Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[OH:29])([CH3:22])[CH3:21])[C:14]3=[O:30])[CH:7]=2)[CH2:3][CH2:2]1.Cl.Cl[CH2:34][CH2:35][N:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C)C=O>[CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]([CH3:22])([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH2:34][CH2:35][N:36]4[CH2:40][CH2:39][CH2:38][CH2:37]4)[CH3:21])[C:14]3=[O:30])[CH:7]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC(C)(C)c2ccccc2O)c1=O
Reactant: ClCCN1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC(C)(C)c2ccccc2OCCN2CCCC2)c1=O
Temperature: 80 °C
Reaction time: 12 h
Yield: 27.6 %

Procedure:
To a stirred solution of N-cyclopropyl-3-(3-(2-(2-hydroxyphenyl)propan-2-ylamino)-2-oxopyrazin-1(2H)-yl)-4-methylbenzamide (Example 134, 0.1 g) in N,N-dimethylformamide (3 mL), N-(2-chloroethyl)-pyrrolidine, hydrochloride (0.12 g) and cesium carbonate (0.47 g) were added. The reaction was stirred under nitrogen at 80° C. for 12 h. After 2 h additional batches of N-(2-chloroethyl)-pyrrolidine hydrochloride (0.12 g) and cesium carbonate (0.47 g) were added. The reaction mixture was stirred at 100° C. for 10 h and then at 90° C. for 10 h. Ethyl acetate was added and the mixture was washed with water and brine. The organic phase was dried (Na2SO4), filtered and concentrated in vacuo. Purification by preparative HPLC (Gemini column—acetonitrile/0.1% ammonia mobile phase) afforded the title compound as a solid (34 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH:6]=[C:5]2[OH:13].CCN(C(C)C)C(C)C.[Br:23][C:24]1[S:28][C:27]([S:29](Cl)(=[O:31])=[O:30])=[CH:26][CH:25]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[O:8][C:7](=[O:12])[CH:6]=[C:5]([O:13][S:29]([C:27]3[S:28][C:24]([Br:23])=[CH:25][CH:26]=3)(=[O:31])=[O:30])[C:4]=2[CH:3]=1
Reactant: O=c1cc(O)c2cc(Cl)ccc2o1
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=c1cc(OS(=O)(=O)c2ccc(Br)s2)c2cc(Cl)ccc2o1
Temperature: 0 °C
Reaction time: 2 h
Yield: 21.3 %

Procedure:
6-Chloro-4-hydroxycoumarin (0.5 mmol, 0.099 g) is suspended in 5 mL of DCM, and enough DIEA is added to bring the pH to 9 as measured by pH paper. The solution is cooled to 0° C., and 5-bromo-thiophene-2-sulfonyl chloride (0.5 mmol, 0.13 g) is added. The solution is warmed to ambient temperature and is stirred 2 hrs. The solvent is removed under reduced pressure and the residue is triturated with Et2O. The resulting solid is filtered, is washed with Et2O, and is dried to afford the title compound (45 mg, 21%). 1H NMR (CDCl3, 300 MHz) δ 7.65 (1H, d, J=4.25 Hz), 7.56 (2H, m), 7.29 (1H, d, J=8.75 Hz), 7.19 (1H, d, J=4.25 Hz), 6.48 (1H, s), MS (ESI, Pos.) calcd for C13H6BrClO5S2 m/z [M+H]=420.9, found 420.9.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][NH:21][C:20](=[O:23])[C@H:19]([NH:24]C(=O)OC(C)(C)C)[CH2:18][CH2:17]1>ClCCl>[NH2:24][C@@H:19]1[CH2:18][CH2:17][C@@H:16]([C:10]2[CH:11]=[CH:12][CH:13]=[C:14]([F:15])[C:9]=2[F:8])[CH2:22][NH:21][C:20]1=[O:23]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)CNC1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H]1CC[C@@H](c2cccc(F)c2F)CNC1=O
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (4 mL) was added to a solution of tert-butyl (3R,6S)-6-(2,3-difluorophenyl)-2-oxoazepan-3-ylcarbamate (82 mg, 0.241 mmol) in dichloromethane (4 mL). After 1 h, the solution was concentrated. Saturated aqueous sodium bicarbonate solution was added and the mixture was extracted with dichloromethane (3×). The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. MS 241.0 (M+1).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([CH2:9][C:10]([O:12][CH3:13])=[O:11])#[N:8].Cl[C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[N+:22]([O-:24])=[O:23].Cl>O.C(OCC)(=O)C.CN(C)C=O>[Cl:21][C:19]1[CH:18]=[CH:17][C:16]([N+:22]([O-:24])=[O:23])=[C:15]([CH:9]([C:7]#[N:8])[C:10]([O:12][CH3:13])=[O:11])[CH:20]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1Cl
Reactant: COC(=O)CC#N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(C#N)c1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 87.7 %

Procedure:
In a flask made of glass equipped with a stirrer, a thermometer, a reflux condenser and a dropping funnel and having an inner volume of 200 ml were charged 7.13 g (51.6 mmol) of potassium carbonate, 20 ml of N,N-dimethylformamide, 5.06 g (50.6 mmol) of methyl cyanoacetate with a purity of 99% and 5.00 g (25.8 mmol) of 2,4-dichloronitrobenzene with a purity of 99% under argon atmosphere, and under stirring, the mixture was reacted at 45° C. for 4 hours. After completion of the reaction, the mixture was cooled to room temperature, 100 ml of ethyl acetate was added to the mixture, and 12.9 ml (77.4 mmol) of 6 mol/l hydrochloric acid was gradually added dropwise to the mixture while stirring. Then, after adding 50 ml of water to the mixture, the organic layer was separated, and washed with 50 ml of a saturated saline solution, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting concentrate was purified by silica gel column chromatography (filler: Daisogel 1002W, eluent: hexane:ethyl acetate=20:1 (volume ratio)) to obtain 5.76 g (isolation yield: 83%) of methyl 2-(5-chloro-2-nitrophenyl)-2-cyanoacetate as white crystals with a purity of 95% (areal percentage by high performance liquid chromatography).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1B(O)O.[C:12]([N:16]1[C:20](=[O:21])[CH:19]=[C:18](Cl)[S:17]1(=[O:24])=[O:23])([CH3:15])([CH3:14])[CH3:13].ClCCl.C(N(CC)CC)C>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:12]([N:16]1[C:20](=[O:21])[CH:19]=[C:18]([C:3]2[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=2[F:1])[S:17]1(=[O:23])=[O:24])([CH3:15])([CH3:13])[CH3:14]
Reactant: Cc1ccc(B(O)O)c(F)c1
Reactant: CC(C)(C)N1C(=O)C=C(Cl)S1(=O)=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Cc1ccc(C2=CC(=O)N(C(C)(C)C)S2(=O)=O)c(F)c1
Temperature: 90 °C
Yield: 64.9 %

Procedure:
(2-Fluoro-4-methylphenyl)boronic acid (19.5 g, 0.127 mol), 2-tert-butyl-5-chloro-1,1-dioxo-1,2-dihydro-1λ6-isothiazol-3-one (30.5 g, 0.136 mol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (10.4 g, 12.7 mmol) were dissolved in toluene (500 mL) and treated with triethylamine (53.0 mL, 0.380 mol). The reaction was degassed and placed under an atmosphere of nitrogen. The reaction was then heated to 90° C. for 18 h. The reaction was diluted with ethyl acetate (500 mL) and washed with 1 N aqueous hydrochloric acid (500 mL). The ethyl acetate was dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was filtered through celite and then silica gel. The crude material was then purified by silica gel chromatography (5–10% ethyl acetate:hexanes) to afford product as a white solid (24.5 g, 65%). 1H NMR (400 MHz, CDCl3): δ 7.85 (t, J=7.8 Hz, 1H), 7.11–7.03 (m2H), 6.86 (d, J=1.8 Hz, 1H), 2.42 (s, 3H), 1.73 (s, 9H).
Reaction SMILES: [C:1]1(=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:7][C@H:8]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9]1.CO.C1(C)C=CC=CC=1.[BH4-].[Na+]>O>[CH:1]1([NH:7][C@H:8]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCCC1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC[C@H](NC2CCCC2)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Cyclopentanone (12.7 ml, 143 mmol) was added to tert-butyl (3S)-3-aminopyrrolidine-1-carboxylate (26.6 g, 143 mmol) in a mixture methanol:toluene 3:1 (600 ml:200 ml) and the reaction mixture was stirred at room temperature for 1.5 hours under nitrogen. The mixture was then evaporated to 50 ml, azeotroped three times with methanol:toluene 3:1 (600 ml:200 ml) and concentrated in vacuo. The reaction mixture was taken up in methanol (250 ml), cooled down to 0° C. and sodium borohydride (7.5 g, 200.2 mmol) was added portionwise. After completion of the reaction, water (50 ml) was added and the solvent was evaporated. The residue was diluted with more water (150 ml) and extracted three times with dichloromethane (250 ml). The organic phases were combined, dried over magnesium sulfate, and concentrated in vacuo to provide the title compound as a gum, 36.1 g (99.4%).
Reaction SMILES: Cl[C:2]1[S:3][CH2:4][CH2:5][N:6]=1.[Na].[CH3:8][CH:9]([O:12][C:13]1[CH:22]=[CH:21][C:16]([O:17][CH2:18][CH2:19][OH:20])=[CH:15][CH:14]=1)[CH2:10][CH3:11].[CH3:23]C(O)COC1C=CC(OC(C)CC)=CC=1>>[CH3:23][CH:18]([O:17][C:16]1[CH:21]=[CH:22][C:13]([O:12][CH:9]([CH3:8])[CH2:10][CH3:11])=[CH:14][CH:15]=1)[CH2:19][O:20][C:2]1[S:3][CH:4]=[CH:5][N:6]=1
Reactant: ClC1=NCCS1
Reactant: CCC(C)Oc1ccc(OCC(C)O)cc1
Reactant: CCC(C)Oc1ccc(OCCO)cc1
Agent: [Na]
Product: CCC(C)Oc1ccc(OC(C)COc2nccs2)cc1

Procedure:
In the same way, 2-chloro-2-thiazoline is reacted with the sodium salt of each of 2-[4-(1-methylpropoxy)phenoxy]ethanol and 1-methyl-2-[4-(1-methylpropoxy)phenoxy]ethanol to give, respectively,
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([NH:11][C:12]2[C:17]([C:18]3[N:19]=[C:20]4[CH:26]=[CH:25][N:24](COCC[Si](C)(C)C)[C:21]4=[N:22][CH:23]=3)=[CH:16][N:15]=[C:14](S(C)(=O)=O)[N:13]=2)[CH2:6]1)(=[O:4])=[O:3].[NH2:39][C@H:40]([CH2:43][CH3:44])[CH2:41][OH:42].CS(C)(=O)=O>O1CCOCC1>[CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([NH:11][C:12]2[C:17]([C:18]3[N:19]=[C:20]4[CH:26]=[CH:25][NH:24][C:21]4=[N:22][CH:23]=3)=[CH:16][N:15]=[C:14]([NH:39][C@H:40]([CH2:43][CH3:44])[CH2:41][OH:42])[N:13]=2)[CH2:6]1)(=[O:3])=[O:4]
Reactant: CC[C@@H](N)CO
Reactant: C[Si](C)(C)CCOCn1ccc2nc(-c3cnc(S(C)(=O)=O)nc3N[C@H]3CCCN(S(C)(=O)=O)C3)cnc21
Agent: CS(C)(=O)=O
Solvent: C1COCCO1
Product: CC[C@H](CO)Nc1ncc(-c2cnc3[nH]ccc3n2)c(N[C@H]2CCCN(S(C)(=O)=O)C2)n1

Procedure:
In a dioxane solution of ((S)-1-methanesulfonyl-piperidin-3-yl)-{2-methanesulfonyl-5-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyrimidin-4-yl}-amine derived from Example 84, step 1, (R)-2-aminobutan-1-ol was used to displace the methylsulfone similar to examples above and the de-protection step was similar to step 5, Example 76, to give (R)-2-[4-((S)-1-methanesulfonyl-piperidin-3-ylamino)-5-(5H-pyrrolo[2,3-b]pyrazin-2-yl)-pyrimidin-2-ylamino]-butan-1-ol. MS: (ES+) 461.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][CH3:9])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.O=P(Cl)(Cl)Cl.[NH3:16]>C1(C)C=CC=CC=1.C(O)CCC>[NH2:16][C:6]1[C:7]([CH2:8][CH3:9])=[C:2]([Cl:1])[N:3]=[CH:4][N:5]=1
Reactant: N
Reactant: CCc1c(Cl)ncnc1Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCCCO
Product: CCc1c(N)ncnc1Cl

Procedure:
Formamidine acetate was reacted with diethyl-ethylmalonate in the presence of sodium ethoxide in dry ethanol to yield 5-ethylpyrimidine-4,6-diol, which was converted to 4,6-Dichloro-5-ethylpyrimidine by POCl3 in the presence of TEA in toluene. 4,6-Dichloro-5-ethylpyrimidine was then reacted with aqueous ammonia in n-butanol at 100° C. to afford 4-amino-5-ethyl-6-chloropyrimidine.
Reaction SMILES: [O:1]=[C:2]([CH2:9][CH2:10][CH3:11])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH:12](OCC)(OCC)OCC.[Br:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1>>[Br:22][C:23]1[CH:29]=[CH:28][C:26]([NH:27][CH:12]=[C:3]([C:2](=[O:1])[CH2:9][CH2:10][CH3:11])[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:25][CH:24]=1
Reactant: CCCC(=O)CC(=O)OCC
Reactant: CCOC(OCC)OCC
Reactant: Nc1ccc(Br)cc1
Product: CCCC(=O)C(=CNc1ccc(Br)cc1)C(=O)OCC
Temperature: 120 °C
Yield: 32 %

Procedure:
A stirred mixture of ethyl 3-oxohexanoate (12.1 mL, 75 mmol), triethyl orthoformate (16.6 mL, 100 mmol), and 4-bromoaniline (12.9 g, 75 mmol) were heated at 120° C. for 4 h with a Dean Stark trap. After this time the reaction was cooled to room temperature. The resultant solid was triturated with diethyl ether to afford the desired product (8.17 g, 32%) as a white solid. ESI MS m/z 340 [C15H18BrNO3+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]3[N:13]=[C:14]([NH:17][CH:18]4[CH2:27][CH2:26][C:21]5(OCC[O:22]5)[CH2:20][CH2:19]4)[CH:15]=[CH:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl.CCOC(C)=O.C([O-])(O)=O.[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]3[N:13]=[C:14]([NH:17][CH:18]4[CH2:19][CH2:20][C:21](=[O:22])[CH2:26][CH2:27]4)[CH:15]=[CH:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cccc(-c2cnc3ccc(NC4CCC5(CC4)OCCO5)nn23)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1CCC(Nc2ccc3ncc(-c4cccc(Cl)c4)n3n2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.4 %

Procedure:
To a solution of 3-(3-chlorophenyl)-N-(1,4-dioxaspiro[4.5]decan-8-yl)imidazo[1,2-b]pyridazin-6-amine (210 mg, 0.55 mmol) in THF (3 mL) was added 3 N HCl (3 mL). The resulting mixture was stirred at room temperature for 2 h. TLC (EtOAc) showed the reaction was complete. The mixture was poured into sat. NaHCO3 (aq) and extracted with EtOAc (100 mL×3). The organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give 4-((3-(3-chlorophenyl)imidazo[1,2-b]pyridazin-6-yl)amino)cyclohexanone (190 mg, 102%) as a yellow solid.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[N:7][CH:6]=[CH:5][N:4]=1)=[CH2:2].[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[N:19]=[C:18]2[NH:26][CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:12][CH:11]=1.C(O)(=O)C>CO>[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[N:19]=[C:18]2[NH:26][CH:27]2[CH2:28][CH2:29][N:30]([CH2:2][CH2:1][C:3]3[CH:8]=[N:7][CH:6]=[CH:5][N:4]=3)[CH2:31][CH2:32]2)=[CH:12][CH:11]=1
Reactant: C=Cc1cnccn1
Reactant: Fc1ccc(Cn2c(NC3CCNCC3)nc3ccccc32)cc1
Solvent: CC(=O)O
Solvent: CO
Product: Fc1ccc(Cn2c(NC3CCN(CCc4cnccn4)CC3)nc3ccccc32)cc1

Procedure:
A mixture of 1.27 parts of 2-ethenylpyrazine, 6.48 parts of 1-[(4-fluorophenyl)methyl]-N-(4-piperidinyl)-1H-benzimidazol-2-amine, 0.3 parts of acetic acid and 40 parts of methanol was stirred and refluxed for 48 hours. The solvent was evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (88:12 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was washed with 2,2'-oxybispropane and crystallized from 27 parts of methylbenzene, yielding 2.4 parts of 1-(4-fluorophenylmethyl)-N-[1-[2-(2-pyrazinyl)ethyl]-4-piperidinyl]-1H-benzimidazol-2-amine; mp. 165.3° C. (compound 101).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](I)=[CH:4][C:3]=1[C:13]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:14].[K].[C:38]1([N:44]2[C:48]([SH:49])=[N:47][N:46]=[N:45]2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.CN(C)C=O>C(O)C>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([S:49][C:48]2[N:44]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[N:45]=[N:46][N:47]=2)=[CH:4][C:3]=1[C:13]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:14]
Reactant: Sc1nnnn1-c1ccccc1
Reactant: CCCCCCCCCCCCCCOc1ccccc1NC(=O)c1cc(I)c2ccccc2c1O
Agent: [K]
Solvent: CN(C)C=O
Solvent: CCO
Product: CCCCCCCCCCCCCCOc1ccccc1NC(=O)c1cc(Sc2nnnn2-c2ccccc2)c2ccccc2c1O
Temperature: 90 °C
Yield: 90 %

Procedure:
1-hydroxy-4-iodo-2'-tetradecyloxy-2-naphthanilide (9 g) and 1-phenyl-5-mercapto-tetrazole potassium salt (3 g) were solubilized im dimethylformamide (25 ml). The solution was heated at 90° C. for 1 hour under stirring. After adding ethanol (25 ml), a white solid precipitated. The solid collected by filtration was crystallized from ethanol. The yield was 90% of 1-hydroxy-4-(1-phenyl-5-tetrazolylthio)-2'-tetradecyloxy-2-naphthanilide of formula ##STR11##
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH:13]([C:15](=[O:22])[CH2:16][C:17](OCC)=[O:18])[CH2:12][CH2:11][N:10]1[C:23]([O:25][CH3:26])=[O:24].[OH-].[Na+].[NH2:29]O.Cl>CO.O.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH:13]([C:15]2[O:22][NH:29][C:17](=[O:18])[CH:16]=2)[CH2:12][CH2:11][N:10]1[C:23]([O:25][CH3:26])=[O:24]
Reactant: CCOC(=O)CC(=O)C1CCN(C(=O)OC)C(c2ccc(F)cc2Cl)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: COC(=O)N1CCC(c2cc(=O)[nH]o2)CC1c1ccc(F)cc1Cl
Temperature: -40 °C
Reaction time: 0.25 h
Yield: 65.4 %

Procedure:
Methyl 2-(2-chloro-4-fluorophenyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1.655 g, 4.29 mmol) was dissolved in MeOH (22 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.180 g, 4.50 mmol) dissolved in water (2.200 mL) was added and the mixture was stirred at −40° C. for 15 min. Hydroxylamine (50% by weight in water, 0.276 mL, 4.50 mmol) was added. The resulting solution was stirred at −40° C. for 1 h. The mixture was then transferred with a pipette into a prewarmed (80° C.) solution of 6 M hydrogen chloride (22.16 mL, 132.98 mmol) and the mixture was stirred at 80° C. for 15 min. Water and DCM were added and the phases separated. The aqueous phase was extracted with DCM and the combined organic layers were filtered through a phase separator and evaporated. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 15-55% Acetonitrile in H2O/MeCN/FA 95/5/0.2 buffer over 25 minutes with a flow of 100 mL/min (3 runs). Methyl 2-(2-chloro-4-fluorophenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (0.995 g, 65.4%) was yielded as a white solid. MS m/z 355 (M+H)+
Reaction SMILES: [O:1]1[CH2:22][CH:2]1[CH2:3][O:4][C:5]1[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)=[O:8].[CH:23]([NH2:26])([CH3:25])[CH3:24]>CO>[CH3:21][C:16]1[C:6]([C:7]([C:9]2[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=2)=[O:8])=[C:5]([CH:19]=[C:18]([CH3:20])[CH:17]=1)[O:4][CH2:3][CH:2]([OH:1])[CH2:22][NH:26][CH:23]([CH3:25])[CH3:24]
Reactant: Cc1ccc(C(=O)c2c(C)cc(C)cc2OCC2CO2)cc1
Reactant: CC(C)N
Solvent: CO
Product: Cc1ccc(C(=O)c2c(C)cc(C)cc2OCC(O)CNC(C)C)cc1

Procedure:
A mixture of 2-(2,3-epoxypropoxy)-4,4',6-trimethylbenzophenone (10.0 g.), isopropylamine (10 ml.) and anhydrous methanol (50 ml.) was heated at reflux for 17 hours. The solution was then evaporated in vacuo, and the residue was dissolved in water (100 ml.) containing concentrated hydrochloric acid (10 ml.). The solution was adjusted to a pH between 6 and 7 and was shaken with ethyl acetate. The aqueous phase was then adjusted to pH 12 by the addition of aqueous sodium hydroxide solution. The precipitated oil was extracted with ethyl acetate and the extract was washed with water, dried over anhydrous sodium sulphate and evaporated. The residue was dissolved in a hot mixture of light petroleum (b.p. 40°-60° C.; 75 ml.) and cyclohexane (3 ml.) and allowed to cool slowly. The solid was filtered off and recrystallized from cyclohexane (25 ml.) to give DL-1-(3,5-dimethyl-2-p-toluoylphenoxy)-2-hydroxy-3-isopropylaminopropane (5.9 g.), m.p. 89°-91° C.
Reaction SMILES: C(OC1C=C2C(=CC=1)NC1C(C)(CC(O)=O)OCCC2=1)C1C=CC=CC=1.[ClH:27].C([O:35][C:36]1[CH:37]=[C:38]2[C:42](=[CH:43][CH:44]=1)[N:41]([CH2:45][CH3:46])[C:40]1[C:47]([CH2:52][CH2:53][N:54]([CH3:56])[CH3:55])([CH3:51])[O:48][CH2:49][CH2:50][C:39]2=1)C1C=CC=CC=1>>[ClH:27].[CH3:56][N:54]([CH3:55])[CH2:53][CH2:52][C:47]1([CH3:51])[C:40]2[N:41]([CH2:45][CH3:46])[C:42]3[C:38]([C:39]=2[CH2:50][CH2:49][O:48]1)=[CH:37][C:36]([OH:35])=[CH:44][CH:43]=3
Reactant: CCn1c2c(c3cc(OCc4ccccc4)ccc31)CCOC2(C)CCN(C)C
Agent: CC1(CC(=O)O)OCCc2c1[nH]c1ccc(OCc3ccccc3)cc21
Agent: Cl
Product: CCn1c2c(c3cc(O)ccc31)CCOC2(C)CCN(C)C

Procedure:
By following the procedure of this example but replacing 6-benzyloxy-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid with an equivalent amount of 6-benzyloxy-1-[2-(dimethylamino)ethyl]-9-ethyl-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole hydrochloride, described in Example 731b, then 1-[2-(dimethylamino)ethyl]-9-ethyl-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-6-ol hydrochloride, is obtained m.p. 213° - 214° C; the corresponding free base of the latter compound has nmr (CDCl3) δ 1.36 (t, J = 7 cps, 3H) 1.6 (s,3H), 2.18 (s,6H). Likewise, replacement with 6-benzyloxy-1,9-dimethyl-1-[2-(dimethylamino)ethyl]-1,3,4,9-tetrahydropyrano[3,4-]indole hydrochloride described in Example 731d, gives 1,9-dimethyl-1-[2-(dimethylamino)ethyl]-1,3,4,9-tetrahydropyrano[3,4-b]indol-6-ol hydrochloride, m.p. 242°-244° C., corresponding free base has nmr (CDCl3) δ 1.6 (s,3H), 2.2 (s,6H), 3.7 (s,3H).
Reaction SMILES: [NH2:1][C@@H:2]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=1[Cl:30])[C:3]1[S:7][C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:22]=[CH:21][C:17]4[O:18][CH2:19][O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])=[N:5][CH:4]=1.[Si:31]([O:38][C@@H:39]([CH2:43]Cl)[CH2:40][CH:41]=O)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32].[BH4-].[Na+]>CO.O>[O:18]1[C:17]2[CH:21]=[CH:22][C:14]([C:11]3([C:9]([NH:8][C:6]4[S:7][C:3]([C@@H:2]([N:1]5[CH2:41][CH2:40][C@@H:39]([O:38][Si:31]([C:34]([CH3:36])([CH3:35])[CH3:37])([CH3:32])[CH3:33])[CH2:43]5)[C:23]5[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=5[Cl:30])=[CH:4][N:5]=4)=[O:10])[CH2:12][CH2:13]3)=[CH:15][C:16]=2[O:20][CH2:19]1
Reactant: N[C@H](c1cnc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)s1)c1ccc(F)cc1Cl
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CCl)CC=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CCN([C@H](c2cnc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)s2)c2ccc(F)cc2Cl)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 59 %

Procedure:
To a solution of (S)-N-(5-(amino(2-chloro-4-fluorophenyl)methyl)thiazol-2-yl)-1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (1.2 mmol) in MeOH (10 mL) was added (R)-3-(tert-butyldimethylsilyloxy)-4-chlorobutanal (341 mg, 1.4 mmol). The reaction mixture was stirred at room temperature for 5 min. Then NaBH4 (68 mg, 1.8 mmol) was added and stirring was continued at room temperature for 1 h. The reaction was diluted with H2O and extracted with EtOAc. The combined organic layers were washed with brine and dried over MgSO4. After the removal of solvent, the residue was purified by column chromatography (10-20% EtOAc/Hexane) to afford 1-(Benzo[d][1,3]dioxol-5-yl)-N-(5-((S)—((R)-3-(tert-butyldimethylsilyloxy)pyrrolidin-1-yl)(2-chloro-4-fluorophenyl)methyl)thiazol-2-yl)cyclopropanecarboxamide (446 mg, 59% over two steps). 1H NMR (400 MHz, CDCl3) δ 8.45 (s, 1H), 7.79 (dd, J=8.6, 6.3 Hz, 1H), 7.25 (d, J=6.4 Hz, 1H), 7.01-6.94 (m, 2H), 6.85 (td, J=8.3, 1.7 Hz, 2H), 6.78 (d, J=7.9 Hz, 1H), 5.99 (s, 2H), 4.99 (s, 1H), 4.35-4.30 (m, 1H), 2.77 (dd, J=9.9, 6.2 Hz, 1H), 2.51-2.48 (m, 2H), 2.36 (dd, J=9.9, 4.3 Hz, 1H), 2.06-2.01 (m, 1H), 1.71-1.65 (m, 3H), 1.18 (t, J=3.0 Hz, 2H), 0.85 (s, 9H), −0.01 (d, J=7.3 Hz, 6H); HPLC ret. time 3.59 min, 10-99% CH3CN, 5 min run; ESI-MS 630.6 m/z (MH+).