Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[CH3:5][C:6]1([CH3:18])[CH2:11][CH:10]([N:12]2[CH2:16][CH2:15][NH:14][C:13]2=[O:17])[CH2:9][CH2:8][O:7]1.N1C=CC=CC=1>C(Cl)Cl>[CH3:5][C:6]1([CH3:18])[CH2:11][CH:10]([N:12]2[CH2:16][CH2:15][N:14]([C:1]([Cl:4])=[O:2])[C:13]2=[O:17])[CH2:9][CH2:8][O:7]1
Reactant: O=C(Cl)Cl
Reactant: CC1(C)CC(N2CCNC2=O)CCO1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(C)CC(N2CCN(C(=O)Cl)C2=O)CCO1
Temperature: 25 °C
Yield: 100 %

Procedure:
A 0° C. solution of phosgene (20% in toluene, 0.361 mL, 0.676 mmol) in DCM (2 mL), under Ar, was treated slowly drop-wise with a solution of 1-(2,2-dimethyltetrahydro-2H-pyran-4-yl)imidazolidin-2-one (0.067 g, 0.338 mmol) and pyridine (0.055 mL, 0.676 mmol) in DCM (1 mL). The mixture was warmed to RT and concentrated to dryness to afford 3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-oxoimidazolidine-1-carbonyl chloride as a yellow solid which was carried on to the next step assuming 100% yield (88 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][CH3:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[O:17][CH3:18])[CH:5]=[CH:4][N:3]=1.[CH3:19][S:20]([C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[C:26]([OH:28])=O)(=[O:22])=[O:21]>>[Cl:1][C:2]1[C:7]([N:8]([CH3:9])[C:26](=[O:28])[C:25]2[CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=[C:23]([S:20]([CH3:19])(=[O:21])=[O:22])[CH:24]=2)=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[O:17][CH3:18])[CH:5]=[CH:4][N:3]=1
Reactant: CNc1c(-c2ccc(F)cc2OC)ccnc1Cl
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Product: COc1cc(F)ccc1-c1ccnc(Cl)c1N(C)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1

Procedure:
The title compound was prepared in analogy to example 90, from [2-chloro-4-(4-fluoro-2-methoxy-phenyl)-pyridin-3-yl]-methyl-amine and 3-methanesulfonyl-5-trifluoromethyl-benzoic acid (example 114, intermediate a) after a reaction time of 66 hours. The compound was purified by silica gel chromatography on a 20 g column using an MPLC (ISCO) system eluting with a gradient of n-heptane:EtOAc (100:0 to 50:50), followed by a second chromatography using preparative HPLC (Gemini NX column) eluting with a gradient of methanol:water (containing 0.1% formic acid) (20:80 to 98:2). Colorless solid (30%). MS (ESI): m/z=517.06 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]=[C:13]([N:15]4[C:19]([CH3:21])([CH3:20])[C:18](=[O:22])[NH:17][C:16]4=[O:23])[S:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:24]=1.CC1(C)C(C)(C)OB([C:33]2[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH:34]=2)O1>>[CH3:20][C:19]1([CH3:21])[N:15]([C:13]2[S:14][C:10]3[CH2:9][CH2:8][O:7][C:6]4[CH:24]=[C:2]([C:33]5[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH:34]=5)[CH:3]=[CH:4][C:5]=4[C:11]=3[N:12]=2)[C:16](=[O:23])[NH:17][C:18]1=[O:22]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: CC1(C)C(=O)NC(=O)N1c1nc2c(s1)CCOc1cc(Br)ccc1-2
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc3c(c2)OCCc2sc(N4C(=O)NC(=O)C4(C)C)nc2-3)CC1
Yield: 19 %

Procedure:
1-(8-Bromo-4,5-dihydrothiazolo[4,5-d]benzo[b]oxepin-2-yl)-5,5-dimethylimidazolidin-2,4-dione was coupled with tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate to give tert-butyl 4-(2-(5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)-4,5-dihydrothiazolo[4,5-d]benzo[b]oxepin-8-yl)-5,6-dihydropyridine-1(2H)-carboxylate. Yield 19%. MS (ESI+): 511.3
Reaction SMILES: FC(F)(F)C(O)=O.C([NH:27][CH2:28][CH2:29][C:30]1([C:43]([O:45]CC)=O)[CH2:35][CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(Cl)Cl.O1CCOCC1.C(N(CC)C(C)C)(C)C>>[C:43]1(=[O:45])[C:30]2([CH2:35][CH2:34][CH2:33][NH:32][CH2:31]2)[CH2:29][CH2:28][NH:27]1
Reactant: CCOC(=O)C1(CCNC(c2ccccc2)(c2ccccc2)c2ccccc2)CCCN(C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C1NCCC12CCCNC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (1.0 mL, 0.013 mol) was added to a solution of 1-tert-butyl 3-ethyl 3-[2-(tritylamino)ethyl]piperidine-1,3-dicarboxylate (0.10 g, 0.00018 mol) in methylene chloride (1.0 mL, 0.016 mol) and the mixture was stirred for 1 h at rt to remove the Boc and trityl groups. Then the solvent was removed under vacuum and to the resultant residue was added 1,4-dioxane (3.0 mL, 0.038 mol) followed by N,N-diisopropylethylamine (0.13 mL, 0.00074 mol) and the resultant mixture was stirred at 150° C. (microwave) for 1 h. The solvent from the mixture was removed under vacuum and the crude product was used in the next step without further purification. LC-MS: 155.2 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[C:11]([O:18][CH3:19])[CH:10]=2)[CH2:5][CH2:4]1)[CH3:2]>[Ni].CO>[CH2:1]([N:3]1[CH2:4][CH2:5][N:6]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([O:18][CH3:19])[CH:10]=2)[CH2:7][CH2:8]1)[CH3:2]
Reactant: CCN1CCN(c2ccc([N+](=O)[O-])c(OC)c2)CC1
Agent: [Ni]
Solvent: CO
Product: CCN1CCN(c2ccc(N)c(OC)c2)CC1
Temperature: 25 °C
Reaction time: 10.5 h

Procedure:
A suspension of 1-ethyl-4-(3-methoxy-4-nitro-phenyl)-piperazine (4 g, 15.1 mmol) and Raney Nickel (1 g) in MeOH (80 mL) is stirred for 10.5 h at RT, under a hydrogen atmosphere. The reaction mixture is filtered through a pad of celite and concentrated to afford the title compound as a brown oil: ESI-MS: 236.2 [MH]+; tR=0.95 min (system 1).
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].CCN(CC)CC.[NH2:19][NH2:20]>CCO>[NH2:11][C:10]1[C:8]2[C:9](=[CH:2][C:3]([C:4]#[N:5])=[CH:6][CH:7]=2)[NH:20][N:19]=1
Reactant: N#Cc1ccc(C#N)c(F)c1
Reactant: NN
Solvent: CCN(CC)CC
Solvent: CCO
Product: N#Cc1ccc2c(N)n[nH]c2c1

Procedure:
To a solution of 2-fluoroterephthalonitrile (500 mg) and Et3N (572 μl) in EtOH (20 ml) was added hydrazine (monohydrate), followed by reaction at 60° C. for 16 hours, and concentrated. The residue was washed with diethyl ether to obtain 3-amino-1H-indazole-6-carbonitrile (488 mg) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][NH:16][CH:15]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:14]3=[O:25])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[C:26]([N:16]1[CH2:17][CH2:18][N:13]([CH2:12][CH2:11][C:6]2[C:5]3[C:9](=[CH:10][C:2]([CH3:1])=[CH:3][CH:4]=3)[NH:8][CH:7]=2)[C:14](=[O:25])[CH:15]1[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCOC(=O)CC1NCCN(CCc2c[nH]c3cc(C)ccc23)C1=O
Reactant: O=C(Cl)c1ccccc1
Product: CCOC(=O)CC1C(=O)N(CCc2c[nH]c3cc(C)ccc23)CCN1C(=O)c1ccccc1

Procedure:
Using the procedure of Step D of Example 1, 10 g of the product of Step C and 3.36 ml of benzoyl chloride were reacted to obtain 13 g of expected product melting at 155° C.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:20])=[CH:16][C:17]([CH3:19])=[CH:18][C:13]=3[O:12][C:11]2=[O:21])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]>C(OCC)(=O)C.CCCCCC>[OH:21][CH2:11][CH:10]([C:14]1[C:15]([CH3:20])=[CH:16][C:17]([CH3:19])=[CH:18][C:13]=1[OH:12])[C:7]1[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=1
Reactant: Cc1cc(C)c2c(c1)OC(=O)C2c1ccc(C(C)C)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1cc(C)c(C(CO)c2ccc(C(C)C)cc2)c(O)c1
Yield: 93 %

Procedure:
Using 3-(4-isopropylphenyl)-4,6-dimethyl-1-benzofuran-2(3H)-one synthesized in Reference Example 4, the title compound was synthesized in the same manner as in Reference Example 8. Yield 93%. Melting point: 101-102° C. (ethyl acetate-hexane).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[F:9].C([Li])CCC.[CH2:15]([N:22]1[CH2:26][CH2:25][C:24](=[O:27])[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Cl-].[NH4+]>C(OCC)C>[CH2:15]([N:22]1[CH2:26][CH2:25][C:24]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=2[F:9])([OH:27])[CH2:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C1CCN(Cc2ccccc2)C1
Reactant: Fc1cccc(Br)c1F
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Product: OC1(c2cccc(F)c2F)CCN(Cc2ccccc2)C1
Temperature: -78 °C
Reaction time: 2 h
Yield: 57.9 %

Procedure:
To a solution of 1-bromo-2,3-difluorobenzene (25 g, 129.5 mmol) in dry diethyl ether (150 mL), under nitrogen at −78° C. was added drop wise n-butyllithium (2.5 M in hexane, 51.8 mL, 129.5 mmol). The mixture was stirred for 30 min after which a solution of 1-benzylpyrrolidin-3-one (20.4 g, 116.5 mmol) in dry diethyl ether (50 mL) was added drop wise. The mixture was stirred at −78° C. for 30 min and for 2 h at ambient temperature. Aqueous saturated ammonium chloride solution (50 mL) was added and the mixture was extracted with ethyl acetate (2×50 mL). The combined organic phase was dried (Na2SO4), filtered and evaporated. Purification by flash chromatography on silica gel (isooctane/ethyl acetate/triethyl amine, 75:20:5) gave the title compound (19.5 g). MS m/z (relative intensity, 70 eV) 289 (M+, 20), 198 (69), 133 (72), 132 (51), 91 (bp).
Reaction SMILES: [F:1][C:2]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][NH:9][C:8](=[O:12])[CH:7]=1.[Cl:18]N1C(=O)CCC1=O.C(#N)C.O.FC(F)(F)C(O)=O>CN(C)C=O.C(OCC)C>[Cl:18][C:7]1[C:8](=[O:12])[NH:9][CH:10]=[CH:11][C:6]=1[O:5][CH2:4][C:3]1[CH:13]=[CH:14][C:15]([F:17])=[CH:16][C:2]=1[F:1]
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=c1cc(OCc2ccc(F)cc2F)cc[nH]1
Solvent: O
Solvent: CCOCC
Solvent: CC#N
Product: O=c1[nH]ccc(OCc2ccc(F)cc2F)c1Cl
Reaction time: 15 h

Procedure:
4-[(2,4-difluorobenzyl)oxy]-pyridin-2(1H)-one (from Step 2) (8.60 g, 36.3 mmol) was stirred in 150 ml dimethylformamide and treated with N-chlorosuccinimide (5.4 g, 39.9 mmol). After 15 hours, the precipitate was collected by filtration (5.11 g, 52%) yielding a lustrous white solid. The mother liquor was diluted to 500 ml with diethyl ether, providing 2.47 g (25%) in a second crop. 1H-NMR (400 MHz, DMSO-d6) δ 11.87 (s, 1H), 7.60 (quartet, J=6.34 Hz, 1H), 7.43 (d, J=7.58 Hz, 1H), 7.31 (dt, J=10.08, 2.21 Hz, 1H), 7.14 (dt, J=8.65, 1.79 Hz, 1H), 6.44 (d, J=7.49 Hz, 1H), 5.28 (s, 1H). 19F-NMR (400 MHz, DMSO-d6) δ −109.58 (quintet, J=7.75 Hz, 1F), −113.68 (quartet, J=8.68 Hz, 1F). LC/MS tr=4.47 minutes (0-95% acetonitrile/water, 0.05% trifluoroacetic acid, over 6 minutes at 1 ml/min with detection at 254 nm, at 50° C.) ES-MS m/z 272, 274 3:1 (M+H).
Reaction SMILES: [Si]([C:5]([F:8])([F:7])[F:6])(C)(C)C.[Cl:9][C:10]1[C:15]([CH3:16])=[CH:14][C:13](/[CH:17]=[N:18]/[S@@:19]([C:21]([CH3:24])([CH3:23])[CH3:22])=[O:20])=[CH:12][C:11]=1[CH3:25]>C1COCC1.CCCC[N+](CCCC)(CCCC)CCCC.C1C=CC([Si-](F)(F)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:9][C:10]1[C:11]([CH3:25])=[CH:12][C:13]([C@H:17]([NH:18][S@@:19]([C:21]([CH3:23])([CH3:22])[CH3:24])=[O:20])[C:5]([F:8])([F:7])[F:6])=[CH:14][C:15]=1[CH3:16]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: Cc1cc(/C=N/[S@](=O)C(C)(C)C)cc(C)c1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: F[Si-](F)(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: Cc1cc([C@H](N[S@](=O)C(C)(C)C)C(F)(F)F)cc(C)c1Cl
Reaction time: 3 h

Procedure:
A solution of TMS-CF3 (0.737 mL, 4.99 mmol) in THF (15 mL) was added to a solution of TBAT (2.469 g, 4.57 mmol) and INT 36 (1.13 g, 4.16 mmol) in THF (60.0 mL) at −65° C. Stirring was continued for 3 hours. Another portion of TBAT (200 mg, 0.37 mmol) was added. After 2 more hours, more TMS-CF3 (0.369 ml, 2.50 mmol) was added. The suspension became a clear solution which was quenched with saturated ammonium chloride solution, diluted with EtOAc and washed with water. The organic layer was dried over sodium sulfate, filtered and concentrated. The crude was purified by chromatography on silica gel (cyclohexane/EtOAc).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][N:5]([C:7]2[S:8][C:9](=[CH:13][C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:25]=3[C:34]([F:37])([F:36])[F:35])[N:18]=[CH:17]4)[C:10](=[O:12])[N:11]=2)[C@@H:4]([CH2:38][OH:39])[CH2:3]1.[CH:40]1([C:43](Cl)=[O:44])[CH2:42][CH2:41]1>>[F:35][C:34]([F:37])([F:36])[C:25]1[CH:26]=[C:27]([C:30]([F:33])([F:31])[F:32])[CH:28]=[CH:29][C:24]=1[CH2:23][N:19]1[C:20]2[C:16](=[CH:15][C:14]([CH:13]=[C:9]3[S:8][C:7]([N:5]4[C@@H:4]([CH2:38][OH:39])[CH2:3][C@@H:2]([NH:1][C:43]([CH:40]5[CH2:42][CH2:41]5)=[O:44])[CH2:6]4)=[N:11][C:10]3=[O:12])=[CH:22][CH:21]=2)[CH:17]=[N:18]1
Reactant: N[C@@H]1C[C@H](CO)N(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)C1
Reactant: O=C(Cl)C1CC1
Product: O=C1N=C(N2C[C@H](NC(=O)C3CC3)C[C@@H]2CO)SC1=Cc1ccc2c(cnn2Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c1

Procedure:
N-{(3R,5R)-1-[5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]-5-(hydroxymethyl)pyrrolidin-3-yl}cyclopropanecarboxamide was prepared from 2-[(2R,4R)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl]-5-({1-[2,4-bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-1,3-thiazol-4(5H)-one (example 258) and Cyclopropylcarbonyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24]Cl)=[CH:20][CH:19]=2)=[N:16][CH:15]=[CH:14][N:13]=1)(=[O:10])=[O:9].[CH3:26][NH:27][C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][N:27]([C:28]3[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=3)[CH3:26])=[CH:20][CH:19]=2)=[N:16][CH:15]=[CH:14][N:13]=1)(=[O:10])=[O:9]
Reactant: O=S(=O)(Nc1nccnc1-c1ccc(CCl)cc1)c1ccccc1Cl
Reactant: CNc1ccc(C#N)cc1
Product: CN(Cc1ccc(-c2nccnc2NS(=O)(=O)c2ccccc2Cl)cc1)c1ccc(C#N)cc1
Yield: 52 %

Procedure:
Following the general method as outlined in Example 1 (Method B), starting from N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(chloro) benzenesulfonamide (Intermediate 8), and 4-(N-methylamino)-benzonitrile, the title compound was isolated as a yellow solid in 52% yield (99% purity by HPLC).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[S:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1.C([C:26]1[C:27]([N:34]=[CH:35][N:36]([CH3:38])C)=[N:28][C:29]([CH2:32][CH3:33])=[CH:30][CH:31]=1)#N.NC1C=C(OCC2C=CC(OC)=CC=2)C=CC=1SC1C=CC(O)=CC=1.C(C1C(N=CN(C)C)=NC(C)=CC=1)#N>>[CH2:9]([O:8][C:6]1[CH:5]=[CH:4][C:3]([S:16][C:17]2[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=2)=[C:2]([NH:1][C:38]2[C:26]3[CH:31]=[CH:30][C:29]([CH2:32][CH3:33])=[N:28][C:27]=3[N:34]=[CH:35][N:36]=2)[CH:7]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Nc1cc(OCc2ccccc2)ccc1Sc1ccc(O)cc1
Reactant: CCc1ccc(C#N)c(N=CN(C)C)n1
Agent: COc1ccc(COc2ccc(Sc3ccc(O)cc3)c(N)c2)cc1
Agent: Cc1ccc(C#N)c(N=CN(C)C)n1
Product: CCc1ccc2c(Nc3cc(OCc4ccccc4)ccc3Sc3ccc(O)cc3)ncnc2n1

Procedure:
The product from Example 27A was reacted with the product from Example 145A using the procedure from Example 10F substituting the product from Example 27A for the product from Example 10E and substituting the product from Example 145A for the product from Example 10B to provide the title product. 1H NMR (300 MHz, DMSO-D6) δ ppm: 1.32 (t, J=7.72 Hz, 3H), 2.95 (q, J=7.72 Hz, 2H), 5.11 (s, 2H), 6.65 (d, J=8.82 Hz, 2H), 6.91-7.05 (m, 1H), 7.10 (d, J=8.46 Hz, 2H), 7.32-7.50 (m, 6H), 8.12 (d, J=6.99 Hz, 1H), 8.66-8.77 (m, 1H), 9.04 (d, J=8.82 Hz, 1H), 9.63 (s, 1H), 10.28 (s, 1H); MS (APCI) m/z 481 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([NH2:13])[CH:7]=1.C([O:17][C:18](=O)[CH:19]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH:36]=[CH:35][CH:34]=[N:33]2)=[CH:28][CH:27]=1)[C:20](=O)[CH:21]([CH3:23])[CH3:22])C>>[CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]2[C:7]=1[C:18](=[O:17])[C:19]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]3[CH:36]=[CH:35][CH:34]=[N:33]3)=[CH:28][CH:27]=1)=[C:20]([CH:21]([CH3:23])[CH3:22])[NH:13]2
Reactant: CCOC(=O)C(Cc1ccc(-n2cccn2)cc1)C(=O)C(C)C
Reactant: COC(=O)COc1ccc(Cl)c(N)c1
Product: COC(=O)COc1ccc(Cl)c2[nH]c(C(C)C)c(Cc3ccc(-n4cccn4)cc3)c(=O)c12

Procedure:
The title compound was prepared by the method of Preparation is using (3-amino-4-chlorophenoxy)acetic acid methyl ester and 4-methyl-3-oxo-2-(4-pyrazol-1-ylbenzyl)pentanoic acid ethyl ester.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([CH:8](O)[CH3:9])=[CH:4][CH:3]=1.[CH2:11]([N:13](CC)[CH2:14]C)C.S(Cl)(C)(=O)=O.CNC>ClC(Cl)C.CO.O>[Br:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([N:13]([CH3:14])[CH3:11])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(O)c1ccc(Br)nc1
Reactant: CCN(CC)CC
Agent: CNC
Agent: CS(=O)(=O)Cl
Solvent: O
Solvent: CO
Solvent: CC(Cl)Cl
Product: CC(c1ccc(Br)nc1)N(C)C
Temperature: 4 °C
Yield: 12.1 %

Procedure:
1-(6-Bromopyridin-3-yl)ethanol (100 mg, 0.54 mmol) was dissolved in dichloroethane (4 ml), 200 mg of triethylamine was added thereto, and the mixture was stirred at 4° C. under ice cooling. Mesyl chloride (68 mg, 0.60 mmol) was added to the reaction solution. After the dropwise addition, the mixture was stirred at 4° C. under ice cooling and was further stirred at room temperature for 30 min. The reaction solution was poured into 10 ml of iced water and was extracted with 20 ml of ethyl acetate. The extract was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under the reduced pressure. The residue was dissolved in DMF (2 ml), and the solution was stirred at room temperature. A 2 M solution (1 ml) of dimethylamine (2 mmol) in methanol was added thereto, and the mixture was stirred at 50° C. for 4 hr. The reaction solution was poured into 10 ml of iced water and was extracted with 20 ml of ethyl acetate. The extract was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under the reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:2) to give 15 mg (yield 33.1%) of the title compound.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]3[CH:12]=[N:13][N:14]=[C:7]3[C@@H:6]([CH2:15][CH3:16])[N:5]([CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[C:4]=2[N:3]=1.[NH2:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([NH:29][CH3:30])=[O:28])=[CH:25][C:24]=1[C:33]([F:36])([F:35])[F:34].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>O1CCOCC1.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:17]1([N:5]2[C:4]3[N:3]=[C:2]([NH:22][C:23]4[CH:32]=[CH:31][C:26]([C:27]([NH:29][CH3:30])=[O:28])=[CH:25][C:24]=4[C:33]([F:34])([F:35])[F:36])[N:11]=[CH:10][C:9]=3[N:8]3[CH:12]=[N:13][N:14]=[C:7]3[C@H:6]2[CH2:15][CH3:16])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CC[C@@H]1c2nncn2-c2cnc(Cl)nc2N1C1CCCC1
Reactant: CNC(=O)c1ccc(N)c(C(F)(F)F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC[C@@H]1c2nncn2-c2cnc(Nc3ccc(C(=O)NC)cc3C(F)(F)F)nc2N1C1CCCC1
Temperature: 150 °C
Reaction time: 1 h
Yield: 46 %

Procedure:
A mixture of (R)-7-chloro-5-cyclopentyl-4-ethyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridine (100 mg, 0.329 mmol), 4-amino-3-trifluoromethyl-N-methylbenzamide, palladium acetate (6 mg), cesium carbonate (214 mg, 0.658 mmol) and xanthphos (20 mg) in dioxane (4 ml) was stirred at 150° C. in a microwave for 1 hour. The mixture was diluted with ethyl acetate and washed with aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate and concentrated. The residue was purified by chromatography on silica gel eluting with 0-12% methanol/ethyl acetate to give 4-((R)-5-cyclopentyl-4-ethyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridine-7-ylamino)-3-trifluoromethyl-N-methylbenzamide as a colourless glass (70 mg, 46%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[C:11]([C:15]1[CH:16]=[C:17]([CH:21]=[C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:23]=1[OH:24])[C:18](Cl)=[O:19])([CH3:14])([CH3:13])[CH3:12]>COCCOC>[C:6]([C:5]1[CH:9]=[CH:10][C:2]([NH:1][C:18](=[O:19])[C:17]2[CH:21]=[C:22]([C:25]([CH3:26])([CH3:27])[CH3:28])[C:23]([OH:24])=[C:15]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:16]=2)=[CH:3][CH:4]=1)([OH:8])=[O:7]
Reactant: CC(C)(C)c1cc(C(=O)Cl)cc(C(C)(C)C)c1O
Reactant: Nc1ccc(C(=O)O)cc1
Solvent: COCCOC
Product: CC(C)(C)c1cc(C(=O)Nc2ccc(C(=O)O)cc2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 32.7 %

Procedure:
A solution of 8.6 g (0.063 mole) of p-aminobenzoic acid in 100 ml of 1,2-dimethoxyethane was added to a suspension of 8.0 g (0.0298 mole) of 3,5-di-t-butyl-4-hydroxybenzoyl chloride in 100 ml of 1,2-dimethoxyethane, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was then filtered. The filtrate was thereafter diluted with 200 ml of water and chilled. The resulting precipitate was collected, and was then recrystallized from a mixture of ethanol and water to give 3.6g of white needles of N-(4-carboxyphenyl)-3,5-di-t-butyl-4-hydroxybenzamide, m.p. 265°-266° C. Analysis: Calculated for C22H27NO4 : %C, 71.5; %H, 7.4; %N, 3.8; Found: %C, 71.7; %H, 7.3; %N, 3.6.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH:16]=1)[C:11]([OH:13])=[O:12].C1(N=C=NC2CCCCC2)CCCCC1.O[N:40]1[C:44](=[O:45])[CH2:43][CH2:42][C:41]1=[O:46]>CCOCC>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH:16]=1)[C:11]([O:13][N:40]1[C:44](=[O:45])[CH2:43][CH2:42][C:41]1=[O:46])=[O:12]
Reactant: O=C1CCC(=O)N1O
Reactant: O=C(O)c1cc(OC2CCCCO2)cc(OC2CCCCO2)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOCC
Product: O=C(ON1C(=O)CCC1=O)c1cc(OC2CCCCO2)cc(OC2CCCCO2)c1
Temperature: 25 °C
Reaction time: 40 h
Yield: 89.8 %

Procedure:
A mixture of 3,5-bis[(tetrahydro-2H-pyran-2-yl)oxy]benzoic acid (5.00 g, 15.5 mmol), 1,3-dicyclohexylcarbodiimide (3.72 g, 18.1 mmol) and N-hydroxysuccinimide (2.08 g, 18.0 mmol) in tetrahydroftiran (100 mL) was stirred at room temperature for 40 h. Ether (100 mL) was added and the mixture was stirred for 20 min. The white solid was filtered off and discarded. The solvent was evaporated from the filtrate, and the residue was coated onto silica gel and chromatographed (50-75% ethyl acetate/hexanes) to give 1-[[3,5-bis[(tetrahydro-2H-pyran-2-yl)oxy]benzoyl]oxy]-2,5-pyrrolidinedione (5.84 g, 90%) as a white solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]=[C:8]([CH3:20])[N:9]2[CH2:14][C:15]([O:17]CC)=[O:16])(=[O:3])[CH3:2].[OH-].[Na+].Cl>C(O)C>[C:1]([NH:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]=[C:8]([CH3:20])[N:9]2[CH2:14][C:15]([OH:17])=[O:16])(=[O:3])[CH3:2]
Reactant: CCOC(=O)Cn1c(C)cc2c(NC(C)=O)cccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(=O)Nc1cccc2c1cc(C)n2CC(=O)O
Temperature: 50 °C

Procedure:
(4-Acetylamino-2-methyl-1H-indol-1-yl)-acetic acid, ethyl ester (2.0 g, 7.3 mmol) was slurried in ethanol (10 ml) at ambient temperature. Aqueous sodium hydroxide (1 M, 10 ml, 10 mmol) was added and the mixture heated to 50° C. The solution obtained at was then allowed to cool back to ambient temperature and aqueous hydrochloric acid (1 M, 11 ml, 11 mmol) added. The resulting solid was collected by filtration, washed with water (2×10 ml) then dried in a vacuum oven at 45° C. overnight to provide (4-acetylamino-2-methyl-1H-indol-1-yl)acetic acid as an off-white solid, 1.66 g (92%).