Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:4]([O:6][CH3:7])=[O:5].Cl[CH2:18][CH2:19][N:20]([CH2:25][CH2:26]Cl)[S:21]([CH3:24])(=[O:23])=[O:22].O>C(N(CC)C(C)C)(C)C>[C:13]([O:12][C:10]([NH:9][CH2:8][C@H:3]([N:2]1[CH2:26][CH2:25][N:20]([S:21]([CH3:24])(=[O:23])=[O:22])[CH2:19][CH2:18]1)[C:4]([O:6][CH3:7])=[O:5])=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: CS(=O)(=O)N(CCCl)CCCl
Reactant: COC(=O)[C@@H](N)CNC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)[C@H](CNC(=O)OC(C)(C)C)N1CCN(S(C)(=O)=O)CC1
Reaction time: 18 h
Yield: 45.2 %

Procedure:
In a Schlenk tube, a solution of 5 g (20 mmol) of methyl (S)-2-amino-3-tert-butoxycarbonylaminopropanoate hydrochloride and 4.3 g (20 mmol) of N,N-bis(2-chloroethyl)methanesulfonamide in 65 ml of N,N-diisopropylethylamine is heated at 127° C. with vigorous stirring for 18 h. After the addition of water, the product is extracted with ethyl acetate. The organic phases are combined, washed with water, dried over magnesium sulfate, filtered and concentrated under vacuum. The crude product obtained is purified by chromatography on silica gel, elution being carried out with a 50/50 heptane/ethyl acetate mixture. 3.3 g (46%) of methyl (S)-3-tert-butoxycarbonylamino-2-(4-methanesulfonylpiperazin-1-yl)propanoate are obtained in the form of a white solid.
Reaction SMILES: [CH3:1][CH:2]([NH:4][CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10](B2OC(C)(C)C(C)(C)O2)[CH:11]=1)[CH3:3].Br[C:22]1[CH:23]=[C:24]2[C:28](=[C:29]([C:31]([NH2:33])=[O:32])[CH:30]=1)[NH:27][CH:26]=[C:25]2[CH:34]1[CH2:39][CH2:38][N:37]([S:40]([CH2:43][CH3:44])(=[O:42])=[O:41])[CH2:36][CH2:35]1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>O>[CH2:43]([S:40]([N:37]1[CH2:36][CH2:35][CH:34]([C:25]2[C:24]3[C:28](=[C:29]([C:31]([NH2:33])=[O:32])[CH:30]=[C:22]([C:10]4[CH:9]=[N:8][CH:7]=[C:6]([CH2:5][NH:4][CH:2]([CH3:1])[CH3:3])[CH:11]=4)[CH:23]=3)[NH:27][CH:26]=2)[CH2:39][CH2:38]1)(=[O:42])=[O:41])[CH3:44]
Reactant: CC(C)NCc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cncc(CNC(C)C)c4)cc23)CC1
Temperature: 150 °C
Reaction time: 0.13 h
Yield: 70.3 %

Procedure:
To a CEM microwave tube containing (1-methylethyl){[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}amine (22 mg, 0.080 mmol) was added 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (50 mg, 0.121 mmol), K2CO3 (100 mg, 0.724 mmol), dioxane (1.5 mL), H2O (0.5 mL), and chloro-2-(dimethylaminormethyl)-ferrocen-1-yl-(dinorbornylphosphine)palladium(II) (7.3 mg, 0.012 mmol). The reaction was heated in a CEM microwave for 30 min at 150° C. The reaction mixture was filtered through a 2 g SCX cartridge (pre-equilibrated with 3 mL MeOH), eluting in sequence with H2O (3 mL), MeOH (6 mL) and a 2 M solution of NH3/MeOH (9 mL). The NH3/MeOH fraction was dried under a stream of nitrogen at 50° C. and purified on an Agilent MDAP (Zorbax Eclipse XDB-C18 column: 21.2×100 mm) eluting at 20 mL per min for 1 min with 10% CH3CN/H2O (0.1% TFA) then a linear gradient of 10% CH3CN/H2O (0.1% TFA) to 95% CH3CN/H2O (0.1% TFA) over 8 min and holding at the final concentration for 30 sec. The fractions containing product were filtered through a 2 g Pharmasil CHQAX column (polymer bound ammonium hydroxide; United Chemical Technologies) to remove TFA and concentrated under a stream of nitrogen at 50° C. to give 27.2 mg of the title compound (70%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([OH:32])=O)[C:25]=1[CH3:33])(=[O:12])=[O:11].[CH:34]1([N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH2:36][CH2:35]1>>[CH:34]1([N:37]2[CH2:42][CH2:41][N:40]([C:30]([C:26]3[C:25]([CH3:33])=[C:24](/[CH:23]=[C:16]4\[C:17](=[O:22])[NH:18][C:19]5[C:15]\4=[CH:14][C:13]([S:10]([CH2:9][C:3]4[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=4[Cl:8])(=[O:11])=[O:12])=[CH:21][CH:20]=5)[NH:28][C:27]=3[CH3:29])=[O:32])[CH2:39][CH2:38]2)[CH2:36][CH2:35]1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)O
Reactant: C1CN(C2CC2)CCN1
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)N1CCN(C2CC2)CC1

Procedure:
5-[5-(2,6-Dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid was coupled with 1-cyclopropyl-piperazine to give the titled compound.
Reaction SMILES: [CH3:1][CH:2]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].Br[CH2:16][CH2:17][CH2:18][CH3:19].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH2:16]([N:8]([CH:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH2:17][CH2:18][CH3:19]
Reactant: CCCCBr
Reactant: CCCCCC(C)Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCC(C)N(CCCC)c1ccccc1
Yield: 44 %

Procedure:
A mixture of N-(1-methylhexyl)aniline (76 parts), 1-bromobutane (66 parts), anhydrous potassium carbonate (65 parts) and DMF (150 parts) was stirred while heating under reflux for 41 hours. An additional quantity of 1-bromobutane (44 parts) was added and the mixture stirred while heating under reflux for a further 19 hours. The cooled mixture was poured into water (400 parts) and the organic phase separated. The aqueous phase was extracted with toluene, the organic phases and toluene extract were combined and washed with water (2×100 parts) before evaporating to leave N-butyl-N-(1-methylhexyl)aniline (72.8 parts, 44%) which was purified by vacuum distillation to give N-butyl-N-(1-methylhexyl)aniline b.pt 73°-80° C., 2.6 mm Hg.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12][CH:13]2[CH2:18][O:17]C(C)(C)[O:15][CH2:14]2)=[C:4]([Cl:21])[N:3]=1>O1CCCC1.Cl>[ClH:21].[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12][CH:13]([CH2:18][OH:17])[CH2:14][OH:15])=[C:4]([Cl:21])[N:3]=1
Reactant: CC1(C)OCC(CCn2cnc3c(Cl)nc(N)nc32)CO1
Agent: Cl
Solvent: C1CCOC1
Product: Nc1nc(Cl)c2ncn(CCC(CO)CO)c2n1
Yield: 125.5 %

Procedure:
To a solution of 2-amino-6-chloro-9-[2-(2,2-dimethyl-1,3-dioxan-5-yl)ethyl]purine (0.46 g, 1.5 mmol) in tetrahydrofuran (4.5 ml), hydrochloric acid (2.0M, 0.5 ml) was added. A white precipitate formed and after 0.5 hour the solution was diluted with further tetrahydrofuran and was filtered to give 2-amino-6-chloro-9-(4-hydroxy-3-hydroxymethylbut-1-yl)purine hydrochloride (290 mg, 63%), decomposed over 165° C.; λmax (H2O, pH5.5) 223 (ε 28,400), 245 (ε 4,620), and 307 (ε 7,620) nm; νmax (KBr) 3370, 3330, 3200, 2500, 1650, 1630, 1595, and 1505 cm−1; δH [(CD3)2SO] 1.53 (1H, m, CHCH2CH2), 1.83 (2H, q, J 7 Hz, CHCH2CH2), 3.35 (4H, d, J 6 Hz, 2×CH2O), 4.19 (2H, t, J 7 Hz, CH2N), 5.85 (9H, s, D2O exchangeable, 2×OH, NH2, HCl and H2O), and 8.57 (1H, s, 8-H). (Found: C, 39.04; H, 4.85; N, 22.36%; C10H14ClN5O4.HCl requires C, 38.98; H, 4.91; N, 22.73.%).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH3:23])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21]Cl)[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:25]([NH:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:26][CH2:27][CH3:28]>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH3:23])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21][N:29]([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:25][CH2:26][CH2:27][CH3:28])[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CN1Cc2c(-c3noc(CCl)n3)ncn2-c2cccc(Cl)c2C1=O
Reactant: CCCCNCCCC
Solvent: CN(C)C=O
Product: CCCCN(CCCC)Cc1nc(-c2ncn3c2CN(C)C(=O)c2c(Cl)cccc2-3)no1
Yield: 61.2 %

Procedure:
1.6 g (4.4 mmol) of 7-chloro-3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one were stirred at room temperature for 48 hours with 3.6 ml (21 mmol) of dibutylamine and 10 ml of N,N-dimethylformamide. By evaporation of the reaction mixture and chromatography of the residue on silica gel while eluting with ethyl acetate there was obtained 1.23 g (61%) of 7-chloro-3-(5-dibutylaminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one of m.p. 140°-142°, which was converted into the hydrochloride of m.p. 184°-187°.
Reaction SMILES: Cl.[CH2:2]([C:5]1[S:6][CH:7]=[C:8]([CH2:10]Cl)[N:9]=1)[CH2:3][CH3:4].[C:12]1([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:2]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][N:21]2[CH2:22][CH2:23][N:18]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:19][CH2:20]2)[N:9]=1)[CH2:3][CH3:4]
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CCCc1nc(CCl)cs1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCc1nc(CN2CCN(c3ccccc3)CC2)cs1

Procedure:
A mixture of 2-n-propyl-4-chloromethylthiazole hydrochloride (3.18g; 0.015 mole), 1-phenylpiperazine (2.43g; 0.015 mole) and sodium carbonate (anhydrous, 10g) in absolute ethanol (60ml) was stirred and boiled under reflux for 6 hours. The suspension was filtered and the filtrate evaporated to a yellow oil. This was dissolved in boiling benzene and treated with decolourising charcoal. After filtration, the benzene was removed giving a yellow oil which crystallised 4.27g. This solid was recrystallised from petroleum ether (b.p. 60°-80° C.) at 0° C. to give a white crystalline solid (m.p. 38°-39° C.)
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[C:5]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][NH:11][C:10]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH3:26])[C:9]=2[C:8]1=[O:31].[C:41]([N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1)(=[O:43])[CH3:42]>>[C:41]([N:44]1[CH2:49][CH2:48][N:47]([C:16]2[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH3:26])[C:9]3[C:8](=[O:31])[N:7]([CH2:6][C:5]4[CH:4]=[C:3]([C:2]([F:40])([F:1])[F:39])[CH:34]=[C:33]([C:35]([F:36])([F:38])[F:37])[CH:32]=4)[CH2:14][CH2:13][CH2:12][NH:11][C:10]=3[N:15]=2)[CH2:46][CH2:45]1)(=[O:43])[CH3:42]
Reactant: COc1ccccc1-c1nc(S(C)(=O)=O)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCN2
Reactant: CC(=O)N1CCNCC1
Product: COc1ccccc1-c1nc(N2CCN(C(C)=O)CC2)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCN2
Yield: 80.9 %

Procedure:
In a similar manner to Example 1, 6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methoxyphenyl)-2-(methylsulfonyl)-5-oxopyrimido[4,5-b][1,5]diazocine (Compound of Reference Example 18; 88.3 mg) was reacted with 1-acetylpiperazine (23.1 mg) to obtain 2-(4-acetylpiperazine-1-yl)-6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methoxyphenyl)-5-oxopyrimido[4,5-b][1,5]diazocine (77.3 mg, 81%).
Reaction SMILES: [CH2:1]([N:3]([CH2:8][C:9]1[C:14]([N+:15]([O-])=O)=[CH:13][CH:12]=[C:11]([Cl:18])[C:10]=1[Cl:19])[CH2:4][C:5]([OH:7])=[O:6])[CH3:2]>[Pt]>[CH2:1]([N:3]([CH2:8][C:9]1[C:14]([NH2:15])=[CH:13][CH:12]=[C:11]([Cl:18])[C:10]=1[Cl:19])[CH2:4][C:5]([OH:7])=[O:6])[CH3:2]
Reactant: CCN(CC(=O)O)Cc1c([N+](=O)[O-])ccc(Cl)c1Cl
Agent: [Pt]
Product: CCN(CC(=O)O)Cc1c(N)ccc(Cl)c1Cl

Procedure:
Ethyl N-(2,3-dichloro-6-nitrobenzyl)glycine (compound VI) may also be catalytically hydrogenated using a sulfided platinum on carbon catalyst under hydrogen pressure. The catalyst is then removed by filtration and the filtrate concentrated, diluted with water and an organic solvent and basified using an alkali to a pH of about 9-10. The organic phase is separated and concentrated and the crude material purified by low temperature recrystallization to give ethyl-(6-amino-2,3-dichlorobenzyl)glycine (compound I). 6,7-dichloro-1,5-dihydroimidazo[2,1-b]quinazoline-2(3H)one (compound III) may be prepared from compound II by suspending 5,6-dichloro-3,4-dihydro-2(1H)iminoquinazoline-3-acetate HBR (compound II) in water and adding an organic base such as TEA. After filtering the solution the filtered cake is washed in water and the solids suspended in alcohol. After filtering, the solids are rinsed in an alcohol and dried to give compound III.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12]([NH2:16])([CH3:15])([CH3:14])[CH3:13]>C(O)C>[C:12]([NH:16][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)N
Reactant: O=[N+]([O-])c1cccc(Cl)c1Cl
Solvent: CCO
Product: CC(C)(C)Nc1c(Cl)cccc1[N+](=O)[O-]

Procedure:
A mixture of 2,3-dichloronitrobenzene (92.5 g), tert-butylamine (138 ml) and ethanol (50 ml) is heated in a bomb at 1500 for 3 days. Dilution with water, extraction with ethylacetate several times, drying with sodium sulfate, and concentration gives the title compound, IR (neat) 2970, 1532, 1484, 1447, 1366, 1348, 1192 and 755 cm-1 ; NMR (CDCl3) 7.73, 7.61, 7.07, 4.77 and 1.22 δ; MS (m/z) 172, 154, 142, 126, 114, 99 and 90.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][N:7]=[C:6]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)[C:5]=2[S:4][CH:3]=1.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][CH2:25]O>>[Br:1][C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH2:25][CH2:24][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=3)[N:7]=[C:6]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)[C:5]=2[S:4][CH:3]=1
Reactant: OCCc1ccccn1
Reactant: O=c1[nH]nc(-c2ccncc2)c2scc(Br)c12
Product: O=c1c2c(Br)csc2c(-c2ccncc2)nn1CCc1ccccn1
Yield: 70 %

Procedure:
The title compound was prepared in analogy to the process described in Example 3.4 starting from 3-bromo-7-pyridin-4-yl-5H-thieno[2,3-d]pyridazin-4-one and 2-pyridin-2-yl-ethanol. Yield: 70%.
Reaction SMILES: [Cl:1][C:2]1[C:11]([Cl:12])=[CH:10][C:9]([O:13]C)=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:15])[NH:7]2.Br>>[Cl:1][C:2]1[C:11]([Cl:12])=[CH:10][C:9]([OH:13])=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:15])[NH:7]2
Reactant: COc1cc(Cl)c(Cl)c2c1NC(=O)CC2
Agent: Br
Product: O=C1CCc2c(Cl)c(Cl)cc(O)c2N1

Procedure:
The thus-obtained 42 g of 5,6-dichloro-8-methoxy-3,4-dihydrocarbostyril are dispersed in 500 ml of 47%-hydrobromic acid aqueous solution and heated for 4 hours under refluxing condition. After cooling the reaction mixture, the insoluble matter is separated by filtration, washed with water and dried. The crude crystals thus obtained are recrystallized from methanol to obtain 29 g or 5,6-dichloro-8-hydroxy-3,4-dihydrocarbostyril in the form of colorless needle-like crystals with a melting point of 233°-235° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[CH:5][C:4]=1[O:15][CH3:16].[Li]CCCC.CN([CH:25]=[O:26])C>C1COCC1>[CH3:14][O:13][C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]([O:2][CH3:1])=[C:4]([O:15][CH3:16])[C:5]=1[CH:25]=[O:26]
Reactant: COc1cc(OC)c2ccccc2c1OC
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1c(C=O)c(OC)c2ccccc2c1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.8 %

Procedure:
According to the procedure by Syper et al.,38 100 (1.07 g, 4.90 mmol) was dissolved in THF (20.0 mL) at 0° C. under Argon, and then nBuLi (1.6 M in hexanes, 4.0 mL, 10.0 mmol) was added at 0° C. The reaction was stirred at 0° C. for 5 hours before DMF (0.850 mL, 11.0 mmol) was added at 0° C. The reaction was stirred for another 30 minutes at room temperature before quenching with water. The reaction was diluted with ethyl ether and washed with saturated brine. The organic layer was dried over MgSO4, filtered, and condensed. Crude product was used as a 5:1 mixture of product:starting material, affording 54 (1.07 g, 4.35 mmol, 89%) as a yellow oil. Following purification via column chromatography (CH2Cl2 to 1:9 EtOAc:CH2Cl2) pure aldehyde 54 was obtained as a yellow solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH:21][C:22](=[O:38])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH:32]=[N:33][CH:34]=[N:35][CH:36]=2)[CH:26]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]4[CH:36]=[N:35][CH:34]=[N:33][CH:32]=4)[CH:26]=3)[CH2:23][C:22](=[O:38])[NH:21][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1NC(=O)CC(=O)c1cccc(-c2cncnc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-c3cncnc3)c2)=Nc2ccc(-c3ccccc3F)cc2N1

Procedure:
The title compound was prepared from {2′-fluoro-3-[3-oxo-3-(3-pyrimidin-5-yl-phenyl)-propionylamino]-biphenyl-4-yl}-carbamic acid tert-butyl ester (Example M96) (0.42 g, 0.80 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (230 mg, 71%).
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN([CH:12]=[C:13]1[C:18](=[O:19])[CH2:17][CH2:16][CH2:15][C:14]1=O)C>>[C:1]1([N:7]2[C:14]3[CH2:15][CH2:16][CH2:17][C:18](=[O:19])[C:13]=3[CH:12]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NNc1ccccc1
Reactant: CN(C)C=C1C(=O)CCCC1=O
Product: O=C1CCCc2c1cnn2-c1ccccc1

Procedure:
Prepared analogously to Example 1 starting from phenylhydrazine and 2-(dimethylaminomethylene)-cyclohexane-1,3-dione.
Reaction SMILES: C(OC([N:8]1[CH2:30][CH2:29][C:11]2[N:12]=[C:13]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[O:28][CH:27]=[N:26][CH:25]=4)=[CH:20][CH:19]=3)[N:14]=[C:15]([OH:16])[C:10]=2[CH2:9]1)=O)(C)(C)C.[C:31]1([CH2:37]O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.Cl>C1COCC1>[CH2:37]([O:16][C:15]1[C:10]2[CH2:9][NH:8][CH2:30][CH2:29][C:11]=2[N:12]=[C:13]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[O:28][CH:27]=[N:26][CH:25]=3)=[CH:22][CH:23]=2)[N:14]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC(C)(C)OC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(O)c2C1
Reactant: OCc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1ccc(COc2nc(Nc3ccc(-c4cnco4)cc3)nc3c2CNCC3)cc1
Temperature: 50 °C
Yield: 45.5 %

Procedure:
tert-Butyl-4-hydroxy-2-(4-(oxazol-5-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (0.2 g, 0.49 mmol, Example 3d), phenylmethanol (0.063 ml, 0.61 mmol) and triphenylphosphine (0.160 g, 0.61 mmol) in THF (5 mL) was stirred for 10 min. Diisopropyl azodicarboxylate (0.119 mL, 0.61 mmol) was added and reaction was stirred at 50° C. over night. HCl (2M aq, 2 mL) was added and the solution was heated to 75° C. for 1 h, allowing THF to evaporate. The remaining solvent was evaporated under reduced pressure. The crude product was dissolved in MeOH/DMSO and purified on preparative HPLC to give 4-(benzyloxy)-N-(4-(oxazol-5-yl)phenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (0.089 g, 39.7%).
Reaction SMILES: N[C@H:2](C)C(C1C=CC=CC=1)(C1C=CC=CC=1)O.[OH:18][C:19]1[CH:31]=[CH:30][C:22]2[C@@H:23]([CH2:26][C:27]([OH:29])=[O:28])[CH2:24][O:25][C:21]=2[CH:20]=1.S(=O)(=O)(O)O>CO>[OH:18][C:19]1[CH:31]=[CH:30][C:22]2[C@@H:23]([CH2:26][C:27]([O:29][CH3:2])=[O:28])[CH2:24][O:25][C:21]=2[CH:20]=1
Reactant: C[C@@H](N)C(O)(c1ccccc1)c1ccccc1
Reactant: O=C(O)C[C@H]1COc2cc(O)ccc21
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)C[C@H]1COc2cc(O)ccc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 91.5 %

Procedure:
[(3R)-6-Hydroxy-2,3-dihydro-1-benzofuran-3-yl]acetic acid (R)-2-amino-1,1-diphenylpropan-1-ol salt (100 g) and sulfuric acid (30.26 g) were added to methanol (120 mL), and the mixture was stirred at 60° C. for 2 hr. After allowing to cool to room temperature, the solvent was concentrated under reduced pressure. To the residue were added toluene (831 mL), tetrahydrofuran (415 mL) and 1M hydrochloric acid (500 mL), and the mixture was partitioned. The organic layer was washed with water (500 mL), 5% aqueous sodium hydrogen carbonate solution (500 mL) and water (500 mL). The organic layer was concentrated, and toluene (110 mL) was added to the residue. The mixture was heated to 50° C., dissolved, allowed to cool to room temperature, and solid precipitation was confirmed. Normal heptane (220 mL) was added, and the mixture was stirred at room temperature for 5 hr. After cooling to 5° C., the solid was collected by filtration, washed with a mixed solution (1:2, 24 mL) of toluene-normal heptane. The solid was dried at 50° C. under reduced pressure to give the title compound (45.19 g). 99.6% ee.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:20][CH:19]([OH:21])[CH2:18]3)=[O:16])[CH2:12][CH:11]([C:22](O)=[O:23])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.O[N:38]=[C:39]([O:41][CH2:42][CH3:43])[NH2:40]>CN(C=O)C.O1CCOCC1>[CH2:42]([O:41][C:39]1[N:40]=[C:22]([CH:11]2[CH2:10][CH:9]([C:6]3[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][CH:7]=3)[CH2:14][N:13]([C:15]([N:17]3[CH2:20][CH:19]([OH:21])[CH2:18]3)=[O:16])[CH2:12]2)[O:23][N:38]=1)[CH3:43]
Reactant: CCOC(N)=NO
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CC(O)C3)C2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CCOc1noc(C2CC(c3ccc(CC)cc3)CN(C(=O)N3CC(O)C3)C2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 80.0 mg (0.241 mmol) of the carboxylic acid from Example 14A in 0.97 ml of DMF and 1.93 ml of 1,4-dioxane were added, at 60° C., 99.8 mg (0.615 mmol) of 1,1′-carbonyldiimidazole, and the mixture was stirred for 3 h. Subsequently, the mixture was admixed with 50.1 mg (0.481 mmol) of ethyl N′-hydroxyimidocarbamate [G. Zinner, G. Nebel, Arch. Pharm. 1970, 303, 385-390] and then stirred at RT for 2 h and then at 120° C. for 2.5 h. The reaction solution was concentrated under reduced pressure and purified directly by means of preparative HPLC. Yield: 33.1 mg (33% of theory)
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].[CH2:10]([N:12](CC)CC)C.CN.C1COCC1>ClCCl>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][S:6]([NH:12][CH3:10])(=[O:8])=[O:7]
Reactant: CCN(CC)CC
Reactant: O=S(=O)(Cl)CCCCCl
Agent: CN
Solvent: C1CCOC1
Solvent: ClCCl
Product: CNS(=O)(=O)CCCCCl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-chlorobutane-1-sulfonyl chloride (117 mmol) and triethyl amine (117 mmol) in dichloro methane (250 ml) at 0° C. was added a 2M solution of methyl amine in THF (117 mmol) dropwise. The mixture was allowed to warm to room temperature with stirring overnight. The organic solution was washed with H2O and extracted with CH2Cl2, dried over MgSO4 and filtered. The solution was concentrated. The product was used without further purification.