Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH2:17])(=[O:16])=[O:15])=[CH:10][C:9]=1[N+:18]([O-])=O)(=[O:7])=[O:6].Cl>O.C(O)C.[Fe]>[OH:1][CH2:2][CH2:3][CH2:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH2:17])(=[O:15])=[O:16])=[CH:10][C:9]=1[NH2:18])(=[O:6])=[O:7]
Reactant: NS(=O)(=O)c1ccc(S(=O)(=O)CCCO)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: Nc1cc(S(N)(=O)=O)ccc1S(=O)(=O)CCCO

Procedure:
A mixture of 4-(3-hydroxypropylsulfonyl)-3-nitrobenzenesulfonamide (4.0 g, 0.012 mol), iron powder (11 g), and 12M HCl (0.6 ml) in 10 ml water and 40 ml ethanol was refluxed on a steam bath for about 2 hours. The reaction mixture was filtered hot, and the solvent evaporated. The residue was taken up in ethyl acetate, washed with water, saturated sodium bicarbonate, water, then brine. After drying, evaporation of solvent left a residue that quickly crystallized. The solid was washed with water and collected. Recrystallization from butanol left 2.0 g of a white solid. M.p.=136.5°-138° C.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:7]3[C:8]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28]CC5C=CC=CC=5)[CH:23]=4)=[C:9]4[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][C:10]4=[CH:11][C:12]=3[CH2:13][C:14]=2[CH:15]=1.C(OC1C=C([Li])C=CC=1)C1C=CC=CC=1>>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[C:7]3[C:8]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=4)=[C:9]4[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:10]4=[CH:11][C:12]=3[CH2:13][C:14]=2[CH:15]=1
Reactant: COc1ccc2c(c1)Cc1cc3cc(OC)ccc3c(-c3cccc(OCc4ccccc4)c3)c1-2
Agent: [Li]c1cccc(OCc2ccccc2)c1
Product: Oc1cccc(-c2c3c(cc4cc(O)ccc24)Cc2cc(O)ccc2-3)c1
Yield: 14 %

Procedure:
Compound 62b was prepared from 2,8-dimethoxy-5-(3-benzyloxyphenyl)-11H-benzo[b]fluorene, 61b, in 14% yield, in the same fashion as described for the preparation of 62a, but using 3-(benzyloxy) phenyl lithium instead of 4-(benzyloxy) phenyl lithium (Rf<0.26 CH2Cl2/methanol (9:1)); ESI-MS: M+H=341.2, M−H=339.0.
Reaction SMILES: CC1C=CC(S([O:11][CH2:12][C@@H:13]2[CH2:18][O:17][C@@H:16]([CH:19]=[CH2:20])[CH2:15][O:14]2)(=O)=O)=CC=1.O.[OH-].[Na+]>C([O-])(=O)C.C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O.CCOC(C)=O>[CH:19]([C@H:16]1[CH2:15][O:14][C@H:13]([CH2:12][OH:11])[CH2:18][O:17]1)=[CH2:20]
Reactant: C=C[C@H]1CO[C@H](COS(=O)(=O)c2ccc(C)cc2)CO1
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: C=C[C@H]1CO[C@H](CO)CO1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of ((2S,5S)-5-vinyl-1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate (2.0 g, 6.70 mmol, Preparation #11) and tetrabutylammonium acetate (2.63 g, 8.71 mmol) in dimethylformamide (5 mL) were heated at about 70° C. for about 3 h. The reaction mixture was cooled to RT and the reaction vessel was charged sequentially with water (2 mL) and 1.0 N aqueous sodium hydroxide (4.0 mL). After stirring for about 20 min at RT, the mixture was diluted with EtOAc with (20 mL) and washed with brine solution (2×20 mL). The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude material obtained was purified by column chromatography eluting with 30-40% EtOAc in hexane. The relevant fractions containing product were combined and concentrated to afford ((2R,5S)-5-vinyl-1,4-dioxan-2-yl)methanol. 0.7 g (72.4%). 1H NMR (400 MHz, CDCl3): δ 5.77-5.68 (m, 1H), 5.38-5.22 (m, 2H), 4.04-3.99 (m, 1H), 3.86-3.81 (m, 2H), 3.68-3.52 (m, 4H), 3.44-3.38 (m, 1H); IR (Neat):3433 cm−1 (OH str)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11](=[O:13])[N:10]([CH2:14][C:15]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])=[O:16])[N:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:36][CH2:37][Cl:38]>C1(C)C=CC=CC=1.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O.C(OCC)(=O)C>[Cl:38][CH2:37][CH2:36][N:12]1[C:11](=[O:13])[N:10]([CH2:14][C:15]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]([F:26])([F:27])[F:28])=[O:16])[N:9]=[C:8]1[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: O=C(Cn1nc(-c2ccc(Cl)cc2)[nH]c1=O)NCc1ccccc1C(F)(F)F
Reactant: ClCCI
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(Cn1nc(-c2ccc(Cl)cc2)n(CCCl)c1=O)NCc1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
500 mg (1.01 mmol) of 2-[3-(4-chlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-[2-(trifluoromethyl)benzyl]-acetamide from Example 243A are dissolved in 10 ml of toluene with 230 mg (1.01 mmol) of benzyltriethylammonium chloride. Next, a solution of 658 mg (2.02 mmol) of caesium carbonate, dissolved in 1.0 ml water, is added, and the mixture vigorously stirred at RT for 30 mins. After addition of 1.92 g (10.13 mmol) of 1-iodo-2-chloroethane, the mixture is heated for 7 hrs at 80° C. with vigorous stirring. The suspension is then diluted with ethyl acetate and washed once each with water, 10% sodium thiosulphate and saturated ammonium chloride solution. The organic phase is dried over sodium sulphate, filtered and concentrated in vacuo. The crude product is purified by preparative HPLC [Method 9]. 195 mg (41% of theory) of the target compound are thus obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][CH3:11])[C:3]=1[C:4]#[N:5].N1C=CC=CC=1.[CH2:18]([O:20][CH2:21][C:22](Cl)=[O:23])[CH3:19].O>C(Cl)Cl>[CH2:18]([O:20][CH2:21][C:22]([NH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][CH3:11])[C:3]=1[C:4]#[N:5])=[O:23])[CH3:19]
Reactant: CNc1cccc(N)c1C#N
Reactant: CCOCC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CCOCC(=O)Nc1cccc(NC)c1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-amino-6-(methylamino)benzonitrile (3.3 g) in methylene chloride (50 ml) is added pyridine (3.9 ml), and thereto is added dropwise ethoxyacetyl chloride (5 ml) which is cooled in an ice bath. The mixture is stirred at room temperature for 1 hour, and thereafter, water is added thereto, and the mixture is extracted with methylene chloride. The organic layer is dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure The resulting crude crystals are recrystallized from ethyl acetate-hexane to give the title compound (3.2 g) having the following physical properties.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:14][CH2:15][CH:16]=[C:17]([Cl:19])[Cl:18])[CH:5]=[C:6]([Cl:13])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][OH:12].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1.N1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([O:14][CH2:15][CH:16]=[C:17]([Cl:19])[Cl:18])[CH:5]=[C:6]([Cl:13])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][O:12][C:28](=[O:29])[NH:27][C:24]1[CH:25]=[CH:26][C:21]([Cl:20])=[CH:22][CH:23]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: OCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: O=C(Nc1ccc(Cl)cc1)OCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reaction time: 3 h
Yield: 77.4 %

Procedure:
A solution of 0.17 g of 3,5-dichloro-4-(3-hydroxypropyloxy)-1-(3,3-dichloro-2-propenyloxy)benzene, 0.09 g of 4-chlorophenyl isocyanate and a catalytic amount of pyridine dissolved in 10 ml of toluene was heated at 60° to 70° C., while stirring, for 3 hours, and the reaction mixture was then concentrated to give a residue. The residue was subjected to silica gel chromatography, which afforded 0.19 g of 3,5-dichloro-4-(3-(N-(4-chlorophenyl)carbamoyloxy)propyloxy)-1-(3,3-dichloro-2-propenyloxy)benzene (77% yield), m.p., 54.3° C.
Reaction SMILES: Cl[C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C:7]2[CH:8]=[C:9]([C:18]([OH:20])=[O:19])[C:10](=[O:17])[N:11]3[C:16]=2[CH:15]=[CH:14][CH:13]=[CH:12]3)=[CH:4][CH:3]=1.[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>C1COCC1.[Pd].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[C:2]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:22]=[CH:21][C:5]([CH2:6][C:7]2[CH:8]=[C:9]([C:18]([OH:20])=[O:19])[C:10](=[O:17])[N:11]3[C:16]=2[CH:15]=[CH:14][CH:13]=[CH:12]3)=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc(Cc2ccc(Cl)cc2)c2ccccn2c1=O
Reactant: OB(O)c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: Cl
Solvent: C1CCOC1
Product: O=C(O)c1cc(Cc2ccc(-c3ccccc3)cc2)c2ccccn2c1=O
Temperature: 100 °C

Procedure:
To a solution of 1-(4-chlorobenzyl)-4-oxo-4H-quinolizine-3-carboxylic acid (0.060 g, 0.19 mmol) in 2 mL of THF under N2(g) was added phenylboronic acid (0.035 g, 0.29 mmol), 1 N cesium carbonate (0.38 mL, 0.38 mmol), and bis (tri-tert-butylphosphine) palladium(0). The reaction was heated to 100° C. for 15 h, cooled to rt, and acidified with 6 N HCl to pH ˜3. The mixture was then filtered and subjected to purification via reverse phase HPLC to yield the title compound that gave a mass ion (ES+) of 356.0 for M+H+. 1H NMR (400 MHz, d6-DMSO) δ 9.40 (d, J=7.2 Hz, 1H), 8.41 (s, 1H), 8.23 (d, J=9.0 Hz, 1H), 8.09-8.05 (m, 1H), 7.69 (d, J=6.9 Hz, 1H), 7.63-7.58 (m, 4H), 7.46-7.42 (m, 2H), 7.35-7.33 (m, 3H), 4.39 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:18]([F:19])=[CH:17][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([O:15]C)[CH:10]=2)=[O:7])=[C:4]([F:20])[CH:3]=1.Br.O>CC(O)=O>[Cl:1][C:2]1[C:18]([F:19])=[CH:17][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=2)=[O:7])=[C:4]([F:20])[CH:3]=1
Reactant: COc1cc(NC(=O)c2cc(F)c(Cl)cc2F)ccn1
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: O=C(Nc1cc[nH]c(=O)c1)c1cc(F)c(Cl)cc1F
Temperature: 90 °C
Reaction time: 5 h
Yield: 33.9 %

Procedure:
To 4-chloro-2,5-difluoro-N-(2-methoxy-4-pyridyl)benzamide (3 g, 10.04 mmol) in HOAc (15.9 mL) was added HBr 33% in HOAc (12.31 mL of 33% w/v, 50.20 mmol) and the mixture was stirred at 90° C. for 5 h. Additional HBr (10 mL, 33% in HOAc) was added and the mixture was stirred at 90° C. overnight. The mixture was cooled to room temperature and was poured into water (100 mL). The mixture was stirred and the solid was collected by filtration. The solid was washed with water (2×50 mL). The solid was slurried in hexanes (2×50 mL) and filtered to give 4-chloro-2,5-difluoro-N-(2-oxo-1H-pyridin-4-yl)benzamide (969.7 mg, 34%) as a cream colored solid. ESI-MS m/z calc. 284.02. found 285.3 (M+1)+; Retention time: 1.36 minutes (3 min run).
Reaction SMILES: [OH:1][CH:2]1[CH:8]([NH:9][C:10](=[O:17])[C@@H:11]([NH2:16])[CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:7][CH2:6][CH2:5][N:4]([S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)(=[O:20])=[O:19])[CH2:3]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[O:41]1[C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=2[CH:43]=[C:42]1[C:50](O)=[O:51]>ClCCl.C(OCC)(=O)C.CO>[CH3:14][CH:13]([CH3:15])[CH2:12][C@H:11]([NH:16][C:50]([C:42]1[O:41][C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=2[CH:43]=1)=[O:51])[C:10](=[O:17])[NH:9][CH:8]1[CH2:7][CH2:6][CH2:5][N:4]([S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)(=[O:20])=[O:19])[CH2:3][CH:2]1[OH:1]
Reactant: CC(C)C[C@H](N)C(=O)NC1CCCN(S(=O)(=O)c2ccccn2)CC1O
Reactant: O=C(O)c1cc2ccccc2o1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CO
Solvent: ClCCCl
Product: CC(C)C[C@H](NC(=O)c1cc2ccccc2o1)C(=O)NC1CCCN(S(=O)(=O)c2ccccn2)CC1O

Procedure:
To a solution of (S)-2-amino-4-methyl-pentanoic acid [3-hydroxy-1-(pyridine-2-sulfonyl)-azepan-4-yl]-amide of Example 28a (0.15 g) in dichloromethane was added TEA (0.11 mL), HOBt (49 mg), EDC (69 mg) and benzofuran-2-carboxylic acid (58 mg). The reaction was stirred until complete. Workup and column chromatography (5% methanol:ethyl acetate) provided the title compound: MS(EI) 529 (M+H+).
Reaction SMILES: [F:1][C:2]([F:24])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:3]1[CH:4]=[N:5][C:6]([N:9]2[CH2:14][CH2:13][N:12](C([O-])=O)[CH2:11][CH2:10]2)=[N:7][CH:8]=1.I[Si](C)(C)C>C(Cl)(Cl)Cl>[F:24][C:2]([F:1])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:3]1[CH:4]=[N:5][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:7][CH:8]=1
Reactant: O=C([O-])N1CCN(c2ncc(C(F)(F)c3ccccc3)cn2)CC1
Agent: C[Si](C)(C)I
Solvent: ClC(Cl)Cl
Product: FC(F)(c1ccccc1)c1cnc(N2CCNCC2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.2 %

Procedure:
To a solution of 4-(5-(difluoro(phenyl)methyl)pyrimidin-2-yl)piperazine-1-carboxylate (180 mg, 0.42 mmol) in chloroform (5.0 mL) was added iodotrimethylsilane (0.8 mL) and the mixture was stirred at room temperature for 0.5 h. The reaction was quenched by methanol (1.0 mL), followed by the addition of 2 N HCl/dioxane (2.0 mL) and evaporated to dryness. The residue was dissolved in methanol (1.5 mL) and dropwise added into acetone (100 mL). The solid was collected by filtration and washed with acetone (10 mL) to afford crude 5-(difluoro(phenyl)methyl)-2-(piperazin-1-yl)pyrimidine (88 mg) as a yellow solid. MS (ES+) C15H16F2N4 requires: 290, found: 291 [M+H]+.
Reaction SMILES: [CH2:1]([O:5][CH:6]([O:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:7][NH2:8])[CH2:2][CH2:3][CH3:4].BrC[CH2:16][CH:17]1[O:22][CH:21]([CH3:23])[CH:20]([CH3:24])[CH2:19][O:18]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:10]([O:9][CH:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[CH2:7][NH:8][CH2:16][CH:17]1[O:22][CH:21]([CH3:23])[CH:20]([CH3:24])[CH2:19][O:18]1)[CH2:11][CH2:12][CH3:13]
Reactant: CCCCOC(CN)OCCCC
Reactant: CC1COC(CCBr)OC1C
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCOC(CNCC1OCC(C)C(C)O1)OCCCC
Temperature: 25 °C

Procedure:
2,2-Dibutoxyethylamine (0.11 mole), 2-bromoethyl-4,5-dimethyl-1,3-dioxane (0.1 mole), triethylamine (20 ml) and toluene (150 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction is heated at reflux for a period of about 12 hours. After this time the reaction mixture is allowed to cool to room temperature and is filtered. The reaction mixture is then stripped of solvent and unreacted starting materials under reduced pressure to yield the desired product N-(2,2-dibutoxyethyl)-N-(4,5-dimethyl-1,3-dioxan-2-ylmethyl)-amine.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[O:8][CH2:7][CH2:6][N:5]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:4]1.N1C=CC=CC=1.[C:22](OC(=O)C)(=[O:24])[CH3:23].C(=O)([O-])O.[Na+].[OH-].[Na+]>C1(C)C=CC=CC=1>[C:22]([NH:1][CH2:2][CH:3]1[O:8][CH2:7][CH2:6][N:5]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:4]1)(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: NCC1CN(Cc2ccccc2)CCO1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(=O)NCC1CN(Cc2ccccc2)CCO1
Reaction time: 1 h
Yield: 44.9 %

Procedure:
To a solution of crude 2-aminomethyl-4-benzylmorpholine (48 g) in toluene (400 ml) was added pyridine (24.5 ml, 0.303 mol) and then acetic anhydride (26.4 ml, 0.280 mol) was added dropwise under ice-cooling over 10 minutes and then allowed to rise to room temperature and the mixture was stirred for one hour. To the reaction mixture was added aqueous saturated sodium hydrogen carbonate (200 ml) under ice-cooling and then 10% aqueous sodium hydroxide was added until the mixture became strongly basic. The reaction mixture was extracted with ethyl acetate (200 ml×3) and the combined organic layer was washed with aqueous saturated sodium chloride (200 ml). The organic layer was dried over potassium carbonate and the solvent was distilled off under reduced pressure. The residue was recrystallized from ethyl acetate-hexane (1/1) to give 2-(N-acetylaminomethyl)-4-benzylmorpholine (25.93 g). A total yield of 3 steps=56%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[C:5]2[O:10]C[N:8]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:7][C:6]=2[CH:15]=1.[F:24][C:25]([F:36])([F:35])[C:26]1[N:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOCCOC.O>[C:11]([NH:8][CH2:7][C:6]1[CH:15]=[C:2]([C:29]2[CH:30]=[N:31][C:26]([C:25]([F:36])([F:35])[F:24])=[CH:27][CH:28]=2)[CH:3]=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[C:5]=1[OH:10])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)N1COc2c(cc(Br)cc2-c2ccc(Cl)c(Cl)c2)C1
Reactant: OB(O)c1ccc(C(F)(F)F)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOCCOC
Product: CC(C)(C)NCc1cc(-c2ccc(C(F)(F)F)nc2)cc(-c2ccc(Cl)c(Cl)c2)c1O
Temperature: 68 °C
Yield: 15.2 %

Procedure:
A mixture of 6-bromo-3-(tert-butyl)-8-(3,4-dichlorophenyl)-3,4-dihydro-2H-benzo[e][1,3]oxazine (0.743 g, 1.80 mmol), (6-(trifluoromethyl)pyridin-3-yl)boronic acid (0.685 g, 2.0 equiv), and potassium carbonate (0.995 g, 4 equiv) in 2-methoxyethyl ether (32 mL) and water (6.5 mL) was purged with nitrogen for 20 minutes. Tetrakis(triphenylphosphine)Pd (0) (0.120 g, 5.8 mol %) was added and the resulting mixture was heated at 65-71° C. for 2 hours. The cooled reaction mixture was concentrated and the resulting residue was purified by column chromatograph to give 3-((tert-butylamino)methyl)-3′,4′-dichloro-5-(6-(trifluoromethyl)pyridine-3-yl)-[1,1′-biphenyl]2-ol (0.128 g). The free base was dissolved in methanol, and to the solution 37% HCl was added. The resulting solid was filtered and rinsed with ethyl acetate to give 3-((tert-butylamino)methyl)-3′,4′-dichloro-5-(6-(trifluoromethyl)pyridine-3-yl)-[1,1′-biphenyl]2-ol hydrochloride (0.126 g).
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[C:8]([OH:9])[C:6]([OH:7])=[C:4]([OH:5])[CH:3]=1.C(O[C:17](=[O:19])[CH3:18])(=O)C.S(=O)(=O)(O)O>O>[C:4]([O:5][C:4]1[CH:3]=[C:2]([CH:10]=[C:8]([O:9][C:17](=[O:19])[CH3:18])[C:6]=1[O:7][C:6](=[O:7])[CH3:8])[C:1]([OH:12])=[O:11])(=[O:5])[CH3:3]
Reactant: O=C(O)c1cc(O)c(O)c(O)c1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)Oc1cc(C(=O)O)cc(OC(C)=O)c1OC(C)=O
Temperature: 25 °C
Reaction time: 0.02 h

Procedure:
In a one liter round bottom flask, with a magnetic stirrer, were combined gallic acid (170.1 g, 1.0 mole) and acetic anhydride (566 ml, 6 moles). The slurry was stirred as sulfuric acid (1.06 ml) was added. The temperature rose rapidly from 21° C. to 75° C. over about 1 minute and the slurry became a clear yellow solution. The mixture was stirred and allowed to cool to ambient temperature over 20 minutes. The solution was then poured into a stirred, four liter Erlenmeyer flask containing three liters of water. After 2.5 hours, white crystalline product was isolated by filtration and washed 3 times with 500 milliliters of water. The product was dried in a stream of air for 3 hours and then vacuum dried overnight. Yield was 262 grams, which was 88% of theoretical yield. Melting point was 166°-168° C. NMR conducted as in the preceeding preparation, but using (CDCl3) gave as peaks, in ppm: 2.30 (s, 9H), 7.86 (s, 2H), 11.95 (broad, 1H).
Reaction SMILES: C([N:3]1[CH2:8][CH2:7][C:6]2([C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([O:22][CH3:23])[C:16]=3[CH2:15][C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:5][CH2:4]1)#N.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].[C:32]([OH:39])(=[O:38])/[CH:33]=[CH:34]\[C:35]([OH:37])=[O:36]>O1CCCC1.CCOCC.C(OCC)(=O)C.O>[C:32]([OH:39])(=[O:38])/[CH:33]=[CH:34]\[C:35]([OH:37])=[O:36].[CH3:23][O:22][C:17]1[C:16]2[CH2:15][C:14]3[C:9]([C:6]4([CH2:7][CH2:8][NH:3][CH2:4][CH2:5]4)[C:21]=2[CH:20]=[CH:19][CH:18]=1)=[CH:10][CH:11]=[CH:12][CH:13]=3
Reactant: COc1cccc2c1Cc1ccccc1C21CCN(C#N)CC1
Agent: O=C(O)/C=C\C(=O)O
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1cccc2c1Cc1ccccc1C21CCNCC1

Procedure:
1'-Cyano-4-methoxy-9,10-dihydroanthracene-9-spiro-4'-piperidine (2.3 g.) in dry tetrahydrofuran (20 ml.) is added dropwise with stirring to a solution of lithium aluminium hydride (1 g.) in dry ether (200 ml.). When addition is complete the solution is stirred and heated under reflux for 1 hour. It is then allowed to cool and water (1 ml.), sodium hydroxide solution (1 ml., 2N), water (3 ml.), and ether (100 ml.) are added in succession and the suspension is stirred for 10 minutes and then filtered. The filtrate is washed with water and with brine, dried (MgSO4), and evaporated to give an oil which is taken up in the minimum volume of ethyl acetate and treated with a saturated solution of maleic acid in ethyl acetate. The precipitated solid is collected and recrystallised twice from isopropanol-ether to give 4-methoxy-9,10-dihydroanthracene-9-spiro-4'-piperidine maleate, m.p. 163°-165°C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5](O)=[O:6].C1C=CC2N(O)N=[N:17][C:15]=2C=1.C(Cl)CCl.CN>CN(C=O)C>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([NH:17][CH3:15])=[O:6]
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1ccnc(I)c1
Agent: CN
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CNC(=O)c1ccnc(I)c1
Yield: 55.7 %

Procedure:
A round-bottomed flask was charged with 2-iodoisonicotinic acid (0.70 g, 2.81 mmol), HOBt (474 mg, 3.09 mmol) and EDC (593 mg, 3.09 mmol). DMF (4 mL) was added followed by methylamine (2.0M solution in THF, 8.0 mL, 16.0 mmol) and the resultant suspension was stirred at room temperature overnight. The reaction mixture was quenched with water and extracted with 70 mL diethyl ether (2×). The combined organic layers were washed twice with ˜5 mL water and once with ˜5 mL brine then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over 24 g silica gel with EtOAc/Hexanes (gradient: 0-60% EtOAc). All fractions containing product were combined and concentrated to give 410 mg (56%) of 2-iodo-N-methyl-isonicotinamide as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>ClCCl>[C:8]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccccc1
Solvent: ClCCl
Product: O=C(Nc1ccccc1)c1ccccc1
Yield: 73.4 %

Procedure:
Benzanilide is prepared by the method of Example 5 using 5.0 mls (0.05 mole) of aniline, 7.5 grams of 3A molecular sieves and 7.48 mls (0.064 mole) of benzoyl chloride in 100 mls of dichloromethane. The separated 3A sieves (16.37 g) are extracted with 200 mls of hot 3A alcohol, and the alcohol extract is evaporated to dryness to obtain 7.24 grams (68% of theoretical) of crude benzanilide; m.p. 161°-163° C. after recrystallization from 3A alcohol. Dichloromethane filtrates from above reaction are evaporated to dryness and extracted with ethyl ether to obtain an additional 1.39 grams of crude benzanilide.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[S:12]1[CH2:16][C:15](=[O:17])[NH:14][C:13]1=[O:18].N1CCCCC1>C(O)C>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[C:16]2[S:12][C:13](=[O:18])[NH:14][C:15]2=[O:17])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C1CSC(=O)N1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1NC(=O)C(=Cc2ccc([N+](=O)[O-])cc2)S1
Yield: 59.2 %

Procedure:
A mixture of 4-nitrobenzaldehyde (15.1 g), 1,3-thiazolidine-2,4-dione (11.70 g), piperidine (1.70 g) and ethanol (300 mL) was heated under reflux for 24 hrs. The reaction mixture was concentrated. The obtained residue was washed with ethanol to give 5-(4-nitrobenzylidene)-1,3-thiazolidine-2,4-dione as yellow crystals (14.8 g, yield 59%). Recrystallization thereof from acetone-hexane gave pale-yellow prism crystals. melting point: 272-273° C.
Reaction SMILES: C([O:4][C:5]([C:7]1([C:13]([O:15]C(C)C)=[O:14])[CH2:10][C:9]([F:12])([F:11])[CH2:8]1)=[O:6])(C)C.[OH-].[Na+]>CO>[F:11][C:9]1([F:12])[CH2:10][C:7]([C:5]([OH:6])=[O:4])([C:13]([OH:15])=[O:14])[CH2:8]1
Reactant: CC(C)OC(=O)C1(C(=O)OC(C)C)CC(F)(F)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1(C(=O)O)CC(F)(F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 184.9 %

Procedure:
A mixture of 3,3-difluoro-cyclobutane-1,1-dicarboxylic acid diisopropyl ester (5.00 g, 18.9 mmol) and sodium hydroxide (3.00 g, 75.7 mmol) in methanol (20 ml) was stirred at room temperature overnight. The formed off-white solid was collected by filtration, washed with ethyl acetate, and dissolved in water. The aqueous solution was acidified with hydrochloric acid (3 N) to pH 3-4. The mixture was concentrated in vacuo to afford 6.293 g of the crude 3,3-difluorocyclobutane-1,1-dicarboxylic acid as a white solid, which was used for next step without further purification.