Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:30]=[C:31]([F:33])[CH:32]=1)[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[N:10]=[CH:9][C:8]=1[CH2:26][C:27]([NH2:29])=[O:28].Br[CH2:35][CH2:36][C:37]#[N:38].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:37]([CH2:36][CH2:35][N:23]1[CH2:24][CH2:25][N:20]([C:17]2[CH:16]=[CH:15][C:14]([NH:13][C:11]3[N:10]=[CH:9][C:8]([CH2:26][C:27]([NH2:29])=[O:28])=[C:7]([NH:6][CH2:5][C:4]4[CH:3]=[C:2]([F:1])[CH:32]=[C:31]([F:33])[CH:30]=4)[CH:12]=3)=[CH:19][CH:18]=2)[CH2:21][CH2:22]1)#[N:38]
Reactant: N#CCCBr
Reactant: NC(=O)Cc1cnc(Nc2ccc(N3CCNCC3)cc2)cc1NCc1cc(F)cc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCCN1CCN(c2ccc(Nc3cc(NCc4cc(F)cc(F)c4)c(CC(N)=O)cn3)cc2)CC1
Temperature: 80 °C
Reaction time: 4 h
Yield: 77.6 %

Procedure:
60 mg of 4-[(3,5-difluorobenzyl)amino]-6-{[4-(piperazin-1-yl)phenyl]amino}pyridine-3-carboxyamide (the compound of Example 221) was dissolved in 0.6 mL of N,N-dimethylformamide, to which 45 mg of 3-bromopropionitrile and 57 mg of potassium carbonate were added, and stirred at 80° C. for 4 hours. After cooling, the solvent was evaporated, the residue was dissolved in chloroform, and the insoluble substances were filtered off. Chloroform was evaporated and the residue was purified by silica gel thin layer chromatography (chloroform:methanol=5:1) to obtain 52 mg (77%) of the title compound as a light yellow crystalline powder.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:26]=[CH:27][CH:28]=1)[O:20][CH2:21][C:22]([CH3:25])(O)[CH3:23]>CS(O)(=O)=O>[CH3:15][O:16][C:17]1[CH:28]=[CH:27][C:26]2[C:22]([CH3:25])([CH3:23])[CH2:21][O:20][C:19]=2[CH:18]=1
Reactant: COc1cccc(OCC(C)(C)O)c1
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: COc1ccc2c(c1)OCC2(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 24.2 %

Procedure:
To a solution of phosphorous pentoxide (55.1 g, 383 mmol) in methanesulfonic acid (100 mL) was added drop wise 1-(3-methoxyphenoxy)-2-methylpropan-2-ol (25 g, 127.6 mmol) over a 30 min period. The reaction mixture was stirred for 3 h at r.t. The reaction mixture was poured into 500 mL of ice water and extracted with ether (200 mL×3). The combined extracts were dried and evaporated. The residue was purified by silica gel column chromatography eluting with petroleum ether/ether (9:1) to afford 6-methoxy-3,3-dimethyl-2,3-dihydrobenzofuran (5.5 g, 25%) as a yellow oil.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH:3]1[C:15]([O:17][CH2:18][CH3:19])=[O:16].[C:20]1([C@H:26]([NH2:28])[CH3:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:20]1([C@H:26]([NH:28][C:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C:3]=2[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCC1=O
Reactant: C[C@@H](N)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1=C(N[C@H](C)c2ccccc2)CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Yield: 48.5 %

Procedure:
A solution of 252A (22 g, 81 mmol) and toluene (400 mL) was treated with (R)-1-phenylethanamine (12.5 mL, 97 mmol) and p-TsOH (1.5 g). The reaction mixture was heated to reflux with a Dean-Stark trap for 23 hours. The mixture was cooled to room temperature, washed with saturated aqueos NaHCO3 (2×200 mL) and brine (2×200 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated. The crude material was filtered through a pad of silica (100% CH2Cl2) and concentrated to provide 14.7 g (yield: 49%) of Compound 252B as an oil.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH2:6][C:7]1[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=1)[CH3:5].Br[CH2:15][CH2:16][CH2:17][N:18]1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28].O>CN(C)C=O>[CH3:5][N:4]([CH2:6][C:7]1[CH:8]=[C:9]([CH:10]=[CH:11][CH:12]=1)[O:13][CH2:15][CH2:16][CH2:17][N:18]1[C:22](=[O:23])[C:21]2[C:20](=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:19]1=[O:28])[CH3:3]
Reactant: CN(C)Cc1cccc(O)c1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)Cc1cccc(OCCCN2C(=O)c3ccccc3C2=O)c1
Reaction time: 2 h
Yield: 84.4 %

Procedure:
A mixture of 80% sodium hydride (2.2 g) and 3-(N,N-dimethylaminomethyl)phenol (6.95 g) in dry dimethylformamide was stirred at 5° for 2 hr. N-(3-Bromopropyl)phthalimide (12.2 g) was then added and after 16 hours the reaction was treated with water and extracted with ethyl acetate. Evaporation of the dried organic extracts gave the title compound as a yellow oil (13 g). TLC silica; ethyl acetate; Rf 0.35. m.p. (oxalate salt) 204°-207°.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([CH3:27])[C:3]=1[O:4][C:5]1[N:9]([CH3:10])[C:8]2[C:11]([CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[CH:12][CH:13]=[C:14]([CH:15]=O)[C:7]=2[N:6]=1.[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(=O)(O)[O-].[Na+].C(OCC)(=O)C>[Cl:1][C:2]1[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([CH3:27])[C:3]=1[O:4][C:5]1[N:9]([CH3:10])[C:8]2[C:11]([CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[CH:12][CH:13]=[C:14]([CH2:15][N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[C:7]=2[N:6]=1
Reactant: CCC(CC)c1ccc(C=O)c2nc(Oc3c(C)cc(Cl)cc3Cl)n(C)c12
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCC(CC)c1ccc(CN2CCCC2)c2nc(Oc3c(C)cc(Cl)cc3Cl)n(C)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.7 %

Procedure:
To a mixture of 2-(2,4-dichloro-6-methylphenoxy)-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole-4-carbaldehyde (93 mg, 0.23 mmol), pyrrolidine (33 mg, 0.46 mmol), acetic acid (0.5 ml) and ethyl acetate (1.5 ml) was added sodium triacetoxyborohydride (244 mg, 1.15 mmol) and the reaction mixture was stirred at room temperature for 1 h. The residue was diluted with aqueous saturated sodium bicarbonate and extracted with ethyl acetate. The extracts were washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on alumina with a 5% ethyl acetate/n-hexane to give 100 mg (0.22 mmol, 94%) of the title compound as a white powder.
Reaction SMILES: [Cl-].[NH4+].[B-](F)(F)(F)F.CCOC(C(C#N)=[N:14]OC(N(C)C)=[N+](C)C)=O.C(N(CC)C(C)C)(C)C.[CH3:34][C:35]1[N:44]([CH2:45][CH2:46][CH3:47])[C:43](=[O:48])[C:42]2[C:37](=[CH:38][CH:39]=[C:40]([C:49]([C:51]3[N:55]4[CH:56]=[CH:57][CH:58]=[CH:59][C:54]4=[C:53]([C:60]4[CH:61]=[C:62]([CH:66]=[CH:67][CH:68]=4)[C:63]([OH:65])=O)[N:52]=3)=[O:50])[CH:41]=2)[N:36]=1>CN(C=O)C>[CH3:34][C:35]1[N:44]([CH2:45][CH2:46][CH3:47])[C:43](=[O:48])[C:42]2[C:37](=[CH:38][CH:39]=[C:40]([C:49]([C:51]3[N:55]4[CH:56]=[CH:57][CH:58]=[CH:59][C:54]4=[C:53]([C:60]4[CH:61]=[C:62]([CH:66]=[CH:67][CH:68]=4)[C:63]([NH2:14])=[O:65])[N:52]=3)=[O:50])[CH:41]=2)[N:36]=1
Reactant: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Reactant: CCCn1c(C)nc2ccc(C(=O)c3nc(-c4cccc(C(=O)O)c4)c4ccccn34)cc2c1=O
Agent: F[B-](F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCn1c(C)nc2ccc(C(=O)c3nc(-c4cccc(C(N)=O)c4)c4ccccn34)cc2c1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 49.4 %

Procedure:
0.107 g (2 mmol) of ammonium chloride, 0.328 g (1 mmol) of TOTU and 0.517 g (4 mmol) of N,N-diisopropylethylamine are added, at ambient temperature under an inert atmosphere, to 0.233 g (0.5 mol) of 3-{3-[(2-methyl-4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)carbonyl]imidazo[1,5-a]pyridin-1-yl}benzoic acid in 30 ml of DMF. The reaction medium is stirred for 5 hours at ambient temperature and then concentrated under reduced pressure. 50 ml of a saturated solution of sodium hydrogen carbonate are added to the residue. The precipitate obtained is filtered off, and then dried under reduced pressure at 50° C. overnight. 0.230 g of a yellow solid is obtained.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][OH:14].O[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1.C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: Oc1ccccn1
Reactant: Cc1onc(-c2ccccc2)c1CO
Agent: CCCCP(CCCC)CCCC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Solvent: C1CCOC1
Product: Cc1onc(-c2ccccc2)c1COc1ccccn1
Temperature: 0 °C
Reaction time: 16 h
Yield: 25.5 %

Procedure:
To a solution of (5-methyl-3-phenyl-isoxazol-4-yl)-methanol (100 mg, 0.53 mmol) in THF (6 mL) was added 2-hydroxypyridine (50 mg, 0.53 mmol) and tributyl phosphine (206 μL, 0.79 mmol) at ambient temperature under an argon atmosphere. After cooling to 0° C., N,N,N′,N′-tetramethylazodicarboxamide (137 mg, 0.79 mmol) was added. The resulting orange solution was stirred for 16 h at ambient temperature followed by 2.5 h at 50° C. Then triphenylphosphine (208 mg, 0.79 mmol), 2-hydroxypyridine (50 mg, 0.53 mmol) and diethyl azodicarboxylate (127 μL, 0.79 mmol) were added and the reaction mixture was stirred for 4 h at 50° C. The reaction mixture was then evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=95:5 to 0:100) afforded the title compound (36 mg, 25%) as a colourless oil. MS: m/e=267.2 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[N:4]=1.CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:55][N:56]([CH3:60])[CH2:57][CH2:58][NH2:59]>C(Cl)Cl>[CH3:55][N:56]([CH3:60])[CH2:57][CH2:58][NH:59][C:12](=[O:14])[C:11]1[CH:10]=[CH:9][C:8]([C:5]2[N:4]=[C:3]([C:2]([F:1])([F:18])[F:17])[O:7][N:6]=2)=[CH:16][CH:15]=1
Reactant: O=C(O)c1ccc(-c2noc(C(F)(F)F)n2)cc1
Reactant: CN(C)CCN
Agent: CCOC(=O)C(C#N)=NOC(N1CCOCC1)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C)CCNC(=O)c1ccc(-c2noc(C(F)(F)F)n2)cc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 79.9 %

Procedure:
To a suspension of Intermediate 12b (1 g, 3.87 mmol) in DCM (20 ml) was added COMU (1.891 g, 4.26 mmol) and DIPEA (0.812 ml, 4.65 mmol). The yellow solution was stirred for 2 min at rt and turned red. 2-Dimethylaminoethylamine (0.518 ml, 4.65 mmol) was added and the reaction mixture was stirred at reflux for 1 hr. After cooling to rt, the mixture was washed with water, saturated aqueous NH4Cl and extrated with EtOAc. The organic layer was dried over Na2SO4 and the solvent was removed in vacuo. The crude product was purified by flash chromatography (ISCO CombiFlash Rf, 120 g silicagel; A=dichloromethane, B=DCM:7N NH3 in MeOH (9:1), 2% hold for 5 min, gradient to 50% B over 15 min). Fractions containing the product where combined to yield 1.355 g. The final product (1.015 g) was obtained after crystallisation from heptane as a white solid.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.[CH2:11]([O:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1)[CH:12]([CH3:14])[CH3:13]>>[F:10][C:4]1[CH:3]=[C:2]([C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([O:15][CH2:11][CH:12]([CH3:14])[CH3:13])[CH:21]=2)[CH:8]=[C:7]([F:9])[C:5]=1[NH2:6]
Reactant: Nc1c(F)cc(Br)cc1F
Reactant: CC(C)COc1cccc(B(O)O)c1
Product: CC(C)COc1cccc(-c2cc(F)c(N)c(F)c2)c1
Yield: 60.1 %

Procedure:
The title compound (0.16 g) was prepared from 4-bromo-2,6-difluoroaniline (0.2 g, 0.96 mmol) and 3-isobutoxyphenylboronic acid (0.242 g, 1.2 mmol) as a yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:10](Cl)(=[O:12])[CH3:11].[Cl-].[Cl-].[Cl-].[Al+3]>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:10](=[O:12])[CH3:11])=[C:4]([OH:9])[CH:3]=1
Reactant: CC(=O)Cl
Reactant: Oc1ccc(Cl)c(Cl)c1
Agent: [Al+3]
Agent: [Cl-]
Product: CC(=O)c1cc(Cl)c(Cl)cc1O
Temperature: 20 °C
Reaction time: 8 h
Yield: 1029.6 %

Procedure:
A solution of 3,4-dichlorophenol [AK Scientific] (30 g, 18 mmol) in acetyl chloride (19 mL, 270 mmol) was stirred at 60° C. for 2 h. The reaction mixture was cooled to 20° C., treated with aluminum trichloride (37 g, 280 mmol) portionwise, and heated at 180° C. for 30 min. The reaction mixture was cooled to 20° C. and the solution hardened into a solid block that was not easy to break apart. This material was cooled to 0° C. and quenched slowly with 1 M HCl in portions. The solid block of material slowly broke apart with enough HCl and this heterogenous mixture was stirred at 20° C. overnight to ensure uniformity. The solid was filtered, washed with copious amounts of water, and dried under vacuum to give the desired product (38 g, quantitative) as a tan solid.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:22])[N:4]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[C:5](=[O:13])[N:6]([CH2:9][CH2:10][CH2:11][CH3:12])[C:7]=1[NH2:8].[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][S:30]([C:33]2[CH:38]=[CH:37][C:36]([CH2:39][C:40](O)=O)=[CH:35][CH:34]=2)(=[O:32])=[O:31])[CH:24]=1>>[CH2:9]([N:6]1[C:7]2[N:8]=[C:40]([CH2:39][C:36]3[CH:35]=[CH:34][C:33]([S:30]([NH:29][C:25]4[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=4)(=[O:31])=[O:32])=[CH:38][CH:37]=3)[NH:1][C:2]=2[C:3](=[O:22])[N:4]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[C:5]1=[O:13])[CH2:10][CH2:11][CH3:12]
Reactant: O=C(O)Cc1ccc(S(=O)(=O)Nc2cccnc2)cc1
Reactant: CCCCn1c(N)c(N)c(=O)n(Cc2ccccc2F)c1=O
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(S(=O)(=O)Nc4cccnc4)cc3)nc21

Procedure:
Prepared from 5,6-diamino-1-butyl-3-(2-fluoro-benzyl)-1H-pyrimidine-2,4-dione (30.6 mg, 0.1 mmol) and [4-(pyridin-3-ylsulfamoyl)-phenyl]-acetic acid. 4-[3-Butyl-1-(2-fluoro-benzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl]-N-pyridin-3-yl-benzenesulfonamide was obtained as a colorless solid; 1H NMR (DMSO-d6, 300 MHz) δH 13.50 (s, 1H), 10.54 (s, 1H), 8.23 (d, J=14.3 Hz, 2H), 7.71 (d, J=8.1 Hz, 2H), 7.55–7.40 (m, 3H), 7.35–6.95 (m, 5H), 5.08 (s, 2H), 4.13 (s, 2H), 3.92 (t, J=7.3 Hz, 2H), 1.59 (t, J=7.1 Hz, 2H), 1.23 (q, J=7.3 Hz, 2H), 0.83 (t, J=7.5 Hz, 3H); FAB-HRMS m/e calculated for C28H27FN6O4S (M+H)+ 563.1877, found 563.1860.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([NH:15][CH2:16][CH2:17][CH2:18][OH:19])[C:12]([C:20]([F:23])([F:22])[F:21])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)[CH3:2].O[C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[C@H:30]([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:29][CH2:28]2.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1COCC1>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:14]=[C:13]([NH:15][CH2:16][CH2:17][CH2:18][O:19][C:25]3[CH:26]=[C:27]4[C:31](=[CH:32][CH:33]=3)[C@H:30]([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:29][CH2:28]4)[C:12]([C:20]([F:21])([F:23])[F:22])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(-c2ccc(C(F)(F)F)c(NCCCO)n2)cc1
Reactant: CCOC(=O)C[C@@H]1CCc2cc(O)ccc21
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCCNc3nc(-c4ccc(CC)cc4)ccc3C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.6 %

Procedure:
To a solution of 3-{[6-(4-ethylphenyl)-3-(trifluoromethyl)-2-pyridinyl]amino}-1-propanol (Example 316) (0.34 g, 1.05 mmol) and ethyl [(1S)-5-hydroxy-2,3-dihydro-1H-inden-1-yl]acetate (Example 6, 0.18 g, 0.84 mmol) in THF (8.50 mL) was added PPh3 (0.29 g, 1.09 mmol) and ADDP (0.28 g, 1.09 mmol) under argon. The golden yellow mixture was stirred at rt for 18 h, and then concentrated under reduced pressure. The product (0.33 g, 74%) was isolated after silica gel flash chromatography (2:1 hexanes/EtOAc). 1H NMR (400 MHz, CD2Cl2) δ 7.99 (d, 2H), 7.72 (d, 1H), 7.25 (d, 2H), 7.12 (d, 1H), 7.01 (d, 1H), 6.76 (d, 1H), 6.68 (dd, 1H), 4.15 (q, 2H), 4.08 (t, 2H), 3.82 (t, 2H), 3.45 (qt, 1H), 2.90-2.68 (m, 5H), 2.42-2.28 (m, 2H), 2.16 (qt, 2H), 1.78-1.68 (m, 1H), 1.30-1.24 (m, 6H).
Reaction SMILES: [CH2:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([C:17]([OH:19])=[O:18])=[CH:16][C:3]1=2>[Pd].C(O)C>[CH3:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([C:17]([OH:19])=[O:18])=[CH:16][C:3]1=2
Reactant: C=C1c2ccccc2COc2ccc(C(=O)O)cc21
Agent: [Pd]
Solvent: CCO
Product: CC1c2ccccc2COc2ccc(C(=O)O)cc21
Reaction time: 0.5 h
Yield: 70.4 %

Procedure:
Dissolve 514 mg of 11-methylene-6,11-dihydrodibenz[b,e]oxepin-2-carboxylic acid in 150 ml. of ethanol. Add 100 mg of 5% palladium on carbon catalyst. Hydrogenate at 20 psi for 30 minutes. Filter and strip the filtrate to dryness. Recrystallize the residue from isopropanol to obtain the title product (yield 365 mg, m.p. 224°-226° C.).
Reaction SMILES: [O:1]1[CH:3]([C:4]([F:7])([F:6])[F:5])[CH2:2]1.[N+:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH2:18][CH2:19][NH:20][CH2:21][CH:22]=2)=[CH:13][CH:12]=1)([O-:10])=[O:9].CCN(C(C)C)C(C)C>CN(C=O)C.O.CCOC(C)=O>[F:5][C:4]([F:7])([F:6])[CH:3]([OH:1])[CH2:2][N:20]1[CH2:19][CH:18]=[C:17]([C:14]2[CH:15]=[CH:16][C:11]([N+:8]([O-:10])=[O:9])=[CH:12][CH:13]=2)[CH2:22][CH2:21]1
Reactant: O=[N+]([O-])c1ccc(C2=CCNCC2)cc1
Reactant: FC(F)(F)C1CO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc(C2=CCN(CC(O)C(F)(F)F)CC2)cc1
Temperature: 45 °C
Yield: 77 %

Procedure:
1,2-Epoxy-3,3,3-trifluoropropane, tech., 85% (2.32 g; 17.63 mmol; 1.20 eq.) was added to a suspension of 4-(4-nitrophenyl)-1,2,3,6-tetrahydropyridine (3.0 g; 14.7 mmol; 1.0 eq.) in DMF (60 mL) and DIEA (2.5 mL, 14.7 mmol, 1 eq.). The reaction mixture was heated at 45° C. for 4 h. It was then allowed to cool down to RT and diluted with water (50 mL) and EtOAc (100 mL). Organic layer was washed with a saturated solution of NH4Cl (2×50 mL) and water, dried over magnesium sulfate, filtered and concentrated to give the expected compound as an orange solid (3.6 g, 77%). UPLC/MS: (MS+) 317.3, (MS−) 315.3.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:16])[NH:10][O:11][CH2:12][C:13]([OH:15])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][C@@H:18]([CH2:42][C:43]([NH:45][C:46]([C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:44])[C:19]([N:21]([C@@H:33]([CH3:41])[CH:34]([O:38][CH2:39][CH3:40])[O:35][CH2:36][CH3:37])[CH2:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)=[O:20]>>[CH2:1]([NH:8][C:9]([NH:10][O:11][CH2:12][C:13]([NH:17][C@@H:18]([CH2:42][C:43](=[O:44])[NH:45][C:46]([C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1)([C:53]1[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=1)[C:59]1[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=1)[C:19]([N:21]([C@@H:33]([CH3:41])[CH:34]([O:35][CH2:36][CH3:37])[O:38][CH2:39][CH3:40])[CH2:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)=[O:20])=[O:15])=[O:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CONC(=O)NCc1ccccc1
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@@H](N)CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)CONC(=O)NCc1ccccc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(3-benzylureidooxy)acetic acid (Compound VI-1) 52 mg (0.23 mmol) was coupled with (S)-2-amino-N1—((S)-1,1-diethoxypropan-2-yl)-N1-(naphthalen-1-ylmethyl)-N4-tritylsuccinamide (Compound IV-19) 100 mg (0.16 mmol) to obtain the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[CH:9]=[N:10][C:11]([N:14]3[CH2:19][CH2:18][O:17][C@H:16]([CH2:20][N:21]4[C:25]5=[N:26][C:27]([C:30]6[CH:31]=[N:32][N:33]([CH3:35])[CH:34]=6)=[CH:28][N:29]=[C:24]5[N:23]=[N:22]4)[CH2:15]3)=[N:12][CH:13]=2)[CH2:4][CH2:3]1>CO.C(Cl)Cl.[Pt]=O>[CH3:35][N:33]1[CH:34]=[C:30]([C:27]2[N:26]=[C:25]3[N:21]([CH2:20][C@H:16]4[O:17][CH2:18][CH2:19][N:14]([C:11]5[N:12]=[CH:13][C:8]([CH:5]6[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]6)=[CH:9][N:10]=5)[CH2:15]4)[N:22]=[N:23][C:24]3=[N:29][CH:28]=2)[CH:31]=[N:32]1
Reactant: CN1CC=C(c2cnc(N3CCO[C@H](Cn4nnc5ncc(-c6cnn(C)c6)nc54)C3)nc2)CC1
Agent: O=[Pt]
Solvent: ClCCl
Solvent: CO
Product: CN1CCC(c2cnc(N3CCO[C@H](Cn4nnc5ncc(-c6cnn(C)c6)nc54)C3)nc2)CC1
Yield: 17.5 %

Procedure:
(S)-4-(5-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-2-yl)-2-((6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholine 75 mg (0.16 mmol) was dissolved in methanol 3 ml and methylene chloride 2 ml, and an excess of platinum oxide was added. The mixture was degassed, and a hydrogen balloon was connected, followed by reaction at room temperature for 1 day. After the reaction, the platinum oxide was removed using a celite filter, and separated by PLC (methylene chloride:methanol=5:1) to give a yellow solid 13.3 mg (18%).
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[C:5]([CH3:7])[N:6]=1.CC1(C)C(C)(C)OB([C:23]2[CH:24]=[CH:25][C:26]3[CH2:33][C@H:32]4[C@:34]5([CH2:38][N:37]([CH2:39][C:40]([F:43])([F:42])[F:41])[S:36](=[O:45])(=[O:44])[NH:35]5)[C@H:29]([CH2:30][CH2:31]4)[CH2:28][C:27]=3[CH:46]=2)O1>>[CH3:7][C:5]1[N:6]=[C:2]([C:23]2[CH:24]=[CH:25][C:26]3[CH2:33][C@H:32]4[C@:34]5([CH2:38][N:37]([CH2:39][C:40]([F:43])([F:42])[F:41])[S:36](=[O:44])(=[O:45])[NH:35]5)[C@H:29]([CH2:30][CH2:31]4)[CH2:28][C:27]=3[CH:46]=2)[S:3][C:4]=1[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1
Reactant: CC1(C)OB(c2ccc3c(c2)C[C@H]2CC[C@@H](C3)[C@]23CN(CC(F)(F)F)S(=O)(=O)N3)OC1(C)C
Reactant: Cc1nc(Br)sc1-c1ccc(F)cc1
Product: Cc1nc(-c2ccc3c(c2)C[C@H]2CC[C@@H](C3)[C@]23CN(CC(F)(F)F)S(=O)(=O)N3)sc1-c1ccc(F)cc1

Procedure:
Prepared from the bromothiazole from Step 3 and the homochiral boronate from Example 24 Step 1 by the method described for Example 36 Step 3. MS (ES+) 552 ([MH]+).
Reaction SMILES: [CH:1]1([C:4]2[CH:13]=[C:7]3[N:8]=[CH:9][CH:10]=[C:11](O)[N:6]3[N:5]=2)[CH2:3][CH2:2]1.P(Cl)(Cl)([Cl:16])=O.[OH-].[Na+].C([O-])(O)=O.[Na+]>>[Cl:16][C:11]1[N:6]2[N:5]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[CH:13]=[C:7]2[N:8]=[CH:9][CH:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ccnc2cc(C3CC3)nn12
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Product: Clc1ccnc2cc(C3CC3)nn12
Temperature: 100 °C

Procedure:
A mixture of 2-cyclopropylpyrazolo[1,5-a]pyrimidin-7-ol (0.400 g, 2.28 mmol) and phosphorous oxychloride (4.26 ml, 45.7 mmol) in a resealable tube was heated to 100° C. After 4 hrs the solution was cooled to RT and slowly poured onto ice. The mixture was made basic using 2 N NaOH and saturated NaHCO3 and extracted with EtOAc. The combined organic fractions were washed with brine and dried with sodium sulfate. The organic phase solution was passed over a plug of silica gel and concentrated in vacuo to afford 7-chloro-2-cyclopropylpyrazolo[1,5-a]pyrimidine as a brown oil that was advanced without further purification. MS: Found M+H+=194.1.