Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:6][C:5]([C:13]2[CH:21]=[C:20]3[C:16]([CH:17]=[N:18][N:19]3[S:22]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=3)(=[O:24])=[O:23])=[C:15]([C:32]3[NH:36][N:35]=NN=3)[CH:14]=2)=[CH:4][N:3]=1.[C:37](Cl)(=[O:39])[CH3:38]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([NH:8][S:9]([CH3:12])(=[O:10])=[O:11])=[CH:6][C:5]([C:13]2[CH:21]=[C:20]3[C:16]([CH:17]=[N:18][N:19]3[S:22]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=3)(=[O:23])=[O:24])=[C:15]([C:32]3[O:39][C:37]([CH3:38])=[N:35][N:36]=3)[CH:14]=2)=[CH:4][N:3]=1
Reactant: CC(=O)Cl
Reactant: Cc1ccc(S(=O)(=O)n2ncc3c(-c4nnn[nH]4)cc(-c4cnc(Cl)c(NS(C)(=O)=O)c4)cc32)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)n2ncc3c(-c4nnc(C)o4)cc(-c4cnc(Cl)c(NS(C)(=O)=O)c4)cc32)cc1
Temperature: 120 °C
Reaction time: 0.17 h
Yield: 31.1 %

Procedure:
N-{2-Chloro-5-[1-[(4-methylphenyl)sulfonyl]-4-(1H-tetrazol-5-yl)-1H-indazol-6-yl]-3-pyridinyl}methanesulfonamide (50 mg, 0.092 mmol) and acetyl chloride (8.48 μl, 0.119 mmol) were placed in toluene (2 ml) and left to stand for 10 mins before heating under microwave irradiation at 120° C. for 40 mins. Additional acetyl chloride (8.48 μl, 0.119 mmol) was added and the reaction mixture heated for a further 40 mins at 120° C. The solvent was removed and the residue purified by column chromatography, on a silica cartridge (20 g) eluting with 0-100% ethyl acetate/cyclohexane followed by 0-20% methanol to give the title compound as a white solid (16 mg).
Reaction SMILES: C(OC(=O)[CH2:5][C:6]([CH:8]=[CH:9][NH:10][C:11]1[O:15][N:14]=[C:13]([CH3:16])[CH:12]=1)=[O:7])C.[C:18]1([O:24]C2C=CC=CC=2)C=CC=CC=1>>[C:6]([C:8]1[C:18]([OH:24])=[C:12]2[C:13]([CH3:16])=[N:14][O:15][C:11]2=[N:10][CH:9]=1)(=[O:7])[CH3:5]
Reactant: c1ccc(Oc2ccccc2)cc1
Reactant: CCOC(=O)CC(=O)C=CNc1cc(C)no1
Product: CC(=O)c1cnc2onc(C)c2c1O
Reaction time: 0.08 h

Procedure:
23.8 g. of (3-methyl-5-isoxazolyl)aminomethyleneacetoacetic acid ethyl ester (0.1 mol.) are quickly added to 100 ml. of vigorously refluxing diphenyl ether. After 5 minutes, the reaction mixture is cooled, as rapidly as possible. After addition of 100 ml. diethyl ether, 5-acetyl-4-hydroxy-3-methylisoxazolo[5,4-b]pyridine crystallizes and is filtered off. Recrystallization from methanol yields 9.5 g. (49.5%) of pure product, m.p. 162°.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:13][C:14]3[N:15]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[CH3:32])[C:16](=[O:25])[C:17]4[C:22]([CH:23]=3)=[CH:21][CH:20]=[CH:19][C:18]=4[CH3:24])[N:9]=[C:10]([CH:11]=[O:12])[C:3]=12.[O-]Cl=O.[Na+].Cl.[NH2:38][C:39]1[N:44]=[CH:43][N:42]=[C:41]2[N:45]([CH2:51][C:52]3[N:53]([C:64]4[CH:69]=[CH:68][CH:67]=[CH:66][C:65]=4[CH3:70])[C:54](=[O:63])[C:55]4[C:60]([CH:61]=3)=[CH:59][CH:58]=[CH:57][C:56]=4[CH3:62])[N:46]=[C:47]([C:48]([OH:50])=[O:49])[C:40]=12>CC(O)(C)C.O.CCC=CC>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:13][C:14]3[N:15]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[CH3:32])[C:16](=[O:25])[C:17]4[C:22]([CH:23]=3)=[CH:21][CH:20]=[CH:19][C:18]=4[CH3:24])[N:9]=[C:10]([C:11]([NH2:38])=[O:12])[C:3]=12.[NH2:38][C:39]1[N:44]=[CH:43][N:42]=[C:41]2[N:45]([CH2:51][C:52]3[N:53]([C:64]4[CH:69]=[CH:68][CH:67]=[CH:66][C:65]=4[CH3:70])[C:54](=[O:63])[C:55]4[C:60]([CH:61]=3)=[CH:59][CH:58]=[CH:57][C:56]=4[CH3:62])[N:46]=[C:47]([C:48]([OH:50])=[O:49])[C:40]=12
Reactant: Cc1ccccc1-n1c(Cn2nc(C=O)c3c(N)ncnc32)cc2cccc(C)c2c1=O
Agent: CC=CCC
Agent: Cc1ccccc1-n1c(Cn2nc(C(=O)O)c3c(N)ncnc32)cc2cccc(C)c2c1=O
Agent: Cl
Solvent: CC(C)(C)O
Solvent: O
Product: Cc1ccccc1-n1c(Cn2nc(C(N)=O)c3c(N)ncnc32)cc2cccc(C)c2c1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 4-amino-1-((8-methyl-1-oxo-2-o-tolyl-1,2-dihydroisoquinolin-3-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carbaldehyde (compound 4502) (400 mg, 0.94 mmol) in t-BuOH (1.8 mL), a solution of NaH2PO4 (3.90 g, 28.27 mmol) in water (4.8 mL), methyl-2-butene (1.0 mL) and (dropwise) a solution of NaClO2 (767 mg, 6.78 mmol) in water (4.8 mL) were added sequentially. The mixture was stirred at RT for 3 h under an argon atmosphere. The pale yellow solution was acidified with aqueous HCl solution (2 M, 4 mL) to PH=2 and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo, and the residue was triturated with anhydrous ethyl ether and ethyl acetate. The solid was collected by filtration to afford the desired product, 4-amino-1-((8-methyl-1-oxo-2-o-tolyl-1,2-dihydroisoquinolin-3-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid (compound 4601) (200 mg, 47% yield) as a yellow solid.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]([F:20])([F:19])[F:18])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](O)=[O:14])[C:7]([CH3:16])=[CH:6]2)#[N:2].[Br:21][C:22]1[CH:23]=[C:24]([C:28]([NH:30][NH2:31])=O)[CH:25]=[N:26][CH:27]=1>>[Br:21][C:22]1[CH:23]=[C:24]([C:28]2[O:14][C:13]([CH2:12][N:8]3[C:9]4[C:5](=[C:4]([C:17]([F:18])([F:19])[F:20])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)[CH:6]=[C:7]3[CH3:16])=[N:31][N:30]=2)[CH:25]=[N:26][CH:27]=1
Reactant: NNC(=O)c1cncc(Br)c1
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC(=O)O
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1nnc(-c2cncc(Br)c2)o1

Procedure:
Synthesized as described in Example 35C using [5-cyano-2-methyl-4-(trifluoromethyl)-1H-indol-1-yl]acetic acid and 5-bromo-3-pyridinecarbohydrazide: 1H NMR (400 MHz, DMSO-d6) δ 9.05 (d, J=1.7 Hz, 1H), 8.93 (d, J=2.0 Hz, 1H), 8.48 (dd, J=2.0 and 1.7 Hz, 1H), 8.07 (d, J=8.5 Hz, 1H), 7.77 (d, J=8.5 Hz, 1H), 6.65 (s, 1H), 5.99 (s, 2H), 2.58 (s, 3H); MS (ES) m/z 462 (M+1, isotope for Br) and 464 (M+1, isotope for Br)
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].P(=O)(O)(O)O.[F:14]F>>[F:14][C:7]1[C:5](=[O:6])[NH:4][C:2](=[O:3])[NH:1][CH:8]=1
Reactant: FF
Reactant: O=c1cc[nH]c(=O)[nH]1
Agent: O=P(O)(O)O
Product: O=c1[nH]cc(F)c(=O)[nH]1

Procedure:
The process comprises reacting uracil in an aqueous phosphoric acid solution with elemental fluorine and heating the resultant reaction solution to form 5-fluorouracil.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[C:14]([F:17])([F:16])[F:15])[C:8]([OH:10])=O.Cl.[CH3:21][NH:22][O:23][CH3:24].CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>CN(C1C=CN=CC=1)C.C(Cl)Cl.CN(C=O)C>[CH3:24][O:23][N:22]([CH3:21])[C:8](=[O:10])[C:7]1[CH:11]=[CH:12][C:13]([C:14]([F:17])([F:16])[F:15])=[C:5]([O:4][CH2:3][C:2]([F:1])([F:19])[F:18])[CH:6]=1
Reactant: O=C(O)c1ccc(C(F)(F)F)c(OCC(F)(F)F)c1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc(C(F)(F)F)c(OCC(F)(F)F)c1
Temperature: 23 °C
Reaction time: 18 h

Procedure:
To a mixture of 3-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-benzoic acid from step 6 (9.22 g, 32 mmol), N,O-dimethylhydroxylamine hydrochloride (5.00 g, 51 mmol), N-methylmorpholine (5.62 mL, 51 mmol) and 4-DMAP (391 mg, 3.2 mmol) in DCM (100 mL) and DMF (20 mL) at 0° C. was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) (7.36 g, 38 mmol) and the mixture was stirred at 23° C. for 18 h. Poured onto ice cold 1 N HCl, extracted with TBME, washed with sat. NaHCO3-sol. and brine, dried over Na2SO4. Removal of the solvent in vacuum left the title compound as a brown oil (10.555 g, 100%), %), which was used without further purification. MS (EI) 331.0 [M].
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]([C:21]3[C:22]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=4)=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:20])=[C:14]([C:37](=[O:41])[N:38]([CH3:40])[CH3:39])[CH:13]=2)[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+]>CO>[CH3:39][N:38]([CH3:40])[C:37]([C:14]1[CH:13]=[C:12]([N:9]2[CH2:10][CH2:11][CH:6]([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]2)[CH:17]=[CH:16][C:15]=1[NH:18][C:19]([C:21]1[C:22]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:34])([F:35])[F:36])=[CH:29][CH:28]=2)=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:20])=[O:41]
Reactant: CCOC(=O)C1CCN(c2ccc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)c(C(=O)N(C)C)c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(C)C(=O)c1cc(N2CCC(C(=O)O)CC2)ccc1NC(=O)c1ccccc1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-{3-Dimethylcarbamoyl-4-[(4′-trifluoromethylbiphenyl-2-carbonyl)amino]phenyl}piperidine-4-carboxylic acid ethyl ester was dissolved in methanol (5 mL), and 4N aqueous sodium hydroxide (1.5 mL) was added thereto. The solution was stirred at room temperature for 2 hours, concentrated, and acidified with 1N hydrochloric acid. The resulting precipitated solid was filtered and washed with water to give the title compound (1.064 g).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.[C:6]([O:10][CH2:11][CH3:12])(=[O:9])[CH:7]=[CH2:8]>N1C=CC=CC=1>[N:1]1([CH:7]([CH3:8])[C:6]([O:10][CH2:11][CH3:12])=[O:9])[CH:5]=[CH:4][N:3]=[N:2]1
Reactant: c1c[nH]nn1
Reactant: C=CC(=O)OCC
Solvent: c1ccncc1
Product: CCOC(=O)C(C)n1ccnn1
Temperature: 90 °C
Yield: 73.2 %

Procedure:
A mixture of 1,2,3-triazole (5 g, 72.4 mmol) and ethyl acrylate (7.8 ml, 72.4 mmol) containing pyridine (50 drops) was heated at 90° C. for 4 hours. After cooling, the volatiles were removed under vacuum and the residue was purified by column chromatography eluting with methylene chloride/ether to give ethyl (1H-1,2,3-triazol-1-yl)propanoate (8.96 g, 73%).
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[CH2:13]([O:15][P:16]([CH2:21][C:22]([OH:24])=O)([O:18][CH2:19][CH3:20])=[O:17])[CH3:14].[NH2:25][CH:26]([C:30]1[CH:59]=[CH:58][C:33]([O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][N:43]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])=[CH:32][CH:31]=1)[CH2:27][CH2:28][CH3:29].C(OCC)(=O)C>CN(C)C1C=CN=CC=1.CN(C)C=O>[CH2:19]([O:18][P:16]([CH2:21][C:22]([NH:25][CH:26]([C:30]1[CH:31]=[CH:32][C:33]([O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][N:43]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[C:44]([O:46][C:47]([CH3:48])([CH3:49])[CH3:50])=[O:45])=[CH:58][CH:59]=1)[CH2:27][CH2:28][CH3:29])=[O:24])([O:15][CH2:13][CH3:14])=[O:17])[CH3:20]
Reactant: CCOP(=O)(CC(=O)O)OCC
Reactant: CCCC(N)c1ccc(OCCOCCOCCN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCC(NC(=O)CP(=O)(OCC)OCC)c1ccc(OCCOCCOCCN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.4 %

Procedure:
A mixture of 4-dimethylaminopyridine (DMAP; 197 mg, 1.61 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HCl; 309 mg, 1.61 mmol) was added to a stirred solution of diethylphosphonoacetic acid (129 μL, 0.805 mmol) and (2-(2-(2-(4-(1-aminobutyl)phenoxy)ethoxy)ethoxy)ethyl)imidodicarbonic acid, 1,3-bis-tert-butyl ester (45; 400 mg, 0.805 mmol) in N,N-dimethylformamide (10 mL). The resulting mixture was stirred under nitrogen for 3 hours at room temperature, and then poured into 100 mL of ethyl acetate. This solution was washed with 1N aqueous HCl (2×) and sat. brine, dried over sodium sulfate, and concentrated to an oil. Purification by flash silica gel column chromatography, eluting with ethyl acetate, afforded 49 (540 mg, quantitative) as a clear oil: MS (ES+) m/z 675.3 (M+H)+.
Reaction SMILES: [Na][Na].N[C:4]1C=C[CH:10]=[C:6]([C:7](O)=[O:8])[C:5]=1[C:13](O)=[O:14].[NH2:16][C:17]1[CH:18]=[C:19]([C:26]([OH:28])=[O:27])[C:20](=[CH:24][CH:25]=1)[C:21]([OH:23])=O>>[CH3:4][C:5]1[C:13](=[O:14])[N:16]([C:17]2[CH:18]=[C:19]3[C:26](=[O:27])[O:28][C:21](=[O:23])[C:20]3=[CH:24][CH:25]=2)[C:7](=[O:8])[C:6]=1[CH3:10]
Reactant: Nc1ccc(C(=O)O)c(C(=O)O)c1
Reactant: Nc1cccc(C(=O)O)c1C(=O)O
Agent: [Na][Na]
Product: CC1=C(C)C(=O)N(c2ccc3c(c2)C(=O)OC3=O)C1=O

Procedure:
If instead of 22.5 g of the disodium salt of 3-aminophthalic acid, an equivalent amount of the disodium salt of 4-aminophthalic acid is employed and in other respects the procedure indicated in the above example is followed, 4-(dimethylmaleinimidyl)-phthalic anhydride of melting point 197° C. is obtained.
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[S:15][C:14]3[CH2:16][CH2:17][CH2:18][CH2:19][C:13]=3[C:12]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N[C:26]1SC2CCCCC=2C=1C(OCC)=O.CC1C=CC=CC=1S(Cl)(=O)=O>>[CH3:26][C:6]1[CH:5]=[CH:4][CH:3]=[CH:2][C:1]=1[S:7]([NH:10][C:11]1[S:15][C:14]2[CH2:16][CH2:17][CH2:18][CH2:19][C:13]=2[C:12]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21])(=[O:9])=[O:8]
Reactant: CCOC(=O)c1c(NS(=O)(=O)c2ccccc2)sc2c1CCCC2
Reactant: CCOC(=O)c1c(N)sc2c1CCCC2
Agent: Cc1ccccc1S(=O)(=O)Cl
Product: CCOC(=O)c1c(NS(=O)(=O)c2ccccc2C)sc2c1CCCC2

Procedure:
Prepared by proceeding in a similar manner to Intermediate 1, starting from ethyl 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate and 2-methylbenzene-sulphonyl chloride.
Reaction SMILES: O[CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Al+3].[Cl-].[Cl-].[Cl-].[CH:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH-].[Na+]>O>[C:12]1([CH:2]2[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: c1ccccc1
Reactant: OC1CCNCC1
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: c1ccc(C2CCNCC2)cc1
Temperature: 25 °C
Yield: 40 %

Procedure:
4-Hydroxypiperidine (10.0 g, 98.9 mmol, 1.00 equiv) and AlCl3 (105.5 g, 791.2 mmol, 8.0 equiv) were stirred in refluxing benzene (350 mL) under a CaSO4 drying tube for 85 hours. The mixture was cooled to room temperature and poured carefully into ice (500 g) and water (50 mL) with stirring. With ice water cooling, the pH was adjusted to 10-11 by addition of solid NaOH. The resulting mixture was extracted with EtOAc (3×250 mL). The combined organic solutions were washed with brine, dried over MgSO4, and concentrated to give 6.5 g of 4-phenylpiperidine (yellow solid, 40%), which was characterized spectroscopically.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]3([CH3:26])[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)=[N:10][C:9]=2[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([NH:33][S:34]([C:37]3[CH:41]=[CH:40][O:39][CH:38]=3)(=[O:36])=[O:35])[C:28]=2[F:42])[CH:5]=[CH:4][N:3]=1.C(O)(C(F)(F)F)=O>ClCCl>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]3([CH3:26])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:27]2[C:28]([F:42])=[C:29]([NH:33][S:34]([C:37]3[CH:41]=[CH:40][O:39][CH:38]=3)(=[O:35])=[O:36])[CH:30]=[CH:31][CH:32]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C)(c2nc(-c3cccc(NS(=O)(=O)c4ccoc4)c3F)c(-c3ccnc(N)n3)s2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(c2nc(-c3cccc(NS(=O)(=O)c4ccoc4)c3F)c(-c3ccnc(N)n3)s2)CCNCC1
Reaction time: 1 h

Procedure:
To a solution of 1,1-dimethylethyl 4-(5-(2-amino-4-pyrimidinyl)-4-{2-fluoro-3-[(3-furanylsulfonyl)amino]phenyl}-1,3-thiazol-2-yl)-4-methyl-1-piperidinecarboxylate (64 mg, 0.104 mmol) in dichloromethane (DCM) (2 mL) was added TFA (500 μl, 6.49 mmol), and the reaction mixture was stirred for 1 h. The reaction mixture was concentrated and the residue was purified using RP-HPLC. The TFA salt was neutralized to the title compound (37 mg). MS (ESI): 515.2 [M+1]+.
Reaction SMILES: [C:1]([S@:5]([NH:7][C@@:8]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[F:28])([CH:19]([F:21])[F:20])[C:9]([F:18])([F:17])[CH:10]=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:6])([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.[Pd]>[C:1]([S@:5]([NH:7][C@@:8]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[F:28])([CH:19]([F:21])[F:20])[C:9]([F:17])([F:18])[CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:6])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)C=CC(F)(F)[C@](N[S@](=O)C(C)(C)C)(c1ccccc1F)C(F)F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CCC(F)(F)[C@](N[S@](=O)C(C)(C)C)(c1ccccc1F)C(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.5 %

Procedure:
To a solution of ethyl (S)-5-(((R)-tert-butylsulfinyl)amino)-4,4,6,6-tetrafluoro-5-(2-fluorophenyl)hex-2-enoate (1.77 g, 4.28 mmol) in ethyl acetate (100 mL) was added Pd/C (400 mg, 10%). The black suspension was stirred at 25° C. for 18 hours under 45-50 psi H2. It was filtrated and concentrated to give ethyl (S)-5-(((R)-tert-butylsulfinyl)amino)-4,4,6,6-tetrafluoro-5-(2-fluorophenyl)hexanoate (1.70 g, 95.5% yield) which was used in the next step immediately without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:21])=[C:7]([C:13]3[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[CH:14]=3)[C:8](=[O:12])[NH:9]2)=[CH:4][C:3]=1[I:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[C:54]([O:58][C:59]([N:61]1[CH2:66][CH2:65][CH2:64][CH2:63][CH:62]1[CH2:67][CH2:68]O)=[O:60])([CH3:57])([CH3:56])[CH3:55]>>[C:54]([O:58][C:59]([N:61]1[CH2:66][CH2:65][CH2:64][CH2:63][CH:62]1[CH2:67][CH2:68][O:21][C:6]1[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[C:3]([I:22])[CH:4]=2)[NH:9][C:8](=[O:12])[C:7]=1[C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[CH:14]=1)=[O:60])([CH3:57])([CH3:56])[CH3:55]
Reactant: CC(C)(C)OC(=O)N1CCCCC1CCO
Reactant: Cc1cc(C)cc(-c2c(O)c3cc(I)c(Cl)cc3[nH]c2=O)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OC(C)(C)C)c3cc(I)c(Cl)cc3[nH]c2=O)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 2-(2-hydroxyethyl)-piperidine-1-carboxylic acid tert-butyl ester (10 g in 450 mL dry tetrahydrofuran) was added 22.3 g of 7-chloro-3-(3,5-dimethylphenyl)-4-hydroxy-6-iodo-1H-quinolin-2-one followed by 13.7 g of triphenylphosphine and the mixture stirred at room temperature. To this was added 8.2 mL of diethyl azodicarboxylate (DEAD) and stirring was continued for 72 hours. At this time the solvents were removed to a minimum volume in vacuo and the mixture filterd through a silica gel pad to remove the phosphine by-products. The filtrate was concentrated in vacuo to provide the partially purified title compound (17.5 g).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[CH2:9]([O:11]/[CH:12]=[CH:13]/B1OC(C)(C)C(C)(C)O1)[CH3:10].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH2:12]([O:11]/[CH:9]=[CH:10]/[C:2]1[N:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1)[CH3:13]
Reactant: Nc1cnc(Br)cn1
Reactant: CCO/C=C/B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: ClCCl
Product: CCO/C=C/c1cnc(N)cn1
Temperature: 130 °C
Reaction time: 0.33 h

Procedure:
To a solution of 5-bromopyrazin-2-amine (200 mg, 1.149 mmol) in DME (2874 μL) was added (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (341 mg, 1.724 mmol), PdCl2(dppf)-CH2Cl2 adduct (94 mg, 0.115 mmol), and 2M Na2CO3 (958 μL). The reaction mixture was stirred at 130° C. in microwave reactor for 20 min. The reaction mixture was filtered through Celite and washed with EtOAc, the filtrate was partition between EtOAc and water. The aqueous was extracted by EtOAc three times, the combined organic was dried and concentrated. The crude material was purified by flash chromatography to give (E)-5-(2-ethoxyvinyl)pyrazin-2-amine. LCMS (m/z): 166.1 (MH+), 0.41 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:10](=[O:20])[CH2:9]2)=[CH:4][C:3]=1[F:21].[Li+].[OH-:23].Cl>C1COCC1.O>[C:16]([O:15][C:13]([NH:11][CH2:12][C@H:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([F:21])[CH:4]=1)[CH2:9][C:10]([OH:23])=[O:20])=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1C[C@H](c2ccc(Cl)c(F)c2)CC1=O
Reactant: [OH-]
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NC[C@@H](CC(=O)O)c1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.4 %

Procedure:
To a solution of 92 (912 mg, 2.91 mmol) in THF/H2O (2:1; 15 mL) was added solid LiOH (209 mg, 8.72 mmol). The reaction mixture was stirred at RT for 18 h. The reaction mixture was acidified with 1M HCl to ca. pH 2-3 then twice extracted with EtOAc. The combined EtOAc layers were dried (Na2SO4), filtered and concentrated to afford 902 mg (93.5%) of (S)-4-(tert-butoxycarbonylamino)-3-(4-chloro-3-fluorophenyl)butanoic acid (100) which was used without further purification.
Reaction SMILES: [CH2:1]([O+](CC)CC)[CH3:2].[F:8][B-:9]([F:12])([F:11])[F:10].[NH:13]1[CH2:17][CH2:16][NH:15][C:14]1=[CH:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:20]>C(Cl)Cl>[CH2:1]([O:20][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[CH:18][C:14]1[NH:13][CH2:17][CH2:16][N:15]=1)[CH3:2].[F:8][B-:9]([F:12])([F:11])[F:10]
Reactant: O=C(C=C1NCCN1)c1ccccc1
Reactant: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CCOC(=CC1=NCCN1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
20 g (0.105 mole) of triethyloxonium-tetrafluoroborate is dissolved in 200 ml of methylene chloride. To the solution is added 18.8 g (0.1 mole) of crystalline 2-(2--imidazolidinylidene)-acetophenone [m.p. 211°-212°, see J. Klosa, Arch. Pharmaz. 286, 397 (1953)]. After the slightly exothermic reaction has subsided, the reaction mixture, a clear yellow solution, is stirred for 16 hours at room temperature; it is subsequently concentrated to dryness in the rotary evaporator; and the crystallising residue is suspended in 300 ml of ethyl acetate. The suspension is cooled to 5°, and the crystals are filtered off with suction to obtain 2-(2-ethoxy-2-phenyl-ethenyl)-2-imidazoline-tetrafluoroborate, m.p. 151°-152°. After drying at 60° in vacuo, the product is further employed without additional purification.
Reaction SMILES: [CH2:1]([N:4]([CH2:23][CH2:24][CH3:25])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:19](OC)=[O:20])[CH:15]=2)[CH2:10]1)[CH2:2][CH3:3].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+].C(OCC)C>O1CCCC1>[CH2:23]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:19][OH:20])[CH:15]=2)[CH2:10]1)[CH2:24][CH3:25]
Reactant: CCCN(CCC)CCCCN1CCc2cc(C(=O)OC)ccc2C1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CCCN(CCC)CCCCN1CCc2cc(CO)ccc2C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 82.1 %

Procedure:
To a solution of the compound 20 (3.02 g) in tetrahydrofuran (25 mL), lithium aluminum hydride (330 mg) was, added at −78° C. The reaction mixture was stirred at −78° C. for 30 minutes. To the reaction mixture, sodium sulfate decahydrate (2.8 g) and diethylether (100 mL) were added and the temperature of the reaction mixture was raised to room temperature. The reaction mixture was filtered through Celite (trade name) and then concentrated. The residue was purified by silica gel column chromatography (ethyl acetate:methanol:triethylamine=10:1:0→10:1:0.5) to obtain the title compound (2.28 g) having the following physical properties.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:22].[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31](Cl)=[O:32])=[CH:26][CH:25]=1>>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]([NH:1][N:2]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:22])=[O:32])=[CH:26][CH:25]=1
Reactant: Nn1nc(-c2ccnc(C(F)(F)F)c2)c2ccccc2c1=O
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Product: O=C(Cc1ccc(Cl)cc1)Nn1nc(-c2ccnc(C(F)(F)F)c2)c2ccccc2c1=O

Procedure:
The product from Example 76B and 2-(4-chlorophenyl)acetyl chloride were processed using a method similar to that described in Example 4C to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.80-11.82 (bs, 1H), 8.96-8.99 (m, 1H), 8.40-8.46 (m, 1H), 8.12 (s, 1H), 7.96-8.04 (m, 3H), 7.71-7.79 (m, 1H), 7.36-7.44 (m, 4H), 3.72 (s, 2H); MS (APCI) M/Z 459 (M+H)+.