Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([NH:16][C:17]([CH:19]4[O:24][CH2:23][CH2:22][NH:21][CH2:20]4)=[O:18])[CH:14]=3)[NH:9][N:8]=2)=[CH:3][CH:2]=1.[F:25][C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH:28]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Na]>C(O)(=O)C.ClCCl>[F:25][C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH2:28][N:21]1[CH2:22][CH2:23][O:24][CH:19]([C:17]([NH:16][C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[NH:9][N:8]=[C:7]3[C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[O:18])[CH2:20]1
Reactant: O=C(Nc1ccc2[nH]nc(-c3ccncc3)c2c1)C1CNCCO1
Reactant: O=Cc1ccccc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [Na]
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(Nc1ccc2[nH]nc(-c3ccncc3)c2c1)C1CN(Cc2ccccc2F)CCO1
Reaction time: 0.25 h

Procedure:
In a flask, dichloromethane (0.5 mL) and acetic acid (3drops) was added to N-(3-(pyridin-4-yl)-1H-indazol-5-yl)morpholine-2-carboxamide (0.014 g, 0.0443 mmol) and 2-fluorobenzaldehyde (0.0112 g, 0.09 mmol). The reaction was stirred for 15 minutes. Sodium triacetoxyborohydride (0.040 g, 0.177 mmol) was added in one portion. The reaction was stirred for an additional 16 hours. Saturated sodium bicarbarbonate (1 mL) was added. The reaction was stirred for an additional 5 minutes and was extracted with dichloromethane (3×1 mL). The extracts were combined, dried with anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting crude product was purified by prep LC/MS. LC-MS: 432.2 [M+H]. LC/MS RT0.869 min.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7](=[O:17])[CH2:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([S:15][CH3:16])[N:10]=2)=[CH:4][CH:3]=1.CO[CH:20](OC)[N:21]([CH3:23])[CH3:22]>>[CH3:20][N:21]([CH3:23])[CH:22]=[C:8]([C:9]1[CH:14]=[CH:13][N:12]=[C:11]([S:15][CH3:16])[N:10]=1)[C:7]([C:5]1[S:6][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:17]
Reactant: CSc1nccc(CC(=O)c2ccc(Cl)s2)n1
Reactant: COC(OC)N(C)C
Product: CSc1nccc(C(=CN(C)C)C(=O)c2ccc(Cl)s2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
A solution of 1-(5-chloro-2-thienyl)-2-[2-(methylsulfanyl)pyrimidin-4-yl]ethanone (1 eq, 104 mmol) in 290 mL N,N-dimethylformamide dimethyl acetal was stirred at 80° C. for 1 h40 min and then stirred overnight at room temperature. The solvent was evaporated under reduced pressure and the residue was purified by chromatography on silica gel (heptane/ethyl acetate 1:1 to 3:7) to afford 32.7 g (86% yield) of 3-(dimethylamino)-1-(5-chloro-2-thienyl)-2-[2-(methylsulfanyl)pyrimidin-4-yl]prop-2-en-1-one.
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:5]=1.CO.[OH-].[Na+].C(Cl)Cl>C1COCC1>[CH2:14]([O:13][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[N+:10]([O-:12])=[O:11])[C:3]([OH:21])=[O:2])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: O=C(O)c1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Temperature: 60 °C
Yield: 85.9 %

Procedure:
Cmpd 2 (1.53 g, 1.0 eq) was dissolved in THF (52.8 mL) and MeOH (26.4 mL) in a round bottom flask, followed by addition of 2N NaOH (13.2 mL, 5.0 eq). The reaction was heated at 60° C. for 3 hours, occasionally opening the flask to release pressure. The reaction was monitored by TLC (5% MeOH:95% DCM). The resulting mixture was concentrated, and the residue was dissolved in water and acidified to pH=2-3 with 1N HCl. The acidic solution was extracted with AcOEt 3×, dried over Na2SO4, filtered and concentrated to afford Cmpd 3 as a light yellowish solid (1.25 g, 96% yield). Analytic: 1H NMR (DMSO d6, 500 mHz): δ 7.99 (d, 1H), 7.87 (s, 1H), 7.66 (dd, 1H), 7.46-7.40 (m, 4H), 7.33 (m, 1H), 5.39 (s, 2H). LCMS (C18, 2-98% CH3CN in 0.1% TFA/H2O over 6 min); Calculated mass for C14H11NO5 (M+H)+274.06. found by LC-MS 274.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]2[O:13][CH2:12][CH2:11][O:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C([Li])(C)(C)C.CCCCC.[CH3:24][C:25]([CH3:27])=[O:26]>C(OCC)C>[Cl:8][C:6]1[CH:7]=[C:2]([C:25]([OH:26])([CH3:27])[CH3:24])[CH:3]=[C:4]([CH:9]2[O:13][CH2:12][CH2:11][O:10]2)[CH:5]=1
Reactant: Clc1cc(Br)cc(C2OCCO2)c1
Reactant: CC(C)=O
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: CCCCC
Product: CC(C)(O)c1cc(Cl)cc(C2OCCO2)c1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To a solution of 2-(3-bromo-5-chlorophenyl)-1,3-dioxolane (3.34 g, 12.68 mmol) in anhydrous diethyl ether (40 mL) in a dried flask was slowly added a 1.70 M solution of tert-butyl lithium in pentane (15.0 mL, 25.50 mmol) at −78° C. under nitrogen to give a pinkish-yellow suspension. The reaction mixture was stirred at −78° C. for 45 min under nitrogen atmosphere. After 45 min, the reaction mixture was warmed to −30° C. and stirred at that temperature for 2 h. Acetone (2.0 mL, 25.35 mmol) was added drop wise to the above solution and the reaction mixture stirred at −30° C. for another 3 h. The reaction mixture was quenched with a saturated NH4Cl solution (20 mL) at −30° C. and the reaction mixture was warmed slowly to room temperature (30 min) and then diluted with diethyl ether (25.0 mL). The ether layer was separated and then washed with water (1×25 mL), dried over anhydrous Na2SO4, filtered and evaporated on the rot-yap to give a pale yellow viscous liquid (5.45 g from two runs). GC-MS analysis (EI mode) of the product shows the desired product's mass: m/z 241 (35ClM+) and m/z 243 (37ClM+), Calcd for C12H15BrClO3: 242.67. LC-MS analysis of the crude product shows the desired product's mass: m/z 243 (35ClM+H), m/z 245 (37ClM+H), m/z 225 (35ClM+H−H2O), m/z 227 (37ClM+H−H2O). 1H NMR (400 MHz, CDCl3): δ 1.54 (s, 6H, (CH3)2C—OH), 3.90-4.25 (M, 4H, 2×—CH2—O—), 5.75 (s, 1H, O—CH-0), 7.34 (s, 1H), 7.43 (d, 2H). 1H NMR spectrum of the sample was consistent with the suggested structure of the product.
Reaction SMILES: Cl[S:2]([OH:5])(=O)=[O:3].[NH:6]([C:13]1[N:18]=[C:17]([C:19]2[N:23]([CH3:24])[CH:22]=[N:21][CH:20]=2)[CH:16]=[CH:15][N:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(C(C)C)CC)(C)C.[CH3:34][O:35][CH2:36][CH2:37][CH2:38][NH2:39]>S(Cl)(Cl)=O.CCOC(C)=O>[CH3:34][O:35][CH2:36][CH2:37][CH2:38][NH:39][S:2]([C:10]1[CH:11]=[CH:12][C:7]([NH:6][C:13]2[N:18]=[C:17]([C:19]3[N:23]([CH3:24])[CH:22]=[N:21][CH:20]=3)[CH:16]=[CH:15][N:14]=2)=[CH:8][CH:9]=1)(=[O:5])=[O:3]
Reactant: COCCCN
Reactant: O=S(=O)(O)Cl
Reactant: Cn1cncc1-c1ccnc(Nc2ccccc2)n1
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COCCCNS(=O)(=O)c1ccc(Nc2nccc(-c3cncn3C)n2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 27.6 %

Procedure:
Chlorosulphonic acid (0.22 ml, 3.18 mmol) was added to suspension of 2-anilino-4-(1-methylimidazol-5-yl)pyrimidine (Example 14; 200 mg, 0.80 mmol) in thionyl chloride (4 ml) cooled at 0° C. The mixture was allowed to warm to ambient temperature, stirred for 15 minutes then heated at reflux for 20 minutes. The volatiles were removed by evaporation and the solid residue dried under high vacuum. The residue was suspended in pyridine (3 ml), cooled to −20° C. and diisopropylethyl amine (0.56 ml, 3.98 mmol) followed by 3-methoxypropyl amine (0.16 ml, 1.60 mmol) was added. The reaction mixture was allowed to warm to ambient temperature and stirred for 30 minutes. EtOAc (15 ml) was added and the mixture washed with saturated aqueous sodium hydrogen carbonate solution (15 ml) and then brine (15 ml). The solvent was removed by evaporation and the residue purified by column chromatography eluting with DCM and 2M methanolic ammonia solution (100:0 increasing in polarity to 85:15) to give the title compound 89 mg, (28%) as a solid product. NMR: 1.75 (m, 2H), 2.76 (q, 2H), 3.14 (s, 3H), 3.22-3.30 (m, 2H), 4.01 (s, 3H), 7.25 (d, 1H), 7.34 (t, 1H), 7.70 (d, 2H), 7.77 (s, 1H), 7.83 (s, 1H), 7.91 (d, 2H), 8.47 (d, 1H), 9.92 (s, 1H); m/z 4.03.
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[C:3]=1[C:16]([O:18][CH3:19])=[O:17].O=P(Cl)(Cl)[Cl:22]>>[F:13][C:12]([F:15])([F:14])[C:4]1[C:3]([C:16]([O:18][CH3:19])=[O:17])=[C:2]([Cl:22])[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=1
Reactant: COC(=O)c1c(O)cc(C(F)(F)F)nc1C(F)(F)F
Reactant: O=P(Cl)(Cl)Cl
Product: COC(=O)c1c(Cl)cc(C(F)(F)F)nc1C(F)(F)F

Procedure:
The enamine 2 so produced is then reacted with 2-2.5 equivalents of a strong base, suitably lithium diisopropylamide to generate in situ a dianion which is then reacted with an ester of trifluoromethyl carboxylic acid. The reaction product is a mixture of a substituted 4-hydroxy-2,6-bis-(trifluoromethyl)-3-(methoxycarbonyl)pyridine and a substituted 2,3-dihydro-2-hydroxy-4-pyridone, which dehydrates readily when heated to form a 4-hydroxy-2,6-bis-(trifluoromethyl)-3-(methoxycarbonyl)pyridine 3. The pyridine 3 is then chlorinated with a suitable chlorinating agent such as POCl3 to form 2,6-bis(trifluoromethyl)-3-methoxycarbonyl-4-chloropyridine 4. Pyridine 4 is then hydrogenated using standard laboratory techniques to form 2,6-bis(trifluoromethyl)-3-methoxycarbonyl pyridine 5. The pyridine 5 is then hydrolyzed with a strong base to form 2,6-bis(trifluoromethyl)-3-hydroxycarbonyl pyridine 6. ##STR5##
Reaction SMILES: [C:1]1([P:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8]2[N:13]=[C:12]([NH2:14])[CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:28](Cl)(=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30]>ClCCl.CN(C)C1C=CN=CC=1>[C:15]1([P:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[N:13]=[C:12]([NH:14][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])[CH:11]=[CH:10][CH:9]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1cccc(P(c2ccccc2)c2ccccc2)n1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1cccc(P(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.1 %

Procedure:
2.0 g (7.2 mmol) of 6-(diphenylphosphino)-2-aminopyridine from example 14.3.1 were dissolved in 40 ml of dichloromethane and admixed with 1.6 ml (1.2 g, 10.8 mmol) of triethylamine and 0.16 g (0.7 mmol) of 4-dimethylaminopyridine (DMAP). After cooling to 0° C. (H2O/ice), 1.2 ml (1.2 g, 8.8 mmol) of pivaloyl chloride were slowly added dropwise and the mixture was kept at this temperature for 3 h. The mixture was allowed to warm to room temperature overnight and the solvent was then removed under reduced pressure. The residue was purified by filtration together with cyclohexane/ethyl acetate (1:1) through a short silica gel column (3×10 cm). The solvent was removed under reduced pressure and the resulting oil crystallized by digesting with petroleum ether (40/60). The solid was filtered off, washed with petroleum ether (40/60) and dried under reduced pressure. 2.25 g (6.2 mmol, 86.1%) of 6-(diphenylphosphino)-2-pivaloylaminopyridine were obtained as a beige-colored solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:30](OC(N1CCN(C2C=NC(N)=CC=2)[C@@H](C)C1)=O)(C)(C)C.BrC1C(=O)N(C)C=C(Br)C=1>>[C:26]([O:25][C:23]([N:20]1[CH2:21][CH2:22][N:17]([C:14]2[CH:15]=[N:16][C:11]([NH:10][C:4]3[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=[C:2]([Br:1])[CH:3]=3)=[CH:12][CH:13]=2)[C@@H:18]([CH3:30])[CH2:19]1)=[O:24])([CH3:29])([CH3:28])[CH3:27]
Reactant: Cn1cc(Br)cc(Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cn2)c1=O
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc(N)nc1
Agent: Cn1cc(Br)cc(Br)c1=O
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc(Nc2cc(Br)cn(C)c2=O)nc1
Yield: 83 %

Procedure:
Following the procedures as described for compound 101i, reaction of 130b (4.0 g) and 3,5-dibromo-1-methylpyridin-2(1H)-one (5.5 g) afforded 130c as a yellow solid (5.4 g, 83%). LCMS: [M+H]+ 478
Reaction SMILES: [C:1]1([S:7]([N:10]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14]([OH:16])=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:27][C:28]1[CH:36]=[C:35]2[C:31]([CH:32]=[N:33][NH:34]2)=[CH:30][CH:29]=1.Cl.CN(C)CCCN=C=NCC.SC1SC2C=CC=CC=2N=1.C(N(CC)CC)C>C(#N)C>[C:1]1([S:7]([N:10]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14]([NH:27][C:28]2[CH:36]=[C:35]3[C:31]([CH:32]=[N:33][NH:34]3)=[CH:30][CH:29]=2)=[O:16])(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1cccc(N(Cc2ccccc2)S(=O)(=O)c2ccccc2)c1
Reactant: Nc1ccc2cn[nH]c2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Sc1nc2ccccc2s1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc2cn[nH]c2c1)c1cccc(N(Cc2ccccc2)S(=O)(=O)c2ccccc2)c1
Yield: 45.7 %

Procedure:
A solution of 3-(benzenesulfonyl-benzyl-amino)-benzoic acid (25 mg, 0.068 mmol), 6-amino-1H-indazole (18 mg, 0.136 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (15 mg, 0.075 mmol), mercaptobenzothiazole (2 mg, 0.007 mmol) and triethylamine (24 μl, 0.17 mmol) in dry acetonitrile (2 ml) were stirred at room temperature for 15 hrs. The reaction mixture was quenched with water (10 ml) and extracted with dichloromethane (3×7 ml). The organics were combined, dried (PTFE frit) and concentrated in vacuo. The crude residue was purified by preparative TLC (10% diethyl ether in dichloromethane) to afford the title compound as a brown solid (15 mg, 45%). HPLC retention time 5.80 min. Mass spectrum (ES+) m/z 483 (M+H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[O:20])[C:10]3[N:14]=[C:13]([O:15]CC)[NH:12][C:11]=3[CH:18]=2)=[C:5]([CH3:27])[O:4][N:3]=1.[CH2:28]([Mg]Br)[CH3:29].CCO.Cl.O1CCOCC1>C1COCC1>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:19]([OH:20])([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[CH2:28][CH3:29])[C:10]3[NH:14][C:13](=[O:15])[NH:12][C:11]=3[CH:18]=2)=[C:5]([CH3:27])[O:4][N:3]=1
Reactant: CC[Mg]Br
Reactant: CCOc1nc2c(C(=O)c3ccccn3)cc(-c3c(C)noc3C)cc2[nH]1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Solvent: C1CCOC1
Product: CCC(O)(c1ccccn1)c1cc(-c2c(C)noc2C)cc2[nH]c(=O)[nH]c12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
(6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazol-4-yl)(pyridin-2-yl)methanone (20 mg, 0.055 mmol) was dissolved in dry THF (0.5 mL) and ethylmagnesium bromide (1.0 M, 0.27 mL, 0.27 mmol) was added dropwise. The reaction was allowed to stir at r.t. for 10 minutes and then a mixture of EtOH (1 mL) and 4.0M HCl/dioxane (0.5 mL) was added and the reaction was heated to 65° C. for 3 hours. The reaction was concentrated and purified by reverse-phase HPLC to afford the desired product as a white powder.
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@H:5]3[C@:20]([CH3:22])([CH2:21][C@@H:2]12)[C@@H:19]1[C@H:8]([C@H:9]2[C@:16]([CH3:24])([CH2:17][C:18]1=[O:23])[C@@H:12]([C:13](=[O:15])[CH3:14])[CH2:11][CH2:10]2)[CH2:7][CH2:6]3.S(=O)(=O)(O)O.[OH2:30].[CH3:31]O>>[OH:30][C@@H:3]1[C@@H:2]([O:1][CH3:31])[CH2:21][C@@:20]2([CH3:22])[C@@H:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:19]2[C:18](=[O:23])[CH2:17][C@@:16]2([CH3:24])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:13](=[O:15])[CH3:14])[CH2:4]1
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H]5O[C@@H]5C[C@]4(C)[C@H]3C(=O)C[C@]12C
Reactant: CO
Reactant: O
Agent: O=S(=O)(O)O
Product: CO[C@H]1C[C@@]2(C)[C@@H](CC[C@H]3[C@@H]4CC[C@H](C(C)=O)[C@@]4(C)CC(=O)[C@@H]32)C[C@@H]1O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
2α,3α-Epoxy-5α-pregnane-11,20-dione (200 mg) was dissolved in dry methanol (20 ml), and concentrated sulphuric acid (0.1 ml.) was added. The solution was stirred at room temperature for 20 minutes, and then poured into water (125 ml.) to give a white crystalline precipitate which was filtered off and dried in vacuo over phosphorus pentoxide to give 3α-hydroxy-2β-methoxy-5α-pregnane-11,20-dione (175 mg.), m.p. 163°-164°, [α]D + 109°.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:10][CH2:9][NH:8][CH2:7]1)=[O:5])C.[ClH:11].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C@H:19]([NH2:24])[C:20]([F:23])([F:22])[F:21])=[CH:15][C:14]=1[CH3:25].[Li+].[OH-]>>[Cl:11][C:13]1[CH:18]=[CH:17][C:16]([NH:24][C@@H:19]([C:16]2[CH:17]=[CH:18][C:13]([Cl:12])=[C:14]([CH3:25])[CH:15]=2)[C:20]([F:22])([F:23])[F:21])=[CH:15][C:14]=1[CH2:25][N:8]1[CH2:9][CH2:10][CH:6]([C:4]([OH:3])=[O:5])[CH2:7]1
Reactant: Cl
Reactant: Cc1cc([C@H](N)C(F)(F)F)ccc1Cl
Reactant: CCOC(=O)C1CCNC1
Agent: [Li+]
Agent: [OH-]
Product: Cc1cc([C@H](Nc2ccc(Cl)c(CN3CCC(C(=O)O)C3)c2)C(F)(F)F)ccc1Cl

Procedure:
The title compound was prepared according to Scheme 4 following a procedure analogous to Example 61 using pyrrolidine-3-carboxylic acid ethyl ester in step 1 and (5)-1-(4-chloro-3-methyl-phenyl)-2,2,2-trifluoro-ethylamine hydrochloride in step 2, followed by a LiOH-mediated ester cleavage.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:21])[N:5]([C:12]1([CH3:20])[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[CH3:22][O:23][CH2:24][C:25](Cl)=[O:26].CO>C1COCC1>[CH3:22][O:23][CH2:24][C:25]([NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:21])[N:5]([C:12]1([CH3:20])[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11])=[O:26]
Reactant: COCC(=O)Cl
Reactant: CC1(N2C(=O)c3cccc(N)c3C2=O)CCC(=O)NC1=O
Solvent: CO
Solvent: C1CCOC1
Product: COCC(=O)Nc1cccc2c1C(=O)N(C1(C)CCC(=O)NC1=O)C2=O
Reaction time: 0.25 h
Yield: 87.5 %

Procedure:
To a suspension of 4-amino-2-(3-methyl-2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione (0.10 g, 0.35 mmol) in THF (1-5 ml) was added methoxyacetyl chloride (0.08 g, 0.70 mmol). The mixture was heated to reflux for 6 hours. The reaction mixture was allowed to cool and to the solution was added methanol (2 ml). The reaction mixture was stirred for an additional 15 minutes followed by solvent evaporation in vacuo. The resulting solid was slurried in diethyl ether (20 ml) and filtered to give 0.11 g (87%) of product as an off-white solid: mp 244-246° C.; 1H NMR (DMSO-d6) 11.07 (s, 1H), 10.26 (s, 1H), 8.68 (d, J=8.3 Hz, 1H), 7.82 (t, J=7.7 Hz, 1H), 7.55 (d, J=7.2 Hz, 1H), 4.10 (s, 2H), 3.47 (s; 3H), 2.77-2.51 (m, 3H), 2.09-2.04 (m, 1H), 1.90 (s, 3H); 13C NMR (DMSO-d6) 172.12, 171.99, 169.15, 168.99, 167.38, 136.22, 135.68, 131.06, 124.25, 117.90, 115.91, 71.43, 59.06, 58.88, 29.01, 28.53, 20.92; Anal. Calcd. For C17H17N3O6: C, 56.48; H, 4.81; N. 11.62. Found: C, 56.10; H, 4.55; N, 11.39+0.12H2O.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:19]([O:20][CH3:21])=[CH:18][C:6]2[CH:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:8][NH:9][CH2:10][CH2:11][C:5]=2[CH:4]=1.[CH2:22]=O>C(O)=O>[CH3:1][O:2][C:3]1[C:19]([O:20][CH3:21])=[CH:18][C:6]2[CH:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:8][N:9]([CH3:22])[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: C=O
Reactant: COc1cc2c(cc1OC)C(c1ccccc1)CNCC2
Solvent: O=CO
Product: COc1cc2c(cc1OC)C(c1ccccc1)CN(C)CC2

Procedure:
A solution of 3.58 g. (0.0126 mol) of 7,8-dimethoxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine in 15 ml. of formic acid and 10 ml. of formaldehyde is refluxed for 18 hours. The reaction mixture is evaporated to dryness, 20 ml. of 6N hydrochloric acid is added and the solution is again evaporated to dryness to give a liquid. The latter is treated with 20 ml. of 10% sodium hydroxide solution and the mixture is extracted with ether. The dried extract is evaporated to give the liquid 7,8-dimethoxy-3-methyl-1-phenyl-2,3,4,5- tetrahydro-1H-3-benzazepine.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:12]=[C:11]([N+:13]([O-])=O)[CH:10]=[CH:9][C:8]=2[O:16][CH3:17])[CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)C.[Pd]>[CH:1]1([O:6][C:7]2[CH:12]=[C:11]([CH:10]=[CH:9][C:8]=2[O:16][CH3:17])[NH2:13])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc([N+](=O)[O-])cc1OC1CCCC1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(N)cc1OC1CCCC1
Reaction time: 4 h
Yield: 95.4 %

Procedure:
To a suspension of 10% Pd on activated carbon (25 g) in ethanol (4 L), under N2 protection, was added 1-cyclopentyloxy-2-methoxy-5-nitrobenzene (250 g, 1.054 mol). The reaction mixture was degassed under vacuum three times. The reaction mixture was stirred vigorously while hydrogen gas was allowed to flow over the reaction mixture. After 4 h the reaction was complete by TLC (5:1 hex:EA). The reaction mixture was filtered through a pad of celite and the celite was rinsed with additional ethanol. The solvent was removed in-vacuo to obtain 208.38 g (95% yield) of 3-cyclopentyloxy-4-methoxyaniline as a red liquid. 1H NMR (CDCl3) δ 6.85 (d. J=8.4 Hz, 1H), 6.29 (s, 1H), 6.19 (dd, J=2.8, 8.4, 1H), 4.69 (p, J=4.4 Hz, 1H), 3.75 (s, 3H), 3.44 (bs, 2H), 1.90–1.81 (m, 6H), 1.61–1.55 (m, 2H).
Reaction SMILES: N[CH2:2][C:3]([OH:5])=[O:4].[CH:6](=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.COC(OC)OC>CN(C=O)C.C(N(CC)CC)C>[C:3]1(=[O:4])[O:5][C:6](=[O:13])[C:7]2=[CH:12][CH:11]=[CH:10][CH:9]=[C:8]2[CH2:2]1
Reactant: NCC(=O)O
Reactant: O=Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: COC(OC)OC
Solvent: CN(C)C=O
Product: O=C1Cc2ccccc2C(=O)O1
Reaction time: 3 h

Procedure:
The teabag containing glycine on resin was placed in a 20 mL bottle and treated with a solution of benzaldehyde (0.508 mL, 5 mmoles) and anhydrous trimethylorthoformate (1.094 mL, 10 mmoles) in anhydrous DMF (9 mL). After shaking for 3 hours, the packet was washed with anhydrous DMF (3×8 mL). A solution of homophthalic anhydride (801 mg, 5 mmoles) and triethylamine (0.044 mL, 0.3 mmoles) was prepared in DMF (10 mL) and added to the teabag. After shaking at room temperature for 16 hours the packet was washed with DMF (6×30 mL) and DCM (4×30 mL) and dried at room temperature.
Reaction SMILES: Cl.[C:2]([NH:12][CH2:13][CH2:14][NH2:15])([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[C:16]([NH:23][C@H:24]([C:26](O)=[O:27])[CH3:25])([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C(N(CC)CC)C>CN(C)C=O>[CH2:5]([O:4][C:2]([NH:12][CH2:13][CH2:14][NH:15][C:26](=[O:27])[C@H:24]([CH3:25])[NH:23][C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: NCCNC(=O)OCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCCNC(=O)OCc1ccccc1
Temperature: 5 °C
Reaction time: 1 h
Yield: 94.3 %

Procedure:
A solution of 10.0 g (0.043 mol) of (1f) and 10.3 g (0.036 mol) of N-BOC-L-alanine, N-hydroxysuccinimide ester in anhydrous N,N-dimethylformamide (50 ml) was cooled with an ice bath. To this was added 7.6 ml (0.054 mol) of triethylamine in anhydrous N,N-dimethylformamide (20 ml) over a period of 30 minutes. The reaction was stirred at ca. 5° C. for 1 hour, then at room temperature for 1 hour. The N,N-dimethylformamide was removed in vacuo and the resulting residue was dissolved in 300 ml of ethyl acetate. The solution was washed with 1M HCl (3×100 ml), water (100 ml), saturated sodium bicarbonate solution (3×100 ml) and finally, with brine (100 ml). After drying over anhydrous magnesium sulfate, the solution was filtered and concentrated in vacuo to give 12.4 g (94% yield) of N-BOC-L-alanine, 2-(benzyloxycarbonylamino)ethyl amide (1g) as a white solid. TLC: Rf 0.67 (chloroform-isopropanol 9:1); 1H NMR(CDCl3) δ 1.27(d, 3H), 1.40(s, 9H), 3.32(m, 4H), 4.15(m,1H), 5.06(s,2H), 5.51(d,1H), 5.90(m,1H), 7.19(m,1H), 7.31(bs,5H) 13C NMR (CDCl3) δ 18.5, 28.2, 39.6, 40.5, 50.1, 66.5, 79.8, 127.9, 128.3, 136.3, 155.4, 156.9, 173.7.
Reaction SMILES: [F:1][CH:2]([F:12])[O:3][C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:5]=1[NH2:6].C(=O)([O-])[O-].[K+].[K+].[Cl:19][CH2:20][C:21](Cl)=[O:22]>CC(C)=O>[Cl:19][CH2:20][C:21]([NH:6][C:5]1[C:7]([CH3:11])=[CH:8][CH:9]=[CH:10][C:4]=1[O:3][CH:2]([F:12])[F:1])=[O:22]
Reactant: Cc1cccc(OC(F)F)c1N
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cccc(OC(F)F)c1NC(=O)CCl
Yield: 94.3 %

Procedure:
The procedures of Example 3 were repeated except that the starting material was 50 ml of an acetone solution containing 8.9 g (51 mmol) of 2-difluoromethoxy-6-methyl aniline, to which 10.5 g (77 mmol) of potassium carbonate and 7.0 g (62 mmol) of chloroacetyl chloride were added. As a result, 12.0 g of 2-chloro-2'-difluoromethoxy-6'-methylacetanilide was obtained. It had a melting point of 85° to 86° C.