Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:33]=[CH:32][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:17]([CH:19]3[CH2:24][CH2:23][N:22](CC4C=CC=CC=4)[CH2:21][CH2:20]3)=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][CH:4]=1.Cl>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:17]([CH:19]3[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]3)=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:32][CH:33]=1
Reactant: COc1ccc(C(=O)Nc2ccccc2NC(=O)C2CCN(Cc3ccccc3)CC2)cc1
Agent: Cl
Solvent: CCO
Product: COc1ccc(C(=O)Nc2ccccc2NC(=O)C2CCNCC2)cc1
Reaction time: 16 h
Yield: 80.7 %

Procedure:
A solution of N1-(4-methoxybenzoyl)-N2-(1-benzylpiperidin-4-ylcarbonyl)-1,2-benzenediamine (1.02 g, 2.30 †mmol), 1 N aqueous hydrochloric acid (5 mL), and 5% pallidium-on-carbon (1.06 g) in ethanol (100 mL) was placed under a hydrogen atmosphere (1 bar). After 16 h, the mixture was filtered through diatomaceous earth and the filtrate concentrated in vacuo. The residue was treated with 1 N aqueous sodium hydroxide followed by ethyl acetate. The aqueous layer was extracted twice with ethyl acetate and the combined organics were washed with 1 N aqueous sodium hydroxide, saturated sodium chloride solution, and dried (potassium carbonate). Concentration and recrystallization yielded 656 mg (81%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Br[C:23]([CH3:32])([CH3:31])[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>C(OCC)(=O)C>[C:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([O:1][C:23]([CH3:32])([CH3:31])[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:3][CH:4]=1)#[N:10]
Reactant: N#CCc1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C(C)(C)Oc1ccc(CC#N)cc1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
4-Hydroxyphenylacetonitrile (13.3 g, 100 mmol) and potassium carbonate (20.73 g, 150 mmol) was added to dimethylformamide (75 mL). Subsequently, tert-butyl 2-bromoisobutyrate (50.41 mL, 250 mmol) was added thereto, and the mixture was stirred for 24 hours at 80° C. The temperature of the reaction mixture was returned to room temperature, and ethyl acetate was added thereto. Washing was performed sequentially with water and saturated brine, followed by drying over sodium sulfate. The resultant mixture was subjected to concentration under reduced pressure and purification by silica gel column chromatography (n-hexane/ethyl acetate=7/1), whereby the target compound was obtained (18.62 g, 67.62 mmol, 67.6%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:6][C:5]([C:14]#[N:15])=[CH:4][C:3]=1[NH:16][C:17]1[N:22]=[C:21]([N:23]([CH:33]2[CH2:35][CH2:34]2)[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[C:20]2=[N:36][CH:37]=[C:38]([C:39]#[N:40])[N:19]2[N:18]=1.O=[C:42]1[CH2:45][N:44]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:43]1.C(O)(=O)C.C([BH3-])#N.[Na+]>C1COCC1.CO>[Cl:1][C:2]1[C:3]([NH:16][C:17]2[N:22]=[C:21]([N:23]([CH:33]3[CH2:34][CH2:35]3)[CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[C:20]3=[N:36][CH:37]=[C:38]([C:39]#[N:40])[N:19]3[N:18]=2)=[CH:4][C:5]([C:14]#[N:15])=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([CH:42]2[CH2:43][N:44]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:45]2)[CH2:10][CH2:9]1
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CCNCC4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CCN(C5CN(C(=O)OC(C)(C)C)C5)CC4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.1 %

Procedure:
To a solution of 2-((2-chloro-5-cyano-3-(piperazin-1-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (500 mg, 0.901 mmol) in THF (2.5 mL) and MeOH (2.5 mL) was added tert-butyl 3-oxoazetidine-1-carboxylate (185 mg, 1.081 mmol), acetic acid (0.052 rnL, 0.901 mmol). The reaction mixture was stirred at room temperature for overnight. The reaction mixture was cooled to 0° C., added sodium cyanoborohydride (113 mg, 1.802 mmol) and the reaction mixture was allowed to come to room temperature and stirred for 5 h at the same temperature. The solvent was removed completely under vacuum, the resultant residue was dissolved in ethyl acetate (100 ml), washed it with 10% NaHCO3 solution, brine, dried over anhydrous Na2SO4 and concentrated. The crude material was purified via ISCO (12 gm silica Redisep, 0 to 10% CH3OH—CHC13 gradient elution). The fractions were concentrated to get the tert-butyl 3-(4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)piperazin-1-yl)azetidine-1-carboxylate (500 mg) as a off white solid.
Reaction SMILES: [O:1]([C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OS([O-])=O.[Na+].[CH3:21][O:22][C:23](=[O:32])[C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[C:26]([NH2:31])[CH:25]=1.C(O)C>O>[O:1]([C:8]1[CH:15]=[CH:14][C:11]([C:12]2[NH:30][C:27]3[CH:28]=[CH:29][C:24]([C:23]([O:22][CH3:21])=[O:32])=[CH:25][C:26]=3[N:31]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Oc2ccccc2)cc1
Reactant: COC(=O)c1ccc(N)c(N)c1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COC(=O)c1ccc2[nH]c(-c3ccc(Oc4ccccc4)cc3)nc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.5 %

Procedure:
To 4-phenoxybenzaldehyde (3.0 g, 0.02 mol) was added 21 mL of 40% NaHSO3 (aq). The mixture was stirred for 1 h at 25° C. Methyl-3,4-diaminobenzoate (2.5 g, 0.02 mol) and ethanol (15 mL) were added. The mixture was refluxed for 4 h. The reaction was then poured into water. The precipitate filtered and recrystallized from EtOAc to afford 2-(4-phenoxyphenyl)-1H-benzimidazole-5-carboxylic acid, methyl ester (5.06 g, 97%) as a white solid.
Reaction SMILES: COC1C=CC(CN(CC2C=CC(OC)=CC=2)C2N=CC(C3C4CCNC=4N=C(N4CCOCC4)N=3)=CN=2)=CC=1.ClC(OCC=C)=O.[CH2:48]([O:51][C:52]([N:54]1[C:58]2[N:59]=[C:60]([N:88]3[CH2:93][CH2:92][O:91][CH2:90][CH2:89]3)[N:61]=[C:62]([C:63]3[CH:64]=[N:65][C:66]([N:69](CC4C=CC(OC)=CC=4)CC4C=CC(OC)=CC=4)=[N:67][CH:68]=3)[C:57]=2[CH2:56][CH2:55]1)=[O:53])[CH:49]=[CH2:50]>>[CH2:48]([O:51][C:52]([N:54]1[C:58]2[N:59]=[C:60]([N:88]3[CH2:89][CH2:90][O:91][CH2:92][CH2:93]3)[N:61]=[C:62]([C:63]3[CH:64]=[N:65][C:66]([NH2:69])=[N:67][CH:68]=3)[C:57]=2[CH2:56][CH2:55]1)=[O:53])[CH:49]=[CH2:50]
Reactant: C=CCOC(=O)N1CCc2c(-c3cnc(N(Cc4ccc(OC)cc4)Cc4ccc(OC)cc4)nc3)nc(N3CCOCC3)nc21
Agent: C=CCOC(=O)Cl
Agent: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Product: C=CCOC(=O)N1CCc2c(-c3cnc(N)nc3)nc(N3CCOCC3)nc21
Yield: 92 %

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (41.4 mg, 0.0769 mmol) and allyl chloroformate (17 μl, 0.160 mmol) instead of acetic anhydride, in the same manner as Example 1-D-01, a crude product of 4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid allyl ester was obtained, and deprotection was further carried out according to the above deprotection reaction method 1, to obtain the desired compound (D-40) as a colorless powder (27.0 mg, 92%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH:11]=[C:10]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[C:9](=[O:17])[NH:8][C:7]1=[O:18].Cl.[F:20][C:21]1[CH:22]=[C:23]2[C:31](=[CH:32][CH:33]=1)[C:26]1([CH2:30][CH2:29][NH:28][CH2:27]1)[CH2:25][CH2:24]2.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>O.CN1C(=O)CCC1>[ClH:1].[F:20][C:21]1[CH:22]=[C:23]2[C:31](=[CH:32][CH:33]=1)[C:26]1([CH2:30][CH2:29][N:28]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[CH:11]=[C:10]([C:12]4[S:13][CH:14]=[CH:15][CH:16]=4)[C:9](=[O:17])[NH:8][C:7]3=[O:18])[CH2:27]1)[CH2:25][CH2:24]2
Reactant: Fc1ccc2c(c1)CCC21CCNC1
Reactant: O=c1[nH]c(=O)n(CCCCCl)cc1-c1cccs1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN1CCCC1=O
Solvent: O
Product: O=c1[nH]c(=O)n(CCCCN2CCC3(CCc4cc(F)ccc43)C2)cc1-c1cccs1
Temperature: 70 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
A mixture of 1-(4-chlorobutyl)-5-(thiophen-2-yl)pyrimidine-2,4(1H,3H)-dione (Prep23, 50 mg, 0.18 mmol), 5-fluoro-2,3-dihydrospiro[indene-1,3′-pyrrolidine]hydrochloride salt (Prep14, 50 mg, 0.26 mmol), potassium carbonate (108 mg, 0.78 mmol), sodium iodide (108 mg, 0.72 mmol) and NMP (1 ml) was stirred at 70° C. overnight. The mixture was then diluted with water and extracted with ethyl acetate. The EA phase was evaporated and the crude purified by preparative TLC to give the free base of the title compound (72 mg). The compound was purified by preparative HPLC and treated with a 1N solution of HCl-ether and freeze-dried to give the title compound (30 mg, y=35%).
Reaction SMILES: ON1C(CC(C)CC(C)(C)C)=CC(C)=CC1=O.[OH:18][N:19]1[C:24]([CH:25]2[CH2:30][CH:29]3C[CH:26]2[CH2:27][CH2:28]3)=[CH:23][C:22]([CH3:32])=[CH:21][C:20]1=[O:33].C1(CCC2C(=O)NC=CC=2)C=CC=CC=1>>[OH:18][N:19]1[C:24]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:23][C:22]([CH3:32])=[CH:21][C:20]1=[O:33]
Reactant: Cc1cc(C2CC3CCC2C3)n(O)c(=O)c1
Agent: Cc1cc(CC(C)CC(C)(C)C)n(O)c(=O)c1
Agent: O=c1[nH]cccc1CCc1ccccc1
Product: Cc1cc(C2CCCCC2)n(O)c(=O)c1

Procedure:
1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2-pyridone, 1-hydroxy-4-methyl-6-n-hexyl, -6-iso-hexyl-, 6-n-heptyl- or -6-isoheptyl-2-pyridone, 1-hydroxy-4-methyl-6-octyl- or -6-isooctyl-2-pyridone, in particular 1-hydroxy-4-methyl-6-cyclohexylmethyl- or 6-cyclohexylethyl-2-pyridone, it being possible for the cyclohexyl radical in each case also to carry a methyl radical, 1-hydroxy-4-methyl-6-(2-bicyclo[2,2,1]heptyl)-2-pyridone, 1-hydroxy-3,4-dimethyl-6-benzyl- or -6-dimethylbenzyl-2-pyridone or 1-hydroxy-4-methyl-6-(β-phenylethyl-2-pyridone.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][N:12]([CH:15]([CH3:23])[C:16]([O:18]C(C)(C)C)=[O:17])[C:11](=[O:24])[CH:10]=1.C(O)(C(F)(F)F)=O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][N:12]([CH:15]([CH3:23])[C:16]([OH:18])=[O:17])[C:11](=[O:24])[CH:10]=1
Reactant: CC(C(=O)OC(C)(C)C)n1ccc(-c2cc(Cl)ccc2Br)cc1=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C(=O)O)n1ccc(-c2cc(Cl)ccc2Br)cc1=O

Procedure:
920 mg (2.2 mmol) of tert-butyl 2-[4-(2-bromo-5-chlorophenyl)-2-oxopyridin-1(2H)-yl]propanoate (racemate) were hydrolysed with TFA according to General Method 6A. Yield: 1110 mg (purity 93%, quant.)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[C@H:5]([O:26][CH2:27][CH3:28])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C@H:14]([C:16]([O:18]CC2C=CC=CC=2)=[O:17])[CH3:15])=[CH:9][CH:8]=1)[CH3:2]>CCO.O.[Pd]>[CH2:1]([O:3][C:4](=[O:29])[C@H:5]([O:26][CH2:27][CH3:28])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C@H:14]([C:16]([OH:18])=[O:17])[CH3:15])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)[C@@H](Cc1ccc(O[C@@H](C)C(=O)OCc2ccccc2)cc1)OCC
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: CCOC(=O)[C@@H](Cc1ccc(O[C@@H](C)C(=O)O)cc1)OCC
Reaction time: 2 h
Yield: 67.4 %

Procedure:
To a solution of (R,S)-3-[4-(1-benzyloxycarbonyl-ethoxy)-phenyl]-2-ethoxy-propionic acid ethyl ester (1.05 g, 2.63 mmol) in EtOH (20 ml) and H2O (0.5 ml) was added a slurry of Pd—C (5%, 100 mg) in EtOH (10 ml). The suspension was hydrogenated under balloon pressure for 2 hours. The mixture was filtered through a pad of celite and concentrated to a residue, the residue was then purified by silica gel chromatography with EtOAc/Hexanes (25% to 100%) to afford the acid product (550 mg, 68%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1([OH:13])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[Cl:14][C:15]1[N:16]=[C:17]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[C:18]2[S:23][C:22]([CH:24]=O)=[CH:21][C:19]=2[N:20]=1>>[Cl:14][C:15]1[N:16]=[C:17]([N:26]2[CH2:27][CH2:28][O:29][CH2:30][CH2:31]2)[C:18]2[S:23][C:22]([CH2:24][N:10]3[CH2:9][CH2:8][C:7]([OH:13])([CH:2]4[CH:3]=[CH:4][CH:5]=[CH:6][NH:1]4)[CH2:12][CH2:11]3)=[CH:21][C:19]=2[N:20]=1
Reactant: OC1(c2ccccn2)CCNCC1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Product: OC1(C2C=CC=CN2)CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1

Procedure:
Reaction of 2′,3′,5′,6′-tetrahydro-1′H-[2,4′]bipyridinyl-4′-ol with 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde 10 using standard reductive amination conditions yielded 1′-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-2′,3′,5′,6′-tetrahydro-1H-[2,4′]bipyridinyl-4′-ol, which was reacted with 2-aminopyrimidine-5-boronic acid in General Procedure A. Purification on silica yielded 402. 400 MHz 1H NMR CDCl3 9.16 (s, 2H); 8.47 (d, 1H, J=4.8 Hz); 7.70 (t, 1H, J=7.7 Hz); 7.45 (d, 1H, J=7.9 Hz); 7.26 (s, 1H); 7.19 (t, 1H, J=6.2 Hz); 4.00 (t, 4H, J=4.6 Hz); 3.87 (s, 2H); 3.85 (t, 4H, J=4.7 Hz); 2.875 (d, 2H, J=11.0 Hz); 2.63 (t, 2H, J=11.2 Hz); 2.16 (m, 2H); 1.63 (d, 2H, J=12.6 Hz). LC-MS (m+1)=505.18
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[N+:7]([C:10]1[CH:11]=[C:12]([C:19]([F:22])([F:21])[F:20])[C:13]([CH2:16][C:17]#[N:18])=[N:14][CH:15]=1)([O-:9])=[O:8].[CH3:23]I>CC#N>[N+:7]([C:10]1[CH:11]=[C:12]([C:19]([F:22])([F:20])[F:21])[C:13]([CH:16]([CH3:23])[C:17]#[N:18])=[N:14][CH:15]=1)([O-:9])=[O:8]
Reactant: N#CCc1ncc([N+](=O)[O-])cc1C(F)(F)F
Reactant: CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C#N)c1ncc([N+](=O)[O-])cc1C(F)(F)F
Temperature: 40 °C
Reaction time: 10 h
Yield: 34.7 %

Procedure:
K2CO3 (359 mg, 2.60 mmol) was added to a solution of 2-(5-nitro-3-(trifluoromethyl) pyridine-2-yl)acetonitrile (200 mg, 0.865 mmol) in MeCN (10 mL). MeI (3071 mg, 21.63 mmol) was added and the mixture was stirred at 40° C. for 10 h. Then the solution was concentrated and distributed between EA and saturated NaHCO3 solution. The combined organic extract was washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by preparative TLC (PE/EA=5:1, Rf=0.5) to yield a light yellow solid of 2-(5-nitro-3-(trifluoromethyl)pyridin-2-yl)propanenitrile (73.6 mg, 0.300 mmol, 34.7% yield): 1H NMR (400 MHz, CDCl3) δ: 9.65 (d, J=2.2 Hz, 1H), 9.54 (d, J=2.2 Hz, 1H), 8.86 (d, J=2.2 Hz, 1H), 8.80 (d, J=2.0 Hz, 1H), 4.47 (q, J=7.1 Hz, 1H), 1.92 (s, 2H), 1.78 (d, J=7.1 Hz, 3H); ES-LCMS m/z 246.0 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:5]2[CH:6]=[N:7][NH:8][C:9]=2[CH:10]=1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH:22]([CH3:24])[CH3:23]>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:5]2[CH:6]=[N:7][N:8]([CH:22]([CH3:24])[CH3:23])[C:9]=2[CH:10]=1
Reactant: COC(=O)c1cc(Br)cc2[nH]ncc12
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)c1cc(Br)cc2c1cnn2C(C)C
Temperature: 90 °C
Reaction time: 2 h
Yield: 33.8 %

Procedure:
To a stirred solution of methyl 6-bromo-1H-indazole-4-carboxylate (4 g, 14.92 mmol) in acetonitrile (30 mL), cesium carbonate (9.7 g, 29.8 mmol) was added followed by 2-iodopropane (3.8 g, 22.3 mmol) and the reaction mixture stirred at 90° C. for 2 h. On completion, the reaction mixture was concentrated under reduced pressure and the residue diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water, brine and dried over sodium sulfate. Solvent was removed under reduced pressure to afford crude material which was purified by column chromatography to afford methyl 6-bromo-1-isopropyl-1H-indazole-4-carboxylate (1.5 g, 32.6%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([NH:6][C:7]([C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[CH:12]=[C:13]([NH2:15])[CH:14]=1)=[O:8])[CH3:5].N([O-])=O.[Na+].[N-:27]=[N+:28]=[N-].[Na+]>FC(F)(F)C(O)=O.O>[CH3:1][O:2][CH2:3][CH:4]([NH:6][C:7]([C:9]1[CH:10]=[C:11]([C:16]2[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=2)[CH:12]=[C:13]([N:15]=[N+:27]=[N-:28])[CH:14]=1)=[O:8])[CH3:5]
Reactant: [N-]=[N+]=[N-]
Reactant: COCC(C)NC(=O)c1cc(N)cc(-c2ccc(C)cc2)c1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COCC(C)NC(=O)c1cc(N=[N+]=[N-])cc(-c2ccc(C)cc2)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 5-amino-4′-methyl-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide (500 mg, 1.68 mmol) in trifluoroacetic acid (10 mL) was added a solution of NaNO2 (21.47 mmol, 1.49 g) in water (10 mL) at 0° C. The mixture was stirred at 0° C. for 10 minutes and a solution of NaN3 (44.43 mmol, 2.89 g) in water (10 mL) was added. The solution was stirred at room temperature for 16 hours. Solvent was removed under reduced pressure and the residue was extracted with ethyl acetate, washed with saturated aqueous NaHCO3, brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give 5-azido-4′-methyl-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide. (80%). MS (M+H)=325.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]([CH3:20])[CH2:9][N:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:11][CH:12]=1)(=O)=O.[CH2:23]([O:25][C:26]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)=[O:27])[CH3:24]>>[CH2:13]([N:10]1[CH2:11][CH:12]=[C:7]([C:32]2[CH:33]=[C:28]([CH:29]=[CH:30][CH:31]=2)[C:26]([O:25][CH2:23][CH3:24])=[O:27])[CH:8]([CH3:20])[CH2:9]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC1CN(Cc2ccccc2)CC=C1OS(=O)(=O)C(F)(F)F
Reactant: CCOC(=O)c1cccc(B(O)O)c1
Product: CCOC(=O)c1cccc(C2=CCN(Cc3ccccc3)CC2C)c1

Procedure:
Ethyl 3-(1-benzyl-3-methyl-1,2,3,6-tetrahydropyridin-4-yl)benzoate was synthesized as described for INTERMEDIATE 6 (step A) using 1-benzyl-3-methyl-1,2,3,6-tetrahydropyridin-4-yl trifluoromethanesulfonate and [3-(ethoxycarbonyl)phenyl]boronic acid as starting materials.
Reaction SMILES: [C:1]([C:4]1[C:12]2[O:11][C:10]([CH:13]3[CH2:18][CH2:17][N:16](C(OCC4C=CC=CC=4)=O)[CH2:15][CH2:14]3)=[N:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:3])[NH2:2].[H][H]>CO.[Pd]>[NH:16]1[CH2:17][CH2:18][CH:13]([C:10]2[O:11][C:12]3[C:4]([C:1]([NH2:2])=[O:3])=[CH:5][CH:6]=[CH:7][C:8]=3[N:9]=2)[CH2:14][CH2:15]1
Reactant: NC(=O)c1cccc2nc(C3CCN(C(=O)OCc4ccccc4)CC3)oc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: NC(=O)c1cccc2nc(C3CCNCC3)oc12
Yield: 32.9 %

Procedure:
A mixture of benzyl 4-(7-carbamoylbenzo[d]oxazol-2-yl)piperidine-1-carboxylate (98 mg, 0.26 mmol), 10% Pd/C (20 mg) in methanol (30 ml) was stirred at room temperature over 1 atm hydrogen for 2 hr. The mixture was filtered, and evaporated under reduced pressure. The residue was purified by pre-HPLC. 21 mg of 2-(piperidin-4-yl)benzo[d]oxazole-7-carboxamide as a solid was obtained, yield 33%. LCMS (ESI) m/z: 246 (M+1)+. 1H-NMR (400 MHz, DMSO-d6): δ 1.24 (brs, 1H), 1.71-1.74 (m, 2H), 2.03-2.06 (d, J=12 Hz, 2H), 2.64 (t, 2H), 3.01-3.04 (t, 2H), 3.14 (t, 1H), 7.41 (t, J=7.2 Hz, 1H), 7.72 (d, J=7.2 Hz, 1H), 7.72 (brs, 1H), 7.78 (brs, 1H), 7.85 (d, J=7.2 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:43]=[CH:42][C:5]2[NH:6][C:7]([C@@H:9]([NH:16][C:17](=[O:41])[C:18]3[CH:23]=[CH:22][C:21]([C:24]([N:26]4[CH2:30][CH2:29][CH2:28][C@H:27]4[CH2:31][NH:32]C(OC(C)(C)C)=O)=[O:25])=[C:20]([Cl:40])[CH:19]=3)[CH2:10][CH2:11][S:12]([CH3:15])(=[O:14])=[O:13])=[N:8][C:4]=2[CH:3]=1.FC(F)(F)C(O)=O.ClCCl.CO.N.ClCl>>[Cl:1][C:2]1[CH:43]=[CH:42][C:5]2[NH:6][C:7]([C@@H:9]([NH:16][C:17](=[O:41])[C:18]3[CH:23]=[CH:22][C:21]([C:24]([N:26]4[CH2:30][CH2:29][CH2:28][C@H:27]4[CH2:31][NH2:32])=[O:25])=[C:20]([Cl:40])[CH:19]=3)[CH2:10][CH2:11][S:12]([CH3:15])(=[O:13])=[O:14])=[N:8][C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)NC[C@@H]1CCCN1C(=O)c1ccc(C(=O)N[C@@H](CCS(C)(=O)=O)c2nc3cc(Cl)ccc3[nH]2)cc1Cl
Agent: ClCl
Agent: N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CS(=O)(=O)CC[C@H](NC(=O)c1ccc(C(=O)N2CCC[C@H]2CN)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 17 from N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-methylsulfonylpropyl]-3-chloro-4-[(2S)-2-(N-tert-butoxycarbonylaminomethyl)pyrrolidin 1-ylcarbonyl]benzamide and trifluoroacetic acid. Yield: quantitative; Rf value: 0.10 (silica gel; dichloromethane/methanol/ammonia=9:1:0.1); C24H27Cl2N5O4S (552.48); mass spectrum: (M+H)+=552/554/556 (chlorine isotope).
Reaction SMILES: [C:1]([N:8]([CH3:20])[C@@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[CH3:22][O:23][C:24](=[O:37])[C@H:25]([CH2:27][C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[NH:30][CH:29]=1)[NH2:26].OC1C2N=NNC=2C=CC=1.CN(C)CCCN=C=NCC>CN(C)C=O.C(OCC)(=O)C>[CH3:22][O:23][C:24](=[O:37])[C@H:25]([CH2:27][C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[NH:30][CH:29]=1)[NH:26][C:17](=[O:19])[C@@H:9]([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[N:8]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH3:20]
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of N-BOC-N-methyl-(D)-phenylalanine (2.1 g, 7.5 mmol) [BOC=tert-butyloxycarbonyl] in dry DMF [N,N-dimethylformamide] (15 ml) are added (L)-tryptophan methyl ester hydrochloride (2 g, 7.8 mmol) and hydroxybenztriazole (1.2 g, 8.8 mmol). The mixture is cooled to 0° and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (1.7 ml, 9.2 mmol) is added dropwise. The reaction mixture is slowly warmed to r.t. (room temperature) and stirring continued for 2 hours. The homogeneous mixture is diluted with ethyl acetate (500 ml) and washed with three portions of water (200 ml). The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo to give N-BOC-N-methyl-(D)-phenylalanyl-(L)-tryptophan methyl ester as a white foam. [a]D =+42° (c=1.0, ethanol).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:39])[NH:5][C:6]1[S:7][C:8]2[C:9]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=3)=[N:10][C:11]([C:15]3[CH:16]=[N:17][C:18]([N:21]4[CH2:26][CH2:25][C:24]([CH3:32])([C:27]([O:29]CC)=[O:28])[CH2:23][CH2:22]4)=[N:19][CH:20]=3)=[CH:12][C:13]=2[N:14]=1)[CH3:2].CC(C)([O-])C.[K+].O>CS(C)=O>[CH2:1]([NH:3][C:4](=[O:39])[NH:5][C:6]1[S:7][C:8]2[C:9]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=3)=[N:10][C:11]([C:15]3[CH:16]=[N:17][C:18]([N:21]4[CH2:26][CH2:25][C:24]([CH3:32])([C:27]([OH:29])=[O:28])[CH2:23][CH2:22]4)=[N:19][CH:20]=3)=[CH:12][C:13]=2[N:14]=1)[CH3:2]
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)nc(-c3ccccn3)c2s1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)O)CC4)nc3)nc(-c3ccccn3)c2s1
Temperature: 25 °C
Reaction time: 0.29 h
Yield: 63.6 %

Procedure:
To a solution of ethyl 1-(5-(2-(3-ethylureido)-4-(pyridin-2-yl)thiazolo[5,4-c]pyridin-6-yl)pyrimidin-2-yl)-4-methylpiperidine-4-carboxylate (0.050 g, 0.091 mmol) in DMSO (2.0 mL) at rt was added potassium tert-butoxide (0.052 g, 0.45 mmol) and the mixture stirred at rt for 15-20 min. After completion of reaction (by TLC), water (25 mL) was added, followed by extraction with EtOAc (3×50 mL) and the organic layer was discarded. The pH of the aqueous layer was adjusted up to 4-5, extracted with hot EtOAc (3×50 mL) and the combined organic layer washed with brine, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue thus obtained was triturated with ether to afford Compound 162 (0.030 g, 64%). 1H NMR (DMSO-d6): δ 1.10 (t, J=7.20 Hz, 3H), 1.20 (s, 3H), 1.44 (m, 2H), 2.04 (m, 2H), 3.22 (m, 2H), 3.37 (m, 2H), 4.35 (m, 2H), 6.86 (br s, 1H), 7.53 (m, 1H), 8.05 (m, 1H), 8.16 (s, 1H), 8.80 (d, J=8.40 Hz, 1H), 8.84 (d, J=4.40 Hz, 1H), 9.26 (s, 2H), 10.93 (br s, 1H) and 12.45 (br s, 1H). MS: 519.28 [M+H]+.