Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]([F:16])[F:15])[N:11]3[N:17]=[CH:18][C:19](I)=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:21].[CH3:22][Si:23]([C:26]#[CH:27])([CH3:25])[CH3:24].C(N(CC)CC)C>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]([F:16])[F:15])[N:11]3[N:17]=[CH:18][C:19]([C:27]#[C:26][Si:23]([CH3:25])([CH3:24])[CH3:22])=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:21]
Reactant: Cc1cc(-c2cc(C(F)F)n3ncc(I)c3n2)ccc1Cl
Reactant: C#C[Si](C)(C)C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(-c2cc(C(F)F)n3ncc(C#C[Si](C)(C)C)c3n2)ccc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 72.6 %

Procedure:
A mixture of 5-(4-chloro-3-methyl-phenyl)-3-iodo-7-difluoromethyl-pyrazolo[1,5-a]pyrimidine (7.01 g, 16.7 mmol), trimethylsilylacetylene (4.16 mL, 30.0 mmol) and triethylamine (4.66 mL, 33.4 mmol) in N,N-dimethylformamide (18 mL) was stirred for 10 min at room temperature while being purged with Argon, then PdCl2(PPh3)2 (117 mg, 1 mol %), PPh3 (44 mg, 1 mol %) and CuI (10 mg, 0.3 mol %) were added. Stirring was continued at 90° C. for 4.5 h. The reaction mixture was cooled to room temperature, diluted with water (100 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with water (2×50 mL) and brine (70 mL), dried (MgSO4), evaporated and further purified by column chromatography on silica gel (dischloromethane/heptane 7:3) to give 5-(4-chloro-3-methyl-phenyl)-7-difluoromethyl-3-trimethylsilanylethynyl-pyrazolo[1,5-a]pyrimidine (4.73 g, 73%) as an orange solid, which was dissolved in THF (74 mL) and MeOH (56 mL), while stirring at 0° C. potassium carbonate (168 mg, 1.22 mmol) was added and the mixture was stirred at 0° C. for 5 h. The mixture was diluted with ice water (250 mL) and extracted with TBME (3×250 mL). The combined organic layers were washed with brine (200 mL), dried (MgSO4) and evaporated. The crude product was further purified by flash chromatography on silica gel (heptane/EtOAc) followed by crystallization from ethyl acetate/hexane to give 5-(4-chloro-3-methyl-phenyl)-3-ethynyl-7-difluoromethyl-pyrazolo[1,5-a]pyrimidine (3.8 g, 72%) as a light brown solid. MS (EI) 317.2 [(M)+]; mp 143° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][C:24]=2[O:25][CH3:26])[N:21]=[CH:20][N:19]=[C:18]3[NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:29]=2[F:35])[CH2:10][C@H:9]1[C:36]([OH:38])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N:40]1CCOCC1.N>C1COCC1.C(Cl)Cl>[NH2:40][C:36]([C@@H:9]1[CH2:10][C@@H:11]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][C:24]=2[O:25][CH3:26])[N:21]=[CH:20][N:19]=[C:18]3[NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:29]=2[F:35])[CH2:12][CH2:13][N:8]1[C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])=[O:38]
Reactant: CN1CCOCC1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@H]1CCN(C(=O)OC(C)(C)C)[C@H](C(=O)O)C1
Agent: N
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@H]1CCN(C(=O)OC(C)(C)C)[C@H](C(N)=O)C1
Temperature: 25 °C
Reaction time: 0.12 h
Yield: 100 %

Procedure:
A stirred solution of (2S,4S)-1-(tert-butoxycarbonyl)-4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)piperidine-2-carboxylic acid (3) (5 g, 9.16 mmol) in THF (50 ml) was cooled to −15° C. (acetone/ice). NMM (1.5 ml, 13.7 mmol) was added to the solution followed by IBCF (1.54 ml, 11.9 mmol). The reaction mixture was held at −15° C. (the formation of the mixed anhydride was monitored by TLC (THF)). After 5-10 minutes, the reaction mixture was treated with concentrated aqueous ammonia (3 ml) at −15° C. and allowed to warm to room temperature. The reaction mixture was diluted with DCM (250 ml), washed with water (2×20 ml) and concentrated to give tert-butyl (2S,4S)-2-(aminocarbonyl)-4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)piperidine-1-carboxylate (4) (5 g, 100%) as a pale yellow foam which was used without further purification; Mass Spectrum: (M+H)+ 546.1.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][CH2:8][CH:9]2[CH2:14][NH2:15].[OH-].[K+].[C:18](OC(=O)C)(=O)[CH3:19]>>[ClH:1].[CH2:18]([NH:15][CH2:14][CH:9]1[C:10]2[C:5](=[C:4]([O:3][CH3:2])[CH:13]=[CH:12][CH:11]=2)[CH2:6][CH2:7][CH2:8]1)[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cccc2c1CCCC2CN
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: CCNCC1CCCc2c(OC)cccc21

Procedure:
The product from Example 14 was treated with KOH to qive the free base, then reacted with acetic anhydride affording the amide. Anal. calcd. for C14H19NO2 : C, 72.07; H, 8.21; N, 6.00. Found: C, 72.03; H, 8.25; N, 6.01. This amide was reduced using the procedure of Example 5 to give the desired compound. Anal. calcd. for C14H22C1NO C, 65.74; H, 8.67; N, 5.48. Found: C, 65.71; H, 8.61; N, 5.47.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:15]([O:17]C)=[O:16])[C:5]2[C:6]([F:14])=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[OH-].[Li+].O.[Al]>O1CCCC1.CO>[Br:1][C:2]1[CH:3]=[C:4]([C:15]([OH:17])=[O:16])[C:5]2[C:6]([F:14])=[CH:7][N:8]([CH:11]([CH3:12])[CH3:13])[C:9]=2[CH:10]=1
Reactant: COC(=O)c1cc(Br)cc2c1c(F)cn2C(C)C
Agent: [Al]
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)n1cc(F)c2c(C(=O)O)cc(Br)cc21
Temperature: 25 °C
Yield: 76.2 %

Procedure:
To a 100 ml round bottom flask was added methyl 6-bromo-3-fluoro-1-isopropyl-1H-indole-4-carboxylate (33.0 mg, 0.105 mmol), Methanol (700 μl), Tetrahydrofuran (THF) (1401 μl) and a magnetic stir bar. To the same was added lithium hydroxide, H2O (13.22 mg, 0.315 mmol) and the mixture was stirred at room temperature. Reaction progress was monitored by LCMS. LCMS (18 h) showed 60% conversion. The reaction was heated to 50° C. in an aluminum heating block with stirring. After complete conversion the solvent was removed in-vacuo and the remaining residue was dissolved with water (1 ml) and 1N HCl was added dropwise (9 drops) until precipitation stopped. The fine pale-yellow solid was collected by vacuum filtration. LCMS and HPLC showed 100% purity and NMR supports the desired structure. The product, 6-bromo-3-fluoro-1-isopropyl-1H-indole-4-carboxylic acid (24 mg, 0.080 mmol, 76% yield), was obtained as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 13.07 (br. s., 1H), 8.12 (t, J=1.89 Hz, 1H), 7.77 (d, J=2.27 Hz, 1H), 7.66 (d, J=1.77 Hz, 1H), 4.88 (qd, J=5.31, 6.65 Hz, 1H), 1.40 (d, 6H). MS(ES) [M+H]+ 300.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH2:27][CH3:28])=[C:12]([C:14]3[C:15](=[O:26])[N:16]([CH3:25])[N:17]=[C:18]([CH3:24])[C:19]=3S(C)(=O)=O)[CH:13]=2)=[CH:4][CH:3]=1.CN1CCCC1=[O:35].[OH-].[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH2:27][CH3:28])=[C:12]([C:14]3[C:15](=[O:26])[N:16]([CH3:25])[N:17]=[C:18]([CH3:24])[C:19]=3[OH:35])[CH:13]=2)=[CH:4][CH:3]=1
Reactant: CN1CCCC1=O
Reactant: CCc1ccc(-c2ccc(Cl)cc2)cc1-c1c(S(C)(=O)=O)c(C)nn(C)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCc1ccc(-c2ccc(Cl)cc2)cc1-c1c(O)c(C)nn(C)c1=O
Temperature: 70 °C
Reaction time: 3 h
Yield: 63.6 %

Procedure:
To a 25 ml volume three-necked flask, 4-[5-(4-chlorophenyl)-2-ethylphenyl]-2,6-dimethyl-5-methylsulfonyl-2,3-dihydro-3-pyridazinone ((2-34)-(1)-67) (290 mg), N-methyl-2-pyrrolidone (890 mg), and aqueous sodium hydroxide solution (410 mg) were added under a nitrogen atmosphere, and stirred at 70° C. for 3 hours. After the reaction mixture was cooled to room temperature, toluene was added and washed. The organic layer was removed. To the resulting aqueous layer, 10 wt % of hydrochloric acid was added to adjust pH to less than 1, and extracted with ethyl acetate times. The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to column chromatography (hexane:ethyl acetate=2:1) to give 157 mg of 4-[5-(4-chlorophenyl)-2-ethylphenyl]-5-hydroxy-2,6-dimethyl-2,3-dihydro-3-pyridazinone ((1-4)-(1)-67).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([CH:5]=[O:6])[C:3]=1[OH:10].[CH:11](I)([CH3:13])[CH3:12].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH3:1][C:2]1[C:3]([O:10][CH:11]([CH3:13])[CH3:12])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: CC(C)I
Reactant: Cc1cccc(C=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc(C=O)c1OC(C)C

Procedure:
Stir a mixture of 3-methylsalicylaldehyde (100 g, 0.73 mol), isopropyl iodide (187 g, 1.1 mol) and K2CO3 (141 g, 1.0 mol) in DMF (400 mL) for 20 hr at room temperature. TLC shows partial reaction; thus, add more isopropyl iodide (43 g, 0.25 mol) and heat the reaction to 45° C. with stirring for an additional 10 hr. Dilute the reaction mixture with H2O (1 L) and extract the resulting mixture with EtOAc. Wash the organic layer with 0.25 M. aqueous NaOH and then with H2O. Dry over MgSO4 and evaporate the solvent to give 3-methyl-2-isopropoxybenzaldehyde, 122 g (94%); 1H-NMR (CDCl3) δ 7.7-7.1 (m, 3H), 4.2 (m, 1H), 2.3 (s, 3H), 1.4 (d. 6H).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=4)=[C:18]([Cl:33])[CH:17]=3)=[N:12][CH:11]=[N:10][C:9]=2[CH:8]=[CH:7]1.C(N(CC)CC)C.[CH3:41][S:42][CH2:43][CH2:44][C:45](Cl)=[O:46].O>O1CCCC1>[Cl:33][C:18]1[CH:17]=[C:16]([NH:15][C:13]2[C:14]3[N:6]([CH2:5][CH2:4][NH:3][C:45](=[O:46])[CH2:44][CH2:43][S:42][CH3:41])[CH:7]=[CH:8][C:9]=3[N:10]=[CH:11][N:12]=2)[CH:21]=[CH:20][C:19]=1[O:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=1
Reactant: CSCCC(=O)Cl
Reactant: NCCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CSCCC(=O)NCCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a mixture of 5-(2-aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride (230 mg) and triethylamine (0.61 mL) in tetrahydrofuran (8.0 mL) was added 3-(methylthio)propionyl chloride (0.15 mL) under ice-cooling. After stirring at room temperature for 20 hrs, water was added, and the mixture was extracted with ethyl acetate. The organic layer washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure, and the residue was separated and purified by basic silica gel column chromatography (eluent, ethyl acetate→ethyl acetate:methanol=9:1) to give the title compound (133 mg) as colorless crystals.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[F:11][C:12]1[CH:13]=[C:14]([CH2:19][C:20]([OH:22])=[O:21])[CH:15]=[C:16](F)[CH:17]=1>CN1C(=O)CCC1>[CH2:1]([O:8][C:16]1[CH:15]=[C:14]([CH2:19][C:20]([OH:22])=[O:21])[CH:13]=[C:12]([F:11])[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: OCc1ccccc1
Product: O=C(O)Cc1cc(F)cc(OCc2ccccc2)c1
Reaction time: 0.33 h

Procedure:
To benzyl alcohol (1.4 g, 12.8 mmol) in NMP (30 mL) was added sodium hydride (60% in mineral oil; 0.5 g, 12.8 mmol), and the mixture was stirred for 20 minutes. 3,5-Difluorophenylacetic acid (1.0 g, 5.8 mmol) was added, and the reaction was stirred at 100° C. for 2 hours, and then 60° C. overnight. The mixture was worked-up to give the title compound, plus ˜30% of benzyl alcohol impurity.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8]/[C:9](=[CH:14]/[CH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)/[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:10]([O:12][CH3:13])=[O:11])[CH2:14][CH:15]1[CH2:16][CH2:17][O:18][CH2:19][CH2:20]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: [H][H]
Reactant: COC(=O)/C(=C\C1CCOCC1)NC(=O)OC(C)(C)C
Solvent: CO
Product: COC(=O)[C@H](CC1CCOCC1)NC(=O)OC(C)(C)C

Procedure:
A 250-mL pressure tube was charged with methyl (2E)-2-((tert-butoxycarbonyl)amino)-3-(tetrahydro-2H-pyran-4-yl)-2-propenoate (8.75 g, 30.7 mmol), MeOH (100 mL), and rhodium[(1R,1′R,2R,2′R)-2,2′-bis(1,1-dimethylethyl)-2,2′,3,3′-tetrahydro-1,1′-bi-1H-isophosphindole-κP2,κP2′][(1,2,5,6-η)-1,5-cyclooctadiene]tetrafluoroborate (0.209 g, 0.30 mmol, ChiralQuest, Monmouth Junction, N.J.). The mixture was stirred under a 50 psi (344 kilopascal) hydrogen atmosphere for 3 h. The mixture was then filtered through a pad of silica, washing with 1:1 EtOAc in hexanes, and then concentrated to give methyl N-(tert-butoxycarbonyl)-3-(tetrahydro-2H-pyran-4-yl)-L-alaninate.
Reaction SMILES: Br[C:2]1[N:3]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[C:4]2[C:9]([C:10]=1[C:11]#[N:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH3:20][NH:21][CH3:22]>CN(C=O)C.O.C(Cl)Cl>[CH3:20][N:21]([CH3:22])[C:2]1[N:3]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[C:4]2[C:9]([C:10]=1[C:11]#[N:12])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: CNC
Reactant: N#Cc1c(Br)n(-c2ccc(O)cc2)c2ccccc12
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: CN(C)c1c(C#N)c2ccccc2n1-c1ccc(O)cc1
Temperature: 80 °C

Procedure:
2-Bromo-1-(4-hydroxy-phenyl)-1H-indole-3-carbonitrile (Example 1) was mixed with excess dimethylamine in DMF (1:3) and the mixture was stirred in a sealed vial at 80° C. over night. The reaction-mixture was cooled to rt, diluted with H2O and DCM and then the phases were separated. The organic phase was evaporated to dryness and subjected to reversed phase preparative HPLC. Appropriate fractions were combined and evaporated, and identified by 1H-NMR and LC/MS. Purity was determined by analytical HPLC, ES/MS m/z: 278.1 (M+H), 276.1 (M−H); 1H NMR (acetone-d6, 500 MHz): 7.42 (m, 1H), 7.33 (m, 2H), 7.17 (m, 1H), 7.09-7.05 (m, 3H), 6.95 (m, 1H) and 2.93 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:3](I)=[CH:4][C:5]([O:24][CH3:25])=[C:6]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])[CH:7]=1.[CH3:27][C@@H:28]1[CH2:32][O:31][C:30](=[O:33])[NH:29]1>>[ClH:1].[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])[C:5]([O:24][CH3:25])=[CH:4][C:3]=1[N:29]1[C@H:28]([CH3:27])[CH2:32][O:31][C:30]1=[O:33]
Reactant: COc1cc(I)c(Cl)cc1C(=O)N1CCN(c2ncc(C)cc2C)CC1
Reactant: C[C@@H]1COC(=O)N1
Product: COc1cc(N2C(=O)OC[C@H]2C)c(Cl)cc1C(=O)N1CCN(c2ncc(C)cc2C)CC1
Product: Cl
Yield: 29.4 %

Procedure:
By reaction and treatment in the same manner as in Example 79 and using (5-chloro-4-iodo-2-methoxyphenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (1.5 g) described in Preparation Example 71 and (R)-4-methyloxazolidin-2-one (400 mg) described in Preparation Example 25, the title compound (225 mg) was obtained.
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH3:17])[CH2:3][CH:4]([CH2:8][C:9]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)=[O:10])[C:5]([OH:7])=O.[NH2:19][CH:20]([CH2:34][CH3:35])[C@@H:21]([C:23]1[O:27][N:26]=[C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:24]=1)[OH:22]>>[C:28]1([C:25]2[N:24]=[C:23]([C:21]([CH:20]([NH:19][C:5](=[O:7])[C@@H:4]([CH2:8][C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[O:10])[CH2:3][C:2]([CH3:1])([CH3:18])[CH3:17])[CH2:34][CH3:35])=[O:22])[O:27][N:26]=2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CCC(N)[C@H](O)c1nc(-c2ccccc2)no1
Reactant: CC(C)(C)CC(CC(=O)N1CCOCC1)C(=O)O
Product: CCC(NC(=O)[C@@H](CC(=O)N1CCOCC1)CC(C)(C)C)C(=O)c1nc(-c2ccccc2)no1

Procedure:
It is similarly prepared according to general procedure given for example 10 above but using 4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-pentanoic acid and (S)-2-Amino-1-(3-phenyl-1,2,4-oxadiazol-5-yl)-butan-1-ol.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH:4]1[CH2:10][N:9]([CH3:11])[C:8](=O)[C:7]2[CH:13]=[N:14][CH:15]=[CH:16][C:6]=2[O:5]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:26])=CC=1>C1(C)C=CC=CC=1>[ClH:1].[Cl:1][CH2:2][CH2:3][CH:4]1[CH2:10][N:9]([CH3:11])[C:8](=[S:26])[C:7]2[CH:13]=[N:14][CH:15]=[CH:16][C:6]=2[O:5]1
Reactant: CN1CC(CCCl)Oc2ccncc2C1=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CN1CC(CCCl)Oc2ccncc2C1=S
Product: Cl

Procedure:
2-(2-Chloroethyl)-2,3-dihydro-4-methylpyrido[3,4-f][1,4]oxazepin-5(4H)-one, 15 g (0.06 mole), was dissolved in 200 ml of dry toluene and 15 g (0.037 mole) of 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiaphosphetane-2,4-disulfide was added. The mixture was refluxed for 2.5 hr and the toluene solution decanted. The residue was partitioned between dilute sodium hydroxide and chloroform. The chloroform was dried and concentrated. The residue was chromatographed on a high pressure liquid chromatograph (Waters 500) using a silica column and eluting with ethyl acetate. The fraction containing material of molecular weight 257 was concentrated. The residue in isopropyl alcohol was treated with hydrogen chloride and the resulting crystals were collected. Yield of hydrochloride salt was 0.1 g (0.6%), m.p. 168°-171° C.
Reaction SMILES: Cl.C([N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([CH2:22][C:23]3[C:31]4[C:26](=[CH:27][CH:28]=[C:29]([F:32])[CH:30]=4)[NH:25][CH:24]=3)[CH2:18][CH2:17]2)[C:6]1=[O:33])(C)=C.ClCCl>C(O)C>[F:32][C:29]1[CH:30]=[C:31]2[C:26](=[CH:27][CH:28]=1)[NH:25][CH:24]=[C:23]2[CH2:22][CH:19]1[CH2:18][CH2:17][N:16]([CH2:15][CH2:14][N:7]2[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[NH:5][C:6]2=[O:33])[CH2:21][CH2:20]1
Reactant: C=C(C)n1c(=O)n(CCN2CCC(Cc3c[nH]c4ccc(F)cc34)CC2)c2ccccc21
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: O=c1[nH]c2ccccc2n1CCN1CCC(Cc2c[nH]c3ccc(F)cc23)CC1
Temperature: 20 °C
Reaction time: 1 h
Yield: 11 %

Procedure:
6N hydrochloric acid (9.3 cc) is introduced at a temperature in the region of 20° C. into a solution of 3-isopropenyl-1-{2-[4-((5-fluoro-3-indolyl)methyl)piperidino]ethyl}-2H-benzimidazol-2-one (4 g) in ethanol (50 cc). The solution is heated to boiling for 1 hour and then cooled to a temperature in the vicinity of 20° C. The reaction medium is taken up with dichloromethane (100 cc) and distilled water (30 cc) and alkalinized to pH 9 with 5N sodium hydroxide. The organic phase is extracted with dichloromethane (3×30 cc), washed with distilled water (90 cc), dried over anhydrous magnesium sulphate, treated with vegetable charcoal, filtered and concentrated to dryness at 40° C. under reduced pressure (20 mm Hg; 2.7 kPa). The residue is recrystallized in methyl ethyl ketone (15 cc). 1-{2-[4-((5-Fluoro-3-indolyl)methyl)piperidino]ethyl}-2H-benzimidazolin-2-one (0.4 g), m.p. 220° C., is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]([NH:14][CH3:15])[C:10]([O:12]C)=O)[CH:6]=[CH:7][CH:8]=1.[Cl:16][C:17]1[CH:18]=[C:19]([N:24]=[C:25]=[O:26])[CH:20]=[CH:21][C:22]=1[Cl:23]>C1COCC1>[Cl:16][C:17]1[CH:18]=[C:19]([N:24]2[C:10](=[O:12])[CH:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[N:14]([CH3:15])[C:25]2=[O:26])[CH:20]=[CH:21][C:22]=1[Cl:23]
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Reactant: CNC(C(=O)OC)c1cccc(OC)c1
Solvent: C1CCOC1
Product: COc1cccc(C2C(=O)N(c3ccc(Cl)c(Cl)c3)C(=O)N2C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3 g of methyl 2-(3-methoxyphenyl)-2-methylaminoacetate were introduced into a 250 mL Woulff bottle at ambient temperature. 2.7 g d of 3,4-dichlorophenyl isocyanate in 50 mL of THF were added and the mixture was stirred for 30 min at ambient temperature. The insoluble matter was filtered, washed with isopropyl ether and dried to yield the product in the form of a white solid (3.9 g; Yd=75%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[Cl-].[Li+].[C:11](Cl)(=[O:14])[CH:12]=[CH2:13].O>CN1CCCC1=O>[OH:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:11](=[O:14])[CH:12]=[CH2:13]
Reactant: Nc1ccccc1O
Reactant: C=CC(=O)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CN1CCCC1=O
Solvent: O
Product: C=CC(=O)Nc1ccccc1O
Yield: 34.1 %

Procedure:
20 g of o-amino phenol was dissolved in 200 mL of N-methyl-2-pyrrolidone (NMP), and then the solution was ice-cooled. To the solution was added 8.546 g (1.1 times in mol) of lithium chloride. After lithium chloride was entirely dissolved, 17.42 g (1.05 times in mol) of acryloyl chloride was dropped into the solution, and the solution was stirred under ice-cooling for 5 hours. The reaction mixture was poured into 1.8 L of water, and an organic layer was extracted with 700 mL of diethyl ether. The diethyl ether layer was sequentially washed with 0.2 N hydrochloric acid, brine and water, and dried over magnesium sulfate. Diethyl ether was evaporated off under a reduced pressure. 80 mL of diisopropyl ether was added to the solidified residue, and the solution was heated and stirred to wash and filter the residue. The same washing process was carried out once again to obtain 10.2 g of N-(2-hydroxyphenyl)acrylamide as white powder (yield: 34%).
Reaction SMILES: [C:1]([CH2:3][C:4]([NH2:6])=[O:5])#[N:2].[Na].[Cl:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=1[Cl:19])[CH2:12][N:13]=[N+:14]=[N-:15]>C(O)C>[Cl:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=1[Cl:19])[CH2:12][N:13]1[C:1]([NH2:2])=[C:3]([C:4]([NH2:6])=[O:5])[N:15]=[N:14]1
Reactant: [N-]=[N+]=NCc1ccc(Cl)c(Cl)c1
Reactant: N#CCC(N)=O
Agent: [Na]
Solvent: CCO
Product: NC(=O)c1nnn(Cc2ccc(Cl)c(Cl)c2)c1N
Temperature: 0 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
A stirred mixture of 3,4-dichlorobenzyl chloride (12.6 g, 64.5 mmol) and sodium azide (7.0 g, 0.11 mole) in absolute ethanol (70 ml) was refluxed for 4.75 hours, cooled and filtered to provide a solution of 3,4-dichlorobenzyl azide. Separately, 2-cyanoacetamide (5.5 g, 65 mmol) was added to a 35° C. solution of sodium (1.5 g, 65 mmol) in absolute ethanol (125 ml), and to the resulting suspension was added the above azide solution dropwise over 10 minutes. The combined mixtures were refluxed for 1 hour, kept 16 hours at ambient temperature and 1 hour at 5° C., and filtered. The crude product was dried under vacuum, dissolved in boiling ethanol (290 ml), filtered hot, and cooled to 0° C. The solid was collected by filtration and dried under vacuum to provide 12.4 g (67%) of 1-(3,4-dichlorobenzyl)-5-amino-1,2,3-triazole-4-carboxamide, m.p. 221°-222° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][C:12]=2[O:20][CH3:21])[C:9]#[N:10])=[CH:4][CH:3]=1.S1C=CC=C1.[H][H]>CO.[Pt]>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]#[N:10])=[C:12]([O:20][CH3:21])[CH:13]=1
Reactant: [H][H]
Reactant: COc1cc([N+](=O)[O-])ccc1C(C#N)c1ccc(Cl)cc1
Agent: [Pt]
Solvent: c1ccsc1
Solvent: CO
Product: COc1cc(N)ccc1C(C#N)c1ccc(Cl)cc1

Procedure:
A mixture of 8.1 parts of α-(4-chlorophenyl)-2-methoxy-4-nitrobenzeneacetonitrile, 2 parts of a solution of thiophene in methanol 4% and 200 parts of methanol is hydrogenated at normal pressure and at 50° C. with 2 parts of platinum-on-charcoal catalyst 5%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated in vacuo. The residue is stirred in a small amount of 2-propanol. The product is filtered off and dried, yielding 4-amino-α-(4-chlorophenyl)-2-methoxybenzeneacetonitrile.