Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([N:14]3[CH2:20][CH:19]4[O:21][CH:16]([CH2:17][CH2:18]4)[CH2:15]3)[N:11]=[C:10]([C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][CH3:32])=[O:30])=[CH:24][CH:23]=3)[N:9]=2)=[CH:4][CH:3]=1.[N:33]1[CH:38]=[CH:37][C:36]([NH:39][C:40](=O)[O:41]C2C=CC=CC=2)=[CH:35][CH:34]=1>>[CH3:32][NH:31][C:29]([NH:28][C:25]1[CH:26]=[CH:27][C:22]([C:10]2[N:11]=[C:12]([N:14]3[CH2:20][CH:19]4[O:21][CH:16]([CH2:17][CH2:18]4)[CH2:15]3)[N:13]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:40](=[O:41])[NH:39][C:36]4[CH:37]=[CH:38][N:33]=[CH:34][CH:35]=4)=[CH:7][CH:6]=3)[N:9]=2)=[CH:23][CH:24]=1)=[O:30]
Reactant: CNC(=O)Nc1ccc(-c2nc(-c3ccc(N)cc3)nc(N3CC4CCC(C3)O4)n2)cc1
Reactant: O=C(Nc1ccncc1)Oc1ccccc1
Product: CNC(=O)Nc1ccc(-c2nc(-c3ccc(NC(=O)Nc4ccncc4)cc3)nc(N3CC4CCC(C3)O4)n2)cc1
Yield: 4 %

Procedure:
The title compound was prepared by following the procedure of example 462 step 7 using 1-(4-(4-(4-aminophenyl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1,3,5-triazin-2-yl)phenyl)-3-methylurea and phenyl pyridin-4-ylcarbamate. Yield 51 mg, 4% yield.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C@H:8]2[CH2:12][CH2:11][C@@:10]3([CH2:16][CH2:15][N:14]([CH3:17])[C:13]3=[O:18])[NH:9]2)[CH:3]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][C:21]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>CC#N.O.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][C:21]=1[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C@H:8]2[CH2:12][CH2:11][C@@:10]3([CH2:16][CH2:15][N:14]([CH3:17])[C:13]3=[O:18])[NH:9]2)[CH:3]=1
Reactant: CN1CC[C@@]2(CC[C@H](c3cc(Br)ccn3)N2)C1=O
Reactant: OB(O)c1cc(O)ccc1F
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CN1CC[C@@]2(CC[C@H](c3cc(-c4cc(O)ccc4F)ccn3)N2)C1=O
Temperature: 100 °C
Yield: 77.9 %

Procedure:
To a solution of (2R,5S)-2-(4-bromo-2-pyridyl)-7-methyl-1,7-diazaspiro[4.4]nonan-6-one (which may be prepared as described in Description 4) (140 mg, 0.4513 mmol) in MeCN (1.5 mL) and water (0.3000 mL) in a Smith microwave vessel was added (2-fluoro-5-hydroxy-phenyl)boronic acid (0.0774 g, 0.4965 mmol), bis(triphenylphosphine)palladium (II) dichloride (0.0095 g, 0.0135 mmol) and sodium carbonate (0.0957 g, 0.9027 mmol). The reaction vessel was sealed and purged with nitrogen. The reaction mixture was heated by microwave at 100° C. for 40 min. The reaction mixture was treated with water and was extracted with DCM twice and the organic layers were collected by passing down a PhaseSep cartridge. Evaporation of solvents gave an amber oil, It was further purified by silica gel chromatography (11 g KPNH silica cartridge) eluting with ethyl acetate in iso-hexane (20-100%) followed by methanol in ethyl acetate (0-18%) to give the desired product (2R,5S)-2-[4-(2-fluoro-5-hydroxy-phenyl)-2-pyridyl]-7-methyl-1,7-diazaspiro[4.4]nonan-6-one (D134) (0.1200 g, 0.3515 mmol, 77.9% yield) as cream solid;
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([C:15]3[C:16]([NH:32][C:33]4[CH:34]=[N:35][C:36]([O:39][CH3:40])=[N:37][CH:38]=4)=[N:17][CH:18]=[C:19]([CH2:21][N:22]4[CH2:27][CH2:26][N:25]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:24][CH2:23]4)[CH:20]=3)[N:12]=[C:11]([CH3:41])[N:10]=2)=CC=1.FC(F)(F)C(O)=O>FC(F)(F)S(O)(=O)=O>[CH3:40][O:39][C:36]1[N:35]=[CH:34][C:33]([NH:32][C:16]2[C:15]([C:13]3[N:12]=[C:11]([CH3:41])[N:10]=[C:9]([NH2:8])[N:14]=3)=[CH:20][C:19]([CH2:21][N:22]3[CH2:23][CH2:24][N:25]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:26][CH2:27]3)=[CH:18][N:17]=2)=[CH:38][N:37]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(S(C)(=O)=O)CC4)cnc3Nc3cnc(OC)nc3)n2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: COc1ncc(Nc2ncc(CN3CCN(S(C)(=O)=O)CC3)cc2-c2nc(C)nc(N)n2)cn1
Temperature: 80 °C
Yield: 32.4 %

Procedure:
A mixture of N,N-bis(4-methoxybenzyl)-4-(2-(2-methoxypyrimidin-5-ylamino)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (301 mg, 0.414 mmol) in trifluoroacetic acid (638 μL, 8.28 mmol) was treated with a couple of drops of trifluoromethanesulfonic acid and the mixture was heated at 80° C. overnight. After cooling, the mixture was concentrated and the residue was dissolved in 5% (2 M NH3 in MeOH)/DCM (5 mL) and the crude product was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep pre-packed silica gel column (pure DCM→3% MeOH in DCM). The isolated yellow solid was dissolved in DMSO and was subjected to a reversed phase preparative HPLC purification (10% MeCN in H2O to 100% MeCN w/0.10% (v/v) TFA). The product fraction was basified with saturated NaHCO3 (aq), extracted with dichloromethane (3×20 mL) and the combined organic layers were dried over Na2SO4, filtered, and concentrated to give 4-(2-(2-methoxypyrimidin-5-ylamino)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (65 mg, 0.134 mmol, 32.3% yield) as a bright yellow solid. 1H NMR (400 MHz, d6-DMSO) δ 11.78 (s, 1H); 9.03 (s, 2H); 8.73 (d, J=1.56 Hz, 1H); 8.23 (d, J=1.76 Hz, 1H); 7.91 (br. s., 1H); 7.75 (br. s., 1H); 3.91 (s, 3H); 3.50 (s, 2H); 3.11 (br. s., 4H); 2.86 (s, 3H); 2.46-2.49 (m, 4H); 2.44 (s, 3H). m/z (ESI, +ve ion) 486.8 (M+H)+.
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:23]1([CH2:29][CH2:30]Cl)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>CC(C)=O.C(=O)([O-])[O-].[K+].[K+]>[C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:30][CH2:29][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:20][CH:21]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClCCN1CCCCC1
Reactant: Oc1ccc(-c2nc3ccccc3n2-c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: c1ccc(-n2c(-c3ccc(OCCN4CCCCC4)cc3)nc3ccccc32)cc1

Procedure:
The title compound was prepared by reacting the compound of Example 29 with 2-(piperdin-1-yl)ethyl chloride in acetone and potassium carbonate as previously described. mp 107° C., NMR, MS 397.
Reaction SMILES: Br[C:2]1[C:3]([Cl:12])=[N:4][C:5]([O:10][CH3:11])=[N:6][C:7]=1[O:8][CH3:9].[CH:13]1(B(O)O)[CH2:15][CH2:14]1.ClCl.C([O-])([O-])=O.[Na+].[Na+]>[Pd].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].C(OCC)(=O)C.COCCOC>[Cl:12][C:3]1[C:2]([CH:13]2[CH2:15][CH2:14]2)=[C:7]([O:8][CH3:9])[N:6]=[C:5]([O:10][CH3:11])[N:4]=1
Reactant: COc1nc(Cl)c(Br)c(OC)n1
Reactant: OB(O)C1CC1
Agent: [Fe+2]
Agent: [Pd]
Agent: ClCl
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COc1nc(Cl)c(C2CC2)c(OC)n1
Temperature: 130 °C
Yield: 65.2 %

Procedure:
In a 5 mL microwave reaction tube, 5-bromo-4-chloro-2,6-dimethoxy-pyrimidine (116 mg, 0.457 mmol), cyclopropyl boronic acid (47 mg, 0.549 mmol, 1.2 eq.) and Pd(dppf(Cl2 (38 mg, 0.1 eq.) was charged with DME (2.5 mL) and 2M Na2CO3 aqueous solution (0.91 mL, 4 eq.). The reaction was heated at 130° C. in the microwave reactor for 30 minutes. Ethyl acetate was added, followed by washing with brine. The organic layer was concentrated down and purified (silica gel, 0-50% EtOAC/hexane) to give white solid (64 mg, 65%). LC-MS shows 215.1 (M+1). 1H NMR (300 MHz, CDCl3): δ 3.98 (dd, 6H), 1.62 (m, 1H), 0.99 (m, 2H), 0.78 (m, 2H).
Reaction SMILES: O[CH:2]1[C:15]2[CH:14]=[C:13]([CH:16]([CH3:19])[CH2:17][OH:18])[CH:12]=[CH:11][C:10]=2[O:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.I>C(O)(=O)C>[CH:14]1[C:15]2[CH2:2][C:3]3[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=3)[O:9][C:10]=2[CH:11]=[CH:12][C:13]=1[CH:16]([CH3:19])[CH2:17][OH:18]
Reactant: CC(CO)c1ccc2c(c1)C(O)c1ccccc1O2
Agent: I
Solvent: CC(=O)O
Product: CC(CO)c1ccc2c(c1)Cc1ccccc1O2

Procedure:
A mixture of 10 g. of 2-(9-hydroxy-2-xanthenyl)-propanol, 45 ml. of acetic acid, and 20 g. of concentrated hydriodic acid is refluxed for 3 minutes. After removal of the solvent by evaporation, 2-(2-xanthenyl)-propanol is obtained, m.p. 86°-89°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH2:9])[CH:3]=1.[C:10](OCC)(=[O:16])[C:11](OCC)=[O:12]>>[OH:12][C:11]1[C:10]([OH:16])=[N:9][C:4]2[C:5](=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:8]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: Nc1ccc(Cl)cc1N
Product: Oc1nc2ccc(Cl)cc2nc1O
Temperature: 25 °C

Procedure:
A mixture consisting of 100 g. (0.07 mole) of 4-chloro-1,2-phenylenediamine and 750 ml. of diethyl oxalate was refluxed overnight and for a period of approximately 16 hours. Upon completion of this step, the reaction mixture was cooled to room temperature (~20° C.), filtered and the recovered product subsequently washed with ethanol and air-dried to constant weight to ultimately afford 140 g. of pure 2,3-dihydroxy-6-chloroquinoxaline, m.p. >260° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7](=[O:31])[NH:8][C:9]=1[CH2:10][S:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=[C:22]([CH3:30])[CH:21]=2)=[CH:14][CH:13]=1)=[O:4].C1COCC1.CO.[OH2:39].OOS([O-])=O.[K+].C([O-])(O)=O.[Na+].[OH2:51]>>[CH3:1][O:2][C:3]([C:5]1[NH:6][C:7](=[O:31])[NH:8][C:9]=1[CH2:10][S:11]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=[C:22]([CH3:30])[CH:21]=2)=[CH:14][CH:13]=1)(=[O:51])=[O:39])=[O:4]
Reactant: COC(=O)c1[nH]c(=O)[nH]c1CSc1ccc(OCc2cc(C)nc3ccccc23)cc1
Reactant: O
Agent: O=C([O-])O
Agent: O=S([O-])OO
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1[nH]c(=O)[nH]c1CS(=O)(=O)c1ccc(OCc2cc(C)nc3ccccc23)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
To a solution of 4e (11 mg, 0.025 mmol) in 5 mL of a mixture of THF:MeOH:H2O (2:1:2) was added a solution of Oxone® (31 mg, 0.05 mmol) in H2O, buffered with NaHCO3 (0.05 mmol). The solution was stirred at 0° C. for 1 h and filtered. The filtrate was concentrated and purified by flash column chromatography to provide 5-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonylmethyl]-2-oxo-2,3-dihydro-1H-imidazole-4-carboxylic acid methyl ester 4f (10 mg, 85%). MS (ESI+) (M+1)=468.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:10]=[C:11]([NH:33][CH2:34][CH2:35][C:36]([O:38]C(C)(C)C)=[O:37])[CH:12]=[CH:13][C:14]=1[C:15]1[S:16][C:17]2[C:22]([N:23]=1)=[CH:21][CH:20]=[C:19]([C:24]1([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:26][CH2:25]1)[N:18]=2>C(Cl)Cl>[F:8][C:9]1[CH:10]=[C:11]([NH:33][CH2:34][CH2:35][C:36]([OH:38])=[O:37])[CH:12]=[CH:13][C:14]=1[C:15]1[S:16][C:17]2[C:22]([N:23]=1)=[CH:21][CH:20]=[C:19]([C:24]1([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:25][CH2:26]1)[N:18]=2
Reactant: CC(C)(C)OC(=O)CCNc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCNc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
2,2,2-Trifluoroacetic acid (360 μl, 4.67 mmol) was added to a solution of tert-butyl 3-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenylamino)propanoate (46.5 mg, 0.095 mmol) in DCM (2.0 mL) at 25° C., and the resulting solution was stirred at 25° C. for 19 h. The reaction solution was then concentrated in vacuo, and the residue was taken up in DMSO (2.0 mL) and purified by rpHPLC (10-100% CH3CN/water+0.1% TFA) to provide 3-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenylamino)propanoic acid as a yellow solid. MS (ESI) m/z: Calculated: 433.1; Observed: 434.0 (M++1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[C:7]([O:14][CH3:15])[CH:6]=2.[CH3:16][C:17]([CH3:22])([CH2:20]O)[CH:18]=[O:19]>CO>[CH3:13][O:12][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[O:14][CH3:15])[N:4]=[CH:3][C:2]([NH:1][CH2:16][C:17]([CH3:22])([CH3:20])[CH2:18][OH:19])=[CH:11]2
Reactant: CC(C)(C=O)CO
Reactant: COc1cc2cc(N)cnc2cc1OC
Solvent: CO
Product: COc1cc2cc(NCC(C)(C)CO)cnc2cc1OC
Yield: 21.5 %

Procedure:
The reaction is run similar to the preparation in Example 11. To a MeOH solution of 4 Å powdered molecular sieves (0.35 g) under argon is added 3-amino-6,7-dimethoxyquinoline (0.32 g, 1.6 mmol) and 2,2-dimethyl-3-hydroxypropionaldehyde (0.19 g, 1.9 mmol). The product mixture is chromatographed (3% MeOH/CHCl3) to afford 0.10 g of material which is partitioned between CH2Cl2/10% NaOH. The organic layer is washed with 10% NaOH, H2O, and brine, then dried (MgSO4), and recrystallized from EtOAc/hexanes to provide a light-orange solid (m.p. 170-173.5° C.). Anal. Calcd. for C16H22N2O3: C, 66.18; H, 7.64; N, 9.65; Found: C, 66.11; H, 7.49; N, 9.33.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH:14]([C:15]4[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([F:22])[C:16]=4[F:23])[C:13](O)=[CH:12][C:11]3=[O:25])=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH:26]1([NH2:32])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH:14]([C:15]4[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([F:22])[C:16]=4[F:23])[C:13]([NH:32][CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)=[CH:12][C:11]3=[O:25])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C1C=C(O)C(c2cc(F)cc(F)c2F)N1c1ccc2[nH]cnc2c1
Reactant: NC1CCCCC1
Product: O=C1C=C(NC2CCCCC2)C(c2cc(F)cc(F)c2F)N1c1ccc2[nH]cnc2c1

Procedure:
The compound was synthesized starting from 1-(1H-benzo[d]imidazol-5-yl)-4-hydroxy-5-(2,3,5-trifluorophenyl)-1H-pyrrol-2(5H)-one (0.115 g, 0.3 mmol) and cyclohexylamine (0.48 ml, 4.2 mmol) according to method 7 described above.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([Cl:4])=[O:3].[Cl:7][C:8](=[CH2:11])[CH2:9][OH:10].Cl>>[Cl:7][C:8](=[CH2:11])[CH2:9][O:10][C:1](=[O:5])[C:2]([Cl:4])=[O:3]
Reactant: C=C(Cl)CO
Reactant: O=C(Cl)C(=O)Cl
Agent: Cl
Product: C=C(Cl)COC(=O)C(=O)Cl
Temperature: 0 °C
Reaction time: 16 h

Procedure:
Oxalyl chloride (130 ml, 1.49 mol) was placed in a dry 3-neck flask under N2 and cooled to 0° C. With stirring, 2-chloroallyl alcohol (138 g, 1.49 mol) was added dropwise in a manner which maintained the temperature at 0°-2° C. and controlled the vigorous evolution of HCl, then allowed to warm to room temperature and held 16 hours and distilled to yield title product, 214 g, b.p. 82°-84° C./23 mm.
Reaction SMILES: C([O-])=O.[NH4+].[N:5]([CH:8]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[N:16]=2)[C:12]2[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:11]=2[N:10]([CH3:28])[C:9]1=[O:29])=[N+]=[N-]>CO.[Pd]>[NH2:5][CH:8]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[N:16]=2)[C:12]2[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:11]=2[N:10]([CH3:28])[C:9]1=[O:29]
Reactant: COc1cccc(C2=NC(N=[N+]=[N-])C(=O)N(C)c3ccc(Cl)cc32)n1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: COc1cccc(C2=NC(N)C(=O)N(C)c3ccc(Cl)cc32)n1
Reaction time: 0.17 h
Yield: 78.2 %

Procedure:
As illustrated in the scheme above, a suspension of Pd/C (0.005 g of 10% on C) in MeOH (0.5 mL) under N2 was treated with ammonium formate (0.0252 g, 0.400 mmol). The mixture was stirred for 10 min. and then transferred via Pasteur pipette to a suspension of 3-azido-7-chloro-1,3-dihydro-5-(6-methoxy-2-pyridinyl)-1-methyl-2H-1,4-benzodiazepin-2-one (0.0204 g, 0.0572 mmol) in MeOH (1.2 mL). The resulting mixture was stirred at room temperature for 3 h and was then filtered through a small pad of Celite. The filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (100% EtOAc, followed by 4:1 CH2Cl2:EtOAc) to provide the title compound (0.0148 g, 78%). 1H-NMR (CDCl3): δ 7.82 (dd, J=0.8 Hz, J=7.6 Hz, 1H), 7.71-7.66 (m, 2H), 7.51 (dd, 2.4 Hz, J=8.8 Hz, 1H), 7.28 (d, J=8.8 Hz, 1H), 6.83 (dd, J=0.8 Hz, J=8.4 Hz, 1H), 4.56 (s, 1H), 3.80 (s, 3H), 3.44 (s, 3H), 2.53 (br s, 2H). MS (ESI) (M+H)+=331.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12](OCC(F)(F)F)[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:41])[CH2:26][C:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=2)[CH:29]=1)(C)(C)C.[C:43](O)([C:45]([F:48])([F:47])[F:46])=[O:44]>C(Cl)Cl>[N:36]1[CH:37]=[CH:38][CH:39]=[C:34]([C:30]2[CH:29]=[C:28]([C:27]3[CH2:26][C:25](=[O:41])[NH:24][C:9]4[CH:10]=[C:11]([C:20]([F:23])([F:22])[F:21])[C:12]([O:44][CH2:43][C:45]([F:48])([F:47])[F:46])=[CH:13][C:8]=4[N:7]=3)[CH:33]=[CH:32][CH:31]=2)[CH:35]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2cccnc2)c1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-c3cccnc3)c2)=Nc2cc(OCC(F)(F)F)c(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from [2-[3-oxo-3-(3-pyridin-3-yl-phenyl)-propionylamino]-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M27) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a white solid (173 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[NH2:6].[CH:14]1[CH:19]=[CH:18][C:17]([O:20][C:21](OC2C=CC=CC=2)=[N:22][C:23]#[N:24])=[CH:16][CH:15]=1.C(N(CC)CC)C>ClCCl>[C:23]([NH:22][C:21](=[N:6][C:5]1[CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=[C:3]([O:2][CH3:1])[CH:4]=1)[O:20][C:17]1[CH:18]=[CH:19][CH:14]=[CH:15][CH:16]=1)#[N:24]
Reactant: COc1cc(N)cc(C(F)(F)F)c1
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(N=C(NC#N)Oc2ccccc2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 12.3 %

Procedure:
To a solution of 3-methyloxy-5-trifluoromethylaniline (11 mmol, 2.10 g) in dichloromethane (25 ml), diphenylcyanocarbonimidate (10 mmol, 2.38 g) and triethylamine (11 mmol, 1.53 ml) were added. The reaction mixture was stirred under nitrogen for 16 h at room temperature. After concentration the residue was stirred with water, the water was decanted followed by concentration. The residue was purified by flash chromatography (ethyl acetate/heptane 1:2) to give 0.413 g of the title compound (12%); Mp 168.5-169.5° C.; 1H-NMR (CDCl3): δ 3.83 (s, 3H), 7.00 (s, 1H), 7.14 (m, 3H), 7,23 (s, 1H), 7.32 (t, 1H), 7.43 ppm (t, 2H), 8.7 (br s, 1H). EI SP/MS: 335 (M+).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][C:7]([NH2:11])=[N:8][CH:9]=2)[N:4]([CH3:12])[N:3]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=1B(O)O.COCCOC.C([O-])([O-])=O.[Na+].[Na+]>CCOC(C)=O.[O-]S([O-])(=O)=O.[Mg+2].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:19][C:20]=1[C:2]1[C:10]2[C:5](=[N:6][C:7]([NH2:11])=[N:8][CH:9]=2)[N:4]([CH3:12])[N:3]=1
Reactant: Cn1nc(Br)c2cnc(N)nc21
Reactant: COc1ccc(C(F)(F)F)cc1B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COc1ccc(C(F)(F)F)cc1-c1nn(C)c2nc(N)ncc12

Procedure:
3-Bromo-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine (Intermediate 3) (0.1 g, 0.44 mmol), 2-methoxy-5-trifluoromethylphenylboronic acid (0.116 g, 0.53 mmol), Pd(dppf)Cl2 (0.032 g, 0.044 mmol), DME (4 ml) and 2M aqueous Na2CO3, are mixed together and heated using microwave radiation at 100° C. for 30 minutes. The reaction mixture is diluted with EtOAc (30 mls), MgSO4 is added and the resulting mixture is filtered through Celite® (filter agent), washing with EtOAc. The reaction mixture is absorbed onto silica and purification by flash chromatography on silica eluting with DCM then MeOH:DCM (5:95) affords the title compound.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N+:13]([O-])=[CH:12][CH:11]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].C[Si]([C:25]#[N:26])(C)C>C(N(CC)CC)C>[CH2:1]([O:3][P:4]([CH2:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=[C:12]([C:25]#[N:26])[CH:11]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]
Reactant: CCOP(=O)(Cc1cc[n+]([O-])c2ccccc12)OCC
Reactant: C[Si](C)(C)C#N
Solvent: CCN(CC)CC
Product: CCOP(=O)(Cc1cc(C#N)nc2ccccc12)OCC

Procedure:
A mixture of 5.9 g of 4-(diethylphosphonomethyl)-quinoline-N-oxide, 15 ml of trimethylsilyl cyanide and 7 ml of triethylamine is heated at 80° for 1 hour and evaporated to dryness. The residue is purified by chromatography on silica gel using methanol/methylene chloride (5:95) as eluent to yield 4-(diethylphosphonomethyl)-2-cyanoquinoline as an oil.
Reaction SMILES: [OH-].[Li+].C[O:4][C:5]([C:7]1[N:8]=[C:9]([CH2:15][CH:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[NH:10][C:11](=[O:14])[C:12]=1[OH:13])=[O:6]>O.C1COCC1>[C:23]1([CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:15][C:9]2[NH:10][C:11](=[O:14])[C:12]([OH:13])=[C:7]([C:5]([OH:6])=[O:4])[N:8]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)c1nc(CC(c2ccccc2)c2ccccc2)[nH]c(=O)c1O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1nc(CC(c2ccccc2)c2ccccc2)[nH]c(=O)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.6 %

Procedure:
A solution of lithium hydroxide (21.9 mg, 913 μmol) in water (2 ml) was added to a flask containing a stirred solution of 2-(2,2-diphenyl-ethyl)-5-hydroxy-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid methyl ester (0.160 g, 457 μmol) in THF (8 ml). The mixture was stirred at room temperature for 8 h, quenched with 1M HCl, extracted into EtOAc, washed with brine, dried (MgSO4) and evaporated to dryness. Purification by preparative HPLC provided the desired product as a white solid (0.024 g; 15%). LCMS: m/z=337 (MH+).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([N+:20]([O-])=O)=[CH:17][CH:18]=3)[NH:13][N:12]=2)=[O:9])[CH2:4][CH2:3]1>C(O)C.[Pd]>[CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([NH2:20])=[CH:17][CH:18]=3)[NH:13][N:12]=2)=[O:9])[CH2:4][CH2:3]1
Reactant: CC1CCN(C(=O)Oc2n[nH]c3cc([N+](=O)[O-])ccc23)CC1
Agent: [Pd]
Solvent: CCO
Product: CC1CCN(C(=O)Oc2n[nH]c3cc(N)ccc23)CC1

Procedure:
30 mg (0.1 mmol) of 6-nitro-1H-indazol-3-yl 4-methylpiperidine-1-carboxylate (Example 5B) in 15 ml of ethanol were hydrogenated in the presence of 10% palladium/carbon under a hydrogen pressure of 2 bar at room temperature for 2.5 h. The catalyst was filtered off with suction, and the filtrate was concentrated. Yield: 21 mg (76%), M+H+: 275.2.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]=[C:22]2[S:26][C:25](=[O:27])[NH:24][C:23]2=[O:28])=[CH:17][N:16]=1>[C].[Pd].O1CCCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]2[S:26][C:25](=[O:27])[NH:24][C:23]2=[O:28])=[CH:17][N:16]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(C=C2SC(=O)NC2=O)cn1
Agent: [Pd]
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CC2SC(=O)NC2=O)cn1
Reaction time: 6 h
Yield: 51.7 %

Procedure:
A mixture of 5-[[2-(5-methyl-2-phenyl-4-oxazolylmethoxy)-5-pyridyl]methylidene]-2,4-thiazolidinedione (1.00 g), palladium-carbon (5%, 1.00 g) and tetrahydrofuran (80 ml) was subjected to catalytic reduction at room temperature and 1 atom for 6 hours. The catalyst was filtered off, and palladium-carbon (2.00 g) was added and the mixture was further subjected to catalytic reduction at room temperature and 1 atom for 6 hours. The catalyst was filtered off. The filtrate was evaporated under reduced pressure and the residue was subjected to silica gel column chromatography. From the fraction eluted with 2% methanol-chloroform, crystals (520 mg, 52%) of 5-[[2-(5-methyl-2-phenyl-4-oxazolylmethoxy)-5-pyridyl]methyl]-2,4-thiazolidinedione were obtained. Recrystallization from dichloromethane-isopropyl ether gave colorless prisms. Melting point: 151°-152° C.