Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH:5]1[C:13]2[C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[O:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.[C:18](Cl)(=[O:20])[CH3:19]>ClC(Cl)C>[C:18]([C:6]1[CH:7]=[CH:8][C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[C:13]=2[CH:5]=1)(=[O:20])[CH3:19]
Reactant: c1ccc2c(c1)oc1ccccc12
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: CC(=O)c1ccc2oc3ccccc3c2c1
Reaction time: 8 h
Yield: 28.3 %

Procedure:
Aluminum chloride (23.8 g, 178.4 mmol) was added portionwise to a solution of dibenzofuran (30.0 g, 178.4 mmol) and acetyl chloride (14.0 g, 178.4 mmol) in dichloroethane at 0° C. After 8 hours, the reaction was quenched with 6N HCl. The layers were separated and the methylene chloride layer was dried (MgSO4), filtered and concentrated to provide a yellow solid. The solid was recrystallized 3 times from hexane to provide 10.6 g (28%) of the title compound as a white solid. 1H NMR (CDCl3, 300 MHz) δ 2.7 (s, 3H), 7.4 (dt, J=7.5 Hz, 0.5 Hz, 1H), 7.5 (dt, J=7.5 Hz, 0.5 Hz, 1H), 7.65 (d, J=7.5 Hz, 2H), 8.0 (d, J=7.5 Hz, 1H), 8.15 (dd, J=7.5 Hz, 0.5 Hz), 8.6 (d, J=0.5 Hz). MS (DCl/NH3) m/e 211 (M+H)+.
Reaction SMILES: [CH:1](=[C:8]1/[C:9]([O:11][C:12](=[O:14])[CH2:13]/1)=[O:10])/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]1[C@@H:23]2[C@@H:18]([CH2:19][CH2:20][CH2:21][CH2:22]2)[CH2:17][NH:16]1.[OH-].[Na+]>ClCCl>[CH:1](=[C:8](/[CH2:13][C:12]([N:16]1[CH2:17][C@H:18]2[C@H:23]([CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:15]1)=[O:14])\[C:9]([OH:11])=[O:10])\[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CC[C@H]2CNC[C@H]2C1
Reactant: O=C1C/C(=C/c2ccccc2)C(=O)O1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(O)/C(=C\c1ccccc1)CC(=O)N1C[C@H]2CCCC[C@H]2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.1 %

Procedure:
To a suspension of (Z)-benzylidenesuccinic anhydride (139 mg) in dichloromethane (30 ml) was added cis-hexahydroisoindoline (120 mg) and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added 2N sodium hydroxide solution and the mixture was extracted with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with dichloromethane. The organic layer was washed with brine and dried over MgSO4. After the solvent was evaporated under reduced pressure, the residue was crystallized from ethyl acetate to give 190 mg of (Z)-2-benzylidene-3-(cis-hexahydro-2-isoindolinylcarbonyl)propionic acid.
Reaction SMILES: C1COCC1.Br[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[CH:14]=2)=[C:9]([F:21])[CH:8]=1.[C:22](=[O:24])=[O:23]>Cl>[F:21][C:9]1[CH:8]=[C:7]([C:22]([OH:24])=[O:23])[CH:12]=[CH:11][C:10]=1[C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[CH:14]=1
Reactant: Fc1cc(F)cc(-c2ccc(Br)cc2F)c1
Reactant: O=C=O
Agent: Cl
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2cc(F)cc(F)c2)c(F)c1
Temperature: 25 °C

Procedure:
In a reactor under an N2-atmosphere, 100 ml of a 1.3M THF solution of isopropyl magnesium chloride/lithium chloride complex (130 mmol) was added and then stirred at room temperature, 28.7 g (100 mmol) of 4-bromo-2,3′,5′-trifluoro-1,1′-biphenyl was slowly added, and then the mixture was stirred at room temperature for 2 hours. Next, while the mixture was cooled to 5-15° C. by an ice bath, dried CO2 gas was blown in without heat generation. The reaction solution was poured in 200 ml of 2N HCl(aq) and extracted by diethyl ether. After the organic layer was collected, washed by saturated saline and dried by anhydrous magnesium sulfate, it was filtered to remove the insoluble substance and concentrated under a reduced pressure. The residue was purified by a fractionation operation utilizing column chromatography, with ethyl acetate as an eluent solvent and silica gel as a filler. The product was further purified by recrystallization using heptane/ethanol in a volume ratio of 30/70, so that 10.3 g of 2,3′,5′-trifluoro-1,1′-biphenyl-4-carboxylic acid was obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:23])[C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][C:17]3=[O:22])=[CH:12][CH:11]=2)=[CH:4][C:3]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1.C=O.[C:32](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:23])[C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19]([CH3:32])[CH2:18][C:17]3=[O:22])=[CH:12][CH:11]=2)=[CH:4][C:3]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(N2CCNCC2=O)cc1
Agent: C=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CN1CCN(c2ccc(C(=O)Nc3ccc(Cl)c(-c4ccccn4)c3)cc2)C(=O)C1
Reaction time: 16 h

Procedure:
120 mg of N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-oxopiperazin-1-yl)benzamide was dissolved in 2 mL of DMF and then treated with 53 mg of paraformaldehyde, 187 mg of sodium triacetoxyborohydride and 0.2 mL of AcOH. After stirring 16 h, the reaction mixture was evaporated and the crude product was purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(4-methyl-2-oxopiperazin-1-yl)benzamide. MS (Q1) 421.3 (M)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:12][C:11]=1[CH:26]([OH:30])[CH:27]([CH3:29])[CH3:28].C(N(CC)CC)C.Cl>CS(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:12][C:11]=1[C:26](=[O:30])[CH:27]([CH3:28])[CH3:29]
Reactant: COc1ccc(COc2ccc(-c3cc(OC)ccc3F)c(C(O)C(C)C)c2)cc1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc(COc2ccc(-c3cc(OC)ccc3F)c(C(=O)C(C)C)c2)cc1
Reaction time: 24 h
Yield: 84.9 %

Procedure:
Under a nitrogen atmosphere, to a solution of 1-(2′-fluoro-5′-methoxy-4-((4-methoxybenzyl)oxy)-[1,1′-biphenyl]-2-yl)-2-methylpropan-1-ol (256.9 mg) in DMSO (4.2 mL) were added triethylamine (523 μL) and sulfur trioxide pyridine complex (299 mg) at room temperature, and the mixture was stirred for 24 hr. To the reaction mixture was added 0.5N hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (217 mg) as a pale-yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:29])[CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]([F:28])([F:27])[CH:24]([F:26])[F:25])=[CH:18][CH:17]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.Cl>C(OCC)C.[BH4-].[Zn+2].[BH4-]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:29])[CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]([F:28])([F:27])[CH:24]([F:26])[F:25])=[CH:18][CH:17]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(Cc1ccc(OC(F)(F)C(F)F)cc1)C(=O)c1ccc(F)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Zn+2]
Solvent: CCOCC
Product: CCOC(=O)C(Cc1ccc(OC(F)(F)C(F)F)cc1)C(O)c1ccc(F)cc1
Reaction time: 2 h

Procedure:
While stirring zinc chloride (5.15 g, 37.8 mmol) in diethyl ether (80 ml), sodium borohydride (2.86 g, 75.6 mmol) was added as it was at room temperature and the mixture was stirred as it was for 2 hrs. The insoluble material of the mixture was removed by filtration and washed with diethyl ether to give a solution of zinc borohydride in diethyl ether. To the obtained solution was added a solution of ethyl 3-(4-fluorophenyl)-3-oxo-2-[4-(1,1,2,2-tetrafluoroethoxy)benzyl]propionate (7.865 g, 18.89 mmol) in diethyl ether (30 ml) at room temperature and the mixture was stirred as it was for 2 hrs. Dilute hydrochloric acid was added to the reaction solution by small portions to decompose excess zinc borohydride. The mixture was extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane/ethyl acetate=6/1−3/1) to give the objective substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[N:7][C:6]([C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])=[CH:5][CH:4]=1.[H][H]>C(O)C.O.[Pt](=O)=O>[CH3:1][O:2][C:3]1[N:8]=[N:7][C:6]([CH:9]([CH:11]2[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]2)[OH:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)c2cccnc2)nn1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CCO
Solvent: O
Product: COc1ccc(C(O)C2CCCNC2)nn1
Yield: 92.5 %

Procedure:
(6-Methoxypyridazin-3-yl)pyrdin-3-ylmethanone (1.31 g, 6.1 mmol) were dissolved in ethanol (100 ml), platinum(IV) oxide hydrate (80% of Pt, 0.5 g, 2.2 mmol) was added, and the mixture was stirred with supply of hydrogen. Conventional work-up gave 1.26 g (93% yield) of (6-methoxypyridazin-3-yl)piperidin-3-ylmethanol as crude product, which was employed directly in the next step;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[C:5]([CH:10]2[CH2:15][C:14]([CH3:17])([CH3:16])[CH2:13][C:12]([CH3:19])([CH3:18])[CH2:11]2)[CH:4]=1.Cl.Cl[CH2:22][CH2:23][NH:24][CH2:25][CH2:26]Cl.C(=O)([O-])O.[Na+]>ClC1C=CC=CC=1Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[C:5]([CH:10]2[CH2:15][C:14]([CH3:17])([CH3:16])[CH2:13][C:12]([CH3:19])([CH3:18])[CH2:11]2)[CH:4]=1
Reactant: COc1ccc(N)c(C2CC(C)(C)CC(C)(C)C2)c1
Reactant: ClCCNCCCl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Clc1ccccc1Cl
Product: COc1ccc(N2CCNCC2)c(C2CC(C)(C)CC(C)(C)C2)c1
Temperature: 220 °C
Reaction time: 2 h

Procedure:
A mixture of the crude product of 4-methoxy-2-(3,3,5,5-tetramethylcyclohexyl)phenylamine produced in Example (85b), bis(2-chloroethyl)amine hydrochloride (770 mg, 4.33 mmol) and 1,2-dichlorobenzene (10 ml) was stirred for 2 hours at an external temperature of 220° C. During the reaction, the excess hydrogen chloride gas in the reactor was removed several times with nitrogen gas. Bis(2-chloroethyl)amine hydrochloride (180 mg, 1.01 mmol) was then added and the mixture was stirred for 1 hour under the same conditions. The reaction mixture was cooled to room temperature, saturated aqueous solution of sodium hydrogencarbonate was added and extraction was performed with chloroform. The aqueous layer was again extracted with chloroform, and the organic layers were combined, washed with brine and then dried over anhydrous magnesium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 660 mg of the title compound as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:11])=[C:4]([C:7]([OH:10])=[CH:8][CH:9]=1)[CH:5]=[O:6].[Cl:12]Cl>C(O)(=O)C.O>[Cl:1][C:2]1[C:3]([F:11])=[C:4]([C:7]([OH:10])=[C:8]([Cl:12])[CH:9]=1)[CH:5]=[O:6]
Reactant: ClCl
Reactant: O=Cc1c(O)ccc(Cl)c1F
Solvent: CC(=O)O
Solvent: O
Product: O=Cc1c(O)c(Cl)cc(Cl)c1F
Temperature: 60 °C
Yield: 85.3 %

Procedure:
To 20 g (114.6 mmole) of 3-chloro-2-fluoro-6-hydroxybenzaldehyde in 250 mL of glacial acetic acid was added 27.8 g of Cl2 gas over a period of 30 min. The mixture was stirred and heated to 60° C. for 2 hrs and allowed to stir at rt overnight. The reaction mixture was diluted with 1L of water and extracted four times with diethyl ether. Combined extracts were washed with water and sat. brine and concd in vacuo to afford a slurry. Addition of 250 mL of water afforded a solid which was collected by filtration and allowed to air dry for 8 hrs to afford 20.42 g (85%) of a yellow solid: mp 58-62° C.; 1H NMR (CDCl3/400 MHz) 7.65 (d, 1H, J=7.5 Hz), 10.26 (s, 1H), 11.88 (s, 1H); 13C NMR (CDCl3/100 MHz) 111.2 (d, J=12.0 Hz), 118.2 (d, J=4.6 Hz), 127.8, 137.6 (C—H, d, J=2.1 Hz), 156.8 (d, J=3.0 Hz), 158.3 (d, J=260.8 Hz), 191.4 (CHO, d, J=8.8 Hz); 19F NMR (CDCl3/400 MHz) −124.7 (d, 1F, J=7.7 Hz); MS (EI) 208 (M+, 100); 207 (91); HRMS (EI) m/z calcd for (C7H3O2Cl2F) 207.9494, found 207.9470.
Reaction SMILES: [NH2:1][C:2]1[CH:33]=[CH:32][C:5]([C:6]([N:8]([CH3:31])[C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=2[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)=[O:23])=[O:7])=[CH:4][C:3]=1[O:34][CH3:35].N1C=CC=CC=1.[N+:42]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[S:51](Cl)(=[O:53])=[O:52])([O-:44])=[O:43]>ClCCl>[N+:42]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[S:51]([NH:1][C:2]1[CH:33]=[CH:32][C:5]([C:6]([N:8]([CH3:31])[C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=2[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)=[O:23])=[O:7])=[CH:4][C:3]=1[O:34][CH3:35])(=[O:53])=[O:52])([O-:44])=[O:43]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1N
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NS(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 5 h
Yield: 101.8 %

Procedure:
To a solution of 4-amino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (327 mg) and pyridine (80.3 mg) in dichloromethane (6 ml) was added dropwise 2-nitrobenzenesulfonyl chloride (150 mg) at ambient temperature and the mixture was stirred at ambient temperature for 5 hours. The resulting mixture was diluted with dichloromethane (10 ml) and the organic layer was washed successively with saturated sodium bicarbonate aqueous solution and brine. Drying, filtering and removal of solvents afforded a crude product. The crude product was chromatographed on silica gel (eluent; 2-4% methanol in chloroform) to give 4-(2-nitrobenzenesulfonyl)amino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (460 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3](OC2C=CC=CC=2)=[N:4][C:5]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:6][C:7]=1[C:8]#[N:9].[NH:23]1[CH2:28][CH2:27][S:26](=[O:29])[CH2:25][CH2:24]1>O>[Cl:1][C:2]1[C:3]([N:23]2[CH2:28][CH2:27][S:26](=[O:29])[CH2:25][CH2:24]2)=[N:4][C:5]([N:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]2)=[N:6][C:7]=1[C:8]#[N:9]
Reactant: N#Cc1nc(N2CCNCC2)nc(Oc2ccccc2)c1Cl
Reactant: O=S1CCNCC1
Solvent: O
Product: N#Cc1nc(N2CCNCC2)nc(N2CCS(=O)CC2)c1Cl

Procedure:
0.3 gm (0.001 mol) of 5-chloro-6-cyano-4-phenoxy-2-piperazino-pyrimidine [m.p. 126°-128°C, obtained from 6-cyano-2,5-dichloro-4-phenoxy-pyrimidine and piperazine in acetone/dioxane (1:1) while cooling] were heated with 2.3 gm (0.02 mol) of thiomorpholine-1-oxide at about 140°C for 90 minutes. The dark colored molten mass was taken up in a small quantity of water, and the precipitated raw reaction product was purified on a silicagel column [eluant: methanol/concentrated ammonia (8:1)]. After reprecipitation from 0.2 N hydrochloric acid with ammonia, 5-chloro-6-cyano-2-piperazino-4-(1-oxido-thiomorpholino)-pyrimidine, m.p. 206°-208°C, was obtained.
Reaction SMILES: C([Li])CCC.[S:6]1[CH:10]=[CH:9][N:8]=[CH:7]1.Cl[Si:12]([CH3:15])([CH3:14])[CH3:13].C(=O)(O)[O-].[Na+]>C(OCC)C>[CH3:13][Si:12]([CH3:15])([CH3:14])[C:7]1[S:6][CH:10]=[CH:9][N:8]=1
Reactant: c1cscn1
Reactant: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOCC
Product: C[Si](C)(C)c1nccs1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Mix n-butyl lithium (20.4 mL, 51.0 mmol, 2.5 M in hexane) with diethyl ether (50 mL) in a three-necked flask, equipped with a dropping funnel and thermometer. Cool to −78° C. and add dropwise a solution of thiazole (4.25 g, 50.0 mmol) in diethyl ether (50 mL). After the addition is complete, stir the reaction mixture at −78° C. for 30 min, followed by addition of chlorotrimethylsilane (5.4 g, 50.0 mmol). Stir at −78° C. for an hour and then warm to room temperature. Quench the reaction by adding saturated sodium bicarbonate. Extract the aqueous layer with diethyl ether. Wash the combined organic portions with brine and dry over sodium sulfate. Filter and concentrate under reduced pressure to give a residue. Purify by distillation to give 8.33 g (52-56° C./15 mm Hg) of title compound. 1H NMR (400 MHz, CDCl3) 8.13 (d, 1H, J=2.6 Hz), 7.54 (d, 1H, J=2.6 Hz), 0.43 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C@H:12]([NH:19]C(=O)C)[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl>C(O)CC>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C@H:12]([NH2:19])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(=O)N[C@@H]1CC[C@@H](c2ccc(Cl)c(Cl)c2)c2ccccc21
Agent: Cl
Solvent: CCCO
Product: N[C@@H]1CC[C@@H](c2ccc(Cl)c(Cl)c2)c2ccccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 158.4 %

Procedure:
A solution of trans-acetamide 4 (9.0 g, 26.9 mmol), n-propanol (45 mL) and 5M hydrochloric acid (45 mL) was refluxed for approximately 48 h (90-93° C.). During this time, the reaction temperature was maintained at ≧90° C. by periodically collecting the distillate until the reaction temperature was >92° C. Additional n-propanol was added periodically to maintain the solution at its original volume. After the hydrolysis was complete, the solution was slowly cooled to 0° C., resulting in a slurry, which was aged for one hour at 0° C. The reaction mixture was filtered, and the cake was washed with 1:1 methanol/water (20 mL), followed by t-butyl methyl ether (20 mL). The wet-cake was dried under vacuum at 45 to 50° C. to afford 7.0 g of the amine hydrochloride 5 (80% yield).
Reaction SMILES: Br[C:2]1[C:3]([OH:12])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[H-].[Na+].C([Li])(C)(C)C.CN([CH:23]=[O:24])C>C1COCC1.CCCCC>[OH:12][C:3]1[N:4]=[CH:5][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][C:2]=1[CH:23]=[O:24]
Reactant: Oc1ncc(C(F)(F)F)cc1Br
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Li]C(C)(C)C
Agent: [Na+]
Solvent: CCCCC
Solvent: C1CCOC1
Product: O=Cc1cc(C(F)(F)F)cnc1O
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 122.9 %

Procedure:
3-Bromo-5-(trifluoromethyl)pyridin-2-ol (8.20 g, 31.2 mmol) was added in small portions to a suspension of sodium hydride (0.8575 g, 33.94 mmol) in anhydrous THF (76 mL) at room temperature. After complete addition, the reaction mixture was cooled to −78° C. and treated with a 1.7 M solution of tert-butyllithium in pentane (40.0 mL) which was added dropwise via a syringe over a period of 15 min. After stirring for 5 min, anhydrous DMF (8.16 mL, 105 mmol) was added slowly while maintaining the temperature below −50° C. The reaction mixture was then stirred overnight allowing it to warm to room temperature. The resulting light brown mixture was quenched by addition of a saturated NH4Cl solution. The pH of the solution was adjusted to 9-10 by addition of aqueous NaHCO3. The resulting solution was extracted with EtOAc four times. The combined extracts were dried (MgSO4), filtered and concentrated to provide a brown solid crude product (7.33 g, >100% crude yield). MS calculated for C7H4F3NO2 (M+H)+192; found 192.1.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:25])[C@H:6]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].[CH3:26][O:27][CH2:28][CH2:29][O:30][CH2:31]Cl.C(N(C(C)C)CC)(C)C>ClCCl>[CH3:26][O:27][CH2:28][CH2:29][O:30][CH2:31][O:1][CH2:2][CH2:3][NH:4][C:5](=[O:25])[C@H:6]([CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[NH:7][C:8]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9]
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)NCCO)OCc1ccccc1
Reactant: COCCOCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCOCOCCNC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-benzyloxycarbonyl-L-phenylalanine-N-(2-hydroxylethyl)amide (7.0 g, 20.4 mmol) in dry dichloromethane (150 ml) under an argon atmosphere was added 2-methoxyethoxymethyl chloride (5.6 ml, 49.0 mmol) and diisopropylethylamine (10.7 ml, 61.4 mmol). The reaction mixture was stirred overnight at room temperature, after which time starting material was still detectable by TLC. The solvent volume was concentrated to one third, an equal volume of DMF was added and the reaction mixture was stirred for a further 60 hours at room temperature. The solvents were removed under reduced pressure, the residue was dissolved in ethyl acetateand washed successively with 1M hydrochloric acid, sat. aq. sodium hydrogencarbonate and brine. The organic phase was dried over sodium sulphate, filtered and concentrated to afford the desired product as a pale yellow oil which crystallised when left under high vacuum for ca. 1 hour. Yield: 8.0 g (90%). 1H--NMR; δ(CDCI3), 7.33-7.14 (10H, m), 6.84 (1H, br s), 5.89 (1H, br s), 5.01 (2H, m), 4.54 (2H, s), 4.46 (1H, m), 3.56-3.26 (11H, m), 3.02 (2H, m).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]3[CH:13]=[CH:14][C:15]([CH3:32])=[C:16]([NH:18][C:19](=[O:31])[C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]5([C:29]#[N:30])[CH2:28][CH2:27]5)[CH:21]=4)[CH:17]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1.C([O:36][CH2:37][C:38](Cl)=[O:39])(=O)C.C(N(CC)CC)C.[OH-].[Na+].Cl>O1CCCC1>[C:29]([C:26]1([C:22]2[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=2)[C:19]([NH:18][C:16]2[CH:17]=[C:12]([O:11][C:9]3[CH:8]=[CH:7][C:5]4[N:6]=[C:2]([NH:1][C:37](=[O:36])[CH2:38][OH:39])[S:3][C:4]=4[CH:10]=3)[CH:13]=[CH:14][C:15]=2[CH3:32])=[O:31])[CH2:27][CH2:28]1)#[N:30]
Reactant: CC(=O)OCC(=O)Cl
Reactant: Cc1ccc(Oc2ccc3nc(N)sc3c2)cc1NC(=O)c1cccc(C2(C#N)CC2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(Oc2ccc3nc(NC(=O)CO)sc3c2)cc1NC(=O)c1cccc(C2(C#N)CC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.8 %

Procedure:
To a solution of N-{5-[(2-amino-1,3-benzothiazol-6-yl)oxy]-2-methylphenyl}-3-(1-cyanocyclopropyl)benzamide (300 mg, 0.681 mmol) produced in Example A3(iv) in tetrahydrofuran (8.0 mL) were added a solution of 2-chloro-2-oxoethyl acetate (77 μL, 0.715 mmol) in tetrahydrofuran (2.0 mL) and triethylamine (141 μL, 1.02 mmol), and the mixture was stirred at room temperature for 30 min. To the reaction mixture were added 2-chloro-2-oxoethyl acetate (154 μL, 1.43 mmol) and triethylamine (290 μL, 2.10 mmol), and the mixture was further stirred at room temperature for 1.5 hr. To the reaction mixture was added 1N aqueous sodium hydroxide solution (10 mL), and the mixture was stirred at room temperature for 30 min and neutralized with 1N hydrochloric acid. The obtained mixture was extracted with ethyl acetate (100 mL×2). The combined organic layer was washed with saturated brine (100 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/methanol=100/0→90/10), and the obtained solution was concentrated under reduced pressure. The residue was triturated with ethyl acetate/diisopropyl ether to give the title compound (220 mg, 65%) as a colorless solid.