Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]1[C:14](=[O:15])[C:13]2[NH:12][C:11]([NH2:16])=[N:10][C:9]=2[N:8]([CH2:17][CH2:18][CH2:19][CH3:20])[C:6]1=[O:7])[CH2:2][CH2:3][CH3:4].Cl.C(N(CC)CC)C.[C:29](OC(=O)C)(=[O:31])[CH3:30]>C1(C)C=CC=CC=1>[CH2:1]([N:5]1[C:14](=[O:15])[C:13]2[NH:12][C:11]([NH:16][C:29](=[O:31])[CH3:30])=[N:10][C:9]=2[N:8]([CH2:17][CH2:18][CH2:19][CH3:20])[C:6]1=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)c2[nH]c(N)nc2n(CCCC)c1=O
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCn1c(=O)c2[nH]c(NC(C)=O)nc2n(CCCC)c1=O

Procedure:
1.3-Di-n-butyl-8-amino xanthine (0.5 g), hydrochloride in toluene (30 ml) was stirred for 30 minutes with triethylamine (0.16 g). After addition of acetic anhydride (0.32 g), the mixture was refluxed for 6 hours. The reaction mixture was extracted with water (4×30 ml), the organic layer separated and dried over anhydrous sodium sulphate. The solvent was then evaporated to yield the product, yield 0.1 g (20%), mpt. 180° C.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.[CH2:14]([NH2:17])[CH:15]=[CH2:16]>>[CH2:14]([NH:17][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1)[CH:15]=[CH2:16]
Reactant: N#Cc1ccc(F)cc1C(F)(F)F
Reactant: C=CCN
Product: C=CCNc1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Synthesized as described in Example 1A from 4-fluoro-2-(trifluoromethyl)benzonitrile and allylamine: MS (APCI) m/z 249 ([M+Na]+).
Reaction SMILES: Cl.[CH:2]([N:5]1[CH2:10][CH2:9][N:8]([C:11]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17]([C:22](O)=[O:23])=[CH:16]3)=[O:12])[CH2:7][CH2:6]1)([CH3:4])[CH3:3].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH3:47][S:48]([N:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1)(=[O:50])=[O:49].C(N(CC)C(C)C)(C)C.[Cl-].[NH4+]>CN(C)C=O>[CH:2]([N:5]1[CH2:6][CH2:7][N:8]([C:11]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17]([C:22]([N:54]2[CH2:55][CH2:56][N:51]([S:48]([CH3:47])(=[O:50])=[O:49])[CH2:52][CH2:53]2)=[O:23])=[CH:16]3)=[O:12])[CH2:9][CH2:10]1)([CH3:4])[CH3:3]
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)O)cc3c2)CC1
Reactant: CS(=O)(=O)N1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCN(S(C)(=O)=O)CC4)cc3c2)CC1
Yield: 65.4 %

Procedure:
To a solution of 1.70 g (4.8 mmol) 5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid hydrochloride in 17 mL N,N-dimethylformamide, were added 1.94 g (6.0 mmol) O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate, 1.0 g (6.0 mmol) 1-methylsulfonyl-piperazine and 4.1 mL (3.1 g, 24.0 mmol) N,N-diisopropylethylamine. After 2 h the solution was poured into 10% aqueous ammonium chloride solution, the phases were separated and the aqueous phase was extracted ten times with ethyl acetate. The combined organic layers were washed three times with water, brine, dried over magnesium sulfate, filtered and evaporated. The residue was flash-chromatographed twice on silica gel with dichloromethane:methanol (9:1 v/v) as eluant to give 1.45 g (65%) of the desired compound as a light-brown foam. MS (ISP): 462.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:21][CH3:22])=[C:17]([OH:20])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].C([O-])([O-])=O.[K+].[K+].Cl[CH2:30][CH2:31][CH2:32][N:33]1[CH2:38][C@H:37]2[C@:35]([OH:39])([CH2:36]2)[CH2:34]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:21][CH3:22])=[C:17]([O:20][CH2:30][CH2:31][CH2:32][N:33]4[CH2:38][C@H:37]5[C@:35]([OH:39])([CH2:36]5)[CH2:34]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O[C@]12C[C@H]1CN(CCCCl)C2
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCN1C[C@@H]2C[C@]2(O)C1
Temperature: 80 °C
Yield: 46.7 %

Procedure:
To a mixture of 4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-ol (136 mg, 0.42 mmol, 1.0 eq) and anhydrous K2CO3 (290 mg, 2.10 mmol, 5.0 eq) in DMF (3 mL) was added a solution of (1R,5S)-3-(3-chloropropyl)-3-azabicyclo[3.1.0]hexan-1-ol (92 mg, 0.52 mmol, 1.2 eq) in DMF (2 mL) at rt. The mixture was heated at 80° C. for 7 h, then cooled to room temperature and quenched with H2O (10 mL). The mixture was diluted with EtOAc (20 mL). The water layer was then extracted with EtOAc (5 mL×3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was chromatographed with a silica gel column (10:1 (v/v) CH2Cl2/CH3OH) to give the crude product, which was recrystallized from CH2Cl2/PE to afford the title compound as a pale yellow solid (90 mg, 46.70%), HPLC:91.67%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 459.2 (M+1); 1H NMR (400 MHz, CDCl3) δ: 0.83 (2H, m), 1.09 (1H, t, J=4.8 Hz), 1.36 (1H, m), 2.57 (2H, m), 2.72 (1H, d, J=8.8 Hz), 3.05 (1H, d, J=8.4 Hz), 3.56 (2H, m), 3.80 (2H, m), 3.99 (3H, s), 4.12 (2H, t, J=6.8 Hz), 7.14 (1H, t, J=8.8 Hz), 7.23 (1H, s), 7.29 (1H, d, J=15.8 Hz), 7.60 (1H, m), 7.89 (1H, dd, J=2.5, 6.5 Hz), 8.63 (1H, s) ppm.
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=CC=2)CCC1.C(OC(=O)[NH:36][C:37]1([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[C:56](=[O:57])[C:55]4[C:50](=[CH:51][C:52]([O:58][C:59]([F:62])([F:61])[F:60])=[CH:53][CH:54]=4)[O:49][C:48]=3[C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)=[CH:43][CH:42]=2)[CH2:40][CH2:39][CH2:38]1)(C)(C)C>>[NH2:36][C:37]1([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[C:56](=[O:57])[C:55]4[C:50](=[CH:51][C:52]([O:58][C:59]([F:62])([F:60])[F:61])=[CH:53][CH:54]=4)[O:49][C:48]=3[C:63]3[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=3)=[CH:43][CH:42]=2)[CH2:40][CH2:39][CH2:38]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4cc(OC(F)(F)F)ccc4c3=O)cc2)CCC1
Agent: NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Product: NC1(c2ccc(-c3c(-c4ccccc4)oc4cc(OC(F)(F)F)ccc4c3=O)cc2)CCC1
Yield: 86 %

Procedure:
Following the procedure used to prepare 3-[4-(1-amino-cyclobutyl)-phenyl]-6-fluoro-2-phenyl-chromen-4-one, {1-[4-(4-oxo-2-phenyl-7-trifluoromethoxy-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester was reacted to give the title compound as a white solid (54 mg, 86%). 1H NMR (400 MHz, CDCl3): δ 8.30 (d, J=8 Hz, 1H), 7.41-7.33 (m, 6H), 7.30-7.25 (m, 3H), 7.19-7.16 (m, 2H), 2.61-2.52 (m, 2H), 2.33-2.24 (m, 2H), 2.16-2.06 (m, 1H), 1.81-1.71 (m, 1H). LCMS (Method E): RT=4.15 min, [M+H]+=452.
Reaction SMILES: [Br-].[C:2]([NH:5][C:6]1[S:7][CH:8]=[C:9]([CH2:11][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:10]=1)(=[O:4])[CH3:3].CC(C)([O-])C.[K+].[O:37]1[CH2:41][CH2:40][O:39][CH:38]1[C:42]1[CH:43]=[C:44]([CH:51]=O)[S:45][C:46]=1[Si:47]([CH3:50])([CH3:49])[CH3:48].Cl>CN(C)C=O.O>[O:37]1[CH2:41][CH2:40][O:39][CH:38]1[C:42]1[CH:43]=[C:44]([CH:51]=[CH:11][C:9]2[N:10]=[C:6]([NH:5][C:2](=[O:4])[CH3:3])[S:7][CH:8]=2)[S:45][C:46]=1[Si:47]([CH3:50])([CH3:49])[CH3:48]
Reactant: CC(=O)Nc1nc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cs1
Reactant: C[Si](C)(C)c1sc(C=O)cc1C1OCCO1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Br-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Nc1nc(C=Cc2cc(C3OCCO3)c([Si](C)(C)C)s2)cs1
Reaction time: 1 h
Yield: 95 %

Procedure:
To a solution of {[2-(acetylamino)-1,3-thiazol-4-yl]methyl}(triphenyl)phosphoniumbromide (7.970 g, 16.03 mmol) in anhydrous N,N-dimethylformamide (32 ml) was added potassium tert-butoxide (3.687 g, 32.86 mmol) at 0° C., and the mixture was stirred for 1 hr. A solution of 4-(1,3-dioxolan-2-yl)-5-(trimethylsilyl)thiophene-2-carbaldehyde (2.740 g, 10.69 mmol) in anhydrous N,N-dimethylformamide (6 ml) was added dropwise, and the mixture was stirred for 1 hr. 1M Hydrochloric acid (17.0 ml) and iced water (170 ml) were added, and the mixture was extracted 3 times with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (FUJI SILYSIA CHEMICAL LTD. BW-300SP 200 g, ethyl acetate:dichloromethane=1:6) to give N-(4-{2-[4-(1,3-dioxolan-2-yl)-5-(trimethylsilyl)thiophen-2-yl]vinyl}-1,3-thiazol-2-yl)acetamide (4.010 g, 10.16 mmol, yield 95.0%) as an off-white solid.
Reaction SMILES: [F:1][C:2]1[C:3]([C:22]2[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=2)=[C:4]2[O:9][CH2:8][CH:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23.[NH3:32]>O1CCCC1>[F:1][C:2]1[C:3]([C:22]2[CH:27]=[CH:26][C:25]([S:28]([NH2:32])(=[O:30])=[O:29])=[CH:24][CH:23]=2)=[C:4]2[O:9][CH2:8][CH:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23
Reactant: CCOC(=O)c1cn2c3c(c(-c4ccc(S(=O)(=O)Cl)cc4)c(F)cc3c1=O)OCC2C
Reactant: N
Solvent: C1CCOC1
Product: CCOC(=O)c1cn2c3c(c(-c4ccc(S(N)(=O)=O)cc4)c(F)cc3c1=O)OCC2C
Temperature: -78 °C
Yield: 56 %

Procedure:
Ethyl 9-fluoro-10-(4-chlorosulfonylphenyl)-3-methyl-7-oxo-2,3-dihydro-(7H)-pyrido-(1,2,3-de)-1,4-benzoxazine-6-carboxylate (0.5 g) was dissolved in dry tetrahydrofuran (80 ml) and the resulting solution was cooled to -78° C. with stirring. Ammonia (5 ml) was condensed into the reaction mixture and the yellow suspension was warmed gradually to ambient temperature over 16 hours. Solvent was removed in vacuo and the residue was triturated with water and filtered. Drying in vacuo afforded a solid (0.3 g, 56% yield): m.p. >250° C. NMR (DMSO-d6, 250 MHz): 8.74 (s, 1H), 7.96 (d, 2H, J=10 Hz), 7.74 (d, 2 H, J= PG,91 10 Hz), 7.60 (d, 1H, J=10 Hz), 7.50 (s, 2H), 4.90-4.75 (m, 1H), 4.55-4.45 (m, 2H), 4.25 (q, 2H, J=7 Hz), 1.45 (d, 3H, J=7 Hz), 1.30 (t, 3H, J=7 Hz).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]([C:19]3[S:23][C:22]([C:24]([NH2:26])=[O:25])=[C:21]([O:27][CH:28]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[Cl:36])[CH3:29])[CH:20]=3)[CH:17]=[N:18][C:12]=2[CH:11]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[Cl:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[CH:28]([O:27][C:21]1[CH:20]=[C:19]([N:16]2[C:13]3[CH:14]=[N:15][C:10]([CH2:9][OH:8])=[CH:11][C:12]=3[N:18]=[CH:17]2)[S:23][C:22]=1[C:24]([NH2:26])=[O:25])[CH3:29]
Reactant: CC(Oc1cc(-n2cnc3cc(CO[Si](C)(C)C(C)(C)C)ncc32)sc1C(N)=O)c1ccccc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(Oc1cc(-n2cnc3cc(CO)ncc32)sc1C(N)=O)c1ccccc1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of 8.19 g of 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3H-imidazo[4,5-c]pyridin-3-yl]-3-[-1-(2-chlorophenyl)ethoxy]thiophene-2-carboxamide in 550 ml THF is cooled to 0° C. At 0° C. 4.14 ml tetra-n-butylammonium fluoride (˜75% in H20) are added. The reaction mixture is allowed to warm to room temperature and stirred for one hour.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][NH2:15])[N:12]=2)=[CH:4][CH:3]=1.[F:18][C:19]([F:35])([F:34])[C:20]1[O:24][N:23]=[C:22]([C:25]2[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=2)[C:28](O)=[O:29])[N:21]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][CH:10]=[C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][NH:15][C:28](=[O:29])[C:27]3[CH:31]=[CH:32][CH:33]=[C:25]([C:22]4[N:21]=[C:20]([C:19]([F:35])([F:34])[F:18])[O:24][N:23]=4)[CH:26]=3)[N:12]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(CN)c1csc(-c2ccc(Cl)cc2)n1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Product: CC(C)(CNC(=O)c1cccc(-c2noc(C(F)(F)F)n2)c1)c1csc(-c2ccc(Cl)cc2)n1
Yield: 25 %

Procedure:
This compound was synthesized from 2-(2-(4-chlorophenyl)thiazol-4-yl)-2-methylpropan-1-amine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (75 mg, yield 25%). 1H NMR (400 MHz, CDCl3) δ 8.53 (m, 1H), 8.27-8.25 (m, 1H), 8.10-8.05 (m, 2H), 7.86-7.84 (d, J=8.5 Hz, 2H), 7.62-7.59 (t, J=7.8 Hz, 1H), 7.33-7.31 (d, J=8.5 Hz, 2H), 7.08 (s, 1H), 3.71-3.69 (d, J=5.3 Hz, 2H), 1.49 (s, 6H). MS (ESI) m/z: Calculated for C23H18ClF3N4O2S: 506.08. found: 507.0 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=4)[CH:15]=3)=[CH:9][N:8]([S:25]([C:28]3[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[C:5]2=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:43]2[CH:44]=[C:45]([NH:49][S:50]([CH3:53])(=[O:52])=[O:51])[CH:46]=[CH:47][CH:48]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>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.C1(C)C=CC=CC=1.C(O)C.O>[CH3:24][O:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][N:14]2[CH:15]=[C:11]([C:10]3[C:4]4[C:5](=[N:6][CH:7]=[C:2]([C:43]5[CH:44]=[C:45]([NH:49][S:50]([CH3:53])(=[O:51])=[O:52])[CH:46]=[CH:47][CH:48]=5)[CH:3]=4)[N:8]([S:25]([C:28]4[CH:29]=[CH:30][C:31]([CH3:32])=[CH:33][CH:34]=4)(=[O:27])=[O:26])[CH:9]=3)[CH:12]=[N:13]2)=[CH:22][CH:21]=1
Reactant: CC1(C)OB(c2cccc(NS(C)(=O)=O)c2)OC1(C)C
Reactant: COc1ccc(Cn2cc(-c3cn(S(=O)(=O)c4ccc(C)cc4)c4ncc(Br)cc34)cn2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(Cn2cc(-c3cn(S(=O)(=O)c4ccc(C)cc4)c4ncc(-c5cccc(NS(C)(=O)=O)c5)cc34)cn2)cc1
Yield: 90.5 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, 5-bromo-3-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (240 mg, 0.44 mmol) was coupled with N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl) methane sulfonamide (intermediate 3) (160 mg, 0.53 mmol) in sodium carbonate (142 mg, 1.34 mmol), bis(triphenyl phosphine)palladium(ii) dichloride (16 mg, 0.022 mmol) and toluene/ethanol/water (7/7/4 ml) to afford 250 mg (89.28% yield) of the pure product after column purification using 35% ethyl acetate in hexane as eluent. MS: m/z=628.3 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][NH2:17])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[CH3:19][C:20]1[C:25]([CH2:26][C:27](O)=[O:28])=[CH:24][CH:23]=[C:22]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=2)[N:21]=1>>[CH2:1]([O:3][C:4](=[O:18])[C:5]([CH3:7])([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][NH:17][C:27](=[O:28])[CH2:26][C:25]2[C:20]([CH3:19])=[N:21][C:22]([C:30]3[CH:35]=[CH:34][C:33]([C:36]([F:37])([F:39])[F:38])=[CH:32][CH:31]=3)=[CH:23][CH:24]=2)[CH:10]=1)[CH3:6])[CH3:2]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CC(=O)O
Reactant: CCOC(=O)C(C)(C)Oc1cccc(CCN)c1
Product: CCOC(=O)C(C)(C)Oc1cccc(CCNC(=O)Cc2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)c1

Procedure:
In analogy to the procedures described in example 26B] and 26C], 2-[3-(2-amino-ethyl)-phenoxy]-2-methyl-propionic acid ethyl ester was reacted with [2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetic acid (example 26E]) to give 2-methyl-2-[3-(2-{2-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetylamino}-ethyl)-phenoxy]-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:5]=1[OH:11])([O-:3])=[O:2].[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1>C1C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][O:12]2)[C:5]=1[OH:11])([O-:3])=[O:2]
Reactant: C1=COCCC1
Reactant: O=[N+]([O-])c1cccc(O)c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: O=[N+]([O-])c1cccc(OC2CCCCO2)c1O
Reaction time: 24 h
Yield: 54.1 %

Procedure:
To a solution of 3-nitrobenzene-1,2-diol (2.78 g) and 3,4-dihydro-2H-pyrane (1.81 g) in benzene (39 ml) was added p-toluenesulfonic acid monohydrate (5 mg) at ambient temperature, and the mixture was stirred for 24 hours. The reaction mixture was washed with saturated sodium bicarbonate solution, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography (chloroform—methanol) and crystallized with n-hexane to give 2-nitro-6-(tetrahydropyran-2-yloxy)phenol (2.32 g).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:14])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH2:15]([N:18]1[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][CH2:26]O)[CH2:20][CH2:19]1)[CH:16]=[CH2:17].N(C([O-])=O)=NC([O-])=O>C(Cl)Cl>[CH2:15]([N:18]1[CH2:19][CH2:20][N:21]([CH2:24][CH2:25][CH2:26][O:14][C:8]2[CH:7]=[C:6]3[C:11]([C:2]([Cl:1])=[N:3][CH:4]=[N:5]3)=[CH:10][C:9]=2[O:12][CH3:13])[CH2:22][CH2:23]1)[CH:16]=[CH2:17]
Reactant: COc1cc2c(Cl)ncnc2cc1O
Reactant: C=CCN1CCN(CCCO)CC1
Agent: O=C([O-])N=NC(=O)[O-]
Solvent: ClCCl
Product: C=CCN1CCN(CCCOc2cc3ncnc(Cl)c3cc2OC)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 4-chloro-7-hydroxy-6-methoxyquinazoline (300 mg, 1.43 mmol), (prepared as described for the starting material in Example 4), in methylene chloride (15 ml) was added triphenylphospbine (522 mg, 2.0 mmol), 3-(4-allylpiperazin-1-yl)propan-1-ol (288 mg, 1.57 mmol), (DE 2755707), and dusopropyl azodicarboxylate (336 μl, 1.71 mmol) and the mixture stirred at ambient temperature for 2 hours. The crude reaction mixture was loaded directly onto a silica chromatography column and eluted with methylene chloride/methanol (95/5). The volatile solvents were removed under vacuum to give 7-[3-(4-allylpiperazin-1-yl)propoxy]-4-chloro-6-methoxyquinazoline as an oil which crystallised on standing (480 mg, 89%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C@@H:13]([NH2:15])[CH3:14])=[N:10][CH:9]=2)=[CH:4][CH:3]=1.[C:16]([O:20][C@@H:21]([C@H:23]1[CH2:27][O:26][C:25](=[O:28])[N:24]1[C:29]1[C:34]([F:35])=[CH:33][N:32]=[C:31](F)[N:30]=1)[CH3:22])([CH3:19])([CH3:18])[CH3:17].C(N(C(C)C)C(C)C)C>CS(C)=O.CCOC(C)=O>[C:16]([O:20][C@@H:21]([C@H:23]1[CH2:27][O:26][C:25](=[O:28])[N:24]1[C:29]1[C:34]([F:35])=[CH:33][N:32]=[C:31]([NH:15][CH:13]([C:11]2[O:12][C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[CH:9][N:10]=2)[CH3:14])[N:30]=1)[CH3:22])([CH3:17])([CH3:18])[CH3:19]
Reactant: C[C@@H](OC(C)(C)C)[C@H]1COC(=O)N1c1nc(F)ncc1F
Reactant: C[C@H](N)c1ncc(-c2ccc(Cl)cc2)o1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncc(F)c(N2C(=O)OC[C@@H]2[C@@H](C)OC(C)(C)C)n1)c1ncc(-c2ccc(Cl)cc2)o1
Temperature: 120 °C
Yield: 73 %

Procedure:
To a solution of (S)-1-(5-(4-chlorophenyl)oxazol-2-yl)ethanamine 75 mg, 0.337 mmol) and (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2,5-difluoropyrimidin-4-yl)oxazolidin-2-one (101 mg, 0.337 mmol) in DMSO (1 ml) was added N-ethyl-N-isopropylpropan-2-amine (2 eq, 0.118 mL, 0.674 mmol) and heated in a microwave at 120° C. for 2 hours. Dilute with EtOAc (25 ml), wash with water (25 ml), brine (25 ml), concentrate in vacuo. Flash column chromatography (silica, 40 g) eluting w/0-10% EtOAc/DCM afforded 124 mg yellow foam: 1H NMR (400 MHz, CDCl3) δ 8.25 (d, J=2.8 Hz, 1H), 7.61-7.49 (m, 2H), 7.45-7.36 (m, 2H), 7.28 (d, J=6.2 Hz, 1H), 5.65 (d, J=8.9 Hz, 1H), 5.43-5.27 (m, 1H), 4.69 (qd, J=5.6, 2.9 Hz, 1H), 4.62-4.35 (m, 2H), 4.23-4.01 (m, 1H), 1.68 (d, J=12.8 Hz, 2H), 1.26-1.16 (m, 2H), 1.12 (s, 8H), 1.05 (d, J=6.4 Hz, 3H). HRMS(C) tR=1.55 min; m/z 503.1736
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3]1[N:23]=[C:6]2[CH:7]=[C:8]([NH:11][C:12]([C:14]3[N:18]([CH3:19])[N:17]=[CH:16][C:15]=3[C:20]([OH:22])=O)=[O:13])[CH:9]=[CH:10][N:5]2[N:4]=1.Cl.[F:26][CH:27]1[CH2:30][NH:29][CH2:28]1.CCCP(=O)=O.C(N(C(C)C)CC)(C)C>O1CCCC1>[CH3:1][N:2]([CH3:24])[C:3]1[N:23]=[C:6]2[CH:7]=[C:8]([NH:11][C:12]([C:14]3[N:18]([CH3:19])[N:17]=[CH:16][C:15]=3[C:20]([N:29]3[CH2:30][CH:27]([F:26])[CH2:28]3)=[O:22])=[O:13])[CH:9]=[CH:10][N:5]2[N:4]=1
Reactant: FC1CNC1
Reactant: CN(C)c1nc2cc(NC(=O)c3c(C(=O)O)cnn3C)ccn2n1
Agent: CCCP(=O)=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)c1nc2cc(NC(=O)c3c(C(=O)N4CC(F)C4)cnn3C)ccn2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.9 %

Procedure:
A mixture of 5-(2-(dimethylamino)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylic acid (150 mg, 455 μmol), 3-fluoroazetidine hydrochloride (152 mg, 1.37 mmol), propylphosphonic anhydride (50% in ethyl acetate, 671 μl, 1.14 mmol) and diisopropylethylamine (398 μl, 2.28 mmol) in tetrahydrofurane (8 ml) is stirred for 18 hours at room temperature under nitrogen atmosphere. The solvent is evaporated and the residue triturated with sat. aqueous sodium hydrogencarbonate solution; the precipitated solid is collected by filtration, washed with water and dried affording N-(2-(dimethylamino)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-(3-fluoroazetidine-1-carbonyl)-1-methyl-1H-pyrazole-5-carboxamide (158 mg, 89.8%) as a white solid. Mp.: 243-4° C. MS: m/z=387.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:18][C:17]3[C:12](=[N:13][C:14](SC)=[N:15][CH:16]=3)[N:11]([CH3:21])[C:10]2=[O:22])[CH:5]=[CH:6][C:7]=1[F:8]>C1COCC1.[Ni]>[NH2:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:18][C:17]3[C:12](=[N:13][CH:14]=[N:15][CH:16]=3)[N:11]([CH3:21])[C:10]2=[O:22])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CSc1ncc2c(n1)N(C)C(=O)N(c1ccc(F)c(N)c1)C2
Agent: [Ni]
Solvent: C1CCOC1
Product: CN1C(=O)N(c2ccc(F)c(N)c2)Cc2cncnc21
Temperature: 60 °C
Reaction time: 5 h
Yield: 76.5 %

Procedure:
To a solution of Example A1 (700 mg, 2.2 mmol) in THF (10 mL) was added Raney-Ni (50% wt slurry in water, 1.0 g) and then the reaction mixture was stirred under 1 atm of H2 at 60° C. for 5 h. The mixture was filtered through diatomite and the cake was washed with THF. The combined filtrate was concentrated to give 3-(3-amino-4-fluoro-phenyl)-1-methyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one (460 mg, 76% yield) as a yellow solid. 1H NMR (300 MHz, DMSO-d6): δ 8.77 (s, 1 H), 8.39 (s, 1 H), 6.99 (dd, J=11.4, 8.7 Hz, 1 H), 6.72 (d, J=8.1 Hz, 1 H), 6.49 (m, 1 H), 5.24 (br s, 2 H), 4.73 (s, 2 H), 3.28 (s, 3 H). MS (ESI) m/z: 274.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14].[CH3:20][O:21][C:22]1[N:27]=[C:26]([O:28][CH3:29])[C:25](B2OC(C)(C)C(C)(C)O2)=[CH:24][N:23]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:25]3[C:26]([O:28][CH3:29])=[N:27][C:22]([O:21][CH3:20])=[N:23][CH:24]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14]
Reactant: CCCCNC(=O)c1nnc2c(Br)cccc2c1N
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)c(OC)n1
Product: CCCCNC(=O)c1nnc2c(-c3cnc(OC)nc3OC)cccc2c1N

Procedure:
The title compound was prepared from 4-amino-8-bromo-N-butyl-cinnoline-3-carboxamide (200.0 mg, 0.62 mmol) and 2,4-dimethoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidine (987.9 mg, 3.72 mmol) according to Method B to afford a white solid (162.1 mg, 69%). 1H NMR (300.132 MHz, CDCl3) δ 8.49 (t, J=5.5 Hz, 1H), 8.33 (s, 1H), 7.90 (dd, J=7.6, 2.1 Hz, 1H), 7.77-7.69 (m, 3H), 4.07 (s, 3H), 3.93 (s, 3H), 3.50 (q, J=6.6 Hz, 2H), 1.63 (quintet, J=7.2 Hz, 2H), 1.44 (sextet, J=7.4 Hz, 2H), 0.95 (t, J=7.3 Hz, 3H). MS APCI, m/z=383.1 (M+H). HPLC 2.52 min.