Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C@H:4]([C@H:14]1[O:18][C:17](=[O:19])[C@H:16]([CH3:20])[CH2:15]1)[CH2:5][O:6]CC1C=CC=CC=1)=[N+]=[N-].[ClH:21].O1CCOCC1.[H][H]>C(O)C.[C].[Pd]>[ClH:21].[NH2:1][C@H:4]([C@H:14]1[O:18][C:17](=[O:19])[C@H:16]([CH3:20])[CH2:15]1)[CH2:5][OH:6]
Reactant: [H][H]
Reactant: C[C@@H]1C[C@@H]([C@H](COCc2ccccc2)N=[N+]=[N-])OC1=O
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: C[C@@H]1C[C@@H]([C@@H](N)CO)OC1=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A suspension of 7.56 g of (3R,5S)-5-[(S)-1-azido-2-benzyloxyethyl]-3-methyldihydrofuran-2-one obtained in Example (76e) (27.5 mmol), 15.0 ml of a solution of 4 N hydrochloric acid in dioxane (60.0 mmol) and 1.88 g of 10% palladium-carbon (50% wet) in ethanol (150 ml) was stirred under a hydrogen atmosphere at room temperature for six hours. Hydrogen in the reaction vessel was replaced by nitrogen, and then the reaction mixture was diluted with 100 ml of ethanol. Palladium-carbon was separated by filtration washed with ethanol. The solvent was evaporated from the filtrate under reduced pressure to obtain crude (3R,5S)-5-[(S)-1-amino-2-hydroxyethyl]-3-methyldihydrofuran-2-one hydrochloride.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:25][N:26]([CH3:34])[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:4][N:5]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23]O)[CH:18]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.CS([Cl:39])(=O)=O.C(N(C(C)C)CC)(C)C>O1CCCC1>[Cl:39][CH2:23][C:19]1[CH:18]=[C:17]([S:14]([N:5]2[C:6]([C:7]3[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=3)=[C:2]([F:1])[C:3]([CH2:25][N:26]([CH3:34])[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:4]2)(=[O:16])=[O:15])[CH:22]=[CH:21][CH:20]=1
Reactant: CN(Cc1cn(S(=O)(=O)c2cccc(CO)c2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(Cc1cn(S(=O)(=O)c2cccc(CCl)c2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 60 h
Yield: 54.5 %

Procedure:
To a solution of tert-butyl [(4-fluoro-5-(2-fluoropyridin-3-yl)-1-{[3-(hydroxymethyl)phenyl]sulfonyl}-1H-pyrrol-3-yl)methyl]methylcarbamate (683 mg) in tetrahydrofuran (5 mL) were added methanesulfonyl chloride (174 mg) and diisopropylethylamine (215 mg) under ice-cooling, and the mixture was stirred at room temperature for 60 hr. The solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→3:1) to give the title compound as a pale-yellow oil (yield 386 mg, 55%).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([OH:7])[C:4]([S:8]([O-:11])(=[O:10])=[O:9])=[CH:3][CH:2]=1.[Na+:12].[CH2:13]([CH:25]1[CH2:30][C:29](=[O:31])[N:28]([CH2:32][C:33](Cl)=[O:34])[C:26]1=[O:27])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>C1(C)C(C)=CC=CC=1>[CH2:13]([CH:25]1[CH2:30][C:29](=[O:31])[N:28]([CH2:32][C:33]([O:7][C:5]2[CH:6]=[CH:1][CH:2]=[CH:3][C:4]=2[S:8]([O-:11])(=[O:9])=[O:10])=[O:34])[C:26]1=[O:27])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].[Na+:12]
Reactant: CCCCCCCCCCCCC1CC(=O)N(CC(=O)Cl)C1=O
Reactant: O=S(=O)([O-])c1ccccc1O
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: CCCCCCCCCCCCC1CC(=O)N(CC(=O)Oc2ccccc2S(=O)(=O)[O-])C1=O

Procedure:
78.5 g (400 mmol) of anhydrous sodium phenolsulfonate and 137.4 g (400 mmol) of ω-(2-dodecylsuccinimido)-acetyl chloride are reacted in 200 g of xylene at 140° C. for 25 hours and the mixture is worked up as described in Example 1. The product is recrystallized from 90% strength ethanol and then dried at 40° C. under a water pump vacuum.
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:35]=[CH:34][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH2:21][CH2:22][C:23]([N:25]([CH3:33])[C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)=[O:24])=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1.C([Si]([O:53][C:54]1[CH:59]=[CH:58][C:57]([O:60][CH2:61][CH:62]2[CH2:64][O:63]2)=[CH:56][CH:55]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>>[Cl:32][C:29]1[CH:28]=[CH:27][C:26]([N:25]([CH3:33])[C:23]([CH2:22][CH2:21][NH:20][C:18]([N:15]2[CH2:14][CH2:13][CH:12]([NH:11][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][NH:4][CH2:64][C@H:62]([OH:63])[CH2:61][O:60][C:57]4[CH:58]=[CH:59][C:54]([OH:53])=[CH:55][CH:56]=4)=[CH:35][CH:34]=3)[CH2:17][CH2:16]2)=[O:19])=[O:24])=[CH:31][CH:30]=1
Reactant: CN(C(=O)CCNC(=O)N1CCC(Nc2ccc(CCN)cc2)CC1)c1ccc(Cl)cc1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Solvent: O=CO
Product: CN(C(=O)CCNC(=O)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1)c1ccc(Cl)cc1

Procedure:
4-[4-(2-Aminoethyl)anilino]-N-(3-[4-chloro(methyl)anilino]-3-oxopropyl)-1-piperidinecarboxamide formate (0.78 g, 1.55 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane according to Procedure G to provide the title compound (0.27 g, 0.3 mmol)
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[N:25][C:5]2[NH:6][C:7]3[C:12]([C:4]=2[CH:3]=1)=[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([CH2:22][CH3:23])(=[O:21])=[O:20])[CH:14]=1)[CH:10]=[CH:9][C:8]=3[OH:24].C(S(C1C=C(C2C=CC(O[CH2:48][CH2:49][CH2:50][N:51]([CH3:53])[CH3:52])=C3C=2C2C=C(C)C=NC=2N3)C=CC=1)(=O)=O)C>>[Cl:1][C:2]1[CH:26]=[N:25][C:5]2[NH:6][C:7]3[C:12]([C:4]=2[CH:3]=1)=[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([CH2:22][CH3:23])(=[O:21])=[O:20])[CH:14]=1)[CH:10]=[CH:9][C:8]=3[O:24][CH2:48][CH2:49][CH2:50][N:51]([CH3:53])[CH3:52]
Reactant: CCS(=O)(=O)c1cccc(-c2ccc(O)c3[nH]c4ncc(Cl)cc4c23)c1
Reactant: CCS(=O)(=O)c1cccc(-c2ccc(OCCCN(C)C)c3[nH]c4ncc(C)cc4c23)c1
Product: CCS(=O)(=O)c1cccc(-c2ccc(OCCCN(C)C)c3[nH]c4ncc(Cl)cc4c23)c1

Procedure:
The title compound was prepared from Compound 218 by using an analogous procedure to that outlined in the preparation of Compound 205. 1H NMR (400 MHz, Methanol-d4) δ 8.35 (s, 1H) 8.15 (m, 1H) 8.07 (m, 1H) 7.97 (m, 1H) 7.88 (t, J=8.0 Hz, 1H) 7.66 (s, 1H) 7.23 (d, J=8.36 Hz, 1H) 7.16 (d, J=8.36 Hz, 1H) 4.44 (t, J=5.8 Hz, 2H) 3.72 (t, J=8.0 Hz, 2H) 3.43 (q, J=7.32 Hz, 2H) 3.03 (s, 6H) 2.41 (m, 2H) 1.34 (t, J=7.32 Hz, 3H). [M+H] calc'd for C24H27ClN3O3S, 472; found, 472.
Reaction SMILES: C(O[CH:4]=[C:5]([C:21](=[O:23])[CH3:22])[C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[N+:18]([O-:20])=[O:19])=[O:7])C.Cl.[NH2:25]O>C(O)C>[N+:18]([C:9]1[CH:10]=[C:11]([C:14]([F:17])([F:16])[F:15])[CH:12]=[CH:13][C:8]=1[C:6]([C:5]1[CH:4]=[N:25][O:23][C:21]=1[CH3:22])=[O:7])([O-:20])=[O:19]
Reactant: CCOC=C(C(C)=O)C(=O)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: NO
Agent: Cl
Solvent: CCO
Product: Cc1oncc1C(=O)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Reaction time: 5 h
Yield: 37.5 %

Procedure:
A mixture of crude 2-ethoxymethylene-1-(2-nitro-4-trifluoromethylphenyl)butan-1,3-dione (13.25 g) and hydroxylamine hydrochloride (3.7 g) in ethanol (80 ml) was stirred for 5 hours. The solution was evaporated almost to dryness and the resultant solution was diluted with ethyl acetate (100 ml). The solution was washed with water (3×40 ml), dried (anhydrous sodium sulphate) and filtered. The filtrate was evaporated to dryness. The residue was triturated with a mixture of ether and petroleum spirit (bp 60°-80° C.) (1:1) and the resultant buff solid was filtered off. The solid was dissolved in dichloromethane (100 ml) and filtered through silica. The silica was washed with dichloromethane (100 ml) and the combined filtrates were evaporated to dryness to give 4-(2-nitro-4-trifluoromethylbenzoyl)-5-methylisoxazole (Compound 1, 4.5 g) as an off-white solid mp 85°-86° C.
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1)[CH2:6][N:7]([CH2:20][C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=1[NH:31][C:32](=[O:36])[O:33][CH2:34][CH3:35])[C:8]1[N:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][N:9]=1.[H-].[Na+].Br[CH2:49][CH2:50][CH2:51][CH2:52][C:53]([O:55][CH2:56][CH3:57])=[O:54]>CN(C)C=O.[Cl-].[Na+].O>[F:45][C:2]([F:1])([F:44])[C:3]1[CH:4]=[C:5]([CH:37]=[C:38]([C:40]([F:42])([F:41])[F:43])[CH:39]=1)[CH2:6][N:7]([CH2:20][C:21]1[CH:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:24]=[CH:23][C:22]=1[N:31]([C:32]([O:33][CH2:34][CH3:35])=[O:36])[CH2:49][CH2:50][CH2:51][CH2:52][C:53]([O:55][CH2:56][CH3:57])=[O:54])[C:8]1[N:13]=[CH:12][C:11]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)=[CH:10][N:9]=1
Reactant: CCOC(=O)CCCCBr
Reactant: CCOC(=O)Nc1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCCN(C(=O)OCC)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1
Reaction time: 0.5 h

Procedure:
Ethyl (2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-carbamate (140 mg) is dissolved in N,N-dimethylformamide (1 ml), and thereto is added sodium hydride (63%) (12 mg) under ice-cooling, and the mixture is stirred at the same temperature for 30 minutes. To the reaction mixture is added ethyl 5-bromo-pentanoate (68 μl), and the mixture is stirred at 0° C. to room temperature overnight. To the reaction mixture is added a saturated brine, and the mixture is extracted with ethyl acetate, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give ethyl 5-[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-ethoxycarbonyl-amino]-pentanoate (137 mg). MS (m/z): 780 [M+H]+
Reaction SMILES: [OH:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:11].[H-].[Na+].[CH2:14]([N:21]1[C:25]2[N:26]=[C:27]([NH2:31])[N:28]=[C:29](Cl)[C:24]=2[CH:23]=[CH:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN1C=CC=CC1=O>[NH2:31][C:27]1[N:28]=[C:29]([O:1][C:2]2[C:3]([CH3:11])=[CH:4][C:5]([C:6]#[N:7])=[CH:8][C:9]=2[CH3:10])[C:24]2[CH:23]=[CH:22][N:21]([CH2:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:25]=2[N:26]=1
Reactant: Nc1nc(Cl)c2ccn(Cc3ccccc3)c2n1
Reactant: Cc1cc(C#N)cc(C)c1O
Agent: Cn1ccccc1=O
Agent: [H-]
Agent: [Na+]
Product: Cc1cc(C#N)cc(C)c1Oc1nc(N)nc2c1ccn2Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 0.1 %

Procedure:
To a solution of 4-hydroxy-3,5-dimethylbenzonitrile (1.62 mg, 11.0 mmol) in 1-methyl-2-pyridone (5 mL) in a sealed tube was added NaH (441 mg, 11.0 mmol). The reaction mixture was stirred at room temperature for 15 min and a solution of 7-benzyl-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine (950 mg, 3.67 mmol) in 1-methyl-2-pyridone (5 mL) was added to the mixture. The mixture was heated at 150° C. for 16 h and cooled to room temperature. The reaction was poured into ice water and extracted with EtOAc (2×50 mL). The combined organic solution was washed with H2O (50 mL) and brine (50 mL), dried with Na2SO4, and concentrated to dryness. Silica gel chromatography (Hexanes:EtOAc=75:25) yielded 1.12 mg (83%) of 4-(2-amino-7-benzyl-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)-3,5-dimethyl-benzonitrile.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH2:8])=[C:6]([NH2:9])[CH:5]=[C:4]([Cl:10])[N:3]=1.N[C:12](N)=[O:13]>O>[Cl:1][C:2]1[C:7]2[NH:8][C:12](=[O:13])[NH:9][C:6]=2[CH:5]=[C:4]([Cl:10])[N:3]=1
Reactant: Nc1cc(Cl)nc(Cl)c1N
Reactant: NC(N)=O
Solvent: O
Product: O=c1[nH]c2cc(Cl)nc(Cl)c2[nH]1
Temperature: 165 °C
Reaction time: 4 h

Procedure:
A mixture of 2,6-dichloro-3,4-dihydropyridine-3,4-diamine (500 mg, 2.8 mmol) from Step B and urea (1.0 g, 16.8 mmol) was stirred as a melt at 165° C. for 4 h, then cooled and H2O (100 mL) was added. The aqueous mixture was heated at reflux until all solid dissolved and the solution was allowed to cool and aged for 18 h. The precipitate was isolated by filtration to give the title compound. MS: m/z=205 (M+1).
Reaction SMILES: CSC.C([O:11][C@H:12]1[C@H:17]([O:18]CC2C=CC=CC=2)[C@@H:16]([O:26]CC2C=CC=CC=2)[C@@H:15]([C:34]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH:37]=[C:36]([CH2:44][C:45]3[S:49][C:48]4[CH:50]=[CH:51][C:52]([CH2:54][CH3:55])=[CH:53][C:47]=4[CH:46]=3)[CH:35]=2)[O:14][CH:13]1[CH2:56][O:57]CC1C=CC=CC=1)C1C=CC=CC=1.CO>C(Cl)Cl>[OH:57][CH2:56][C@@H:13]1[C@@H:12]([OH:11])[C@H:17]([OH:18])[C@@H:16]([OH:26])[C@H:15]([C:34]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH:37]=[C:36]([CH2:44][C:45]3[S:49][C:48]4[CH:50]=[CH:51][C:52]([CH2:54][CH3:55])=[CH:53][C:47]=4[CH:46]=3)[CH:35]=2)[O:14]1
Reactant: CCc1ccc2sc(Cc3cc([C@H]4OC(COCc5ccccc5)[C@@H](OCc5ccccc5)[C@H](OCc5ccccc5)[C@H]4OCc4ccccc4)c4ccccc4c3)cc2c1
Solvent: CSC
Solvent: ClCCl
Solvent: CO
Product: CCc1ccc2sc(Cc3cc([C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)c4ccccc4c3)cc2c1
Temperature: 25 °C
Reaction time: 36 h
Yield: 31.6 %

Procedure:
Under a nitrogen atmosphere, dimethylsulfide (2.66 ml) and a boron trifluoride-diethyl ether complex (1.03 ml, 8.12 mmol) were added to a solution of (3R,4R,5S,6R)-3,4,5-trisbenzyloxy-2-benzyloxymethyl-6-[3-(5-ethylbenzo[b]-thiophen-2-ylmethyl)naphthalen-1-yl]tetrahydropyran (670 mg, 0.81 mmol) in methylene chloride (4 ml) under cooling with ice. The reaction mixture was stirred at room temperature for 1.5 days, and then a 50% methanol aqueous solution (20 ml) was added under cooling with ice and the mixture was extracted with methylene chloride. The organic layer was washed with a saturated sodium chloride aqueous solution and dried with sodium sulfate, and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=methylene chloride:methanol (50:1)] to obtain the title compound (119 mg, 32%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O[CH:30]1[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH:30]1[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Oc1ccc(F)cc1F
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(F)cc2F)CC1
Temperature: 40 °C
Reaction time: 16 h
Yield: 82.9 %

Procedure:
To a solution of 2,4-difluorophenol (10 g, 77 mmol), PPh3 (30.2 g, 115 mmol) and tert-butyl 4-hydroxypiperidine-1-carboxylate (30.9 g, 154 mmol) in THF (400 mL) was added DEAD (18.3 mL, 115 mmol) at 0° C. dropwise. After the addition was completed, the resulting mixture was allowed to stir at 40° C. for 16 h. The mixture was poured into water and extracted with EtOAc (3×400 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated to give the crude product. Purification by flash silica gel chromatography, eluting with 80:1 PE:EtOAc, gave tert-butyl 4-(2,4-difluorophenoxyl)piperidine-1-carboxylate as an oil (20 g, 83%).
Reaction SMILES: [CH:1]([OH:3])=O.N1(C(N2C=CN=C2)=O)C=CN=C1.C(OC([N:23]1[C:27]2[N:28]=[CH:29][N:30]=[C:31]([N:32]3[CH2:39][C:36]4([CH2:38][CH2:37]4)[N:35]([S:40](=[O:43])(=[O:42])[NH2:41])[CH2:34][CH2:33]3)[C:26]=2[CH:25]=[CH:24]1)=O)(C)(C)C.C1CCN2C(=NCCC2)CC1>C1COCC1>[N:28]1[C:27]2[NH:23][CH:24]=[CH:25][C:26]=2[C:31]([N:32]2[CH2:33][CH2:34][N:35]([S:40]([NH:41][CH:1]=[O:3])(=[O:43])=[O:42])[C:36]3([CH2:38][CH2:37]3)[CH2:39]2)=[N:30][CH:29]=1
Reactant: O=CO
Reactant: CC(C)(C)OC(=O)n1ccc2c(N3CCN(S(N)(=O)=O)C4(CC4)C3)ncnc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: O=CNS(=O)(=O)N1CCN(c2ncnc3[nH]ccc23)CC12CC2
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
Formic acid (0.24 mmol) was dissolved in dry THF (0.5 mL), added di(imidazol-1-yl)methanone (0.29 mmol) and then stirred at 50° C. for 30 min. before being cooled to rt and added 4-(4-Sulfamoyl-4,7-diaza-spiro[2.5]oct-7-yl)-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid tert-butyl ester (Intermediate 2) (0.24 mmol) and DBU (0.29 mmol). The reaction mixture was stirred at rt for 16 h. The pure compounds were obtained by standard preparative HPLC purification of the reaction mixture.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:13])[CH2:9][CH:10]([CH3:12])[CH3:11].[F:14][C:15]1[N:19]([CH3:20])[N:18]=[C:17]([CH3:21])[C:16]=1[C:22](Cl)=[O:23].C(N(CC)CC)C>O1CCCC1>[CH3:12][CH:10]([CH3:11])[CH2:9][C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:22]([C:16]1[C:17]([CH3:21])=[N:18][N:19]([CH3:20])[C:15]=1[F:14])=[O:23])=[O:13]
Reactant: CC(C)CC(=O)c1ccccc1N
Reactant: Cc1nn(C)c(F)c1C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1nn(C)c(F)c1C(=O)Nc1ccccc1C(=O)CC(C)C
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
At room temperature, 355.0 mg (2.0 mmol) of 1-(2-aminophenyl)-3-methylbutan-1-one are added to a solution comprising 388.5 mg (2.2 mmol) of 5-fluoro-1,3-dimethyl-1H-pyrazole-4-carbonyl chloride and 0.45 ml (3.2 mmol) of triethylamine in 20 ml of tetrahydrofuran. The reaction mixture is stirred at 60° C. for 1.5 h, filtered through silica gel and concentrated. Column chromatography (cyclohexane/ethyl acetate: 3/1) gives 577.7 mg (1.8 mmol, 88% of theory) of N-[2-(3-methylbutyryl)phenyl-5-fluoro-1,3-dimethyl-1H-pyrazole-4-carboxamide of logP (pH=2.3)=3.42.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[Cl:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18]Br>CN(C)C=O>[Cl:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][N:5]1[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]1
Reactant: OC1CCNCC1
Reactant: Clc1ccccc1CBr
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: OC1CCN(Cc2ccccc2Cl)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
0.202 g (0.002 mol) of 4-hydroxypiperidine, 1.22 ml (0.0088 mol) of triethylamine and 0.43 g (0.0021 mol) of 2-chlorobenzyl bromide were dissolved in 5 ml of dimethylform-amide and stirred at room temperature for 2 hrs. The solvent was distilled off and the residue was taken up in dichloromethane and washed with saturated bicarbonate solution and sodium chloride solution. The organic phase was dried over sodium sulfate and concentrated. 0.28 g (62%) 1-(2-chloro-benzyl)-piperidin-4-ol was obtained as a colorless oil.
Reaction SMILES: [O:1]=[C:2]1[C:11]([C:12]([OH:14])=O)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.CN1CCOCC1.C(Cl)(=O)OCC(C)C.[CH2:30]([NH:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>O1CCCC1.CN(C)C=O>[CH2:37]([N:36]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:12]([C:11]1[C:2](=[O:1])[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:14])[CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]
Reactant: O=C(O)c1cc2ccccc2[nH]c1=O
Reactant: CCCCCCNCCCCCC
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCCCCCN(CCCCCC)C(=O)c1cc2ccccc2[nH]c1=O
Temperature: -15 °C
Reaction time: 0.17 h
Yield: 75.8 %

Procedure:
In a mixture of 50 ml of tetrahydrofuran and 250 ml of N,N-dimethylformamide were dissolved 9.46 g of 1,2-dihydro-2-oxoquinoline-3-carboxylic acid and 5.06 g of N-methylmorpholine, and after cooling to −15° C., 6.83 g of isobutyl chlorocarbonate was added dropwise over 10 minutes. After stirring at −15° C. for 10 minutes, 9.73 g of dihexylamine was added dropwise over 5 minutes. After stirring at −15° C. for 4 hours and then at room temperature overnight, the reaction mixture was concentrated under reduced pressure, and the residue, after addition of ethyl acetate, was washed with water, 1N hydrochloric acid, a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the filtrate was concentrated under reduced pressure. The residue was recrystallized from hexane to give 13.51 g of N,N-dihexyl-1,2-dihydro-2-oxoquinoline-3-carboxamide.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[C:19]([F:20])=[CH:18][CH:17]=[C:16]([F:21])[C:12]=1[C:13]([OH:15])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[O:44]=[C:45]([N:62]1[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]1)[CH2:46][NH:47][C:48]([C:50]1[CH:55]=[CH:54][C:53]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)=[CH:52][CH:51]=1)=[O:49]>CN(C=O)C.O>[O:44]=[C:45]([N:62]1[CH2:67][CH2:66][N:65]([C:13](=[O:15])[C:12]2[C:16]([F:21])=[CH:17][CH:18]=[C:19]([F:20])[C:11]=2[F:10])[CH2:64][CH2:63]1)[CH2:46][NH:47][C:48]([C:50]1[CH:51]=[CH:52][C:53]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)=[CH:54][CH:55]=1)=[O:49]
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(-c2ccccc2)cc1
Reactant: O=C(O)c1c(F)ccc(F)c1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCN(C(=O)c2c(F)ccc(F)c2F)CC1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.9 %

Procedure:
DIPEA (149.8 mg, 1.15 mmol) was added to a stirred solution of 2,3,6-trifluoro-benzoic acid (45.3 mg, 0.26 mmol) in DMF (3 mL), HOBt (38.2 mg, 0.28 mmol) and EDCI.HCl (123.4 mg, 0.64 mmol) at room temperature. After 2 minutes biphenyl-4-carboxylicacid (2-oxo-2-piperazin-1-yl-ethyl)-amide (100 mg, 0.31 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added, and the resulting precipitate was filtered. The residue was purified by column chromatography (using 60-120 mesh silica gel and 60% EtOAc in hexane as eluent) to afford 45 mg (36.2% yield) of biphenyl-4-carboxylicacid {2-oxo-2-[4-(2,3,6-trifluoro-benzoyl)-piperazin-1-yl]-ethyl}-amide, LC-MS purity: 92.11%, 1H NMR: (DMSO) δ 7.97-7.9 (d, 2H), 7.74-7.6 (q, 4H), 7.52-7.44 (t, 2H), 7.44-7.36 (m, 1H), 7.36-7.28 (m, 1H), 7.02-6.92 (m, 1H), 4.4-4.26 (dd, 2H), 3.98-3.82 (m, 3H), 3.78-3.72 (t, 1H), 3.68-3.62 (t, 1H), 3.58-3.52 (m, 1H), 3.48-3.38 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19](Cl)=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:21][C:22]([F:34])([F:33])[O:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=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>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([C:27]3[CH:26]=[CH:25][C:24]([O:23][C:22]([F:21])([F:33])[F:34])=[CH:29][CH:28]=3)=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2Cl)CC1
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: Cc1ccccc1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2nccnc2-c2ccc(OC(F)(F)F)cc2)CC1
Yield: 93.9 %

Procedure:
Dissolve 3′-chloro-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid t-butyl ester (0.400 g, 1.34 mmol) in toluene (2.68 mL). Add 4-(trifluoromethoxy)phenylboronic acid (0.303 g, 1.47 mmol), followed by tetrakis(triphenylphosphine)palladium(0) (0.077 g, 0.067 mmol). Add ethanol (2.68 mL), followed by a 2 N aqueous sodium carbonate solution (2.68 mL). Reflux reaction for 18 hr. Cool reaction to room temperature and concentrate. Add ethyl acetate and wash with water. Extract water layer one time with ethyl acetate. Dry (magnesium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 0:100 to 20:80 ethyl acetate:hexanes), to give 3′-(4-trifluoromethoxyphenyl)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid t-butyl ester (534 mg, 94%). MS (ES): m/z=425 [M+H]+.