Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH:5]([C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1)[O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)=[CH:9][CH:8]=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30].O>C(Cl)Cl>[CH3:28][S:29]([O:1][CH2:2][CH2:3][CH2:4][CH:5]([C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1)[O:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)=[CH:11][CH:12]=1)(=[O:31])=[O:30]
Reactant: CS(=O)(=O)Cl
Reactant: N#Cc1ccc(C(CCCO)Oc2ccc(OC3CCCCO3)cc2)cc1
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)OCCCC(Oc1ccc(OC2CCCCO2)cc1)c1ccc(C#N)cc1
Yield: 100 %

Procedure:
A solution of 4-{4-hydroxy-1-[4-(tetrahydro-2H-pyran-2-yloxy)phenoxy]butyl}benzonitrile (see step (ii) above; 2.37 g, 6.45 mmol) and TEA (1.35 mL, 9.68 mmol) in DCM (10 mL) was cooled to −5° C. Methanesulfonyl chloride (0.65 mL, 8.38 mmol) in DCM (5 mL) was added slowly. After addition was complete, the temperature was maintained below 5° C. for 1 h before DCM and water were added. The organic layer was washed with water, dried (Na2SO4) and then evaporated to yield 2.87 g (100%) of the sub-title compound. This was used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]([C:4](F)(F)F)=O.[NH2:8][C:9](=[NH:42])[N:10]1[CH2:14][C@@H:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C@H:12]([C:22]([N:24]2[CH2:28][CH2:27][C@H:26]([N:29]([C@H:35]3[CH2:40][CH2:39][C@@H:38]([CH3:41])[CH2:37][CH2:36]3)[C:30](=[O:34])[CH:31]([CH3:33])[CH3:32])[CH2:25]2)=[O:23])[CH2:11]1.C(OC(=O)C)(=O)C>C(Cl)Cl>[C:2]([NH:42][C:9](=[NH:8])[N:10]1[CH2:14][C@@H:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C@H:12]([C:22]([N:24]2[CH2:28][CH2:27][C@H:26]([N:29]([C@H:35]3[CH2:36][CH2:37][C@@H:38]([CH3:41])[CH2:39][CH2:40]3)[C:30](=[O:34])[CH:31]([CH3:33])[CH3:32])[CH2:25]2)=[O:23])[CH2:11]1)(=[O:1])[CH3:4]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)C(=O)N([C@H]1CCN(C(=O)[C@@H]2CN(C(=N)N)C[C@H]2c2ccc(Cl)cc2)C1)[C@H]1CC[C@@H](C)CC1
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: CC(=O)NC(=N)N1C[C@@H](C(=O)N2CC[C@H](N(C(=O)C(C)C)[C@H]3CC[C@@H](C)CC3)C2)[C@H](c2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of N-[(3S)-1-{[(3S,4R)-1-[amino(imino)methyl]-4-(4-chlorophenyl)pyrrolidine-3-yl]carbonyl}pyrrolidine-3-yl]-2-methyl-N-(cis-4-methylcyclohexyl)propaneamide TFA salt (185 mg, 0.3 mmol) prepared in Example E9 in DCM (3 ml) was added acetic acid anhydride (46 mg, 0.45 mmol) and TEA (71 mg, 0.7 mmol), and stirred at rt for 6 h. After the reaction finished, the solvent was concentrated in vacuo, extracted with water and EtOAc, and the organic layer was dried over MgSO4. The organic solution was concentrated in vacuo, and purified by HPLC to give the title compound (139 mg, 85%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[NH:13][N:12]=[N:11][N:10]=2)=[C:6]([CH:8]=1)[NH2:7].[O:14]1[C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=[N:15]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[NH:13][N:12]=[N:11][N:10]=2)=[C:6]([NH:7][C:19]([C:18]2[O:14][N:15]=[CH:16][CH:17]=2)=[O:20])[CH:8]=1
Reactant: Nc1cc(Cl)ccc1-c1nnn[nH]1
Reactant: O=C(Cl)c1ccno1
Product: O=C(Nc1cc(Cl)ccc1-c1nnn[nH]1)c1ccno1
Yield: 21 %

Procedure:
The title compound was prepared essentially according to the method of Example 4, but using 5-Chloro-2-(1H-tetrazol-5-yl)aniline (1.0 mmol) and isoxazole-5-carbonyl chloride. After precipitation the product was further purified by reverse phase C18 preparative HPLC (water/acetonitrile containing 0.1% formic acid 30%-100% gradient) to yield the desired product (61.1 mg, 21%). 1H NMR (400 MHz, d6-DMSO): δ 11.90 (s, 1H), 8.90 (s, 1H), 8.52 (s, 1H), 8.06 (d, 1H), 7.96 (s, 1H), 7.56 (dd, 1H), 7.30 (s, 1H). MS (EI) for C11H7ClN6O2: 290.7 (M+H).
Reaction SMILES: Cl.[CH2:2]([NH2:13])[C:3]1[CH:12]=[CH:11][C:8]([O:9][CH3:10])=[C:5]([O:6][CH3:7])[CH:4]=1.[O-:14][C:15]#[N:16].[Na+]>O>[CH3:7][O:6][C:5]1[CH:4]=[C:3]([CH:12]=[CH:11][C:8]=1[O:9][CH3:10])[CH2:2][NH:13][C:15]([NH2:16])=[O:14]
Reactant: N#C[O-]
Reactant: COc1ccc(CN)cc1OC
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COc1ccc(CNC(N)=O)cc1OC
Reaction time: 8 h

Procedure:
60 ml of 5n HCl were added at room temperature within 45 min to a solution of 49.5 ml (300 mM) of 90% veratrylamine and 20.40 g (307 mM) of 98% sodium cyanate in 500 ml of water. After stirring overnight the crystals were collected: 52.66 g (83.5%) of urea with a melting point of 172-3° C. (sublimation 157° C.).
Reaction SMILES: [C:1]([O:4][C@H:5]([CH3:20])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:15](=[O:16])[CH:14]=[C:13]([NH2:17])[N:12]([CH3:18])[C:11]1=[O:19])(=[O:3])[CH3:2].[CH2:21]=[C:22]1O[C:24](=[O:25])[CH2:23]1>ClCCCl>[C:1]([O:4][C@H:5]([CH3:20])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:15](=[O:16])[C:14]2[C:24](=[O:25])[CH:23]=[C:22]([CH3:21])[NH:17][C:13]=2[N:12]([CH3:18])[C:11]1=[O:19])(=[O:3])[CH3:2]
Reactant: C=C1CC(=O)O1
Reactant: CC(=O)O[C@H](C)CCCCn1c(=O)cc(N)n(C)c1=O
Solvent: ClCCCl
Product: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(=O)cc(C)[nH]c2n(C)c1=O
Temperature: 25 °C
Yield: 48.5 %

Procedure:
A mixture of (R)-3-(5-acetoxyhexyl)-6-amino-1-methyluracil (500 mg, 1.77 mmol), 1,2-dichloroethane (5 ml) and diketene (0.14 ml, 1.77 mmol) was heated at reflux for 18 hours. Another portion of diketene (0.2 ml) was added and the mixture was heated at reflux for an additional 18 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with ethyl acetate-hexane (1:1) to provide (R)-3-(5-acetoxyhexyl)-1,7-dimethylpyrido[2,3-d]pyrimidine-2,4,5(1H,3H,8H)-trione (300 mg, 49% yield) as an oil. 1H NMR (300 MHz, CDCl3) δ 1.20 (d, 3H), 1.25-1.71 (m, 6H), 2.00 (s, 3H), 2.46 (s, 3H), 3.62 (s, 3H), 4.00 (t, 2H), 4.86 (sextet, 1H), 6.49 (s, 1H), 12.15 (s, 1H). 13C NMR (75 MHz, CDCl3) δ 19.64, 20.96, 22.46, 25.02, 27.19, 29.15, 35.19, 40.67, 70.29, 94.48, 105.71, 150.09, 150.73, 164.92, 165.18, 167.82, 170.15.
Reaction SMILES: C(O[C:6]([N:8]1[CH:13]([C:14](=[O:30])[NH:15][C:16]2[CH:17]=[C:18]([Cl:29])[CH:19]=[C:20]3[C:28]=2[NH:27][C:26]2[CH:25]=[N:24][CH:23]=[CH:22][C:21]3=2)[CH2:12][O:11][C:10]([CH3:32])([CH3:31])[CH2:9]1)=O)(C)(C)C.C(OC(=O)[NH:39][CH:40](C=O)[CH2:41][CH3:42])(C)(C)C>>[Cl:29][C:18]1[CH:19]=[C:20]2[C:28](=[C:16]([NH:15][C:14]([CH:13]3[CH2:12][O:11][C:10]([CH3:31])([CH3:32])[CH2:9][N:8]3[CH2:6][CH:40]([NH2:39])[CH2:41][CH3:42])=[O:30])[CH:17]=1)[NH:27][C:26]1[CH:25]=[N:24][CH:23]=[CH:22][C:21]2=1
Reactant: CCC(C=O)NC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)N1CC(C)(C)OCC1C(=O)Nc1cc(Cl)cc2c1[nH]c1cnccc12
Product: CCC(N)CN1CC(C)(C)OCC1C(=O)Nc1cc(Cl)cc2c1[nH]c1cnccc12

Procedure:
Method C was followed, using 5-(6-chloro-9H-β-carbolin-8-ylcarbamoyl)-2,2-dimethyl-morpholine-4-carboxylic acid tert-butyl ester and the appropriate aldehyde, (1-formyl-propyl)-carbamic acid tert-butyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[CH3:41][O:42][C:43](=[O:51])[C:44]1[CH:49]=[CH:48][CH:47]=[C:46](Br)[CH:45]=1>>[CH3:41][O:42][C:43](=[O:51])[C:44]1[CH:49]=[CH:48][CH:47]=[C:46]([N:27]2[C:17]3[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=[C:15]([C:12]4[CH:11]=[N:10][C:9]([N:8]([CH2:7][C:6]5[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=5)[CH2:30][C:31]5[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=5)=[N:14][CH:13]=4)[C:16]=3[CH2:29][CH2:28]2)[CH:45]=1
Reactant: COC(=O)c1cccc(Br)c1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Product: COC(=O)c1cccc(N2CCc3c(-c4cnc(N(Cc5ccc(OC)cc5)Cc5ccc(OC)cc5)nc4)nc(N4CCOCC4)nc32)c1

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 (15.0 mg, 0.0278 mmol) and 3-bromobenzoic acid methyl ester (7.1 mg, 0.033 mmol) instead of 4-bromobenzoic acid methyl ester, in the same manner as Example 1-D-08, a crude product of 3-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-benzoic acid methyl ester was obtained, and then the PMB groups were removed according to the above Deprotection method 2, to obtain the desired compound (D-52) as a yellow powder (10.4 mg, 86%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH:12]([F:14])[F:13])=[CH:8][C:7]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([OH:27])=O)[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.Cl.[N:29]([C@H:32]1[CH2:36][C@H:35]([NH2:37])[C@@H:34]([CH3:38])[CH2:33]1)=[N+:30]=[N-:31]>>[N:29]([C@@H:32]1[CH2:36][C@@H:35]([NH:37][C:25]([C:21]2[C:17]3[N:18]=[CH:19][N:20]=[C:15]([C:7]4[CH:8]=[C:9]([CH:12]([F:14])[F:13])[CH:10]=[CH:11][C:6]=4[O:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)[C:16]=3[NH:23][C:22]=2[CH3:24])=[O:27])[C@H:34]([CH3:38])[CH2:33]1)=[N+:30]=[N-:31]
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)O
Reactant: C[C@H]1C[C@@H](N=[N+]=[N-])C[C@@H]1N
Agent: Cl
Product: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@@H]1C[C@@H](N=[N+]=[N-])C[C@H]1C

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.g1) and (1S*,2S*,4R*)-4-azido-2-methylcyclopentanamine hydrochloride (example C34) the title compound is obtained as pale yellow foam.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([C:23]([F:26])([F:25])[F:24])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[N:8]=1)=O.[Cl:28][C:29]1[C:30]([F:37])=[C:31]([NH:35][NH2:36])[CH:32]=[CH:33][CH:34]=1>>[Cl:28][C:29]1[C:30]([F:37])=[C:31]([N:35]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:15]=[CH:16][C:17]([S:20]([C:23]([F:26])([F:24])[F:25])(=[O:22])=[O:21])=[CH:18][CH:19]=4)[N:8]=3)=[CH:4][CH:3]=[N:36]2)[CH:32]=[CH:33][CH:34]=1
Reactant: NNc1cccc(Cl)c1F
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(S(=O)(=O)C(F)(F)F)cc2)ccc1=O
Product: O=c1ccn(-c2ccc(S(=O)(=O)C(F)(F)F)cc2)nc1-c1ccnn1-c1cccc(Cl)c1F

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-trifluoromethansulfonyl-phenyl)-1H-pyridazin-4-one (A-27) and 3-chloro-2-fluoro-phenylhydrazine according to the method described for example 1. MS: M=499.0 (M+H)+
Reaction SMILES: Br[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][N:13]1[CH2:18][CH2:17][N:16]([C:19]2[C:24]3[CH:25]=[CH:26][NH:27][C:23]=3[CH:22]=[CH:21][N:20]=2)[CH2:15][CH2:14]1.CN(C)[CH:30]=[O:31].[NH4+].[Cl-]>O1CCCC1.CCCCCC>[NH:27]1[C:23]2[CH:22]=[CH:21][N:20]=[C:19]([N:16]3[CH2:17][CH2:18][N:13]([CH2:12][CH2:11][C:5]4[C:4]5[C:8](=[CH:9][CH:10]=[C:2]([CH:30]=[O:31])[CH:3]=5)[NH:7][CH:6]=4)[CH2:14][CH2:15]3)[C:24]=2[CH:25]=[CH:26]1
Reactant: CN(C)C=O
Reactant: Brc1ccc2[nH]cc(CCN3CCN(c4nccc5[nH]ccc45)CC3)c2c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=Cc1ccc2[nH]cc(CCN3CCN(c4nccc5[nH]ccc45)CC3)c2c1
Reaction time: 1 h

Procedure:
A solution at −78° C. of 1.5 mmol of the compound obtained in Step 3 in tetrahydrofuran is treated with 9 mmol of tert-butylithium (1.8M in hexane). After stirring the mixture for 1 hour, 12 mmol of dimethylformamide are added and the mixture is brought to ambient temperature. After reaction for 4 hours, the solution is hydrolysed by a saturated solution of NH4Cl and then extracted with dichloromethane. After treating the organic phase in conventional manner, chromatography of the residue on silica gel enables the expected product to be isolated.
Reaction SMILES: C[O:2][C:3](=[O:40])[CH:4]([O:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([NH:23][C:24]([C:26]3[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=4[O:28][C:27]=3[CH2:35][CH2:36][CH2:37][CH3:38])=[O:25])[CH:19]=2)[C:14]=1[Br:39])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[OH-].[Na+].O>CO>[Br:39][C:14]1[C:15]2[C:20](=[CH:19][C:18]([NH:23][C:24]([C:26]3[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=4[O:28][C:27]=3[CH2:35][CH2:36][CH2:37][CH3:38])=[O:25])=[CH:17][CH:16]=2)[CH:21]=[CH:22][C:13]=1[O:12][CH:4]([CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:3]([OH:40])=[O:2]
Reactant: CCCCc1oc2ccccc2c1C(=O)Nc1ccc2c(Br)c(OC(Cc3ccccc3)C(=O)OC)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCc1oc2ccccc2c1C(=O)Nc1ccc2c(Br)c(OC(Cc3ccccc3)C(=O)O)ccc2c1
Yield: 81.9 %

Procedure:
A mixture of 2-{1-bromo-6-[(2-butyl-benzofuran-3-carbonyl)-amino]-naphthalen-2-yloxy}-3-phenyl-propionic acid methyl ester (139 mg, 0.231 mmol), prepared in the previous step, and 1 N NaOH (231 μL, 0.231 mmol) in 75 mL of methanol was refluxed for 4 h. By TLC starting material remained. Water (10 mL) and 1 N NaOH (231 μL, 0.231 mmol) were added and the mixture refluxed for 18 h (overnight). The reaction was filtered and 2 mL of 1 N HCL was added to the filtrate. The filtrate was concentrated under reduced pressure to remove the methanol. The solid formed was collected by filtration, rinsed with water and dried under reduced pressure to give the title compound (111 mg, 81%) as a white solid, mp 191-195° C.
Reaction SMILES: Cl[CH:2]([CH2:5][C:6]1[CH:16]=[CH:15][C:9]2[N:10]=[C:11]([S:13][CH3:14])[S:12][C:8]=2[CH:7]=1)[CH:3]=O.[Cl:17][C:18]1[N:23]=[N:22][C:21]([NH2:24])=[CH:20][CH:19]=1.O>C(O)CCC>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]2[N:22]([C:2]([CH2:5][C:6]3[CH:16]=[CH:15][C:9]4[N:10]=[C:11]([S:13][CH3:14])[S:12][C:8]=4[CH:7]=3)=[CH:3][N:24]=2)[N:23]=1
Reactant: CSc1nc2ccc(CC(Cl)C=O)cc2s1
Reactant: Nc1ccc(Cl)nn1
Solvent: CCCCO
Solvent: O
Product: CSc1nc2ccc(Cc3cnc4ccc(Cl)nn34)cc2s1
Temperature: 25 °C
Yield: 83.9 %

Procedure:
A mixture of 2-chloro-3-(2-(methylthio)benzo[d]thiazol-6-yl)propanal from Step 4 of Example 117 (1.5 g, 5.5 mmol) and 6-chloropyridazin-3-amine (1.4 g, 11 mmol) in 1-butanol (60 mL) was heated at reflux overnight. Then the mixture was cooled to rt and water (120 mL) was added. The mixture was extracted with EtOAc (60 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 50:1 to 20:1 DCM/MeOH to afford 6-((6-chloroimidazo[1,2-b]pyridazin-3-yl)methyl)-2-(methylthio)benzo[d]thiazole as a yellow solid (1.6 g, 84%). 1H NMR (300 MHz, CDCl3) δ 7.89 (d, J=9.6 Hz, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.68 (dd, J=0.6, 1.2 Hz, 1H), 7.53 (s, 1H), 7.37 (dd, J=1.8, 8.4 Hz, 1H), 7.03 (d, J=9.3 Hz, 1H), 4.40 (s, 2H), 2.78 (s, 3H). LCMS (ESI) m/z 347 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:29]=[CH:30][C:31]=3[CH3:32])[C:22]([N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:37].[CH3:38][N:39]1[CH2:44][CH2:43][CH:42]([NH2:45])[CH2:41][CH2:40]1>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:45][CH:42]3[CH2:43][CH2:44][N:39]([CH3:38])[CH2:40][CH2:41]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:29]=[CH:30][C:31]=3[CH3:32])[C:22]([N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:37]
Reactant: CN1CCC(N)CC1
Reactant: CCN(CC)C(=O)c1ccc(C)c(-c2nc(S(C)(=O)=O)nc3c2CNC(=O)N3c2c(F)cccc2F)c1
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1ccc(C)c(-c2nc(NC3CCN(C)CC3)nc3c2CNC(=O)N3c2c(F)cccc2F)c1
Reaction time: 8 h

Procedure:
3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N,N-diethyl-4-methylbenzamide-(0.053 g, 0.1 mmol) was dissolved in THF (5 mL) and 1-methyl-4-piperidinamine (0.044 g, 0.5 mmol) was added. The reaction was stirred under argon overnight. The solvents were pumped off in vacuo, and the residue was purified by mass directed auto prep. The fractions were evaporated, and aqueous basic workup gave the title compound as a white amorphous solid. mp 165-169° C. LC-MS m/z 564 (M+H)+, 1.44 min (ret time).
Reaction SMILES: Cl.[NH2:2][N:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8].[CH2:9]([O:11][C:12](=[O:22])[CH2:13][C:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[CH3:10].N1C=CC=CC=1>O>[CH2:9]([O:11][C:12](=[O:22])[CH2:13][C:14](=[N:2][N:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[CH3:10]
Reactant: NN1CCCC1=O
Reactant: CCOC(=O)CC(=O)c1ccccn1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)CC(=NN1CCCC1=O)c1ccccn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 98 %

Procedure:
Place 1-aminopyrrolidin-2-one hydrochloride (Zubek, A. Z. Chem., 1969, 9(2), 58; 155.6 g, 1.14 mol) in a 3 L flask equipped with mechanical stirrer and nitrogen inlet. Add 3-oxo-3-pyridin-2-yl-propionic acid ethyl ester (Preparation 3-A; 200 g, 1.04 mol) and pyridine (400 mL). Stir the reaction mixture at room temperature for 20 h. Dilute the mixture with water (500 mL) and extract with toluene (2×500 mL). Combine the organic layers, dry (sodium sulfate), filter, and concentrate in vacuo to yield 280 g (98%) of the subtitled compound as a dark oil. MS ES+ m/e 276 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5](COCC[Si](C)(C)C)[C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([CH2:25][CH3:26])[CH:22]=[C:21]([Cl:27])[CH:20]=2)[C:12]=1[F:28])=[O:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([CH2:25][CH3:26])[CH:22]=[C:21]([Cl:27])[CH:20]=2)[C:12]=1[F:28])=[O:8]
Reactant: CCc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3c(Cl)ncn3COCC[Si](C)(C)C)c2F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]cnc3Cl)c2F)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 56.3 %

Procedure:
To a solution of 4-chloro-N-({4-chloro-3-[(3-chloro-5-ethylphenyl)oxy]-2-fluorophenyl}methyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (64 mg, 0.112 mmol) in DCM (5 ml) was added TFA (2.0 ml) and the reaction mixture was stirred for 5 hours at room temperature. The reaction was quenched with saturated sodium bicarbonate and the organic layer was separated. The solvent was removed and the crude material was purified via silica gel chromatography to give 4-chloro-N-({4-chloro-3-[(3-chloro-5-ethylphenyl)oxy]-2-fluorophenyl}methyl)-1H-imidazole-5-carboxamide (28 mg, 0.063 mmol, 57% yield). 1H NMR (400 MHz, DMSO-d5) δ ppm 12.83-13.43 (m, 1H), 8.20 (d, 1H), 7.73 (s, 1H), 7.44 (d, 1H), 7.29 (t, 1H), 7.01 (s, 1H), 6.73 (s, 1H), 6.66 (s, 1H), 4.48 (d, 2H), 2.53 (q, 2H), 1.08 (t, 3H). LC-MS (ES+) m/z 441.59, [M+H].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH:5]([N:14]([CH:28]1[CH2:30][CH2:29]1)[C:15](=O)[C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=1)[C:6](=O)[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)[CH3:2].FC(F)(F)C([O-])=O.[NH4+:39]>CCO>[CH2:1]([O:3][C:4]([C:5]1[N:14]([CH:28]2[CH2:30][CH2:29]2)[C:15]([C:16]2[CH:17]=[CH:18][C:19]([O:22][C:23]([F:25])([F:26])[F:24])=[CH:20][CH:21]=2)=[N:39][C:6]=1[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)=[O:31])[CH3:2]
Reactant: CCOC(=O)C(C(=O)c1cccnc1)N(C(=O)c1ccc(OC(F)(F)F)cc1)C1CC1
Reactant: [NH4+]
Agent: O=C([O-])C(F)(F)F
Solvent: CCO
Product: CCOC(=O)c1c(-c2cccnc2)nc(-c2ccc(OC(F)(F)F)cc2)n1C1CC1
Temperature: 110 °C
Yield: 71.9 %

Procedure:
To 1.2 g (3 mmol) of 2-[cyclopropyl-(4-trifluoromethoxy-benzoyl)-amino]-3-oxo-3-pyridin-3-yl-propionic acid ethyl ester in 10 ml of EtOH was added 1.4 g (11 mmol) of ammonium trifluoroacetate. The EtOH was evaporated and the residue heated to 110° C. for 4 h. The cooled residue was partitioned between saturated sodium hydrogen carbonate solution and CH2Cl2. The organic phase was dried with sodium sulfate and concentrated. Purification by flash column chromatography [n-heptane/EtOAc 3:7 to 1:1] afforded 0.9 g (80%) of the title compound as a colorless solid. MS: 418.2 (MH+).
Reaction SMILES: O.[OH-].[Li+].[C:4]([C:6]1[CH:7]=[C:8]([C:13]2[N:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[N:25])[CH:19]=3)[N:16]=[C:15]([C:26]([O:28]CC)=[O:27])[CH:14]=2)[CH:9]=[C:10]([F:12])[CH:11]=1)#[N:5].Cl>C1COCC1>[C:4]([C:6]1[CH:7]=[C:8]([C:13]2[N:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[N:25])[CH:19]=3)[N:16]=[C:15]([C:26]([OH:28])=[O:27])[CH:14]=2)[CH:9]=[C:10]([F:12])[CH:11]=1)#[N:5]
Reactant: CCOC(=O)c1cc(-c2cc(F)cc(C#N)c2)n(-c2cccc(C#N)c2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1cc(F)cc(-c2cc(C(=O)O)nn2-c2cccc(C#N)c2)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
15.0 ml of water and 797 mg of lithium hydroxide (33.3 mmol) are added to 1.20 g (3.00 mmol) of the carboxylic ester of Example 134A with 90% purity in 45.0 ml of THF. The mixture is stirred at RT for 5 h and a 1N aqueous hydrogen chloride solution is subsequently added to the reaction solution. The mixture is extracted with dichloromethane and the combined organic phases are dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient). 821 mg (82% of theory) of the title compound are obtained.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]3[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([N:23]5[CH2:31][C:30]6[C:25](=[CH:26][C:27](OC)=[CH:28][CH:29]=6)[C:24]5=[O:34])[C:18]=4[CH3:35])=[CH:15][N:14]=[C:13]([C:36]([NH2:38])=[O:37])[C:9]=3[NH:10]2)=[CH:6][CH:5]=1)#[N:2].[Cl:39]C1C=CC(C=O)=C(C=1)C(O)=O.[BH4-].[Na+]>CO>[Cl:39][C:27]1[CH:26]=[C:25]2[C:30]([CH2:31][N:23]([C:19]3[C:18]([CH3:35])=[C:17]([C:16]4[C:8]5[C:7]6[C:11](=[CH:12][C:4]([CH2:3][C:1]#[N:2])=[CH:5][CH:6]=6)[NH:10][C:9]=5[C:13]([C:36]([NH2:38])=[O:37])=[N:14][CH:15]=4)[CH:22]=[CH:21][CH:20]=3)[C:24]2=[O:34])=[CH:29][CH:28]=1
Reactant: COc1ccc2c(c1)C(=O)N(c1cccc(-c3cnc(C(N)=O)c4[nH]c5cc(CC#N)ccc5c34)c1C)C2
Reactant: O=Cc1ccc(Cl)cc1C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1c(-c2cnc(C(N)=O)c3[nH]c4cc(CC#N)ccc4c23)cccc1N1Cc2ccc(Cl)cc2C1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 17 %

Procedure:
A mixture of 3-(1-aminoxycarbonyl)-7-cyanomethyl)-9H-pyrido[3,4-b]indole-4-yl-2-methylaniline 7 (40 mg, 0.112 mmol), 5-chloro-2-formylbenzoic acid (51.6 mg, 0.28 mmol) and 4 angstrom molecular sieves (0.5 g) in methanol (15 mL) was stirred at RT for 24 h. After that the mixture was cooled to −20° C. and sodium borohydride (29.6 mg, 0.78 mmol) was added and the reaction mixture was allowed to warm up to 10° C. The solvent was removed under reduced pressure, quenched with saturated NH4Cl solution (5 ml) and extracted with EtOAc (2×10 ml). Combined organic extracts were washed with water, brine, dried over Na2SO4 and concentrated. The crude product obtained was purified by silica gel column chromatography eluting with 5% MeOH in CHCl3 to give the desired product (10 mg, 0.019 mmol, 17% yield) as a yellow sticky solid.
Reaction SMILES: [NH2:1][CH:2]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:13][S:14][CH2:15][C:16](O)=[O:17]>>[CH3:13][S:14][CH2:15][C:16]([NH:1][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:17]
Reactant: CSCC(=O)O
Reactant: CCOC(=O)C(N)C(=O)OCC
Product: CCOC(=O)C(NC(=O)CSC)C(=O)OCC
Yield: 68.4 %

Procedure:
Diethyl 2-aminomalonate (3.5 g) and methylsulfenylacetic acid (2.2 g) are treated in the same manner as described in Reference Example 1 to give diethyl 2-[(methylsulfenylacetyl)amino]malonate (3.6 g), m.p. 56°-58° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([NH2:11])[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.Cl.[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=1>>[Cl:1][C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:13](=[O:20])[C:14]3[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1nc2cccc(Cl)n2n1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Product: O=C(Nc1nc2cccc(Cl)n2n1)c1cccnc1

Procedure:
The title compound was prepared following procedure described for intermediate B1, but starting from 5-chloro[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A4), 14.60 g; 86.60 mmol; 1.0 eq.) and nicotinoyl chloride hydrochloride (18.5 g; 104 mmol; 1.2 eq.) as a greenish solid (20.61 g; 87%). HPLC, Rt: 1.19 min. (purity 99.4%). LC/MS, M+(ESI): 274.3, M+(ESI): 272.3.