Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:35]=[C:34]([CH3:36])[CH:33]=[C:32]([CH3:37])[C:3]=1[C:4]([C:6]1[CH:18]=[C:17]2[C:9]([N:10]([C:19]3[CH:24]=[CH:23][C:22]([C:25](=[O:27])[CH3:26])=[CH:21][CH:20]=3)[C:11]3[C:16]2=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:8]2[CH:28]=[CH:29][CH:30]=[CH:31][C:7]=12)=[O:5].[C:38](Cl)(=[O:43])[CH2:39][CH:40]([CH3:42])[CH3:41].[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[C:25]([C:22]1[CH:21]=[CH:20][C:19]([N:10]2[C:9]3[C:17](=[CH:18][C:6]([C:4](=[O:5])[C:3]4[C:32]([CH3:37])=[CH:33][C:34]([CH3:36])=[CH:35][C:2]=4[CH3:1])=[C:7]4[CH:31]=[CH:30][CH:29]=[CH:28][C:8]4=3)[C:16]3[C:11]2=[CH:12][CH:13]=[C:14]([C:38](=[O:43])[CH2:39][CH:40]([CH3:42])[CH3:41])[CH:15]=3)=[CH:24][CH:23]=1)(=[O:27])[CH3:26]
Reactant: CC(C)CC(=O)Cl
Reactant: CC(=O)c1ccc(-n2c3ccccc3c3cc(C(=O)c4c(C)cc(C)cc4C)c4ccccc4c32)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1ccc(-n2c3ccc(C(=O)CC(C)C)cc3c3cc(C(=O)c4c(C)cc(C)cc4C)c4ccccc4c32)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To 1-{4-[5-(2,4,6-trimethyl-benzoyl)-benzo[a]carbazol-11-yl]-phenyl}-ethanone (383 mg, 0.795 mmol) in CH2Cl2 (10 mL) are added isovaleroyl chloride (120 mg, 0.995 mmol) and AlCl3 (350 mg, 2.62 mmol) at 0° C. After stirring for 2 hours, the reaction mixture is poured into ice-water, and the crude product is extracted with CH2Cl2. The organic layer is washed with water and brine, dried over MgSO4. After concentration, the crude product is purified by column chromatography on silica gel eluting with CH2Cl2 to obtain an off-white solid (345 mg; 76%). The structure is confirmed by 1H-NMR spectrum (CDCl3). δ [ppm]: 1.02 (d), 2.22 (s), 2.34 (m), 2.43 (s), 2.78 (s), 2.94 (d), 7.00 (s), 7.14 (d), 7.33 (t), 7.48 (d), 7.64-7.68 (m), 7.98 (d), 8.31 (d), 8.43 (s), 8.67 (s), 9.47 (d).
Reaction SMILES: [CH3:1][Si:2]([CH3:21])([CH3:20])[O:3][CH:4]1[CH2:12][CH2:11][CH2:10][C@@:9]2([CH3:13])[CH:5]1[CH2:6][CH2:7][C@@H:8]2[C@H:14]([CH3:19])[CH2:15][CH2:16][CH:17]=[O:18].[C:22]([O:25][CH2:26][C:27]([CH2:29][Si](C)(C)C)=[CH2:28])(=[O:24])[CH3:23].ClCCl>C(N(CC)CC)C>[C:22]([O:25][CH2:26][C:27]([CH2:29][CH:17]([OH:18])[CH2:16][CH2:15][C@H:14]([C@@H:8]1[C@:9]2([CH3:13])[CH:5]([CH:4]([O:3][Si:2]([CH3:1])([CH3:20])[CH3:21])[CH2:12][CH2:11][CH2:10]2)[CH2:6][CH2:7]1)[CH3:19])=[CH2:28])(=[O:24])[CH3:23]
Reactant: C[C@H](CCC=O)[C@H]1CCC2C(O[Si](C)(C)C)CCC[C@@]21C
Reactant: C=C(COC(C)=O)C[Si](C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(COC(C)=O)CC(O)CC[C@@H](C)[C@H]1CCC2C(O[Si](C)(C)C)CCC[C@@]21C
Temperature: -78 °C
Yield: 57 %

Procedure:
A 1.72 g amount of the compound (4-7), (4R)-4-[(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl]-pentanal and 1.10 g of 2-(trimethylsilyl-methyl)-2-propenyl acetate were taken in a 200 ml eggplant-shaped flask, then 30 ml of dichloromethane was added and the solution stirred at −78° C. To this was added 0.86 ml of BF•Et2O, then the solution stirred at −78° C. for 1 hour. Further, 3 ml of triethylamine was added to stop the reaction, then the solvent was distilled off under reduced pressure. The obtained residue was purified by a silica gel column (IR-60, 150 g, hexane/ethyl acetate=50/1 to 9/1) to obtain the desired product (4-8), (7R)-2-acetoxymethyl-7-[(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl]-octen-4-ol in an amount of 1.32 g (yield 57%).
Reaction SMILES: [C:1]([C:3]1[C:8]([Cl:9])=[C:7]([F:10])[N:6]=[C:5]([F:11])[C:4]=1[Cl:12])#N.[H-].C([Al+]CC(C)C)C(C)C.CO.S(=O)(=O)(O)[OH:26]>C1(C)C=CC=CC=1>[Cl:12][C:4]1[C:5]([F:11])=[N:6][C:7]([F:10])=[C:8]([Cl:9])[C:3]=1[CH:1]=[O:26]
Reactant: O=S(=O)(O)O
Reactant: N#Cc1c(Cl)c(F)nc(F)c1Cl
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CO
Product: O=Cc1c(Cl)c(F)nc(F)c1Cl
Temperature: 25 °C

Procedure:
To a mixture, of 10.1 g (0.048 mole) of 4-cyano-3,5-dichloro-2,6-difluoropyridine (from Step A) in 50 ml of toluene that had been cooled to 0° C. was added 6.9 g (0.049 mole) of diisobutylaluminum hydride. After complete addition the reaction mixture was allowed to warm to room temperature and was stirred for approximately seventeen hours. A mixture of methanol and petroleum ether (2:1) was added to the reaction mixture which was then acidified with dilute sulfuric acid. The organic layer was separated from the aqueous layer and was dried over anhydrous sodium sulfate. After being filtered, the solvent was evaporated under reduced pressure, leaving 6.0 g of 3,5-dichloro-2,6-difluoropyridine-4-carboxaldehyde as a residue.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH:4]1[O:6][CH2:5]1.[NH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18]>C(OCC)(=O)C.CO>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH:4]([OH:6])[CH2:5][NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18]
Reactant: NCCCCCCO
Reactant: Clc1ccccc1C1CO1
Solvent: CCOC(C)=O
Solvent: CO
Product: OCCCCCCNCC(O)c1ccccc1Cl
Yield: 41 %

Procedure:
From 2-chlorostyrene oxide and 6-amino-1-hexanol. Working up by means of chromatography (ethyl acetate/methanol 1:1). Yield: 41%.
Reaction SMILES: [NH2:1][CH:2]([C:9]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[O:17][CH3:18])[CH2:3][CH2:4][C:5]([O:7]C)=O.[C:19]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:22]([CH:25]=O)=[CH:21][CH:20]=1>>[C:19]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:20]=[CH:21][C:22]([CH2:25][N:1]2[CH:2]([C:9]3[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=3[O:17][CH3:18])[CH2:3][CH2:4][C:5]2=[O:7])=[CH:23][CH:24]=1
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Reactant: COC(=O)CCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCC(=O)N1Cc1ccc(-c2ccccc2)cc1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of methyl 4-amino-4-(2,6-dimethoxyphenyl)butanoate with commercially available [1,1′-biphenyl]-4-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.91 min.; [M+H]+: 388.12 g/mol.
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH2:25][OH:26])[C:5]1=[O:29])[CH:2]=[CH2:3].[H-].[Na+].Br[CH2:33][CH:34]1[CH2:36][CH2:35]1>CN(C=O)C>[CH2:1]([C@H:4]1[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@H:24]([CH2:27][CH3:28])[CH2:25][O:26][CH2:33][CH:34]2[CH2:36][CH2:35]2)[C:5]1=[O:29])[CH:2]=[CH2:3]
Reactant: BrCC1CC1
Reactant: C=CC[C@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CO)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CC[C@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CC)COCC2CC2)C1=O
Temperature: 0 °C
Reaction time: 0.03 h

Procedure:
To a solution of (3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)piperidin-2-one (98 mg, 0.227 mmol) in DMF (1.10 mL) was added 60% sodium hydride in mineral oil (27.2 mg, 0.680 mmol) at 0° C. After being stirred at 0° C. for 2 min, (bromomethyl)cyclopropane (47.3 μL, 0.680 mmol) was added. The mixture was stirred at 0° C. for 2 h and then warmed to rt. Then the reaction was stirred at rt overnight. The reaction was quenched (sat aq. NH4Cl), extracted (2×EtOAc) and washed (sat. aq. NaCl solution). The combined organic layer was dried (Na2SO4) and concentrated under reduced pressure. Purification by chromatography on silica gel (10% to 20% EtOAc/Hexanes gradient) provided (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((R)-1-(cyclopropylmethoxy)butan-2-yl)piperidin-2-one as the less polar isomer and the title compound as the more polar stereoisomer.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.OS(O)(=O)=O.[N+:14]([O-])([OH:16])=[O:15].N>>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15]
Reactant: Nc1ccc(F)cc1
Reactant: O=[N+]([O-])O
Agent: N
Agent: O=S(=O)(O)O
Product: Nc1ccc(F)c([N+](=O)[O-])c1
Temperature: 5 °C

Procedure:
To a solution of 139 g. of p-fluoroaniline in 834 g. of H2SO4, 100%, a mixture of 81.3 g. of HNO3, 100% in 489 g. H2SO4, 100%, is slowly added at 8°-10°C. One hour after this addition, the mixture is poured on 800 g. of ice and the resulting solution made alkaline with 2300 ml. of conc. aqua ammonia. On cooling to approxiamtely 5°C., the orange crude product is filtered off, sharply sucked off, and stirred with 600 ml. of water and 120 ml. of conc. HCl at room temperature. The insoluble, dark-brown solid is filtered off, the filtrate made alkaline with 82 g. of solid sodium carbonate, and the solid filtered off and dried in vacuo at 60°-70°C or in the air.
Reaction SMILES: O.[C:2]1([CH3:19])[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:18][CH2:17][CH2:16][C@H:12]2[C:13]([OH:15])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.C[O:22][C:23](=[O:29])[C@H:24]([CH:26]([CH3:28])[CH3:27])[NH2:25].[Li+].[OH-]>C1COCC1.O>[C:2]1([CH3:19])[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH2:18][CH2:17][CH2:16][C@H:12]2[C:13]([NH:25][C@H:24]([C:23]([OH:29])=[O:22])[CH:26]([CH3:28])[CH3:27])=[O:15])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H](N)C(C)C
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)O)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)N[C@H](C(=O)O)C(C)C)cc1

Procedure:
N-(Toluene-4-sulfonyl)-L-proline hydrate was coupled to L-valine methyl ester hydrochloride using the procedure described in Method 3. The title compound was prepared via hydrolysis of the methyl ester using LiOH in THF/water.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]2[NH:11][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH3:21])=[N:13][C:9]=2[CH:8]=[CH:7][C:6]=1[CH:22](C(OCC)=O)[C:23]([O:25]CC)=[O:24])=[O:4].[OH-].[Na+]>C1COCC1.CO>[C:23]([CH2:22][C:6]1[CH:7]=[CH:8][C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH3:21])[NH:11][C:10]=2[C:5]=1[C:3]([OH:4])=[O:2])([OH:25])=[O:24]
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc2nc(-c3ccccc3OC)[nH]c2c1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccccc1-c1nc2ccc(CC(=O)O)c(C(=O)O)c2[nH]1
Temperature: 0 °C
Yield: 100.9 %

Procedure:
A solution of diethyl [7-(methoxycarbonyl)-2-(2-methoxyphenyl)-1H-benzimidazol-6-yl]malonate (4.96 g, 11.3 mmol) and aqueous 2 N NaOH solution (50.0 mL, 100 mmol) in THF (112 mL) and MeOH (45 mL) was stirred at room temperature for 17 h. The mixture was concentrated under reduced pressure. The residual aqueous solution was cooled to 0° C. and aqueous 2 N HCl solution (50 mL) was slowly added (pH 4 obtained). The resulting suspension was heated at 70° C. for 15 h. The cooled suspension was filtered to give the title compound (3.72 g, 100% yield) as a white solid.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl[CH2:6][C:7]#[C:8][CH2:9][N:10]1[CH2:33][CH2:32][CH2:31][C@:12]2([O:16][CH2:15][C@H:14]([C:17]3[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=3[O:27][CH:28]([CH3:30])[CH3:29])[CH2:13]2)[C@@H:11]1[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CS(C)=O.O>[N:1]([CH2:6][C:7]#[C:8][CH2:9][N:10]1[CH2:33][CH2:32][CH2:31][C@:12]2([O:16][CH2:15][C@H:14]([C:17]3[CH:22]=[C:21]([C:23]([F:25])([F:24])[F:26])[CH:20]=[CH:19][C:18]=3[O:27][CH:28]([CH3:30])[CH3:29])[CH2:13]2)[C@@H:11]1[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[N+:2]=[N-:3]
Reactant: CC(C)Oc1ccc(C(F)(F)F)cc1[C@H]1CO[C@]2(CCCN(CC#CCCl)[C@H]2c2ccccc2)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)Oc1ccc(C(F)(F)F)cc1[C@H]1CO[C@]2(CCCN(CC#CCN=[N+]=[N-])[C@H]2c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.7 %

Procedure:
Sodium azide (15 mg) was added to a solution of (3S,5R,6S)-7-(4-chlorobut-2-yn-1-yl)-3-[2-isopropoxy-5-(trifluoromethyl)phenyl]-6-phenyl-1-oxa-7-aza-spiro[4,5]decane (Description 75, 100 mg) in dimethylsulfoxide (1 ml). The mixture was stirred at room temperature overnight, diluted with water (20 ml) and extracted with ether (3×5 ml). The combined organic fractions were washed with brine, dried (MgSO4) and the solvent was evaporated under pressure to give the title compound as a colorless oil (98 mg). m/z (ES+) m/z 513 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([N+]([O-])=O)[CH:3]=1.[N+](C1C=CC(N)=CC=1O)([O-])=[O:15]>[Cu]Cl>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[OH:15])([O-:10])=[O:9]
Reactant: Nc1ccc([N+](=O)[O-])c(O)c1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1[N+](=O)[O-]
Agent: Cl[Cu]
Product: O=[N+]([O-])c1ccc(Cl)cc1O

Procedure:
It is known that the fluorine compound mentioned may be prepared over long reaction times (32 hours) in ethers such as dioxane, using phase transfer catalysis at low temperatures (30° C.) (JP 63310851 A2). Working in water produces an isomeric ratio of about 7:1. Nothing is known from this source about the separation of the isomers. Furthermore, it is known that the chlorine compound may also be prepared in solvent/water mixtures in yields of about 90% (DE 29 39 056). In an earlier known process (DE 29 35 629) aqueous alkali metal hydroxide solutions are used in polar aprotic solvents and emulsifiers (20 hours, 60° C., 81%) for this reaction. Finally it is known that in general 2-nitrohalophenols may be prepared by the reaction of the corresponding nitrohalobenzenes at high temperatures (155° C., 2 hours) in anhydrous media. 4,5-dichloro-2-nitrophenol may be obtained in 77% yield in this way (DE 26 14 264). 2-nitro-5-chlorophenol may be obtained by reacting 4-chloronitrobenzene with KOH at 50° C. in the presence of glass bodies (FR 1 581 400). The same oxidation may be performed in 85-87% yield in solvents, for example 1,2-dimethoxyethane, using phase transfer catalysis (18-crown-6) (Izv. Akad. Nauk. SSSR, Ser. Khim., (11) 2635-2636). Yields of about 90% may be obtained in tertiary alcohols when using aqueous potassium hydroxide solution (6 hours, 60° C.) (JP 52142031). Nitration of 3-chlorophenol has long been known (Uhlemann, Chem. Ber. (1878), 1161; De Kiewiet, Stephen, J. Chem. Soc. (1931), 84). This nitration may also be performed in acetic acid at 0° C. (Roberts, Rhys, J. Chem. Soc. (1937), 39, 41) or using sodium nitrate and dilute sulfuric acid (Hodgson, Moore, J. Chem. Soc. 127 (1925), 1600). A variant is the reaction of 3-chloroaniline with dilute nitric acid (Uhlemann, loc. cit.) or gases containing nitrogen oxides (NOx); however, isomers are produced besides the desired product (v. Auwers, Deines, Fortschr. Ch. Phys. 18, 59; Chem. Zentralblatt, 1924 (II) 2268). In addition, reactions of 4-chloro-1,2-dinitrobenzene with aqueous alkali metal hydroxide solution (Laubenheimer, Chem. Ber. 9 (1876), 768) and of 2-nitro-5-aminophenol with copper(I) chloride in the sense of a Sandmeyer reaction (Phillips, J. Chem. Soc. (1930), 1910, 1913) are known, 2-nitro-5-chlorophenol being obtained.
Reaction SMILES: Cl.Cl.C([O:6][C:7](=[O:15])[C@H:8]([CH2:10][CH2:11][CH2:12][CH2:13][NH2:14])[NH2:9])CC.[OH-].[Na+]>CO>[NH2:9][C@H:8]([C:7]([OH:15])=[O:6])[CH2:10][CH2:11][CH2:12][CH2:13][NH2:14]
Reactant: CCCOC(=O)[C@@H](N)CCCCN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: NCCCC[C@H](N)C(=O)O
Temperature: 110 °C

Procedure:
2.62 Grams (10 mmol) of L-lysine n-propyl ester dihydrochloride was dissolved in 2 ml of methanol, and 5 ml of 2 N aqueous sodium hydroxide solution was added thereto to prepare a treating agent solution. An untreated cotton cloth (160 mm×170 mm, 5.0 g) was allowed to uniformly absorb the total amount of the above treating agent solution and then air-dried for an hour and 15 minutes at room temperature. The dried cloth was heat-treated for 20 minutes at 140° C. in a batch type hot air oven (“IPHH-2000”, an inert oven manufactured by Tabaiesbeck Co., Ltd.) and washed with water. It was further washed with 5% aqueous sodium bicarbonate solution and rinsed three times with water and subsequently was washed with 10% aqueous citric acid solution and rinsed three times with water, and finally washed with household washing detergent solution, rinsed with water and air-dried. A part of the cloth was cut and a solution of ninhydrin in butanol was sprayed on it. Thereafter, it was heated for 10 minutes in an oven of 110° C. to cause coloring thereby the presence of the amino acid was confirmed. As a result of determination for the amount of the bonded L-lysine, it was 0.08 mmol based on 1 g of the cloth. The degree of esterfication was 0.013.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:10][CH2:11][CH2:12][C:13]([F:24])([F:23])[C:14]([O:17][CH:18]([O:20][CH2:21][CH3:22])[CH3:19])([CH3:16])[CH3:15])(=O)C>CCOCC>[CH2:21]([O:20][CH:18]([O:17][C:14]([CH3:16])([CH3:15])[C:13]([F:23])([F:24])[CH2:12][CH2:11][OH:10])[CH3:19])[CH3:22]
Reactant: CCOC(C)OC(C)(C)C(F)(F)CCOC(C)=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CCOC(C)OC(C)(C)C(F)(F)CCO
Temperature: 35 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 2.25 g (0.059 mol) of lithium aluminum hydride in 50 mL of ether at 0° C. was added dropwise, 11.30 g (0.040 mol) of 4-(1-ethoxyethoxy)-3, 3-difluoro-4-methyl-1-pentanol 1-acetate in 130 mL of ether. The mixture was heated at reflux (35° C.) for 3 hr and then was recooled to 0° C. The mixture was quenched by adding dropwise 4.5 mL of water followed by 3.6 mL of 10% aqueous sodium hydroxide. The mixture was stirred at 25° C. for 0.5 hr and was filtered. Evaporation of solvent and column chromatography of the residue on 0.06-0.20 mm silica gel afforded 4-(1-ethoxyethoxy)-3,3-difluoro-4-methyl-1-pentanol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:33])=[C:14]([C:28]([O:30]CC)=O)[C:15](=[O:27])[N:16]3[CH2:19][C:20](=[O:26])[N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:34][NH2:35]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:33])=[C:14]([C:28]([NH:35][CH3:34])=[O:30])[C:15](=[O:27])[N:16]3[CH2:19][C:20](=[O:26])[N:21]3[CH2:22][CH2:23][CH2:24][CH2:25]3)=[N:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: CN
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N2CCCC2)c1=O
Product: CNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N2CCCC2)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[2-oxo-2-(1-pyrrolidinyl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and methylamine employing methods similar to those those described in Example 9 and was purified by reverse phase preparative HPLC (C-18 stationary phase;10-100% CH3CN/water/0.1% formic acid mobile phase). The product was obtained as a white solid: 1H NMR (CDCl3) δ 14.3 (1H, br), 9.94 (1H, m), 8.54 (1H, s), 7.14 (3H, m), 7.02 (2H, t, J=8.6 Hz), 4.86 (2H, s), 4.11 (2H, s), 3.51 (2H, t, J=7 Hz), 3.46 (2H, t, J=7 Hz), 2.99 (3H, d, J=5 Hz), 2.05 (2H, m, J=7 Hz), 1.89 (2H, m, J=7 Hz); HRMS calcd for C23H23FN4O4+H+: 439.1782. Found: 439.1794.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][C@H:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][CH2:17][CH2:18]Br)=[CH:12][CH:13]=2)[CH2:8][CH2:7]1)[CH3:2].[CH2:21]([C:23]1[N:24]=[C:25]([C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([O:35][CH3:36])[CH:29]=2)[O:26][CH:27]=1)[CH3:22].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[CH2:21]([C:23]1[N:24]=[C:25]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:18][CH2:17][CH2:16][O:15][C:11]3[CH:10]=[C:9]4[C:14](=[CH:13][CH:12]=3)[C@H:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:20])[CH2:7][CH2:8]4)=[C:30]([O:35][CH3:36])[CH:29]=2)[O:26][CH:27]=1)[CH3:22]
Reactant: CCc1coc(-c2ccc(O)c(OC)c2)n1
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCBr)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCCOc3ccc(-c4nc(CC)co4)cc3OC)ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.3 %

Procedure:
To a solution of [(1S-5-(3-bromopropoxy)-2,3-dihydro-1H-inden-1-yl]acetate (Example 45) (93.4mg, 0.274 mmol) and 4-(4-ethyl-1,3-oxazol-2-yl)-2-methoxyphenol (40.0 mg, 0.182 mmol) (Example 172) in DMF (4 mL) was added Cs2CO3 (118.9 mg, 0.365 mmol) and water (4 drops). The reaction mixture was stirred at rt for 16 h, then filtered, and the filtrate concentrated under reduced pressure. Purification by preparative HPLC (acetonitrile/water (v/v)=1:1 to 9:1 gradient) gave 73.6 mg (84%) of the title compound as an off-white solid. 1H NMR (400 MHz, CD2Cl2) δ 7.57 (d, 2H), 7.41 (s, 1H), 7.05 (d, 1H), 6.98 (d, 1H), 6.80 (s, 1H), 6.72 (d, 1H), 4.25 (t, 2H), 4.17 (m, 4H), 3.93 (s, 3H), 3.51 (m, 1H), 2.85 (m, 2H), 2.71 (dd, 1H), 2.62 (q, 2H), 2.40 (m, 2H), 2.31 (t, 2H), 1.76 (m, 1H), 1.29 (m, 6H).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([F:30])[CH:20]=[C:21]([C:22]4[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:23]=4[CH3:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:31][NH2:32]>>[CH3:29][C:23]1[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:22]=1[C:21]1[C:15]2[O:14][CH:13]([CH2:12][NH:32][CH3:31])[CH2:17][C:16]=2[CH:18]=[C:19]([F:30])[CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(F)cc(-c4cc(C)ccc4C)c3O2)cc1
Reactant: CN
Product: CNCC1Cc2cc(F)cc(-c3cc(C)ccc3C)c2O1

Procedure:
The title compound was prepared (0.76 g, 48%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(2,5-dimethylphenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.21 g, 0.49 mmol) and methylamine (0.152 g, 4.9 mmol). mp 186-188° C.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.[O:7]1[CH:12]=[CH:11][CH2:10][CH2:9][CH2:8]1.C(O)(C(F)(F)F)=O.[H-].[Na+]>>[CH3:1][C:2]1[CH:6]=[CH:5][N:4]([CH:8]2[CH2:9][CH2:10][CH2:11][CH2:12][O:7]2)[N:3]=1
Reactant: C1=COCCC1
Reactant: Cc1cc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccn(C2CCCCO2)n1
Temperature: 85 °C
Reaction time: 6 h

Procedure:
A mixture of 3-methylpyrazole (3.0 g, 35.4 mmol), 3,4-dihydro-2H-pyrane (4.97 mL, 53.2 mmol) and TFA (0.02 mL, 0.260 mmol) was stirred at 85° C. for 6 h under an argon atmosphere. The RM was cooled to RT and NaH 60% in mineral oil (0.061 g, 1.524 mmol) was and the RM was stirred for 10 min. The RM was purified by bulb-to-bulb distillation to give 3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (b.p. 150-170° C., 12 mbar). A solution of n-1.6 M BuLi in n-hexane (3.38 mL, 5.41 mmol) was added dropwise over 10 min to a solution of 3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (1.0 g, 5.41 mmol) in THF (12 mL) at −70° C. under a nitrogen atmosphere and The RM was stirred for 10 min and then treated dropwise with 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.898 g, 5.69 mmol) and stirred at −70° C. for 1 h. The RM was allowed to warm to RT, treated with n-hexane and the product was filtered, dissolved in water (10 mL) and acidified to pH 6 with 10% aqueous citric acid. The water was evaporated off under reduced pressure and the aqueous residue extracted with EtOAc, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the title product as a yellow resin. UPLC-MS (Condition 3) tR=0.56 min, m/z=211.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][NH2:15])[CH2:8][CH2:7]1.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[S:30][C:29]([S:31](Cl)(=[O:33])=[O:32])=[CH:28][CH:27]=1>N1C=CC=CC=1.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[O:5][CH:6]1[CH2:7][CH2:8][N:9]([CH2:12][CH2:13][CH2:14][NH:15][S:31]([C:29]2[S:30][C:26]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=3)=[CH:27][CH:28]=2)(=[O:32])=[O:33])[CH2:10][CH2:11]1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccn2)s1
Reactant: NCCCN1CCC(Oc2ccc(F)c(F)c2)CC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(NCCCN1CCC(Oc2ccc(F)c(F)c2)CC1)c1ccc(-c2ccccn2)s1
Reaction time: 1 h
Yield: 21.9 %

Procedure:
The product of Example 3, Step (d) (0.3 g) was dissolved in pyridine (1 ml) and CH2Cl2 (4 ml). 5-Pyridin-2-yl-thiophene-2-sulfonyl chloride (0.317 g) [dissolved in CH2Cl2 (4 ml)] was then added and the reaction left to stir for 1 hr. The reaction mixture was poured onto flash silica and the silica flushed with 5% MeOH/94% CH2Cl2/1% aq NH3 as eluent. Evaporation of solvent and purification using reverse phase HPLC {with a gradient eluent system [25% MeCN/NH4OAcaq (0.1%) to 95% MeCN//NH4OAcaq (0.1%)]} gave the title compound as a solid (0.120 g).