Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)=[CH:10][C:9]([CH:22]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:8][C:7]=2I)[CH2:3][CH2:2]1.[C:33]([Cu])#[N:34]>CN1C(=O)CCC1>[C:33]([C:7]1[CH:8]=[C:9]([CH:22]([CH2:28][CH:29]([CH3:30])[CH3:31])[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:10]=[C:11]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([F:20])([F:21])[F:19])=[CH:16][CH:17]=2)[C:6]=1[O:5][CH2:4][CH:1]1[CH2:3][CH2:2]1)#[N:34]
Reactant: CCOC(=O)C(CC(C)C)c1cc(I)c(OCC2CC2)c(-c2ccc(C(F)(F)F)cc2)c1
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Product: CCOC(=O)C(CC(C)C)c1cc(C#N)c(OCC2CC2)c(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 200 °C
Reaction time: 2 h
Yield: 60.9 %

Procedure:
To a stirred solution of ethyl 2-(6-(cyclopropylmethoxy)-5-iodo-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate (0.25 g, 0.447 mmol) in NMP (10 mL) was added CuCN (50 mg, 0.536 mmol) at RT under inert atmosphere. The reaction mixture was stirred at 200° C. temperature over a period of 2 h. After completion of starting material (by TLC), the reaction mixture was cooled to RT and extracted with EtOAc (3×20 mL). Combined organic layers were washed with water (3×15 mL), brine and dried over Na2SO4. After filtration and evaporation, the crude material was purified by column chromatography to afford ethyl 2-(5-cyano-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate (0.125 g) a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][CH2:14][C:15]([F:18])([F:17])[F:16])[C:11](=[O:19])[N:10]([CH2:20][C:21]([O:23]C)=[O:22])[N:9]=2)=[CH:4][CH:3]=1.[OH-].[Li+]>CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][CH2:14][C:15]([F:17])([F:16])[F:18])[C:11](=[O:19])[N:10]([CH2:20][C:21]([OH:23])=[O:22])[N:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)Cn1nc(-c2ccc(Cl)cc2)n(CCC(F)(F)F)c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)Cn1nc(-c2ccc(Cl)cc2)n(CCC(F)(F)F)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Of the compound from Example 176A, 1.27 g (3.49 mmol), were introduced in 200 ml of methanol and 100 ml of water. Then 6.98 ml (6.98 mmol) of 1M aqueous lithium hydroxide solution were added. The mixture was stirred at RT for 2 h. For purification, 15 ml of 1N hydrochloric acid were added and the mixture was freed from methanol on a rotary evaporator. The residue was diluted with 100 ml of water and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulphate, filtered and freed from the solvent on a rotary evaporator, and dried in an HV. This gave 1.11 g (91% of theory) of the title compound.
Reaction SMILES: CN(CCOCCOCCOCCC(OC(C)(C)C)=O)[C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[CH2:10][CH2:11][N:12]([CH3:55])[C:13](=[O:54])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20](=[O:53])[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)[CH:15]=1)=[O:4].[CH3:74][O:75][CH2:76][CH2:77][O:78][CH2:79][CH2:80][O:81][CH2:82][CH2:83][O:84][CH2:85][CH2:86][O:87][CH2:88][CH2:89][O:90][CH2:91][CH2:92][O:93][CH2:94][CH2:95][O:96][CH2:97][CH2:98][NH2:99]>>[CH3:74][O:75][CH2:76][CH2:77][O:78][CH2:79][CH2:80][O:81][CH2:82][CH2:83][O:84][CH2:85][CH2:86][O:87][CH2:88][CH2:89][O:90][CH2:91][CH2:92][O:93][CH2:94][CH2:95][O:96][CH2:97][CH2:98][NH:99][C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[CH2:10][CH2:11][N:12]([CH3:55])[C:13](=[O:54])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]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:53])[CH:15]=1)=[O:4]
Reactant: COCCOCCOCCOCCOCCOCCOCCOCCN
Reactant: CN(CCN1CCC[C@H]1C(=O)N(C)CCOCCOCCOCCC(=O)OC(C)(C)C)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Product: COCCOCCOCCOCCOCCOCCOCCOCCNC(=O)[C@@H]1CCCN1CCN(C)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1

Procedure:
This compound was prepared according to the procedure described for the synthesis of tert-butyl 2-methyl-1-((S)-1-(2-(N-methyl-3-((4-(piperidin-1-yl)-2-(4-(((S)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyridin-2-yl)phenyl)carbamoyl)benzamido)ethyl)pyrrolidin-2-yl)-1-oxo-5,8,11-trioxa-2-azatetradecan-14-oate Example 190, using 2,5,8,11,14,17,20,23-octaoxapentacosan-25-amine in place of tert-butyl 5,8,11-trioxa-2-azatetradecan-14-oate. MS (ES, m/z): 1094.47 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:14](=[O:15])[C:13]2[CH:16]=[C:17]([F:21])[C:18](Cl)=[N:19][C:12]=2[N:11]([CH2:22][CH3:23])[C:10]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>ClCCl>[CH2:1]([O:8][N:9]1[C:14](=[O:15])[C:13]2[CH:16]=[C:17]([F:21])[C:18]([N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[N:19][C:12]=2[N:11]([CH2:22][CH3:23])[C:10]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCn1c(=O)n(OCc2ccccc2)c(=O)c2cc(F)c(Cl)nc21
Reactant: C1CCNC1
Solvent: ClCCl
Product: CCn1c(=O)n(OCc2ccccc2)c(=O)c2cc(F)c(N3CCCC3)nc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 74.3 %

Procedure:
To a solution of 3-benzyloxy-7-chloro-1-ethyl-6-fluoro-1H-pyrido[2,3-d]-pyrimidine-2,4-dione (Example N-2, 146 mg, 0.42 mmol) in dichloromethane (3 mL) was added pyrrolidine (0.070 mL, 0.84 mmol) and the mixture was stirred at room temperature for 10 minutes. The reaction was diluted with dichloromethane (10 mL). The organic phase was washed with saturated aqueous sodium bicarbonate, dried on MgSO4, and concentrated. Washing the solid residue with hexane afforded 120 mg of the title compound as a solid, mp 189-190° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:20][OH:21])[CH:5]=[C:6]([F:19])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1.C(OC([N:29]1[C:37]2[N:32]([C:33](=[O:39])[N:34]=[C:35](Cl)[CH:36]=2)[CH2:31][C:30]1([CH3:41])[CH3:40])=O)(C)(C)C>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:19])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]([F:16])([F:17])[F:18])[CH:10]=1)[CH2:20][O:21][C:35]1[CH:36]=[C:37]2[NH:29][C:30]([CH3:41])([CH3:40])[CH2:31][N:32]2[C:33](=[O:39])[N:34]=1
Reactant: CC(C)(C)OC(=O)N1c2cc(Cl)nc(=O)n2CC1(C)C
Reactant: OCc1cc(F)c(Oc2ccnc(C(F)(F)F)c2)c(F)c1
Product: CC1(C)Cn2c(cc(OCc3cc(F)c(Oc4ccnc(C(F)(F)F)c4)c(F)c3)nc2=O)N1

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from (3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)methanol and tert-butyl-7-chloro-2,2-dimethyl-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH2:12][C:13]([OH:15])=[O:14])=[CH:7][CH:6]=2.[CH3:16][N:17]1[CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=[N:18]1.O1CCOCC1.C(=O)([O-])[O-].[K+].[K+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH3:16][N:17]1[CH:21]=[C:20]([C:2]2[CH:3]=[N:4][C:5]3[C:10]([CH:11]=2)=[CH:9][C:8]([CH2:12][C:13]([OH:15])=[O:14])=[CH:7][CH:6]=3)[CH:19]=[N:18]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=C(O)Cc1ccc2ncc(Br)cc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1cc(-c2cnc3ccc(CC(=O)O)cc3c2)cn1
Temperature: 130 °C

Procedure:
To a 20 mL microwave vial was added (3-bromo-quinolin-6-yl)-acetic acid (1 g, 3.77 mmol), 1-methyl-4-pyrazoleboronic acid pinacol ester and 1,4-dioxane (10 mL). Nitrogen was bubbled through the mixture for 10 minutes. Potassium carbonate (1.56 g, 11.3 mmol) was and water (5 mL) were then added, and nitrogen was bubbled through the mixture for a further three minutes. After such time dichlorobis(triphenylphosphine)palladium (138 mg, 0.19 mmol) was added, the vial sealed and heated in a microwave for 1250 seconds at 130° C. The mixture was then filtered through celite, which was washed with water and saturated aqueous sodium bicarbonate. The 1,4-dioxane in the solution was removed under vacuum and the remaining aqueous solution washed with dichloromethane three times. The water layer was acidified to pH 6 using 4M hydrochloric acid and the formed precipitate collected via filtration and dried to return the title compound as an off white solid. (500 MHz, DMSO-d6): ES-MS m/z: 268 (M+H+).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2=[CH:17][C:18]([F:21])=[C:19]([Cl:20])[C:12]3=[C:13]2[N:8]([CH:9]([CH2:23][CH3:24])[CH2:10][C:11]3=[O:22])[CH:7]=1)=[O:5])C>Cl.C(O)(=O)C>[Cl:20][C:19]1[C:12]2=[C:13]3[N:8]([CH:9]([CH2:23][CH3:24])[CH2:10][C:11]2=[O:22])[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[C:15](=[O:16])[C:14]3=[CH:17][C:18]=1[F:21]
Reactant: CCOC(=O)c1cn2c3c(c(Cl)c(F)cc3c1=O)C(=O)CC2CC
Agent: Cl
Solvent: CC(=O)O
Product: CCC1CC(=O)c2c(Cl)c(F)cc3c(=O)c(C(=O)O)cn1c23
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.8 %

Procedure:
24.62 g (0.07 mole) of 8-chloro-9-fluoro-5-ethyl-6,7-dihydro-1,7-dioxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid ethyl ester was suspended in a mixture of 50 ml of concentrated hydrochloric acid and 200 ml of acetic acid, and this suspension was stirred at 110°-120° C. for 3 hours to hydrolyze the starting material. The resulting reaction solution was allowed to cool to room temperature. The precipitate which separated out was collected by filtration and washed with water to obtain 16.95 g (74.8% yield) of 8-chloro-9-fluoro-5-ethyl-6,7-dihydro-1,7-dioxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid in the form of pale-yellow crystals.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:14]([OH:22])[CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:23](Cl)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].O>C1COCC1.C(OCC)(=O)C>[CH2:23]([O:22][C:14]1[CH:13]=[C:12]([O:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: ClCc1ccccc1
Reactant: COC(=O)c1ccc(OCCNC(=O)OC(C)(C)C)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OCCNC(=O)OC(C)(C)C)cc1OCc1ccccc1
Temperature: 90 °C
Yield: 64.4 %

Procedure:
To a solution of (1) (1.07 g, 3.44 mmol) and benzyl chloride (0.43 mL, 3.78 mmol) in THF (100 mL) was added potassium carbonate (1.57 g, 11 mmol), then the reaction was heated to 90° C. for 18 h. After cooling to room temperature, water (200 mL) and ethyl acetate (200 mL) were added; the organic layer was separated and washed with water (2×200 mL), dried over MgSO4, filtered and evaporated to dryness under reduced pressure. The crude product was purified by silcagel column chromatography eluting with a gradient from 10%-50% ethyl acetate in hexane. Fractions containing the pure desired product were combined and solvent was removed under reduced pressure to produce a colorless oil (890 mg, 64%).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:18]2[CH:24]=[CH:23][CH:22]=[C:20]([NH2:21])[CH:19]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc(Br)c1
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Nc1cccc(-c2ccc(Oc3ccccc3)cc2)c1
Temperature: 25 °C
Yield: 54 %

Procedure:
4-phenoxyphenyl boronic acid (0.148 g, 0.693 mmol) and 3-bromoaniline (0.05 mL, 0.462 mmol) in DME (2 mL) were combined in a flame-dried, round-bottom flask. Na2CO3 (2M, 0.485 mL, 0.970 mmol) and Pd(PPh3)4 (0.017 g, 0.014 mmol) were added to the stirred solution. The reaction was refluxed overnight under argon flow, and subsequently cooled to room temperature. The solvent was removed under vacuum and the resulting residue was resuspended in H20 and extracted with CH2Cl2. The organic phase was dried over MgSO4 and concentrated under vacuum. The crude product was purified by silica column chromatography (0-20% EtOAc/hexanes). The purification was monitored by TLC. The solvent was removed under vacuum from fractions containing product, resulting in 0.065 g in 54% yield.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]([C:12]2[CH:35]=[CH:34][C:15]3[N:16]([CH2:30][CH2:31][O:32][CH3:33])[C:17]([NH:19][C:20]4[S:21][C:22]5[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:23]=5[N:24]=4)=[N:18][C:14]=3[CH:13]=2)=[O:11])[CH2:5][CH2:4]1.[O:36]1CC(O)O[CH2:38][CH:37]1O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[OH:36][CH2:37][CH2:38][N:3]1[CH2:4][CH2:5][CH:6]([NH:9][C:10]([C:12]2[CH:35]=[CH:34][C:15]3[N:16]([CH2:30][CH2:31][O:32][CH3:33])[C:17]([NH:19][C:20]4[S:21][C:22]5[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:23]=5[N:24]=4)=[N:18][C:14]=3[CH:13]=2)=[O:11])[CH2:7][CH2:8]1
Reactant: COCCn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NC3CCNCC3)ccc21
Reactant: OC1COC(O)CO1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: COCCn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NC3CCN(CCO)CC3)ccc21
Yield: 37.8 %

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-1-(2-methoxy-ethyl)-1H-benzoimidazole-5-carboxylic acid [1-(2-hydroxy-ethyl)-piperidin-4-yl]-amide (52 mg) was prepared by following General Procedure P starting from 2-(6-chloro-benzothiazol-2-ylamino)-1-(2-methoxy-ethyl)-1H-benzoimidazole-5-carboxylic acid piperidin-4-ylamide dihydrochloride (145 mg), [1,4]dioxane-2,5-diol (55 mg), and Na(OAc)3BH (95 mg) in DCM (2 mL). LC/MS: m/z 528.6.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:28](=[O:29])[N:27]([CH3:30])[C:12]2[N:13]([CH3:26])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[NH:21][N:22]=[CH:23][C:24]=1[CH3:25])=[CH:16][CH:15]=3.[CH3:31][O:32][CH2:33][C:34](Cl)=[O:35]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:28](=[O:29])[N:27]([CH3:30])[C:12]2[N:13]([CH3:26])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[C:24]([CH3:25])=[CH:23][N:22]([C:34](=[O:35])[CH2:33][O:32][CH3:31])[N:21]=1)=[CH:16][CH:15]=3
Reactant: COCC(=O)Cl
Reactant: Cc1cn[nH]c1-c1ccc2c(c1)c1cc(-c3ccc(Cl)cc3Cl)c(=O)n(C)c1n2C
Product: COCC(=O)n1cc(C)c(-c2ccc3c(c2)c2cc(-c4ccc(Cl)cc4Cl)c(=O)n(C)c2n3C)n1

Procedure:
The process is carried out as indicated in Example 70 above, with the compound from Example 53 3-(2,4-dichlorophenyl)-1,9-dimethyl-6-(4-methyl-2H-pyrazol-3-yl)-1,9-dihydropyrido[2,3-b]indol-2-one and methoxyacetyl chloride.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15](=O)[CH3:16])[C:10]=2[OH:18])[CH:5]=[CH:6][C:7]=1[CH3:8].[NH:19]([C:21]([NH:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=1)=[S:22])[NH2:20].CN(C)C=O>Cl.O>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15](=[N:20][NH:19][C:21]([NH:23][C:24]3[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=3)=[S:22])[CH3:16])[C:10]=2[OH:18])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: CC(=O)c1nn(C)c(-c2ccc(C)c(C)c2)c1O
Reactant: NNC(=S)Nc1ccc(C(=O)O)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC(=NNC(=S)Nc1ccc(C(=O)O)cc1)c1nn(C)c(-c2ccc(C)c(C)c2)c1O
Yield: 68.2 %

Procedure:
1-[5-(3,4-Dimethylphenyl)-1-methyl-4-hydroxy-1H-pyrazol-3-yl]ethanone (0.2423 mmol, HPLC purity 84.3%, 70.2 mg) and 4-hydrazinocarbonothioylaminobenzoic acid (0.2423 mmol, 51.2 mg) were stirred with dimethylformamide (3 mL) and three drops of concentrated hydrochloric acid at room temperature for 8.5 hours. After addition of water, the precipitated yellow solid was recovered by filtration, washed with water and dried by means of a vacuum pump. The resulting solid was stirred with chloroform/n-hexane for a while, then recovered by filtration and dried by means of a vacuum pump to give the desired product as a pale yellow solid (72.3 mg, yield 68%).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@@:13]([CH2:16][O:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])([CH2:14][OH:15])[O:12][C@@H:11]([N:28]2[CH:36]=[C:34]([CH3:35])[C:32](=[O:33])[NH:31][C:29]2=[O:30])[C@@H:10]1[OH:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:38][O:39][C:40]1[CH:61]=[CH:60][C:43]([C:44](Cl)([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[C:45]2[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=2)=[CH:42][CH:41]=1>N1C=CC=CC=1.ClCCl>[CH2:1]([O:8][C@H:9]1[C@@:13]([CH2:16][O:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])([CH2:14][O:15][C:44]([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)([C:45]2[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=2)[C:43]2[CH:42]=[CH:41][C:40]([O:39][CH3:38])=[CH:61][CH:60]=2)[O:12][C@@H:11]([N:28]2[CH:36]=[C:34]([CH3:35])[C:32](=[O:33])[NH:31][C:29]2=[O:30])[C@@H:10]1[OH:37])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@]2(CO)O[C@@H](n3cc(C)c(=O)[nH]c3=O)[C@H](O)[C@H]2OCc2ccccc2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(C(OC[C@@]2(COS(=O)(=O)c3ccc(C)cc3)O[C@@H](n3cc(C)c(=O)[nH]c3=O)[C@H](O)[C@H]2OCc2ccccc2)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 23 h
Yield: 74.5 %

Procedure:
To a solution of nucleoside 6 (3.66 g, 6.88 mmol) in anhydrous pyridine (25 cm3) was added N,N-(dimethylamino)pyridine (0.84 g, 6.81 mmol) and 4,4′-dimethoxytrityl chloride (3.5 g, 13.2 mmol) and the mixture was stirred for 23 h at room temperature. Additional N,N-(dimethylamino)pyridine (0.250 g, 2.06 mmol) and 4,4′-dimethoxytrityl chloride (0.700 g, 2.06 mmol) was added, and stirring was continued for 36 h at room temperature. Ice cold H2O (50 cm3) was added and the reaction mixture was diluted with dichloromethane (150 cm3). The organic phase was separated and washed with saturated aqueous solutions of sodium hydrogen carbonate (25 cm3×3) and brine (40 cm3×3), dried (Na2SO4) and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography using dichloromethane/methanol/pyridine (0.75–1.5% methanol; 0.5% pyridine, v/v/v) as eluent to afford nucleoside 7 (4.28 g, 75%) as a white solid material after evaporation of the solvents under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:21][C@H:22]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1)[CH3:23]>>[Cl:1][C:2]1[CH:10]=[C:6]([C:7]([NH:21][C@H:22]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=2)[CH3:23])=[O:9])[C:5]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[N:4][CH:3]=1
Reactant: O=C(O)c1cc(Cl)cnc1COc1ccc(F)cc1
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2COc2ccc(F)cc2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 6 of Example 1 from 5-chloro-2-[(4-fluorophenoxy)methyl]nicotinic acid (step 1) and methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 5 of Example 1):
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[NH2:17][C:18]1[N:23]=[C:22]([C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[C:26]([F:32])[CH:25]=2)[CH:21]=[C:20]([N:33]2[C@H:38]([CH3:39])[CH2:37][O:36][C@H:35]([CH2:40][NH2:41])[CH2:34]2)[N:19]=1>C1COCC1>[NH2:17][C:18]1[N:19]=[C:20]([N:33]2[C@H:38]([CH3:39])[CH2:37][O:36][C@H:35]([CH2:40][NH:41][C:8](=[O:15])[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:34]2)[CH:21]=[C:22]([C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[C:26]([F:32])[CH:25]=2)[N:23]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C[C@@H]1CO[C@H](CN)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@@H]1CO[C@H](CNC(=O)c2ccccc2)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 112 %

Procedure:
Triethylamine (48 μL, 0.34 mmol) and benzoyl chloride (31 μL, 0.27 mmol) were added to a solution of 4-{2-amino-6-[(2R,5R)-2-(aminomethyl)-5-methyl-4-morpholinyl]-4-pyrimidinyl}-2-fluorobenzonitrile (77 mg, 0.23 mmol) in THF (5 mL), and the mixture was stirred at room temperature under nitrogen for 30 minutes. The mixture was quenched with saturated aqueous NaHCO3 (15 mL) and extracted with EtOAc (2×10 mL). The extracts were washed with brine (10 mL), dried (Na2SO4), filtered, and concentrated in vacuo to give the title compound (115 mg) as a yellow glass. LC-MS (ES) m/z=447 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:4][C:3]=1[O:13][CH3:14].[OH-].[Na+].CO.[CH:19]1[C:24](=[O:25])[C:23]([OH:26])=[CH:22][O:21][C:20]=1[CH2:27]Cl>CN(C)C=O.C(OCC)(=O)C>[OH:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([O:10][CH2:27][C:20]2[O:21][CH:22]=[C:23]([OH:26])[C:24](=[O:25])[CH:19]=2)=[O:9])=[CH:4][C:3]=1[O:13][CH3:14]
Reactant: COc1cc(C=CC(=O)O)ccc1O
Reactant: O=c1cc(CCl)occ1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CN(C)C=O
Product: COc1cc(C=CC(=O)OCc2cc(=O)c(O)co2)ccc1O
Temperature: 110 °C
Reaction time: 2 h
Yield: 46.5 %

Procedure:
0.87 g(4.5 mmol) of 4-hydroxy-3-methoxycinnamic acid and 0.18 g(4.5 mmol) of sodium hydroxide were dissolved into 40 ml of methanol. Residue obtained after distillating methanol was dissolved in 70 ml of N,N-dimethylformamide and 0.65 g (4.05 mmol) of chlorokojic acid prepared in the Reference Example was added thereto. The resulting mixture was heated with stirring for 2 hours in an oil bath of 110° C. After distillating the solvent, the residue was dissolved in 300 ml of ethyl acetate. The ethyl acetate solution was washed with 5% hydrochloric acid and distilled water, dried over magnesium sulfate, decolored with active charcoal and filtered. The filtrate was concentrated to give 0.6g(41.9%) of 2-(4-hydroxy-3-methoxy cinnamoyl)oxymethyl-5-hydroxy-4H-pyran-4-one as a solid.
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][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[CH2:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:57][N:58]1[CH2:63][CH2:62][CH:61]([NH2:64])[CH2:60][CH2:59]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:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:64][CH:61]5[CH2:62][CH2:63][N:58]([CH3:57])[CH2:59][CH2:60]5)=[O:28])=[CH:24][C:23]=4[CH2:31][CH3:32])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN1CCC(N)CC1
Reactant: CCc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CCc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-ethylbenzoic acid as described in the General procedure for amide bond synthesis using HATU and 1-methylpiperidin-4-amine. The final compound was purified by reverse phase HPLC and basified to give the free base 1H NMR (400 MHz, DMSO-d6) δ ppm 1.14 (t, J=8.0 Hz, 3 H) 1.23-1.69 (m, 11 H) 1.77 (m, 4 H) 1.99 (m, 2 H) 2.20 (s, 3 H) 2.69 (q, J=7.3 Hz, 2 H) 3.75 (s, 1 H) 3.97 (t, J=14.2 Hz, 2 H) 4.54 (t, J=8.1 Hz, 1 H) 7.57-7.81 (m, 3 H) 8.12 (d, J=7.8 Hz, 1 H) 8.17 (s, 1 H) 8.61 (s, 1 H). [M+H] calc'd for C28H37F2N7O2, 542; found 542.