Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][CH:7]([C:13]([F:16])([F:15])[F:14])[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5]2.C(=O)([O-])[O-].[K+].[K+].Cl[C:29]1[N:34]=[CH:33][C:32]([CH2:35][CH3:36])=[CH:31][N:30]=1.CCOC(C)=O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:29]1[N:34]=[CH:33][C:32]([CH2:35][CH3:36])=[CH:31][N:30]=1)[O:8][CH:7]([C:13]([F:16])([F:15])[F:14])[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5]2
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(O)cc2OC1C(F)(F)F
Reactant: CCc1cnc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=Cc2cc(Cl)c(Oc3ncc(CC)cn3)cc2OC1C(F)(F)F
Temperature: 130 °C
Yield: 97.8 %

Procedure:
To a mixture of ethyl 6-chloro-7-hydroxyl-2-(trifluoromethyl)-2H-chromene-3-carboxylate (0.2g, 0.62 mmol) and potassium carbonate (342 mg, 2.48 mmol) in 3 mL of dry DMF was added a reagent of 2-chloro-5-ethylpyrimidine (450 uL, 3.72 mmol). The reaction was then heated at 130° C. for 51 hours. After cooling to room temperature, to the reaction was added 150 mL of EtOAc. The resulting organic phase was washed with brine, and dried over anhydrous magnesium sulfate. After removing the solvents, the residue was purified on a short silica gel column with EtOAc/Hexane to afford 260 mg of a brown oil, which was used in the next step without further purification.
Reaction SMILES: [C:1]([N:3]([CH2:23][CH2:24][CH2:25][CH3:26])[C:4](=[O:22])[CH:5]([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14]CC2C=CC=CC=2)=[CH:10][CH:9]=1)[CH3:6])#[N:2].[H][H]>O1CCOCC1.[Pd]>[C:1]([N:3]([CH2:23][CH2:24][CH2:25][CH3:26])[C:4](=[O:22])[CH:5]([O:7][C:8]1[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=1)[CH3:6])#[N:2]
Reactant: CCCCN(C#N)C(=O)C(C)Oc1ccc(OCc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1COCCO1
Product: CCCCN(C#N)C(=O)C(C)Oc1ccc(O)cc1
Yield: 60.8 %

Procedure:
16.5 g (0.047 mole) of 2-(4-benzyloxyphenoxy)propionic acid N-cyano-N-butylamide, prepared according to Example b), are hydrogenated with hydrogen in 170 ml of dioxan, in the presence of 1.7 g of 5% palladium on carbon catalyst. The catalyst is then removed by filtration and the filtrate is concentrated by evaporation. The residue is chromatographed through silica gel eluted with ethyl acetate/hexane (1:3), affording 7.5 g (61% of theory) of 2-(4-hydroxyphenoxy)propionic acid N-cyano-N-butylamide as a colourless oil. nD25 : 1.5132.
Reaction SMILES: F[C:2](F)(F)C(O)=O.[OH:8][C:9]1[C:10]([O:30][CH3:31])=[CH:11][C:12]2[C:21]3[CH:22]=[C:23]4[O:28][CH2:27][O:26][C:24]4=[CH:25][C:20]=3[CH2:19][CH:18]3[C:13]=2[C:14]=1[CH2:15][N:16]([CH3:29])[CH2:17]3.C1(C)C=CC=CC=1.[OH-].C1([N+](C)(C)C)C=CC=CC=1>CN(C)C=O>[CH3:31][O:30][C:10]1[C:9]([O:8][CH3:2])=[C:14]2[CH2:15][N:16]([CH3:29])[CH2:17][CH:18]3[CH2:19][C:20]4[CH:25]=[C:24]5[O:26][CH2:27][O:28][C:23]5=[CH:22][C:21]=4[C:12](=[C:13]23)[CH:11]=1
Reactant: O=C(O)C(F)(F)F
Reactant: COc1cc2c3c(c1O)CN(C)CC3Cc1cc3c(cc1-2)OCO3
Agent: C[N+](C)(C)c1ccccc1
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1cc2c3c(c1OC)CN(C)CC3Cc1cc3c(cc1-2)OCO3

Procedure:
10.65 g. (±)-5,6,6a,7-tetrahydro-3-hydroxy-2-methoxy-9,10-methylenedioxy-5-methyl-4H-dibenz(de,g)isoquinoline trifluoroacetate (see Example 1) are dissolved in 500 ml. of a mixture of toluene and dimethyl formamide (9:1) in a manner analogous to that described in Example 7 and methylated with phenyltrimethyl ammonium hydroxide. When the methylation is finished (monitoring with TLC), the reaction mixture is evaporated in a vacuum. After partitioning the residue between water and methylene chloride, working up the organic phase and crystallising from methanol/chloroform, there is obtained (±)-5,6,6a,7-tetrahydro-2,3-dimethoxy-9,10-methylenedioxy-5-methyl-4H-dibenz(de,g)isoquinoline in the form of cream-coloured crystals; m.p. 169°-172° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([OH:12])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:16])=O.CN(C=O)C>C(Cl)Cl>[CH2:1]([O:8][CH2:9][C:10]([Cl:16])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)COCc1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)COCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of benzyloxyacetic acid (4.6 g, 28.0 mmol, 4.0 mL) in DCM (52 mL) was added oxalyl chloride (7.7 g, 61 mmol, 5.3 mL) and a drop of DMF. The reaction mixture was stirred at room temperature for 4 h. Excess of oxalyl chloride was removed in vacuo to give benzyloxy-acetyl chloride. The crude acyl chloride was diluted into DCM (100 mL) and triethylamine (5.3 mL, 41.6 mmol, 4.2 g) was added followed by 4-fluoroaniline (3.5 g, 32 mmol, 3.0 mL). The reaction mixture was stirred at RT overnight. The reaction was then quenched with 1 M aqueous HCl (100 mL), dried and concentrated in vacuo to give 7.1 g (95%) of 2-benzyloxy-N-(4-fluoro-phenyl)-acetamide (33) as a yellow oil which was used in the next step without purification. The structure was confirmed by 13C NMR (75 MHz, CDCl3) δC 69.2, 73.5, 115.4 (d, JCF=22 Hz), 121.4 (d, JCF=7 Hz), 127.9, 128.2, 128.5, 132.5 (d, JCF=3 Hz), 136.3, 157.6, 160.8, and 167.5.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=[O:11])=[CH:9][C:4]=2[CH2:3][CH2:2]1.C([O-])(=O)C.[Na+].[Br:17]Br>C(O)(=O)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>[Br:17][C:6]1[C:5]2[O:1][CH2:2][CH2:3][C:4]=2[CH:9]=[C:8]([CH:10]=[O:11])[CH:7]=1
Reactant: BrBr
Reactant: O=Cc1ccc2c(c1)CCO2
Agent: CC(=O)[O-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(=O)O
Product: O=Cc1cc(Br)c2c(c1)CCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.3 %

Procedure:
To a solution of 2,3-dihydro-1-benzofuran-5-carbaldehyde (1.0 g, 6.75 mmol) in glacial acetic acid (8 ml) was added sodium acetate (664 mg, 8.1 mmol) and bromine (0.7 ml, 13.5 mmol) at 10° C. slowly. The reaction was stirred for 2 h at room temperature. The reaction was diluted with a saturated aqueous solution of sodium thiosulfate (10 ml), washed with a saturated aqueous solution of sodium bicarbonate, and then extracted with ethyl acetate. Organics were combined, dried over sodium sulfate and dried in vacuo to give the desired compound (1.4 g, 91%).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:15])[N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]([CH3:8])[C:6]=1[CH3:7].[C:16]1([CH3:23])[C:21]([OH:22])=[CH:20][CH:19]=[CH:18][CH:17]=1.N>O.CC(O)C.[Fe-3](C#N)(C#N)(C#N)(C#N)(C#N)C#N.[K+].[K+].[K+]>[CH3:8][N:5]1[C:6]([CH3:7])=[C:2](/[N:1]=[C:18]2\[CH:17]=[C:16]([CH3:23])[C:21](=[O:22])[CH:20]=[CH:19]\2)[C:3](=[O:15])[N:4]1[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Cc1c(N)c(=O)n(-c2ccccc2)n1C
Reactant: Cc1ccccc1O
Agent: N#C[Fe-3](C#N)(C#N)(C#N)(C#N)C#N
Agent: N
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Product: CC1=C/C(=N\c2c(C)n(C)n(-c3ccccc3)c2=O)C=CC1=O

Procedure:
10 mmol of 4-amino-1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one was dissolved in 30 ml of water. This solution was admixed with 10 mmol of o-cresol in solution in 30 ml of 2-propanol, 3 ml of 20% aqueous ammonia and 22 mmol of potassium ferricyanide at a temperature ranging from 5 to 10° C.
Reaction SMILES: CO[C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].[NH2:22][CH:23]([CH2:26][OH:27])[CH2:24][OH:25]>>[OH:25][CH2:24][CH:23]([NH:22][C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4])[CH2:26][OH:27]
Reactant: NC(CO)CO
Reactant: CCCCc1noc(C)c1COc1cc(C(=O)OC)[nH]n1
Product: CCCCc1noc(C)c1COc1cc(C(=O)NC(CO)CO)[nH]n1
Yield: 10 %

Procedure:
As described for example 27, 5-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-2H-pyrazole-3-carboxylic acid methyl ester (100 mg, 0.34 mmol) was converted, using 2-amino-1,3-propandiol instead of L-alaninol, to the title compound (12 mg, 10%) which was obtained as a white solid. MS: m/e=353.3 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([CH:9]=[CH:10][N:11]=2)[N:5]=[C:6]([Cl:8])[CH:7]=1.CC1C=CC(S(O)(=O)=O)=CC=1.[CH:23]1([NH2:26])[CH2:25][CH2:24]1>CS(C)=O>[Cl:8][C:6]1[CH:7]=[C:2]([NH:26][CH:23]2[CH2:25][CH2:24]2)[C:3]2[N:4]([CH:9]=[CH:10][N:11]=2)[N:5]=1
Reactant: NC1CC1
Reactant: Clc1cc(Br)c2nccn2n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CS(C)=O
Product: Clc1cc(NC2CC2)c2nccn2n1
Temperature: 100 °C
Yield: 80 %

Procedure:
To a solution of 8-bromo-6-chloroimidazo[1,2-b]pyridazine (1.00 g, 3.21 mmol, 1.0 equiv) and p-TSA (611 mg, 3.21 mmol, 1.0 equiv) in DMSO (10.0 mL) was added cyclopropylamine (1.13 mL, 16.1 mmol, 5.0 equiv) and heated to 100° C. for 24 h. Purification by column chromatography using 50% ethyl acetate in hexanes elution gave 536 mg of the white solid, 80%.
Reaction SMILES: C([O:5][C:6](=[O:33])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([S:29]([CH3:32])(=[O:31])=[O:30])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[S:25][CH:26]=[CH:27][N:28]=3)=[CH:20][CH:19]=2)[CH:10]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:32][S:29]([N:16]([CH2:15][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[O:8][CH2:7][C:6]([OH:33])=[O:5])[CH2:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[S:25][CH:26]=[CH:27][N:28]=2)=[CH:22][CH:23]=1)(=[O:30])=[O:31]
Reactant: CC(C)(C)OC(=O)COc1cccc(CN(Cc2ccc(-c3nccs3)cc2)S(C)(=O)=O)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)N(Cc1ccc(-c2nccs2)cc1)Cc1cccc(OCC(=O)O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.1 %

Procedure:
A solution of (3-{[methanesulfonyl-(4-thiazol-2-yl-benzyl)-amino]-methyl}-phenoxy)-acetic Acid Tert-butyl Ester (0.074 g) in 2 mL CH2Cl2 was cooled to 0° C. and 2 mL trifluoroacetic Acid was added. The reaction was stirred at room temperature for 2 hours. The solvent was removed by evaporation azeotroping with CH2Cl2 to afford the title compound (40 mg). 1H NMR (400 MHz, CDCl3) δ 9.94 (bs, 1H), 8.14 (s, 1H), 7.81 (d, 2H), 7.55 (s, 1H), 7.37 (d, 2H), 7.18 (m, 1H), 6.90 (d, 1H), 6.80 (d, 1H), 6.63 (s, 1H), 4.58 (s, 2H), 4.35 (s, 2H), 4.29 (s, 2H), 2.93 (s, 3H); MS 431 (M−1).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22]([S:33][C:34]3[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][CH:35]=3)[NH:23][C:24]=2[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:16][CH:15]=1>ClCCl>[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[N:21]=[C:22]([S:33]([C:34]3[CH:39]=[CH:38][C:37]([C:40]([F:42])([F:43])[F:41])=[CH:36][CH:35]=3)=[O:9])[NH:23][C:24]=2[C:25]2[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)=[CH:18][CH:19]=1
Reactant: COc1ccc(-c2nc(Sc3ccc(C(F)(F)F)cc3)[nH]c2-c2ccc(OC)cc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1ccc(-c2nc(S(=O)c3ccc(C(F)(F)F)cc3)[nH]c2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.9 %

Procedure:
A solution of 2.164 g of 3-chloroperbenzoic acid (80%) in 150 ml of dichloromethane is added dropwise to a solution of 4.57 g of 4,5-bis(4-methoxyphenyl)-2-(4-trifluoromethylphenylthio)imidazole in 100 ml of dichloromethane. The mixture is agitated for 3 hours at room temperature, the solution is washed with sodium bicarbonate solution, dried over sodium sulfate, and concentrated to dryness under vacuum. The residue is chromatographed on 150 g of silica gel with acetone/hexane, thus producing 3.78 g of 4,5-bis-(4-methoxyphenyl)-2-(4-trifluoromethylphenylsulfinyl)imidazole as an amorphous foam.
Reaction SMILES: [CH:1]1[C:14]2[CH:13]([CH2:15][C:16](Cl)=[O:17])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:19]([C:21]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]([OH:31])[CH2:29][CH3:30])[C:22]=1[NH2:23])[CH3:20]>>[CH2:19]([C:21]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]([O:31][C:16](=[O:17])[CH2:15][CH:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[O:6][C:5]3[C:14]2=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH2:29][CH3:30])[C:22]=1[NH:23][C:16](=[O:17])[CH2:15][CH:13]1[C:14]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[O:6][C:7]2[C:12]1=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:20]
Reactant: CCc1cccc(C(O)CC)c1N
Reactant: O=C(Cl)CC1c2ccccc2Oc2ccccc21
Product: CCc1cccc(C(CC)OC(=O)CC2c3ccccc3Oc3ccccc32)c1NC(=O)CC1c2ccccc2Oc2ccccc21

Procedure:
Following a procedure similar to that described in Example 21, but using 2.2 equivalents of 2-(9H-xanthen-yl)acetyl chloride and one equivalent of 2-ethyl-6-(1-hydroxypropyl)aniline, the title compound was obtained as a foam-like material.
Reaction SMILES: [CH3:1][S:2]([O:5]S(C)(=O)=O)(=[O:4])=[O:3].[CH3:10][C@@H:11](O)[CH2:12][CH3:13].C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:5][C@H:11]([CH3:10])[CH2:12][CH3:13])(=[O:4])=[O:3]
Reactant: CC[C@@H](C)O
Reactant: CS(=O)(=O)OS(C)(=O)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@@H](C)OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of methanesulphonic anhydride (8.33 g, 47.8 mmol) in dichloromethane (30 ml) was added dropwise over 30 minutes to an ice-cooled solution of (R)-2-butanol (4.0 ml, 43.5 mmol) and triethylamine (6.65 ml, 47.8 mmol) in dichloromethane (70 ml). The reaction was then allowed to warm to room temperature and stirred for 18 hours. The mixture was then washed with water, 2N hydrochloric acid, then dried (Na2SO4) and evaporated under reduced pressure to give the title compound as a pale yellow oil, 7.0 g.
Reaction SMILES: [CH3:1][C@@H:2]1[N:7]([C:8]2[C:17]3[C:12](=[CH:13][C:14](B(O)O)=[CH:15][CH:16]=3)[CH:11]=[N:10][N:9]=2)[CH2:6][CH2:5][O:4][CH2:3]1.[CH:21]1([NH:24][C:25]2[C:29]3[CH:30]=[CH:31][C:32]([CH3:35])=[C:33](I)[C:28]=3[O:27][N:26]=2)[CH2:23][CH2:22]1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.CCOC(C)=O.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>[CH:21]1([NH:24][C:25]2[C:29]3[CH:30]=[CH:31][C:32]([CH3:35])=[C:33]([C:14]4[CH:13]=[C:12]5[C:17](=[CH:16][CH:15]=4)[C:8]([N:7]4[CH2:6][CH2:5][O:4][CH2:3][C@@H:2]4[CH3:1])=[N:9][N:10]=[CH:11]5)[C:28]=3[O:27][N:26]=2)[CH2:23][CH2:22]1
Reactant: Cc1ccc2c(NC3CC3)noc2c1I
Reactant: C[C@H]1COCCN1c1nncc2cc(B(O)O)ccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1ccc2c(NC3CC3)noc2c1-c1ccc2c(N3CCOC[C@@H]3C)nncc2c1
Temperature: 130 °C

Procedure:
A mixture of (S)-1-(3-methylmorpholino)phthalazin-6-ylboronic acid (0.11 g, 0.41 mmol), N-cyclopropyl-7-iodo-6-methylbenzo[d]isoxazol-3-amine (0.100 g, 0.32 mmol), tetrakis(triphenylphosphine)palladium (18 mg, 0.016 mmol) in 1,4-dioxane (2.0 mL) and 2 N aqueous sodium carbonate (0.2 mL, 0.4 mmol) in a sealed glass tube was heated in a Personal Chemistry microwave at 130° C. for 20 min. The mixture was diluted with EtOAc (30 mL) and washed with saturated aqueous solution of sodium bicarbonate, and brine. The resulting organic solution was then dried over magnesium sulfate and concentrated under reduced pressure. Flash chromatography on silica gel (ethyl acetate: chloroform 80:20) afforded the titled compound as a yellow solid. MS (ESI, pos.ion) m/z: 416.1 (M+1).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH:7]1([NH2:10])[CH2:9][CH2:8]1.Br[CH:12]1[CH2:17][CH2:16][O:15][C:13]1=[O:14].O>C(#N)C>[CH:7]1([NH:10][CH:12]2[CH2:17][CH2:16][O:15][C:13]2=[O:14])[CH2:9][CH2:8]1
Reactant: O=C1OCCC1Br
Reactant: NC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=C1OCCC1NC1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.2 %

Procedure:
After potassium carbonate (18.24 g, 132.0 mmol) was added to a solution of cyclopropylamine (5.50 ml, 80.0 mmol) and (±)-α-bromo-γ-butyrolactone (3.32 ml, 42.0 mmol) in acetonitrile (80 ml), the mixture was stirred at room temperature for 8 hours. To the reaction mixture, water was added and then this was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane/ethyl acetate=1/1 as the eluant to give (±)-α-cyclopropylamino-γ-butyrolactone (4.10 g, yield 73%) as a yellow oil.
Reaction SMILES: [CH3:1][CH:2]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:3]([C:5]1[CH:6]=[C:7]([OH:12])[CH:8]=[C:9]([CH:11]=1)[OH:10])[CH3:4].C[O:19][C:20]([CH:22]1[C:27](=O)[CH2:26][CH2:25][CH2:24][S:23]1)=O.Cl>C(O)C>[OH:10][C:9]1[C:8]2[C:27]3[CH2:26][CH2:25][CH2:24][S:23][C:22]=3[C:20](=[O:19])[O:12][C:7]=2[CH:6]=[C:5]([CH:3]([CH:2]([CH3:1])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH3:4])[CH:11]=1
Reactant: CCCCCC(C)C(C)c1cc(O)cc(O)c1
Reactant: COC(=O)C1SCCCC1=O
Agent: Cl
Solvent: CCO
Product: CCCCCC(C)C(C)c1cc(O)c2c3c(c(=O)oc2c1)SCCC3
Reaction time: 48 h

Procedure:
A solution of 14.2 g. (0.06 mole) of 5-(3-methyl-2-octyl)resorcinol and 11.1 g. (0.063 mole) of methyl-3-oxo2,3,4,5-tetrahydro-6H-thiopyran-2-carboxylate in 90 ml. of absolute ethanol was cooled in an ice-salt bath and saturated with anhydrous hydrogen chloride. After standing for 2 days at room temperature, the ethanol was removed on a rotary evaporator. The residue was dissolved in ether, washed with sodium bicarbonate solution and dried over sodium sulfate. Evaporation of the solvent gave 28.0 g. of residue which was chromatographed using Florisil (60-100 mesh) and graded methanol/chloroform solvent mixtures. A total of 10 g. of crude solid was obtained from the 1% methanol/chloroform fractions. The material was recrystallized twice from ethyl acetate/hexane to give 8.5 g. (40%) colorless crystals, m.p. 131°-133°. The proposed structure was confirmed by IR and nmr.
Reaction SMILES: [C:1]([CH:6]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:3][CH2:4][CH3:5])=[O:2].[CH:26]1([OH:35])[CH:34]2[CH:29]([CH2:30][CH2:31][CH2:32][CH2:33]2)[CH2:28]O1>C(#N)C>[OH:35][CH2:26][CH:34]1[CH2:33][CH2:32][CH2:31][CH2:30][CH:29]1/[CH:28]=[CH:6]/[C:1]([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OC1OCC2CCCCC21
Solvent: CC#N
Product: CCOC(=O)/C=C/C1CCCCC1CO
Temperature: 85 °C
Reaction time: 2 h

Procedure:
DIBAL-H (1M in toluene) (35.2 mmol, 35.2 mL) was added dropwise to a solution of hexahydroisobenzofuran-1(3H)-one (33.5 mol, 4.7 g) in anhydrous ether (100 mL) at −10° C. under argon. The resulting mixture was stirred at −10° C. for 30 min under argon and quenched with MeOH (30 mL). The mixture was stirred at rt for overnight and the resulting suspension was added saturated Rochelle's salt aqueous solution and stirred for additional 30 min at rt. The organic layer was separated and washed with saturated Rochelle's salt aqueous solution. The combined aqueous layer was extracted with ether (3×). The organic layer were combined, dried with dried with MgSO4 and concentrated in vacuo to give lactol octahydroisobenzofuran-1-ol which was used for next step without further purification. (Carbethoxymethylene)triphenylphosphorane (17.7 g, 50.7 mmol) was added to a solution of the above described octahydroisobenzofuran-1-ol in acetonitrile (100 mL) and the resulting mixture was refluxed at 85° C. overnight. Acetonitrile was removed in vacuo and the resulting residue was diluted with ether which was stirred at rt for 2 h. The white precipitate was filtered off and washed with cold ether. All ether portion was combined and concentrated in vacuo to give crude product which was purified by chromatograph to afford desired (E)-ethyl 3-(2-(hydroxymethyl)cyclohexyl)acrylate as colorless oil (Y: 78.9% over two steps). 1H NMR (CDCl3, 400 MHz) δ 7.12-7.05 (m, 1H), 5.80 (d, 1H), 4.15-4.09 (m, 2H), 3.40-3.37 (m, 2H), 2.63-2.59 (m, 1H), 1.80-1.29 (m, 9H), 1.25-1.19 (m, 3H).
Reaction SMILES: [N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[C:21]([I:23])[CH:20]=[CH:19][C:15]=3[C:16](O)=[O:17])(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12.Cl.[NH2:25][C@H:26]([CH3:36])[C@H:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([Br:35])[CH:30]=1)[OH:28]>>[N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[C:21]([I:23])[CH:20]=[CH:19][C:15]=3[C:16]([NH:25][C@H:26]([CH3:36])[C@H:27]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([Br:35])[CH:30]=3)[OH:28])=[O:17])(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12
Reactant: O=C(O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nsnc12
Reactant: C[C@@H](N)[C@@H](O)c1cccc(Br)c1
Agent: Cl
Product: C[C@@H](NC(=O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nsnc12)[C@@H](O)c1cccc(Br)c1

Procedure:
2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodobenzoic acid was coupled with (1S,2R)-2-amino-1-(3-bromo-phenyl)-propan-1-ol hydrochloride salt (EXAMPLE 108, Part E) as in Example 1, Part C (11 mg, 16%). HPLC: RT=10.19 min. MS (ESI−): mass calcd. for C22H18BrIN4O4S2, 673.34; m/z found, 671/673 [M−H]−. 1H NMR (500 MHz, CDCl3): 11.45 (s, 1H), 8.37 (d, J=7.0, 1H), 8.23 (d, J=8.8, 1H), 8.08 (d, J=1.5, 1H), 7.73 (dd, J=8.8, 7.1, 1H), 7.55-7.53 (m, 1H), 7.47-7.43 (m, 1H), 7.33 (dd, J=8.2, 1.5, 1H), 7.31-7.21 (m, 3H), 6.99 (d, J=8.3, 1H), 6.19 (d, J=8.6, 1H), 4.95-4.94 (m, 1H), 4.44-4.40 (m, 1H), 2.60 (s, 1H), 1.03 (d, J=6.9, 3H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([CH3:5])=[O:4].[C-:8]#[N:9].[C-]#N.[Na+].Cl>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:4])([CH3:5])[C:8]#[N:9]
Reactant: CC(=O)C(F)(F)F
Reactant: [C-]#N
Agent: Cl
Agent: [Na+]
Product: CC(O)(C#N)C(F)(F)F

Procedure:
In Scheme 2, 1,1,1-trifluoroacetone (1) is reacted with a cyanide such as sodium cyanide in the presence of an acid such as hydrochloric acid to form racemic 3,3,3-trifluoro-2-hydroxy-2-methylpropanenitrile (2). The racemic 3,3,3-trifluoro-2-hydroxy-2-methylpropanenitrile (2) is then hydrolyzed with, for example, hydrochloric acid or sulfuric acid to provide racemic 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (3). Racemic (3) is then selectively crystallized with a resolving agent such as (lR,2S)-norephedrine (4) to form a salt (5) which may be recrystallized to diastereomeric purity. The purified salt (6) contains (S)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (7). (S)-3,3,3-Trifluoro-2-hydroxy-2-methylpropanoic acid (7) after liberation from the salt is reacted with 4-aminobenzophenone (8) and SOCl2 using an organic base such as triethylamine or Hunig's base to form (S)-(−)-N-(4-benzoylphenyl)-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide (9), which can then be purified by recrystallization.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[Br:26])[CH2:5][N:6]1[N:15]=[C:14]([CH2:16][C:17]([O:19]CC)=[O:18])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:22].[OH-].[K+].O>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[Br:26])[CH2:5][N:6]1[N:15]=[C:14]([CH2:16][C:17]([OH:19])=[O:18])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:22]
Reactant: CCOC(=O)Cc1nn(Cc2ccc(Br)c(Cl)c2)c(=O)c2ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)Cc1nn(Cc2ccc(Br)c(Cl)c2)c(=O)c2ccccc12
Yield: 59.5 %

Procedure:
A solution of ethyl 2-(3-chloro-4-bromobenzyl)-1,2-dihydro-1-oxophthalazin-4-ylacetate (7.0 g.) in ethanol (70 ml.) containing potassium hydroxide (7.0 g.) was heated under reflux for 30 minutes. The solution was then poured into water (250 ml.) and the aqueous solution was extracted with ether (2×150 ml.). The aqueous phase was acidified to pH 2 with concentrated hydrochloric acid. The solid which was thus precipitated was separated, washed with water, dried in vacuo and then recrystallised from a 6:2:3 v/v/v mixture of toluene, propan-2-ol and petrol (60-80) to give 2-(3-chloro-4-bromobenzyl)-1,2-dihydro-1-oxophthalazin-4-ylacetic acid (3.9 g.), m.p. 186° C.