Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:43])[O:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]([C:20](=[O:42])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]2[CH:32]=[CH:31][C:30]([N:33]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH3:34])=[CH:29][CH:28]=2)[CH3:19])[CH2:12][CH2:11]1.[H-].[Na+].Cl[C:53]([O:55][CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)=[O:54].O>O1CCCC1.C(OCC)(=O)C>[C:1]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([O:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]([CH3:19])[C:20](=[O:42])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]([C:27]2[CH:28]=[CH:29][C:30]([N:33]([C:35]([O:37][C:38]([CH3:41])([CH3:39])[CH3:40])=[O:36])[CH3:34])=[CH:31][CH:32]=2)[C:53](=[O:54])[O:55][CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[CH2:12][CH2:11]1)=[O:43]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCCNc1ccc(N(C)C(=O)OC(C)(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCCN(C(=O)OCc1ccccc1)c1ccc(N(C)C(=O)OC(C)(C)C)cc1
Reaction time: 0.25 h
Yield: 92.7 %

Procedure:
The compound (593 mg, 0.883 mmol) obtained in Example 97a was dissolved in tetrahydrofuran (9 mL), 55% sodium hydride (42 mg, 0.971 mmol) was added under ice cooling, and the mixture was stirred under ice cooling under a nitrogen atmosphere for 15 minutes. Subsequently, benzyl chloroformate (0.19 mL, 1.32 mmol) was added, and the mixture was stirred at room temperature for 18 hours. After the reaction was completed, water was added, and ethyl acetate was further added to separate the layers. The resulting organic layer was separated, washed with saturated sodium chloride solution, and then dried with anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (hexane:ethyl acetate, 1:5→1:15, v/v) to give the title compound (660 mg; yield, 93%) as a colorless oily substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:12])[O-])=[CH:5][C:4]=1[C:13]([F:16])([F:15])[F:14].[CH3:17][O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][C:28]=1[O:29][CH2:30][CH2:31][O:32][CH3:33])[N:25]=[CH:24][N:23]=[C:22]2[O:34][C:35]1[CH:36]=[C:37]([CH:39]=[CH:40][CH:41]=1)[NH2:38].C(N(C(C)C)CC)(C)C>CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([NH:38][C:37]2[CH:39]=[CH:40][CH:41]=[C:35]([O:34][C:22]3[C:21]4[C:26](=[CH:27][C:28]([O:29][CH2:30][CH2:31][O:32][CH3:33])=[C:19]([O:18][CH3:17])[CH:20]=4)[N:25]=[CH:24][N:23]=3)[CH:36]=2)=[O:12])=[CH:5][C:4]=1[C:13]([F:16])([F:15])[F:14]
Reactant: COCCOc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: COc1ccc(NC(=O)[O-])cc1C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: COCCOc1cc2ncnc(Oc3cccc(NC(=O)Nc4ccc(OC)c(C(F)(F)F)c4)c3)c2cc1OC
Yield: 10 %

Procedure:
According to the procedure for Example 138B, 4-methoxy-3-(trifluoromethyl)phenylcarbamate described in Example 138A (104 mg, 0.34 mmol) was reacted with 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)aniline described in Example 117B (100 mg, 0.28 mmol). To this solution was added diisopropylethyl amine (74 μL, 0.42 mmol) and DMAP (20.0 mg, 0.16 mmol). The reaction was concentrated to dryness and partitioned between water and dichloromethane, and extracted twice. The combined extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude oil was purified by silica gel chromatography (methanol/dichloromethane 0-5%) to give 1-(4-methoxy-3-(trifluoromethyl)phenyl)-3-(3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)phenyl)urea as a white solid (18.6 mg, 10% yield). 1H (DMSO-d6) 8.90 (s, 1H), 8.80 (s, 1H), 8.60 (s, 1H), 7.85 (s, 1H), 7.60 (m, 3H), 7.40 (m, 2H), 7.25 (m, 2H), 6.90 (d, 1H), 4.35 (m, 2H), 3.99 (s, 3H), 3.80 (s, 3H), 3.75 (m, 2H), 3.30 (s, 3H). LCMS (ESI) m/z 559 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[C:14]([CH2:16]O)[CH:13]=[N:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C1(P([N:32]=[N+:33]=[N-:34])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>C1COCC1>[N:32]([CH2:16][C:14]1[CH:13]=[N:12][N:11]([C:8]2[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=2)[CH:15]=1)=[N+:33]=[N-:34]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CS(=O)(=O)c1ccc(-n2cc(CO)cn2)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(-n2cc(CN=[N+]=[N-])cn2)cc1
Reaction time: 8 h
Yield: 96.2 %

Procedure:
To a solution of [1-(4-methanesulfonyl-phenyl)-1H-pyrazol-4-yl]-methanol (1.80 g, 7.12 mmol, 1.00 equiv) and diphenylphosphoryl azide (2.35 g, 8.54 mmol, 1.2 equiv) in THF (15 mL) at rt was added 1,8-diazabicyclo[5.4.0]undec-7-ene (1.3 g, 8.54 mmol, 1.2 equiv). The resulting solution was stirred overnight, concentrated and chromatographically purified (15% ethyl acetate in hexanes) to give 4-azidomethyl-1-(4-methanesulfonyl-phenyl)-1H-pyrazole (1.90 g, 97%). LCMS: (MH)+=278.0 (1.45 min).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]2[NH:10][CH:11]=[C:12]([I:13])[C:5]=12.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.C([O-])(O)=O.[Na+]>C(OCC)(=O)C.C1COCC1>[Cl:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]2[N:10]([S:20]([C:17]3[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=3)(=[O:22])=[O:21])[CH:11]=[C:12]([I:13])[C:5]=12
Reactant: Clc1ccnc2[nH]cc(I)c12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3c(Cl)ccnc32)cc1
Reaction time: 0.25 h
Yield: 59.7 %

Procedure:
Under protective gas atmosphere (argon), 63.5 g (1.59 mol) of sodium hydride were suspended in 1000 ml of abs. THF. To this were added dropwise with cooling at a temperature of 0-5° C. a solution of 402 g (1.44 mol) of 4-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridine in 3000 ml of abs. THF, and the reaction mixture was left to stir for a further 15 minutes after completion of addition. Subsequently, 358 g (1.88 mol) of p-toluenesulphonyl chloride were added in portions to the reaction mixture in such a way that the temperature was kept between 5-10° C. After the addition had ended, the mixture was allowed to come to 20° C. and stirred at this temperature for a further hour. On completion of conversion (TLC monitoring of conversion), the reaction mixture was admixed with 20 l of saturated NaHCO3 solution and 10 l of ethyl acetate, and extracted, and the organic phase was removed. The aqueous phase was extracted twice more with 10 l each time of ethyl acetate, and the organic phases were combined, dried and freed of volatile constituents in a water-jet vacuum. To purify the crystalline crude product, it was taken up in dichloromethane and chromatographed using silica gel (CH2Cl2: 40/60 petroleum ether=3:7). After the solvents had been removed, the crystal slurry was extractively stirred in diethyl ether, and the solids were filtered off with suction and dried at 20° C. under high vacuum. A total of 372 g (0.86 mol, 60%) of 4-chloro-1-(toluene-4-sulphonyl)-3-iodo-1H-pyrrolo[2,3-b]pyridine were isolated as a colourless solid.
Reaction SMILES: [N+:1]([C:4]1[C:26](F)=[C:25]([F:28])[C:7]([O:8][C:9]2[C:14]([F:15])=[C:13]([F:16])[C:12]([N+:17]([O-:19])=[O:18])=[C:11]([O:20][CH2:21][CH:22]=[CH2:23])[C:10]=2[F:24])=[C:6]([F:29])[C:5]=1[F:30])([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[K+].[OH2:42]>CS(C)=O>[OH:42][C:26]1[C:25]([F:28])=[C:7]([C:6]([F:29])=[C:5]([F:30])[C:4]=1[N+:1]([O-:3])=[O:2])[O:8][C:9]1[C:14]([F:15])=[C:13]([F:16])[C:12]([N+:17]([O-:19])=[O:18])=[C:11]([O:20][CH2:21][CH:22]=[CH2:23])[C:10]=1[F:24]
Reactant: O
Reactant: C=CCOc1c(F)c(Oc2c(F)c(F)c([N+](=O)[O-])c(F)c2F)c(F)c(F)c1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C=CCOc1c(F)c(Oc2c(F)c(O)c([N+](=O)[O-])c(F)c2F)c(F)c(F)c1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 24 h

Procedure:
44.2 g of 1-(4-nitro-2,3,5,6-tetrafluorophenoxy)-3-(prop-2-enyloxy)-4-nitro-2,5,6-trifluorobenzene prepared as described in Example 9 (0.1 mol) are dissolved in a mixture of 200 ml of dimethyl sulfoxide and 30 ml of water in a three-neck flask fitted with reflux condenser and stirrer. 15 g of potassium carbonate (0.11 mol) and 10 g of potassium hydrogen carbonate (0.1 mol) are added in portions to the solution, and the mixture is then stirred at 80° C. for 24 hours. The reaction solution is then filtered via a fluted filter, and the crude product is extracted by shaking with 200 ml of ethyl acetate and 400 ml of water. The organic phase is washed three times with water, dried over sodium sulfate and evaporated to half in a rotary evaporator. The precipitated reaction product is then recrystallized from a mixture of methylene chloride and petrol ether (volume ratio 1:1) and then dried for 48 hours under nitrogen at 40° C./10 mbar in a vacuum drying cabinet.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C@H:12]([OH:14])[CH3:13])[N:6]=[C:5]2[C:15]#[N:16].N1C=CN=C1.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C@H:12]([O:14][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH3:13])[N:6]=[C:5]2[C:15]#[N:16]
Reactant: C[C@@H](O)Cn1nc(C#N)c2cc(N)ccc21
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: C[C@H](Cn1nc(C#N)c2cc(N)ccc21)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.8 %

Procedure:
(R)-5-amino-1-(2-hydroxypropyl)-1H-indazole-3-carbonitrile (180 mg, 0.832 mmol) was taken up in DCM (6 mL) and imidazole (227 mg, 3.33 mmol) and DMAP (10.17 mg, 0.083 mmol) were added, followed by TBS-Cl (439 mg, 2.91 mmol). The reaction was stirred at rt overnight. The reaction mixture was quenched with sat'd NH4Cl solution and diluted with DCM. The organic layer was collected and washed with brine, dried over Na2SO4, filtered, and concentrated. The crude material was purified by flab column chromatography eluting with 0-40% EtOAc/Hex. (R)-5-amino-1-(2-((tert-butyldimethylsilyl)oxy)propyl)-1H-indazole-3-carbonitrile (230.5 mg) was obtained as an orange solid.
Reaction SMILES: [F:1][C:2]([C:5]1[CH:9]=[C:8]([NH2:10])[O:7][N:6]=1)([CH3:4])[CH3:3].C(C1C=C(N[C:20](=[O:28])[O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)ON=1)(C)C>>[F:1][C:2]([C:5]1[CH:9]=[C:8]([NH:10][C:20](=[O:28])[O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:7][N:6]=1)([CH3:4])[CH3:3]
Reactant: CC(C)(F)c1cc(N)on1
Reactant: CC(C)c1cc(NC(=O)Oc2ccccc2)on1
Product: CC(C)(F)c1cc(NC(=O)Oc2ccccc2)on1
Yield: 68 %

Procedure:
Prepared from 3-(2-fluoropropan-2-yl)isoxazol-5-amine (4.83 g, 33.54 mmol) according to the method described for phenyl 3-isopropylisoxazol-5-ylcarbamate in Example 122A Step 3, to afford phenyl 3-(2-fluoropropan-2-yl)isoxazol-5-ylcarbamate as a colorless solid (6.04 g, 68%). 1H NMR (300 MHz, CDCl3) δ 7.80 (brs, 1H), 7.39-7.45 (m, 2H), 7.18-7.32 (m, 3H), 6.27 (s, 1H), 1.74 (d, J=21 Hz, 6H); LC-MS (ESI) m/z 265 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[C:18]([NH:22][S:23]([C:26]3[C:31](F)=CC=C[C:27]=3F)(=[O:25])=[O:24])[CH:19]=[CH:20][CH:21]=2)[CH:5]=[CH:4][N:3]=1.ClC1N=C(C2SC(C(C)C)=NC=2C2C=C(C=CC=2)N)C=CN=1.[CH3:56][N:57]1C=C(S(Cl)(=O)=O)C=[N:58]1>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[C:18]([NH:22][S:23]([C:26]3[CH:31]=[N:58][N:57]([CH3:56])[CH:27]=3)(=[O:24])=[O:25])[CH:19]=[CH:20][CH:21]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Reactant: Cn1cc(S(=O)(=O)Cl)cn1
Agent: CC(C)c1nc(-c2cccc(N)c2)c(-c2ccnc(Cl)n2)s1
Product: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3cnn(C)c3)c2)c(-c2ccnc(Cl)n2)s1
Yield: 58.6 %

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14, using 3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]aniline (600 mg, 1.8 mmol) and 1-methyl-1H-pyrazole-4-sulfonyl chloride (0.49 g, 2.7 mmol) the title compound was obtained (500 mg, 58.6% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.31 (d, J=5.3 Hz, 1H), 7.72 (d, J=0.9 Hz, 1H), 7.65 (d, J=0.9 Hz, 1H), 7.32-7.37 (m, 1H), 7.21-7.30 (m, 2H), 6.94 (S, 1H), 6.92 (d, J=5.3 Hz, 1H), 3.86 (S, 3H), 3.31-3.41 (m, 1H), 1.44 (d, J=6.8, 6H). MS (ES+): 475 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:16][C:17](OC(C)=O)=[O:18]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:15])[NH:7][CH:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:17](=[O:18])[CH3:16])[CH2:12][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)NC1CCC(N)CC1
Solvent: ClCCl
Product: CC(=O)NC1CCC(NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a cooled suspension of (4-amino-cyclohexyl)-carbamic acid tert-butyl ester (15 g) in DCM (300 mL) was added Ac2O (10.8 mL) followed by TEA (2.19 mL), and the resulting mixture was stirred at RT for 3 h. The reaction mixture was then partitioned between DCM and water, and isopropyl amine was added to facilitate the separation. The organic layer was washed with dilute aqueous NaHCO3, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was triturated with Et2O, the solid was collected by filtration and dried under reduced pressure to afford 14.3 g of (4-acetylamino-cyclohexyl)-carbamic acid tert-butyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[F:9][C:10]([F:23])([O:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=O)[CH:11]([F:13])[F:12].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[F:9][C:10]([F:23])([O:14][C:15]1[CH:16]=[C:17]([CH2:18][NH:1][C:2]2[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=2)[CH:20]=[CH:21][CH:22]=1)[CH:11]([F:12])[F:13]
Reactant: O=Cc1cccc(OC(F)(F)C(F)F)c1
Reactant: Nc1cccc(O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Oc1cccc(NCc2cccc(OC(F)(F)C(F)F)c2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 83.3 %

Procedure:
EX-20A) To a solution of 3-aminophenol (4.91 g, 45.0 mmol) and 3-(1,1,2,2-tetrafluoroethoxy)benzaldehyde (10.0 g, 45.0 mmol) in 100 mL of 1,2-dichloroethane was added sodium triacetoxyborohydride (14.28 g 67.5 mmol) and glacial acetic acid (2.7 mL, 47.3 mmol). The reaction mixture was stirred at room temperature for 6 h then quenched with water and extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium bicarbonate, dried over MgSO4, and concentrated in vacuo to give 11.82 g (83%) of the desired 3-[[[3-(1,1,2,2-tetrafluoro-ethoxy)phenyl]methyl]amino]phenol product as a dark orange oil. 1H NMR (acetone-d6) δ 7.01-7.38 (m, 5H), 6.26-6.44 (m, 3H), 6.08 (t, 1H), 5.88 (tt, 1H), 4.34 (s, 2H).
Reaction SMILES: C(O)(C(F)(F)F)=O.C([O:12][C:13]([C:15]1[CH:16]=[C:17]([C:21]2[C:22]([N:42]([CH3:47])[S:43]([CH3:46])(=[O:45])=[O:44])=[CH:23][C:24]3[O:28][C:27]([C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=4)=[C:26]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:25]=3[CH:41]=2)[CH:18]=[CH:19][CH:20]=1)=[O:14])(C)(C)C>ClCCCl>[CH2:39]([O:38][C:36]([C:26]1[C:25]2[CH:41]=[C:21]([C:17]3[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=3)[C:13]([OH:14])=[O:12])[C:22]([N:42]([CH3:47])[S:43]([CH3:46])(=[O:45])=[O:44])=[CH:23][C:24]=2[O:28][C:27]=1[C:29]1[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=1)=[O:37])[CH3:40]
Reactant: CCOC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3cccc(C(=O)OC(C)(C)C)c3)cc12
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3cccc(C(=O)O)c3)cc12
Yield: 102.2 %

Procedure:
TFA (2 mL, 26.0 mmol) was added to a stirring solution of ethyl 5-(3-(tert-butoxycarbonyl)phenyl)-2-(4-fluorophenyl)-6-(N-methylmethylsulfonamido)benzofuran-3-carboxylate (100 mg, 0.176 mmol) in DCE (9 mL) at 25° C. It was allowed to stir for several hours then concentrated to give the titled compound (92 mg, quant). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.05-8.12 (3H, m), 7.92-8.03 (3H, m), 7.65-7.75 (1H, m), 7.53-7.64 (1H, m), 7.44 (2H, t, J=8.91 Hz), 4.33 (2H, q, J=7.03 Hz), 3.12 (3H, s), 2.93 (3H, s), 1.26 (3H, t, J=7.15 Hz). LC-MS retention time: 1.17 min; m/z (MH−): 510. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[C:6]([F:10])[C:7]=1[CH2:8][OH:9].[CH2:12](Br)[CH2:13][CH3:14]>>[Cl:1][C:2]1[CH:3]=[C:4]([O:11][CH2:12][CH2:13][CH3:14])[CH:5]=[C:6]([F:10])[C:7]=1[CH2:8][OH:9]
Reactant: CCCBr
Reactant: OCc1c(F)cc(O)cc1Cl
Product: CCCOc1cc(F)c(CO)c(Cl)c1
Yield: 69 %

Procedure:
This compound was prepared from 3-Chloro-5-fluoro-4-hydroxymethyl-phenol and propylbromide according to the procedure described in Example 179 to give the product as a yellowish oil (259 mg, 69%); MS (EI): 218.1 (M)+.
Reaction SMILES: [C:1]([C:3]1[CH:14]=[CH:13][C:6]([CH:7]=[CH:8][C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:4]=1)#[N:2].[ClH:15].[Cl:16][C:17]([Cl:21])([Cl:20])[C:18]#[N:19]>[Br-].[Al+3].[Br-].[Br-].ClCCl>[Cl:16][C:17]([Cl:21])([Cl:20])[C:18]1[N:19]=[C:18]([C:17]([Cl:20])([Cl:16])[Cl:15])[N:19]=[C:1]([C:3]2[CH:14]=[CH:13][C:6]([CH:7]=[CH:8][C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:4]=2)[N:2]=1
Reactant: Cl
Reactant: N#CC(Cl)(Cl)Cl
Reactant: COC(=O)C=Cc1ccc(C#N)cc1
Agent: [Al+3]
Agent: [Br-]
Solvent: ClCCl
Product: COC(=O)C=Cc1ccc(-c2nc(C(Cl)(Cl)Cl)nc(C(Cl)(Cl)Cl)n2)cc1
Temperature: 28 °C

Procedure:
Methyl 4-cyanocinnamate (46 pw) is suspended in the absence of moisture and at 24 to 28° C. in a mixture of trichloroacetonitrile (208.2 pw) and aluminum bromide (7.68 pw). The mixture is stirred, and hydrogen chloride is introduced at constant temperature. Temporarily, an almost clear solution is formed, but soon thereafter the mixture becomes syrup-like. Introduction of hydrogen chloride gas is stopped after 4 hours, stirring is discontinued and the mixture is maintained at 28° C. for 12 hours. The resulting solid material is dissolved in 500 pw of dichloromethane and washed twice with 250 pw of water. The organic phase is dried over calcium chloride, and the solvent is evaporated. The residue is recrystallized from a 1:1 mixture of methanol and 2-methoxyethanol.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[C:12]3[CH:37]=[CH:36][CH:35]=[CH:34][C:13]3=[C:14]([CH2:19][N:20]3[CH2:25][CH2:24][C:23]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)([C:26]#[N:27])[CH2:22][CH2:21]3)[CH:15]=2)[N:10]=[CH:9]1.Cl.ClC1C=C(C=CC=1)C(OO)=[O:44].C(#N)C>C1COCC1.O>[OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[C:12]3[CH:37]=[CH:36][CH:35]=[CH:34][C:13]3=[C:14]([CH2:19][N+:20]3([O-:44])[CH2:25][CH2:24][C:23]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)([C:26]#[N:27])[CH2:22][CH2:21]3)[CH:15]=2)[N:10]=[CH:9]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: N#CC1(c2ccccn2)CCN(Cc2cc3c(=O)n([C@H]4CCCC[C@@H]4O)cnc3c3ccccc23)CC1
Agent: Cl
Solvent: CC#N
Solvent: O
Solvent: C1CCOC1
Product: N#CC1(c2ccccn2)CC[N+]([O-])(Cc2cc3c(=O)n([C@H]4CCCC[C@@H]4O)cnc3c3ccccc23)CC1
Reaction time: 1 h

Procedure:
To a solution 1-({3-[(1S,2S)-2-hydroxycyclohexyl]-4-oxo-3,4-dihydrobenzo[h]quinazolin-6-yl}methyl)-4-pyridin-2-ylpiperidine-4-carbonitrile (Example 2, 9.0 mg, 0.018 mmol) in 1.5 mL of THF and 0.018 mL HCl (1 M in dioxane, 0.18 mL, 0.18 mmol) was added m-chloroperoxybenzoic acid (3.2 mg, 0.18 mmol). After 1 h, acetonitrile (1 mL) was added. After 15 h, additional m-chloroperbenzoic acid (1.6 mg, 0.090 mmol) was added. After 30 min, the reaction was treated with water and extracted 3× with ethyl acetate. The combined organic solution was dried over sodium sulfate, filtered, and concentrated in vacuo. The resultant residue was purified via preparative TLC eluting with 10% methanol in dichloromethane to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 510.2505 for [M+H]+ [Cal'd for C30H32N5O3, [M+H]+=510.2500]: 1H NMR (400 MHz, CDCl3) δ 9.05 (d, J=8.4 Hz, 1H), 8.61 (d, J=4.9 Hz, 1H), 8.54 (d, J=8.5 Hz, 1H), 8.46 (s, 1H), 8.38 (s, 1H), 8.06 (s, 1H), 7.95-7.92 (m, 1H), 7.84 (t, J=7.8 Hz, 1H), 7.75-7.71 (m, 2H), 7.47 (d, J=8.0 Hz, 1H), 4.65 (br s, 1H), 4.05 (br s, 1H), 3.95-3.85 (m, 2H), 3.84-3.82 (m, 2H), 3.68-3.49 (m, 1H), 3.21-3.14 (m, 1H), 2.26-1.71 (m, 6H), 1.68-0.83 (m, 6H).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].C(N(CC)CC)C.Cl.[Br:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH2:19])=[C:16]([F:22])[CH:15]=1>C(Cl)Cl>[Br:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH:19][C:1](=[O:3])[CH3:2])=[C:16]([F:22])[CH:15]=1
Reactant: NCc1ccc(Br)cc1F
Reactant: CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCc1ccc(Br)cc1F
Reaction time: 1.5 h
Yield: 73.4 %

Procedure:
Acetyl chloride (0.7 mL, 9.9 mmol) followed by triethylamine (2.8 mL, 19.9 mmol) were added to a suspension of 4-bromo-2-fluorobenzylamine hydrochloride (2 g, 8.3 mmol) in CH2Cl2 (20 mL). The mixture was stirred for 90 mins and then partitioned between 1 N HCl and EtOAc. The organic layers were brine, dried over Na2SO4 and concentrated. Purification by flash column chromatography (0% to 60% EtOAc in hexanes) gave the product as a clear oil (1.5 g, 74%). MS (ESI): 246.10, 248.10 (M+H)+
Reaction SMILES: [OH:1][CH:2]([CH3:21])[CH2:3][O:4][C:5]1[C:10]2[C:11](=[O:20])[CH:12]=[C:13]([C:15](OCC)=[O:16])[O:14][C:9]=2[CH:8]=[CH:7][CH:6]=1.[NH3:22]>>[OH:1][CH:2]([CH3:21])[CH2:3][O:4][C:5]1[C:10]2[C:11](=[O:20])[CH:12]=[C:13]([C:15]([NH2:22])=[O:16])[O:14][C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: N
Reactant: CCOC(=O)c1cc(=O)c2c(OCC(C)O)cccc2o1
Product: CC(O)COc1cccc2oc(C(N)=O)cc(=O)c12

Procedure:
By the method of Example 1 (c) 32 parts of 5-(2-hydroxypropoxy)-4-oxo-4H-1-benzopyran-2-carboxylic acid, ethyl ester were treated with ethanolic ammonia to give 23.3 parts of 5-(2-hydroxypropoxy)-4-oxo-4H-1-benzopyran-2-carboxamide, which crystallised from a mixture of ethanol and chloroform as a white solid, melting point 229°-231°C.