Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH3:19])[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[N:9][CH:10]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>>[OH:18][C:15]1[CH:14]=[CH:13][C:12]([O:11][C:8]2[N:9]=[CH:10][C:5]([O:4][CH2:3][C@@H:2]([NH:1][C:20](=[O:22])[CH3:21])[CH3:19])=[CH:6][CH:7]=2)=[CH:17][CH:16]=1
Reactant: CC(=O)OC(C)=O
Reactant: C[C@H](N)COc1ccc(Oc2ccc(O)cc2)nc1
Product: CC(=O)N[C@@H](C)COc1ccc(Oc2ccc(O)cc2)nc1

Procedure:
4-[5((S)-2-Aminopropoxy)pyridin-2-yloxy]phenol (42 mg, 0.16 mmol) were reacted with acetic anhydride in analogy to example 2a. Yield: 33 mg (68%), M+H+: 303.05.
Reaction SMILES: [OH-].[Na+].O.C([O:6][C:7]([CH2:9][N:10]1[C:15]2[CH:16]=[C:17]([N+:21]([O-:23])=[O:22])[C:18]([F:20])=[CH:19][C:14]=2[O:13][CH2:12][C:11]1=[O:24])=[O:8])C>O1CCOCC1>[C:7]([CH2:9][N:10]1[C:15]2[CH:16]=[C:17]([N+:21]([O-:23])=[O:22])[C:18]([F:20])=[CH:19][C:14]=2[O:13][CH2:12][C:11]1=[O:24])([OH:8])=[O:6]
Reactant: CCOC(=O)CN1C(=O)COc2cc(F)c([N+](=O)[O-])cc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)CN1C(=O)COc2cc(F)c([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 88.9 %

Procedure:
Sodium hydroxide (0.9 g) and water (20 ml) were added to a mixture of 4-ethoxycarbonylmethyl-7-fluoro-6-nitro-2H-1,4-benzoxazin-3(4H)-one (5.96 g) and 1,4-dioxane (50 ml). The mixture was stirred at room temperature for one day. Afterthe solvent was distilled off, the residue was mixed with water (100 ml), then filtered. The filtrate was acidified with hydrochloric acid, and extracted with methyl isobutyl ketone (150 ml). After the extract was washed with water, it was dried with anhydrous sodium sulfate, and then the solvent was distilled off to give the desired 4-carboxymethyl-7-fluoro-6-nitro-2H-1,4-benzoxazin-3(4H)-one (4.8 g). mp. 177°-183° C.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[N:15]([CH3:16])[N:14]=[C:13]([C:17]2[S:18][CH:19]=[CH:20][N:21]=2)[C:12]=1[C:22]1[CH:23]=[CH:24][C:25]2[O:30][CH2:29][CH2:28][CH2:27][C:26]=2[CH:31]=1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+]>C(O)C.O>[C:1]([O:5][CH:6]([C:11]1[N:15]([CH3:16])[N:14]=[C:13]([C:17]2[S:18][CH:19]=[CH:20][N:21]=2)[C:12]=1[C:22]1[CH:23]=[CH:24][C:25]2[O:30][CH2:29][CH2:28][CH2:27][C:26]=2[CH:31]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc3c(c2)CCCO3)c(-c2nccs2)nn1C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cn1nc(-c2nccs2)c(-c2ccc3c(c2)CCCO3)c1C(OC(C)(C)C)C(=O)O
Yield: 90.9 %

Procedure:
A mixture of methyl 2-(tert-butoxy)-2-[4-(3,4-dihydro-2H-1-benzopyran-6-yl)-1-methyl-3-(1,3-thiazol-2-yl)-1H-pyrazol-5-yl]acetate (8h) (50 mg, 0.11 mmol) and potassium hydroxide (55 mg, 0.45 mmol) in a mixture of ethanol (1.0 mL) and water (1.0 mL) was refluxed overnight. The mixture was concentrated in vacuo. Water (2 mL) was added to the residue and the aqueous layer was washed with ethyl acetate (2 mL), acidified with 1M hydrochloric acid until pH 3 and extracted with ethyl acetate (2×3 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to provide 2-(tert-butoxy)-2-[4-(3,4-dihydro-2H-1-benzopyran-6-yl)-1-methyl-3-(1,3-thiazol-2-yl)-1H-pyrazol-5-yl]acetic acid (example 8) (45 mg, 0.10 mmol, 93%).
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C@@H:12]2[O:25][C:16]3=[C:17]4[C:21](=[CH:22][CH:23]=[C:15]3[O:14][CH2:13]2)[NH:20][C:19](=[O:24])[CH2:18]4)(=O)=O)=CC=1.[F:27][C:28]([F:38])([F:37])[C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32][NH2:33].O>CS(C)=O>[F:27][C:28]([F:37])([F:38])[C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32][NH:33][CH2:11][CH:12]1[O:25][C:16]2=[C:17]3[C:21](=[CH:22][CH:23]=[C:15]2[O:14][CH2:13]1)[NH:20][C:19](=[O:24])[CH2:18]3
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4c(c3O2)CC(=O)N4)cc1
Reactant: NCc1cccc(C(F)(F)F)c1
Solvent: CS(C)=O
Solvent: O
Product: O=C1Cc2c(ccc3c2OC(CNCc2cccc(C(F)(F)F)c2)CO3)N1
Temperature: 85 °C
Yield: 19.6 %

Procedure:
(R)-2-(Toluene-4-sulfonyloxymethyl)-2,3,8,9-tetrahydro-7H-1,4-dioxino[2,3-e]indol-8-one (1.01 g, 2.70 mmole) and 3-trifluoromethylbenzylamine (1.75 ml, 12.0 mmole) were combined in 15 ml of dry DMSO and heated to 85° C. for 4 hours under a nitrogen atmosphere. After cooling to room temperature, 200 ml of water was added and the mixture was extracted twice with 250 ml portions of 50% ethyl acetate in hexane. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated in vacuum to yield an oil, which was column chromatographed on silica gel using 2% methanol/CH2Cl2 as eluant. The free base of the title compound (0.20 g, 20%) thus obtained was crystallized from isopropanol with the addition of one equivalent of fumaric acid to give 0.17 g of the (S) enantiomer of the title compound as a light yellow solid fumarate, one-half hydrate, m.p. 158-160° C.
Reaction SMILES: [F:1][C@H:2]1[C@@H:7]([OH:8])[CH2:6][CH2:5][N:4]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:38](O)(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[C:38]([O:8][C@@H:7]1[CH2:6][CH2:5][N:4]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:3][C@H:2]1[F:1])(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: O=C(O)c1ccccc1
Reactant: O=C(OCc1ccccc1)N1CC[C@H](O)[C@H](F)C1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(O[C@@H]1CCN(C(=O)OCc2ccccc2)C[C@H]1F)c1ccccc1
Temperature: 0 °C
Reaction time: 168 h
Yield: 89 %

Procedure:
Non-racemic (cis)-benzyl 3-fluoro-4-hydroxypiperidine-1-carboxylate (Peak 1 of Example 94, Step 3D; 0.306 g, 1.21 mmol) was treated with triphenylphosphine (0.475 g, 1.81 mmol) and benzoic acid (0.221 g, 1.81 mmol) and the solids were dissolved in THF (5 mL), then cooled to 0° C. The solution was treated dropwise with diisopropyl azodicarboxylate (0.357 mL, 1.81 mmol) dissolved in THF (1 mL). The solution was warmed to ambient temperature with a bath and stirred for 7 days, then concentrated in vacuo. The residue was dissolved in CH2Cl2 and washed with saturated NH4Cl, water, 50% saturated NaHCO3, dried over Na2SO4 and concentrated in vacuo to a colorless oil. The oil was chromatographed on SiO2 eluting with 1:12 acetone/hexanes. The desired fraction was isolated to provide the desired product as a colorless oil (385 mg).
Reaction SMILES: [CH:1]1([CH2:10][C:11]([OH:13])=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.Cl.[CH2:26]([O:28][C:29](=[O:35])[C@@H:30]1[CH2:34][S:33][CH2:32][NH:31]1)[CH3:27]>C(Cl)Cl>[CH2:26]([O:28][C:29](=[O:35])[C@@H:30]1[CH:34]([C:11](=[O:13])[CH2:10][CH:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH2:3][CH2:2]2)[S:33][CH2:32][NH:31]1)[CH3:27]
Reactant: CCOC(=O)[C@@H]1CSCN1
Reactant: O=C(O)CC1CCc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)[C@H]1NCSC1C(=O)CC1CCc2ccccc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 57.1 %

Procedure:
While chilling with ice water, 1.4 g of 2-indanyl-acetic acid and 1.9 g of WSC.HCl were added to 15 ml of methylene chloride, and the mixture was stirred at room temperature for 5 minutes. Then, 1.3 g of L-thioproline ethyl ester dissolved in 10 ml of methylene chloride were added at room temperature, and the mixture was stirred further for 5 hours. The resultant liquid reaction mixture was washed with water, diluted hydrochloric acid and a saturated aqueous solution of sodium bicarbonate in that order. After an organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resultant residue was subjected to column chromatography on silica gel, thereby obtaining 1.45 g (57%) of 3-(2-indanylacetyl)-L-thioproline ethyl ester in the form of colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.N1C=CC=CC=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>O>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH:1][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: N#Cc1ccc(N)cc1
Solvent: O
Solvent: c1ccncc1
Product: N#Cc1ccc(NS(=O)(=O)c2ccc(Cl)cc2)cc1
Temperature: 15 °C
Reaction time: 18 h
Yield: 76 %

Procedure:
To a solution of 4-aminobenzonitrile (2.36 g (20.0 mmol))in pyridine (10 ml), 4-chlorobenzenesulfonyl chloride (4.35 g (20.6 mmol)) was added under cooling in a water bath (15° C.). After 18 hours' stirring at room temperature, water (100 ml) was added to the reaction mixture and the stirring was continued to bring about separation of crystals, which were then collected by filtration and washed with water to give 4.45 g (76%) of 4-chloro-4′-cyanobenzenesulfonanilide as pale orange crystals.
Reaction SMILES: [CH2:1]([N:8]([CH3:22])[CH:9]1[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([N:8]([CH3:22])[CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(Cc1ccccc1)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(Cc1ccccc1)C1CCNCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl 4-(benzyl(methyl)amino)piperidine-1-carboxylate (1.2 g, 3.947 mmol, 1.0 eq.) was dissolved in DCM (10 ml); TFA (1.2 ml) was added at 0° C. and the mixture was stirred for 2 hours at RT. The reaction mixture was concentrated under reduced pressure, taken up several times in toluene and dried. The crude product was used in the next stage without being purified further.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[C:25]([O:29][C:30]([NH:32][C:33]1([C:48](O)=[O:49])[CH2:38][CH2:37][N:36]([C:39]2[C:40]3[CH:47]=[CH:46][NH:45][C:41]=3[N:42]=[CH:43][N:44]=2)[CH2:35][CH2:34]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].Cl.[CH3:52][O:53][C:54](=[O:65])[CH2:55][CH:56]([NH2:64])[C:57]1[CH:62]=[CH:61][C:60]([Cl:63])=[CH:59][CH:58]=1.C(N(CC)C(C)C)(C)C>CN1CCCC1=O>[C:25]([O:29][C:30]([NH:32][C:33]1([C:48]([NH:64][CH:56]([C:57]2[CH:58]=[CH:59][C:60]([Cl:63])=[CH:61][CH:62]=2)[CH2:55][C:54]([O:53][CH3:52])=[O:65])=[O:49])[CH2:38][CH2:37][N:36]([C:39]2[C:40]3[CH:47]=[CH:46][NH:45][C:41]=3[N:42]=[CH:43][N:44]=2)[CH2:35][CH2:34]1)=[O:31])([CH3:26])([CH3:28])[CH3:27]
Reactant: COC(=O)CC(N)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(c2ncnc3[nH]ccc23)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: COC(=O)CC(NC(=O)C1(NC(=O)OC(C)(C)C)CCN(c2ncnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Reaction time: 5 h
Yield: 63.7 %

Procedure:
O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate (84 mg, 0.22 mmol) was added in one portion to 4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 1) (72.3 mg, 0.20 mmol), 3-amino-3-(4-chloro-phenyl)-propionic acid methyl ester hydrochloride (50 mg, 0.20 mmol) and N,N-diisopropylethylamine (0.104 mL, 0.60 mmol) in N-methyl-2-pyrrolidinone (1.5 mL) at 20° C. under argon. The resulting solution was stirred for 5 h. The reaction mixture was purified by preparative HPLC using a Waters X-Bridge reverse-phase column (C-18, 5 microns silica, 19 mm diameter, 100 mm length, flow rate of 40 ml/minute) with decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions containing the desired compound were evaporated to dryness to afford methyl 3-(4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamido)-3-(4-chlorophenyl)propanoate (71.0 mg, 63.8%) as a white crystalline solid.
Reaction SMILES: [Br:1][C:2]1[C:7]2[C:8](=[O:19])[N:9]([CH3:18])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]#[N:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl.[NH2:27][OH:28]>C(O)C.O>[Br:1][C:2]1[C:7]2[C:8](=[O:19])[N:9]([CH3:18])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16](=[N:27][OH:28])[NH2:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CN1Cc2c(C#N)ncn2-c2cccc(Br)c2C1=O
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CN1Cc2c(C(N)=NO)ncn2-c2cccc(Br)c2C1=O
Yield: 86 %

Procedure:
17.85 g (56.3 mmol) of 7-bromo-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carbonitrile were stirred with 10.3 g (97.7 mmol) of sodium carbonate and 8 g (115.1 mmol) of hydroxylamine hydrochloride in 300 ml of ethanol and 60 ml of water at 50° for 1 hour and at 75° for 20 minutes. After dilution with 50 ml of water the suspension was suction filtered and the crystals were dried. There were obtained 16.95 g (86%) of 7-bromo-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamidoxime of m.p. 265°-266°.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[N:10]2[CH:11]=[CH:12][C:13]([C:15]([F:18])([F:17])[F:16])=[N:14][C:9]2=[N:8][CH:7]=1)CCC.[Br:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30](Br)[N:29]=1>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>[Br:27][C:28]1[N:29]=[C:30]([C:6]2[N:10]3[CH:11]=[CH:12][C:13]([C:15]([F:16])([F:17])[F:18])=[N:14][C:9]3=[N:8][CH:7]=2)[CH:31]=[CH:32][CH:33]=1
Reactant: Brc1cccc(Br)n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(F)(F)F)ccn12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: FC(F)(F)c1ccn2c(-c3cccc(Br)n3)cnc2n1

Procedure:
To the degassed solution of 3-tributylstannyl-7-trifluoromethyl-imidazo[1,2-α]pyrimidine was added 2,6-dibromopyridine (1.8 g, 7.5 mmol) and tetrakis(triphenylphosphine)palladium(0) (218 mg, 0.18 mmol) and the mixture heated at reflux for 3 h. The crude reaction was adsorbed onto silica and purified by chromatography on silica gel eluting with isohexane on a gradient of ethyl acetate (20-60%) to give a yellow solid. Crystallisation from ethyl acetate/isohexane afforded 3-(6-bromopyridin-2-yl)-7-trifluoromethylimidazo[1,2-α]pyrimidine (702 mg) as a white solid: δH (400 MHz, DMSO) 7.64 (1H, d, J 9), 7.83 (1H, d, J 8), 7.93 (1H, dd, J 9 and 9), 8.20 (1H, d, J 9), 8.92 (1H, s), 10.18 (1H, d, J 9); m/z (ES+) 343, 345 (M++H).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C:15]2[C:10](=[CH:11][C:12]([F:21])=[C:13]([C:16]3[O:17][CH:18]=[CH:19][CH:20]=3)[N:14]=2)[C:9](=[O:22])[C:8]([C:23]([OH:25])=[O:24])=[CH:7]1>FC(F)(F)C(O)=O>[F:21][C:12]1[CH:11]=[C:10]2[C:15](=[N:14][C:13]=1[C:16]1[O:17][CH:18]=[CH:19][CH:20]=1)[NH:6][CH:7]=[C:8]([C:23]([OH:25])=[O:24])[C:9]2=[O:22]
Reactant: COc1ccc(Cn2cc(C(=O)O)c(=O)c3cc(F)c(-c4ccco4)nc32)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1c[nH]c2nc(-c3ccco3)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of EXAMPLE 30B (130 mg) in trifluoroacetic acid (8 mL) was heated at 50° C. for 2 hours then cooled and concentrated. The concentrate was diluted with diethyl ether, stirred at ambient temperature for 4 hours, and filtered to provide the desired product. NMR (300 MHz, DMSO-d6) δ 14.05 (br s, 1H), 8.78 (s, 1H), 8.53 (m, 1H), 8.14 (m, 1H), 7.48 (m, 1H), 6.87 (m, 1H), 6.55 (s, 1H).
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[O:8][CH:9]=[CH:10][CH:11]=1.[F:12][CH2:13][C:14]1([CH:18]=[O:19])[CH2:17][O:16][CH2:15]1.[Cl-].[NH4+]>CCCCCC.O1CCCC1>[F:12][CH2:13][C:14]1([CH:18]([C:9]2[O:8][C:7]([CH3:6])=[CH:11][CH:10]=2)[OH:19])[CH2:17][O:16][CH2:15]1
Reactant: Cc1ccco1
Reactant: O=CC1(CF)COC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1ccc(C(O)C2(CF)COC2)o1
Temperature: -70 °C
Reaction time: 3 h
Yield: 106.3 %

Procedure:
11.0 ml (27 mmol, 1.5 eq) of a 2.5 M solution of n-butyllithium in hexane were added dropwise to a solution of 2.25 g (27 mmol, 1.5 eq) of 2-methylfuran in 40 ml of tetrahydrofuran cooled to −70° C. The reaction medium was stirred and allowed to return to ambient temperature for 3 hours. The reaction medium was cooled to −70° C. and then 2.16 g (18 mmol, 1 eq) of 3-fluoromethyloxetane-3-carbaldehyde were added. The reaction medium was stirred at ambient temperature for two and a half hours. The reaction medium was treated with a saturated ammonium chloride solution and extracted with ethyl acetate. The organic phases were combined, washed with a saturated sodium chloride solution and evaporated. 3.83 g of (3-fluoromethyloxetan-3-yl)-(5-methylfuran-2-yl)methanol were obtained in the form of a dark orange oil. Yield=71%. TLC SiO2/CH2Cl2:MeOH (96/4), developing with KMnO4.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([O:13]C)=[O:12])=[N:3]1.[OH-].[Na+]>CO.O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([OH:13])=[O:12])=[N:3]1
Reactant: COC(=O)c1nn(C)c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cn1nc(C(=O)O)c2ccccc21
Yield: 92.1 %

Procedure:
A solution of 1-methylindazole-3-carboxylic acid, methyl ester (1.00 g, 0.0053 mol) was stirred in a mixture of methanol (10 mL)/2 N NaOH solution (120 mL) at reflux temperature for 2 hours. After cooling, the mixture was diluted with water (100 mL) and acidified with 6 N HCI solution. The white solid that formed was collected by filtration and dried under ambient conditions for 6 days to give 0.86 g (92% yield) of the product; mp 215°-216° C.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([NH2:13])=[CH:10][CH:11]=2)[C:6]([NH:14][C:15](=[O:17])[CH3:16])=[N:5]1)(=[O:3])[CH3:2].[CH2:18]=[C:19]1[O:23][C:21](=[O:22])[CH2:20]1>C(#N)C>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([NH:13][C:21](=[O:22])[CH2:20][C:19](=[O:23])[CH3:18])=[CH:10][CH:11]=2)[C:6]([NH:14][C:15](=[O:17])[CH3:16])=[N:5]1)(=[O:3])[CH3:2]
Reactant: C=C1CC(=O)O1
Reactant: CC(=O)Nc1nn(C(C)=O)c2ccc(N)cc12
Solvent: CC#N
Product: CC(=O)CC(=O)Nc1ccc2c(c1)c(NC(C)=O)nn2C(C)=O
Temperature: 50 °C
Yield: 73 %

Procedure:
The product from Step (c) above (2.6 g, 11.4 mmol) was dissolved in acetonitrile (20 mL) and diketene (0.86 mL, 11.2 mmol) was added in portions over min, then the solution was sealed and heated to 50° C. overnight. The reaction mixture was then cooled, filtered and the filtrate was concentrated to give the title compound as a dark tan solid (2.6 g, 73%). NMR 1H NMR (400 MHz, DMSO-D6) δ 10.86 (s, 1H), 10.32 (s, 1H), 8.25-8.20 (m, 2H), 7.75 (dd, J=8.9, 2.0, 1H), 3.59 (s, 2H), 2.63 (s, 3H), 2.22 (s, 3H), 3.18 (s, 3H) MS m/z 317.0 [M+H]+
Reaction SMILES: NO.C[N:4](C)[CH:5]=[CH:6][C:7]([C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][N:13]1[C:23](=[O:24])[CH2:22][NH:21][C:20](=[O:25])[CH:19]=[C:14]12)=[O:8]>CO>[O:8]1[C:7]([C:9]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:10]=2[CH2:11][CH2:12][N:13]2[C:23](=[O:24])[CH2:22][NH:21][C:20](=[O:25])[CH:19]=[C:14]23)=[CH:6][CH:5]=[N:4]1
Reactant: CN(C)C=CC(=O)c1cccc2c1CCN1C(=O)CNC(=O)C=C21
Agent: NO
Solvent: CO
Product: O=C1C=C2c3cccc(-c4ccno4)c3CCN2C(=O)CN1
Yield: 62.2 %

Procedure:
100-3. NH2OH*HCl (51 mg, 0.74 mmol) was added to a mixture of (E)-9-(3-(dimethylamino)acryloyl)-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione (160 mg, 0.49 mmol) in MeOH (5 mL) and the solution was heated to reflux for 1 h. The mixture was then concentrated in vacuo and the crude product was purified by flash chromatography (SiO2, DCM/MeOH 99:1 to 90:10) to afford the title compound (90 mg) as a beige solid. UPLC-MS: MS 296.1 (M-FH+). UPLC rt 0.65 nm.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=O)=[N+:2]=[N-:3].S(Cl)([Cl:13])=O>>[N:1]([CH2:4][CH2:5][CH2:6][CH2:7][C:8]([Cl:13])=[O:10])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCCCCC(=O)O
Reactant: O=S(Cl)Cl
Product: [N-]=[N+]=NCCCCC(=O)Cl
Temperature: 60 °C
Reaction time: 2 h

Procedure:
In a one neck round bottom flask containing 5-azidopentanoic acid (0.88 g, 0.068 mol) was added thionyl chloride (7.35 ml, 0.102 mol). The reaction mixture was stirred at 60° C. for 2 h and the thionyl chloride was evaporated under reduced pressure to give crude 5-azidopentanoyl chloride. The distillation of crude acyl chloride gave a colorless liquid; 6.93 (62%), bp 111°-4° C. (1.2-1.4 mm); ir (neat) νmax : 2100 (N3) and 1800 cm-1 (C=O); 1Hmr (CDCl3) δ: 3.37 (2H,δ-H), 3.00 (2H, α-H) and 2.1-1.2 ppm (4H, β-H and γ-H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[NH2:23]>>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[NH:23][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1
Reactant: COc1ccc(N)cc1OC
Reactant: FC(F)(F)c1cc(Cl)nc(-c2ccccc2)n1
Product: COc1ccc(Nc2cc(C(F)(F)F)nc(-c3ccccc3)n2)cc1OC

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-phenyl-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 3,4-dimethoxyaniline (44 mg, 0.290 mmol) similar to Example 75. The mixture was extracted with ethyl acetate (75 ml), washed with water (2×25 ml), washed with aqueous saturated NaCl (1×25 ml), and dried over anhydrous sodium sulfate. The ethyl acetate solution was rotary evaporated to dryness. The residual was purified by column chromatography and isolated as a yellow oil (35 mg, 48%). 1H NMR (CDCl3): 8.45–8.42 (m, 2H), 7.50–7.44 (m, 3H), 7.25 (s, 1H), 7.02 (s, 1H), 6.90 (s, 2H), 6.74 (s, 1H), 3.91 (s, 3H), 3.87 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:28][CH2:29][C:30]1[CH:39]=[CH:38][CH:37]=[C:36]2[C:31]=1[C:32](=[O:49])[N:33]([CH:41]1[CH2:46][CH2:45][C:44](=[O:47])[NH:43][C:42]1=[O:48])[C:34]([CH3:40])=[N:35]2>CN(C=O)C>[O:48]=[C:42]1[CH:41]([N:33]2[C:32](=[O:49])[C:31]3[C:36](=[CH:37][CH:38]=[CH:39][C:30]=3[CH2:29][NH:28][C:10](=[O:12])[CH2:9][C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:14])[F:13])=[CH:8][CH:7]=3)[N:35]=[C:34]2[CH3:40])[CH2:46][CH2:45][C:44](=[O:47])[NH:43]1
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Reactant: Cc1nc2cccc(CN)c2c(=O)n1C1CCC(=O)NC1=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: Cc1nc2cccc(CNC(=O)Cc3ccc(C(F)(F)F)cc3)c2c(=O)n1C1CCC(=O)NC1=O
Reaction time: 1 h
Yield: 71.2 %

Procedure:
To a stirred solution of (4-trifluoromethyl-phenyl)-acetic acid (0.26 g, 1.3 mmol) in DMF (8 mL) in a 40° C. oil bath, was added 1,1′carbonyldiimidazole (0.22 g, 1.4 mmol) and stirred for one hour. To the mixture, 3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.42 g, 1.3 mmol) was added, and the mixture was stirred for 15 minutes. The solvent was evaporated, and the residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-2-(4-trifluoromethyl-phenyl)-acetamide as an off-white solid (450 mg, 74% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, grad. to 95/5 in 5 min, kept 5 min, 6.36 min (99.1%); mp, 199-201° C.; 1HNMR (DMSO-d6)2.14-2.19 (m, 1H, CHH), 2.57-2.87 (m, 6H, CHCH2, CH3), 3.66 (s, 2H, ArCH2), 4.75-4.86 (m, 2H, CH2NH), 5.24 (dd, J=6, 11 Hz, 1H, CH), 7.27-7.72 (m, 7H, Ar), 8.48 (t, J=6 Hz, 1H, CH2NH), 11.02 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.74, 23.28, 30.58, 41.75, 41.93, 56.48, 117.69, 124.72, 125.01 (d, JC-F=4 Hz), 125.01 (d, JC-F=10 Hz), 125.61, 129.91, 133.82, 140.58, 141.19, 148.45, 154.81, 160.90, 169.50, 169.54, 172.59. LCMS MH=487; Anal Calcd For C24H21N4O4F3: C, 57.76; H, 4.52; N, 11.23; F, 11.42. Found: C, 57.38; H, 4.49; N, 11.07; F, 11.64.