Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:17])[CH2:5][CH:6]=[CH2:7].I[C:21]1[CH:26]=[CH:25][C:24]([N:27]([CH2:34][CH2:35][O:36][CH3:37])[C:28]2[N:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:11]([Cl:17])=[CH:12][CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:5]/[CH:6]=[CH:7]/[C:21]1[CH:22]=[CH:23][C:24]([N:27]([CH2:34][CH2:35][O:36][CH3:37])[C:28]2[N:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[CH:25][CH:26]=1
Reactant: COCCN(c1ccc(I)cc1)c1ncccn1
Reactant: C=CCC(NC(=O)c1c(Cl)cccc1Cl)C(=O)OC
Product: COCCN(c1ccc(/C=C/CC(NC(=O)c2c(Cl)cccc2Cl)C(=O)OC)cc1)c1ncccn1
Yield: 77 %

Procedure:
In the same manner as in Example 1, 2-(2,6-dichlorobenzamido)pent-4-enoic acid methyl ester (89 mg) was reacted with N-(4-iodophenyl)-N-(2-methoxyethyl)pyrimidin-2-amine (116 mg) to obtain (E)-2-(2,6-dichlorobenzamido)-5-[4-((2-methoxyethyl)-pyrimidin-2-ylamino)phenyl]pent-4-enoic acid methyl ester (120 mg). Column chromatography (silica gel, eluent: cyclohexane/chloroform=2/1→cyclohexane/chloroform=1/1→cyclohexane/chloroform=1/2) was used for purification.
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl[CH:39]([CH3:48])[C:40]([N:42]1[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1)=O>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:36][CH:39]([CH3:48])[CH2:40][N:42]2[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]2)=[CH:34][CH:35]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CC(Cl)C(=O)N1CCCCC1
Product: CCN(Cc1ccc(OC(C)CN2CCCCC2)cc1)c1cc(OC)ccc1C1CCc2cc(O)ccc2C1
Yield: 42.5 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (29 mg) and 2-chloro-1-piperidin-1-ylpropan-1-one (20 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (13 mg) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[C:16]([C:17]3[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([N:24]([CH2:34][C:35]4[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=4)[CH2:25][C:26]4[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=4)[N:18]=3)=[CH:15][C:14]([CH2:43][N:44]3[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]3)=[CH:13][N:12]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9].ClCCl.C(N(CC)CC)C.[CH3:60][S:61](Cl)(=[O:63])=[O:62]>>[F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[C:16]([C:17]3[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([N:24]([CH2:25][C:26]4[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=4)[CH2:34][C:35]4[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=4)[N:18]=3)=[CH:15][C:14]([CH2:43][N:44]3[CH2:49][CH2:48][N:47]([S:61]([CH3:60])(=[O:63])=[O:62])[CH2:46][CH2:45]3)=[CH:13][N:12]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCNCC4)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(S(C)(=O)=O)CC4)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Temperature: -15 °C
Yield: 94.4 %

Procedure:
A 1 L 3-neck round-bottomed flask equipped with a thermometer was charged with 4-(2-(5-fluoro-6-methoxypyridin-3-ylamino)-5-(piperazin-1-ylmethyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (25.1 g, 37.7 mmol) in dichloromethane (500 mL, 37.7 mmol). The suspension was stirred at −15° C. and treated with dropwise with triethylamine (52.4 mL, 377 mmol). The resulting solution was treated with methanesulfonyl chloride (8.92 mL, 113 mmol) and stirred at 0° C. for 1 h. The resulting mixture was sonicated and the solid was filtered, washed with water and dried in vacuo to give 4-(2-(5-fluoro-6-methoxypyridin-3-ylamino)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (26.5 g, 35.6 mmol, 94% yield). m/z (ESI, positive ion) m/z 744 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:25][C@H:26]1[CH2:31][CH2:30][CH2:29][C@H:28]([OH:32])[CH2:27]1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]2[C:3]3[C:2]([NH:25][C@H:26]4[CH2:31][CH2:30][CH2:29][C@H:28]([OH:32])[CH2:27]4)=[N:7][CH:6]=[N:5][C:4]=3[O:8][C:9]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:12][CH:13]=1
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(Cl)c23)cc1
Reactant: N[C@H]1CCC[C@H](O)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(N[C@H]4CCC[C@H](O)C4)c23)cc1
Temperature: 120 °C

Procedure:
Initially charge 1.0 g (2.97 mmol) of 4-chloro-5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidine and 513 mg (approx. 4.5 mmol) of (+/−)-cis/trans-3-aminocyclohexanol (approx. 3:1 cis/trans mixture; prepared according to J. Chem: Soc. Perkin Trans. I, 1994, 537) in 2.7 ml of DMF. After adding 1.03 ml (5.94 mmol) of DIEA, heat the mixture to 120° C. for 2 h. After cooling, add to ice-water. Filter off the precipitated solid with suction, wash with water and dry under reduced pressure. Purify the crude product by chromatography on silica gel (eluent: cyclohexane/ethyl acetate 2:1→1:2). 1.05 g (85.1% of theory) of the target product are obtained as a cis/trans mixture.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:10]1([CH2:16][C:17]2[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[C:18]=2[OH:25])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>C1C=CC=CC=1>[N:10]1([CH2:16][C:17]2[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[C:18]=2[O:25][C:8](=[O:9])[NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: Cc1cc(C)c(O)c(CN2CCCCC2)c1
Reactant: O=C=Nc1ccccc1
Solvent: c1ccccc1
Product: Cc1cc(C)c(OC(=O)Nc2ccccc2)c(CN2CCCCC2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
29.75 g (0.25 mol) of phenylisocyanate are introduced dropwise at 0° to 5°C into a solution of 54.75g (0.25 mol) of 2-(piperidinomethyl)-4,6-dimethylphenol in 80 ml of anhydrous benzene. The reaction mixture is stirred at room temperature for 4 hours. The precipitated carbamic acid ester is suction filtered and washed with petroleum ether (b.p. 30°-50°C).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CC#N>[CH2:16]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[CH3:9])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: Cc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cc(Br)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 89.3 %

Procedure:
To 4-bromo-2-methylphenol (1.25 g, 6.67 mmol) in 20 ml MeCN were added dry K2CO3 (1.84 g, 13.34 mmol, 2 equiv) and benzylbromide (0.872 ml, 7.34 mmol, 1.1 equiv) and reaction is stirred for 24 h at room temperature. Reaction mixture was filtered through Celite, solution was concentrated and purified by silica gel column chromatography (Hexane to 8% EtOAc/Hexane) to give 1.65 g 17 in 89% yield. Rf=0.90 (20% EtOAc/Hexane);
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[CH2:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25](Cl)(=[O:27])=[O:26])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(C1C=CC=CC=1)CCCCCC>N1C=CC=CC=1>[CH2:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25]([NH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2)(=[O:27])=[O:26])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: Nc1cccc2cccnc12
Reactant: CCCCCCCc1ccccc1S(=O)(=O)Cl
Agent: CCCCCCCc1ccccc1
Solvent: c1ccncc1
Product: CCCCCCCc1ccccc1S(=O)(=O)Nc1cccc2cccnc12
Yield: 97.35 %

Procedure:
Example II was essentially repeated using 46.4 g. (0.32 mole) 8-aminoquinoline, 180 ml. pyridine and 82.35 g. (0.3 mole) heptylbenzenesulfonyl chloride. The latter reactant was as prepared in Table 2 from the heptylbenzene of Table 1. There was obtained 112.6 g. (97.35% yield) of 8-(heptylbenzenesulfonamido)quinoline of the structure ##STR23## where a+b equals 4.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:10]([O:14][C:15]([CH2:17][O:18][C:19]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][C:20]=1[CH:21]=[O:22])=[O:16])([CH3:13])([CH3:12])[CH3:11].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[C:10]([O:14][C:15]([CH2:17][O:18][C:19]1[CH:26]=[CH:25][C:24]([O:27][CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:23][C:20]=1[CH:21]=[O:22])=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CCOC(=O)CCCBr
Reactant: CC(C)(C)OC(=O)COc1ccc(O)cc1C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)CCCOc1ccc(OCC(=O)OC(C)(C)C)c(C=O)c1
Temperature: 100 °C
Reaction time: 7 h
Yield: 29.6 %

Procedure:
Ethyl 4-bromobutyrate (1.48 g) and 2-(tert-butoxycarbonylmethoxy)-5-hydroxybenzaldehyde (1.28 g) were dissolved in methyl ethyl ketone (20 ml). To the solution was added powdered potassium carbonate (1.05 g), and the mixture was stirred in an oil bath at 100° C. for seven hours. The reaction mixture was concentrated, diluted with water, and was extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. After concentration, the crude product was purified by a silica gel column (35 g) eluting with a mixed solvent of toluene and ethyl acetate (from 19:1 to 4:1) to give ethyl 4-(4-tert-butoxycarbonylmethoxy-3-formylphenoxy)butyrate as an oil (0.55 g)
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[C:37]([Cl:40])[CH:38]=2)[N:33]([CH3:41])[CH:32]=1)=[O:30]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]3[C:39]4[C:34](=[CH:35][CH:36]=[C:37]([Cl:40])[CH:38]=4)[N:33]([CH3:41])[CH:32]=3)=[O:30])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: Cn1cc(C(=O)CCCCCBr)c2cc(Cl)ccc21
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCC(=O)c2cn(C)c3ccc(Cl)cc23)CC1

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride as starting compound and 6-bromo-1-(5-chloro-1-methyl-1 H-indol-3-yl)-1-hexanone are reacted and treated in the same manner as in Example 199 to give 4-amino-5-chloro-2-methoxy-N-((1-(6-(5-chloro-1-methyl-1 H-indol-3-yl)-6-oxohexyl)piperidin-4-yl)methyl)benzamide.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]2[CH:10]=[C:9]([C:11]3[CH:12]=[C:13]([CH:20]=[CH:21][C:22]=3[CH3:23])[C:14]([NH:16][CH:17]3[CH2:19][CH2:18]3)=[O:15])[S:8][C:7]=12.[F:24][C:25]1[C:26]([O:34][CH3:35])=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>COCCOC.CO.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>[CH:17]1([NH:16][C:14](=[O:15])[C:13]2[CH:20]=[CH:21][C:22]([CH3:23])=[C:11]([C:9]3[S:8][C:7]4=[C:2]([C:27]5[CH:28]=[CH:29][CH:30]=[C:25]([F:24])[C:26]=5[O:34][CH3:35])[N:3]=[N:4][CH:5]=[C:6]4[CH:10]=3)[CH:12]=2)[CH2:19][CH2:18]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1cc2cnnc(Cl)c2s1
Reactant: COc1c(F)cccc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: COCCOC
Solvent: O
Product: COc1c(F)cccc1-c1nncc2cc(-c3cc(C(=O)NC4CC4)ccc3C)sc12
Temperature: 150 °C

Procedure:
A mixture of 3-(7-chlorothieno[2,3-d]pyridazin-2-yl)-N-cyclopropyl-4-methylbenzamide (90 mg, 0.26 mmol), 3-fluoro-2-methoxyphenylboronic acid (67 mg, 0.39 mmol), Pd(PPh3)2Cl2 (18 mg, 0.03 mmol), and sodium carbonate (83 mg, 0.78 mmol) in a mixture of DME, ethanol and H2O (7:2:3, 2 ml) was heated to 150° C. for 15 min in the Emrys Optimizer® microwave. The mixture was diluted with MeOH and concentrated over SiO2. Column chromatography (MeOH/CH2Cl2=0→2%) afforded the desired product. Yield: 59 mg. MS (ESI, pos. ion) m/z: 434 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)=[N:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].Br[C:32]1[CH:33]=[N:34][CH:35]=[N:36][CH:37]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CO>[N:34]1[CH:33]=[C:32]([O:20][C:17]2[CH:18]=[CH:19][C:14]([C:12]3[O:13][C:9]([NH:8][C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)=[N:10][N:11]=3)=[CH:15][CH:16]=2)[CH:37]=[N:36][CH:35]=1
Reactant: Oc1ccc(-c2nnc(Nc3cccc(Cl)c3)o2)cc1
Reactant: Brc1cncnc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: Clc1cccc(Nc2nnc(-c3ccc(Oc4cncnc4)cc3)o2)c1
Temperature: 80 °C
Yield: 40.8 %

Procedure:
4-{5-[(3-chlorophenyl)amino]-1,3,4-oxadiazol-2-yl}phenol (143.8 mg, 0.5 mmol) was dissolved in 3 mL of anhydrous DMF in a 2-5 mL microwave vial (Personal Chemistry). Solid potassium bis(trimethylsilyl)amide (200.0 mg, 1.0 mmol) was added and the reaction mixture was stirred with heating at 80° C. for 10 min, then 5-bromopyrimidine (95.4 mg, 0.6 mmol) was added, followed by anhydrous K2CO3 (69.1 mg, 0.5 mmol). Then the vial was capped and microwaved at 180° C. for 30 min. Then the reaction mixture was diluted with ca. 1 mL of MeOH, filtered through 0.22 um syringe filter and purified by reverse-phase preparative HPLC in acetonitrile/water system with 0.01% TFA. Fractions, containing the product, were partitioned between ca. 50 mL of EtOAc and ca. 50 mL of saturated aqueous NaHCO3. EtOAc layer was washed with brine, dried over anhydrous Na2SO4 and filtered. Solvent was removed in vacuo to give the title product as a light-yellow solid (74.7 mg). Yield 40.8%.
Reaction SMILES: [NH3:1].C(O)C.[Br:5][C:6]1[CH:7]=[CH:8][C:9]([CH:25]=O)=[C:10]([NH:12][C:13](=O)[CH:14]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH3:15])[CH:11]=1>>[Br:5][C:6]1[CH:11]=[C:10]2[C:9]([CH:25]=[N:1][C:13]([CH:14]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH3:15])=[N:12]2)=[CH:8][CH:7]=1
Reactant: CC(O[Si](C)(C)C(C)(C)C)C(=O)Nc1cc(Br)ccc1C=O
Reactant: N
Solvent: CCO
Product: CC(O[Si](C)(C)C(C)(C)C)c1ncc2ccc(Br)cc2n1
Temperature: 150 °C
Yield: 94 %

Procedure:
A solution of ammonia in ethanol (2 M, 14 mL, 28 mmol) was added to N-(5-bromo-2-formyl-phenyl)-2-(tert-butyl-dimethyl-silanyloxy)-propionamide (0.5 g, 1.36 mmol). The mixture was heated in a microwave reactor at 150° C. for 2 h. A second solution of ammonia in ethanol (2 M, 14 mL, 28 mmol) was added to N-(5-bromo-2-formyl-phenyl)-2-(tert-butyl-dimethyl-silanyloxy)-propionamide (1.0 g, 2.72 mmol). The mixture was heated in a microwave reactor at 150° C. for 2 h. The two resultant solutions were combined and evaporated and the residue purified by silica gel chromatography using iso-hexanes/dichloromethane 1:1 to 1:3 to 0:1 to yield the title compound (1.34 g, 94%) as a yellow gum. 1H NMR (300 MHz, CDCl3) δ 0.08 (s, 6H), 0.91 (s, 9H), 1.64 (d, J=6.7 Hz, 3H), 5.22 (q, J=6.5 Hz, 1H), 7.71-7.83 (m, 2H), 8.26 (s, 1H), 9.40 (s, 1H). LCMS (m/z) 367.0, 369.0 [M+H], Tr=4.00 min.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]2[C:23](=[O:27])[CH2:24][CH2:25][CH2:26][C:15]=12.[CH3:28][C:29]1[C:34]([CH:35]=[O:36])=[CH:33][CH:32]=[CH:31][N:30]=1.C(O)(=O)C(O)=O>O1CCCC1.CCCCCC.O>[OH:36][CH:35]([C:34]1[C:29]([CH3:28])=[N:30][CH:31]=[CH:32][CH:33]=1)[CH:24]1[C:23](=[O:27])[N:16]2[C:17]3[C:22]([C:14]([CH3:13])=[C:15]2[CH2:26][CH2:25]1)=[CH:21][CH:20]=[CH:19][CH:18]=3
Reactant: Cc1ncccc1C=O
Reactant: Cc1c2n(c3ccccc13)C(=O)CCC2
Agent: O=C(O)C(=O)O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: O
Solvent: CCCCCC
Product: Cc1ncccc1C(O)C1CCc2c(C)c3ccccc3n2C1=O
Reaction time: 0.33 h

Procedure:
To a solution of diisopropylamine (1.01 g) in tetrahydrofuran (15 ml) at -70° C. under a nitrogen atmosphere was added 1.64M butyllithium in hexane (6.1 ml). After being stirred at the same temperature for 20 minutes, the mixture was treated with a solution of 8,9-dihydro-10-methylpyrido[1,2-a]indol-6(7H)-one (1.99 g) in tetrahydrofuran (25 ml) over 20 minutes. The mixture was stirred at -70° C. for 30 minutes, and a solution of 2-methyl-3-pyridinecarbaldehyde (1.21 g) in tetrahydrofuran (20 ml) was added dropwise over 20 minutes. After the mixture was stirred at -70° C. for further 60 minutes and at ambient temperature for 60 minutes, it was diluted with water and adjusted to pH 9 with oxalic acid. The separated organic layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo, to give 8,9-dihydro-7-[(hydroxy)(2-methylpyridin- 3-yl)-methyl]-10-methylpyrido[1,2-a]indol-6(7H)-one
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([F:14])([F:13])[F:12])=[CH:8][CH:9]=2)[C:4]([C:15]2[N:20]=[C:19]3[C:21]([C:32]([O:34]C)=[O:33])=[CH:22][N:23](COC(=O)C(C)(C)C)[C:18]3=[N:17][CH:16]=2)=[N:3]1.[OH-].[Na+]>O1CCOCC1.O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([F:13])([F:14])[F:12])=[CH:8][CH:9]=2)[C:4]([C:15]2[N:20]=[C:19]3[C:21]([C:32]([OH:34])=[O:33])=[CH:22][NH:23][C:18]3=[N:17][CH:16]=2)=[N:3]1
Reactant: COC(=O)c1cn(COC(=O)C(C)(C)C)c2ncc(-c3nn(C)c4ccc(C(F)(F)F)cc34)nc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)O)c3n2)c2cc(C(F)(F)F)ccc21
Temperature: 90 °C
Reaction time: 7 h
Yield: 110.7 %

Procedure:
To a suspension of methyl 2-(1-methyl-5-(trifluoromethyl)-1H-indazol-3-yl)-5-(pivaloyloxymethyl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylate (50 mg, 0.1 mmol) in dioxane/water (4 mL/4 mL) was added NaOH (40 mg, 1.0 mmol), the reaction mixture was heated to 90° C. with stirring for 7 hours, the dioxane was removed under reduced pressure, the aqueous layer was adjusted to pH=3 with 1 N HCl, the precipitate was collected by filtration and washed with water (5 mL) and dried to afford 2-(1-methyl-5-(trifluoromethyl)-1H-indazol-3-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylic acid (40 mg, crude) as an orange solid. LCMS: (M+H)+=362.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:15]3[N:16]=[CH:17][CH:18]=[CH:19][C:14]=3[C:13](=[O:20])[NH:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[H-].[Na+].S(OC)(O[CH3:27])(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>O.CN(C)C=O>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:15]3[N:16]=[CH:17][CH:18]=[CH:19][C:14]=3[C:13](=[O:20])[N:12]([CH3:27])[CH2:11]2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: COS(=O)(=O)OC
Reactant: O=C1NCN(c2cccc([N+](=O)[O-])c2)c2ncccc21
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CN(c2cccc([N+](=O)[O-])c2)c2ncccc2C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
To a solution of 2.7 g of 1-(m-nitrophenyl)-4-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine and 20 ml of dry dimethylformamide was added 0.48 g of approximately 55% sodium hydride and the mixture was stirred at room temperature for 30 minutes. To this was added dropwise 2.52 g of dimethyl sulfate and the whole was stirred at room temperature for 3 hours. The reaction mixture was neutralized with sodium carbonate and concentrated under reduced pressure to leave a residue, to which was added water to precipitate a crude product. This product was collected by filtration and recrystallized from a mixture of dimethylformamide and methanol to give 1.96 g of 1-(m-nitrophenyl)-3-methyl-4-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine as yellow needles, melting at 247° - 248° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C@H:16]([CH2:22][OH:23])[CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])[CH2:12][CH:13]([CH3:15])[CH3:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:24][O:25][C:26]([NH:28][C@@H:29]([CH:33]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:30](O)=[O:31])=[O:27]>>[CH3:24][O:25][C:26](=[O:27])[NH:28][C@H:29]([C:30](=[O:31])[NH:21][CH2:20][CH2:19][CH2:18][CH2:17][C@H:16]([N:11]([S:8]([C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])[CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:22][OH:23])[CH:33]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC(C)CN([C@H](CO)CCCCN)S(=O)(=O)c1ccc(N)cc1
Reactant: COC(=O)N[C@H](C(=O)O)C(c1ccccc1)c1ccccc1
Product: COC(=O)N[C@H](C(=O)NCCCC[C@@H](CO)N(CC(C)C)S(=O)(=O)c1ccc(N)cc1)C(c1ccccc1)c1ccccc1

Procedure:
The title compound was prepared from (1S)-4-amino-N-(5-amino-1-hydroxymethyl-pentyl)-N-isobutyl-benzenesulfonamide (XII) (example 28, step D) as described in general procedure B using (2S)-2-methoxycarbonylamino-3,3-diphenyl-propionic acid (step A). The final product was obtained in 67% yield (121 mg).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:20]=1.O.C1(C)C(S(O)(=O)=O)=CC=CC=1.[NH2:33][C:34]1[CH:48]=[CH:47][C:37]([C:38]([NH:40][CH:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)=[O:39])=[CH:36][C:35]=1[O:49][CH3:50]>C(O)(C)C>[CH:16]1([N:7]2[CH2:8][C:9]([F:15])([F:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:33][C:34]4[CH:48]=[CH:47][C:37]([C:38]([NH:40][CH:41]5[CH2:42][CH2:43][O:44][CH2:45][CH2:46]5)=[O:39])=[CH:36][C:35]=4[O:49][CH3:50])=[N:20][C:6]2=3)[CH2:19][CH2:18][CH2:17]1
Reactant: COc1cc(C(=O)NC2CCOCC2)ccc1N
Reactant: CN1C(=O)C(F)(F)CN(C2CCC2)c2nc(Cl)ncc21
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: CC(C)O
Solvent: O
Product: COc1cc(C(=O)NC2CCOCC2)ccc1Nc1ncc2c(n1)N(C1CCC1)CC(F)(F)C(=O)N2C
Yield: 43.8 %

Procedure:
A mixture of 0.0605 g (0.20 mmole) 2-chloro-9-cyclobutyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-1), 0.0571 g (0.30 mmole) of toluenesulfonic acid monohydrate, 0.0501 g (0.20 mmole) of 4-amino-3-methoxy-N-(tetrahydro-2H-pyran-4-yl) benzamide and 1 mL of isopropanol was heated in a sealed vessel at 140 degrees for 19.5 hours, cooled and concentrated under reduced pressure. The residue taken up in ethyl acetate and washed successively with 50 mL of saturated aqueous sodium bicarbonate, 50 mL of water, 50 mL of brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was recrystallized from acetonitrile-methanol to give 0.0452 g 4-(9-cyclobutyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(tetrahydro-pyran-4-yl)-benzamide (I-7).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[N:5][C:6]([C:10]([O:12]CC)=O)=[C:7](Cl)[N:8]=1.CSC1NC(=O)C(C(OCC)=O)=NN=1.S(Cl)(Cl)=O.Cl.[CH2:34]([O:37][C:38]1[CH:46]=[CH:45][CH:44]=[CH:43][C:39]=1[C:40]([NH2:42])=[NH:41])[CH:35]=[CH2:36]>C(#N)C.C(N(CC)CC)C>[CH3:1][S:2][C:3]1[N:4]=[N:5][C:6]2[C:10](=[O:12])[NH:42][C:40]([C:39]3[CH:43]=[CH:44][CH:45]=[CH:46][C:38]=3[O:37][CH2:34][CH:35]=[CH2:36])=[N:41][C:7]=2[N:8]=1
Reactant: C=CCOc1ccccc1C(=N)N
Reactant: CCOC(=O)c1nnc(SC)nc1Cl
Agent: CCOC(=O)c1nnc(SC)[nH]c1=O
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: C=CCOc1ccccc1-c1nc2nc(SC)nnc2c(=O)[nH]1
Reaction time: 8 h

Procedure:
A cooled (5° C.) solution of 3-methylthio-5-chloro-6-carboethoxy-1,2,4-triazine (prepared by heating 3-methylthio-5-oxo-6-carboethoxy-4,5-dihydro-1,2,4-triazine, 1.5 g, with thionyl chloride, 30 ml, under reflux for two hours and thereafter removing thionyl chloride) in acetonitrile (30 ml) was added to a cooled stirred mixture of 2-allyloxybenzamidine hydrochloride (2.23 g) and triethylamine (1.06 g) in acetonitrile (50 ml). The mixture was stirred with cooling (0°-5° C.) for 15 minutes, then more triethylamine (0.71 g) was added and the reaction mixture was stirred at ambient temperature for two hours and left standing overnight. A yellow precipitate was collected, washed with water and recrystallised from acetonitrile and then from acetonitrile/ethanol (50%) to afford the title compound, 0.35 g, m.p. 238°-239° C.