Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[F:23][C:24]([F:70])([F:69])[C:25]1[CH:26]=[C:27]([C@H:35]2[O:39][C:38](=[O:40])[N:37]([CH2:41][C:42]3[CH:47]=[C:46]([C:48]([F:51])([F:50])[F:49])[CH:45]=[CH:44][C:43]=3[C:52]3[C:57]([Cl:58])=[CH:56][CH:55]=[C:54]([C:59]4[CH:64]=[CH:63][C:62]([CH2:65][OH:66])=[CH:61][C:60]=4[CH3:67])[CH:53]=3)[C@H:36]2[CH3:68])[CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1.CCOC(C)=O.CCCCCC>C(Cl)Cl>[F:70][C:24]([F:23])([F:69])[C:25]1[CH:26]=[C:27]([C@H:35]2[O:39][C:38](=[O:40])[N:37]([CH2:41][C:42]3[CH:47]=[C:46]([C:48]([F:49])([F:51])[F:50])[CH:45]=[CH:44][C:43]=3[C:52]3[CH:53]=[C:54]([C:59]4[CH:64]=[CH:63][C:62]([CH:65]=[O:66])=[CH:61][C:60]=4[CH3:67])[CH:55]=[CH:56][C:57]=3[Cl:58])[C@H:36]2[CH3:68])[CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1
Reactant: Cc1cc(CO)ccc1-c1ccc(Cl)c(-c2ccc(C(F)(F)F)cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1cc(C=O)ccc1-c1ccc(Cl)c(-c2ccc(C(F)(F)F)cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dess-Martin Periodinane (145 mg, 0.34 mmol) was added to a solution of alcohol from Example 49 (200 mg, 0.285 mmol) in methylene chloride (5 ml) at room temperature. The resulting slurry was stirred at room temperature for 1 h. No starting material was seen by TLC (EtOAc/hexane 2:8). The solid was filtered. The filtrate was concentrated. The residue was purified by flash column on silica gel, eluting with EtOAc/hexane (30:70) to give the title compound as a colorless solid. 1H NMR (CDCl3, 500 MHz): δ a mixture of 6:4 atopoisomers 10.03 (s, 1H), 7.90 (s, 2/5H), 7.89 (s, 3/5H), 7.83 (s, 1H), 7.78 (d, J=8.0 Hz, 3/5H), 7.75 (d, J=8.0 Hz, 2/5 H), 7.74 (s, 1.2H), 7.73 (s, 0.8H), 7.72 (s, 2/5H), 7.70 (s, 3/5H), 7.64 (d, J=8.0 Hz, 1H), 7.52 (d, J=8.0 Hz, 3/5H), 7.47 (d, J=8.0 Hz, 2/5H), 7.46 (d, J=8.0 Hz, 3/5H), 7.43 (d, J=8.0 Hz, 2/5H),7.40 (m, 1H), 7.28 (m, 1.5H), 7.23 (d, J=2.0 Hz, 0.5H), 5.64 (d, J=8.0 Hz, 1H), 5.04 (d, J=15.5 Hz, 3/5H), 4.83 (d, J=16 Hz, 2/5H), 4.09 (d, J=16 Hz, 2/5H), 4.01 (d, J=15.0 Hz, 3/5H), 4.00 (m, 2/5H), 3.91 (m, 3/5H), 2.43 (s, 1.8H), 2.41 (s, 1.2H), 0.65 (d, J=6.5 Hz, 1.8H), 0.61 (d, J=7.0 Hz, 1.2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1.FC(F)(F)S(O[CH2:33][CH:34]1[CH2:39][CH2:38][CH:37]([O:40][CH3:41])[CH2:36][CH2:35]1)(=O)=O>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:33][CH:34]3[CH2:39][CH2:38][CH:37]([O:40][CH3:41])[CH2:36][CH2:35]3)[C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(CC(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Reactant: COC1CCC(COS(=O)(=O)C(F)(F)F)CC1
Solvent: C1CCOC1
Product: COc1cn(C(CC2CCC(OC)CC2)C(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
5.40 g (14.4 mmol) of tert-butyl [4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate, 5.97 g (21.6 mmol) of (4-methoxycyclohexyl)methyl trifluoromethanesulphonate (cis/trans isomer mixture) and 15.8 ml (15.8 mmol) of bis(trimethylsilyl)lithium amide (1M in THF) in 114 ml of THF were reacted according to General Method 7B. Yield: 10.8 g (purity 51%) of crude product
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH2:12][CH3:13])[C:10]#[N:11])=[CH:5][CH:4]=1.[CH2:16](N)[CH2:17][NH2:18]>>[F:1][C:2]([F:14])([F:15])[C:3]1[CH:4]=[CH:5][C:6]([CH:9]([C:10]2[NH:18][CH2:17][CH2:16][N:11]=2)[CH2:12][CH3:13])=[CH:7][CH:8]=1
Reactant: CCC(C#N)c1ccc(C(F)(F)F)cc1
Reactant: NCCN
Product: CCC(C1=NCCN1)c1ccc(C(F)(F)F)cc1

Procedure:
rac-2-[1-(4-Trifluoromethyl-phenyl)-propyl]-4,5-dihydro-1H-imidazole was prepared from rac-2-(4-trifluoromethyl-phenyl)-butyronitrile and ethylene diamine in analogy to Example 22: colourless powder; MS (ISP): 257.0 ((M+H)+.).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:32]=[N:31][N:30]([CH:33]([CH3:35])[CH3:34])[C:16]=2[N:17]=[C:18]([C:20]2[CH2:21][CH2:22][N:23]([S:26]([CH3:29])(=[O:28])=[O:27])[CH2:24][CH:25]=2)[CH:19]=1)=[O:13]>CCO.[Pd]>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:32]=[N:31][N:30]([CH:33]([CH3:35])[CH3:34])[C:16]=2[N:17]=[C:18]([CH:20]2[CH2:21][CH2:22][N:23]([S:26]([CH3:29])(=[O:28])=[O:27])[CH2:24][CH2:25]2)[CH:19]=1)=[O:13]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(C3=CCN(S(C)(=O)=O)CC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(C)c(CNC(=O)c2cc(C3CCN(S(C)(=O)=O)CC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 12 %

Procedure:
To a stirred solution of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-6-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (0.08 g, 0.16 mmol) in EtOH (2 mL), 10% Pd/C in catalytic amount was added and stirred it at room temperature under hydrogen pressure (balloon pressure) for 3-4 hr. On completion of reaction, reaction mass was filtered through celite bed, then filtrate was concentrated under reduce pressure, finally the residue was washed with diethyl ether to provide the desired compound (12% yield). LCMS: 501.15 (M+1)+; HPLC: 94.05% (@ 254 nm) (Rt; 6.087); 1H NMR (DMSO-d6, 400 MHz) δ 11.55 (s, 1H), 8.77 (t, 1H, J=4.8 Hz), 8.29 (s, 1H), 7.56 (s, 1H), 5.89 (s, 1H), 5.21-5.17 (m, 1H), 4.37 (d, 2H, J=4.4 Hz), 3.69 (m, 2H), 3.01-2.96 (m, 1H), 2.91 (s, 3H), 2.87-2.84 (m, 2H), 2.20 (s, 3H), 2.12 (s, 3H), 2.08-1.99 (m, 2H), 1.93-1.83 (m, 2H), 1.49 (d, 6H, J=6.8 Hz).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][CH2:14][C:15]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)=[CH:9][C:8]([O:26][CH3:27])=[CH:7][CH:6]=2.ClCCS[CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+].[C:46](#N)[CH3:47]>>[CH:32]1([CH2:46][CH2:47][N:18]2[CH2:19][CH2:20][C:15]([CH2:14][CH2:13][CH2:12][C:11]3[C:10]4[C:5](=[CH:6][CH:7]=[C:8]([O:26][CH3:27])[CH:9]=4)[N:4]=[CH:3][C:2]=3[F:1])([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:16][CH2:17]2)[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]1
Reactant: CC#N
Reactant: CCOC(=O)C1(CCCc2c(F)cnc3ccc(OC)cc23)CCNCC1
Reactant: ClCCSC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: CCOC(=O)C1(CCCc2c(F)cnc3ccc(OC)cc23)CCN(CCC2CCCCC2)CC1
Temperature: 70 °C
Reaction time: 18 h

Procedure:
A mixture of 0.4 g of ethyl 4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]piperidine-4-carboxylate, 0.23 g of 2-chloroethylthiocyclohexane, 0.18 g of potassium iodide and 0.74 g of potassium carbonate in 15 cm3 of acetonitrile was stirred for 18 hours at a temperature in the region of 70° C. After cooling to about 20° C., the reaction mixture was concentrated to dryness under reduced pressure (5 kPa) at a temperature in the region of 40° C. The evaporation residue was purified by chromatography under atmospheric pressure, on a cartridge of silica gel (Bond Elut; particle size 70-200μ; mass 12 g), eluting with a mixture of ethyl acetate/40-60° C. petroleum ether (8/2 by volume). The fractions containing the product were combined and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. 0.32 g of ethyl 1-(2-cyclohexylethyl)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]piperidine-4-carboxylate was obtained.
Reaction SMILES: N[C:2](N)=[O:3].[CH:5]1([NH:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.N>O>[CH:5]1([N:11]2[CH2:12][CH2:13][CH2:14][NH:15][C:2]2=[O:3])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: NCCCNC1CCCCC1
Reactant: NC(N)=O
Agent: N
Solvent: O
Product: O=C1NCCCN1C1CCCCC1
Temperature: 25 °C

Procedure:
The reaction apparatus is a 500 ml flask, equipped with thermometer, reflux condenser and magnetic stirrer. The top of the reflux condenser is connected to a bubbler containing water. Before adding the reagents, the flask is weighed. Then 30 g of urea (0.5 mols) and 156 g of N-cyclohexyl-1,3-propanediamine (1 mol) are put into the flask, which is then slowly heated. Ammonia begins to evolve. Heating is continued until 18 g of ammonia have evolved. The reaction mixture is allowed to cool to room temperature. The solid which precipitates is separated by filtration on a Buchner funnel and dried in vacuo. The weight is 78 g and the melting point is 175° C. The raw reaction product is recrystallized from boiling ethanol. The melting point of the recrystallized product is 198° C. The nitrogen content is 15.25%, whereas the theoretical value is 15.37%. The structure of the product as confirmed by a combination of elemental analysis, 13C NMR and 1H NMR is determined as follows: ##STR3## The structure of this compound has been corroborated by IR and VPO molecular weight measurements. The elemental analysis is as follows:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([O:17][CH3:18])=[CH:11][C:12]([Br:16])=[C:13]([OH:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:21]I>O>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH3:21])[C:12]([Br:16])=[CH:11][C:10]=1[O:17][CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: COc1cc(Br)c(O)cc1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COc1cc(OCc2ccccc2)c(OC)cc1Br
Reaction time: 0.33 h
Yield: 28.7 %

Procedure:
5-Benzyloxy-2-bromo-4-methoxy-phenol 3 (2.76 g, 89.0 mmol) and NaH (0.89 g, 13.0 mmol, 60% dispersion in oil) were added to a flask and flushed with Ar. Dry THF (50 mL) was added and the suspension was stirred in an ice bath for 20 min. CH3I (1.7 mL, 27.0 mmol, filtered through basic alumina) was added and the mixture stirred at room temperature under Ar for 18 h. After cooling the reaction mixture in an ice bath, water was added slowly. The mixture was extracted with ethyl acetate, dried and concentrated to give yellow oil that solidified under vacuum. The oil was purified by silica gel chromatography using silica gel with (10% ethyl acetate/hexanes) to give 2.5 g (88%) of 4 as a white solid. 1H-NMR (400 MHz, CDCl3) dH 3.75 (3H, s, OCH3), 3.84 (3H, s, OCH3), 5.15 (2H, s, CH2Ph), 6.57 (1H, s, ArH), 7.07(1H,s,ArH), 7.32-7.42(5H,m,CH2Ph).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)([CH2:16][C:17]([OH:20])([CH3:19])[CH3:18])[O:12][C:11]2=[O:28])[CH3:9])=[CH:4][CH:3]=1.[CH3:29][C:30]1[CH:35]=[C:34](B(O)O)[CH:33]=[CH:32][N:31]=1>>[F:27][C:24]1[CH:25]=[CH:26][C:21]([C@:13]2([CH2:16][C:17]([OH:20])([CH3:19])[CH3:18])[O:12][C:11](=[O:28])[N:10]([C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([C:34]4[CH:33]=[CH:32][N:31]=[C:30]([CH3:29])[CH:35]=4)=[CH:3][CH:4]=3)[CH3:9])[CH2:15][CH2:14]2)=[CH:22][CH:23]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)O)(c2ccc(F)cc2)OC1=O
Reactant: Cc1cc(B(O)O)ccn1
Product: Cc1cc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccc(F)cc4)OC3=O)cc2)ccn1

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-1,3-oxazinan-2-one and 2-methylpyridine-4-boronic acid following a procedure analogous to that described in Example 75. Step 1. LC-MS Method 2 tR=0.976 min, m/z=463.8; 1H NMR (CDCl3) 1.09 (d, 6H), 1.49 (d, 3H), 2.16 (m, 4H), 2.35 (m, 1H), 2.56 (d, 3H), 2.85 (m, 1H), 5.65 (m, 1H), 6.94-7.05 (m, 4H), 7.17-7.26 (m, 4H), 7.34 (d, 2H), 8.47 (d, 1H).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[CH2:14][CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1.C(Cl)[Cl:21]>[OH-].[K+].CCO>[ClH:21].[CH:11]1(/[CH:12]=[C:14]2/[C:15](=[O:19])[C:16]3[C:11]([CH2:12][CH2:13]/2)=[CH:10][C:9]([O:8][CH2:7][CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:18][CH:17]=3)[CH2:16][CH2:17][CH2:18][CH2:9][CH2:10]1
Reactant: O=C1CCCc2cc(OCCn3ccnc3)ccc21
Reactant: ClCCl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cl
Product: O=C1/C(=C/C2CCCCC2)CCc2cc(OCCn3ccnc3)ccc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 10 %

Procedure:
A solution of 0.2 g (0.8 mmol) of 6-[2-(1H-1-imidazolyl)ethoxy]-1,2,3,4-tetrahydro-1-naphthalenone in 2 mL of 4% KOH in EtOH was treated with 0.1 mL (0.8 mmol) of cyclohexylaldehyde and the solution allowed to stir at room temperature for 3 days. The solution was diluted with CH2Cl2 and the layers separated. The CH2Cl2 was washed with saturated NaCl and dried over MgSO4. The CH2Cl2 was treated with HCl gas and the solvent removed. The residue was taken up in H2O and freeze-dried. There was obtained 35 mg (10% yield) of a hygroscopic solid. The structure was confirmed by mass spectroscopy. MS m/z 351 (m+H+).
Reaction SMILES: C(O)(C)(C)C.C([Li])CCC.C(O[C@@:20]1([C:30]#[C:31]/[C:32](/[CH3:36])=[CH:33]/[CH2:34][OH:35])[C@H:25]([CH3:26])[CH2:24][C@@H:23]([OH:27])[CH2:22][C:21]1([CH3:29])[CH3:28])(=O)C1C=CC=CC=1>CCCCCC.C1(C)C=CC=CC=1>[OH:27][C@H:23]1[CH2:22][C:21]([CH3:28])([CH3:29])[C:20]([C:30]#[C:31][CH:32]([CH3:36])/[CH:33]=[CH:34]/[OH:35])=[C:25]([CH3:26])[CH2:24]1
Reactant: C/C(C#C[C@]1(OC(=O)c2ccccc2)[C@H](C)C[C@@H](O)CC1(C)C)=C\CO
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Solvent: CCCCCC
Product: CC1=C(C#CC(C)/C=C/O)C(C)(C)C[C@H](O)C1
Temperature: -25 °C
Reaction time: 0.5 h
Yield: 79.2 %

Procedure:
In a sulphonation flask equipped with a stirrer, a thermometer, a dropping funnel, a reflux condenser and an apparatus for inert gasification 16 ml of tert.butanol and 20 ml of absolute toluene were placed under argon and cooled to -25° C. This solution was treated dropwise at -30° C. to -20° C. within 10 minutes with 52 ml of a 1.56M solution of butyl lithium in hexane and the mixture was stirred for a further 30 minutes without cooling. There was subsequently added to the thus-prepared solution of lithium tert.-butylate at about 20° C. in one portion a solution of 14.4 g of (1S,4R,6R)-4-hydroxy-1-(5-hydroxy-3-methyl-3E-penten-1-ynyl)-2,2,6-trimethylcyclohexyl benzoate in 120 ml of absolute toluene. The suspension obtained was heated carefully to 65° C. with the aid of an oil bath and stirred at this temperature for 1.5 hours. Thereafter, the mixture was poured on to 150 ml of ice/water. The aqueous phase was separated and extracted twice with 150 ml of diethyl ether each time. The organic phases were washed with 150 ml of saturated sodium chloride solution, combined, dried over sodium sulphate and concentrated on a rotary evaporator at about 40° C. and the residue was then dried at room temperature for 1 hour in a high vaccum. The crude product obtained (12.0 g) was chromatographed on silica gel with diethyl ether/hexane (vol. 1:1). From the product-containing fractions there was obtained a total of 7.5 g (80%) of (4R)-5-(4-hydroxy-2,6,6-trimethyl-1-cyclohexen-1-yl)-3-methyl-2E-penten-4-yn-1-ol as yellowish crystals (purity 98.8%, content of 2Z isomer 1.1%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH:16]([CH3:18])[CH3:17])[CH3:15])[C:11]([Cl:19])=[CH:10][C:9]=1[NH2:20])([CH3:4])([CH3:3])[CH3:2].C([O:26][C:27](=O)[CH2:28][C:29](=[O:49])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([N:36]2[C:40]([CH2:41][O:42][CH:43]3[CH2:48][CH2:47][CH2:46][CH2:45][O:44]3)=[CH:39][N:38]=[N:37]2)[CH:31]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH:16]([CH3:17])[CH3:18])[CH3:15])[C:11]([Cl:19])=[CH:10][C:9]=1[NH:20][C:27](=[O:26])[CH2:28][C:29](=[O:49])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([N:36]2[C:40]([CH2:41][O:42][CH:43]3[CH2:48][CH2:47][CH2:46][CH2:45][O:44]3)=[CH:39][N:38]=[N:37]2)[CH:31]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1
Reactant: CC(C)N(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Product: CC(C)N(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3nncc3COC3CCCCO3)c2)cc1Cl

Procedure:
The title compound was prepared from [2-amino-4-chloro-5-(isopropyl-methyl-amino)-phenyl]-carbamic acid tert-butyl ester (Example J26) (300 mg, 0.96 mmol) and (RS)-3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionic acid tert-butyl ester (Example K5) (383 mg, 0.96 mmol) according to the general procedure M. Obtained as a light yellow oil (530 mg, 86%).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH3:21])([CH3:20])[CH2:5][CH2:6][CH2:7][CH:8]([CH3:19])[CH2:9]/[CH:10]=[CH:11]/[C:12]([CH3:18])=[CH:13][C:14]([O:16]C)=[O:15])[CH3:2].CO.[OH-].[K+]>O>[CH2:1]([O:3][C:4]([CH3:20])([CH3:21])[CH2:5][CH2:6][CH2:7][CH:8]([CH3:19])[CH2:9]/[CH:10]=[CH:11]/[C:12]([CH3:18])=[CH:13][C:14]([OH:16])=[O:15])[CH3:2]
Reactant: CCOC(C)(C)CCCC(C)C/C=C/C(C)=CC(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCOC(C)(C)CCCC(C)C/C=C/C(C)=CC(=O)O

Procedure:
A mixture of 1 g. of trans methyl 11-ethoxy-3,7,11-trimethyldodeca-2,4-dienoate, 60 ml. of methanol, 0.5 g. of potassium hydroxide and 6 ml. of water is heated at reflux for about 8 hours. The mixture is then diluted with water, neutralized and extracted with ether. The organic phase is washed with water, dried over sodium sulfate and evaporated to yield trans 11-ethoxy-3,7,11-trimethyldodeca-2,4-dienoic acid.
Reaction SMILES: Cl[CH2:2]/[CH:3]=[CH:4]/[C:5]([NH:7][C:8]1[CH:9]=[C:10]([CH:38]=[CH:39][CH:40]=1)[O:11][C:12]1[N:13]=[C:14]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]3)=[CH:27][CH:26]=2)[C:15]([C:21]([NH2:23])=[O:22])=[N:16][C:17]=1[CH:18]([CH3:20])[CH3:19])=[O:6].CN(C)C=O.C(N(C(C)C)CC)(C)C.[NH:55]1[CH2:60][CH2:59][O:58][CH2:57][CH2:56]1>O>[CH:18]([C:17]1[N:16]=[C:15]([C:21]([NH2:23])=[O:22])[C:14]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]3)=[CH:27][CH:26]=2)=[N:13][C:12]=1[O:11][C:10]1[CH:38]=[CH:39][CH:40]=[C:8]([NH:7][C:5](=[O:6])/[CH:4]=[CH:3]/[CH2:2][N:55]2[CH2:60][CH2:59][O:58][CH2:57][CH2:56]2)[CH:9]=1)([CH3:20])[CH3:19]
Reactant: CC(C)c1nc(C(N)=O)c(Nc2ccc(N3CCN(C)CC3)cc2)nc1Oc1cccc(NC(=O)/C=C/CCl)c1
Reactant: C1COCCN1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1nc(C(N)=O)c(Nc2ccc(N3CCN(C)CC3)cc2)nc1Oc1cccc(NC(=O)/C=C/CN2CCOCC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 5-(3-{[(2E)-4-chlorobuta-2-enoyl]amino}phenoxy)-6-isopropyl-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide (80 mg) and N,N-dimethylformamide (800 μL) were added diisopropylethylamine (25 μL) and morpholine (11 μL), followed by stirring at room temperature overnight. Water was added thereto, and the precipitated solid was collected by filtration and purified by silica gel column chromatography (eluent; chloroform:methanol:28% aqueous ammonia=1:0:0-100:10:1). Diisopropyl ether was added thereto and the precipitated solid was collected by filtration and then dried under reduced pressure to obtain 6-isopropyl-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-5-(3-{[(2E)-4-(morpholin-4-yl)but-2-enoyl]amino}phenoxy)pyrazine-2-carboxamide (27 mg) as a solid.
Reaction SMILES: Br[C:2]1[C:3]([F:19])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]([OH:30])([C:28]#[CH:29])[CH3:27]>>[F:19][C:3]1[C:2]([C:29]#[C:28][C:26]([OH:30])([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=2)[CH3:27])=[CH:18][C:6]2[C:7]3[N:8]([CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=3)[CH2:9][CH2:10][O:11][C:5]=2[CH:4]=1
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1OCC2
Reactant: C#CC(C)(O)c1ccccn1
Product: CC(O)(C#Cc1cc2c(cc1F)OCCn1cc(C(N)=O)nc1-2)c1ccccn1
Yield: 30 %

Procedure:
Similar to as described in General Procedure G 10-bromo-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with 2-(pyridin-2-yl)but-3-yn-2-ol to give the titled compound (80 mg, 30%).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:18])[CH:11]=[CH:12][C:13]=1[O:14][CH:15]([CH3:17])[CH3:16].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:18][C:27]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=2)=[O:28])[CH:11]=[CH:12][C:13]=1[O:14][CH:15]([CH3:16])[CH3:17]
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: CC(C)Oc1ccc(N)cc1-c1c(Br)cnn1C
Solvent: ClCCl
Product: CC(C)Oc1ccc(NC(=O)Nc2ccc(Cl)cc2)cc1-c1c(Br)cnn1C
Yield: 87.5 %

Procedure:
3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-isopropoxy-phenylamine (0.024 g, 0.08 mmol) was treated with 4-chlorophenyl isocyanate (0.014 g, 0.09 mmol, 1.1 equiv.) in CH2Cl2 (1 mL), in a similar manner as described in Example 1.10 to afford Compound 59 (0.034 g, 0.07 mmol, 91%) as a white solid. LCMS m/z (%)=463 (M+H79Br35Cl, 22), 465 (M+H81Br35Cl, 100), 467 (M+H81Br37Cl, 29). 1H NMR (400 MHz, acetone-d6) δ: 8.24 (s, 1H), 8.17 (s, 1H), 7.65 (dd, J=2.5, 8.9 Hz, 1H), 7.55 (d, J=8.6 Hz, 2H), 7.49 (s, 1H), 7.42 (d, J=2.5 Hz, 1H), 7.28 (d, J=8.6 Hz, 2H), 4.42-4.52 (m, 1H), 3.70 (s, 3H), 1.26 (d, J=6.0 Hz, 3H), 1.11 (d, J=6.0 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[C:10]([CH:11]=[O:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[C:16]([C:22]([F:25])([F:24])[F:23])[CH:15]=1>>[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][N:6]2[C:7]3[C:3](=[C:2]([F:1])[C:10]([CH:11]=[O:12])=[CH:9][CH:8]=3)[CH:4]=[N:5]2)=[C:16]([C:22]([F:23])([F:24])[F:25])[CH:15]=1
Reactant: O=Cc1ccc2[nH]ncc2c1F
Reactant: FC(F)(F)c1cc(Cl)ccc1CBr
Product: O=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1F

Procedure:
[4-Chloro-2-(trifluoromethyl)benzyl]-4-fluoro-1H-indazol-5-carbaldehyde was prepared from 4-fluoro-1H-indazole-5-carbaldehyde and 4-chloro-2-(trifluoromethyl)benzyl bromide following General Procedure A.
Reaction SMILES: [CH2:1]1COCC1.Cl.[F:7][C:8]1[CH:9]=[C:10]([N+:27]([O-:29])=[O:28])[C:11]([C:18](=[O:26])[CH2:19][C:20]2[N:24]=[CH:23][N:22](C)[N:21]=2)=[C:12]([CH:17]=1)[C:13](OC)=[O:14]>CCCCCCC>[F:7][C:8]1[CH:17]=[C:12]2[C:11](/[C:18](=[CH:19]/[C:20]3[N:21]([CH3:1])[N:22]=[CH:23][N:24]=3)/[O:26][C:13]2=[O:14])=[C:10]([N+:27]([O-:29])=[O:28])[CH:9]=1
Reactant: C1CCOC1
Reactant: COC(=O)c1cc(F)cc([N+](=O)[O-])c1C(=O)Cc1ncn(C)n1
Agent: Cl
Solvent: CCCCCCC
Product: Cn1ncnc1/C=C1\OC(=O)c2cc(F)cc([N+](=O)[O-])c21

Procedure:
An alternative workup procedure to that illustrated in Example 2A follows. Instead of evaporating the reaction mixture to dryness, it was condensed to 2 volumes, followed by solvent exchange with 12 volumes of THF, and then 12 volumes of heptane. The slurry mixture was concentrated to 2 volumes and filtered to give the product. As such, 1.8 kilograms of (Z)-6-fluoro-3-((1-methyl-1H-1,2,4-triazol-3-yl)methylene)-4-nitroisobenzofuran-1(3H)-one (3) gave 2.15 kilograms (yield 96.4%) of the product methyl 5-fluoro-2-(2-(1-methyl-1H-1,2,4-triazole-3-yl)acetyl)-3-nitrobenzoate hydrochloride (4).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[O-]CC.[Na+].Br[CH2:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[Cl:25])=[O:17]>C(O)C.C(O)C.C1(C)C=CC=CC=1>[C:3]([CH:2]([CH2:15][C:16](=[O:17])[C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[Cl:25])[C:1]([O:7][CH2:8][CH3:9])=[O:6])(=[O:4])[CH3:5]
Reactant: CCOC(=O)CC(C)=O
Reactant: O=C(CBr)c1ccc(Cl)cc1Cl
Agent: CC[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)C(CC(=O)c1ccc(Cl)cc1Cl)C(C)=O
Reaction time: 0.25 h

Procedure:
To a solution of 3.26 ml of ethyl acetoacetate in ethanol (20 ml) is added dropwise 0.5 ml of a sodium ethoxide solution (21% in EtOH) at 0° C. The mixture is stirred for 15 minutes and 5.82 g de 2-bromo-1-(2,4-dichlorophenyl)ethanone predissolved in 30 ml of an ethanol/toluene mixture (2/1; v/v) is then added. The mixture is stirred for 4 hours at RT and then concentrated to dryness. The residue is purified by chromatography on silica gel to give 3.8 g of liquid corresponding to the expected product.