Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([C:13]([O:15][CH3:16])=[O:14])[N:3]=1.[CH3:17][Sn](C)(C)C>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([CH3:17])=[N:3][C:4]=1[C:13]([O:15][CH3:16])=[O:14]
Reactant: C[Sn](C)(C)C
Reactant: COC(=O)c1nc(Cl)c2ccccc2c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)c1nc(C)c2ccccc2c1O
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 87.5 %

Procedure:
A mixture of methyl 1-chloro-4-hydroxyisoquinoline-3-carboxylate (1.00 g, 4.21 mmol, from Aldrich), tetramethylstannane (3.01 g, 16.8 mmol), and bis(triphenylphosphine)-palladium(II) chloride (0.295 g, 0.421 mmol) in N,N-dimethylformamide (30 mL) was stirred at 130° C. for 30 minutes. The mixture was cooled to room temperature, quenched with water and then filtered. The filtrate was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified on silica gel chromatography, eluting with 0 to 10% MeOH in dichloromethane, to give the desired product (0.80 g, 88%). LCMS calculated for C12H12NO3 (M+H)+: m/z=218.1; Found: 218.1.
Reaction SMILES: [C:1]([N:11]([CH2:13][C:14]([OH:16])=O)[CH3:12])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C(OC(Cl)=O)C(C)C.Cl.[C:26]([O:30][C:31](=[O:37])[C@@H:32]1[CH2:36][CH2:35][CH2:34][NH:33]1)([CH3:29])([CH3:28])[CH3:27]>O1CCCC1.CN1CCOCC1>[C:26]([O:30][C:31](=[O:37])[C@@H:32]1[CH2:36][CH2:35][CH2:34][N:33]1[C:14](=[O:16])[CH2:13][N:11]([C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2])[CH3:12])([CH3:29])([CH3:27])[CH3:28]
Reactant: CN(CC(=O)O)C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CN(CC(=O)N1CCC[C@H]1C(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: -10 °C
Reaction time: 0.08 h

Procedure:
4.5 g of CBZ-sarcosine is dissolved in 100 ml tetrahydrofuran and 2.4 ml of n-methylmorpholine is added. The reaction mixture is cooled to -10° C. and stirred while 2.6 ml of isobutylchloroformate is added. After 5 minutes of additional stirring at -10° C. 4.15 g L-proline-t-butylester hydrochloride in 100 ml of tetrahydrofuran and 3.0 ml of n-methylmorpholine are added to the reaction mixture. The reaction mixture is stirred overnight and slowly warmed to room temperature. The solvent is evaporated under reduced pressure at 30° C. and the residue is dissolved in 600 ml ethylacetate. The ethylacetate layer is washed with (3×150 ml), lN sodium hydroxide, water (1×200 ml) 10% citric acid (3×150 ml), and water (3×150 ml). The organic layer is dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure to provide carbobenzoxysarcosyl-proline-t-butyl ester (CBZ-Sar-L-Pro-O-t-But). 6.5 g of this material is dissolved in 15 ml of methylene chloride and 25 ml of trifluoroacetic acid is then added. The reaction mixture is kept at room temperature for 45 minutes and then the solvent is evaporated under reduced pressure at 30° C. The residue is triturated with hexane (3×50 ml) and the hexane removed by decantation. The residue is evaporated from (2×50 ml) of benzene to provide an oily residue which is carbobenzoxysarcosyl-L-proline (CBZ-Sar-L-Pro). 5.4 g of this material and 3.45 g of N-hydroxysuccinimide are dissolved in 100 ml of tetrahydrofuran and cooled to 0° C. To this cooled reaction mixture is added 4.12 g of dicyclohexylcarbodiimide. The reaction mixture is stirred overnight at 4° C. and the solvent is evaporated under reduced pressure. The residue is dissolved in 400 ml of ethylacetate and the dicyclohexyl urea is filtered off. The filtrate is washed with lN-hydrochloric acid (3×100 ml), water (1×100 ml), saturated sodium bicarbonate solution (2×100 ml) and water (2×100 ml). The organic layer is dried over anhydrous magnesium sulfate, filtered and the solvent is evaporated under reduced pressure to provide carbobenzoxy-sarcosyl-L-proline-succinimidyl ester.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:21])[NH:10][C@H:11]1[CH2:16][CH2:15][C@@H:14]([OH:17])[CH2:13][C@@H:12]1[CH:18]=[CH:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:21])[NH:10][C@H:11]1[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][C@@H:12]1[CH:18]=[CH:19][CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC=C[C@H]1C[C@H](O)CC[C@@H]1NC(=O)OCc1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC=C[C@H]1CC(=O)CC[C@@H]1NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 67.8 %

Procedure:
A solution of [(1S,2R,4R)-(4-hydroxy-2-propenyl-cyclohexyl)]-carbamic acid benzyl ester as a colorless oil (0.56 g, 1.9 mmol) in CH2Cl2 (20 mL) was charged with pyridine (0.8 mL, 9.5 mmol) and Dess-Martin Periodinane (0.9 g, 2.1 mmol). The reaction was stirred at RT for 12 h and concentrated in vacuo. Purification of the residue via flash chromatography afforded the desired [(1S,2R)-(4-oxo-2-propenyl-cyclohexyl)]-carbamic acid benzyl ester (0.37 g) as a 3:1 mixture of Z and E diastereomers. This material was dissolved in titanium tetraisopropoxide (2 mL) and N-methylisopropylamine (3 mL) with agitation. The resultant solution was stirred for 1 h at RT and then charged with MeOH (6 mL) and sodium borohydride (100 mg; added slowly—vigorous gas evolution was observed). The reaction was stirred for 1.5 h and then quenched with 0.2 N NaOH. The resultant mixture was diluted with CH2Cl2 and stirred vigorously before being filtered through Celite. The phases were separated and the organic phase was washed with brine, dried (MgSO4), filtered, and concentrated in vacuo to give the desired [(1S,2R,4R)-4-(isopropyl-methyl-amino)-2-propenyl-cyclohexyl]-carbamic acid benzyl ester (295 mg, mixture of olefin diastereomers, some 4S diastereomer present) as a light yellow oil. MS found: (M+H)+=345.31.
Reaction SMILES: [CH2:1]([N:3]1[N:7]=[C:6]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17](/[N:20]=[CH:21]/[C:22]4[O:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=4)=[CH:16][C:15]=3[F:30])[CH2:10][CH2:9]2)[O:5][C:4]1=[O:31])[CH3:2].C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CC(O)=O.CO>[CH2:1]([N:3]1[N:7]=[C:6]([CH:8]2[CH2:9][CH2:10][N:11]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][CH2:21][C:22]4[O:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=4)=[CH:16][C:15]=3[F:30])[CH2:12][CH2:13]2)[O:5][C:4]1=[O:31])[CH3:2]
Reactant: CCn1nc(C2CCN(c3ccc(/N=C/c4ccc([N+](=O)[O-])o4)cc3F)CC2)oc1=O
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCn1nc(C2CCN(c3ccc(NCc4ccc([N+](=O)[O-])o4)cc3F)CC2)oc1=O
Yield: 82.8 %

Procedure:
3-Ethyl-5-[1-(2-fluoro-4-[(E)-1-(5-nitro-2-furyl)methylidene]aminophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (9 g, 0.43 g, 1 mmol) on reduction with sodiumcyanoborohydride (0.12 g, 2 mmol) in the presence of catalytic amount of CH3COOH (3 drops) in methanol at 0° C. for 12 h. After completion of the reaction as indicated by TLC, the reaction mixture is neutralized with sodium bi carbonate and extracted into chloroform. The crude product thus obtained was purified by column chromatography using ethyl acetate-hexane (8:2) as eluant to obtain product 3-ethyl-5-[1-(2-fluoro-4-[(5-nitro-2-furyl)methyl]aminophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadi azol-2-one (10g, 357 mg, 83%).
Reaction SMILES: [N:1]([CH2:4][CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:23])[O:6]1)=[C:2]=[O:3].[NH4+:24].[OH-]>C1COCC1>[O:23]=[C:15]1[C:14](=[C:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:5]([CH2:4][NH:1][C:2]([NH2:24])=[O:3])[O:6]2)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16]1
Reactant: O=C=NCC1OC(=C2C(=O)Nc3ccccc32)c2ccccc21
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=O)NCC1OC(=C2C(=O)Nc3ccccc32)c2ccccc21
Reaction time: 0.08 h
Yield: 68 %

Procedure:
To a solution of 3-(3-Isocyanatomethyl-3H-isobenzofuran-1-ylidene)-1,3-dihydro-indol-2-one (65 mg, 0.21 mmol) in THF (4 ml) at room temperature was added concentrated NH4OH (2 ml). The reaction was stirred 5 minutes and then partitioned between EtOAc and water. The organic layer was washed with very dilute HCl, brine, dried with anhydrous Na2SO4 and rotary evaporated to obtain a solid. The solid was recrystallized from EtOAc/MeOH to give [3-(2-oxo-1,2-dihydro-indol-3-ylidene)-1,3-dihydro-isobenzofuran-1-ylmethyl]-urea as a yellow solid (46 mg, 68%).
Reaction SMILES: [OH:1][C:2]1[CH:38]=[CH:37][C:5]([C:6]([CH2:8][CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=2[CH:20]2[CH2:29][CH2:28][C:27]3[CH:26]=[C:25]([O:30]C(=O)C(C)(C)C)[CH:24]=[CH:23][C:22]=3[CH2:21]2)=O)=[CH:4][CH:3]=1.Cl[CH2:40][C:41]([N:43]1[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1)=O>>[CH3:19][O:18][C:16]1[CH:15]=[CH:14][C:13]([CH:20]2[CH2:29][CH2:28][C:27]3[CH:26]=[C:25]([OH:30])[CH:24]=[CH:23][C:22]=3[CH2:21]2)=[C:12]([NH:11][CH2:10][CH2:9][CH2:8][CH2:6][C:5]2[CH:37]=[CH:38][C:2]([O:1][CH2:40][CH2:41][N:43]3[CH2:48][CH2:47][O:46][CH2:45][CH2:44]3)=[CH:3][CH:4]=2)[CH:17]=1
Reactant: O=C(CCl)N1CCOCC1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCCCC(=O)c2ccc(O)cc2)c1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(NCCCCc2ccc(OCCN3CCOCC3)cc2)c1
Yield: 87.4 %

Procedure:
Synthesized from pivalic acid 6-{2-[(4-hydroxybenzoyl)propylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (30 mg) and 2-chloro-1-morpholin-4-ylethanone (19 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (27 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=S)[CH:9]([CH3:13])[N:8]=[C:7](C3C=CC=CC=3)[C:6]=2[CH:20]=1.[C:21]1([CH2:27][C:28]([NH:30][NH2:31])=O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.N#N>C(O)CCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:28]([CH2:27][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:30][N:31]=[C:10]3[CH:9]([CH3:13])[N:8]=[CH:7][C:6]=2[CH:20]=1
Reactant: CC1N=C(c2ccccc2)c2cc(Cl)ccc2NC1=S
Reactant: NNC(=O)Cc1ccccc1
Agent: N#N
Solvent: CCCCO
Product: CC1N=Cc2cc(Cl)ccc2-n2c(Cc3ccccc3)nnc21
Yield: 48 %

Procedure:
A stirred mixture of 7-chloro-1,3-dihydro-3-methyl-5-phenyl-2H-1,4 -benzodiazepine-2-thione (3.0 g, 0.01 mol), phenyl acetic acid hydrazide (4.95 g, 0.033 mol) and butanol (150 ml) was refluxed for 16 hours while N2 was being bubbled through the mixture. The reaction mixture was concentrated under high vacuum, and the residue mixed with iced H2O. The product was filtered and dissolved in CH2Cl2. The CH2Cl2 was washed with dilute HCl and brine, dried over Na2SO4 and concentrated in vacuo. At this point it appeared that complete cyclization had not been achieved. Therefore, the residue was combined with acetic acid (100 ml) and refluxed for 2 hours under N2. The reaction mixture was concentrated in vacuo and the residue mixed with CH2Cl2 and H2O. The CH2Cl2 was washed with NaHCO3 and brine, dried over Na2SO4 and concentrated in vacuo. The material was crystallized from EtOAc-Skelly B to give 1.55 g, mp 195°-197° of the subtitled intermediate, which had a C:H:N:Cl ratio of 72.38:4.85:14.16:8.81. Calculated for C24H19N4Cl: 72.26:4.80:14.05:8.89.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[CH:16]=[C:15]([C:18]3[C:23]([O:24][CH3:25])=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:26])[C:14]3[C:27](=[O:31])[NH:28][C:29](=[O:30])[C:13]=3[C:12]=2[C:11]2[CH:10]=[C:9]([OH:32])[CH:8]=[CH:7][C:6]1=2.[CH3:33][C@H:34]1[CH2:39][NH:38][CH2:37][C@@H:36]([CH3:40])[NH:35]1>>[Cl:26][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]([O:24][CH3:25])[C:18]=1[C:15]1[C:14]2[C:27](=[O:31])[NH:28][C:29](=[O:30])[C:13]=2[C:12]2[C:11]3[CH:10]=[C:9]([OH:32])[CH:8]=[CH:7][C:6]=3[N:5]([CH2:4][CH2:3][CH2:2][N:38]3[CH2:37][C@H:36]([CH3:40])[NH:35][C@H:34]([CH3:33])[CH2:39]3)[C:17]=2[CH:16]=1
Reactant: COc1cccc(Cl)c1-c1cc2c(c3c1C(=O)NC3=O)c1cc(O)ccc1n2CCCBr
Reactant: C[C@@H]1CNC[C@H](C)N1
Product: COc1cccc(Cl)c1-c1cc2c(c3c1C(=O)NC3=O)c1cc(O)ccc1n2CCCN1C[C@@H](C)N[C@@H](C)C1
Reaction time: 20 h
Yield: 98 %

Procedure:
Bromide (207) (60 mg, 0.12 mmol), prepared as described in example 176, was reacted with cis-2,6-dimethylpiperazine according to the procedure described in example 179 except that the reaction was performed at room temperature for 20 h, to give amine (218) (63 mg, 98%) as a yellow powder, mp 199–202° C. 1H NMR δ [(CD3)2SO] 10.99 (br s, 1H), 9.37 (br s, 1H), 8.36 (d, J=2.4 Hz, 1H), 7.75 (s, 1H), 7.57 (d, J=8.8 Hz, 1H), 7.43 (t, J=8.2 Hz, 1H), 7.15 (m, 3H), 4.45 (t, J=6.1 Hz, 2H), 3.67 (s, 3H), 2.49 (m, 4H), 2.11 (m, 2H), 1.90 (m, 2H), 1.27 (m, 2H), 0.79 (m, 6H). Found: C, 61.35; H, 5.68; N, 9.14. C30H31ClN4O4.2¼H2O requires: C, 61.32; H, 6.09; N, 9.54.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][C:9]#[CH:10])=[C:3]1[CH3:11].N1C=CN=C1.[C:17]([Si:21]([CH3:24])([CH3:23])Cl)([CH3:20])([CH3:19])[CH3:18].C(O)(=O)C(O)=O>CN(C)C=O>[Si:21]([O:1][C@H:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][C:9]#[CH:10])=[C:3]1[CH3:11])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C#CCC1=C(C)[C@@H](O)CC1=O
Agent: O=C(O)C(=O)O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C#CCC1=C(C)[C@@H](O[Si](C)(C)C(C)(C)C)CC1=O
Reaction time: 13 h
Yield: 86.3 %

Procedure:
1 (S)-4-hydroxy-3-methyl-2-(2-propynyl)-cyclopent-2-ene-1-one (50.0 g) was dissolved in dry dimethylformamide (600 ml), and imidazole (27.3 g) was added to the dimethylformamide solution. Tert-butyldimethylchlorosilane (55.3 g) was added to the solution under ice-water cooling and the resulting mixture was allowed to react for 2 hours, then for 13 hours at 20° C. The reaction solution was poured into an aqueous oxalic acid solution under ice-water cooling, and extracted three times with diethyl ether (200 ml). The ether layers were combined, and the combined layer was washed with saturated aqueous sodium bicarbonate solution and brine in sequence. After dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. The resultant residue was subjected to distillation under reduced pressure to afford (S)-4-tert-butyldimethylsilyloxy-3-methyl-2-(2-propynyl)cyclopent-2-ene-1-one (76.0 g, yield 86.0%) as a pale yellow oil.
Reaction SMILES: COC([CH2:5][N:6]1[CH2:10][C@@H:9]([C:11]([O:13][CH3:14])=[O:12])[C@H:8]([C:15]([O:17][CH3:18])=[O:16])[CH2:7]1)=O.[CH3:19]C(C)([O-])C.[K+].Cl>C1(C)C=CC=CC=1>[CH3:14][O:13][C:11]([CH:9]1[CH:8]2[CH2:7][N:6]([CH2:5][C:15]2([O:16][CH3:19])[O:17][CH3:18])[CH2:10]1)=[O:12]
Reactant: COC(=O)CN1C[C@@H](C(=O)OC)[C@H](C(=O)OC)C1
Reactant: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Product: COC(=O)C1CN2CC1C(OC)(OC)C2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 12 %

Procedure:
A solution of 1-methoxycarbonylmethyl-trans-3,4-dimethoxycarbonylpyrrolidine (5 g, 19.31 mmol) in toluene (75 ml) was added dropwise over a 1 hour period to a rapidly stirred solution of potassium-t-butoxide (9 g, 80 mmol) in toluene (250 ml) at 130° C. The mixture was refluxed for 4 hours, cooled to room temperature and concentrated hydrochloric acid (75 ml) added dropwise and stirred for 0.25 hours. The organic phase was extracted with further portions of hydrochloric acid (3×50 ml) and the combined aqueous heated at 110° C. for 16 hours. The solvent was then removed in vacuo, the residue dried and taken up into methanol (saturated with hydrogen chloride, 150 ml). The mixture was stirred at room temperature for 24 hours and the solvent removed under vacuum. The residue was dissolved in water (50 ml), basified to pH>10 with potassium carbonate and extracted with dichloromethane (5×150 ml). The combined extracts were dried (Na2SO4) and the residue remaining after removal of the solvents was chromatographed through silica-gel, using dichloromethane/methanol (93:7) as eluant, to give the title ester as a yellow liquid (0.5 g). An analytical sample was prepared as the hydrogen oxalate salt, mp 134.5°-136.5° C. (propan-2-ol); (Found: C, 47.04; H, 6.20; N, 4.50. C10H17NO4.(CO2H)2 requires C, 47.21; H, 6.27; N, 4.59%); δ (360 MHz, CDCl3) 2.44 (1H, dd, J=9.8 and 3.2 Hz), 2.63 (1H, dd, J=12.7 and 3.2 Hz), 2.77 (1H, d, J=12.7 Hz), 2.80-3.10 (5H, m), 3.11 (3H, s, OCH3), 3.24 (3H, s, OCH3), 3.71 (3H, s, CO2CH3).
Reaction SMILES: [CH2:1]([Mg]Cl)[CH2:2][CH3:3].[CH:6]([C:8]1[C:16]2[O:15][CH2:14][CH:13]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]([CH3:25])[CH3:24])=[CH:19][CH:18]=3)[C:12]=2[C:11]([CH3:26])=[C:10]([NH:27][C:28](=[O:34])[CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:9]=1[CH3:35])=[O:7]>O>[OH:7][CH:6]([C:8]1[C:16]2[O:15][CH2:14][CH:13]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]([CH3:25])[CH3:24])=[CH:19][CH:18]=3)[C:12]=2[C:11]([CH3:26])=[C:10]([NH:27][C:28](=[O:34])[CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:9]=1[CH3:35])[CH2:1][CH2:2][CH3:3]
Reactant: Cc1c(C=O)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Reactant: CCC[Mg]Cl
Solvent: O
Product: CCCC(O)c1c(C)c(NC(=O)CC(C)(C)C)c(C)c2c1OCC2c1ccc(C(C)C)cc1
Reaction time: 1 h
Yield: 25.7 %

Procedure:
To propylmagnesium chloride (2.0 M, THF solution 10.0 mL, 20.0 mmol) was added N-(7-formyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide (2.2 g, 5.40 mmol) obtained in Example 20 at 0° C. and the reaction solution was stirred at the same temperature for 1 hour. The reaction solution was added to water and the product was extracted with ethyl acetate. The organic layer was washed with water and 1 N hydrochloric acid, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane ethyl acetate=4:1) to obtain 627 mg (yield: 26%) of the title compound as a low polarity isomer. Melting point: 162-163° C. (hexane-ethyl acetate).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][C@@H:11]([NH:14][CH:15]3[CH2:18][O:17][CH2:16]3)[C@H:10]([OH:19])[CH2:9]2)=[CH:6][C:5]([C:20]#[N:21])=[CH:4][C:3]=1[NH:22][C:23]1[N:28]=[C:27]([NH:29][CH2:30][CH3:31])[C:26]2=[N:32][CH:33]=[C:34]([C:35]#[N:36])[N:25]2[N:24]=1.[C:37](N1C=CN=C1)(N1C=CN=C1)=[O:38]>CN(C=O)C>[Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][C@H:11]3[N:14]([CH:15]4[CH2:16][O:17][CH2:18]4)[C:37](=[O:38])[O:19][C@@H:10]3[CH2:9]2)=[CH:6][C:5]([C:20]#[N:21])=[CH:4][C:3]=1[NH:22][C:23]1[N:28]=[C:27]([NH:29][CH2:30][CH3:31])[C:26]2=[N:32][CH:33]=[C:34]([C:35]#[N:36])[N:25]2[N:24]=1
Reactant: CCNc1nc(Nc2cc(C#N)cc(N3CC[C@@H](NC4COC4)[C@H](O)C3)c2Cl)nn2c(C#N)cnc12
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CCNc1nc(Nc2cc(C#N)cc(N3CC[C@@H]4[C@@H](C3)OC(=O)N4C3COC3)c2Cl)nn2c(C#N)cnc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 51.5 %

Procedure:
To (+/−)-2-((2-chloro-5-cyano-3-((3R,4R)-3-hydroxy-4-(oxetan-3-ylamino)piperidin-1-yl)phenyl)amino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (90 mg, 0.177 mmol) in DMF (5 mL) was added 1,1′-carbonyldiimidazole (200 mg, 1.233 mmol) and the reaction stirred at 25° C. 16 hr. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19×mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 30-70% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to afford rac-2-((2-chloro-5-cyano-3-((3aR,7aR)-1-(oxetan-3-yl)-2-oxohexahydrooxazolo[5,4-c]pyridin-5 (2H)-yl)phenyl)amino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (48.8 mg).
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:14][CH:13]=[CH:12][C:11]([C:15]([O:17]C)=[O:16])=[CH:10]1)=O)(C)(C)C.[OH-].[Na+].[ClH:21]>CO.O>[ClH:21].[NH2:8][CH:9]1[CH2:14][CH:13]=[CH:12][C:11]([C:15]([OH:17])=[O:16])=[CH:10]1
Reactant: COC(=O)C1=CC(NC(=O)OC(C)(C)C)CC=C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: NC1C=C(C(=O)O)C=CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.4 g of methyl 3-(tert-butoxycarbonylamino)-1,5-cyclohexadienecarboxylate is treated with 164 mg of sodium hydroxide in 2 ml of methanol and 1 ml of water. The solution is stirred at about 25° C. for 3 hours, acidified to a pH of 3 with dilute hydrochloric acid and evaporated to dryness in vacuo. The residue is treated with 7 ml of methanol and 3.5 ml of 5% hydrochloric acid for 24 hours at 25° C. after which the solution is concentrated and washed with ether. The aqueous phase is evaporated in vacuo, and the residue is recrystallized from methanol-ether to afford 20 mg of 3-amino-1,5-cyclohexadiene carboxylic acid hydrochloride. M.P. 180°-184° C.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][CH2:6][C@@H:5]([NH:9]C(=O)OC(C)(C)C)[CH2:4]1.[C:17]([OH:23])([C:19]([F:22])([F:21])[F:20])=[O:18]>C(Cl)Cl>[F:20][C:19]([F:22])([F:21])[C:17]([OH:23])=[O:18].[CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][CH2:6][C@@H:5]([NH2:9])[CH2:4]1
Reactant: CO[C@H]1CCC[C@@H](NC(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CO[C@H]1CCC[C@@H](N)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of tert-butyl (1R,3S)-3-methoxycyclohexylcarbamate (1.0686 g, 4.66 mmol) in anhydrous DCM (18.64 mL) was added TFA (3.59 mL, 46.6 mmol) and the resulting solution was stirred at room temperature for 1 h. After that, the solvents were removed in vacuo, and the resulting residue was triturated with ethyl ether (2×50 mL) to afford (1R,3S)-3-methoxycyclohexanamine trifluoroacetate (1.133 g, 4.66 mmol, 100% yield) as a white solid. The crude product was used without further purification in the next step.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13](Br)=[C:12]([Br:17])[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:18][C:19]([OH:24])([CH3:23])[CH2:20][CH2:21][OH:22]>>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:22][CH2:21][CH2:20][C:19]([OH:24])([CH3:23])[CH3:18])=[C:12]([Br:17])[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=c1c(Br)c(Br)cnn1-c1ccc(F)c(F)c1
Reactant: CC(C)(O)CCO
Product: CC(C)(O)CCOc1c(Br)cnn(-c2ccc(F)c(F)c2)c1=O

Procedure:
The dibromo-intermediate from Example 471B was reacted according to the procedure described in Example 194B, substituting 3-methyl-1,3-butanediol in place of methanol, to selectively react at the 4-position and provide the title intermediate.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([S:11](Cl)(=[O:13])=[O:12])=[C:8](C)[N:9]=1)(=[O:3])[CH3:2].[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.O>C(Cl)Cl>[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([S:11]([C:7]2[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][CH:8]=2)(=[O:13])=[O:12])[CH2:18][CH2:17]1
Reactant: CN1CCNCC1
Reactant: CC(=O)Nc1nc(C)c(S(=O)(=O)Cl)s1
Solvent: O
Solvent: ClCCl
Product: CC(=O)Nc1ncc(S(=O)(=O)N2CCN(C)CC2)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-acetamido-4-methyl-5-thiazolesulfonyl chloride (3 g, 11.8 mmol) in DCM (50 mL) and TEA (3.2 mL, 23.6 mmol) was slowly added N-methylpiperazine (1.2 g, 12.4 mmol). The reaction mixture was stirred at room temperature for 2 hours. Water (50 mL) was added, and the organic phase was isolated. The water phase was extracted with DCM (3×75 mL). The combined organic phase was dried with anhydrous magnesium sulphate, filtered, and evaporated in vacuo to give 2.6 g of yellow, impure crystals. Purification on a silica gel column (Eluent: DCM:MeOH (9:1)) gave N-[5-(4-methylpiperazine-1-sulfonyl)-thiazol-2-yl]-acetamide as light yellow crystals of N-[5-(4-methylpiperazine-1-sulfonyl)-thiazol-2-yl]-acetamide. Yield: 1.52 g (41%). 1H-NMR (CDCl3): δ3.20 (m, 4H); 2.55 (m, 7H); 2.32 (s, 3H); 2.29 (s, 3H).