Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][N:3]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:6](=[O:7])[C:4]1=[O:5].S(Cl)([Cl:16])=O>>[Cl:16][CH2:2][N:3]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:6](=[O:7])[C:4]1=[O:5]
Reactant: O=C1C(=O)N(CO)c2ccccc21
Reactant: O=S(Cl)Cl
Product: O=C1C(=O)N(CCl)c2ccccc21

Procedure:
N-Hydroxymethylisatin (10 g, 0.056 mol) was added to thionyl chloride (100 ml) and the mixture was heated under reflux for 2 hours. N-Chloromethylisatin (about 11 g) was obtained by distilling the remaining thionyl chloride under reduced pressure. The melting point was 121° to 123° C.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([I:11])=[CH:4][N:3]=1.Cl.[CH2:13]([O:15][C:16](=[O:19])[CH2:17][NH2:18])[CH3:14].C(N(CC)CC)C>C(O)C>[CH2:13]([O:15][C:16](=[O:19])[CH2:17][NH:18][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([I:11])=[CH:4][N:3]=1)[CH3:14]
Reactant: O=[N+]([O-])c1cc(I)cnc1Cl
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)CNc1ncc(I)cc1[N+](=O)[O-]
Yield: 82 %

Procedure:
2-Chloro-5-iodo-3-nitro-pyridine (13 g) was dissolved in ethanol. Glycine ethyl ester HCl was added (5.0 eq) followed by triethylamine (5.0 eq). The reaction mixture was heated to 80° C. for four (4) hours. The reaction mixture was concentrated to dryness and triturated with H2O to give the title compound as a white solid (82-94% yield). M.p. 200° C. (dec), LCMS: m/z=352.08 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 1.30 (t, J=7.1 Hz, 3H), 4.25 (q, J=7.1 Hz, 2H), 4.33 (d, J=5.6 Hz, 2H), 8.44 (bs, 1H), 8.52 (d, J=2.0 Hz, 1H), 8.69 (d, J=2.0 Hz, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:27])[C:3]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:8][CH2:7][C:6](=[CH:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[O:11])[CH2:5][CH2:4]1.[Cl:28][Si](C)(C)C>CC(CC)=O>[ClH:28].[CH3:27][N:2]([CH3:1])[C:3]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:4][CH2:5][C:6](=[CH:9][C:10]([NH:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)=[O:11])[CH2:7][CH2:8]1
Reactant: C[Si](C)(C)Cl
Agent: CN(C)C1(c2ccccc2)CCC(=CC(=O)NCc2ccc(F)cc2)CC1
Solvent: CCC(C)=O
Product: Cl

Procedure:
2-(4-Dimethylamino-4-phenylcyclohexylidene)-N-(4-fluorobenzyl)acetamide (252 mg, 0.688 mmol) was dissolved in ethyl methyl ketone (10 ml) with gentle heating and chlorotrimethylsilane (0.126 ml, 1.0 mmol) was added. After 2.5 h the hydrochloride was isolated as a colourless solid with an m.p. of 214-218° C. and a yield of 71% (196 mg).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH2:14]O)[CH:11]=[CH:12][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:17][CH2:18][CH2:19][SH:20].CCOCC.C(=O)([O-])[O-].[Na+].[Na+]>Cl>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH2:14][S:20][CH2:19][CH2:18][NH2:17])[CH:11]=[CH:12][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCCS
Reactant: OCc1cccc(CN2CCCCC2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Product: NCCSCc1cccc(CN2CCCCC2)c1
Yield: 68.4 %

Procedure:
A mixture of 3-(1-piperidinylmethyl)benzenemethanol (10.8 g) and cysteamine hydrochloride (6.48 g) in concentrated hydrochloric acid (25 ml) was heated at 100° for 3 h. The cooled mixture was added to ether (500 ml) and treated with an excess of sodium carbonate. The organic solution was filtered and distilled to give the title compound as an oil (9.51 g) b.p. 175° (6×10-2 mm). TLC silica; ethyl acetate:water:isopropanol:0.88 ammonia 25:8:15:2; Rf 0.7.
Reaction SMILES: C([O:8][C:9]1[CH:30]=[CH:29][C:12]([CH2:13][N:14]2[CH:18]=[C:17]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]([O:26][CH2:27][CH3:28])=[N:15]2)=[CH:11][CH:10]=1)C1C=CC=CC=1>[C].[Pd].O1CCCC1>[CH2:27]([O:26][C:16]1[C:17]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:18][N:14]([CH2:13][C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:30][CH:29]=2)[N:15]=1)[CH3:28]
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3ccccc3)cc2)nc1OCC
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)nc1OCC
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.9 %

Procedure:
A mixture of ethyl 3-[1-(4-benzyloxybenzyl)-3-ethoxy-1H-pyrazol-4-yl]propionate (5.32 g), 5% palladium-carbon (3.45 g), and tetrahydrofuran (100 ml) was stirred for 3 hours at room temperature under a hydrogen atmosphere. After the palladium-carbon was removed by filtration, the filtrate was concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[3-ethoxy-1-(4-hydroxybenzyl)-1H-pyrazol-4-yl]propionate (3.56 g, yield: 86%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][CH3:13])[CH:11]=1)[N:8]=[C:7]([CH3:14])[CH:6]=[CH:5]2.[Se](=O)=[O:16]>O1CCOCC1.O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][CH3:13])[CH:11]=1)[N:8]=[C:7]([CH:14]=[O:16])[CH:6]=[CH:5]2
Reactant: COc1cc(F)cc2ccc(C)nc12
Reactant: O=[Se]=O
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(F)cc2ccc(C=O)nc12
Yield: 78.7 %

Procedure:
To 6-fluoro-8-methoxy-2-methylquinoline (500 mg, 2.62 mmol) in dioxane/water (5 mL/0.5 mL) at ambient temperature was added selenium dioxide (348 mg, 3.14 mmol) and the reaction was heated to reflux for 2-3 hours. After cooling, the reaction was filtered and the solids were washed with DCM. The filtrate was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (SP4, 25M, eluting with a gradient of water/ACN 100:0 to 0:100, 20 column volumes) to yield 6-fluoro-8-methoxyquinoline-2-carbaldehyde (423 mg, 78.8% yield) as a tan solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5]2.[B-](F)(F)(F)[F:18].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>CC#N>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:5]2[F:18]
Reactant: F[B-](F)(F)F
Reactant: CCOC(=O)c1cc2cc(Br)ccc2n1C
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: CCOC(=O)c1c(F)c2cc(Br)ccc2n1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 28 %

Procedure:
To a stirred solution of ethyl 5-bromo-1-methyl-1H-indole-2-carboxylate (2.93 g, 10.39 mmol) in MeCN (52 mL) was added Selectfluor® (3.87 g, 10.92 mmol, 1.05 eq) at 0° C. in three portions with an interval of 10 min. The reaction was stirred at 0° C. for 30 min before it was allowed to warm to room temperature then stirred for an additional 30 min. The reaction was monitored by TLC analysis. Once the starting material was completely consumed, the reaction was quenched with sat. NaHCO3 and then extracted by CH2Cl2 (4×25 mL). The solvent was removed to give a crude product which was purified by flash column chromatography (0-10% EtOAc in hexanes) to afford the desired product (860 mg, 2.87 mmol) in 28% yield.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:14][O:15][C:16](=[O:31])[CH2:17][C:18]1[N:19]=[C:20]([C:24]2[CH:25]=[N:26][C:27](Cl)=[CH:28][CH:29]=2)[O:21][C:22]=1[CH3:23]>>[CH3:14][O:15][C:16](=[O:31])[CH2:17][C:18]1[N:19]=[C:20]([C:24]2[CH:25]=[N:26][C:27]([C:8]3[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=3)=[CH:28][CH:29]=2)[O:21][C:22]=1[CH3:23]
Reactant: COC(=O)Cc1nc(-c2ccc(Cl)nc2)oc1C
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Product: COC(=O)Cc1nc(-c2ccc(-c3ccc(S(C)(=O)=O)cc3)nc2)oc1C

Procedure:
The titled compound is prepared substantially in accordance with the procedure of Example 4 using 4-(methanesulfonyl)benzene boronic acid and [2-(6-Chloro-pyridin-3-yl)-5-methyl-oxazol-4-yl]-acetic acid methyl ester [CAS 478540-95-3].
Reaction SMILES: [C:1]([CH:3]([C:5]1[CH:14]=[C:13]2[C:8]([C:9]([CH3:16])([CH3:15])[CH2:10][CH2:11][S:12]2)=[CH:7][CH:6]=1)[OH:4])#[CH:2].I[C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=1>>[OH:4][CH:3]([C:5]1[CH:14]=[C:13]2[C:8]([C:9]([CH3:16])([CH3:15])[CH2:10][CH2:11][S:12]2)=[CH:7][CH:6]=1)[C:1]#[C:2][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=1
Reactant: C#CC(O)c1ccc2c(c1)SCCC2(C)C
Reactant: COC(=O)c1ccc(I)cc1
Product: COC(=O)c1ccc(C#CC(O)c2ccc3c(c2)SCCC3(C)C)cc1
Yield: 57.1 %

Procedure:
Following the basic procedure of Example 11(d), by reacting 2 g (8.6 mmol) of α-ethynyl-4,4-dimethyl-7-thiochromanmethanol with 2.25 g (8.6 mmol) of methyl 4-iodobenzoate, 1.8 g (57%) of the expected ester was obtained in the form of an yellow oil.
Reaction SMILES: CN([CH2:4][C:5]1[C:9]2[CH:10]=[C:11]([Cl:14])[CH:12]=[CH:13][C:8]=2[NH:7][CH:6]=1)C.[NH:15]1[CH:19]=[CH:18][N:17]=[CH:16]1>C1(C)C(C)=CC=CC=1>[Cl:14][C:11]1[CH:10]=[C:9]2[C:8](=[CH:13][CH:12]=1)[NH:7][CH:6]=[C:5]2[CH2:4][C:16]1[NH:15][CH:19]=[CH:18][N:17]=1
Reactant: CN(C)Cc1c[nH]c2ccc(Cl)cc12
Reactant: c1c[nH]cn1
Solvent: Cc1ccccc1C
Product: Clc1ccc2[nH]cc(Cc3ncc[nH]3)c2c1
Yield: 84.5 %

Procedure:
A solution of 5-chlorogramine (3.73 g) and imidazole (1.22 g) in xylene (20 ml) was heated under reflux for 3 hours and the cooled. The solid was filtered off, washed with toluene followed by petrol and then crystallised from a mixture of isopropanol and petrol (b.p. 60°-80° C.) to give 5-chloro-3-(1-imidazolylmethyl)indole (3.50 g), m.p. 195°-197° C. Found: C, 62.48; H, 4.31; N, 18.09. C12H10ClN3 requires: C, 62.20; H, 4.35; N, 18.14%.
Reaction SMILES: [Cl:1][C:2]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:5]2[O:6][CH:7]([CH2:9][NH2:10])[CH2:8][C:4]=2[CH:3]=1.C(N(C(C)C)CC)(C)C.Cl[C:27]([O:29][CH3:30])=[O:28].CC1C=CC(S(OC)(=O)=O)=CC=1>>[Cl:1][C:2]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:5]2[O:6][CH:7]([CH2:9][NH:10][C:27](=[O:28])[O:29][CH3:30])[CH2:8][C:4]=2[CH:3]=1
Reactant: COC(=O)Cl
Reactant: NCC1Cc2cc(Cl)c3ccccc3c2O1
Agent: COS(=O)(=O)c1ccc(C)cc1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)NCC1Cc2cc(Cl)c3ccccc3c2O1
Yield: 92.6 %

Procedure:
Treatment of (±)-(5-chloro-2,3-dihydronaphtho[1,2-b]furan-2-yl)methylamine (2.60 g, 9.62 mmol) with diisopropylethylamine (3.73 g, 28.85 mmol) and methyl chloroformate (1.36 g, 9.62 mmol) generally according to the procedure described for Intermediate 7 afforded 2.60 g (93%) of (±)-methyl (5-chloro-2,3-dihydronaphtho[1,2-b]furan-2-yl)methylcarbamate as a white solid. mp 128-130° C.; Anal. calcd. for C15H14ClNO3: C, 61.76; H, 4.84; N, 4.80. Found: C, 61.43; H, 4.87; N, 4.68.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([S:20][CH2:21][CH3:22])[N:15]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:21]([S:20][C:16]1[N:15]=[C:14]([C:12]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:10])[N:13]=2)[CH:19]=[CH:18][CH:17]=1)[CH3:22]
Reactant: COC(=O)c1ccccc1S
Reactant: CCSc1cccc(C#N)n1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCSc1cccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 14 %

Procedure:
A mixture of methyl thiosalicylate (1.21 g, 7.2 mmol), 2-cyano-6-ethylthiopyridine (1.02 g, 6.2 mmol), triethylamine (1.5 ml, 10.8 mmol) and toluene (30 ml) was refluxed for 48 hrs. The reaction mixture was concentrated under reduced pressure to give precipitated crystals, which were recrystallized from ethanol to give the titled compound (0.26 g, 14%)
Reaction SMILES: [F:1][C:2]1[CH:47]=[CH:46][CH:45]=[C:44]([F:48])[C:3]=1[CH2:4][N:5]1[C:10]2[S:11][C:12]([C:24]3[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][O:34][CH3:35])=[O:32])=[CH:26][CH:25]=3)=[C:13]([CH2:14][N:15]([CH3:23])[CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[C:9]=2[C:8](=[O:36])[N:7]([CH2:37][CH2:38][C:39](OC)=O)[C:6]1=[O:43].NC(CC)[CH2:51][CH2:52][CH2:53][OH:54]>>[F:1][C:2]1[CH:47]=[CH:46][CH:45]=[C:44]([F:48])[C:3]=1[CH2:4][N:5]1[C:10]2[S:11][C:12]([C:24]3[CH:25]=[CH:26][C:27]([NH:30][C:31]([NH:33][O:34][CH3:35])=[O:32])=[CH:28][CH:29]=3)=[C:13]([CH2:14][N:15]([CH3:23])[CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[C:9]=2[C:8](=[O:36])[N:7]([CH:37]2[CH2:38][CH2:39][CH:53]([OH:54])[CH2:52][CH2:51]2)[C:6]1=[O:43]
Reactant: CONC(=O)Nc1ccc(-c2sc3c(c2CN(C)Cc2ccccn2)c(=O)n(CCC(=O)OC)c(=O)n3Cc2c(F)cccc2F)cc1
Reactant: CCC(N)CCCO
Product: CONC(=O)Nc1ccc(-c2sc3c(c2CN(C)Cc2ccccn2)c(=O)n(C2CCC(O)CC2)c(=O)n3Cc2c(F)cccc2F)cc1
Yield: 44.6 %

Procedure:
The similar reaction as described in Example 5 by using the compound obtained in Example 28 (320 mg, 0.5 mmol) and 4-aminohexanol (86 mg, 0.75 mmol) gave the title compound (154 mg, 45%) as colorless crystals.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:19][C:20]4[N:25]([CH3:26])[C:24](=[O:27])[CH2:23][O:22][C:21]=4[N:28]=3)=[CH:13][CH:12]=2)[CH2:10][CH2:9]1)(C)(C)C.Cl.C(OCC)C>O1CCOCC1>[NH2:7][C:8]1([C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:19][C:20]4[N:25]([CH3:26])[C:24](=[O:27])[CH2:23][O:22][C:21]=4[N:28]=3)=[CH:15][CH:16]=2)[CH2:9][CH2:10]1
Reactant: CN1C(=O)COc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CC4)cc3)c(-c3ccccc3)cc21
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CN1C(=O)COc2nc(-c3ccc(C4(N)CC4)cc3)c(-c3ccccc3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.2 %

Procedure:
To a solution of tert-butyl(1-(4-(1-methyl-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclopropyl)carbamate (60 mg, 0.127 mmol) in 1,4-dioxane (1 mL) was added dropwise 4M HCl in 1,4-dioxane (0.5 mL, 2.00 mmol) and the resulting solution stirred at room temperature for 1 hour. The reaction mixture was diluted by the dropwise addition of diethyl ether (6 mL) and stirred for 15 minutes to give a white precipitate. The layers were allowed to settle and the supernatant solution removed. The solid was washed twice more with diethyl ether (6 mL), allowing to settle and removing the supernatant solvent each time. The remaining solvent was removed by concentration to dryness under reduced pressure, then freeze-drying over the weekend to give the desired product as an off-white solid (27 mg, 52% yield). 1H-NMR (500 MHz, MeOD) δ 7.53 (1H, s), 7.34 (2H, d), 7.31 (2H, d), 7.25-7.29 (3H, m), 7.18-7.23 (2H, m), 4.94 (2H, s), 3.41 (3H, s), 1.29-1.35 (2H, m), 1.24-1.29 (2H, m). LCMS (Method D): RT=0.75 min, M+H+=372.10.
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([NH:14][C:15](=[O:22])[CH2:16][CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[CH:9][CH:10]=2)[N:5]1[CH2:23][C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][C:25]=1[O:34][CH3:35])[CH:2]=[CH2:3]>C(OCC)(=O)C.[Pd]>[CH:17]1([CH2:16][C:15]([NH:14][C:8]2[CH:7]=[C:6]3[C:11]([C:12](=[O:13])[N:4]([CH2:1][CH2:2][CH3:3])[N:5]3[CH2:23][C:24]3[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][C:25]=3[O:34][CH3:35])=[CH:10][CH:9]=2)=[O:22])[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: C=CCn1c(=O)c2ccc(NC(=O)CC3CCCC3)cc2n1Cc1ccc(C(=O)OC)cc1OC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCn1c(=O)c2ccc(NC(=O)CC3CCCC3)cc2n1Cc1ccc(C(=O)OC)cc1OC
Reaction time: 5 h
Yield: 84 %

Procedure:
Palladium-on-carbon (5% w/w, 0.095 g.) was added to a solution of methyl 4-[2-allyl-6-(2-cyclopentylacetamido)-3-oxo-2H,3H-indazol-1-ylmethyl]-3-methoxybenzoate (0.462 g.) in ethyl acetate (20 ml.). The mixture was hydrogenated at 1.1 bar for 5 hours. The catalyst was removed by filtration through diatomaceous earth, the filtrate evaporated and the residue purified by flash chromatography on silica gel (40 g.), eluting with 1:3:7 v/v/v acetic acid:ethyl acetate:dichloromethane. The chromatographed product was dissolved in acetone and toluene, and the solution evaporated to give the title compound in 84% yield, as a solid glass, m.p. 74.5°-77° C.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]([NH:12][C:13]3[CH:17]=[N:16][N:15]([CH3:18])[C:14]=3[C:19]([OH:21])=O)=[O:11])[C:7]([NH:22][C:23]3[CH:24]=[N:25][CH:26]=[N:27][CH:28]=3)=[N:6][CH:5]=2)[CH2:3][CH2:2]1.Cl.[C:30]([O:34][C:35]([N:37]1[CH2:41][CH2:40][CH:39]([NH2:42])[CH2:38]1)=[O:36])([CH3:33])([CH3:32])[CH3:31]>>[C:30]([O:34][C:35]([N:37]1[CH2:41][CH2:40][CH:39]([NH:42][C:19]([C:14]2[N:15]([CH3:18])[N:16]=[CH:17][C:13]=2[NH:12][C:10]([C:8]2[C:7]([NH:22][C:23]3[CH:28]=[N:27][CH:26]=[N:25][CH:24]=3)=[N:6][CH:5]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[N:9]=2)=[O:11])=[O:21])[CH2:38]1)=[O:36])([CH3:33])([CH3:31])[CH3:32]
Reactant: Cn1ncc(NC(=O)c2nc(C3CC3)cnc2Nc2cncnc2)c1C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCC(N)C1
Agent: Cl
Product: Cn1ncc(NC(=O)c2nc(C3CC3)cnc2Nc2cncnc2)c1C(=O)NC1CCN(C(=O)OC(C)(C)C)C1

Procedure:
The product was obtained starting from 4-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyrazine-2-carbonyl]-amino}-2-methyl-2H-pyrazole-3-carboxylic acid (30 mg, 79 μmol) and tert-butyl-3-aminopyrrolidine-1-carboxylate hydrochloride (23 mg, 103 μmol) according to the method described in example 64, step 6 after purification by preparative HPLC using an acetonitrile/water gradient as yellow solid (28 mg, 65%).
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:7]2[N:21]=[CH:22][C:23]([C:24]#[N:25])=[C:6]12)=[O:4].S(=O)(=O)(O)[OH:27]>>[Cl:1][CH2:2][C:3]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:7]2[N:21]=[CH:22][C:23]([C:24]([NH2:25])=[O:27])=[C:6]12)=[O:4]
Reactant: N#Cc1cnn2c1N(C(=O)CCl)CC=C2c1cccc(C(F)(F)F)c1
Reactant: O=S(=O)(O)O
Product: NC(=O)c1cnn2c1N(C(=O)CCl)CC=C2c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2 g of 4-(chloroacetyl)-4,5-dihydro-7-[3-(trifluoromethyl)phenyl]pyrazolo[1,5-a]-pyrimidine-3-carbonitrile and 20 ml of concentrated sulfuric acid was stirred at room temperature for 2 hours, then poured into ice water, stirred, and filtered. The product was washed with water and dried giving 2 g of the desired intermediate, mp 174°-176°.
Reaction SMILES: [C:1]([C:5]1[S:6][CH:7]=[C:8](/[CH:10]=[CH:11]/[C:12]2[C:13]([O:23][CH2:24][C:25]3[CH:50]=[CH:49][C:28]([O:29][CH2:30][C:31]4[N:32]=[C:33]([C:37]5[CH:42]=[CH:41][C:40]([CH2:43][C:44]([O:46]CC)=[O:45])=[CH:39][CH:38]=5)[O:34][C:35]=4[CH3:36])=[C:27]([O:51][CH3:52])[CH:26]=3)=[N:14][N:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:16]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[C:1]([C:5]1[S:6][CH:7]=[C:8](/[CH:10]=[CH:11]/[C:12]2[C:13]([O:23][CH2:24][C:25]3[CH:50]=[CH:49][C:28]([O:29][CH2:30][C:31]4[N:32]=[C:33]([C:37]5[CH:38]=[CH:39][C:40]([CH2:43][C:44]([OH:46])=[O:45])=[CH:41][CH:42]=5)[O:34][C:35]=4[CH3:36])=[C:27]([O:51][CH3:52])[CH:26]=3)=[N:14][N:15]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:16]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C/c4csc(C(C)(C)C)n4)cc3OC)c(C)o2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: COc1cc(COc2nn(-c3ccccc3)cc2/C=C/c2csc(C(C)(C)C)n2)ccc1OCc1nc(-c2ccc(CC(=O)O)cc2)oc1C
Temperature: 50 °C
Reaction time: 1 h
Yield: 79.7 %

Procedure:
To a mixture of ethyl {4-[4-({4-[({4-[(E)-2-(2-tert-butyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}acetate (0.77 g), tetrahydrofuran (9 mL) and ethanol (3 mL) was added 1N aqueous sodium hydroxide solution (2 mL), and the mixture was stirred at 50° C. for 1 hr. To the reaction mixture were added 1N hydrochloric acid (2 mL) and water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give {4-[4-({4-[({4-[(E)-2-(2-tert-butyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}acetic acid as crystals (0.59 g, yield 80%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 113-115° C.
Reaction SMILES: BrN1C(=O)CCC1=O.[C:9]([OH:12])(=[O:11])[CH3:10].[C:13]([OH:16])(=[O:15])[CH3:14].[C:17]([OH:20])(=[O:19])[CH3:18].[F:21][C:22]([F:56])([F:55])[C:23](O)([CH2:28][CH2:29][CH2:30][C@H:31]([C@@H:33]1[C@:51]2([CH3:52])[C@H:36]([C@H:37]3[C@H:48]([CH2:49][CH2:50]2)[C@:46]2([CH3:47])[C:40]([CH2:41][C@H:42]([CH2:44][C@@H:45]2O)O)=[CH:39][CH2:38]3)[CH2:35][CH2:34]1)[CH3:32])[C:24]([F:27])([F:26])[F:25]>C(Cl)(Cl)(Cl)Cl>[F:21][C:22]([F:55])([F:56])[C:23]([O:19][C:17](=[O:20])[CH3:18])([CH2:28][CH2:29][CH2:30][C@H:31]([C@@H:33]1[C@:51]2([CH3:52])[C@H:36]([C:37]3[C@H:48]([CH2:49][CH2:50]2)[C@:46]2([CH3:47])[C:40]([CH2:41][C@@H:42]([O:15][C:13](=[O:16])[CH3:14])[CH2:44][C@@H:45]2[O:11][C:9](=[O:12])[CH3:10])=[CH:39][CH:38]=3)[CH2:35][CH2:34]1)[CH3:32])[C:24]([F:25])([F:27])[F:26]
Reactant: CC(=O)O
Reactant: C[C@H](CCCC(O)(C(F)(F)F)C(F)(F)F)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H]([C@H](C)CCCC(OC(C)=O)(C(F)(F)F)C(F)(F)F)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1
Reaction time: 0.33 h
Yield: 27.3 %

Procedure:
N-bromosuccinimide (14 mg) was added to a refluxing solution of 35 mg of triacetate (6) in 2 ml of CCl4 and the reaction mixture was refluxed further under argon atmosphere. After cooling in an ice-water bath, the resulting precipitate was filtered off. The filtrate was evaporated to dryness below 40° C. The residue is xylene (1 ml) was added dropwise to a refluxing solution of xylene (1.5 ml) and s-collidine (0.5 ml) and refluxing was continued under argon atmosphere for 20 min. The reaction mixture was extracted with AcOEt, washed with 2 N-HCl, sat. NaHCO3, brine and the solution was dried over MgSO4. After removal of the solvent, the residue was treated with a catalytic amount of pTsOH in acetone (10 ml) at room temperature for 16 hr under argon in the dark. The mixture was extracted with AcOEt and the extract was washed with sat. NaHCO3 and brine, and then dried over MgSO4. Removal of the solvent gave a crude 5,7-diene, which was purified by preparative TLC developed twice with a solvent of n-hexane-AcOEt (10:1). The band of Rf value 0.26 was scraped off and eluted with AcOEt. Removal of the solvent gave 8.8 mg (25%) of the product (7); UV(EtOH)λmax, 294, 282, 272 nm.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[CH3:21])=[CH:10][C:9]=1[NH:22][C:23](=[O:38])[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N:33]2[CH:37]=[CH:36][N:35]=[CH:34]2)[CH:28]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[C:25]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([N:33]5[CH:37]=[CH:36][N:35]=[CH:34]5)[CH:28]=4)[CH2:24][C:23](=[O:38])[NH:22][C:9]=3[CH:10]=2)=[C:15]([CH3:21])[CH:16]=1
Reactant: Cc1cc(F)ccc1-c1ccc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3ccnc3)c2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(F)ccc1-c1ccc2c(c1)NC(=O)CC(c1cccc(-n3ccnc3)c1)=N2

Procedure:
Prepared from {4′-fluoro-3-[3-(3-imidazol-1-yl-phenyl)-3-oxo-propionylamino]-2′-methyl-biphenyl-4-yl}-carbamic acid tert.-butyl ester (Example K50) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a beige solid (82 mg).
Reaction SMILES: [N:1]1([N:7]2[C:16]3[C:11](=[CH:12][C:13]([CH2:17][N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:14][CH:15]=3)[C:10](=[O:24])[C:9]([C:25](OCC)=[O:26])=[CH:8]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH2:36])=[CH:33][CH:32]=1>>[Cl:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH:36][C:25]([C:9]2[C:10](=[O:24])[C:11]3[C:16](=[CH:15][CH:14]=[C:13]([CH2:17][N:18]4[CH2:19][CH2:20][O:21][CH2:22][CH2:23]4)[CH:12]=3)[N:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[CH:8]=2)=[O:26])=[CH:33][CH:32]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cn(N2CCOCC2)c2ccc(CN3CCOCC3)cc2c1=O
Product: O=C(NCc1ccc(Cl)cc1)c1cn(N2CCOCC2)c2ccc(CN3CCOCC3)cc2c1=O
Temperature: 190 °C
Yield: 79 %

Procedure:
Ethyl 1-(4-morpholinyl)-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylate (5.0 g) from Preparation No. 56 and 4-chlorobenzylamine (7.6 mL) are combined and heated to 190° C. for 7 hours. After cooling to room temperature, the mixture solidifies. The solid is triturated with a 10:1 mixture of EtOAc/MTBE (30 mL) and filtered on a frit. The crude solid is triturated again, this time with a hot mixture of 10:1 EtOAc/MTBE (110 mL). The suspension is cooled to room temperature and filtered on a frit to afford 4.9 g (79%) of the title compound as a white solid.