Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[NH2:6].[OH-].[Na+].Cl[C:15]([O:17][CH3:18])=[O:16].O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:6][C:15]([O:17][CH3:18])=[O:16])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(N)cc1OC
Reactant: COC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: COC(=O)Nc1ccc(OC)c(OC)c1
Temperature: -5 °C
Reaction time: 1.5 h
Yield: 90.7 %

Procedure:
A solution of 15.3 g (0.1 mol) of 3,4-dimethoxyaniline in 60 mL of methylene chloride was treated with 55 mL of 2N sodium hydroxide. The reaction mixture was cooled to -5° C. and 7.4 mL (0.096 mol) of methyl chloroformate was added keeping the reaction temperature between 15°-25° C. The reaction was stirred 1.5 hr at 10°-20° C. and then 50 mL of water was added. The layers were separated and the aqueous layer was extracted with 4×100 mL of methylene chloride. The combined methylene chloride layers were dried over sodium sulfate and Darco treated. Evaporation gave a paste which was recrystallized from 10 mL of ethyl acetate and 10 mL of hexanes to give 18.4 g (98%) of the product, mp 83°-87° C. NMR (CDCl3) δ 3.75 (s, 3H, OCH3), 3.85 (s, 3H, OCH3), 6.63 (br s, 1H, NH), 6.73 (m, 2H, ArH), 7.13 (m, 1H, ArH).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:34])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[S:19][CH:20]=[C:21]([C:23]([NH:25][C@@H:26]([CH:31]([CH3:33])[CH3:32])[C:27]([O:29]C)=[O:28])=[O:24])[N:22]=2)=[CH:14][CH:13]=1.CO.[Li+].[OH-]>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:34])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[S:19][CH:20]=[C:21]([C:23]([NH:25][C@@H:26]([CH:31]([CH3:32])[CH3:33])[C:27]([OH:29])=[O:28])=[O:24])[N:22]=2)=[CH:14][CH:13]=1
Reactant: COC(=O)[C@@H](NC(=O)c1csc(-c2ccc(NC(=O)Nc3ccc(F)cc3F)cc2)n1)C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)[C@H](NC(=O)c1csc(-c2ccc(NC(=O)Nc3ccc(F)cc3F)cc2)n1)C(=O)O
Reaction time: 2.5 h

Procedure:
To a solution of (S)-methyl 2-(2-(4-(3-(2,4-difluorophenyl)ureido)phenyl)thiazole-4-carboxamido)-3-methylbutanoate (100 mg, 0.204 mmol) in THF (4 mL)+MeOH (1 ml), 1 ml of 1N LiOH (42.99 mg, 1.024 mmol) was added at RT and stirred for 2-3 hr. After completion of reaction, THF was removed under reduced pressure. Obtained material was dissolved in water, acidified with 1N HCl and white solid precipitated out. It was filtered and dried.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]([C:9]2[C:13]3[N:14]=[CH:15][N:16]=[C:17]([C:18]4[C:26]5[O:25][CH2:24][O:23][C:22]=5[CH:21]=[CH:20][C:19]=4[O:27][CH2:28][CH2:29][CH3:30])[C:12]=3[NH:11][CH:10]=2)=[O:8])[CH2:2]1.Cl[C:32]([O:34][CH2:35][CH3:36])=[O:33]>>[CH2:35]([O:34][C:32]([N:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]([C:9]2[C:13]3[N:14]=[CH:15][N:16]=[C:17]([C:18]4[C:26]5[O:25][CH2:24][O:23][C:22]=5[CH:21]=[CH:20][C:19]=4[O:27][CH2:28][CH2:29][CH3:30])[C:12]=3[NH:11][CH:10]=2)=[O:8])[CH2:2]1)=[O:33])[CH3:36]
Reactant: CCOC(=O)Cl
Reactant: CCCOc1ccc2c(c1-c1ncnc3c(C(=O)N[C@@H]4CCNC4)c[nH]c13)OCO2
Product: CCCOc1ccc2c(c1-c1ncnc3c(C(=O)N[C@@H]4CCN(C(=O)OCC)C4)c[nH]c13)OCO2

Procedure:
Starting from 4-(5-propoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (R)-pyrrolidin-3-ylamide (example A178) and ethyl chloroformate the title compound was obtained as colorless solid.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8]([CH2:15][C:16]#[N:17])=[CH:9][NH:10]2)([O-:5])=[O:4].Br[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>CN(C=O)C>[C:16]([CH2:15][C:8]1[C:7]2[C:11](=[CH:12][CH:13]=[CH:14][C:6]=2[N+:3]([O-:5])=[O:4])[N:10]([CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:9]=1)#[N:17]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: N#CCc1c[nH]c2cccc([N+](=O)[O-])c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Cn1cc(CC#N)c2c([N+](=O)[O-])cccc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride (198 mg of a 60% dispersion in mineral oil, 5.0 mmol) was added to a solution of (4-nitro-1H-indol-3-yl)acetonitrile from Step B (910 mg, 4.52 mmol) in DMF (15 mL). After 10 min, tert-butyl bromoacetate (0.801 mL, 5.4 mmol) was added dropwise and the reaction mixture was stirred at ambient temperature for 1.5 h. The mixture was partitioned between H2O (50 mL) and EtOAc (100 mL) and the organic extract was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 0:100, to give the title compound. MS: m/z=316 (M+1).
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.O[NH:27][C:28](=[NH:39])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([S:35](=[O:38])(=[O:37])[NH2:36])[CH:30]=1>>[F:25][CH:2]([F:1])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]3[O:14][N:39]=[C:28]([C:29]4[CH:30]=[C:31]([S:35]([NH2:36])(=[O:37])=[O:38])[CH:32]=[CH:33][CH:34]=4)[N:27]=3)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:17][CH:16]=2)[CH:4]=1
Reactant: N=C(NO)c1cccc(S(N)(=O)=O)c1
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: NS(=O)(=O)c1cccc(-c2noc(-c3cnn4c(C(F)F)cc(-c5ccc(C(F)(F)F)cc5)nc34)n2)c1

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) (179 mg, 0.5 mmol) and N-hydroxy-3-sulfamoyl-benzamidine [CAS-No. 9000-88-7] (161 mg, 0.75 mmol) according to general procedure II. Obtained after purification by column chromatography (dichloromethane/MeOH/NH4OH) and crystallization (ethyl acetate/hexane) as a yellow solid (198 mg, 74%). MS (ISN) 535.3 [(M−H)−]; mp 267° C.
Reaction SMILES: [CH2:1]([NH:3][C:4]([N:6]=[C:7](OC)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5])[CH3:2].Cl.Cl.[NH2:18][CH:19]([CH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)[C:20]([NH:22][C:23]1([C:30]#[N:31])[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]1)=[O:21].C(N(CC)C(C)C)(C)C>CO>[C:30]([C:23]1([NH:22][C:20](=[O:21])[CH:19]([NH:18][C:7](=[N:6][C:4](=[O:5])[NH:3][CH2:1][CH3:2])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:32][CH:33]2[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]2)[CH2:24][CH2:25][N:26]([CH3:29])[CH2:27][CH2:28]1)#[N:31]
Reactant: CN1CCC(C#N)(NC(=O)C(N)CC2CCCCC2)CC1
Reactant: CCNC(=O)N=C(OC)c1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CCNC(=O)N=C(NC(CC1CCCCC1)C(=O)NC1(C#N)CCN(C)CC1)c1ccccc1
Yield: 42.9 %

Procedure:
A solution of 1-ethyl-3-(methoxy-phenyl-methylene)-urea (350 mg, 1.70 mmol), 2-amino-N-(4-cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-propionamide bis hydrochloride salt (512 mg, 1.40 mmol) and N,N-diisopropylethylamine (352 mg, 2.73 mmol) in dry methanol (5.0 mL) was stirred at room temperature for 60 h. The reaction mixture was concentrated and the resulting residue was chromatographed over 50 g of flash silica gel using dichloromethane to 5% methanol in dichloromethane as the eluant. This provided the desired product as a light yellow solid (280 mg, 43%) which was further purified by HPLC using a 20×250 mm C18 reverse phase column with the method being 20% acetonitrile in water to 90% acetonitrile in water. MS, m/z 467=M+1.
Reaction SMILES: CCCCCC.C([Li])CCC.Br[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:24]=[C:23]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:27][CH:26]=3)[N:22]=[C:21]([C:35]3[CH:40]=[CH:39][C:38]([C:41]([CH3:44])([CH3:43])[CH3:42])=[CH:37][CH:36]=3)[N:20]=2)=[CH:15][CH:14]=1.Br[C:46]1[CH:51]=[CH:50][C:49]([C:52]2[CH:57]=[CH:56][C:55]([C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)=[CH:54][N:53]=2)=[CH:48][CH:47]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCCC1>[C:31]([C:28]1[CH:29]=[CH:30][C:25]([C:23]2[N:22]=[C:21]([C:35]3[CH:36]=[CH:37][C:38]([C:41]([CH3:42])([CH3:44])[CH3:43])=[CH:39][CH:40]=3)[N:20]=[C:19]([C:16]3[CH:15]=[CH:14][C:13]([C:46]4[CH:47]=[CH:48][C:49]([C:52]5[CH:57]=[CH:56][C:55]([C:58]6[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=6)=[CH:54][N:53]=5)=[CH:50][CH:51]=4)=[CH:18][CH:17]=3)[N:24]=2)=[CH:26][CH:27]=1)([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)c1ccc(-c2nc(-c3ccc(Br)cc3)nc(-c3ccc(C(C)(C)C)cc3)n2)cc1
Reactant: Brc1ccc(-c2ccc(-c3ccccc3)cn2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)c1ccc(-c2nc(-c3ccc(-c4ccc(-c5ccc(-c6ccccc6)cn5)cc4)cc3)nc(-c3ccc(C(C)(C)C)cc3)n2)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 43.1 %

Procedure:
Under a stream of argon, 0.35 ml of a hexane solution containing 0.55 mmol of butyl lithium was slowly added to 15 ml of tetrahydrofuran cooled to −78° C. in which 0.25 g of 2-(4-bromophenyl)-4,6-bis(4-tert-butylphenyl)-1,3,5-triazine obtained by Reference Example 1 had been dissolved. After stirring at −78° C. for 15 minutes, 0.15 g of dichloro(tetramethylethylenediamine)zinc(II) was added thereto and stirred at −78° C. for 10 minutes and then at room temperature for 2 hours. A 5 ml portion of tetrahydrofuran prepared by dissolving 0.19 g of 2-(4-bromophenyl)-5-phenylpyridine and 0.03 g of tetrakis(triphenylphosphine)palladium(0) therein was added to this solution and stirred under heating reflux for 14 hours. The reaction solution was concentrated under a reduced pressure and the thus obtained solid was recrystallized from dichloromethane-methanol. The thus obtained crude product was purified by a silica gel column chromatography (eluting solution hexane:chloroform=1:1 to 4:5) and then again recrystallized from dichloromethane-methanol to obtain a white solid of the intended 2,4-bis(4-tert-butylphenyl)-6-[4′-(5-phenylpyridin-2-yl)biphenyl-4-yl]-1,3,5-triazin (0.14 g, yield 43%). Its melting point is shown in Table 4. In this case, a distinct point of glass transition was not observed.
Reaction SMILES: C1(CNC([NH:11][CH:12]([CH2:16][C:17]([NH2:19])=[O:18])[C:13]([NH2:15])=[O:14])=O)C=CC=CC=1.C(O)C.[N:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[C:33]([O-:35])=O>[Pd].ClCCl>[N:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[C:33]([NH:11][CH:12]([CH2:16][C:17]([NH2:19])=[O:18])[C:13]([NH2:15])=[O:14])=[O:35]
Reactant: NC(=O)CC(NC(=O)NCc1ccccc1)C(N)=O
Reactant: O=C([O-])c1ccc2ccccc2n1
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Product: NC(=O)CC(NC(=O)c1ccc2ccccc2n1)C(N)=O

Procedure:
A solution of [1S-[1R*(R*),2S*]]-N1[3-[[[(1,1-dimethylethyl)amino]carbonyl]n-butyl)amino]-2-hydroxy-1-(phenylmethy)propyl]-2-[(phenylmethylcarbamoyl)amino]-butanediamide (1.03 g, 1.77 mmol) in 40 mL of abs. ethanol is then deprotected by hydrogenolysis in the presence of 10% palladium on carbon catalyst to give, after filtration and concentration, the free amine (428 mg) which was coupled with N-hydroxysuccinimide ester of 2-quinoline carboxylate (270 mg, 1.0 mmol) in dichloromethane for 16 h to give 380 mg, 63% of [1S-[1R*(R*),2S*]]-N1[3-[[[1,1-dimethylethyl)amino]carbonyl](n-butyl)amino]-2-hydroxy-1-(phenylmethyl)propyl]-2-[(2-quinolinylcarbonyl)amino]-butanediamide, mp 102.1°-103° C.
Reaction SMILES: N1C=CC=CC=1.[S:7]([O:17][CH:18]([CH3:22])[C:19](Cl)=[O:20])([C:10]1[CH:16]=[CH:15][C:13]([CH3:14])=[CH:12][CH:11]=1)(=[O:9])=[O:8].[CH3:23][Si:24]([CH2:27][OH:28])([CH3:26])[CH3:25].C1(C)C=CC=CC=1>O>[S:7]([O:17][CH:18]([CH3:22])[C:19]([O:28][CH2:27][Si:24]([CH3:26])([CH3:25])[CH3:23])=[O:20])([C:10]1[CH:16]=[CH:15][C:13]([CH3:14])=[CH:12][CH:11]=1)(=[O:9])=[O:8]
Reactant: Cc1ccc(S(=O)(=O)OC(C)C(=O)Cl)cc1
Reactant: C[Si](C)(C)CO
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OC(C)C(=O)OC[Si](C)(C)C)cc1

Procedure:
33 g (0.41 mole) of pyridine are slowly added dropwise to a mixture of 109 g (0.41 mole) of the S-enantiomer of tosyloxy-propionic acid chloride, 43.4 g (0.41 mole) of trimethylsilyl-methanol and 250 ml of toluene at 20° C., with stirring. The mixture is subsequently stirred at room temperature for 24 hours. Working up is then carried out by a procedure in which the reaction mixture is poured into water and extracted with toluene and the organic phase is concentrated by stripping off the diluent under reduced pressure. 130 g (96% of theory) of the S-enantiomer of trimethylsilyl-methyl 2-tosyloxy-propionate are obtained in this manner in the form of an oily product.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][C:16]=1[O:17][CH2:18][CH2:19][O:20][CH3:21])[C:13](=[O:22])[C:12](=[N:23]O)[CH2:11]2.C1(C)C=CC(S(Cl)(=O)=[O:32])=CC=1>O>[C:12]([CH2:11][C:10]1[CH:9]=[C:8]([O:7][CH2:6][CH2:5][O:4][CH3:3])[C:16]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[CH:15][C:14]=1[C:13]([OH:22])=[O:32])#[N:23]
Reactant: COCCOc1cc2c(cc1OCCOC)C(=O)C(=NO)C2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COCCOc1cc(CC#N)c(C(=O)O)cc1OCCOC
Temperature: 50 °C
Yield: 0.1 %

Procedure:
To a solution of NaOH (0.55 g, 13.64 mmol) in H2O (10 ml) was added 5,6-Bis-(2-methoxy-ethoxy)-indan-1,2-dione 2-oxime (1.11 g, 3.59 mmol), and the mixture was heated to 50° C. Then p-Toluenesulfonyl chloride (0.89 g, 4.66 mmol) was added in portions to the mixture, and then the mixture was heated at 80° C. for 15 min. After cooling careful to room temperature, the precipitate (a little) was filtered off, the filtrate was acidified by concentrated HCl to PH=3-4. The precipitate was collected and dried to give product (0.777 mg, yield 70%). LC-MS: m/e 208 (M−1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH:19]3[CH2:24][CH2:23][CH2:22][N:21]([CH3:25])[CH2:20]3)[CH2:14][CH2:13]2)=S)[CH:5]=[CH:6][C:7]=1[Cl:8].CO.[NH3:28]>C1COCC1.ClCCl.[O-]S(C(F)(F)F)(=O)=O.[Ag+]>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH:19]3[CH2:24][CH2:23][CH2:22][N:21]([CH3:25])[CH2:20]3)[CH2:14][CH2:13]2)=[NH:28])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN1CCCC(CN2CCN(C(=S)Nc3ccc(Cl)c(Cl)c3)CC2)C1
Reactant: N
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: CN1CCCC(CN2CCN(C(=N)Nc3ccc(Cl)c(Cl)c3)CC2)C1
Temperature: -30 °C

Procedure:
N-(3,4-Dichlorophenyl)-4-[(1-methylpiperidin-3-yl)methyl]piperazine-1-carbothioamide (0.53 g) was dissolved in a mixture of saturated ammonia in THF (1 ml) and dichloromethane (20 ml). The reaction mixture was cooled to −30° C. under an atmosphere of argon then silver triflate (0.34 g) was added. The reaction mixture was allowed to warm to room temperature then methanol (4 ml) was added. The soluble material was separated the concentrated in vacuo. The crude product was subjected to reverse phase HPLC using a gradient of 95% water/acetonitrile/0.1% TFA through to 50% water/acetonitrile/0.1% TFA. The combined product fractions were concentrated in vacuo then separated between dichloromethane (50 ml) and saturated sodium bicarbonate solution (100 ml). The dichloromethane layer was separated, dried over magnesium sulphate, filtered and concentrated in vacuo to give the title compound (209.1 mg).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]3[NH:22][CH:21]([CH2:23][C:24]([F:27])([F:26])[F:25])[CH2:20][O:19][C:11]3=2)[N:6]=1)([CH3:3])[CH3:2].[CH2:28]=O.[BH3-]C#N.[Na+].[C:34](O)(=O)[CH3:35]>>[CH2:34]([C:21]1([CH2:23][C:24]([F:25])([F:26])[F:27])[CH2:20][O:19][C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[C:10]2[N:22]1[CH3:28])[N:6]=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[CH:14]=[C:13]3[C:15]([F:16])([F:17])[F:18])[CH3:35]
Reactant: CC(C)Oc1cc(C(F)(F)F)c2c3c(ccc2n1)NC(CC(F)(F)F)CO3
Reactant: C=O
Reactant: CC(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCC1(CC(F)(F)F)COc2c(ccc3nc(OC(C)C)cc(C(F)(F)F)c23)N1C
Yield: 65 %

Procedure:
This compound was prepared by General Method 5 (EXAMPLE 1) from (±)-3,4-dihydro-8-isopropoxy-3-(2,2,2-trifluoroethyl)-10-(trifluoromethyl)-2H-[1,4]oxazino[2,3-f]quinoline (0.025 g, 0.06 mmol), paraformaldehyde (0.02 g, 0.6 mmol) and NaCNBH3 (0.04 g, 0.6 mmol) in 2 mL glacial acetic acid to afford 0.017 g (65%) of (±)-3-ethyl-3,4-dihydro-8-isopropoxy-4-methyl-3-(2,2,2-trifluoroethyl)-10-(trifluoromethyl)-2H-[1,4]oxazino[2,3-f]quinoline, of sufficient purity as to be used directly in the next reaction. 1H NMR (500 MHz, CDCl3) 7.48 (d, J=8.8, 1H), 7.22 (d, J=9.3, 1H), 7.21 (s, 1H), 5.49 (m, 1H), 4.37 (d, J=10.7, 1H), 4.08 (d, J=10.7, 1H), 3.68 (m, 1H), 3.05 (s, 3H), 2.40 (m, 2H), 1.39 (d, J=6.3, 3H), 1.38 (d, J=6.3, 3H).
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][NH:7][C:8]1[C:9]([C:13]2[N:17]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([Br:25])[CH:19]=3)[C:16](=[O:26])[O:15][N:14]=2)=[N:10][O:11][N:12]=1)=[N+]=[N-].[I-:27].[Na+].Cl[Si](C)(C)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>CO.O>[IH:27].[NH2:1][CH2:4][CH2:5][CH2:6][NH:7][C:8]1[C:9]([C:13]2[N:17]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([Br:25])[CH:19]=3)[C:16](=[O:26])[O:15][N:14]=2)=[N:10][O:11][N:12]=1
Reactant: [N-]=[N+]=NCCCNc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1
Reactant: [I-]
Agent: C[Si](C)(C)Cl
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CO
Product: I
Product: NCCCNc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 92.8 %

Procedure:
A solution of 3-{4-[(3-azidopropyl)amino]-1,2,5-oxadiazol-3-yl}-4-(3-bromo-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one (2.0 g, 4.7 mmol) in methanol (36 mL) was treated with sodium iodide (4.2 g, 28 mmol) and stirred at 25° C. for 5 min. The reaction mixture was treated with a solution of chlorotrimethylsilane (3.6 mL, 28 mmol) in methanol (7 mL) dropwise and stirred at 25° C. for 40 min. The reaction mixture was slowly poured into a solution of sodium thiosulfate (5.0 g, 32 mmol) in water (200 mL) that was cooled at 0° C. The solid that precipitated was filtered, washed with water, and dried to give the desired product (2.3 g, 93%) as a solid. LCMS for C13H13BrFN6O3 (M+H)+: m/z=399.0, 401.0. 1H NMR (400 MHz, DMSO-d6): δ 8.08 (dd, J=6.1, 2.3 Hz, 1H), 7.74-7.70 (m, 1H), 7.60 (dd, J=8.8, 8.6 Hz, 1H), 7.22 (br s, 2H), 6.69 (br s, 1H), 2.81-2.77 (m, 2H), 1.86-1.79 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6]([OH:9])=[N:7][O:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:19]([CH3:24])[C:20]([O:22][CH3:23])=[O:21].Cl>CN(C)C=O.O>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6]([O:9][CH:19]([CH3:24])[C:20]([O:22][CH3:23])=[O:21])=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Oc1noc2cc(Cl)ccc12
Reactant: COC(=O)C(C)Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(C)Oc1noc2cc(Cl)ccc12
Temperature: 25 °C

Procedure:
A mixture of 6-chloro-1,2-benzisoxazol-3-ol (6.8 g, 40.1 mmol), potassium carbonate (8.3 g, 60 mmol) and methyl 2-bromopropionate (10.0 g, 60.1 mmol) in N,N-dimethylformamide is stirred at room temperature over-night and diluted with water. The resultant aqueous mixture is acidified with concentrated hydrochloric acid (pH5-pH6) and extracted with methylene chloride. The combined organic extracts are diluted with hexanes, washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a residue. Column chromatography of the residue using silica gel and ethyl acetate/hexanes solutions gives the title product as a gold oil which is identified by NMR spectral analyses.
Reaction SMILES: ClC1C=C(N[C:18]2[C:19]3[N:26]([CH2:27][C:28](O)=O)[CH:25]=[CH:24][C:20]=3[N:21]=[CH:22][N:23]=2)C=CC=1OCC1C=CC=C(F)C=1.[Cl:31][C:32]1[CH:33]=[C:34]([CH:36]=[CH:37][C:38]=1[O:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([C:46]([F:49])([F:48])[F:47])[CH:41]=1)[NH2:35].[CH:50]([OH:53])(C)C>C(=O)([O-])O.[Na+]>[Cl:31][C:32]1[CH:33]=[C:34]([NH:35][C:18]2[C:19]3[N:26]([CH2:27][CH2:28][CH2:50][OH:53])[CH:25]=[CH:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH:36]=[CH:37][C:38]=1[O:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([C:46]([F:47])([F:48])[F:49])[CH:41]=1
Reactant: Nc1ccc(Oc2cccc(C(F)(F)F)c2)c(Cl)c1
Reactant: O=C(O)Cn1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c21
Reactant: CC(C)O
Agent: O=C([O-])O
Agent: [Na+]
Product: OCCCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a solution of 3-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)propan-1-ol (201 mg) synthesized in Example 53 (ii) in isopropyl alcohol (2.5 mL) was added 3-chloro-4-[3-(trifluoromethyl)phenoxy]aniline (381 mg), and the mixture was stirred in an oil bath at a temperature of 100° C. for 2.0 hrs. The reaction mixture was allowed to cool to room temperature, diluted with 5% aqueous sodium hydrogen carbonate solution (25 mL), and extracted with ethyl acetate (30 mL×3). The organic layer washed successively with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to basic silica gel chromatography (eluent:hexane/ethyl acetate=95/5→20/80). The object fraction was concentrated under reduced pressure and dried. Ethanol/diisopropyl ether (1/9) was added to the residue, and the mixture was stirred with heating to 80° C., allowed to cool to room temperature, and stood still. The resultant precipitate was collected by filtration. The obtained precipitate washed with diisopropyl ether and dried under reduced pressure to give the title compound (375 mg) as white powder crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C@H:13]3[CH2:18][CH2:17][C@@H:16]([NH:19]C4C5C(=CC(Cl)=CC=5)N=CC=4)[CH2:15][CH2:14]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[Br:31][C:32]1[CH:33]=[C:34]([CH:38]=[C:39]([F:41])[CH:40]=1)[C:35]([OH:37])=O.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC>ClCCl>[Br:31][C:32]1[CH:33]=[C:34]([CH:38]=[C:39]([F:41])[CH:40]=1)[C:35]([NH:19][CH:16]1[CH2:15][CH2:14][CH:13]([NH:12][C:6]2[C:5]3[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]=[CH:8][CH:7]=2)[CH2:18][CH2:17]1)=[O:37]
Reactant: O=C(O)c1cc(F)cc(Br)c1
Reactant: Clc1ccc2c(N[C@H]3CC[C@@H](Nc4ccnc5cc(Cl)ccc45)CC3)ccnc2c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=C(NC1CCC(Nc2ccnc3cc(Cl)ccc23)CC1)c1cc(F)cc(Br)c1
Reaction time: 3 h
Yield: 40.8 %

Procedure:
A mixture of 23A cis-N,N′-bis(7-chloroquinolin-4-yl)cyclohexane-1,4-diamine (500 mg, 3.6 mmol), 3-bromo-5-fluorobenzoic acid (600 mg, 5.4 mmol), 1-hydroxybenzotriazole (245 mg, 3.6 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide(348 mg, 3.6 mmol) in 30 mL dichloromethane was stirred for 3 hours. The reaction was incomplete. 3-bromo-5-fluorobenzoic acid (160 mg, 0.9 mmol), 1-hydroxybenzotriazole (61 mg, 0.9 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (87 mg, 0.9 mmol) was added and the solution was allowed to stir overnight. The solution was then washed with 1N NaOH, dried (Na2SO4), and concentrated. The residue was purified by flash chromatography (10% methanol in dichloromethane) to provide 700 mg of pure compound, an 81% yield. MS (ESI(+)Q1MS m/z 477 (M+2 H)+; 1H NMR (300 MHz, MeOH) δ ppm 8.36-8.42 (m, 3 H), 7.95 (t, 1 H), 7.69-7.79 (m, 3 H), 7.45 (dd, 1 H), 6.83 (d, 1 H), 6.54 (d, 1 H), 3.95 (m, 1 H), 3.68 (m, 1 H), 1.66-1.98 (m, 8 H).