Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[CH:12]=[CH:11][C:10]=1[CH2:18][CH2:19][NH:20]C(=O)OC(C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.[ClH:31]>C(O)C>[ClH:31].[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[CH:12]=[CH:11][C:10]=1[CH2:18][CH2:19][NH2:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1ccc(CCNC(=O)OC(C)(C)C)c(OCc2ccccc2)c1
Agent: Cl
Solvent: CCO
Product: CC(C)c1ccc(CCN)c(OCc2ccccc2)c1
Reaction time: 2 h

Procedure:
To a solution of 0.300 g of tert-butyl N-[2-(2-benzyloxy-4-isopropylphenyl)ethyl]carbamate in 2 mL of ethanol was added 2 mL of 21% hydrogen chloride ethanol solution at room temperature. After being stirred at the same temperature for 2 hours, the reaction mixture was concentrated under reduced pressure to give 0.261 g of 2-(2-benzyloxy-4-isopropylphenyl)ethylamine hydrochloride.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([C:14]3[C:19]([F:20])=[C:18]([F:21])[C:17]([C:22]4[CH:27]=[CH:26][C:25]([CH:28]=O)=[CH:24][CH:23]=4)=[C:16]([F:30])[C:15]=3[F:31])[NH:10][C:9]=2[CH:8]=[C:7]([CH3:32])[CH:6]=1)=[O:4].[NH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([C:14]3[C:15]([F:31])=[C:16]([F:30])[C:17]([C:22]4[CH:23]=[CH:24][C:25]([CH2:28][N:33]5[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]5)=[CH:26][CH:27]=4)=[C:18]([F:21])[C:19]=3[F:20])[NH:10][C:9]=2[CH:8]=[C:7]([CH3:32])[CH:6]=1)=[O:4]
Reactant: C1CCNCC1
Reactant: COC(=O)c1cc(C)cc2[nH]c(-c3c(F)c(F)c(-c4ccc(C=O)cc4)c(F)c3F)nc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1cc(C)cc2[nH]c(-c3c(F)c(F)c(-c4ccc(CN5CCCCC5)cc4)c(F)c3F)nc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.7 %

Procedure:
To a solution of 6-methyl-2-(2,3,5,6-tetrafluoro-4′-formyl-biphenyl-4-yl)-1H-benzoimidazole-4-carboxylic acid methyl ester (0.13 g, 0.29 mmol) in tetrahydrofuran (100 mL) was added piperidine (0.03 g, 0.35 mmol). The reaction mixture was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (0.374 g, 1.76 mmol) was added and stirring continued for another 1 hour. The progression of the reaction was monitored by TLC. The reaction mixture quenched with sodium bicarbonate solution (3 mL) and concentrated. The residue was then extracted with ethyl acetate and the combined organic layered were washed with water and brine, dried over anhydrous sodium sulphate and concentrated to get the title compound (0.145 g, 96.66%) which was directly taken to next step.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][OH:14].O[C:16]1[CH:20]=[C:19]([CH3:21])[O:18][N:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:16]1[CH:20]=[C:19]([CH3:21])[O:18][N:17]=1
Reactant: Cc1onc(-c2ccccc2)c1CO
Reactant: Cc1cc(O)no1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(OCc2c(-c3ccccc3)noc2C)no1
Temperature: 25 °C
Reaction time: 3 h
Yield: 39.6 %

Procedure:
To a solution of (5-methyl-3-phenyl-isoxazol-4-yl)-methanol (378 mg, 2.0 mmol) in THF (7 mL) was added 3-hydroxy-5-methylisoxazole (200 mg, 2.0 mmol) and triphenylphosphine (629 mg, 2.0 mmol) at room temperature under an argon atmosphere. Then diethyl azodicarboxylate (˜40% in toluene, 1.1 mL, 2.5 mmol) was added and the reaction mixture was stirred for 3 h at room temperature. Concentration and purification by chromatography (silica, heptane:ethyl acetate=6:4 to 0:1) afforded the title compound (214 mg, 40%) as a colourless oil. MS: m/e=271.0 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:13])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[ClH:14].O=[C:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH:17]1[C:22](OC)=[O:23]>>[ClH:14].[CH3:12][O:11][C:7]1[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[C:4]2[C:16]3[CH2:21][CH2:20][NH:19][CH2:18][C:17]=3[C:22](=[O:23])[O:13][C:5]=2[CH:6]=1
Reactant: COC(=O)C1CNCCC1=O
Reactant: COc1cc(O)cc(OC)c1OC
Agent: Cl
Product: COc1cc2oc(=O)c3c(c2c(OC)c1OC)CCNC3
Yield: 55 %

Procedure:
Prepared by the method described in Example 1 from 3,4,5-trimethoxyphenol (25 g, 0.14 moles) and methyl 4-oxo-3-piperidinecarboxylate hydrochloride (18.8 g, 0.097 moles). Recrystallization from dilute aqueous hydrochloric acid yielded the product (17.5 g) as the hydrochloride, mp 232°-234° C.
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH2:18][CH3:19])([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])(C)(C)C.[CH2:25]([C:27]1[CH:34]=[CH:33][C:30]([CH:31]=[O:32])=[CH:29][CH:28]=1)[CH3:26].[Cl-].[NH4+]>C1COCC1.CCCCC>[CH2:25]([C:27]1[CH:34]=[CH:33][C:30]([CH:31]([C:2]2[C:7]([O:8][CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH2:18][CH3:19])([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:6][CH:5]=[CH:4][N:3]=2)[OH:32])=[CH:29][CH:28]=1)[CH3:26]
Reactant: CCc1ccc(C=O)cc1
Reactant: CC[Si](CC)(CC)CCOCOc1cccnc1Br
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: CCCCC
Solvent: C1CCOC1
Product: CCc1ccc(C(O)c2ncccc2OCOCC[Si](CC)(CC)CC)cc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 33.7 %

Procedure:
Next, to a solution of 2-bromo-3-[2-(triethylsilyl)ethoxymethoxy]pyridine (2.0 g, 6.57 mmol) in THF (22 mL), a 1.47 M n-pentane solution of tert-butyllithium (9.6 mL, 14.1 mmol) was slowly added dropwise at −78° C. After 20 minutes, a solution of 4-ethylbenzaldehyde (1.0 g, 7.45 mmol) in THF (5 mL) was added dropwise to the reaction mixture. After stirring at −78° C. for 10 minutes, the reaction mixture was warmed to room temperature and saturated aqueous ammonium chloride was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give 4-ethylphenyl-[3-[2-(triethylsilyl)ethoxymethoxy]]pyridin-2-yl-methanol (0.89 g, 38%).
Reaction SMILES: [Br-:1].[Li+].C[Si](Cl)(C)C.[CH3:8][C:9]1([CH3:20])[CH2:13][C:12]2[CH:14]=[CH:15][CH:16]=[C:17]([CH2:18]O)[C:11]=2[O:10]1>C(#N)C.C(OCC)C>[CH3:8][C:9]1([CH3:20])[CH2:13][C:12]2[CH:14]=[CH:15][CH:16]=[C:17]([CH2:18][Br:1])[C:11]=2[O:10]1
Reactant: [Br-]
Reactant: CC1(C)Cc2cccc(CO)c2O1
Agent: C[Si](C)(C)Cl
Agent: [Li+]
Solvent: CCOCC
Solvent: CC#N
Product: CC1(C)Cc2cccc(CBr)c2O1
Temperature: 25 °C

Procedure:
Under a nitrogen atmosphere, a mixture of 8.7 grams (0.1 mole) of lithium bromide in 100 mL of acetonitrile is stirred, and 13.5 grams (0.125 mole) of trimethylsilyl chloride is added. Upon completion of addition, a solution of 8.9 grams (0.05 mole) of 2,3-dihydro-2,2-dimethylbenzofuran-7-ylmethanol in 50 mL of acetonitrile is added. Upon completion of addition, the reaction mixture is warmed to reflux, where it is stirred for about 18 hours. After this time the reaction mixture is cooled to ambient temperature and then is taken up in 200 mL of diethyl ether. The mixture is then washed with 25 mL of water and then with 25 mL of an aqueous solution saturated with sodium chloride. The organic layer is then dried with magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure to a residue, yielding 2,3-dihydro-2,2-dimethylbenzofuran-7-ylmethyl bromide.
Reaction SMILES: [O:1]=[C:2]([CH3:16])[CH2:3][O:4][C:5]1[CH:15]=[CH:14][C:8]2[CH:9]=[CH:10][C:11](=[O:13])[O:12][C:7]=2[CH:6]=1.C1(C=CC(O)=CC=1)O.Br[CH2:26][C:27](=[CH2:33])[C:28](OCC)=[O:29]>O1CCCC1.[Zn]>[CH3:16][C:2]1([CH2:3][O:4][C:5]2[CH:15]=[CH:14][C:8]3[CH:9]=[CH:10][C:11](=[O:13])[O:12][C:7]=3[CH:6]=2)[CH2:33][C:27](=[CH2:26])[C:28](=[O:29])[O:1]1
Reactant: CC(=O)COc1ccc2ccc(=O)oc2c1
Reactant: C=C(CBr)C(=O)OCC
Agent: Oc1ccc(O)cc1
Agent: [Zn]
Solvent: C1CCOC1
Product: C=C1CC(C)(COc2ccc3ccc(=O)oc3c2)OC1=O
Temperature: 0 °C
Reaction time: 36 h
Yield: 79.7 %

Procedure:
To a solution of 3a (0.655 g, 3 mmol) in dry tetrahydrofuran (60 ml) were added activated zinc powder (0.255 g, 3.9 mmol), hydroquinone (6 mg), and ethyl 2-(bromomethyl)acrylate (0.78 g, 4 mmol). The mixture was reflued under nitrogen atmosphere for 36 h. (monitored by TLC). After cooling it was poured into an ice-cold 5% HCl solution (300 ml) and extracted with CH2Cl2 (75 ml×3). The dichloromethane extracts were combined and washed with saline, dried over Na2SO4, and then evaporated to give a residual solid which was crystallized from ethyl acetate to afford the title compound; Yield: 79.7%; mp: 123°-124° C.; IR(KBr) νmax : 1755, 1727, 1626; UV(CHCl3) λmax (log ε): 312 (4.18), 243 (3.58); 1H-NMR (CDCl3): δ1.58 (s, 3H, 5'-CH3), 2.79 (dt, 1H, 4'-H), 3.18 (dt, 1H, 4'-H), 3.99, 4.09 (two d, 2H, OCH2), 5.69 (t, 1H, vinylic H), 6.26 (d, 1H, 3-H), 6.29 (t, 1H, vinylic H), 6.76-6.84 (m, 2H, 6 and 8-H). 7.38 (d, 1H, 5-H), 7.65 (d, 1H, 4-H). Anal Calcd for C16H14O5 : C, 67.13; H, 4.93. Found: C, 66.95; H. 5.10.
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:30]1[CH:39]=[CH:38][C:37]([OH:40])=[C:36]2[C:31]=1[CH:32]=[CH:33][C:34](=[O:41])[NH:35]2)[CH2:10][NH:11][CH2:12][CH2:13][CH2:14]C#CC1C=CC(NC(=O)C(F)(F)F)=CC=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].BrCCC[CH2:46][CH2:47][CH2:48][O:49][CH2:50][CH2:51][CH2:52][CH2:53][C:54]1[CH:59]=[CH:58][C:57]([N+:60]([O-:62])=[O:61])=[CH:56][CH:55]=1>>[OH:40][C:37]1[CH:38]=[CH:39][C:30]([C@H:9]([CH2:10][NH:11][CH2:12][CH2:13][CH2:14][CH2:46][CH2:47][CH2:48][O:49][CH2:50][CH2:51][CH2:52][CH2:53][C:54]2[CH:55]=[CH:56][C:57]([N+:60]([O-:62])=[O:61])=[CH:58][CH:59]=2)[O:8][Si:1]([CH3:2])([CH3:3])[C:4]([CH3:6])([CH3:7])[CH3:5])=[C:31]2[C:36]=1[NH:35][C:34](=[O:41])[CH:33]=[CH:32]2
Reactant: O=[N+]([O-])c1ccc(CCCCOCCCCCCBr)cc1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CNCCCC#Cc1ccc(NC(=O)C(F)(F)F)cc1)c1ccc(O)c2[nH]c(=O)ccc12
Product: CC(C)(C)[Si](C)(C)O[C@@H](CNCCCCCCOCCCCc1ccc([N+](=O)[O-])cc1)c1ccc(O)c2[nH]c(=O)ccc12

Procedure:
The title compound was prepared in a manner analogous to that described for Intermediate 37, using Intermediate 27 in place of Intermediate 26. ES/MS calcd. for C33H50N3O6Si+ 612.4. found m/z=612.5 (M+H)+.
Reaction SMILES: [ClH:1].[C:2]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][O:15][C@H:14]([C@@H:18]([OH:32])[C:19]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[C:24]([CH2:30][NH2:31])[CH:23]=3)=[O:20])[C:13]2=[O:33])=[CH:8][CH:7]=1)(=[O:4])[CH3:3]>CCO>[ClH:1].[C:2]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH2:17][CH2:16][O:15][C@H:14]([C@@H:18]([OH:32])[C:19]([NH:21][C:22]3[CH:23]=[C:24]4[C:25](=[CH:26][CH:27]=3)[C:28](=[NH:29])[NH:31][CH2:30]4)=[O:20])[C:13]2=[O:33])=[CH:10][CH:11]=1)(=[O:4])[CH3:3]
Reactant: CC(=O)Nc1ccc(N2CCO[C@H]([C@@H](O)C(=O)Nc3ccc(C#N)c(CN)c3)C2=O)cc1
Agent: Cl
Solvent: CCO
Product: CC(=O)Nc1ccc(N2CCO[C@H]([C@@H](O)C(=O)Nc3ccc4c(c3)CNC4=N)C2=O)cc1
Yield: 79.2 %

Procedure:
Compound 39-6 (1.2 g) was suspended in EtOH (30 mL) and the mixture was refluxed for 6 hours. After cooling, the precipitate was collected by filtration to obtain EXAMPLE 39 (0.95 g) as a colorless amorphous solid.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Cl-].[NH4+].[F:7][C:8]1[CH:9]=[C:10]([CH:15]2[CH2:17][O:16]2)[CH:11]=[CH:12][C:13]=1[F:14].C(OCC)(=O)C.CCCCCC>CO.O>[N:1]([CH2:17][CH:15]([C:10]1[CH:11]=[CH:12][C:13]([F:14])=[C:8]([F:7])[CH:9]=1)[OH:16])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: Fc1ccc(C2CO2)cc1F
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: [N-]=[N+]=NCC(O)c1ccc(F)c(F)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Sodium azide (625 mg, 9.6 mmol) followed by ammonium chloride (514 mg, 9.6 mmol) were added to a solution of 2-(3,4-difluorophenyl)oxirane (1 g, 6.4 mmol) in methanol (10 mL) and water (2.5 mL). After stirring at 80° C. overnight, the reaction mixture was concentrated to give a residue. The residue was partitioned between water and ethyl acetate. The organic phase was washed with brine, dried (sodium sulfate) and concentrated to give a residue. Chromatography of the residue over silica gel eluting with 10-50% ethyl acetate/hexane afforded 2-azido-1-(3,4-difluorophenyl)ethanol.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])=[CH:8][CH:7]=1)=[O:5].[Br:24][CH2:25][C:26](Br)=[O:27].C(=O)(O)[O-].[Na+]>CCOCC>[Br:24][CH2:25][C:26]([NH:1][C:2]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:3]=1[C:4]([C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:13](=[O:18])[C:14]([F:15])([F:16])[F:17])=[CH:10][CH:11]=1)=[O:5])=[O:27]
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccc(NC(=O)C(F)(F)F)cc1
Reactant: O=C(Br)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: O=C(CBr)Nc1ccc(Cl)cc1C(=O)c1ccc(NC(=O)C(F)(F)F)cc1
Reaction time: 1.5 h
Yield: 87.3 %

Procedure:
To a stirred mixture of 56 g (0.163 mole) of 2-amino-5-chloro-4'-(2,2,2-trifluoroacetamido)-benzophenone in 900 ml of ether was added 43 g (0.213 mole) of bromoacetyl bromide and a saturated aqueous solution of sodium bicarbonate in portions, keeping the solution slightly basis during the addition. The reaction was stirred for 90 min and filtered to give 66 g of product. The ether layer was dried and evaporated and the residual oil was crystallized from methanol to give an additional 10 g of the product for a total yield of 76 g (96%). Recrystallization from a mixture of dichloromethane, methanol and petroleum ether gave an analytical sample of off white rods, mp 198°-201° ir (KBr) 1750, 1663, 1640 cm-1 (3C=O).
Reaction SMILES: CON(C)[C:4]([C:6]1[C:10]([Cl:11])=[CH:9][N:8]([CH2:12][CH:13]([F:15])[F:14])[N:7]=1)=[O:5].[CH3:17][Mg]Br>>[Cl:11][C:10]1[C:6]([C:4](=[O:5])[CH3:17])=[N:7][N:8]([CH2:12][CH:13]([F:15])[F:14])[CH:9]=1
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)c1nn(CC(F)F)cc1Cl
Product: CC(=O)c1nn(CC(F)F)cc1Cl
Yield: 66 %

Procedure:
In a manner analogous to that described in Example 14 b), the Grignard reaction of 4-chloro-1-(2,2-difluoro-ethyl)-1H-pyrazole-3-carboxylic acid methoxy-methyl-amide with methylmagnesium bromide yielded the title compound (66% yield) as a colorless oil. MS (ISP): m/z=209.0 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([CH2:11][O:12][CH3:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O.O.C(OCC)(=O)C>[NH2:1][C:2]1[N:10]=[C:9]([CH2:11][O:12][CH3:13])[CH:8]=[CH:7][C:3]=1[C:4]([NH:27][CH2:26][C:25]1[CH:24]=[CH:23][C:22]([O:21][CH2:20][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][N:14]=2)=[CH:29][CH:28]=1)=[O:6]
Reactant: NCc1ccc(OCc2ccccn2)cc1
Reactant: COCc1ccc(C(=O)O)c(N)n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCc1ccc(C(=O)NCc2ccc(OCc3ccccn3)cc2)c(N)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
To a solution of 2-amino-6-methoxymethyl-nicotinic acid described in Preparation Example A-11 (100 mg, 0.55 mmol) and 4-(pyridin-2-ylmethoxy)-benzylamine described in Preparation Example 171 (170 mg, 0.82 mmol) in N,N-dimethylformamide (5 mL) were added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (290 mg, 0.66 mmol) and triethylamine (0.23 mL, 1.7 mmol), and the solution was stirred overnight at room temperature. Ethyl acetate and water were added to the reaction solution for extraction, the organic layer was washed with brine, then, the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (heptane:ethyl acetate=1:2), and the title compound (150 mg, 0.40 mmol, 73%) was obtained as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]=O)[C:13]=2[O:20][CH3:21])[CH:3]=1.CN.[C:24]([BH3-])#[N:25].[Na+].[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32]>C(O)(=O)C.CO>[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32].[Cl:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][NH:25][CH3:24])[C:13]=2[O:20][CH3:21])[CH:3]=1
Reactant: COc1c(C=O)cccc1Oc1cc(Cl)c(F)cc1C#N
Reactant: [BH3-]C#N
Agent: CN
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CNCc1cccc(Oc2cc(Cl)c(F)cc2C#N)c1OC
Yield: 58.5 %

Procedure:
4-Chloro-5-fluoro-2-(3-formyl-2-methoxyphenoxy)benzonitrile (0.29 g, 0.95 mmol), methylamine (33% in ethanol, 1.0 mL, 8.0 mmol) and sodium cyanoborohydride (90 mg, 1.4 mmol) were stirred at ambient temperature in a 1% acetic acid/methanol solution (50 mL) for 44 h. The solvent was removed in vacuo. The residue was treated with 10% sodium carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was separated and fumaric acid (65 mg, 0.56 mmol) was added. After the solvent was removed in vacuo, the residue was triturated with ethyl acetate overnight, collected by filtration, and dried to give 4-chloro-5-fluoro-2-(2-methoxy-3-methylaminomethylphenoxy)benzonitrile fumarate (143 mg, 35%) as a white solid.
Reaction SMILES: C1(O)C=CC=CC=1.[Cl:8][C:9]1[C:15]([Cl:16])=[CH:14][C:13]([Cl:17])=[C:12]([Cl:18])[C:10]=1[NH2:11].I.[H][H].[OH-].[Na+]>[Pt].O.[Ta].C1(C)C=CC=CC=1>[Cl:16][C:15]1[CH:9]=[C:10]([CH:12]=[C:13]([Cl:17])[CH:14]=1)[NH2:11].[Cl:8][C:9]1[C:15]([Cl:16])=[CH:14][C:13]([Cl:17])=[C:12]([Cl:18])[C:10]=1[NH2:11]
Reactant: [H][H]
Agent: [Pt]
Agent: [Ta]
Agent: I
Solvent: Oc1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: Nc1cc(Cl)cc(Cl)c1
Temperature: 155 °C

Procedure:
200 parts of phenol, 197 parts of 2,3,5,6-tetrachloroaniline, 20 parts of platinum-on-charcoal catalyst (3.7% strength) and 15 parts of aqueous hydroiodic acid (57% strength) are dehalogenated with hydrogen in a tantalum autoclave (0.85 l) during the course of 3.5 hours, whilst stirring, under a maximum pressure of 50 bars and at 155° C. After cooling of the reaction vessel and after releasing the pressure, the reaction mixture is diluted with 500 parts by volume of water, made alkaline with concentrated sodium hydroxide solution, mixed with toluene and separated from the platinum-on-charcoal catalyst by filtration under suction. The organic phase obtained by layer separation is freed from the solvent by distillation. 99.3% strength, 3,5-dichloroaniline is obtained in a yield of 97%, with complete conversion of 2,3,5,6-tetrachloroaniline, by distillation over a simple distillation bridge.
Reaction SMILES: C[S:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[CH:5]=[N:6]O.S(Cl)([Cl:14])=O.ClCl>ClC1C=CC=CC=1>[Cl:14][C:5]1[C:4]2[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=2[S:2][N:6]=1
Reactant: CSc1ccccc1C=NO
Reactant: O=S(Cl)Cl
Agent: ClCl
Solvent: Clc1ccccc1
Product: Clc1nsc2ccccc12
Yield: 97.6 %

Procedure:
In a 300 ml four-necked flask equipped with a stirrer, a thermometer, and a condenser, 100 g of monochlorobenzene was placed in advance, to which 33.4 g (0.2 mol) of 2-(methylthio)benzaldehyde oxime was added under nitrogen atmosphere. 25.2 g (0.21 mol) Of thionyl chloride was added dropwise thereto while stirring at a temperature of from -10° to -15° C. and allowed to react for 1 hour at the same temperature. After the termination of the reaction, 15.6 g (0.22 mol) of chlorine was continuously blown into the reaction mixture while stirring at a temperature of from 70° to 80° C. and allowed to react for 1 hour at the same temperature. After the termination of the reaction, the solvent was distilled off to give 33.1 g of 3-chloro-1,2-benzisothiazole.
Reaction SMILES: NC1C=CC=CC=1.ClC1C=CC(C(Cl)=O)=CN=1.[Cl:18][C:19]1[CH:35]=[CH:34][C:22]([C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29](I)=[C:28](C)[CH:27]=2)=[O:24])=[CH:21][N:20]=1>>[Cl:18][C:19]1[CH:35]=[CH:34][C:22]([C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:24])=[CH:21][N:20]=1
Reactant: Cc1cc(NC(=O)c2ccc(Cl)nc2)ccc1I
Agent: O=C(Cl)c1ccc(Cl)nc1
Solvent: Nc1ccccc1
Product: O=C(Nc1ccccc1)c1ccc(Cl)nc1

Procedure:
6-Chloro-N-phenyl-nicotinamide was prepared from aniline and 6-chloronicotinoyl chloride following a procedure similar to the one described in the synthesis of 6-chloro-N-(4-iodo-3-methyl-phenyl)-nicotinamide, above. The product was isolated after precipitation out of small volume of CH2Cl2 with hexanes. HRMS m/z calcd for C12H9N2OCl [M+H]+: 233.0476. Found: 233.0476
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:12]([C:13]3[CH:18]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:16]=[C:15]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:14]=3)=[CH:11][C:10]([S:27]([NH2:30])(=[O:29])=[O:28])=[C:9]2[CH3:31])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.I[CH2:43][CH3:44]>C1COCC1>[CH:1]1([CH2:7][N:8]2[C:12]([C:13]3[CH:18]=[C:17]([C:19]([CH3:22])([CH3:20])[CH3:21])[CH:16]=[C:15]([C:23]([CH3:24])([CH3:25])[CH3:26])[CH:14]=3)=[CH:11][C:10]([S:27]([NH:30][CH2:43][CH3:44])(=[O:29])=[O:28])=[C:9]2[CH3:31])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1c(S(N)(=O)=O)cc(-c2cc(C(C)(C)C)cc(C(C)(C)C)c2)n1CC1CCCCC1
Reactant: CCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCNS(=O)(=O)c1cc(-c2cc(C(C)(C)C)cc(C(C)(C)C)c2)n(CC2CCCCC2)c1C
Reaction time: 0.5 h
Yield: 9.6 %

Procedure:
To a solution of compound 1 (500 mg, 1.10 mmol) in dry THF (20 mL) was added LiHMDS (1.0 mL, 1.0 mmol) at −10° C. under N2. After stirring for 30 min, iodoethane (312 mg, 2.0 mmol) was added. The solution was stirred for another 3 h at 35° C., then quenched with water and extracted with EA twice. The combined organic phases were washed with water and brine, dried over Na2SO4, filtered, concentrated and purified by CC (EA/PE=1/5) to give compound 2 (50 mg, 10%) as a solid. 1H-NMR (400 MHz, CDCl3) δ: 0.63-0.65 (m, 2H), 0.97-1.03 (m, 3H), 1.13-1.17 (m, 3H), 1.34 (s, 18H), 1.32-1.35 (m, 3H), 1.50-1.55 (m, 3H), 2.52 (s, 3H), 3.04-3.07 (m, 2H), 3.72 (d, J=6.8 Hz, 2H), 4.12 (m, 1H), 6.41 (s, 1H), 7.15 (s, 2H), 7.40 (s, 1H). MS Calcd.: 472; MS Found: 473 (M+1).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH2:11]([NH:14][CH2:15][CH2:16][CH3:17])[CH2:12][CH3:13]>>[CH2:11]([N:14]([CH2:15][CH2:16][CH3:17])[C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([I:1])=[CH:3][CH:4]=1)[CH2:12][CH3:13]
Reactant: CCCNCCC
Reactant: O=C(Cl)c1ccc(I)cc1
Product: CCCN(CCC)C(=O)c1ccc(I)cc1

Procedure:
0.48 was prepared from 4-iodobenzoyl chloride (10.0 g) and dipropylamine (4.10 g) according to the method of Intermediate 20.
Reaction SMILES: C([O:7][C:8]1[CH:9]=[C:10]([CH2:14][C@H:15]([O:20][CH:21]([CH3:23])[CH3:22])[C:16]([O:18][CH3:19])=[O:17])[CH:11]=[CH:12][CH:13]=1)(=O)C(C)(C)C.S(=O)(=O)(O)O.C1(C)C=CC=CC=1.O>CO>[OH:7][C:8]1[CH:9]=[C:10]([CH2:14][C@H:15]([O:20][CH:21]([CH3:23])[CH3:22])[C:16]([O:18][CH3:19])=[O:17])[CH:11]=[CH:12][CH:13]=1
Reactant: COC(=O)[C@H](Cc1cccc(OC(=O)C(C)(C)C)c1)OC(C)C
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: CO
Solvent: O
Product: COC(=O)[C@H](Cc1cccc(O)c1)OC(C)C
Temperature: 60 °C
Reaction time: 19 h
Yield: 98.6 %

Procedure:
Methyl (2S)-3-(3-pivaloyloxyphenyl)-2-isopropoxypropionate (12.1 kg, 37.5 mol) was dissolved in methanol (49 L) and then cooled, followed by adding dropwise concentrated sulfuric acid (3 L) to the reaction mixture at an internal temperature of 8.8° C. After stirring the reaction mixture at 60° C. for 19 hours, toluene (121 L) and water (61 L) were added to the mixture for separating. The aqueous layer was again extracted with toluene (121 L). The organic layers were then combined. The resultant organic layer was washed with a 5% sodium bicarbonate aqueous solution (57 L) and with water (61 L) and then dried with anhydrous magnesium sulfate, followed by vacuum concentration to obtain 8.81 kg of the title compound in the form of oily matter (yield: 99%).