Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)=[CH:10][C:9]=2[CH2:25][CH2:26][C:27]2[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=2)[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.[NH:45]1[C:49]([NH2:50])=[N:48][N:47]=[N:46]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)=[CH:10][C:9]=2[CH2:25][CH2:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([NH:50][C:49]3[NH:48][N:47]=[N:46][N:45]=3)=[O:32])=[CH:29][CH:28]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1nnn[nH]1
Reactant: O=C(O)c1ccc(CCc2cc(-c3ccc(OC(F)(F)F)cc3)ccc2-c2cccc(Cl)c2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1nnn[nH]1)c1ccc(CCc2cc(-c3ccc(OC(F)(F)F)cc3)ccc2-c2cccc(Cl)c2)cc1
Temperature: 50 °C

Procedure:
A DMF solution (1 mL) containing 4-{2-[3-chloro-4″-(trifluoromethoxy)-1,1′:4′,1″-terphenyl-2′-yl]ethyl}benzoic acid (12 mg, 0.024 mmol), prepared using the procedures described in EXAMPLE 1, DIEA (21 μg, 0.12 mmol), 1H-tetrazol-5-amine (3 mg, 0.036 mmol), and BOP (21 mg, 0.048 mmol) was heated at 50° C. for 30 minutes. The solution was then purified directly by RP-HPLC to give the title compound. LCMS1 4.36 min (N+H)=564
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[N:2]1.[NH:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[CH2:25][C@H:14]12.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:13]3[CH2:18][CH2:17][CH2:16][C@@H:15]4[C:19]5[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=5[CH2:25][C@H:14]34)=[O:12])=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: O=C(O)c1ccc2[nH]nnc2c1
Reactant: c1ccc2c(c1)C[C@@H]1NCCC[C@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(c1ccc2[nH]nnc2c1)N1CCC[C@@H]2c3ccccc3C[C@@H]21
Yield: 19 %

Procedure:
The title compound is prepared from 1H-benzotriazole-5-carboxylic acid and cis-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 19% of theory; LC (method 4): tR=1.87 min; Mass spectrum (ESI+): m/z=319 [M+H]+.
Reaction SMILES: [Na].[CH3:2][O:3][C:4]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7].[N+:16]([CH:19]([CH3:21])[CH3:20])([O-:18])=[O:17]>CO.C(O)(=O)C>[CH3:2][O:3][C:4]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=[CH:8][C:5]=1[CH:6]([OH:7])[C:19]([CH3:21])([N+:16]([O-:18])=[O:17])[CH3:20]
Reactant: CC(C)[N+](=O)[O-]
Reactant: COc1ccc(C=O)c(OC)c1OC
Agent: [Na]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(C(O)C(C)(C)[N+](=O)[O-])c(OC)c1OC
Temperature: 15 °C
Reaction time: 0.67 h
Yield: 86.7 %

Procedure:
6.4 g of sodium are added to 250 ml of anhydrous methanol, and 50 g of 2,3,4-trimethoxybenzaldehyde and 54.4 g of 2-nitropropane are added dropwise thereto at 15° C. for 40 minutes under stirring. The mixture is stirred at 25° C. for 24 hours, and 17 ml of acetic acid and 20 ml of methanol are added to said mixture under ice-cooling. The mixture is evaporated to remove solvent, and the residue is extracted with benzene. The extract is washed with water, an aqueous sodium bisulfite solution, water and a saturated sodium chloride solution, successively. The washed extract is dried and then evaporated to remove solvent. 63 g of 1-(2,3,4-trimethoxyphenyl)-2-methyl-2-nitropropanol are thereby obtained as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[CH:15][C:11]3[O:12][CH2:13][O:14][C:10]=3[CH:9]=2)[C:5]([C:17]#[N:18])=[C:4]([S:19]([CH3:22])(=O)=O)[N:3]=1.[C:23]1(S)[CH:28]=[CH:27]C=[CH:25][CH:24]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[CH:15][C:11]3[O:12][CH2:13][O:14][C:10]=3[CH:9]=2)[C:5]([C:17]#[N:18])=[C:4]([S:19][C:22]2[CH:27]=[CH:28][CH:23]=[CH:24][CH:25]=2)[N:3]=1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccc3c(c2)OCO3)c1C#N
Reactant: Sc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: N#Cc1c(Sc2ccccc2)nc(N)nc1-c1ccc2c(c1)OCO2

Procedure:
From 2-amino-4-benzo[1,3]dioxol-5-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile, thiophenol and DBU in DME. EI-MS m/e (%): 348 (M+, 96), 347 ([M—H]+, 100).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:14]2[C:9](=[C:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][CH:6]=1)=O.[CH3:25][NH2:26]>>[CH3:25][NH:26][C:3]([C:5]1[C:14]2[C:9](=[C:10]([NH:15][S:16]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)(=[O:18])=[O:17])[CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: COC(=O)c1ccnc2c(NS(=O)(=O)c3ccccc3)cccc12
Reactant: CN
Product: CNC(=O)c1ccnc2c(NS(=O)(=O)c3ccccc3)cccc12
Yield: 50 %

Procedure:
In a similar fashion using route 53 general procedure 122, 8-benzenesulfonylamino-quinoline-4-carboxylic acid methyl ester 225 (50 mg, 0.15 mmol) and methyl amine (33% in EtOH, 3 ml) gave the title compound (23 mg, 50%) after purification by column chromatography with DCM/MeOH (95:5) as the eluent.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:12][C:13]([CH3:18])=[CH:14][C:15](Cl)=[O:16].C(N(CC)CC)C>C(OCC)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:11][C:15](=[O:16])[CH:14]=[C:13]([CH3:18])[CH3:12])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)=CC(=O)Cl
Reactant: CC(C)(C)c1ccc(O)cc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(C)=CC(=O)Oc1ccc(C(C)(C)C)cc1
Temperature: 25 °C

Procedure:
To a chilled solution of 4-tert-butylphenol (15 g, 100 mmol) and 11.12 mL of 3-methylbut-2-enoyl chloride in 200 mL of diethyl ether at 0° C. was added 13.9 mL of triethylamine by addition funnel. The reaction mixture was warmed to room temperature and stirred until TLC indicated the reaction was complete. The reaction mixture was then filtered through diatomaceous earth, and the diethyl ether layer was washed two times with water, washed with brine, dried over magnesium sulfate, and concentrated in vacuo to leave 23 g of 3-methylbut-2-enoic acid 4-tert-butylphenyl ester as a brown oil that partially crystallized upon standing.
Reaction SMILES: CO[C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([NH:24][CH2:25][CH:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[N:6][CH:5]=1.[CH3:30][O:31][CH2:32][CH2:33][NH2:34]>>[CH2:25]([NH:24][C:23]1[C:18]([N:15]2[CH2:16][CH2:17][N:12]([C:10]([C:7]3[CH:8]=[CH:9][C:4]([C:3](=[O:29])[NH:34][CH2:33][CH2:32][O:31][CH3:30])=[CH:5][N:6]=3)=[O:11])[CH2:13][CH2:14]2)=[N:19][CH:20]=[CH:21][CH:22]=1)[CH:26]([CH3:28])[CH3:27]
Reactant: COC(=O)c1ccc(C(=O)N2CCN(c3ncccc3NCC(C)C)CC2)nc1
Reactant: COCCN
Product: COCCNC(=O)c1ccc(C(=O)N2CCN(c3ncccc3NCC(C)C)CC2)nc1
Yield: 65 %

Procedure:
By the same procedure as described in the example 25, the synthesis was carried out starting with 6-[1-[3-(isobutylamino)-2-pyridyl]piperazin-4-yl-carbonyl]nicotinic acid methyl ester and using 2-methoxyethylamine. And then, the product was recrystallized with isopropanol to give a desired compound.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[F:15][C:16]1[CH:53]=[CH:52][C:19]([O:20][C:21]2[CH:26]=[CH:25][C:24]([S:27]([N:30]3[CH2:39][CH2:38][C:37]4[C:32](=[CH:33][CH:34]=[C:35]([O:40][CH2:41][CH2:42][N:43]5[CH2:48][CH2:47][O:46][CH2:45][CH2:44]5)[CH:36]=4)[CH:31]3[C:49](O)=[O:50])(=[O:29])=[O:28])=[CH:23][CH:22]=2)=[CH:18][CH:17]=1.[O:54]1[CH2:59][CH2:58][CH2:57][CH2:56][CH:55]1[O:60][NH2:61]>CN(C=O)C>[O:54]1[CH2:59][CH2:58][CH2:57][CH2:56][CH:55]1[O:60][NH:61][C:49]([CH:31]1[C:32]2[C:37](=[CH:36][C:35]([O:40][CH2:41][CH2:42][N:43]3[CH2:44][CH2:45][O:46][CH2:47][CH2:48]3)=[CH:34][CH:33]=2)[CH2:38][CH2:39][N:30]1[S:27]([C:24]1[CH:25]=[CH:26][C:21]([O:20][C:19]2[CH:18]=[CH:17][C:16]([F:15])=[CH:53][CH:52]=2)=[CH:22][CH:23]=1)(=[O:28])=[O:29])=[O:50]
Reactant: NOC1CCCCO1
Reactant: O=C(O)C1c2ccc(OCCN3CCOCC3)cc2CCN1S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(NOC1CCCCO1)C1c2ccc(OCCN3CCOCC3)cc2CCN1S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
A solution of 40 mg (0.264 mmol) of HOBt and 51 mg (0.264 mmol) of EDC in 2 ml of DMF was added dropwise to a solution of 98 mg (0.176 mmol) of 2-[4-(4-fluoro-phenoxy)benzenesulfonyl]-6-(2-morpholin-4-ylethoxy)-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid and 46 mg (0.325 mmol) of O-(tetrahydropyran-2-yl)hydroxylamine in 3 ml of DMF at 0° C., and the mixture was stirred at room temperature. After standing overnight, it was poured onto H2O and extracted with ethyl acetate. The organic phase was dried with MgSO4 and concentrated. The residue was chromatographed on silica gel (dichloromethane→dichloromethane/methanol 99:1), the title compound being isolated as a colorless solid. Yield: 80%.
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.C[C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1.[CH3:16][CH:17]=C(C)C>C1CCCCC1>[C:11]1(=[O:12])[C:10]2[C:14](=[CH:15][CH:7]=[CH:8][CH:9]=2)[CH2:17][CH2:16]1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: CC=C(C)C
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: C1CCCCC1
Product: O=C1CCc2ccccc21
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
100 g Tin (IV) chloride is added at 10° C. to a solution of 79 g p-methyl benzoyl chloride and 40 g trimethyl ethene in 100 ml cyclohexane. The reaction mixture is then stirred at 10° C. during 30 min., subsequently poured out into ice and extracted with ether. The solution in ether is washed neutral, dried and evaporated. The residue is added to a solution of 72 g AlCl3 in 200 ml nitropropane, in the course of which the temperature is kept at 25°-30° C. Then the reaction mixture is stirred during five hours at 20° C. After that it is poured out into ice and extracted with ether. The solution in ether is washed neutral, dried and evaporated. The residue is distilled under diminished pressure yielding 45.4 g of the desire indanone. B.p. 95° C./1 mm Hg.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:17]=[CH:16][N:15]=3)[CH2:10][CH2:9]2)[N:5]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[N:3]=1.C[O:31][C:32]([CH2:34][CH2:35][C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1)=[O:33].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.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>[N:24]1([C:4]2[N:3]=[C:2]([C:38]3[CH:37]=[C:36]([CH2:35][CH2:34][C:32]([OH:33])=[O:31])[CH:41]=[CH:40][CH:39]=3)[CH:7]=[C:6]([N:8]3[CH2:9][CH2:10][N:11]([C:14]4[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:17]=[CH:16][N:15]=4)[CH2:12][CH2:13]3)[N:5]=2)[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1
Reactant: FC(F)(F)c1cccnc1N1CCN(c2cc(Cl)nc(N3CCOCC3)n2)CC1
Reactant: COC(=O)CCc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=C(O)CCc1cccc(-c2cc(N3CCN(c4ncccc4C(F)(F)F)CC3)nc(N3CCOCC3)n2)c1
Temperature: 80 °C

Procedure:
Purge a solution of 4-{4-chloro-6-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-pyrimidin-2-yl}-morpholine (142 mg, 0.33 mmol), (3-(2-methoxycarbonylethyl)phenyl)boronic acid (Combi-Blocks, Inc., San Diego, Calif.; 104 mg, 0.5 mmol) and K3PO4 (2M, 331 μL) in dioxane with nitrogen for 10 minutes. Add Pd(PPh3)4 (19 mg, 0.017 mmol) and purge for an additional 5 minutes. Seal the contents in a reaction vial and heat at 80° C. for 16 hours. Partition the mixture between EtOAc and water, dry (Na2SO4) the organic layer and concentrate under reduced pressure. Filter the residue through a small pad of silica gel eluting with 50% EtOAc/hexanes. Concentrate under reduced pressure to give the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([NH:6][NH:7][C:8]([C:10]1[NH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[N:19]([CH3:28])[S:20]([C:23]1[S:24][CH:25]=[CH:26][CH:27]=1)(=[O:22])=[O:21])=O)=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:38])=CC=1>O1CCCC1>[CH3:1][O:2][CH2:3][C:4]1[S:38][C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][C:13]=3[N:19]([CH3:28])[S:20]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)(=[O:22])=[O:21])=[N:7][N:6]=1
Reactant: COCC(=O)NNC(=O)c1cc2cccc(N(C)S(=O)(=O)c3cccs3)c2[nH]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: COCc1nnc(-c2cc3cccc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)s1
Temperature: 50 °C
Reaction time: 8 h
Yield: 62.4 %

Procedure:
A mixture of N-(2-{[2-(methoxyacetyl)hydrazino]carbonyl}-1H-indol-7-yl)-N-methylthiophene-2-sulfonamide (0.29 g), Lawesson's reagent (0.31 g) and tetrahydrofuran (10 mL) was stirred at 50° C. overnight. The reaction mixture was concentrated, and methanol was added to the residue. The resulting crystals were filtrated, washed with methanol, and dried to give the title compound (0.18 g, yield 62%) as pale-yellow crystals. melting point>238° C. (decomposition).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]2[NH:21][C:12]3[N:13]=[CH:14][CH:15]=[C:16]([C:17]([NH:19][NH2:20])=[O:18])[C:11]=3[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:22]([O-])([O-])(OCC)[CH3:23]>>[CH3:22][C:23]1[O:18][C:17]([C:16]2[CH:15]=[CH:14][N:13]=[C:12]3[NH:21][C:9]([CH2:8][CH2:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[CH:10][C:11]=23)=[N:19][N:20]=1
Reactant: NNC(=O)c1ccnc2[nH]c(CCc3ccccc3)cc12
Reactant: CCOC(C)([O-])[O-]
Product: Cc1nnc(-c2ccnc3[nH]c(CCc4ccccc4)cc23)o1
Temperature: 140 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
A mixture of 2-(2-phenylethyl)-1H-pyrrolo[2,3-b]pyridine-4-carbohydrazide (104 mg, 0.371 mmol) and ethyl orthoacetate (5 mL) was stirred at 120° C. for 1 hr and at 140° C. for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1-0/1) and basic silica gel column chromatography (hexane/ethyl acetate=4/1-0/1), and recrystallized from hexane/ethyl acetate to give the title compound (85 mg, yield 75%) as pale-yellow crystals.
Reaction SMILES: [CH3:1][C@@H:2]1[C@H:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:5][C:4](=[O:13])[N:3]1[C:14](=[O:32])[CH:15]([C:17]1[CH:22]=[CH:21][C:20](B2OC(C)(C)C(C)(C)O2)=[CH:19][CH:18]=1)[CH3:16].[Cl:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C@H:40]([O:42][C:43](=[O:58])[NH:44][C:45]1[C:46]([CH3:57])=[N:47][O:48][C:49]=1[C:50]1[CH:55]=[CH:54][C:53](Br)=[CH:52][CH:51]=1)[CH3:41]>>[Cl:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C@H:40]([O:42][C:43](=[O:58])[NH:44][C:45]1[C:46]([CH3:57])=[N:47][O:48][C:49]=1[C:50]1[CH:55]=[CH:54][C:53]([C:20]2[CH:19]=[CH:18][C:17]([CH:15]([CH3:16])[C:14]([N:3]3[C@H:2]([CH3:1])[C@H:6]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)[O:5][C:4]3=[O:13])=[O:32])=[CH:22][CH:21]=2)=[CH:52][CH:51]=1)[CH3:41]
Reactant: CC(C(=O)N1C(=O)O[C@@H](c2ccccc2)[C@H]1C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)O[C@H](C)c1ccccc1Cl
Product: Cc1noc(-c2ccc(-c3ccc(C(C)C(=O)N4C(=O)O[C@@H](c5ccccc5)[C@H]4C)cc3)cc2)c1NC(=O)O[C@H](C)c1ccccc1Cl

Procedure:
Diastereomer B—Prepared as described in Example 36, Step 6 using (4R,5S)-4-methyl-5-phenyl-3-{2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propionyl}-oxazolidin-2-one (Diastereomer B) and [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid (R)-1-(2-chloro-phenyl)-ethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[N:8][CH2:7][CH2:6]2.C(N(CC)CC)C.[CH3:26][N:27]1[CH:31]=[C:30]([S:32](Cl)(=[O:34])=[O:33])[N:29]=[CH:28]1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([CH:13]1[CH2:18][CH2:17][N:16]([S:32]([C:30]3[N:29]=[CH:28][N:27]([CH3:26])[CH:31]=3)(=[O:34])=[O:33])[CH2:15][CH2:14]1)=[N:8][CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCN=C2C1CCNCC1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2c(c1)CCN=C2C1CCN(S(=O)(=O)c2cn(C)cn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.1 %

Procedure:
To a stirred solution of 6-methoxy-1-piperidin-4-yl-3,4-dihydro-isoquinoline (0.094 g, 0.385 mmol) and triethylamine (0.078 g, 0.77 mmol) in CH2Cl2 (3 ml) was added 1-methyl-1H-imidazole-4-sulfonyl chloride (0.070 g, 0.385 mmol). The reaction mixture was stirred at RT under an atmosphere of N2 overnight. The reaction mixture was diluted with CH2Cl2 (10 ml) and washed with water (2×5 ml). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified via radial chromatography (SiO2, 1 mm, CH2Cl2 to 5% MeOH/CH2Cl2) to give the product as an oil (0.084 g, 0.216 mmol, 56% yield).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:16][C:17]([F:28])([F:27])[C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>COCCOC.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>[Cl:1][C:2]1[N:3]=[C:4]([CH3:9])[CH:5]=[C:6]([C:21]2[CH:22]=[CH:23][C:18]([C:17]([F:28])([F:27])[F:16])=[CH:19][CH:20]=2)[N:7]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: Cc1cc(Cl)nc(Cl)n1
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(Cl)n1
Temperature: 90 °C
Yield: 58.5 %

Procedure:
To a solution of 2,4-dichloro-6-methyl-pyrimidine (5 g, 30.67 mmol) in 1,2-dimethoxyethane (35 mL) and water (25 mL) was added sodium carbonate (9.75 g, 92.03 mmol), and 4-(trifluoromethyl)-phenylboronic acid (5.53 g, 29.14 mmol). This was degassed with nitrogen for 5 minutes. The bis(triphenylphosphine)palladium (II) dichloride (1.08 g, 1.53 mmol) was then added and the reaction was heated to 90° C. overnight. The solvent was evaporated and the residue was partitioned between water (300 mL) and EtOAc (300 mL). The organics were washed with brine (100 mL), dried over MgSO4 and concentrated in vacuo to afford a yellow oil. The material was purified using a Biotage SP4, 0 to 50% i-hexane/EtOAc and the fractions containing the lower (major) spot were collected and the solvent evaporated to afford the 2-chloro-4-methyl-6-[4-(trifluoromethyl)-phenyl]pyrimidine (D5) (4.65 g, 17.06 mmol, 55.6% yield) as a colourless solid.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1.[F:22][C:23]1([F:33])[O:27][C:26]2[CH:28]=[CH:29][CH:30]=[C:31]([NH2:32])[C:25]=2[O:24]1>>[CH:16]1([N:7]2[CH2:8][C:9]([F:15])([F:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:32][C:31]4[C:25]5[O:24][C:23]([F:33])([F:22])[O:27][C:26]=5[CH:28]=[CH:29][CH:30]=4)=[N:21][C:6]2=3)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Reactant: Nc1cccc2c1OC(F)(F)O2
Product: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3cccc4c3OC(F)(F)O4)ncc21

Procedure:
The title compound was synthesized from 2-chloro-9-cyclopentyl-7,7-difluoro-5-methyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one and 2,2-difluorobenzo[d][1,3]dioxol-4-amine using the procedure described in the general Buchwald Reaction Scheme. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.20-1.84 (m, 9 H) 3.97 (t, J=14.40 Hz, 2 H) 4.50-4.70 (m, 1 H) 7.14 (d, J=2.27 Hz, 1 H) 7.31 (dd, J=7.45, 2.15 Hz, 1 H) 8.21 (s, 1 H) 9.39 (s, 1 H). [M+H] calculated for C20H19F4N5O3, 454; found 454.
Reaction SMILES: [OH-:1].[Na+].[I:3][C:4]1[C:11]([I:12])=[CH:10][C:9]([I:13])=[CH:8][C:5]=1[CH2:6]Br.O>CN1C(=O)CCC1>[I:3][C:4]1[C:11]([I:12])=[CH:10][C:9]([I:13])=[CH:8][C:5]=1[CH2:6][O:1][CH2:6][C:5]1[CH:8]=[C:9]([I:13])[CH:10]=[C:11]([I:12])[C:4]=1[I:3]
Reactant: BrCc1cc(I)cc(I)c1I
Reactant: [OH-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Ic1cc(I)c(I)c(COCc2cc(I)cc(I)c2I)c1
Temperature: 130 °C
Reaction time: 0.08 h

Procedure:
447 mg of PVA 13 kDa (9 mmol, 1 eq) was dissolved in 30 ml of dry NMP (concentration of PVA: 0.3M) under nitrogen gas flow. The reaction mixture was stirred for 5 minutes at 130° C.; then the temperature was decreased to 50° C. 727 mg of ground and dried NaOH (18 mmol, 2 eq) was added and the mixture was stirred for 10 minutes. Then, 5 g of 2,3,5-triiodobenzyl bromide (9 mmol, 1 eq) was added. After 30 minutes, the mixture was cooled to room temperature and 30 ml of cold water was added under stirring. A solid precipitate appeared, was filtered and washed with methanol. After conventional steps of purification, 800 mg of TIB-PVA 13 kDa including 26% of residual NMP was obtained (representing 208 mg of NMP and 592 mg of TIB-PVA 13 kDa).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][NH2:7].C[Al](C)C.[F:17][C:18]1[C:23]([C:24]2[CH:25]=[C:26]([C:36](OC)=[O:37])[C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)=[N:28][CH:29]=2)=[CH:22][C:21]([CH3:40])=[CH:20][N:19]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][NH:7][C:36]([C:26]1[C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)=[N:28][CH:29]=[C:24]([C:23]2[C:18]([F:17])=[N:19][CH:20]=[C:21]([CH3:40])[CH:22]=2)[CH:25]=1)=[O:37]
Reactant: COc1ccc(CN)cc1OC
Reactant: COC(=O)c1cc(-c2cc(C)cnc2F)cnc1-c1ccccn1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccc(CNC(=O)c2cc(-c3cc(C)cnc3F)cnc2-c2ccccn2)cc1OC
Temperature: 100 °C
Reaction time: 0.75 h

Procedure:
To a solution of 3,4-dimethoxybenzylamine (0.15 g, 0.89 mmol, 8.0 equiv) in toluene (2.2 mL) was added a solution of trimethylaluminum (0.39 mL, 0.78 mmol, 7.0 equiv, 2 M in toluene) at ambient temperature and the reaction mixture was stirred for 45 minutes. To the reaction mixture was added a solution of methyl 2″-fluoro-5″-methyl-2,2′:5′,3″-terpyridine-3′-carboxylate (0.036 g, 0.11 mmol, 1.0 equiv) in toluene (2 mL) and the reaction mixture was heated to 100° C. for 15 h. The reaction mixture was cooled and diluted with ethyl acetate (30 mL) and quenched with Rochelle's salts (20 mL, saturated solution). The organic phase was washed with Rochelle's salts (3×20 mL, saturated solution), dried over magnesium sulfate and concentrated. The residue was purified via normal phase chromatography (15 to 100% EtOAc in hexanes, silica) to afford the desired product (11-4) as a white solid after concentration. 1H NMR (500 MHz, CDCl3) δ 8.92-8.90 (m, 1H), 8.35 (d, J=4.0 Hz, 1H), 8.25 (bs, 1H), 8.07 (bs, 1H), 8.02 (d, J=7.6 Hz, 1H), 7.82 (td, J=7.6, 1.6 Hz, 1H), 7.78 (dd, J=9.6, 2.0 Hz, 1H), 7.70 (bs, 1H), 7.30-7.27 (m, 1H), 6.83-6.79 (m, 3H), 4.51 (d, J=5.6 Hz, 2H), 3.88 (s, 3H), 3.81 (s, 3H), 2.41 (s, 3H). HRMS [M+H] C26H23FN4O3 calc'd 459.1827. found 459.1827.