Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:20])[CH:5]=[C:6]([F:19])[C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[C:25]([CH3:29])=[CH:24][C:23]=1[S:30](Cl)(=[O:32])=[O:31]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:20][S:30]([C:23]2[CH:24]=[C:25]([CH3:29])[C:26]([Cl:28])=[CH:27][C:22]=2[Cl:21])(=[O:32])=[O:31])[CH:5]=[C:6]([F:19])[C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: Nc1cc(F)c(Oc2cnc3ccccc3c2)c(Cl)c1
Reactant: Cc1cc(S(=O)(=O)Cl)c(Cl)cc1Cl
Solvent: c1ccncc1
Product: Cc1cc(S(=O)(=O)Nc2cc(F)c(Oc3cnc4ccccc4c3)c(Cl)c2)c(Cl)cc1Cl
Reaction time: 1 h
Yield: 73.5 %

Procedure:
To a solution of 3-chloro-5-fluoro-4-(quinolin-3-yloxy)phenylamine (50.2) (0.420 g) in pyridine (2.2 mL), was added 2,4-dichloro-5-methylbenzenesulfonylchloride 0.360 g. The mixture was stirred at room for 1 h. The reaction mixture was purified directly by column chromatography (silica gel, AcOEt:hexane=1:3). The product was triturated by hexane to give title compound (0.522 g). Yield 73% as a solid. 1H NMR (300 MHz/CDCl3) δ 2.43 (3H, s), 7.05 (1H, d, J=2.6 Hz), 7.09-7.11 (1H, m), 7.21 (1H, d, J=2.6 Hz), 7.36 (1H, brs), 7.49-7.66 (4H, m), 7.96 (1H, s), 8.10 (1H, d, J=8.2 Hz), 8.80 (1H, brs). MS (M+H) 511. mp 187° C.
Reaction SMILES: [CH:1]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>C(O)C.O>[CH:11]1[C:12]2[C:7](=[N:6][C:5]3[C:14]([N:13]=2)=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH:8]=[CH:9][CH:10]=1
Reactant: c1ccc2c(c1)Nc1ccccc1N2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: c1ccc2nc3ccccc3nc2c1
Temperature: 25 °C
Yield: 40 %

Procedure:
5,10-dihydrophenazine in an amount of 10 g is dissolved in 100 ml ethanol and added to 2.6 g NaOH dissolved in 2 ml of water. The mixture was heated to reflux and O2 bubbled through for 30 minutes. TLC shows that the 5,10-dihydrophenazine is converted completely to phenazine. The mixture was stripped to a volume of 45 ml and 25 ml water added. After cooling in a refrigerator, 8.0 grams of crude phenazine is collected by filtration. The crude phenazine is dissolved in 80 ml toluene, filtered hot, and stripped to 25 ml. When cooled, 5.86 of still somewhat brown phenazine is collected. After an additional recrystallization from toluene, a further toluene solution (50 ml) is treated with 1.0 g charcoal, reduced to 20 ml, cooled to room temperature and then under refrigeration, to yield 4.0 g (40%) of yellow phenazine.
Reaction SMILES: [F:1][CH:2]([F:22])[O:3][C:4]1[CH:5]=[N:6][C:7]2[N:8]([N:10]=[CH:11][C:12]=2[C:13]2[CH:14]=[C:15]([C:19](O)=[O:20])[S:16][C:17]=2[CH3:18])[CH:9]=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.[NH2:50][C@H:51]1[C:56]([F:58])([F:57])[CH2:55][CH2:54][CH2:53][C@H:52]1[NH:59][C:60](=[O:66])[O:61][C:62]([CH3:65])([CH3:64])[CH3:63].C(N(C(C)C)CC)(C)C>CN(C=O)C.ClCCl>[C:62]([O:61][C:60](=[O:66])[NH:59][C@@H:52]1[CH2:53][CH2:54][CH2:55][C:56]([F:58])([F:57])[C@@H:51]1[NH:50][C:19]([C:15]1[S:16][C:17]([CH3:18])=[C:13]([C:12]2[CH:11]=[N:10][N:8]3[CH:9]=[C:4]([O:3][CH:2]([F:1])[F:22])[CH:5]=[N:6][C:7]=23)[CH:14]=1)=[O:20])([CH3:65])([CH3:63])[CH3:64]
Reactant: Cc1sc(C(=O)O)cc1-c1cnn2cc(OC(F)F)cnc12
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC(F)(F)[C@@H]1N
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1sc(C(=O)N[C@@H]2[C@H](NC(=O)OC(C)(C)C)CCCC2(F)F)cc1-c1cnn2cc(OC(F)F)cnc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 68.2 %

Procedure:
4-[6-(Difluoromethoxy)pyrazolo[1,5-a]pyrimidin-3-yl]-5-methylthiophene-2-carboxylic acid (0.768 g, 2.36 mmol) and BOP (3.13 g, 7.08 mmol) were dissolved in DMF (15.7 mL) and stirred at room temperature for 5 min. To the reaction solution was added tert-butyl [(1R,2R)-2-amino-3,3-difluorocyclohexyl]carbamate (0.650 g, 2.60 mmol) and diisopropylethyl amine (619, 3.54 mmol) and the reaction stirred at room temperature for 16 h. The reaction mixture was diluted with dichloromethane and washed with saturated sodium bicarbonate twice and brine once. The organic layer was dried with sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (0-100% EtOAc/Hex) to give the title compound (0.900 g, 1.61 mmol). LRMS (APCI) calc'd for (C24H27F4N5O4S) [M+H]+, 558.2; found 558.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[N:6][C:7]=1[Cl:8].Br[CH:11]([CH2:16][CH3:17])[C:12]([O:14][CH3:15])=[O:13]>>[Cl:1][C:2]1[CH:3]=[C:4]([O:9][CH:11]([CH2:16][CH3:17])[C:12]([O:14][CH3:15])=[O:13])[CH:5]=[N:6][C:7]=1[Cl:8]
Reactant: CCC(Br)C(=O)OC
Reactant: Oc1cnc(Cl)c(Cl)c1
Product: CCC(Oc1cnc(Cl)c(Cl)c1)C(=O)OC

Procedure:
5,6-Dichloropyridin-3-ol was reacted with methyl 2-bromobutyrate using a similar procedure to that described in Example 1, Stage 1 to give methyl 2-(5,6-dichloro-3-pyridyloxy)butyrate, orange liquid.
Reaction SMILES: [CH2:1]([N:8]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:9]([CH2:14][O:15][CH:16]([F:18])[F:17])[C:10]([O:12]C)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-].Cl>C1COCC1.C(OCC)(=O)C>[CH2:19]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:9]([CH2:14][O:15][CH:16]([F:18])[F:17])[C:10]([OH:12])=[O:11])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)C(COC(F)F)N(Cc1ccccc1)Cc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(O)C(COC(F)F)N(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.5 %

Procedure:
Methyl 2-dibenzylamino-3-difluoromethoxy-propionate (1.2 g, 3.43 mmol) was stirred with 1N LiOH (10.3 mL, 10.3 mmol) in THF (40 mL) at 50° C. for 2 hours and then stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and acidified with 1N HCl. The organic layer was dried with sodium sulfate and concentrated with silica gel. The product was purified by column chromatography, eluting with 10-50% ethyl acetate in hexanes, to give 2-(dibenzylamino)-3-(difluoromethoxy)propanoic acid (730 mg, 63.5%) as a white solid. 1H NMR (300 MHz, CDCl3): (ppm) 7.26-7.42 (m, 10H), 6.29 (bt, 1H), 4.45 (dd, 1H), 4.28 (dd, 1H), 3.94 (q, 4H) and 3.85 (m, 1H).
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:8]C(Cl)(Cl)C([N:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:19]=[C:20]([S:26](Cl)(=[O:28])=[O:27])[CH:21]=[CH:22][C:23]=2[O:24][CH3:25])[CH2:14][CH2:13]1)=O>ClCCl>[ClH:8].[CH:1]1([NH:7][S:26]([C:20]2[CH:21]=[CH:22][C:23]([O:24][CH3:25])=[C:18]([N:15]3[CH2:16][CH2:17][NH:12][CH2:13][CH2:14]3)[CH:19]=2)(=[O:27])=[O:28])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1N1CCN(C(=O)C(Cl)(Cl)Cl)CC1
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)NC2CCCCC2)cc1N1CCNCC1
Product: Cl
Reaction time: 8 h
Yield: 15.7 %

Procedure:
A solution of cyclohexylamine (91 mg) in dichloromethane (1 ml) was added slowly to a stirred solution of 3-(4-trichloroacetylpiperazin-1-yl)-4-methoxybenzenesulfonyl chloride (D2) (200 mg) in dichloromethane (2 ml). The mixture was stirred overnight then washed with 1M HCl (4 ml) and water (4 ml), dried and concentrated to a solid. The solid was dissolved in tetrahydrofuran or 1,4-dioxane (5 ml) and to the solution was added 0.15M potassium hydroxide solution (5 ml) and the whole stirred at ambient temperature for 8 hours. The solution was concentrated to remove the organic solvent and the aqueous residue was extracted with dichloromethane (2×20 ml). The combined extracts were dried, acidified with 1M ethereal hydrogen chloride (1 ml), concentrated to an oil and stirred with acetone/diethyl ether to afford the title compound (E1) (28 mg, 21%). δH (250 MHz, d6-DMSO) 1.10 (5H, br, s), 1.56 (5H, br, s), 2.86 (1H, br, s), 3.21 (8H, br, s), 3.87 (3H, s), 7.13 (1H, d, J=8.0 Hz), 7.33 (1H, s), 7.46-7.52 (2H, m), 9.19 (2H, br, s), MH+354.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[N:27]=[C:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:29][C:30]=1[CH3:31])[CH2:6][O:7][C:8]1[C:12]([CH:13]=O)=[CH:11][N:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]=1.Cl.NO.[N:41]1C=CC=CC=1.Cl>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[N:27]=[C:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:29][C:30]=1[CH3:31])[CH2:6][O:7][C:8]1[C:12]([C:13]#[N:41])=[CH:11][N:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]=1
Reactant: c1ccncc1
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2ccccc2)oc1C
Agent: Cl
Agent: NO
Solvent: CCO
Product: COc1cc(COc2nn(-c3ccccc3)cc2C#N)ccc1OCc1nc(-c2ccccc2)oc1C
Yield: 90 %

Procedure:
A mixture of 3-{[3-methoxy-4-(5-methyl-2-phenyl-1,3-oxazol-4-ylmethoxy)benzyl]oxy}-1-phenyl-1H-pyrazole-4-carbaldehyde (950 mg), hydroxylamine hydrochloride (150 mg), pyridine (1 mL) and ethanol (20 mL) was refluxed for 3 hrs. After concentration of the reaction mixture, dilute hydrochloric acid was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was dissolved in acetic anhydride (20 mL), and the mixture was refluxed for 5 hrs. After concentration of the reaction mixture, the residue was subjected to silica gel column chromatography to give 3-{[3-methoxy-4-(5-methyl-2-phenyl-1,3-oxazol-4-ylmethoxy)benzyl]oxy}-1-phenyl-1H-pyrazole-4-carbonitrile (850 mg, yield 90%) as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:2, v/v). The crystals were recrystallized from acetone-hexane. melting point: 174-175° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C:4]1[C:9]([NH:10][CH:11]([CH2:15][CH3:16])[C:12](=O)[CH3:13])=[CH:8][C:7]([CH3:17])=[N:6][C:5]=1[O:18][C:19]1[C:24]([CH3:25])=[CH:23][C:22]([Cl:26])=[CH:21][C:20]=1[CH3:27].[CH3:29][NH2:30]>>[CH3:1][O:2][C:3](=[O:28])[C:4]1[C:9]([NH:10][C@@H:11]([CH2:15][CH3:16])[C@@H:12]([NH:30][CH3:29])[CH3:13])=[CH:8][C:7]([CH3:17])=[N:6][C:5]=1[O:18][C:19]1[C:24]([CH3:25])=[CH:23][C:22]([Cl:26])=[CH:21][C:20]=1[CH3:27]
Reactant: CN
Reactant: CCC(Nc1cc(C)nc(Oc2c(C)cc(Cl)cc2C)c1C(=O)OC)C(C)=O
Product: CC[C@H](Nc1cc(C)nc(Oc2c(C)cc(Cl)cc2C)c1C(=O)OC)[C@H](C)NC

Procedure:
The title compound was prepared by a reductive amination as shown above starting with 2-(4-Chloro-2,6-dimethyl-phenoxy)-4-(1-ethyl-2-oxo-propylamino)-6-methyl-nicotinic acid methyl ester and methyl amine. APCl M+1 [420.2], 1H NMR(CDCl3)
Reaction SMILES: [CH:1]([C:4]1[N:8]=[C:7]([CH2:9][CH2:10][NH:11]C(=O)OC(C)(C)C)[O:6][N:5]=1)([CH3:3])[CH3:2].[ClH:19]>ClCCl>[ClH:19].[CH:1]([C:4]1[N:8]=[C:7]([CH2:9][CH2:10][NH2:11])[O:6][N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1noc(CCNC(=O)OC(C)(C)C)n1
Agent: Cl
Solvent: ClCCl
Product: CC(C)c1noc(CCN)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
900 mg (3.53 mmol) tert-butyl [2-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-ethyl]-carbamate are placed in 10 ml dichloromethane, 20 ml 1 molar ethereal hydrochloric acid are added. The reaction mixture is stirred for 16 hours at ambient temperature. After the further addition of 10 ml ethereal hydrochloric acid the mixture is stirred for another 72 hours at ambient temperature and 4 hours at 40° C. The suspension is evaporated down. The residue is dissolved in acetone, mixed with diethyl ether and suction filtered.
Reaction SMILES: [Br-].C1(C([PH3+])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:22][C:23]([CH3:26])([O-])[CH3:24].[K+].O=C1C[CH2:33][CH:32]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:31]C1.O>C1COCC1>[CH2:22]=[C:23]1[CH2:26][CH2:33][CH:32]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:31][CH2:24]1
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Agent: [PH3+]C(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: C=C1CCC(C(=O)OCC)CC1
Temperature: 0 °C
Yield: 95.7 %

Procedure:
Triphenylmethylphosphonium bromide (53.7 g, 0.15 mol) was dissolved in 500 mL of THF, and potassium tert-butoxide (16.8 g, 0.15 mol) was added at −20° C. Reacted for 0.5 h after the temperature was raised to 0° C. Subsequently, ethyl 4-oxo-cyclohexylcarboxylate (Compound 8-1) (17 g, 0.1 mol) was dissolved in 100 mL of THF and added dropwise to the flask under nitrogen, reacted at room temperature for 3 hours, then a small amount of water was added to dissolve the solid, and rotary evaporated to remove THF, extracted with anhydrous diethyl ether, dried, and concentrated, the concentrate was dissolved in n-hexane, and filtered by silica gel, then concentrated to give Compound 8-2 as a colorless liquid (16.1 g, 95.7% yield).
Reaction SMILES: [F:1][C:2]1[CH:38]=[CH:37][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19]([OH:20])=[C:18]3[C:13]([CH:14]=[CH:15][CH:16]=[N:17]3)=[C:12]([N:21]3[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23][S:22]3(=[O:36])=[O:35])[N:11]=2)=[O:9])=[CH:4][CH:3]=1.[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42]>C(Cl)Cl>[F:39][C:40]([F:45])([F:44])[C:41]([O-:43])=[O:42].[F:1][C:2]1[CH:38]=[CH:37][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19]([OH:20])=[C:18]3[C:13]([CH:14]=[CH:15][CH:16]=[N:17]3)=[C:12]([N:21]3[CH2:27][CH2:26][NH2+:25][CH2:24][CH2:23][S:22]3(=[O:35])=[O:36])[N:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(C(=O)NCc3ccc(F)cc3)c(O)c3ncccc23)S(=O)(=O)CC1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NCc1ccc(F)cc1)c1nc(N2CC[NH2+]CCS2(=O)=O)c2cccnc2c1O
Product: O=C([O-])C(F)(F)F

Procedure:
A solution of tert-butyl 2-(7-{[(4-fluorobenzyl)amino]carbonyl}-8-hydroxy-1,6-naphthyridin-5-yl)-1,2,5-thiadiazepane-5-carboxylate 1,1-dioxide (0.088 g, 0.185 mmol) in methylene chloride (5 mL) was treated with trifluoroacetic acid (2 mL) at room temperature. After 6 hr the solvent was evaporated in vacuo and the residue purified by preparative HPLC (Gilson semi preparative HPLC system and a YMC Combiprep Pro Column (50×20 mm I.D., C18, S-5 um, 120A) eluting with 5-95% acetonitrile/water (0.1% TFA) at 15 ml/min) to afford the title compound after lyophilization.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:6]=[C:7]([C:11]([O:13][CH3:14])=[S:12])[S:8][C:9]=1[CH3:10])=O.[NH2:15][C:16]([NH2:18])=[S:17].[C:19]1([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[BrH:1].[C:19]1([CH:25]([NH:15][C:16]2[S:17][CH:2]=[C:3]([C:5]3[CH:6]=[C:7]([C:11]([O:13][CH3:14])=[S:12])[S:8][C:9]=3[CH3:10])[N:18]=2)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NC(N)=S
Reactant: COC(=S)c1cc(C(=O)CBr)c(C)s1
Reactant: c1ccc(Cc2ccccc2)cc1
Product: Br
Product: COC(=S)c1cc(-c2csc(NC(c3ccccc3)c3ccccc3)n2)c(C)s1
Yield: 180.2 %

Procedure:
Methyl 4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate (50 mg, 0.16 mmol) was allowed to react with diphenylmethane thiourea (38 mg) as described in Example 154, step (a), to give 145 mg (100% yield) of methyl 4-{2-[(diphenylmethyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxylate hydrobromide after removal of solvent in vacuo. 1H NMR (DMSO-d6, 300 MHz) δ2.50 (s, 3H), 2.80 (s, 3H), 6.13, 6.18 (d, 1H rotomer, J=7.9 Hz), 7.23-7.41 (m, 11H), 8.00, 8.02 (s, 1H rotomer), 8.73, 8.86 (d, 1H, rotomer, J=8.0 Hz); Mass Spectrum (ESI) m/z calcd. for C23H20N2O2S3, 452.62 (M+H), found 453.0.
Reaction SMILES: [NH:1]([C:14]([O:16]CC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[N:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34]([CH:41]=O)=[CH:33][CH:32]=1.[F:43][C:44]([F:56])([F:55])[S:45]([C:48]1[CH:54]=[CH:53][C:51]([NH2:52])=[CH:50][CH:49]=1)(=[O:47])=[O:46]>>[F:43][C:44]([F:56])([F:55])[C:11]([OH:13])=[O:12].[OH:10][C:7]1[CH:6]=[CH:5][C:4]([CH2:3][C@H:2]2[N:1]([CH2:41][C:34]3[C:35]4[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=4)[N:31]=[CH:32][CH:33]=3)[C:14](=[O:16])[N:52]([C:51]3[CH:53]=[CH:54][C:48]([S:45]([C:44]([F:56])([F:43])[F:55])(=[O:47])=[O:46])=[CH:49][CH:50]=3)[C:11]2=[O:13])=[CH:9][CH:8]=1
Reactant: Nc1ccc(S(=O)(=O)C(F)(F)F)cc1
Reactant: O=C(N[C@H](Cc1ccc(O)cc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Reactant: O=Cc1ccnc2ccccc12
Product: O=C(O)C(F)(F)F
Product: O=C1[C@@H](Cc2ccc(O)cc2)N(Cc2ccnc3ccccc23)C(=O)N1c1ccc(S(=O)(=O)C(F)(F)F)cc1

Procedure:
The compound is prepared from 0.05 mmol of resin, 0.15 mmol of N-Fmoc-D-Tyr(OH), 0.25 mmol of 4-quinolinecarboxaldehyde and 0.125 mmol of 4-(trifluoromethanesulfonyl)aniline, in the same way as in Example 1. After purification by preparative LC-MS, 1.8 mg of expected product are obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[CH:16]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([F:24])[CH:18]=2)[NH:15][C:14]([O:25][CH3:26])=[N:13][C:12]=1[CH2:27][CH3:28])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:30]([O:32][CH3:33])=[O:31]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:1]([O:8][C:9]([C:11]1[CH:16]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([F:24])[CH:18]=2)[N:15]([C:30]([O:32][CH3:33])=[O:31])[C:14]([O:25][CH3:26])=[N:13][C:12]=1[CH2:27][CH3:28])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)Cl
Reactant: CCC1=C(C(=O)OCc2ccccc2)C(c2ccc(F)c(F)c2)NC(OC)=N1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCC1=C(C(=O)OCc2ccccc2)C(c2ccc(F)c(F)c2)N(C(=O)OC)C(OC)=N1
Yield: 67.5 %

Procedure:
To a well stirred solution of (−)-5-(benzyloxycarbonyl)-1,6-dihydro-2-methoxy-4-ethyl-6-(3,4-diflurophenyl)pyrimidine (0.6 g, 1.5 mmol) and 4-(N,N-dimethylamino)pyridine (0.32 g, 2.66 mmol) in CH2Cl2 (6 mL) was added methyl chloroformate (0.2 mL, 2.66 mmol) at room temperature. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel with 3:1 Petroleum ether/EtOAC as the eluting system to obtain 0.45 g (78% yield) of (−)-5-(benzyloxycarbonyl)-4-ethyl-1,6-dihydro-2-methoxy-6-(3,4-difluorophenyl)-1-[methoxycarbonyl]pyrimidine as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[C:5]([F:10])=[CH:4][N:3]=1.[F:11][C:12]1[CH:13]=[C:14]2[C:20](B3OC(C)(C)C(C)(C)O3)=[CH:19][N:18]([S:30]([C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=3)(=[O:32])=[O:31])[C:15]2=[N:16][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.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>[F:11][C:12]1[CH:13]=[C:14]2[C:20]([C:2]3[N:7]=[C:6]([S:8][CH3:9])[C:5]([F:10])=[CH:4][N:3]=3)=[CH:19][N:18]([S:30]([C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=3)(=[O:31])=[O:32])[C:15]2=[N:16][CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(F)cnc32)cc1
Reactant: CSc1nc(Cl)ncc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CSc1nc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncc(F)cc23)ncc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Chloro-5-fluoro-4-methylsulfanyl-pyrimidine (34.1 g, 191.0 mmol), 5-fluoro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine, 44a, (53.0 g, 127.3 mmol) and Na2CO3 (40.5 g, 381.9 mmol) were dissolved in a mixture of DME (795 mL) and water (159 mL). The mixture was purged with nitrogen for 20 minutes and treated with Pd(PPh3)4 (7.4 g, 6.6 mmol). After purging with nitrogen for another 20 minutes, the reaction was heated to reflux overnight, cooled to room temperature and diluted with water (600 mL). The resulting suspension was stirred at room temperature for 30 minutes and the precipitate was then collected by filtration, washed with water and acetonitrile and dried at 50° C. to afford 48.2 g of 5-fluoro-3-[5-fluoro-4-(methylthio)pyrimidin-2-yl]-1-tosyl-1H-pyrrolo[2,3-b]pyridine as a white solid.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([N:18]3[CH2:23][CH2:22][CH:21]([N:24]4[C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=5[CH2:27][O:26][C:25]4=[O:34])[CH2:20][CH2:19]3)=[O:17])=[C:11]([O:35][CH2:36][C:37]([F:40])([F:39])[F:38])[CH:10]=2)[CH2:4][CH2:3]1.[CH3:41][N:42]([CH3:46])[C:43](Cl)=[O:44].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:41][N:42]([CH3:46])[C:43]([N:2]1[CH2:3][CH2:4][CH:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([N:18]3[CH2:23][CH2:22][CH:21]([N:24]4[C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=5[CH2:27][O:26][C:25]4=[O:34])[CH2:20][CH2:19]3)=[O:17])=[C:11]([O:35][CH2:36][C:37]([F:40])([F:38])[F:39])[CH:10]=2)[CH2:6][CH2:7]1)=[O:44]
Reactant: O=C(Cc1ccc(OC2CCNCC2)cc1OCC(F)(F)F)N1CCC(N2C(=O)OCc3ccccc32)CC1
Reactant: CN(C)C(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)N1CCC(Oc2ccc(CC(=O)N3CCC(N4C(=O)OCc5ccccc54)CC3)c(OCC(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 1-(1-(4-(4-piperidinyloxy)-2-(2,2,2-trifluoroethoxy)phenylacetyl)piperidin-4-yl)-4H-3,1-benzoxazin-2(1H)-one hydrochloride (0.20 g, 0.35 mmol) from Example 2 in CH2Cl2 (20 mL) was added dimethylcarbamoyl chloride (0.042 g, 0.39 mmol) and DIEA (0.14 mL, 0.80 mmol). The solution was stirred at ambient temperature for 6 h and the solvent was removed under reduced pressure. The residue was dissolved in EtOAc (50 mL) and washed with 0.25 M aqueous citric acid (25 mL), H2O (25 mL), and saturated aqueous NaHCO3 (25 mL). The organic phase was dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using 97:3 CH2Cl2 :MeOH as eluant to give the title compound as an amorphous solid.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[C:11]([O:15][CH2:16][CH3:17])(=[O:14])[CH:12]=O.CC(OC(C)=O)=O>>[CH2:16]([O:15][C:11](=[O:14])/[CH:12]=[CH:1]/[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1)[CH3:17]
Reactant: CCOC(=O)C=O
Reactant: Cc1ccc(C(=O)O)cn1
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)/C=C/c1ccc(C(=O)O)cn1
Temperature: 130 °C
Yield: 145.7 %

Procedure:
6-Methylnicotinic acid (5 g, 36 mmol) and ethyl glyoxalate (50% solution in toluene—8.7 mL, 44 mmol) were added to Ac2O (25 mL) and stirred under a nitrogen atmosphere. The reaction was heated at 130° C. for 3 h then allowed to cool to RT over 17 h. The reaction was then quenched with water (10 mL) and concentrated to dryness in vacuo to afford the product as a brown solid (11.6 g, >100%). m/z=222 [M+H]+.
Reaction SMILES: CO[C:3](=[O:13])[C:4]1[C:9]([I:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11]Br.[CH3:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][NH2:18].C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[I:10][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:4]=1[C:3](=[O:13])[N:18]([CH2:17][C:16]1[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=1[CH3:14])[CH2:11]2
Reactant: Cc1ccccc1CN
Reactant: COC(=O)c1c(I)cccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1ccccc1CN1Cc2cccc(I)c2C1=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 51.4 %

Procedure:
A mixture of 2-bromomethyl-6-iodo-benzoic acid methyl ester (0.107 g, 0.3 mmol), 2-methyl-benzylamine (0.063 mL, 0.5 mmol), and K2CO3 (0.138 g, 1.0 mmol) in toluene (4 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 7-iodo-2-(2-methyl-benzyl)-2,3-dihydro-isoindol-1-one (0.056 g, 51%). 1H NMR (300 MHz, CDCl3): δ (ppm) 2.35 (s, 3H), 4.14 (s, 2H), 4.82 (s, 2H), 7.11-7.38 (m, 6H), 7.91 (d, 1H). GC-MS: m/z 363 (M)+.