]
Product: Nc1ccc(-c2cccc(C(=O)O)c2)cc1

Procedure:
The title compound can be prepared by palladium catalyzed hydrogenation of 4-nitro-3′-biphenyl carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[N:5](CC2C=CC(OC)=CC=2)[C:4](=[O:22])[C:3]=1[C:23]#[N:24]>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[NH:5][C:4](=[O:22])[C:3]=1[C:23]#[N:24]
Reactant: COc1ccc(Cn2c(=O)c(C#N)c(Cl)c3cc(Cl)cnc32)cc1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1c(Cl)c2cc(Cl)cnc2[nH]c1=O
Yield: 95.4 %

Procedure:
4,6-dichloro-1-(4-methoxybenzyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (95) (8.2 g, 22.70 mmol) in neat TFA was refluxed for 24 h. The solution was cooled and excess TFA was distilled off under reduced pressure. The residue was taken in water, basified by solid NaHCO3 and filtered. The solids were washed with excess water and dried to yield 5.2 g (96%) of 4,6-dichloro-2-oxo-1,2-dihydro-[1,8]-naphthyridine-3-carbonitrile (97) as yellow solids. MP: 247° C.; 1H-NMR (DMSO-d6): δ 8.45 (dd, J=2.4 Hz, 1H), 8.82 (d, J=2.4 Hz, 1H), 13.17 (S, 1H); EIMS: 240 (M).
Reaction SMILES: [C:1]([O:4][CH:5]1[C:14]2[C:9](=[C:10]([N:15]3[CH2:20][CH2:19][C:18](=[N:21]O)[CH2:17][CH2:16]3)[CH:11]=[CH:12][CH:13]=2)[O:8][CH2:7][CH2:6]1)(=[O:3])[CH3:2]>C(O)C.[NH4+].[OH-].[Ni]>[C:1]([O:4][CH:5]1[C:14]2[C:9](=[C:10]([N:15]3[CH2:16][CH2:17][CH:18]([NH2:21])[CH2:19][CH2:20]3)[CH:11]=[CH:12][CH:13]=2)[O:8][CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1CCOc2c1cccc2N1CCC(=NO)CC1
Agent: [Ni]
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: CC(=O)OC1CCOc2c1cccc2N1CCC(N)CC1
Yield: 93.6 %

Procedure:
0.28 g of the compound of Step 4 is dissolved in a solution of 6 ml of ethanol and 0.3 ml of NH4OH. 0.3 ml of Raney nickel is added and the whole is hydrogenated at room temperature under atmospheric pressure. After filtering off the catalyst, rinsing and evaporating, 0.25 g of the expected product is obtained. Yield: 96%.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[C:11]([OH:13])=O.Cl.[NH:15]1[CH2:18][CH:17]([C:19]2[C:24]([Cl:25])=[N:23][CH:22]=[CH:21][N:20]=2)[CH2:16]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CN1CCOCC1>CN(C=O)C.O>[Cl:25][C:24]1[C:19]([CH:17]2[CH2:18][N:15]([C:11]([C:3]3[N:2]([CH3:1])[C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=4[N:4]=3)=[O:13])[CH2:16]2)=[N:20][CH:21]=[CH:22][N:23]=1
Reactant: Clc1nccnc1C1CNC1
Reactant: Cn1c(C(=O)O)nc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(C(=O)N2CC(c3nccnc3Cl)C2)nc2ccccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 91.5 %

Procedure:
A mixture of 1-methyl-1H-benzoimidazole-2-carboxylic acid (82) (176 mg, 1.0 mmol), 2-Azetidin-3-yl-3-chloro-pyrazine hydrochloride (8) (169 mg, 1.0 mmol), HOBt (151 mg, 1.2 mmol), EDCI (231 mg, 1.2 mmol) and N-methyl-morpholine (NMM) (300 mg, 3.0 mmol) in DMF (5 mL) was stirred at RT for 24 h. The mixture was diluted with water (20 mL), and filtered. The filter cake was washed with water and dried in vacuo to provide [3-(3-chloro-pyrazin-2-yl)-azetidin-1-yl]-(1-methyl-1H-benzoimidazol-2-yl)-methanone (83) (300 mg, yield 90%).
Reaction SMILES: [CH2:1]1COCC1.[OH:6]/[N:7]=[C:8](\[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20])/[C:9]([O:11][CH2:12][CH3:13])=[O:10].[H-].[Na+].S(OC)(OC)(=O)=O>C(OCC)(=O)C.O>[CH3:1][O:6]/[N:7]=[C:8](\[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20])/[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)/C(=N/O)c1ccccc1C
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COS(=O)(=O)OC
Product: CCOC(=O)/C(=N/OC)c1ccccc1C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
To 50 ml of a THF solution with 10.0 g of ethyl (E)-α-hydroxyimino-o-tolylacetate (48 mmol), 2.2 g of 60%-sodium hydride (53 mmol) was added under ice-cooling and the solution was stirred for 30 minutes. The solution, to which 6.7 g of dimethyl sulfate (53 mmol) was added dropwise, was stirred at room temperature for one more hour. Water and ethyl acetate were added to the reaction solution, and the organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated to give 10.4 g of ethyl (E)-α-methoxyimino-o-tolylacetate (yield; 98%).
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[N:7][C:8]([Cl:12])=[CH:9][C:10]=1Cl)=[O:4].Cl.[CH2:14]([O:16][C:17](=[O:21])[CH2:18][NH:19][CH3:20])[CH3:15].C(N(CC)CC)C>C(#N)C>[CH2:14]([O:16][C:17]([C:18]1[N:19]([CH3:20])[C:10]2[CH:9]=[C:8]([Cl:12])[N:7]=[N:6][C:5]=2[C:3]=1[OH:4])=[O:21])[CH3:15]
Reactant: COC(=O)c1nnc(Cl)cc1Cl
Reactant: CCOC(=O)CNC
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(O)c2nnc(Cl)cc2n1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.7 %

Procedure:
To a stirred solution of 4,6-dichloro-pyridazine-3-carboxylic acid methyl ester (2.9 g, 14 mmol) and sarcosine ethyl ester hydrochloride (2.15 g, 14 mmol) in acetonitrile (75 ml) was added triethylamine (4.9 mL, 35 mmol). The resultant reaction mixture was stirred at room temperature for 2 hours before adding further triethylamine (4.9 mL, 35 mmol) and heating the reaction mixture at 80° C. for 18 hours. After cooling to room temperature, the reaction mixture was concentrated in vacuo and the resultant residue treated with water and extracted with ethyl acetate (×3), the combined organic extracts dried (Na2SO4), filtered and concentrated in vacuo to give a solid. The solid was triturated in hot methanol to give the title compound as a yellow solid (1.6 g, 45%). LCMS (method B): RT=2.64 min, M+H+=256.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([N+:20]([O-])=O)=[CH:17][CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1)#[CH:2].Cl[Sn]Cl>C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([NH2:20])=[CH:17][CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1)#[CH:2]
Reactant: C#Cc1cccc(Nc2ncnc3cc([N+](=O)[O-])ccc23)c1
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Product: C#Cc1cccc(Nc2ncnc3cc(N)ccc23)c1
Yield: 89.2 %

Procedure:
N-(3-ethynylphenyl)-7-nitroquinazolin-4-amine (2.0 g, 6.89 mmol), SnCl2 (5.0 g, 26.37 mmol), and ethyl acetate (50 mL) was refluxed for 3 h. The mixture was subjected to extraction with ethyl acetate (20 mL). The combined organic layers were washed with brine (20 mL×2), dried over Na2SO4, and concentrated in vacuo to afford 1.6 g (86%) of N4-(3-ethynylphenyl)quinazoline-4,7-diamine as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10](OCC)=[O:11])=[C:6]([Cl:15])[N:5]=[C:4](/[CH:16]=[CH:17]/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:3]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:15][C:6]1[C:7]2[O:8][CH2:9][C:10](=[O:11])[NH:1][C:2]=2[N:3]=[C:4](/[CH:16]=[CH:17]/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:5]=1
Reactant: CCOC(=O)COc1c(N)nc(/C=C/c2ccccc2)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1COc2c(Cl)nc(/C=C/c3ccccc3)nc2N1
Temperature: 75 °C
Yield: 99 %

Procedure:
To a solution of ethyl ({4-amino-6-chloro-2-[(E)-2-phenylethenyl]-5-pyrimidinyl}oxy)acetate (0.55 g, 1.65 mmol) in DMF (5 mL) was added solid K2CO3 (0.46 g, 3.3 mmol) and the resulting mixture was heated at 75° C. for 1 h. The solvent was evaporated under reduced pressure and the residue was extracted with 10% methanol in DCM (3×100 ml). The organic extracts were combined, dried over anhydrous MgSO4, filtered and evaporated under reduced pressure to give a solid which was purified by column chromatography (silica gel) with a 0-10% methanol in DCM gradient to give the desired product as a solid (0.47 g, 99%).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C([Li])CCC.C[Si](Cl)(C)C.[Cl:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH:21]=[O:22].C(=O)([O-])O.[Na+]>C(OCC)C>[Cl:17][C:18]1[CH:19]=[C:20]([CH:21]([C:4]2[S:3][CH:2]=[N:6][CH:5]=2)[OH:22])[CH:23]=[CH:24][C:25]=1[Cl:26]
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: Brc1nccs1
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Li]CCCC
Solvent: CCOCC
Product: OC(c1ccc(Cl)c(Cl)c1)c1cncs1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2-Bromothiazole (5 g) in dry diethyl ether (20 ml) was added dropwise to a stirred solution of n-butyllithium (1.6M in hexanes, 21 ml) in diethyl ether (20 ml) at -70° C. under an atmosphere of dry nitrogen. After 30 minutes, trimethylsilylchloride (3.9 ml) was added and the mixture was allowed to warm to 0° C. The mixture was then cooled to -70° C. and further n-butyllithium (21 ml) was added. The mixture was warmed to 0° C. and after 30 minutes was cooled again to -70° C. and 3,4-dichlorobenzaldehyde (5.8 g) in diethyl ether (40 ml) was added. The mixture was then allowed to warm to room temperature and after 30 minutes saturated aqueous sodium hydrogen carbonate was added. The mixture was extracted with dichloromethane and the material thus obtained was purified by chromatography on silica gel to give the title compound. The hydrochloride salt was prepared. M.p. 167°-170° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][CH2:11][C@@H:12]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:13])[CH:5]=[N:6][C:7]=1[C:8]#[N:9].[NH2:22][C:23]1[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([CH3:30])[N:24]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[C:8]([C:7]1[N:6]=[CH:5][C:4]([NH:10][CH2:11][C@@H:12]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:13])=[CH:3][C:2]=1[NH:22][C:23]1[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([CH3:30])[N:24]=1)#[N:9]
Reactant: C[C@@H](CNc1cnc(C#N)c(Br)c1)NC(=O)OC(C)(C)C
Reactant: Cc1cc(C)nc(N)c1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: Cc1cc(C)nc(Nc2cc(NC[C@H](C)NC(=O)OC(C)(C)C)cnc2C#N)c1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a flask were added tert-butyl {(2S)-1-[(5-bromo-6-cyanopyridin-3-yl)amino]propan-2-yl}carbamate (200 mg, 0.56 mmol), 2-amino-4,6-dimethylpyridine (103 mg, 0.844 mmol), tris(dibenzylideneacetone)dipalladium(0)-dichloromethane complex (52 mg, 0.051 mmol), Xantphos (65 mg, 0.11 mmol), and cesium carbonate (367 mg, 1.13 mmol). 1,4-Dioxane (3 mL) was then added and nitrogen was bubbled into the reaction for 5 minutes. The reaction mixture was then stirred at 80° C. for 16 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The mixture was washed with saturated aqueous ammonium chloride, and the organics were separated, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel to afford tert-butyl [(2S)-1-({6-cyano-5-[(4,6-dimethylpyridin-2-yl)-amino]pyridin-3-yl}amino)propan-2-yl]carbamate. MS ESI calc'd. for C21H29N6O2 [M+H]+ 397. found 397.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15](=[O:34])[NH:16][C:17]2[C:18](=[O:33])[N:19]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[F:32])[C:20](=[O:24])[NH:21][C:22]=2[NH2:23])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:36](OC(N(C)C1C=CC(CC(O)=O)=CC=1)=O)(C)(C)C>>[C:1]([O:5][C:6](=[O:35])[N:7]([C:8]1[CH:9]=[CH:10][C:11]([CH2:14][C:15](=[O:34])[NH:16][C:17]2[C:18](=[O:33])[N:19]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[F:32])[C:20](=[O:24])[NH:21][C:22]=2[NH2:23])=[CH:12][CH:13]=1)[CH3:36])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(CC(=O)O)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(CC(=O)Nc2c(N)[nH]c(=O)n(Cc3ccccc3F)c2=O)cc1
Product: CN(C(=O)OC(C)(C)C)c1ccc(CC(=O)Nc2c(N)[nH]c(=O)n(Cc3ccccc3F)c2=O)cc1

Procedure:
Prepared by the same procedure as described for the preparation of (4-{[6-amino-3-(2-fluoro-benzyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-ylcarbamoyl]-methyl}-phenyl)-carbamic acid tert-butyl ester (example 1, step 4) except that [4-(tert-butoxycarbonyl-methyl-amino)-phenyl]-acetic acid was used in place of (4-tert-butoxycarbonylamino-phenyl)-acetic acid. Crude (4-{[6-amino-3-(2-fluoro-benzyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-ylcarbamoyl]-methyl}-phenyl)-methyl-carbamic acid tert-butyl ester was obtained as a yellow solid which was of sufficient purity for subsequent used without additional purification.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:11])[CH:3]=1.[CH3:12][CH:13]([NH2:15])[CH3:14]>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:15][CH:13]([CH3:14])[CH3:12])=[O:8])=[C:4]([F:11])[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1F
Reactant: CC(C)N
Product: CC(C)NC(=O)c1ccc(Br)cc1F

Procedure:
The sub-title compound was prepared by the method of example 18 step a) using 4-bromo-2-fluorobenzoic acid and 2-propanamine.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[C:7]([CH3:17])[C:6]=2[CH:5]=[C:4]([C:18]#[N:19])[CH:3]=1.[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:17][C:7]1[C:6]2[CH:5]=[C:4]([C:18]#[N:19])[CH:3]=[C:2]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:10]=2[N:9]2[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]=12
Reactant: OB(O)c1ccccc1
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCCNC2=O
Product: Cc1c2n(c3c(-c4ccccc4)cc(C#N)cc13)CCCNC2=O

Procedure:
The title compound, off-white solid (60 mg, 76%), MS (ISP) m/z=316.5 [(M+H)+], mp 258° C., was prepared in accordance with the general method of example 1 from 7-bromo-11-methyl-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 17) (79.5 mg, 0.25 mmol) and commercially available phenylboronic acid (39.6 mg, 0.325 mmol).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:9][NH:10][C:11](=[O:38])[CH2:12][CH2:13][C:14]([NH:16][CH2:17][C:18]2[C:19]([NH:31][CH:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[C:20]3[CH:28]=[N:27][N:26]([CH2:29][CH3:30])[C:21]3=[N:22][C:23]=2[CH2:24][CH3:25])=[O:15])[CH:5]=[CH:6][C:7]=1[F:8].[CH:39]([C:41]1[CH:42]=[C:43](B(O)O)[CH:44]=[CH:45][CH:46]=1)=[O:40].C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:29]([N:26]1[C:21]2=[N:22][C:23]([CH2:24][CH3:25])=[C:18]([CH2:17][NH:16][C:14](=[O:15])[CH2:13][CH2:12][C:11]([NH:10][CH2:9][C:4]3[CH:3]=[C:2]([C:45]4[CH:44]=[CH:43][CH:42]=[C:41]([CH:39]=[O:40])[CH:46]=4)[C:7]([F:8])=[CH:6][CH:5]=3)=[O:38])[C:19]([NH:31][CH:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[C:20]2[CH:28]=[N:27]1)[CH3:30]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CCC(=O)NCc1ccc(F)c(Br)c1
Reactant: O=Cc1cccc(B(O)O)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CCC(=O)NCc1ccc(F)c(-c2cccc(C=O)c2)c1
Yield: 80.8 %

Procedure:
A mixture of N-[(3-bromo-4-fluorophenyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}butanediamide (1.08 g, 1.832 mmol), (3-formylphenyl)boronic acid (0.330 g, 2.2 mmol), tetrakis (triphenylphosphine) palladium (0) (0.092 g, 0.08 mmol), sodium carbonate (0.530 g, 5.0 mmol) and 1,4-dioxane (12 mL) and water (4 mL) was microwaved at 140° C. for 30 min. The reaction mixture was diluted with water and extracted with EtOAc twice. The organic layer was filtered through a glass-fiber filter, washed with saturated NaCl, and then dried over Na2SO4. The organic layer was evaporated to dryness and taken up in a small amount of DCM and introduced onto a Chromatotron Plate for purification eluting with DCM-MeOH (2-7%). The product fractions were combined to give N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(6-fluoro-3′-formyl-3-biphenylyl)methyl]butanediamide (910 mg, 81%) as a glassy solid. LC-MS m/z 615.4 (M+H)+, 0.82 min (ret time).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[NH:7][C:6]([C:13]([OH:15])=O)=[CH:5]2.[CH3:16][CH:17]([NH:19][C:20]1[C:21]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[N:22][CH:23]=[CH:24][CH:25]=1)[CH3:18].C(N=C=NCCCN(C)C)C>>[CH3:18][CH:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[N:22][C:21]=1[N:26]1[CH2:27][CH2:28][N:29]([C:13]([C:6]2[NH:7][C:8]3[C:4](=[CH:3][C:2]([F:1])=[C:10]([O:11][CH3:12])[CH:9]=3)[CH:5]=2)=[O:15])[CH2:30][CH2:31]1)[CH3:16]
Reactant: COc1cc2[nH]c(C(=O)O)cc2cc1F
Reactant: CC(C)Nc1cccnc1N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Product: COc1cc2[nH]c(C(=O)N3CCN(c4ncccc4NC(C)C)CC3)cc2cc1F

Procedure:
Following the general procedure of EXAMPLE 16A and making non-critical variations but starting with 5-fluoro-6-methoxyindole-2-carboxylic acid (PREPARATION 92, 0.30 g), 1-[3-(1-methylethylamino)-2-pyridinyl]piperazine (0.32 g) and 1-(ethyl)-3-(dimethylaminopropyl)carbodiimide (0.33 g), the title compound is obtained, mp 193°-194°.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][N:6]=[C:5]1[CH3:12].[Na].[CH2:14]([S:16]([OH:18])=[O:17])[CH3:15]>CS(C)=O>[CH2:14]([S:16]([CH2:2][CH2:3][N:4]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][N:6]=[C:5]1[CH3:12])(=[O:18])=[O:17])[CH3:15]
Reactant: CCS(=O)O
Reactant: Cc1ncc([N+](=O)[O-])n1CCBr
Agent: [Na]
Solvent: CS(C)=O
Product: CCS(=O)(=O)CCn1c([N+](=O)[O-])cnc1C

Procedure:
5.83 g. (25 m moles) of 1-(2'-bromoethyl)-2-methyl-5-nitroimidazole is dissolved in 50 ml. of dimethylsulfoxide and 5.48 g. (30 m mole) of the sodium salt of ethyl sulfinic acid (CH3CH2SO2Na) is added. The reaction mixture is maintained for 21/2 hours at 100°-110° C. thereafter the solvent is removed under vacuum and the solid residue is washed with water and recrystallized from ethanol. The yield is 2.28 (37%) of 1-[2'-(ethylsulfonyl)-ethyl]-2-methyl-5-nitroimidazole, M.P. 124°-126° C.