Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:31])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16](=O)[N:17]([C:21]1[CH:26]=[C:25]([C:27]#[N:28])[CH:24]=[CH:23][C:22]=1[NH2:29])[CH2:18][CH2:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O1CCOCC1>CO>[CH2:1]([O:8][C:9](=[O:31])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[N:17]([CH2:18][CH2:19][CH3:20])[C:21]2[CH:26]=[C:25]([C:27]#[N:28])[CH:24]=[CH:23][C:22]=2[N:29]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCN(C(=O)CCCCCNC(=O)OCc1ccccc1)c1cc(C#N)ccc1N
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CCCn1c(CCCCCNC(=O)OCc2ccccc2)nc2ccc(C#N)cc21
Reaction time: 16 h
Yield: 95.9 %

Procedure:
The compound (317 mg) obtained in Example 48-2 was dissolved in methanol (5.0 ml) and added with a 4 mol/l hydrogen chloride/dioxane solution (2.0 ml) and the whole was stirred for 16 hours. The residue obtained by distilling the solvent off was dissolved in methanol and the solution was neutralized with an anion-exchange resin (Amberlite IRA-410). The resin was filtrated out and the solvent was distilled off, thereby obtaining the subject compound (291 mg) as a colorless oily substance.
Reaction SMILES: C(O)(=O)C(O)=O.[C:7]([C:11]1[CH:15]=[C:14]([NH2:16])[N:13]([CH2:17][CH3:18])[N:12]=1)([CH3:10])([CH3:9])[CH3:8].C(=O)([O-])[O-].[K+].[K+].C(N(CC)C(C)C)(C)C.Cl[C:35]([O:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:36]>ClCCl>[C:7]([C:11]1[CH:15]=[C:14]([NH:16][C:35](=[O:36])[O:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[N:13]([CH2:17][CH3:18])[N:12]=1)([CH3:10])([CH3:8])[CH3:9]
Reactant: CCn1nc(C(C)(C)C)cc1N
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCn1nc(C(C)(C)C)cc1NC(=O)Oc1ccccc1
Yield: 76.8 %

Procedure:
To a stirred mixture of 3-tert-butyl-1-ethyl-1H-pyrazol-5-amine oxalate (350 mg, 1.36 mmol), potassium carbonate (280 mg, 2 mmol) and N,N-diisopropylethylamine (170 mg, 1.3 mmol) in dichloromethane (3 mL) at rt, was added dropwise, phenyl chloroformate (220 mg, 1.4 mmol) and the reaction mixture was stirred for a further 3 h. The reaction mixture was filtrated, the filtrate concentrated under reduced pressure and the residue partitioned between dichloromethane and water. The organic layer was separated and washed with brine, then concentrated under reduced pressure to give a solid which was recrystallized from diethyl ether to afford phenyl 3-tert-butyl-1-ethyl-1H-pyrazol-5-ylcarbamate (300 mg, 77%) as a colorless solid. LC-MS (ESI) m/z 288 (M+H)+.
Reaction SMILES: [OH:1][NH2:2].C(O[C:6](=[O:30])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[N:21]=[CH:22][C:23]2[C:28]([CH:29]=1)=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)C>CN(C=O)C.CO>[OH:1][NH:2][C:6](=[O:30])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[N:21]=[CH:22][C:23]2[C:28]([CH:29]=1)=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: NO
Reactant: CCOC(=O)CCCCCCN(c1ccccn1)c1cc2ccccc2cn1
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(CCCCCCN(c1ccccn1)c1cc2ccccc2cn1)NO
Reaction time: 72 h
Yield: 54 %

Procedure:
HONH2 (50% aqueous, 1 mL) was added to II (40 mg, 0.1 mmol) in DMF (0.5 mL) and MeOH (1 mL) at rt. The reaction mixture was stirred for 72 h, after which the solvents were evaporated under reduced pressure. The resulting residue was dissolved and co-evaporated with toluene (2×2 mL) then was purified by silica gel column chromatography eluting with CH2Cl2/MeOH (100:3 to 100:8) to furnish III as a colourless oil (19 mg, 54%).
Reaction SMILES: [NH2:1][C@@H:2]1[C:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:15])([CH3:14])[C@H:3]1[OH:16].[CH:17]1[CH:22]=[CH:21][C:20]([O:23][C:24](OC2C=CC=CC=2)=[N:25][C:26]#[N:27])=[CH:19][CH:18]=1>C(O)(C)C>[C:26]([N:25]=[C:24]([NH:1][C@@H:2]1[C:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:14])([CH3:15])[C@H:3]1[OH:16])[O:23][C:20]1[CH:21]=[CH:22][CH:17]=[CH:18][CH:19]=1)#[N:27]
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](N)[C@@H]1O
Solvent: CC(C)O
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](NC(=NC#N)Oc2ccccc2)[C@@H]1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.4 %

Procedure:
To a solution of (trans)-4-amino-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (prepared according to Evans et al., J. Med. Chem., 1983, 26, 1582 and J. Med. Chem., 1986, 29, 2194) (5.0 g, 23 mmol) in isopropanol (50 mL), diphenylcyanocarbonimidate (5.5 g, 25 mmol) was added at room temperature and the reaction mixture was allowed to stir at room temperature for 16 hours. Most of the isopropanol was evaporated and the residue was dissolved in ethyl acetate. The resulting solution was washed successively with 10% citric acid, 1N sodium hydroxide solution and brine. It was dried over anhydrous magnesium sulfate, concentrated and the residue was crystallized from chloroform-isopropyl ether to yield the title A compound (4.2 g) as a colorless solid, m.p. 186°-188° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4]2[C:5]3[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]=3[CH:13]=[CH:14][CH:15]=2.[C:16](OC(=O)C)(=[O:18])[CH3:17]>>[C:16]([N:8]1[C:9]2[C:5]3[C:4](=[CH:15][CH:14]=[CH:13][C:6]=3[C:7]1=[O:12])[C:3]([S:2][CH3:1])=[CH:11][CH:10]=2)(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: CSc1ccc2c3c(cccc13)C(=O)N2
Product: CSc1ccc2c3c(cccc13)C(=O)N2C(C)=O

Procedure:
A mixture of 1 g of 6-(methylthio)-benz[cd]-indol-2(1H)-one (Example 2) and 10 ml of acetic anhydride is stirred and heated at reflux for 2 hours, cooled and filtered. The cake is washed with ethanol and ether then dried. The dried cake is suspended in 15 ml of hot ethanol, filtered and the cake crystallized from 150 ml of ethanol to afford the desired product as a solid.
Reaction SMILES: CS(O[CH2:6][C@@H:7]1[CH2:11][S:10][C:9]([C:12]2[NH:13][C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([O:21][CH2:22][CH2:23][O:24][CH3:25])=[CH:16][C:15]=3[N:26]([CH3:36])[S:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)(=[O:29])=[O:28])=[N:8]1)(=O)=O.[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:25][O:24][CH2:23][CH2:22][O:21][C:17]1[CH:18]=[C:19]2[C:14](=[C:15]([N:26]([CH3:36])[S:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)(=[O:29])=[O:28])[CH:16]=1)[NH:13][C:12]([C:9]1[S:10][CH2:11][C@@H:7]([CH2:6][N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)[N:8]=1)=[CH:20]2
Reactant: C1COCCN1
Reactant: COCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C3=N[C@H](COS(C)(=O)=O)CS3)cc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C3=N[C@H](CN4CCOCC4)CS3)cc2c1
Temperature: 50 °C
Reaction time: 6 h
Yield: 2 %

Procedure:
A solution of ((4R)-2-{5-(2-methoxyethoxy)-7-[methyl(pyridin-2-ylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-4-yl)methyl methanesulfonate (0.1 g), morpholine (0.032 mL) and potassium carbonate (0.050 g) in N,N-dimethylformamide (5 mL) was stirred at room temperature for 18 hr, and the mixture was stirred at 50° C. for 6 hr. The same amount of morpholine (0.032 mL) and potassium carbonate (0.050 g) were added, and the mixture was stirred at 80° C. for 18 hr. The reaction mixture was concentrated, and the residue was extracted with ethyl acetate. The ethyl acetate layer was washed with 1N hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography, and eluted with hexane-ethyl acetate-methanol (4:1:0-0:10:1, volume ratio) to give the title compound (0.002 g, yield 2%) as a colorless amorphous solid.
Reaction SMILES: [C:1]([N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]1=[O:14])(=[O:4])[CH2:2][CH3:3].[CH:15](=[O:20])[CH2:16][CH2:17][CH:18]=[CH2:19]>>[CH3:3][C@H:2]([C@@H:15]([OH:20])[CH2:16][CH2:17][CH:18]=[CH2:19])[C:1]([N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]1=[O:14])=[O:4]
Reactant: C=CCCC=O
Reactant: CCC(=O)n1c(=O)oc2ccccc21
Product: C=CCC[C@H](O)[C@@H](C)C(=O)n1c(=O)oc2ccccc21

Procedure:
Was prepared according to the method of paragraph C by reaction of N-propionyl-2-benzoxazolinone with 4-pentenal. 13C-NMR (CDCl3, 100 MHz): δ 176.28, 151.07, 142.20, 137.96, 127.75, 125.50, 124.89, 116.26, 115.19, 109.89, 70.93, 43.76, 33.12, 30.16, 10.21.
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]([CH3:11])[N+:7]([O-:10])=[CH:8][CH:9]=1)([O-])=O.C([Br:15])(=O)C>>[Br:15][C:4]1[CH:5]=[C:6]([CH3:11])[N+:7]([O-:10])=[CH:8][CH:9]=1
Reactant: Cc1cc([N+](=O)[O-])cc[n+]1[O-]
Reactant: CC(=O)Br
Product: Cc1cc(Br)cc[n+]1[O-]
Yield: 31.1 %

Procedure:
4-Nitro-2-picoline N-oxide (1.0 g, 6.5 mmol) was treated with acetyl bromide (3.5 mL, 47 mmol) as described in Example 65b to provide the title compound (0.38 g, 31%) as an orange-brown oil.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)=[O:4].[CH2:13]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:14].C(N(C(C)C)CC)(C)C>C(#N)C>[CH2:13]([N:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)=[O:4])[CH3:14]
Reactant: O=C(CCl)Nc1ccc(O)cc1
Reactant: CCNc1ccccc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC(=O)Nc1ccc(O)cc1)c1ccccc1
Temperature: 60 °C
Reaction time: 12 h
Yield: 40.7 %

Procedure:
To a solution of compound 17a (250 mg, 1.35 mmol) and N-ethylaniline (0.326 mg, 2.69 mmol) in acetonitrile (6.0 mL) was added diisopropylethylamine (0.55 mL, 4.04 mmol) dropwise. After the addition was complete, the reaction was stirred at 60° C. for 12 hours. The reaction mixture was concentrated and purified by column chromatography to isolate the compound 17 as a colorless oil (150 mg, 0.55 mmol 41% yield). MS (ESI, positive) m/z calcd. for C16H19N2O2 [M+H]+: 271.14, found: 270.95. 1H NMR (CDCl3, 400 MHz) δ 8.34 (s, 1H), 7.27-7.31 (m, 4H), 6.88 (t, J=7.2 Hz, 1H), 6.80 (t, J=8.4 Hz, 4H), 3.96 (s, 2H), 3.53 (q, J1=J2=7.2, 2H), 2.20 (s, 1H), 1.24 (t, J=6.8 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([N+:18]([O-])=O)=[C:16]([CH3:17])[C:11]=2[N:10]=[C:9]1[CH3:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OCC)(=O)C.C([O-])=O.[NH4+]>CO.[Pd]>[NH2:18][C:15]1[CH:14]=[CH:13][C:12]2[N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:9]([CH3:21])=[N:10][C:11]=2[C:16]=1[CH3:17]
Reactant: Cc1c([N+](=O)[O-])ccc2c1nc(C)n2C(=O)OC(C)(C)C
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1c(N)ccc2c1nc(C)n2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1-t-butoxycarbonyl-2,4-dimethyl-5-nitrobenzimidazole (1.26 g, 4.32 mmol) in methanol (15 mL)/ethyl acetate (100 mL) are added 10% palladium-on-carbon (0.1 g) and ammonium formate (1.09 g, 17.3 mmol). The mixture is stirred at room temperature for 3 hours, then filtered on Celite with a methanol wash of the solids. The filtrate is rotary evaporated and the residue is purified by flash chromatography on silica gel, eluting with 20% ethyl acetate in hexane to afford 5-amino-1-t-butoxycarbonyl-2,4-dimethylbenzimidazole as a white solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([CH2:13][C:14]([O:16]C)=[O:15])=[CH:8][CH:7]=2.[F:18][C:19]([F:38])([F:37])[C:20]1[CH:36]=[CH:35][C:23]([O:24][C:25]2[CH:30]=[CH:29][C:28](O)=[C:27]([CH2:32][CH2:33][CH3:34])[CH:26]=2)=[CH:22][CH:21]=1>>[F:18][C:19]([F:37])([F:38])[C:20]1[CH:36]=[CH:35][C:23]([O:24][C:25]2[CH:30]=[CH:29][C:28]([O:1][CH2:2][CH2:3][C:4]3[NH:5][C:6]4[C:11]([CH:12]=3)=[CH:10][C:9]([CH2:13][C:14]([OH:16])=[O:15])=[CH:8][CH:7]=4)=[C:27]([CH2:32][CH2:33][CH3:34])[CH:26]=2)=[CH:22][CH:21]=1
Reactant: CCCc1cc(Oc2ccc(C(F)(F)F)cc2)ccc1O
Reactant: COC(=O)Cc1ccc2[nH]c(CCO)cc2c1
Product: CCCc1cc(Oc2ccc(C(F)(F)F)cc2)ccc1OCCc1cc2cc(CC(=O)O)ccc2[nH]1

Procedure:
Using the procedures in Example 15, steps F and G, the title compound was prepared from methyl 2-(2-hydroxyethyl)indole-5-acetate and 4-(4-trifluoromethylphenoxy)-2-propylphenol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:20])[C:10]([C:15]1C=CN[N:16]=1)=[CH:11][N:12]([CH3:14])[CH3:13].[N:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2NC=1CC(C1C=CC(Cl)=CC=1Cl)=O>>[N:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[NH:16][C:15]=1[C:10](=[CH:11][N:12]([CH3:13])[CH3:14])[C:9]([C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])=[O:20]
Reactant: O=C(Cc1nc2ccccc2[nH]1)c1ccc(Cl)cc1Cl
Reactant: CN(C)C=C(C(=O)c1ccc(Cl)cc1Cl)c1cc[nH]n1
Product: CN(C)C=C(C(=O)c1ccc(Cl)cc1Cl)c1nc2ccccc2[nH]1

Procedure:
Made using the same procedure as for 1-(2,4-dichlorophenyl)-3-(dimethylamino)-2-pyrazolylprop-2-en-1-one except that 2-benzimidazolyl-1-(2,4-dichlorophenyl)ethan-1-one (V, 1.0 g, 3.3 mmol) was used. The crude residue was used without purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C@@H:16]([F:44])[CH2:17][O:18][CH2:19][C:20]([O:23][C:24]([F:43])([F:42])[C:25]([F:41])([F:40])[O:26][C:27]([F:39])([F:38])[C:28]([F:37])([F:36])[C:29]([F:35])([F:34])[C:30]([F:33])([F:32])[F:31])([F:22])[F:21])=[C:10]([F:45])[C:9]=2[F:46])=[N:6][CH:7]=1.[CH2:47](Br)[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[CH2:47]([O:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C@@H:16]([F:44])[CH2:17][O:18][CH2:19][C:20]([O:23][C:24]([F:42])([F:43])[C:25]([F:40])([F:41])[O:26][C:27]([F:38])([F:39])[C:28]([F:36])([F:37])[C:29]([F:34])([F:35])[C:30]([F:31])([F:32])[F:33])([F:21])[F:22])=[C:10]([F:45])[C:9]=2[F:46])=[N:4][CH:3]=1)[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54]
Reactant: Oc1cnc(-c2ccc(OC[C@@H](F)COCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c(F)c2F)nc1
Reactant: CCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCCCCCCCOc1cnc(-c2ccc(OC[C@@H](F)COCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c(F)c2F)nc1

Procedure:
The title compound was prepared essentially as in Example 18 by combining 5-hydroxy-2-[4-(3-(2-(2-(nonafluorobutoxy)tetrafluoroethoxy)-2,2-difluoroethoxy)-(S)-2-fluoropropoxy)-2,3-difluorophenyl]pyrimidine (0.89 g, 1.24 mmol), octyl bromide (0.3 g, 1.5 mmol), and potassium carbonate (0.2 g, 1.5 mmol) in acetonitrile (12 mL). The resulting mixture was heated to reflux overnight, deionized water (20 mL) was added, and the resulting crude product was collected by filtration. The product was recrystallized from methanol to yield 0.35 g.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH2:13][C@H:12]3[C@@H:7]([CH2:8][CH2:9][CH2:10][N:11]3[CH2:14][CH2:15][CH3:16])[CH2:6][C:5]=2[N:17]=1.S(=O)(=O)(O)[OH:19].[OH-].[NH4+]>>[CH2:14]([N:11]1[C@@H:12]2[C@H:7]([CH2:6][C:5]3[NH:17][C:2](=[O:19])[S:3][C:4]=3[CH2:13]2)[CH2:8][CH2:9][CH2:10]1)[CH2:15][CH3:16]
Reactant: O=S(=O)(O)O
Reactant: CCCN1CCC[C@H]2Cc3nc(Br)sc3C[C@@H]21
Agent: [NH4+]
Agent: [OH-]
Product: CCCN1CCC[C@H]2Cc3[nH]c(=O)sc3C[C@@H]21
Temperature: 100 °C
Reaction time: 48 h

Procedure:
About 1.9 millimoles of trans-(±)-2-bromo-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydrothiazolo[4,5-g]quinoline were dissolved in 10 ml. of 20% aqueous sulfuric acid. The solution was heated at about 100° C. for about five hours and then was cooled. The cooled solution was allowed to remain at ambient temperature for an additional 48 hours. The reaction mixture was then made basic with concentrated aqueous ammonium hydroxide. The aqueous mixture was extracted several times with equal volumes of chloroform. The chloroform extracts were combined, and the combined extracts washed with saturated aqueous sodium chloride and then dried. Evaporation of the chloroform in vacuo yielded trans-(±)-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydrothiazolo[4,5-g]quinolin-2(1H)-one which was one spot material by TLC (9:1 CHCl3 /MeOH+trace NH4OH); Rf =0.37. The compound showed a strong band at 1650 cm-1 in the infrared indicating a carbonyl.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].CCN(CC)CC.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C(Cl)Cl>[CH3:18][S:19]([N:8]([S:19]([CH3:18])(=[O:21])=[O:20])[C:7]1[CH:9]=[CH:10][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N(c1ccc([N+](=O)[O-])cc1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 162.3 %

Procedure:
To a solution of 4-nitroaniline (5.04 g, 36.5 mmol) in CH2Cl2 (100 ml) cooled to 0° C. were added Et3N (6.61 mL, 47.4 mmol) and MsCl (3.39 mL, 43.8 mmol) and the mixture was stirred at room temperature overnight to give dimethanesulfonyl-(4-nitro-phenyl)-amine as a yellow solid (10.46 g, 98%) following work-up.
Reaction SMILES: [Br:1][C:2]1[C:11]([OH:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[OH:13].C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl>CN(C=O)C.O>[CH2:20]([O:12][C:11]1[CH:10]=[C:5]([CH:4]=[C:3]([OH:13])[C:2]=1[Br:1])[C:6]([O:8][CH3:9])=[O:7])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)c1cc(O)c(Br)c(O)c1
Reactant: BrCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(O)c(Br)c(OCc2ccccc2)c1
Reaction time: 8 h
Yield: 52 %

Procedure:
To a mixture of methyl 4-bromo-3,5-dihydroxybenzoate (18.8 g, 76 mmol) and potassium carbonate (5.26 g, 38.1 mmol) in DMF (190 mL) was added benzyl bromide (3.17 mL, 26.6 mmol). The mixture was stirred overnight, diluted with 200 mL water and acidified to pH 1 by slow addition of concentrated hydrochloric acid. The solution was extracted with 1:1 ethyl acetate/ether (6×) and the combined extracts were washed with water (8×), saturated sodium bicarbonate, brine, dried over magnesium sulfate and concentrated to an orange solid. The solids were suspended in DCM (200 mL) and stirred overnight. The solids (primarily unreacted 4-bromo-3,5-dihydroxybenzoate) were removed by filtration and the filtrate was concentrated to an orange oil which was purified by column chromatography (80 g silica gel, 2:1 DCM in heptane elution, followed by DCM elution) to provide methyl 3-(benzyloxy)-4-bromo-5-hydroxybenzoate (4.66 g). MS (M+1)=337.0. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.32-7.57 (m, 6H), 7.26 (d, J=1.52 Hz, 1H), 5.77 (s, 1H), 5.22 (s, 2H), 3.93 (s, 3H) as well as the di-benzylated methyl 3,5-bis(benzyloxy)-4-bromobenzoate (1.8 g).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([N:5]1[CH:9]=[CH:8][C:7]([C:10]2[CH:17]=[C:16]([F:18])[C:13]([C:14]#[N:15])=[C:12]([F:19])[CH:11]=2)=[N:6]1)[CH3:4].[C:20]([C:23]1[O:27][N:26]=[C:25]([C:28](O)=[O:29])[CH:24]=1)(=[O:22])[CH3:21].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[C:20]([C:23]1[O:27][N:26]=[C:25]([C:28]([NH:1][CH2:2][C@H:3]([N:5]2[CH:9]=[CH:8][C:7]([C:10]3[CH:17]=[C:16]([F:18])[C:13]([C:14]#[N:15])=[C:12]([F:19])[CH:11]=3)=[N:6]2)[CH3:4])=[O:29])[CH:24]=1)(=[O:22])[CH3:21]
Reactant: C[C@H](CN)n1ccc(-c2cc(F)c(C#N)c(F)c2)n1
Reactant: CC(=O)c1cc(C(=O)O)no1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)c1cc(C(=O)NC[C@@H](C)n2ccc(-c3cc(F)c(C#N)c(F)c3)n2)no1

Procedure:
The title compound was synthesized from (R)-4-(1-(1-aminopropan-2-yl)-1H-pyrazol-3-yl)-2,6-difluorobenzonitrile (0.955 g, 3.64 mmol), 5-acetylisoxazole-3-carboxylic acid (0.565 g, 3.64 mmol), HOBt (0.738 g, 5.46 mmol), DIPEA (1.9 mL, 10.92 mmol) and EDCI (1.05 g, 5.46 mmol) using DMF (10 mL) as solvent using the method of Example 34(d). The product was purified with CombiFlash to afford 60 mg of pure product. 1H NMR (400 MHz; CDCl3): δ 1.63 (d, 3H), 2.64 (s, 3H), 3.82 (m, 1H), 3.95 (m, 1H), 4.64 (m, 1H), 6.61 (d, 1H), 7.29 (s, 1H), 7.52 (m, 3H), 7.62 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C1COCC1.CC([O-])(C)C.[K+].CS([C:31]1[CH:36]=[CH:35][C:34]([S:37]([CH3:40])(=[O:39])=[O:38])=[CH:33][N:32]=1)(=O)=O>O>[CH3:40][S:37]([C:34]1[CH:35]=[CH:36][C:31]([O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[O:15])=[CH:6][CH:7]=2)=[N:32][CH:33]=1)(=[O:39])=[O:38]
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Reactant: CS(=O)(=O)c1ccc(S(C)(=O)=O)nc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(Oc2ccc(C(=O)c3ccccc3)cc2)nc1

Procedure:
To 5.5 g of p-hydroxybenzophenone in a 25 ml THF/25 ml DMSO mixture was added 3.6 g of t-BuOK and then 6.51 g of 2,5-bis(methylsulfonyl)pyridine, and the resulting mixture was heated at 62° C. for 11/2 hrs. The reaction mixture was cooled and added to approximately 3 to 4 volumes of water and stirred. The crude product which formed was filtered and dried. Recrystallization from ethanol gave purified (4-((5-(methylsulfonyl)-2-pyridinyl)oxy)phenyl)phenylmethanone, m.p. 130°-131.5° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1Br.[CH:10]([C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1)=[O:11]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([CH:10]=[O:11])[CH:17]=1
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: Fc1cccc(F)c1Br
Product: O=Cc1cccc(-c2c(F)cccc2F)c1

Procedure:
The title compound was synthesized in the same manner as in Reference Example 206 from 1,3-difluoro-2-bromobenzene and 3-formylphenylboronic acid. colorless oil (3.0 g, yield 93%).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[O:6][C:7]3[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=3[C@H:9]3[CH2:13][N:12]([CH3:14])[C:11](=[O:15])[C@H:10]3[C:4]=2[CH:3]=1.[OH-].[K+].C(OCC)(=[O:26])C>C(O)C>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[O:6][C:7]3[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=3[C@@H:9]([CH2:13][NH:12][CH3:14])[C@H:10]([C:11]([OH:15])=[O:26])[C:4]=2[CH:3]=1
Reactant: CN1C[C@@H]2c3ccccc3Oc3ccc(Cl)cc3[C@@H]2C1=O
Reactant: CCOC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CNC[C@@H]1c2ccccc2Oc2ccc(Cl)cc2[C@H]1C(=O)O
Yield: 52 %

Procedure:
To a solution of cis-1′-chloro-2,3,3a,12b-tetrahydro-2-methyl-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrol-1-one (V) (2 gram, 6.7 mmol) in ethanol (20 mL), was added potassium hydroxide (3.8 g, 67 mmol). The reaction mixture was heated to reflux for 5 hours. The reaction mixture was evaporated and water was added (50 mL). The water phase was washed with diethyl ether (2×25 mL). The aqueous phase was acidified with concentrated hydrochloric acid to a pH between 5 and 6, resulting in a gum precipitate. Ethyl acetate was added (25 mL), which slowly dissolved the gum and resulted in the formation of fine crystals of the product. The crystals were filtered and dried to give trans-8-chloro-10,11-dihydro-11-[(methylamino)-methyl]-dibenz[b,f]oxepin-10-carboxylic acid (I) (1.1 g, 52%); mp 154.4° C.; 1H-NMR (399.87 MHz in MeOD relative to TMS) δ 2.09 (s, 3H), 2.45 and 2.66 (2×m, 2H), 3.23 (s, 1H), 3.50 (m, 1H), 3.92 (d, 1H), 6.96-7.20 (m, 6H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:16][CH2:17][C:18]([F:21])([F:20])[F:19])[C:11]#[N:12].O>C(OCC)C>[F:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:16][CH2:17][C:18]([F:19])([F:20])[F:21])[CH2:11][NH2:12]
Reactant: N#Cc1ccc(OCC(F)(F)F)c(F)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: NCc1ccc(OCC(F)(F)F)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.5 %

Procedure:
1.40 g of lithium aluminum hydride was suspended in 50 ml of diethyl ether, and a solution of 8.00 g of 3-fluoro-4-(2,2,2-trifluoroethoxy)benzonitrile in ml of diethyl ether was added dropwise. After the addition, the mixture was stirred at room temperature for 30 minutes and subsequently, 10 ml of water was added dropwise over 30 minutes. The insoluble matter was removed by filtration. The ether layer was dried. Diethyl ether was evaporated under reduced pressure to give 7.54 g of crude 3-fluoro-4-(2,2,2-trifluoroethoxy)benzylamine as an oil.