Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH2:18][CH3:19])CC2C=CC(OC)=CC=2)[C:5]2=[N:20][CH:21]=[C:22]([C:23]#[N:24])[N:4]2[N:3]=1.[NH2:25][C:26]1[C:27]([Cl:51])=[C:28]([N:34]2[CH2:43][CH2:42][C@@H:41]3[C@H:36]([O:37][CH2:38][CH2:39][N:40]3C(OC(C)(C)C)=O)[CH2:35]2)[CH:29]=[C:30]([C:32]#[N:33])[CH:31]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=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.[Fe+2].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[Cl:51][C:27]1[C:28]([N:34]2[CH2:43][CH2:42][C@@H:41]3[C@H:36]([O:37][CH2:38][CH2:39][NH:40]3)[CH2:35]2)=[CH:29][C:30]([C:32]#[N:33])=[CH:31][C:26]=1[NH:25][C:2]1[N:7]=[C:6]([NH:8][CH2:18][CH3:19])[C:5]2=[N:20][CH:21]=[C:22]([C:23]#[N:24])[N:4]2[N:3]=1
Reactant: CCN(Cc1ccc(OC)cc1)c1nc(Cl)nn2c(C#N)cnc12
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H]2CN(c3cc(C#N)cc(N)c3Cl)CC[C@H]21
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: CCNc1nc(Nc2cc(C#N)cc(N3CC[C@H]4NCCO[C@@H]4C3)c2Cl)nn2c(C#N)cnc12
Temperature: 100 °C
Reaction time: 3 h

Procedure:
2-chloro-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Intermediate 10) (85.0 mg, 0.248 mmol), (+/−)-(4aR,8aR)-tert-butyl 6-(3-amino-2-chloro-5-cyanophenyl)octahydro-1H-pyrido[3,4-b][1,4]oxazine-1-carboxylate (97.0 mg, 0.248 mmol), DPPF (9.62 mg, 0.017 mmol), Cs2CO3 (137 mg, 0.422 mmol), Xantphos (14.35 mg, 0.025 mmol), Palladium(II)Acetate (16.7 mg, 0.074 mmol) and 1,4-dioxane (2 ml) were combined in a microwave vial. The vial was evacuated and backfilled with Nitrogen (3×). The reaction stirred at 100° C. for 3 hr.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]3[CH2:25][CH2:24][CH:23]([N:26]([CH3:34])[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22]3)=[N:19][CH:20]=1)=[CH:11][C:10](Br)=[CH:9][CH:8]=2)(=[O:3])[CH3:2].[Cl:36][C:37]1[CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:40]=[C:39]([F:52])[C:38]=1[OH:53]>>[C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]3[CH2:25][CH2:24][CH:23]([N:26]([CH3:34])[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22]3)=[N:19][CH:20]=1)=[CH:11][C:10]([C:41]1[CH:40]=[C:39]([F:52])[C:38]([OH:53])=[C:37]([Cl:36])[CH:42]=1)=[CH:9][CH:8]=2)(=[O:3])[CH3:2]
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1Nc1ccc(N2CCC(N(C)C(=O)OC(C)(C)C)C2)nc1
Product: CC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)cc2c1Nc1ccc(N2CCC(N(C)C(=O)OC(C)(C)C)C2)nc1
Yield: 93.5 %

Procedure:
Following general procedure M, tert-butyl (1-(5-((3-acetyl-6-bromoquinolin-4-yl)amino)pyridin-2-yl)pyrrolidin-3-yl)(methyl)carbamate (80 mg, 0.15 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (68 mg, 0.25 mmol) to afford the desired product (85 mg, 95%) as a brown solid. ESI MS m/z 606 [C32H33ClFN5O4+H]+
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:6][CH:5]=1)([OH:3])=[O:2].S(Cl)(Cl)=O.[CH3:19]O>>[CH3:19][O:13][C:12](=[O:14])[CH2:11][CH2:10][C:7]1[CH:8]=[CH:9][C:4]([C:1]([OH:3])=[O:2])=[CH:5][CH:6]=1
Reactant: O=C(O)CCc1ccc(C(=O)O)cc1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)CCc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
To a suspension of 3-(4-carboxyphenyl)propionic acid (2.0 g, 10.1 mmol) in methanol (20 mL) was added thionyl chloride (38 μL, 0.50 mmol). The reaction mixture was stirred at room temperature for 16 h, and a clear solution was obtained. The solvent was removed under reduced pressure. The residue was taken up in ether (100 mL), washed with saturated aqueous NaHCO3 (2×50 mL) and water (50 mL). The combined NaHCO3 and water extract was acidified with concentrated HCl in an ice bath. The precipitated white solid was collected, washed with water and dried to yield 1.76 g (84%) of compound 166 as off-white solid. The material was used without further purification. mp 146-148° C. 1H NMR (400 MHz, CDCl3): δ 2.66 (t, J=7.7 Hz, 2H), 3.02 (t, J=7.7 Hz, 2H), 3.67 (s, 3H), 7.30 (d, J=8.3 Hz, 2H), 8.03 (d, J=8.1 Hz, 2H). LCMS (ES), m/z, 209 (M+H)+, 207 (M−H)−.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.C([O:14][C:15](=O)[CH2:16][C:17]([C:19]1[C:20]([NH:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[N:21][C:22]([S:25][CH3:26])=[N:23][CH:24]=1)=[O:18])C.CCN(C(C)C)C(C)C>>[CH:28]1([N:27]2[C:20]3[N:21]=[C:22]([S:25][CH3:26])[N:23]=[CH:24][C:19]=3[C:17]([OH:18])=[CH:16][C:15]2=[O:14])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: CCOC(=O)CC(=O)c1cnc(SC)nc1NC1CCCCC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCN(C(C)C)C(C)C
Product: CSc1ncc2c(O)cc(=O)n(C3CCCCC3)c2n1
Temperature: 125 °C
Reaction time: 8 h
Yield: 107.2 %

Procedure:
DBU (11.05 mL) was added dropwise, under argon atmosphere, to a mixture of 3-(4-cyclohexylamino-2-methylsulfanyl-pyrimidin-5-yl)-3-oxo-propionic acid ethyl ester (21.5 g) and DIPEA (85 mL), and the resulting mixture heated at 125° C. for 1 h, then stirred at RT overnight. The volatiles were evaporated under reduced pressure, and the residue was diluted with EtOAc and HCl (1 M aq). The solid residue was collected by filtration, the organic layer was separated, and the aqueous layer was extracted 3× with EtOAc. The combined organic extracts were dried over Na2SO4, filtered and evaporated under reduced pressure. The combined solids were washed 3× with NaHSO4 (aq 10%), twice with water, hexane (8×100 mL), and a 2:1 mixture of hexane and EtOAc (4×100 mL) to give, after drying under reduced pressure, 19.9 g (99% yield) of 8-cyclohexyl-5-hydroxy-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one without further purifications.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH3:21])[C:5]2[NH:6][C:7](=[O:20])[C:8]3[CH:18]=[C:17]([Br:19])[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1.C1C=CN=CC=1.[FH:28].N([O-])=O.[Na+].[OH-].[Na+]>>[Br:19][C:17]1[CH:16]=[N:15][C:9]2[N:10]([CH2:13][CH3:14])[C:11]3[N:12]=[C:2]([F:28])[CH:3]=[C:4]([CH3:21])[C:5]=3[NH:6][C:7](=[O:20])[C:8]=2[CH:18]=1
Reactant: CCN1c2ncc(Br)cc2C(=O)Nc2c(C)cc(N)nc21
Reactant: F
Agent: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: CCN1c2ncc(Br)cc2C(=O)Nc2c(C)cc(F)nc21
Temperature: 0 °C
Reaction time: 16 h
Yield: 83.9 %

Procedure:
A plastic bottle was charged with 2-amino-8-bromo-5,11-dihydro-11-ethyl-4-methyl-6H-dipyrido[3,2-b:2′,3′-e][1,4]diazepin-6-one (5.10 g, 14.6 mmol). HF-pyridine (100 g) was added and the resulting suspension was cooled to 0° C. Sodium nitrite (1.12 g, 16.1 mmol) was added in several portions over 30 min to produce a purple solution. The mixture was then stirred for 16 h at room temperature. The reaction mixture was poured onto ice and 6 N NaOH. The beige suspension was extracted with EtOAc. The organic extracts were combined, dried over MgSO4, filtered and concentrated. The residue was triturated with Et2O/hexane to give the title compound (4.30 g, 84% yield).
Reaction SMILES: C([SnH](CCCC)CCCC)CCC.[C:14]([N:17]1[C:25]2[C:20](=[CH:21][C:22]([S:27][CH2:28][C:29]3[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH:34]=3)=[C:23](I)[CH:24]=2)[CH2:19][CH2:18]1)(=[O:16])[CH3:15].CC(N=NC(C#N)(C)C)(C#N)C.C(OCC)(=O)C>C1C=CC=CC=1>[C:14]([N:17]1[C:25]2[CH:24]=[C:23]3[C:29]4([CH2:28][S:27][C:22]3=[CH:21][C:20]=2[CH2:19][CH2:18]1)[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]4)(=[O:16])[CH3:15]
Reactant: CC(=O)N1CCc2cc(SCC3=CCN(C)CC3)c(I)cc21
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CC(=O)N1CCc2cc3c(cc21)C1(CCN(C)CC1)CS3
Reaction time: 0.75 h
Yield: 33.3 %

Procedure:
A solution of tributyltin hydride (0.251 ml, 0.934 mmol) in benzene (10 ml) was added dropwise over 30 minutes to a stirred solution of 1-acetyl-2,3-dihydro-6-iodo-5-[(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)methylthio]-1H-indole (D51) (0.200 g, 0.467 mmol) and AIBN (5 mg) in benzene (20 ml) under argon at reflux. Reflux was continued for a further 0.75 h. The reaction mixture was then allowed to cool. Ethyl acetate (10 ml) was then added and the mixture washed with 2.5M HCl (3×10 ml). The combined aqueous washings were then basified with solid potassium carbonate and the resultant suspension was extracted with dichloromethane (3×15 ml). The combined organic extracts were then dried (Na2SO4) and evaporated under reduced pressure to give a pale yellow solid which was dried in vacuo (0.127 g). The solid was purified by prep. TLC (15% MeOH/CH2Cl2 as eluant) to give the title compound as a cream solid (0.047 g, 33%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([O:10]CC2C=CC(OC)=CC=2)[N:7]=[CH:6][C:5]=1[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:29][C:30]2[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[C:32]([C:40]3[O:41][C:42]([CH3:45])=[N:43][N:44]=3)[CH:31]=2)=[O:28])=[C:22]([F:46])[CH:21]=1)[CH3:2]>CO.[Pd]>[CH2:1]([O:3][C:4]1[C:5]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:29][C:30]3[CH:35]=[C:34]([C:36]([F:38])([F:39])[F:37])[CH:33]=[C:32]([C:40]4[O:41][C:42]([CH3:45])=[N:43][N:44]=4)[CH:31]=3)=[O:28])=[C:22]([F:46])[CH:21]=2)=[CH:6][NH:7][C:8](=[O:10])[CH:9]=1)[CH3:2]
Reactant: CCOc1cc(OCc2ccc(OC)cc2)ncc1-c1ccc(CC(=O)Nc2cc(-c3nnc(C)o3)cc(C(F)(F)F)c2)c(F)c1
Agent: [Pd]
Solvent: CO
Product: CCOc1cc(=O)[nH]cc1-c1ccc(CC(=O)Nc2cc(-c3nnc(C)o3)cc(C(F)(F)F)c2)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
A mixture of 2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(3-(5-methyl-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)phenyl)acetamide (60 mg, 0.094 mmol) and Pd/C (10.03 mg, 0.094 mmol) in MeOH (15 mL) was stirred for 0.5 h under a H2 atmosphere at 25° C. Then the mixture was filtered and the filtrate was concentrated to give the residue which was purified by preparative HPLC to yield 2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(3-(5-methyl-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)phenyl)acetamide (41.53 mg, 0.079 mmol, 84% yield): 1H NMR (400 MHz, DMSO-d6) 611.40-11.29 (m, 1H), 10.86 (s, 1H), 8.50 (s, 1H), 8.21 (s, 1H), 7.86 (s, 1H), 7.40-7.29 (m, 2H), 7.23 (d, J=2.6 Hz, 2H), 5.78 (s, 1H), 4.02 (q, J=7.1 Hz, 2H), 3.79 (s, 2H), 2.58 (s, 3H), 1.26 (t, J=6.9 Hz, 3H); ES-LCMS m/z 517 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:12])[CH:8]=2)[N:3]=1.[CH3:13][N:14]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:15](Cl)=[O:16].N12CCN(CC1)CC2>ClCCl>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][C:15](=[O:16])[N:14]([CH3:13])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:8]=2)[N:3]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: Cc1ccc2cc(O)ccc2n1
Agent: C1CN2CCN1CC2
Solvent: ClCCl
Product: Cc1ccc2cc(OC(=O)N(C)c3ccccc3)ccc2n1
Yield: 89.3 %

Procedure:
A solution of 2-methylquinolin-6-ol (1.00 g, 6.28 mmol), N-methyl-N-phenylcarbamoyl chloride (1.07 g, 6.28 mmol) and 1,4-diazabicyclo[2,2,2]octane (0.70 g, 6.28 mmol) in dichloromethane (10 mL) was stirred at room temperature for 18 hours. Extra dichloromethane was added and the solution was extracted twice with water, dried over sodium sulphate and filtered. Some ethyl acetate and heptane were added and the solution was slowly evaporated in vacuo yielding the title compound (1.64 g, 89% yield) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[C:16](I)[C:17]3[C:22]([CH3:24])([CH3:23])[C:21](=[O:25])[NH:20][C:18]=3[N:19]=2)=[N:6]1.[CH3:31][C:32]1[CH:36]=[C:35]([CH3:37])[NH:34][N:33]=1.C(=O)([O-])[O-].[Cs+].[Cs+].OC1C=CC=CC=1C=NO>C(#N)C.[Cu-]=O>[CH3:31][C:32]1[CH:36]=[C:35]([CH3:37])[N:34]([C:16]2[C:17]3[C:22]([CH3:24])([CH3:23])[C:21](=[O:25])[NH:20][C:18]=3[N:19]=[C:14]([C:7]3[C:8]4[C:9](=[N:10][CH:11]=[CH:12][CH:13]=4)[N:5]([CH2:4][C:3]4[CH:27]=[CH:28][CH:29]=[CH:30][C:2]=4[F:1])[N:6]=3)[N:15]=2)[N:33]=1
Reactant: Cc1cc(C)[nH]n1
Reactant: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(I)c21
Agent: O=[Cu-]
Agent: O=C([O-])[O-]
Agent: ON=Cc1ccccc1O
Solvent: CC#N
Product: Cc1cc(C)n(-c2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc3c2C(C)(C)C(=O)N3)n1
Temperature: 150 °C

Procedure:
Under argon atmosphere, 150 mg (purity 62%, 0.18 mmol) of 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-iodo-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one (example 15A) was suspended in 2 ml of absolute acetonitrile, and 26 mg (0.27 mmol) of 3,5-dimethyl-1H-pyrazole, 118 mg (0.36 mmol) of caesium carbonate, 5 mg (0.04 mmol) of copper(I) oxide and 20 mg (0.15 mmol) of 2-hydroxybenzaldehyde-oxime were added. The mixture was heated in the microwave for 1 h at 150° C. Then 346 mg (3.62 mmol) of 3,5-dimethyl-1H-pyrazole was added and the mixture was heated in the microwave for 45 min at 200° C. The reaction solution was filtered and purified by preparative HPLC (eluent: acetonitrile/water, gradient 20:80→100:0). 20 mg (23% of theor.) of the target compound was obtained.
Reaction SMILES: [F:1][C:2]1([F:43])[CH2:7][C@H:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([N:18](CC3C=CC(OC)=CC=3OC)[C:19]3[CH:24]=[CH:23][N:22]=[CH:21][N:20]=3)(=[O:17])=[O:16])=[C:11]([F:36])[CH:10]=2)[C@@H:5]([C:37]2[N:41]([CH3:42])[N:40]=[CH:39][CH:38]=2)[CH2:4][CH2:3]1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:43][C:2]1([F:1])[CH2:7][C@H:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]3[CH:24]=[CH:23][N:22]=[CH:21][N:20]=3)(=[O:16])=[O:17])=[C:11]([F:36])[CH:10]=2)[C@@H:5]([C:37]2[N:41]([CH3:42])[N:40]=[CH:39][CH:38]=2)[CH2:4][CH2:3]1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc(O[C@H]3CC(F)(F)CC[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nccc1[C@H]1CCC(F)(F)C[C@@H]1Oc1ccc(S(=O)(=O)Nc2ccncn2)c(F)c1
Yield: 73.8 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 4-{[(1S*,2R*)-5,5-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide (0.18 g, 0.29 mmol) prepared in Example 110a, triethylsilane (0.20 mL), trifluoroacetic acid (2.0 mL) and dichloromethane (2.0 mL), to yield the title compound (100 mg, 73%) as a colorless solid.
Reaction SMILES: [H-].[Na+].[Si:3]([O:10][CH2:11][C@H:12]1[O:17][C@:16]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([F:36])[C:29]=3[F:37])[CH:21]=2)([O:18][CH3:19])[C@H:15]([OH:38])[C@@H:14]([OH:39])[C@@H:13]1[OH:40])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].[CH2:41](Br)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>O1CCCC1>[C:6]([Si:3]([CH3:5])([CH3:4])[O:10][CH2:11][C@@H:12]1[C@@H:13]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C@H:14]([O:39][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C@@H:15]([O:38][CH2:16][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@@:16]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([F:36])[C:29]=3[F:37])[CH:21]=2)([O:18][CH3:19])[O:17]1)([CH3:8])([CH3:9])[CH3:7]
Reactant: COc1ccc(Cc2cc([C@]3(OC)O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)c(F)c1F
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(Cc2cc([C@]3(OC)O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)c(F)c1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 200 %

Procedure:
To a suspension of sodium hydride (24.0 g, 0.6 mol, 60% dispersion in Mineral oil) in anhydrous tetrahydrofuran (150 mL) was added a solution of (2S,3R,4S,5S,6R)-6-[[tert-butyhdimethyl) silyl]oxymethyl]-2-[4-chloro-3-[(2,3-difluoro-4-methoxy-phenyl)methyl]phenyl]-2-methoxy-tetrahydropyran-3,4,5-triol 21i (49.5 g, 86 mmol) in anhydrous tetrahydrofuran (400 mL) slowly at 0° C. The mixture was stirred at 0° C. for 1 hour, and then benzyl bromide (81 mL, 690 mmol) was added. The mixture was warmed up to room temperature and further stirred for 12 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (1000 mL) and extracted with ethyl acetate (300 mL×2). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound 21j as yellow oil (72.7 g, 100%). This material was not further purified.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([C:14]([OH:16])=O)=[CH:10][N:9]=2)=[CH:4][CH:3]=1.O[N:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2N=N1.C1CCC(N=C=NC2CCCCC2)CC1.NC1C=CC=CC=1.C(O)C(N)(CO)CO>CN(C=O)C>[C:22]1([NH:18][C:14]([C:11]2[CH:12]=[N:13][C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[N:9][CH:10]=2)=[O:16])[CH:23]=[CH:24][CH:25]=[CH:26][CH:21]=1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1cnc(-c2ccc(F)cc2)nc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: NC(CO)(CO)CO
Solvent: Nc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1)c1cnc(-c2ccc(F)cc2)nc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 86 %

Procedure:
A mixture of 2-(4-fluoro-phenyl)-pyrimidine-5-carboxylic acid (107 mg, 0.49 mmol, prepared according to the general procedure described in Example 2, steps 1 and 2), 1-hydroxybenzotriazole (75 mg, 0.56 mmol) and PS-DCC (511 mg, 1.28 mmol/g, 0.65 mmol) in DMF (8 mL) is shaken at room temperature for 15 min. Aniline (30.4 mg, 0.33 mmol) is added. The mixture is shaken at room temperature for 18 hours. PS-trisamine (392 mg, 3.75 mmol/g, 1.47 mmol) is added and the mixture is continually shaken at room temperature for 18 hours. The solid is filtered and washed with EtOAc. The filtrate is concentrated to afford 2-(4-fluoro-phenyl)-pyrimidine-5-carboxylic acid phenylamide (83.4 mg, 86%) as a solid. MS: 294 (M+H).
Reaction SMILES: O=[C:2]1[C:11]2[CH:12]=[CH:13][S:14][C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([C:15]([O:17][CH3:18])=[O:16])=[CH:5][C:4]=2[NH:3]1.O=P(Cl)(Cl)[Cl:21].CCN(C(C)C)C(C)C.O>C1(C)C=CC=CC=1>[Cl:21][C:2]1[C:11]2[CH:12]=[CH:13][S:14][C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([C:15]([O:17][CH3:18])=[O:16])=[CH:5][C:4]=2[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1ccc2c(c1)[nH]c(=O)c1ccsc12
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)c1ccc2c(c1)nc(Cl)c1ccsc12
Temperature: 120 °C
Reaction time: 3 h
Yield: 641.4 %

Procedure:
Methyl 4-oxo-4,5-dihydrothieno[3,2-c]quinoline-7-carboxylate (1.0 eq, 1.50 g, 5.79 mmol) was suspended in dry toluene (15 ml). POCl3 (1.2 eq, 0.64 mmol, 6.99 mmol) and DIEA (0.8 eq, 0.81 mmol, 4.65 mmol) were added and the mixture vigorously stirred at 120° C. for 3 hours under nitrogen atmosphere. The mixture was hydrolyzed by addition of ice and water. The compound was extracted with CH2Cl2 (4×). The combined extracts were dried over Na2SO4 and the black solution filtered through a pad of celite. After evaporation of the volatiles in vacuo, the resulting solid was triturated in a mixture of AcOEt and hexanes. Filtration and drying provided methyl 4-chlorothieno[3,2-c]quinoline-7-carboxylate as a yellow fluffy solid (1.14 g, 71% yield). LCMS (ES): 95% pure, m/z 278 [M+l]+, 1H NMR (CDCl3, 400 MHz) δ 4.01 (s, 3H), 7.72 (d, J=4.8, 1H), 7.74 (d, J=5.2, 1H), 8.14 (d, J=8.4, 1H), 8.25 (d, J=8.4, 1H), 8.85 (d, J=1.6, 1H) ppm.
Reaction SMILES: C([N:8]1[CH2:12][C@@H:11]([N:13]([C:22](=[O:24])[CH3:23])[CH:14]2[CH2:19][CH2:18][C:17]([CH3:21])([CH3:20])[CH2:16][CH2:15]2)[CH2:10][C@H:9]1[C:25]([N:27]1[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]1)=[O:26])(OC(C)(C)C)=O.Cl>C(Cl)Cl>[CH3:20][C:17]1([CH3:21])[CH2:18][CH2:19][CH:14]([N:13]([C@H:11]2[CH2:10][C@@H:9]([C:25]([N:27]3[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH2:32]3)=[O:26])[NH:8][CH2:12]2)[C:22](=[O:24])[CH3:23])[CH2:15][CH2:16]1
Reactant: CC(=O)N(C1CCC(C)(C)CC1)[C@H]1C[C@@H](C(=O)N2CCN(C)CC2)N(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: ClCCl
Product: CC(=O)N(C1CCC(C)(C)CC1)[C@@H]1CN[C@H](C(=O)N2CCN(C)CC2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
(2S,4S)-1-BOC-4-[acetyl(4,4-dimethylcyclohexyl)amino]-2-[(4-methylpiperazin-1-yl)carbonyl]pyrrolidine (1.06 g, 2.28 mmol) obtained in Step D was dissolved in DCM (1 mL) and 4M HCl (1 mL) was added dropwise thereto. After the reaction solution was stirred at room temperature for 1 hour, the solution was concentrated in vacuo. The residue was concentrated in vacuo to give the title compound (830 mg, 99.8%).
Reaction SMILES: F[C:2](F)(F)C(O)=O.[OH:8][C:9]1[C:10]([CH:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]([CH2:29][C@H:30]3[CH2:34][CH2:33][CH2:32][O:31]3)[C:21]2=[O:35])=[CH:11][C:12]2[O:17][CH2:16][CH2:15][N:14]([CH3:18])[C:13]=2[CH:19]=1.C1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[CH3:18][N:14]1[C:13]2[CH:19]=[C:9]3[O:8][CH2:2][C:20]4([C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[N:22]([CH2:29][C@H:30]5[CH2:34][CH2:33][CH2:32][O:31]5)[C:21]4=[O:35])[C:10]3=[CH:11][C:12]=2[O:17][CH2:16][CH2:15]1
Reactant: O=C(O)C(F)(F)F
Reactant: CN1CCOc2cc(C3C(=O)N(C[C@H]4CCCO4)c4ccccc43)c(O)cc21
Agent: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Product: CN1CCOc2cc3c(cc21)OCC31C(=O)N(C[C@H]2CCCO2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 3-(6-hydroxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl)-1-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-dihydro-2H-indol-2-one trifluoroacetate to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 4-methyl-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-3,4-dihydro-2H-spiro[furo[2,3-g][1,4]benzoxazine-8,3′-indol]-2′(1′H)-one was obtained (62%) as a pale yellow solid: mp 138-140° C. (diethyl ether/hexanes); 1H NMR (300 MHz, CDCl3) (diastereomers) δ 7.26 (dd, J=7.7, 7.7 Hz, 1H), 7.16-6.99 (m, 3H), 6.29 (s, 1H), 6.122, 6.117 (s, 1H), 4.86 (d, J=8.9 Hz, 1H), 4.61 (d, J=8.9 Hz, 1H), 4.31-4.21 (m, 1H), 4.13 (dd, J=4.5, 4.5 Hz, 2H), 3.99-3.66 (m, 4H), 3.23 (dd, J=4.5, 4.2 Hz, 2H), 2.87 (s, 3H), 2.07-1.83 (m, 3H), 1.81-1.67 (m, 1H); 13C NMR (75 MHz, CDCl3) (diastereomers) δ178.5, 178.3, 156.1, 143.1, 142.9, 139.0, 137.8, 132.7, 132.6, 128.7, 128.6, 123.84, 123.76, 123.2, 116.41, 116.35, 110.26, 110.22, 109.7, 109.4, 94.4, 80.2, 80.1, 77.3, 76.8, 68.38, 68.35, 64.5, 58.3, 49.2, 44.64, 44.58, 39.0, 29.4, 29.0, 25.9, 25.7; MS (ES+) m/z 393.0 (M+1).
Reaction SMILES: Cl[C:2]1[C:3]([CH:8]2[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[C:15]([O:14][C:12]([N:10]1[CH2:11][CH:8]([C:3]2[C:2]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[N:7][CH:6]=[CH:5][N:4]=2)[CH2:9]1)=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)N1CC(c2nccnc2Cl)C1
Product: CC(C)(C)OC(=O)N1CC(c2nccnc2N2CCOCC2)C1
Temperature: 160 °C
Yield: 94 %

Procedure:
A mixture of 3-(3-chloro-pyrazin-2-yl)-azetidine-1-carboxylic acid tert-butyl ester (7) (269 mg, 1.0 mmol) in morpholine was heated by microwave at 160° C. for 2 h. The mixture was concentrated to give the crude compound and which was purified by column chromatography to afford pure product (11) (300 mg, yield 94%) as solid. ESI-MS (M+1): 321 calc. for C16H24N4O3 320.