Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:17][C:18]([CH3:26])([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:19])=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:27]2[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[C:29](F)[CH:28]=2)[N:3]=1.CCO.CCN(C(C)C)C(C)C.[NH2:48][NH2:49]>CO>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:17][C:18]([CH3:26])([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:19])=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:27]2[CH:28]=[C:29]3[C:30]([C:33]([NH2:34])=[N:48][NH:49]3)=[CH:31][CH:32]=2)[N:3]=1
Reactant: NN
Reactant: C[C@@H]1CC[C@H](C(=O)NC(C)(C)c2ccccc2)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Solvent: CO
Product: C[C@@H]1CC[C@H](C(=O)NC(C)(C)c2ccccc2)CN1c1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Temperature: 110 °C
Reaction time: 8 h
Yield: 44.3 %

Procedure:
Into a sealable tube, (3S,6R)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-6-methyl-N-(1-methyl-1-phenylethyl)-3-piperidinecarboxamide (222 mg, 0.47 mmol), EtOH (5 mL), Hunig's base (0.082 ml, 0.47 mmol), and hydrazine anhydrous (0.089 mL, 2.82 mmol) were added, and the yellow suspension mixture was heated overnight at 110° C. in an oil bath. When the temperature of the reaction reached to 100° C., the solid in the mixture was all dissolved. After overnight, there was a yellow solution as well as a little amount of black colored solid formed. LCMS showed mainly product. CH3OH (5 mL) was added to the solution. The black solid was filtered from the yellow solution. Water (20 mL) was added to the yellow solution, and a solid was formed. The solid was filtered, washed by water, and dried in vacuum. The solid was recrystallized from CH3CN, and the solid was filtered, washed by CH3CN, and dried in vacuum to afford the title compound (101 mg) as a light yellow solid. LC-MS (ES) m/z=485 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.11 (d, J=6.6 Hz, 3H), 1.53 (s, 3H), 1.62 (s, 3H), 1.71 (m, 4H), 2.32-2.44 (m, 2H), 2.84 (m, 1H), 5.38 (s, 2H), 6.09 (s, 2H), 6.57 (s, 1H), 7.11-7.22 (m, 1H), 7.30-7.42 (m, 4H), 7.52-7.60 (m, 1H), 7.71 (d, J=8.3 Hz, 1H), 7.94 (s, 1H), 8.16 (s, 1H), 11.50 (s, 1H).
Reaction SMILES: C([O:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]2[C:14]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)=[C:15](Br)[CH:16]=[N:17][C:10]=2[N:9]([CH3:27])[C:8]1=[O:28])=O.[F:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.CCO.CC(=O)OCC.O.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>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][C:14]2[C:11]3[C:12](=[O:13])[N:7]([CH2:6][CH2:5][CH2:4][OH:3])[C:8](=[O:28])[N:9]([CH3:27])[C:10]=3[N:17]=[CH:16][C:15]=2[C:34]2[CH:33]=[CH:32][CH:31]=[C:30]([F:29])[CH:35]=2)=[CH:21][CH:22]=1
Reactant: Cn1c(=O)n(CCCOC=O)c(=O)c2c(Cc3ccc(Cl)cc3)c(Br)cnc21
Reactant: OB(O)c1cccc(F)c1
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: O
Solvent: C1CCOC1
Solvent: CCO
Product: Cn1c(=O)n(CCCO)c(=O)c2c(Cc3ccc(Cl)cc3)c(-c3cccc(F)c3)cnc21
Temperature: 100 °C
Yield: 73.4 %

Procedure:
To a solution of 3-(6-bromo-5-(4-chlorobenzyl)-1-methyl-2,4-dioxo-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)propyl formate (70 mg, 0.15 mmol), 3-fluorophenylboronic acid (31 mg, 0.22 mmol), Na2CO3(0.6 ml) in THF (3.2 mL) and EtOH (1.6 mL) was added Pd(PPh3)4 (25 mg, 0.015 mmol). The reaction was heated at 100° C. for 18 h, cooled to RT then diluted with EA (20 mL) and water (20 mL). The organic layer was dried over Na2SO4, and concentrated to a residue which was purified by Prep HPLC to give 5-(4-chlorobenzyl)-6-(3-fluorophenyl)-3-(3-hydroxy propyl)-1-methylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (50 mg, 85% yield) as white solid. 1H NMR (CDCl3) δ: 8.53 (s, 1H), 7.36 (dd, J=8.0, 6.0 Hz, 1H), 7.19-7.06 (m, 3H), 6.97-6.86 (m, 2H), 6.77 (d, J=8.3 Hz, 2H), 4.63 (s, 2H), 4.19 (t, J=6.1 Hz, 2H), 3.78 (s, 3H), 3.47 (dd, J=11.7, 6.1 Hz, 2H), 2.92 (t, J=6.9 Hz, 1H), 1.96-1.77 (m, 2H). LCMS: MH+ 454 and TR=3.00 min.
Reaction SMILES: [NH2:1][C:2]1[C:12]([Br:13])=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=1.CO[CH:16](OC)[CH2:17]Br.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Li+].[Cl-]>CN(C)C=O>[Br:13][C:12]1[C:2]2[N:3]([CH:16]=[CH:17][N:1]=2)[CH:4]=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:11]=1
Reactant: CCOC(=O)c1cnc(N)c(Br)c1
Reactant: COC(CBr)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(Br)c2nccn2c1
Temperature: 90 °C
Reaction time: 18 h

Procedure:
To a solution of ethyl 6-amino-5-bromonicotinate (5.0 g, 20.4 mmol) in N,N-dimethylformamide (204 mL) were added bromoacetaldehyde dimethylacetal (3.45 g, 20.4 mmol) and p-toluenesulfonic acid (0.53 g, 3.1 mmol). The mixture was heated to 90° C. After 18 h, additional bromoacetaldehyde dimethylacetal (3.45 g, 20.4 mmol) and 4A° molecular sieves were added. The mixture was stirred at 90° C. for another 24 h. The mixture was warmed to ambient temperature and aqueous LiCl (3.0 M) was added. The mixture was extracted with ethyl acetate (3×). The combined organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. There was still some DMF in the crude product. Water was added and the mixture was extracted with t-butyl methyl ether, washed with brine, dried over sodium sulfate, filtered and concentrated. The mixture was carried on to the next step: LC-MS [M]=269.0.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:35][CH2:36][CH2:37][NH:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=2)=[C:4]2[O:9][CH2:8][C@H:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:6]3[CH:16]=[C:17]([C:32]([OH:34])=[O:33])[C:18](=[O:31])[C:19]([C:20]=1[NH:21]CC1C=CC(OC)=CC=1)=[C:5]23.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:21][C:20]1[C:19]2[C:18](=[O:31])[C:17]([C:32]([OH:34])=[O:33])=[CH:16][N:6]3[C@@H:7]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)[CH2:8][O:9][C:4]([C:5]=23)=[C:3]([NH:35][CH2:36][CH2:37][NH:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=2)[C:2]=1[F:1]
Reactant: COc1ccc(CNc2c(F)c(NCCNc3ccccn3)c3c4c2c(=O)c(C(=O)O)cn4[C@@H](c2ccccc2)CO3)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1c(F)c(NCCNc2ccccn2)c2c3c1c(=O)c(C(=O)O)cn3[C@@H](c1ccccc1)CO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.5 %

Procedure:
To a solution of (S)-9-fluoro-2,3-dihydro-8-(4-methoxybenzylamino)-7-oxo-3-phenyl-10-[2-(2-pyridylamino)ethylamino]-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid (355 mg, 0.596 mmol) in CH2Cl2 (4 mL) was added TFA (2.0 mL, 26.9 mmol) at 0° C. and the mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo. The solution of the residue in DMSO (3 mL) was added water and 2M aq. NaOH was added to adjust pH=7. A precipitate formed and was collected by filtration. The cake was added to EtOH (10 mL), and boiled on water-bath. A precipitate was collected by and then dried to give (S)-8-amino-9-fluoro-2,3-dihydro-7-oxo-3-phenyl-10-[2-(2-pyridylamino)ethylamino]-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid (163 mg, 58%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[C:6]([OH:8])=O.[NH2:18][C:19]1[C:24](O)=[CH:23][CH:22]=[C:21]([CH3:26])[CH:20]=1.C[Si](OP(=O)=O)(C)C.C([O-])(O)=O.[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]2[O:8][C:24]3[CH:23]=[CH:22][C:21]([CH3:26])=[CH:20][C:19]=3[N:18]=2)[CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: COc1cc(C(=O)O)ccc1-c1ccccn1
Reactant: Cc1ccc(O)c(N)c1
Agent: C[Si](C)(C)OP(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: COc1cc(-c2nc3cc(C)ccc3o2)ccc1-c1ccccn1

Procedure:
3-Methoxy-4-pyridin-2-yl benzoic acid (490 mg, 2.1 mmol), 2-amino-p-cresol (527 mg, 4.28 mmol) and trimethylsilyl polyphosphate (2 mL) was refluxed overnight under argon. Added water (100 mL) to the cooled reaction mixture and basified to pH 8 (solid NaHCO3). Extracted with EtOAc (3×60 mL), dried (Na2SO4) and concentrated in vacuo. The resulting yellow residue was purified by flash chromatography using a gradient elution of 1:9 EtOAc:hexanes to 1:4 EtOAc:hexanes to give the desired compound, 2-(3-methoxy-4-pyridin-2-ylphenyl)-5-methyl-1,3-benzoxazole, as a yellow solid. 1H NMR (CDCl3, 300 MHz) δ 8.74 (m, 1H), 7.98–7.16 (m, 10H), 4.03 (s, 3H), 2.51 (s, 3H). (ESI) 317 (M+H)+.
Reaction SMILES: S1[CH:5]=[CH:4][C:3]([CH2:6][CH:7]=[O:8])=[CH:2]1.[Br:9][C:10]1C=C(C(O)C)C=C[CH:15]=1>C(Cl)Cl.CCOCC>[Br:9][C:10]1[CH:2]=[C:3]([CH2:6][CH:7]=[O:8])[CH:4]=[CH:5][CH:15]=1
Reactant: CC(O)c1cccc(Br)c1
Reactant: O=CCc1ccsc1
Solvent: CCOCC
Solvent: ClCCl
Product: O=CCc1cccc(Br)c1

Procedure:
The title compound is prepared as described in Example 12 (Procedure B) for 3-thiophenylacetaldehyde but using 3-bromophenyl-ethanol. The title compound: ES-MS: 196.9 [M-2]−; single peak at tR=3.89 min (System 2); Rf=0.66 (CH2Cl2/Et2O, 95/5).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[C:6]([CH3:11])[CH:5]=2.C([Li])CCC.Br[CH2:18][C:19]([O:21][CH3:22])=[O:20].Cl>C1COCC1.CCCCCC.CCOCC.[Cl-].[Cl-].[Zn+2].CCOC(C)=O>[CH3:22][O:21][C:19](=[O:20])[CH2:18][C:10]1[C:9]2[C:4](=[CH:5][C:6]([CH3:11])=[CH:7][CH:8]=2)[NH:3][C:2]=1[CH3:1]
Reactant: COC(=O)CBr
Reactant: Cc1ccc2cc(C)[nH]c2c1
Agent: Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COC(=O)Cc1c(C)[nH]c2cc(C)ccc12
Reaction time: 0.25 h
Yield: 73 %

Procedure:
To a cooled solution of 2.9 g (0.02 mol) of 2,6-dimethyl-1H-indole in 40 ml of THF was added 12.5 mL (0.02 mol) of a 1.6M solution of n-butyl lithium in hexane keeping the temperature below 10° C. with an ice-ethanol bath. After 0.25 hours, 20.0 ml (0.0277 mol) of a 1M solution of ZnCl2 in ether was added. The cooling bath was removed and the mixture stirred for 2 hours, then concentrated at reduced pressure to a wax which was dissolved in 40 ml of toluene. To this solution was added 1.89 ml (0.02 mol) of methyl 2-bromoacetate, the mixture was stirred 24 hours and poured into 100 ml of 1N HCl and 100 ml of EtOAc. The organic layer was washed twice with water, dried (Na2SO4), and concentrated at reduced pressure. The residue was chromatographed on silica and eluted with 10% EtOAc/toluene to give 3.17 g (73%) of 2,6-dimethyl-1H-indole-3-acetic acid methyl ester as an oil.
Reaction SMILES: [CH3:1][CH2:2][C@@H:3]1[NH:46][C:44](=[O:45])[C@H:43]([C@H:47]([OH:54])[C@@H:48]([CH2:50]/[CH:51]=[CH:52]/[CH3:53])[CH3:49])[N:42]([CH3:55])[C:40](=[O:41])[C@H:39]([CH:56]([CH3:58])[CH3:57])[N:38]([CH3:59])[C:36](=[O:37])[C@H:35]([CH2:60][CH:61]([CH3:63])[CH3:62])[N:34]([CH3:64])[C:32](=[O:33])[C@H:31]([CH2:65][CH:66]([CH3:68])[CH3:67])[N:30]([CH3:69])[C:28](=[O:29])[C@@H:27]([CH3:70])[NH:26][C:24](=[O:25])[C@H:23]([CH3:71])[NH:22][C:20](=[O:21])[C@H:19]([CH2:72][CH:73]([CH3:75])[CH3:74])[N:18]([CH3:76])[C:16](=[O:17])[C@H:15]([CH:77]([CH3:79])[CH3:78])[NH:14][C:12](=[O:13])[C@H:11]([CH2:80][CH:81]([CH3:83])[CH3:82])[N:10]([CH3:84])[C:8](=[O:9])[CH2:7][N:6]([CH3:85])[C:4]1=[O:5].[C:86]([O:89]C(=O)C)(=[O:88])[CH3:87].C(N(CC)CC)C.CN(C1C=CC=CN=1)C>O1CCCC1>[CH3:1][CH2:2][C@@H:3]1[NH:46][C:44](=[O:45])[C@H:43]([C@H:47]([OH:54])[C@@H:48]([CH2:50]/[CH:51]=[CH:52]/[CH3:53])[CH3:49])[N:42]([CH3:55])[C:40](=[O:41])[C@H:39]([CH:56]([CH3:57])[CH3:58])[N:38]([CH3:59])[C:36](=[O:37])[C@H:35]([CH2:60][CH:61]([CH3:62])[CH3:63])[N:34]([CH3:64])[C:32](=[O:33])[C@H:31]([CH2:65][CH:66]([CH3:68])[CH3:67])[N:30]([CH3:69])[C:28](=[O:29])[C@@H:27]([CH3:70])[NH:26][C:24](=[O:25])[C@H:23]([CH3:71])[NH:22][C:20](=[O:21])[C@H:19]([CH2:72][CH:73]([CH3:75])[CH3:74])[N:18]([CH3:76])[C:16](=[O:17])[C@H:15]([CH:77]([CH3:79])[CH3:78])[NH:14][C:12](=[O:13])[C@H:11]([CH2:80][CH:81]([CH3:83])[CH3:82])[N:10]([CH3:84])[C:8](=[O:9])[CH2:7][N:6]([CH3:85])[C:4]1=[O:5].[C:86]([O-:89])(=[O:88])[CH3:87]
Reactant: CC(=O)OC(C)=O
Agent: C/C=C/C[C@@H](C)[C@@H](O)[C@H]1C(=O)N[C@@H](CC)C(=O)N(C)CC(=O)N(C)[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N(C)[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@H](C)C(=O)N(C)[C@@H](CC(C)C)C(=O)N(C)[C@@H](CC(C)C)C(=O)N(C)[C@@H](C(C)C)C(=O)N1C
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)[O-]

Procedure:
To a stirred solution of 3.6 g (30 mmol) of cyclosporin A in 100 ml tetrahydrofuran were added 1.5 equivalents of acetic anhydride, 1.5 equivalents of triethylamine, and 0.3 g of dimethylaminopyridine. The mixture was refluxed for 18 hours. The solvent was evaporated under reduced pressure and the residue was dissolved in ethyl acetate, washed sequentially with 1N hydrochloric acid solution, water, dried over MgSO4 and evaporated. The crude product was chromatographed to give a title compound of 3.2 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:22](=[O:23])[N:21]([CH3:24])[C:12]2[N:13]=[C:14](S(C)(=O)=O)[N:15]=[CH:16][C:11]=2[CH:10]=1.[CH3:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:22](=[O:23])[N:21]([CH3:24])[C:12]2=[N:13][CH2:14][N:15]([NH:30][C:29]3[CH:31]=[CH:32][C:26]([CH3:25])=[CH:27][CH:28]=3)[CH:16]=[C:11]2[CH:10]=1
Reactant: Cn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(S(C)(=O)=O)nc21
Reactant: Cc1ccc(N)cc1
Product: Cc1ccc(NN2C=c3cc(-c4c(Cl)cccc4Cl)c(=O)n(C)c3=NC2)cc1
Temperature: 180 °C

Procedure:
A mixture of 0.113 g (0.29 mmol) of 6-(2,6-dichlorophenyl)-2-methanesulfonyl-8-methyl-8H-pyrido[2,3-d]pyrimidin-7-one of Example 39 and 0.50 g (4.70 mmol) of 4-methylaniline was heated, with stirring, in a 180° C. oil bath. The resulting solution was heated for 10 minutes. Much of the excess 4-methylaniline was evaporated at reduced pressure. The remainder was dissolved in 1 mL of ethyl acetate. The crystals that separated from the dark solution were filtered and washed with 2 mL of ethyl acetate and then ether; wt 0.111 g. Recrystallization from ethyl acetate gave pure product; wt 0.050 g; mp 243°-245° C.
Reaction SMILES: C([NH:4][C:5]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:20][CH:19]=1)(C(OCC)=O)[C:6]([O:8]CC)=[O:7])(=O)C.[OH-].[Na+]>>[NH2:4][CH:5]([CH2:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:22][CH:23]=1)[C:6]([OH:8])=[O:7]
Reactant: CCCCCCCCc1ccc(CCC(NC(C)=O)(C(=O)OCC)C(=O)OCC)cc1
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCc1ccc(CCC(N)C(=O)O)cc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 99.8 %

Procedure:
A mixture of 13.25 g (30.6 mmol) of diethyl 2-acetamido-2-(2-(4-octylphenyl)ethyl)propandioate (prepared according to the procedure described by Durand, et.al., Synthesis, 2000, 505-506, which is hereby incorporated by reference in its entirety) and 75 mL of concentrated HCL were stirred at 100° C. for 16 h. The mixture was cooled and 75 g of ice was added. The mixture was neutralized (pH=7) with 5 N NaOH. The precipitate was filtered, rinsed with water and dried to afford 8.9 g of the title compound: HPLC B: 2.68 min; ESI-MS 292 (M+H).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([NH:9][C:10]2[N:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]([CH:19]3[CH2:21][CH2:20]3)=[O:18])[CH:11]=2)[C:6](=[O:22])[N:5]2[C:23]3([CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[NH:24][C:25](=[O:26])[C:4]=12)=[O:2]>CO.O1CCCC1.[BH4-].[Na+].O>[OH:2][CH2:1][C:3]1[CH:8]=[C:7]([NH:9][C:10]2[N:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]([CH:19]3[CH2:20][CH2:21]3)=[O:18])[CH:11]=2)[C:6](=[O:22])[N:5]2[C:23]3([CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[NH:24][C:25](=[O:26])[C:4]=12
Reactant: O=Cc1cc(Nc2cc(NC(=O)C3CC3)ncn2)c(=O)n2c1C(=O)NC21CCCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C1NC2(CCCCC2)n2c1c(CO)cc(Nc1cc(NC(=O)C3CC3)ncn1)c2=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred solution of N-(6-((8′-formyl-1′,5′-dioxo-1′,5′-dihydro-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridin]-6′-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide (1.2 g, 2.85 mmol) in methanol/tetrahydrofuran (1:2, 30 mL), sodium borohydride was added portion wise at 0° C. The reaction mass was stirred at 0° C. for 2 h. After completion, the reaction mixture was diluted with water (100 mL) and the mixture was extracted with 10% methanol in dichloromethane (2×50 mL). The organics were then separated and dried (magnesium sulfate) and concentrated to dryness under vacuum to afford N-(6-((8′-(hydroxymethyl)-1′,5′-dioxo-1′,5′-dihydro-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridin]-6′-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide (5) as brown solid. Yield: 0.7 g, 62%; MS (ESI) m/z 423.43 [M−1]−; 1H NMR (400 MHz, DMSO-d6) δ 10.86 (s, 1H), 10.24-10.18 (m, 1H), 8.71-8.62 (m, 1H), 8.56-8.52 (m, 1H), 7.84 (s, 1H), 6.13-5.33 (m, 1H), 4.47-4.33 (m, 3H), 3.16-2.84 (m, 4H), 2.01-1.86 (m, 2H), 1.72-1.66 (m, 5H), 1.43-1.40 (m, 2H), 1.34-1.16 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][CH:13]([F:28])[C:14]1[N:19]=[CH:18][C:17]([CH:20]([CH2:23][C:24]2([F:27])[CH2:26][CH2:25]2)[CH2:21][NH2:22])=[CH:16][N:15]=1>>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH:22][CH2:21][CH:20]([C:17]1[CH:18]=[N:19][C:14]([CH:13]([F:28])[F:12])=[N:15][CH:16]=1)[CH2:23][C:24]1([F:27])[CH2:26][CH2:25]1)=[O:6]
Reactant: NCC(CC1(F)CC1)c1cnc(C(F)F)nc1
Reactant: O=C(O)c1ccc(Cl)cc1Cl
Product: O=C(NCC(CC1(F)CC1)c1cnc(C(F)F)nc1)c1ccc(Cl)cc1Cl

Procedure:
The racemic mixture which was prepared in a similar manner to example 3a from 2,4-dichlorobenzoic acid and 2-(2-(difluoromethyl)pyrimidin-5-yl)-3-(1-fluorocyclopropyl)propan-1-amine was separated into the two enantiomers by preparative SFC to yield the title compound. LCMS (MH+): m/z=418.1, tR (minutes, Method F)=2.93. [α]D20=25.40 (c=3.42 mg/mL,CHCl3)
Reaction SMILES: [C:1]1([NH:7][NH:8][C:9]([NH2:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:12](O)=O.S(=O)(=O)(O)O>O>[C:1]1([N:7]2[CH:12]=[N:11][C:9]([OH:10])=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=CO
Reactant: NC(=O)NNc1ccccc1
Agent: O=S(=O)(O)O
Solvent: O
Product: Oc1ncn(-c2ccccc2)n1

Procedure:
151 g of 1-phenyl semicarbazide, 135.3 g (2.5 mols) of 85% formic acid (technical) and 25 g (0.25 mol) of concentrated sulfuric acid were stirred for six hours at 95° to 100° C. The viscous mass obtained was diluted with 400 ml of water and cooled. The precipitate consisting of 1-phenyl-1,2,4-triazolone-3 was filtered off and washed neutral with water. Drying at 100° C. and 200 mbar gave 145.5 g=90.3% of the theory, of 1-phenyl-1,2,4-triazolone-3 having a melting point of 285° to 286° C. ##STR2##
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:19]4[CH:27]=[C:26]([C:28]5[O:29][C:30]([C:33]67OCC(C)(C[O:38]6)C[O:34]7)=[CH:31][CH:32]=5)[N:25]=[CH:24][C:20]=4[N:21]=[CH:22][N:23]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:42]>C1COCC1.O>[ClH:42].[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:19]4[CH:27]=[C:26]([C:28]5[O:29][C:30]([C:33]([OH:38])=[O:34])=[CH:31][CH:32]=5)[N:25]=[CH:24][C:20]=4[N:21]=[CH:22][N:23]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC12COC(c3ccc(-c4cc5c(Nc6ccc7c(cnn7Cc7ccccc7)c6)ncnc5cn4)o3)(OC1)OC2
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(-c2cc3c(Nc4ccc5c(cnn5Cc5ccccc5)c4)ncnc3cn2)o1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
(1-Benzylindazol-5-yl)-(6-(5-(4-methyl-2,6,7-trioxa-bicyclo[2,2,2]oct-1-yl)-furan-2-yl]-pyrido-[3,4-d]pyrimidin-4-yl)-amine (0.445 g, 0.81 mmol) was suspended in a mixture of THF (15 ml) and dilute HCl (15 ml) and stirred at room temperature for 18 hours. The mixture was diluted with water to preciptate the intermediate (partial hydrolysis) which was collected by filtration and washed with water. This solid was suspended in a mixture of THF (10 ml) and NaOH (1M, 10 ml) and stirred at room tmperature for 18 hours. The THF was removed in vacuo and the residue was acidified to pH1 with dilute HCl to give the product as an orange solid, which was collected by filtration (0.322 g, 0.645 mmol, 79%); δH [2H6]DMSO 10.63(1H,s), 9.19(1H,s), 8.89(1H,s), 8.64 (1H,s), 8.17-8.22 (2H,m), 7.67-7.80 (2H,m), 7.46 (1H,s), 7.23-7.39 (6H,m), 5.70 (2H,s); m/z (M+1+) 463.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[CH:10]([OH:13])[CH:11]=[CH2:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].CO[C:23]([CH3:25])=[CH2:24].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C(=O)(O)[O-].[Na+]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH:9]([CH2:14][CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]2)[CH:10]([CH:11]=[CH2:12])[O:13][C:23]1([CH3:25])[CH3:24])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=CC(O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Reactant: C=C(C)OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C=CC1OC(C)(C)N(C(=O)OC(C)(C)C)C1CC1CCCCC1
Reaction time: 1 h
Yield: 124.9 %

Procedure:
The procedure of S. Thaisrivong (J. Med. Chem. 1987, 30, 976) was employed. A solution of 40 g of the resultant compound of Example 17 and 102 g of 2-methoxypropene in 250 ml of dichloromethane was stirred at room temperature. Solid pyridinium p-toluenesulfonate (PPTS) (177 g) was added slowly to the reaction mixture. After addition was complete, the reaction was stirred for 1 h and neutralized by addition of solid sodium bicarbonate. The solids were filtered and the filtrate was concentrated. Flash chromatography on silica gel gave 57 g of the desired compound. IR (CDCl3) 1690 (C=O carbamate) cm-1 ; 1H NMR (CDCl3) δ5.95 (m,1H), 5.32 (m,1H), 5.20 (dt,1H), 4.27 (dd,1H), 1.47 (s,9H).
Reaction SMILES: [NH2:1][C:2]1[N:28]=[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[CH:12]=[C:13]([NH:18][C:19]([C:21]4[N:25]([CH3:26])[N:24]=[C:23]([CH3:27])[CH:22]=4)=[O:20])[CH:14]=[C:15]([CH3:17])[CH:16]=3)=[CH:9][N:4]2[N:3]=1.[CH:29]1([C:32](Cl)=[O:33])[CH2:31][CH2:30]1>CN(C)C(=O)C>[CH:29]1([C:32]([NH:1][C:2]2[N:28]=[C:5]3[CH:6]=[CH:7][C:8]([O:10][C:11]4[CH:12]=[C:13]([NH:18][C:19]([C:21]5[N:25]([CH3:26])[N:24]=[C:23]([CH3:27])[CH:22]=5)=[O:20])[CH:14]=[C:15]([CH3:17])[CH:16]=4)=[CH:9][N:4]3[N:3]=2)=[O:33])[CH2:31][CH2:30]1
Reactant: O=C(Cl)C1CC1
Reactant: Cc1cc(NC(=O)c2cc(C)nn2C)cc(Oc2ccc3nc(N)nn3c2)c1
Solvent: CC(=O)N(C)C
Product: Cc1cc(NC(=O)c2cc(C)nn2C)cc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Yield: 52.6 %

Procedure:
In the same manner as in Example 28-2 and using N-{3-[(2-amino[1,2,4]triazolo[1,5-a]pyridin-6-yl)oxy]-5-methylphenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide (303 mg, 0.803 mmol), cyclopropanecarbonyl chloride (74.0 μL, 0.815 mmol) and N,N-dimethylacetamide (10 mL) as starting materials, the title compound (188 mg, 53%) was obtained as a white solid.
Reaction SMILES: CS(O[CH2:6][C:7]1[N:12]=[CH:11][C:10]2[N:13]=[CH:14][N:15]([C:16]3[S:17][C:18]([C:34](=[O:36])[NH2:35])=[C:19]([O:21][C@@H:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]([F:33])([F:32])[F:31])[CH3:23])[CH:20]=3)[C:9]=2[CH:8]=1)(=O)=O.[C:37]1([CH:43]([N:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[CH3:44])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>ClCCl>[C:37]1([CH:43]([N:45]2[CH2:46][CH2:47][N:48]([CH2:6][C:7]3[N:12]=[CH:11][C:10]4[N:13]=[CH:14][N:15]([C:16]5[S:17][C:18]([C:34]([NH2:35])=[O:36])=[C:19]([O:21][C@@H:22]([C:24]6[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=6[C:30]([F:31])([F:32])[F:33])[CH3:23])[CH:20]=5)[C:9]=4[CH:8]=3)[CH2:49][CH2:50]2)[CH3:44])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CC(c1ccccc1)N1CCNCC1
Reactant: C[C@@H](Oc1cc(-n2cnc3cnc(COS(C)(=O)=O)cc32)sc1C(N)=O)c1ccccc1C(F)(F)F
Solvent: ClCCl
Product: CC(c1ccccc1)N1CCN(Cc2cc3c(cn2)ncn3-c2cc(O[C@H](C)c3ccccc3C(F)(F)F)c(C(N)=O)s2)CC1

Procedure:
In a similar manner as described for example 58, 108 mg of [1-(5-carbamoyl-4-{(1R)-1-[2-(trifluoromethyl)phenyl]ethoxy}-2-thienyl)-1H-imidazo[4,5-c]pyridin-6-yl]methyl methanesulfonate and 190.3 mg of 1-(1-phenylethyl)piperazine in 2.5 ml dichloromethane give the title compound.