Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:8])(=O)[CH:2]=[CH:3][CH:4]=[CH:5][CH3:6].ClC(OCC)=O.C(N(CC)CC)C.[CH:22]1([NH2:25])[CH2:24][CH2:23]1.[Cl-].[Na+]>C1COCC1>[CH:22]1([NH:25][C:1](=[O:8])/[CH:2]=[CH:3]/[CH:4]=[CH:5]/[CH3:6])[CH2:24][CH2:23]1
Reactant: NC1CC1
Reactant: CC=CC=CC(=O)O
Agent: CCOC(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C/C=C/C=C/C(=O)NC1CC1
Yield: 51 %

Procedure:
2,4-Hexadienoic acid 1 eq, ethyl chloroformate 1.05 eq, triethylamine 1.2 eq, cyclopropylamine 1.3 eq as a 2.0M solution in THF, quench with 10% sodium chloride solution, yield=51%. 0.54 ppm (m, 2H), 0.79 ppm (m, 2H), 1.82 ppm (d, 3H, J=5.93 Hz), 2.80 ppm (m, 1H), 5.72 ppm (d, 1H), 6.00 ppm (br. s, 1H), 6.03-6.15 ppm (m, 2H), 7.18 ppm (d, 1H, J=14.98 Hz, of d, J=10.02 Hz).
Reaction SMILES: Br[C:2]1[C:7]2[NH:8][C:9]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][N:18]=4)[CH2:13][C@H:12]3[CH3:24])=[N:10][C:6]=2[CH:5]=[C:4]([C:25]([F:28])([F:27])[F:26])[CH:3]=1.[F:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][C:35]=1[O:36][CH3:37]>>[Cl:23][C:22]1[C:17]([N:14]2[CH2:15][CH2:16][N:11]([C:9]3[NH:8][C:7]4[C:2]([C:32]5[CH:33]=[CH:34][C:35]([O:36][CH3:37])=[C:30]([F:29])[CH:31]=5)=[CH:3][C:4]([C:25]([F:26])([F:27])[F:28])=[CH:5][C:6]=4[N:10]=3)[C@H:12]([CH3:24])[CH2:13]2)=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: COc1ccc(B(O)O)cc1F
Reactant: C[C@@H]1CN(c2ncccc2Cl)CCN1c1nc2cc(C(F)(F)F)cc(Br)c2[nH]1
Product: COc1ccc(-c2cc(C(F)(F)F)cc3nc(N4CCN(c5ncccc5Cl)C[C@H]4C)[nH]c23)cc1F

Procedure:
7-Bromo-2-[(2R)-4-(3-chloropyridin-2-yl)-2-methylpiperazin-1-yl]-5-(trifluoromethyl)-1H-benzoimidazole (95 mg, 0.2 mmol, Example 77) and 3-fluoro-4-methoxyphenylboronic acid (43 mg, 0.25 mmol, Aldrich) reacted under the conditions of Example 51a to give the title compound as a white amorphous solid. MS (ESI, pos. ion) m/z: 520 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:12][O:11][C:10](=[O:13])[N:9]2[C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([C:23]4[CH:32]=[CH:31][C:26]([C:27]([NH:29][NH2:30])=[O:28])=[CH:25][CH:24]=4)=[C:16]3[N:15]=2)=[CH:4][CH:3]=1.[N:33]#[C:34]Br.C([O-])(O)=O.[Na+]>O1CCOCC1.O.CCOC(C)=O>[NH2:33][C:34]1[O:28][C:27]([C:26]2[CH:31]=[CH:32][C:23]([C:22]3[CH:21]=[N:20][N:17]4[CH:18]=[CH:19][C:14]([N:9]5[C@@H:8]([C:5]6[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=6)[CH2:12][O:11][C:10]5=[O:13])=[N:15][C:16]=34)=[CH:24][CH:25]=2)=[N:29][N:30]=1
Reactant: N#CBr
Reactant: NNC(=O)c1ccc(-c2cnn3ccc(N4C(=O)OC[C@@H]4c4ccc(F)cc4)nc23)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: Nc1nnc(-c2ccc(-c3cnn4ccc(N5C(=O)OC[C@@H]5c5ccc(F)cc5)nc34)cc2)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.6 %

Procedure:
To a suspension of (S)-4-(5-(4-(4-fluorophenyl)-2-oxooxazolidin-3-yl)pyrazolo[1,5-a]pyrimidin-3-yl)benzohydrazide (0.040 g, 0.0925 mmol) in dioxane (4 mL) was added cyanic bromide (0.0216 g, 0.204 mmol) followed by a solution of NaHCO3 (0.00933 g, 0.111 mmol) in water (0.9 mL). The resulting mixture was stirred at ambient temperature overnight, then diluted with EtOAc. The organic layer was washed with brine and water, dried (phase separator silicone treated filter paper) and concentrated. The crude material was purified on silica gel (2-5% MeOH in DCM) to provide (S)-3-(3-(4-(5-amino-1,3,4-oxadiazol-2-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)-4-(4-fluorophenyl)oxazolidin-2-one (0.0066 g, 16% yield). LCMS (APCI+) m/z 458 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][CH:38]=1)[CH2:5][NH:6][C:7]([C:9]1[N:10]([CH2:30][CH:31](OC)OC)[CH:11]=[C:12]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:13](=[O:23])[C:14]=1[O:15]CC1C=CC=CC=1)=[O:8].Cl>C(O)(=O)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][CH:38]=1)[CH2:5][N:6]1[CH:31]=[CH:30][N:10]2[CH:11]=[C:12]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:13](=[O:23])[C:14]([OH:15])=[C:9]2[C:7]1=[O:8]
Reactant: COC(Cn1cc(-c2ccccc2)c(=O)c(OCc2ccccc2)c1C(=O)NCc1cccc(Cl)c1)OC
Agent: Cl
Solvent: CC(=O)O
Product: O=c1c(-c2ccccc2)cn2ccn(Cc3cccc(Cl)c3)c(=O)c2c1O
Temperature: 90 °C
Reaction time: 2 h
Yield: 192.5 %

Procedure:
3-Benzyloxy-1-(2,2-dimethoxyethyl)-4-oxo-5-phenyl-1,4-dihydropyridine-2-carboxylic acid 3-chlorobenzylamide (52 mg) was dissolved in acetic acid (0.5 ml) and conc. hydrochloric acid (0.5 ml) was added, and the mixture was stirred at 90° C. for 2 hr. The reaction mixture was concentrated, toluene was added to the residue and the mixture was concentrated, which operations were performed twice. Methanol was further added and the mixture was concentrated and crystallized from ethyl acetate-diisopropyl ether to give 2-(3-chlorobenzyl)-9-hydroxy-7-phenyl-2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride (39 mg).
Reaction SMILES: [I-].[NH2:2][N+:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[C:15]([O:20][CH2:21][CH3:22])(=[O:19])[C:16]#[C:17][CH3:18]>CN(C=O)C>[CH3:18][C:17]1[C:16]([C:15]([O:20][CH2:21][CH3:22])=[O:19])=[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][N:3]2[N:2]=1
Reactant: N[n+]1ccccc1
Reactant: CC#CC(=O)OCC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)nn2ccccc12
Reaction time: 8 h

Procedure:
To a mixture of 1-aminopyridinium iodide (19 g, 86 mmol) and potassium carbonate (12 g, 86 mmol) in DMF (100 mL) was added ethyl 2-butynoate (8.0 g, 71 mmol) and the reaction stirred overnight. The DMF was removed by rotary evaporation and the resulting solid was taken up in EtOAc (200 ml) and water (200 ml), partitioned and the aqueous phase extracted with 2×150 ml EtOAc. The combined organics were washed with brine, dried over MgSO4 and concentrated.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@@H:8]([CH3:12])[C:9]([OH:11])=O.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>O1CCCC1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@@H:8]([CH3:12])[C:9]([N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)=[O:11]
Reactant: C1COCCN1
Reactant: C[C@H](OC1CCCCO1)C(=O)O
Solvent: C1CCOC1
Product: C[C@H](OC1CCCCO1)C(=O)N1CCOCC1
Temperature: 25 °C
Yield: 42.5 %

Procedure:
To (2S)-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propionic acid (29.5 g) was added anhydrous tetrahydrofuran (250 ml). To the mixture was added, with stirring at room temperature, 1,1-carbonyldiimidazole (33.1 g), taking 10 minutes. The mixture was stirred for 30 minutes at room temperature and cooled with ice, to which was added dropwise morpholine (34.8 g) during 15 minutes. The resultant mixture was stirred for 15 minutes on an ice bath, then the reaction mixture was concentrated under reduced pressure. The concentrate was dissolved in dichloromethane (300 ml), which was washed with a saturated aqueous sodium chloride solution (50 ml) and dried over anhydrous magnesium sulfate, followed by distilling off the solvent. The residue was purified by means of a silica gel chromatography (eluent:hexane:ethyl acetate=1:4) to afford N-[(2S)-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propionyl]morpholine (17.5 g).
Reaction SMILES: [C:1]([CH2:3][C:4](OC)(OC)[O:5][CH3:6])#[N:2].[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.CO>[C:1]([CH2:3][C:4](=[N:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[O:5][CH3:6])#[N:2]
Reactant: COC(CC#N)(OC)OC
Reactant: Nc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: COC(CC#N)=Nc1ccccc1
Yield: 54 %

Procedure:
In a 250-mL flask was placed 87 g (0.6 mol) of 2-cyano-1,1,1-trimethoxyethane, 46.5 g (0.5 mol) of aniline, and 1.0 g (0.005 mol) of p-toluenesulfonic acid monohydrate. The mixture was placed in a pre-heated oil bath at 120° C. and stirred rapidly. The methanol by-product of the reaction was allowed to boil off. When the internal reaction temperature reached 110° C., the reaction flask was fitted with a water aspirator vacuum take-off, and the residual methanol was removed at approximately 20 mm Hg. The crude product mixture was then distilled under high vacuum and the fraction distilling at 115°-125° C. (0.5 mm Hg) was collected to give 47.6 g (0.27 mol, 54.6% yield) of methyl 2-cyano-N-phenylacetimidate as a light yellow liquid, which was characterized by NMR and mass spectral data. HPLC analysis showed this material to be 96% pure. Elemental analysis: Calculated: C, 68.95; H, 5.79; N, 16.08. Found: C, 66.80, H, 5.72, N, 15.36.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19].[C:22]1(B(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[F-].[K+].C1(P(C2C=CC=CC=2C2C=CC=CC=2)C2CCCCC2)CCCCC1>CC([O-])=O.CC([O-])=O.[Pd+2].C1COCC1>[CH3:17][C:15]1[CH:14]=[CH:13][C:11]2[N:12]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[C:3]([C:18]([F:21])([F:20])[F:19])[CH:4]=3)[S:9][C:10]=2[CH:16]=1
Reactant: Cc1ccc2nc(-c3ccc(Cl)c(C(F)(F)F)c3)sc2c1
Reactant: OB(O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1ccc2nc(-c3ccc(-c4ccccc4)c(C(F)(F)F)c3)sc2c1
Temperature: 120 °C
Yield: 62.6 %

Procedure:
A microwave vial is charged with 2-(4-chloro-3-trifluoromethyl-phenyl)-6-methylbenzothiazole (170 mg, 0.519 mmol), phenylboronic acid (95 mg, 1.5 eq.), KF (90 mg, 3 eq.), Pd(OAc)2 (6 mg, 5 mol %), (dicyclohexylphosphino)biphenyl (18 mg, 10 mol %) and THF (0.5 mL). The mixture is heated to 120° C. for 30 minutes using microwave irradiation. The mixture is then filtered through celite and washed with EtOAc. The filtrate is concentrated and purified by column chromatography (EtOAc/Hexane, 5/95) to give 120 mg (63%) of 6-methyl-2-(2-trifluoromethyl-biphenyl-4-yl)benzothiazole.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7]([NH:12][CH:13]3[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.Cl.CO>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([NH:12][CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cccc3c(N)nccc23)CC1
Agent: Cl
Solvent: CO
Product: Nc1nccc2c(NC3CCNCC3)cccc12
Yield: 71.7 %

Procedure:
According to the method of Example 1, Step C, deprotection was performed (room temperature, 2 hours) by using Intermediate 133 (199 mg) and 10% hydrogen chloride/methanol solution (3 ml). The solvent was evaporated under reduced pressure, and the residue was added with methanol (1 ml) and diethyl ether (3 ml). The deposited precipitates were collected by filtration and washed with diethyl ether to obtain the title compound (101 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]([N:5]1[CH2:9][CH:8]2[CH2:10][C:11]([NH2:14])([CH3:13])[CH2:12][CH:7]2[CH2:6]1)=[O:4].Cl[CH2:17][C:18]([N:20]1[CH2:24][C@@H:23]([F:25])[CH2:22][C@H:21]1[C:26]#[N:27])=[O:19].C(=O)([O-])[O-].[K+].[K+]>ClCCl.CN(C)C=O>[C:26]([C@@H:21]1[CH2:22][C@H:23]([F:25])[CH2:24][N:20]1[C:18](=[O:19])[CH2:17][NH:14][C:11]1([CH3:13])[CH2:12][CH:7]2[CH2:6][N:5]([C:3]([N:2]([CH3:1])[CH3:15])=[O:4])[CH2:9][CH:8]2[CH2:10]1)#[N:27]
Reactant: CN(C)C(=O)N1CC2CC(C)(N)CC2C1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(C)C(=O)N1CC2CC(C)(NCC(=O)N3C[C@@H](F)C[C@H]3C#N)CC2C1
Yield: 57.7 %

Procedure:
5-Amino-5-methyl-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid dimethylamide 12f (130 mg, 0.616 mmol), (2S,4S)-1-(2-chloroacetyl)-4-fluoropyrrolidine-2-carbonitrile 13g (117.4 mg, 0.616 mmol) and potassium carbonate (85 mg, 0.616 mmol) were dissolved in the solvent mixture of 2 mL of dichloromethane and 2 mL of N,N-dimethylformamide with stirring under nitrogen atmosphere. The reaction mixture was reacted overnight at room temperature. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was concentrated under reduced pressure to remove N,N-dimethylformamide and dichloromethane. The resulting residue was purified by silica gel column chromatography to obtain 5-[2-((2S,4S)-2-cyano-4-fluoro-pyrrolidin-1-yl)-2-oxo-ethylamino]-N,N,5-trimethyl-hexahydro-cyclopenta[c]pyrrole-2(1H)-carboxamide 13h (0.13 g, yield 58%) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:48]=[CH:47][C:6]([CH2:7][N:8]([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[S:31][CH:32]=[C:33]([C:35]([OH:37])=O)[N:34]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[CH2:49]([N:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1)[CH3:50].C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C>[CH3:46][O:45][C:42]1[CH:41]=[CH:40][C:39]([CH2:38][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:48][CH:47]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[S:31][CH:32]=[C:33]([C:35]([N:54]6[CH2:55][CH2:56][N:51]([CH2:49][CH3:50])[CH2:52][CH2:53]6)=[O:37])[N:34]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:44][CH:43]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3nc(C(=O)O)cs3)cn2)cc1
Reactant: CCN1CCNCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN1CCN(C(=O)c2csc(N3CCc4c(-c5cnc(N(Cc6ccc(OC)cc6)Cc6ccc(OC)cc6)nc5)nc(N5CCOCC5)nc43)n2)CC1

Procedure:
To 2-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-thiazole-4-carboxylic acid (77 mg), N-ethylpiperazine (36 μl), WSCI (68 mg), HOBt (48 mg) and triethylamine (48 μl) were left to act in DMF (3 ml), to obtain a crude product of [2-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-thiazol-4-yl]-(4-ethyl-piperazin-1-yl)-methanone, and then the PMB groups were removed according to Deprotection method 3, to obtain the desired compound (D-120) as an ivory powder (38 mg, 63%).
Reaction SMILES: [I-].C[N+]1[CH:7]=[CH:6][N:5]([C:8]([N:10]2[CH2:19][CH2:18][C:17]3[N:16]=[CH:15][C:14]([C:20]([F:23])([F:22])[F:21])=[CH:13][C:12]=3[CH2:11]2)=[O:9])[CH:4]=1.N1CC[CH:26]([OH:29])C1.CCN(CC)CC>C(Cl)Cl>[OH:29][CH:26]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:19][CH2:18][C:17]3[N:16]=[CH:15][C:14]([C:20]([F:21])([F:23])[F:22])=[CH:13][C:12]=3[CH2:11]2)=[O:9])[CH2:4]1
Reactant: OC1CCNC1
Reactant: C[n+]1ccn(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)c1
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(N1CCc2ncc(C(F)(F)F)cc2C1)N1CCC(O)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.9 %

Procedure:
To a solution of 1-methyl-3-(3-trifluoromethyl-7,8-dihydro-5H-[1,6]naphthyridine-6-carbonyl)-3H-imidazol-1-ium iodide (preparation #3) (0.046 g, 0.10 mmol) in DCM (1 mL) was added pyrrolidin-3-ol (0.009 g, 0.10 mmol) and Et3N (0.014 mL, 0.10 mmol) and the reaction mixture was shaken at ambient temperature for about 30 min. The reaction mixture was dried in vacuo (Genevac®) and the residue purified by RP-HPLC (10% acetonitrile/0.05M aqueous ammonium acetate, buffered to pH 4.5 for 3 min., 10% to 65% acetonitrile/0.05M aqueous ammonium acetate over 6 min at 22.5 mL/min with 2.5 mL/min. acetonitrile at-column dilution; APCI positive mode detection; Xterra prep. MS C18. 19×50 mm column) to afford (3-hydroxy-pyrrolidin-1-yl)-(3-trifluoromethyl-7,8-dihydro-5H-[1,6]naphthyridin-6-yl)-methanone (0.011 g, 33%). RP-HPLC (Table 1, Method a) Rt 1.72 min; m/z: (M+H)+ 316.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=[N:8][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:21])[F:20])[CH:13]=2)[C:10]=1[CH3:11])=[O:5])C.O.[OH-].[Li+]>C1COCC1.CO.O.CCOC(C)=O>[CH3:11][C:10]1[N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:21])([F:20])[F:22])[CH:13]=2)[N:8]=[C:7]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)[C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1c(-c2ccncc2)nn(-c2cccc(OC(F)(F)F)c2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(C(=O)O)c(-c2ccncc2)nn1-c1cccc(OC(F)(F)F)c1
Temperature: 80 °C
Yield: 77.4 %

Procedure:
To a solution of 5-methyl-3-pyridin-4-yl-1-(3-trifluoromethoxy-phenyl)-1H-pyrazole-4-carboxylic acid ethyl ester (605 mg, 1.55 mmol) in 5 ml THF, 2.5 ml methanol and 2.5 ml water, was added lithium hydroxide monohydrate (111 mg, 4.63 mmol). The solution was heated at 80° C. for 2 h. The reaction mixture was cooled, diluted with EtOAc and washed twice with 10% KHSO4 and brine. The aqueous phases were extracted with EtOAc and with three portions of CH2Cl2. The combined organic layers were dried over magnesium sulfate, and evaporated. The residue was precipitated from tBuOMe to give a white solid (436 mg, 76%) of the title compound. MS: 364.1 (MH+).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)[CH3:2].C(N(CC)CC)C.[C:19](Cl)([O:21][CH2:22][CH3:23])=[O:20].[OH-].[Na+]>C(Cl)(Cl)Cl>[C:19]([N:3]([CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][N:9]=[CH:10][CH:11]=1)[CH2:1][CH3:2])([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCNCCc1ccncc1
Reactant: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N(CC)CCc1ccncc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A mixture of 3.0 g. of 4-[2-(ethylamino)ethyl]-pyridine and 2.0 g. of triethylamine in 60 ml. of dry chloroform is treated at 0°C. with a solution of 2.1 g. of carboethoxy chloride in 10 ml. of dry chloroform. After stirring for two hours, the mixture is poured into ice water and 5 percent aqueous sodium hydroxide added. The chloroform layer is separated, washed with water and dried over potassium carbonate. The solvent is evaporated and the residue distilled in vacuo to give 4-[2-(N-carboethoxy-N-ethylamino)ethyl]pyridine.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:7]2[CH2:11][CH2:10][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[C:8]2=[O:23])[S:5][CH:6]=1.[Br:24]N1C(=O)CCC1=O>C(#N)C>[Br:24][C:6]1[S:5][C:4]([N:7]2[CH2:11][CH2:10][N:9]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=3)[C:8]2=[O:23])=[N:3][C:2]=1[CH3:1]
Reactant: Cc1csc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: Cc1nc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)sc1Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
To a solution of 1-(4-methylthiazol-2-yl)-3-(4-(trifluoromethyl)benzyl)-imidazolidin-2-one (1.40 g, 4.10 mmol) in acetonitrile (40 mL) was added N-bromosuccinimide (0.73 g, 4.10 mmol). The reaction mixture was stirred at 0° C. for 1 h, quenched with 10% sodium thiosulfate solution (10 mL), diluted with ethyl acetate (200 mL), washed with water and brine. The organic solution was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography to afford the title compound as a colorless solid in 69% yield (1.20 g): mp 107-108° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.59 (d, J=7.8 Hz, 2H), 7.39 (d, J=7.8 Hz, 2H), 4.51 (s, 2H), 4.08-3.99 (m, 2H), 3.47-3.41 (m, 2H), 2.25 (s, 3H); MS (ES+) m/z 420.1 (M+1), 422.1 (M+1).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH3:13])=[C:8]([CH2:14][CH3:15])[CH:7]=1)=[O:5]>S(=O)(=O)(O)O>[CH2:12]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[CH2:14][CH3:15])[C:4](=[O:5])[CH2:3][CH2:2]2)[CH3:13]
Reactant: CCc1ccc(C(=O)CCCl)cc1CC
Agent: O=S(=O)(O)O
Product: CCc1cc2c(cc1CC)C(=O)CC2
Temperature: 90 °C

Procedure:
3-chloro-1-(3,4-diethylphenyl)-1-propanone (15.5 g) is dissolved in 66 mL concentrated sulphuric acid and heated to 90° C. for 4 hours. The reaction mixture is cooled, ice (70 g) is added, and the aqueous solution extracted twice with toluene. The organic layer is washed with sodium bicarbonate, saturated aqueous NaCl, and treated with activated charcoal and magnesium suphate. After filtration, the solvent is removed in vacuo. The product is purified by flash column chromatography (silica, hexane/ethylacetate 10:1), and further crystallised in hexane.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH:8]=O.[NH2:10][C:11]1[C:12]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[N:13][CH:14]=[C:15]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH:16]=1>>[F:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][C:15]2[CH:16]=[C:11]([NH:10][CH2:8][CH2:7][N:3]3[CH2:4][CH2:5][CH2:6][C:2]3=[O:1])[C:12]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[N:13][CH:14]=2)=[CH:19][CH:20]=1
Reactant: CCOC(=O)c1ncc(Cc2ccc(F)cc2)cc1N
Reactant: O=CCN1CCCC1=O
Product: CCOC(=O)c1ncc(Cc2ccc(F)cc2)cc1NCCN1CCCC1=O

Procedure:
(2-Oxopyrrolidin-1-yl)acetaldehyde and ethyl 3-amino-5-(4-fluorobenzyl)-2-pyridinecarboxylate were treated in a manner similar to that described in Example 5, Step 1 to yield the product as an amber oil: 1H NMR (CDCl3) δ 7.89 (1H, d, J=1.4 Hz), 7.83 (1H, br t, J˜6 Hz), 7.15 (2H, dd, J˜9, 6 Hz), 6.98 (2H, t, J˜9 Hz), 6.92 (1H, s), 4.42 (2H, q, J=7 Hz), 3.92 (2H, s), 3.49 (2H, m), 3.41 (2H, t, J=7 Hz), 3.35 (2H, q, J=6 Hz), 2.36 (2H, t, J=8 Hz), 1.99 (2H, m), 1.42 (3H, t, J=7 Hz); HRMS calcd for C21H24FN3O3+H+: 386.1880. Found: 386.1880.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9](=[NH:12])[NH:10][NH2:11])=[N:6][C:7]=1[CH3:8].[CH:13](O)=O>CO>[Br:1][C:2]1[C:7]([CH3:8])=[N:6][C:5]([C:9]2[NH:12][CH:13]=[N:11][N:10]=2)=[CH:4][CH:3]=1
Reactant: O=CO
Reactant: Cc1nc(C(=N)NN)ccc1Br
Solvent: CO
Product: Cc1nc(-c2nnc[nH]2)ccc1Br
Temperature: 100 °C

Procedure:
5-Bromo-6-methylpicolin-imido-hydrazide (1 equiv) and formic acid (15 equiv) were combined and heated to 100° C. for 6 h. The reaction was cooled to room temperature and diluted with methanol. The resulting slurry was partially concentrated under reduced pressure and the resulting mixture was diluted with methanol and partially concentrated under reduced pressure. The resulting solids were collected by filtration, washed with water and dried to provide the desired product, as a solid. MS (ESI) m/z 238.9 [M]+, 240.9 [M+2]+.
Reaction SMILES: O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.Br/[C:18](=[CH:26]\[C:27]1[C:35]2[C:30](=[CH:31][C:32]([Cl:37])=[CH:33][C:34]=2[Cl:36])[N:29]([S:38]([C:41]2[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=2)(=[O:40])=[O:39])[C:28]=1[C:48]([O:50][CH2:51][CH3:52])=[O:49])/[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].[S:53]1[CH:57]=[CH:56][C:55](B(O)O)=[CH:54]1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.C1CCCCC1.C1CCCCC1.CCOCC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[S:53]1[CH:57]=[CH:56][C:55](/[C:18](=[CH:26]\[C:27]2[C:35]3[C:30](=[CH:31][C:32]([Cl:37])=[CH:33][C:34]=3[Cl:36])[N:29]([S:38]([C:41]3[CH:42]=[CH:43][C:44]([CH3:47])=[CH:45][CH:46]=3)(=[O:40])=[O:39])[C:28]=2[C:48]([O:50][CH2:51][CH3:52])=[O:49])/[C:19]([O:21][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:20])=[CH:54]1
Reactant: OB(O)c1ccsc1
Reactant: CCOC(=O)c1c(/C=C(\Br)C(=O)OC(C)(C)C)c2c(Cl)cc(Cl)cc2n1S(=O)(=O)c1ccc(C)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: C1CCCCC1
Product: CCOC(=O)c1c(/C=C(/C(=O)OC(C)(C)C)c2ccsc2)c2c(Cl)cc(Cl)cc2n1S(=O)(=O)c1ccc(C)cc1
Temperature: 60 °C
Reaction time: 0.08 h

Procedure:
Combine tris(dibenzylideneacetone)dipalladium(0) (204 mg, 0.223 mmol) and tri-(fur-2-yl)phosphine (413 mg, 1.78 mmol) in tetrahydrofuran (60 mL). After 5 minutes, add (Z)-2-bromo-3-(1-p-toluenesulfonyl-2-carboethoxy-4,6-dichloroindol-3-yl)propenoic acid, t-butyl ester (1.85 g, 3.0 mmol), thiophene-3-boronic acid (1.16 g, 9.1 mmol), and powdered potassium carbonate (1.27 g, 9.2 mmol). Heat to 60° C. After 6 days, add thiophene-3-boronic acid (744 mg, 5.8 mmol), tri-(fur-2-yl)phosphine (206 mg, 0.887 mmol), tris(dibenzylideneacetone)dipalladium(0) (102 mg, 0.111 mmol), and powdered Potassium carbonate (800 mg, 5.80 mmol). After 3 more days, dilute the reaction mixture with cyclohexane (60 mL) and chromatograph on silica gel eluting with 3/1 cyclohexane/ether to give the title compound. 1H NMR (CDCl3) δ 7.94 (d, 1H, J=1.7 Hz), 7.74 (d, 2H, J=8.4 Hz), 7.72 (s, 1H), 7.26 (d, 2H, J=8.0 Hz), 7.24 (d, 1H, J=1.7 Hz), 7.03 (d, 1H, J=4.4 Hz), 7.02 (d, 1H, J=1.5 Hz), 6.77 (dd, 1H, J=4.7, 1.6 Hz), 4.20 (q, 2H, J=7.15 Hz), 2.40 (s, 3H), 1.55 (s, 9H), 1.28 (t, 3H, J=7.15 Hz).