Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[S:2]1(=[O:26])[CH2:7][CH2:6][N:5]([C:8]2[N:9]=[C:10]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[C:11]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13][C:12]=3[N:18]=2)[CH2:4][CH2:3]1.IC.[CH2:29](N(C(C)C)C(C)C)C>C(Cl)Cl>[O:26]=[S:2]1(=[O:1])[CH2:3][CH2:4][N:5]([C:8]2[N:9]=[C:10]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[C:11]3[CH2:17][CH2:16][N:15]([CH3:29])[CH2:14][CH2:13][C:12]=3[N:18]=2)[CH2:6][CH2:7]1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1ccc(-c2nc(N3CCS(=O)(=O)CC3)nc3c2CCNCC3)cc1
Solvent: CI
Solvent: ClCCl
Product: Cc1ccc(-c2nc(N3CCS(=O)(=O)CC3)nc3c2CCN(C)CC3)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 16.2 %

Procedure:
A mixture of 2-(1,1-dioxo-1λ6-thiomorpholin-4-yl)-4-p-tolyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine (0.060 g, 0.00016 mol), iodomethane (0.015 mL, 0.00016 mol) and N-ethyl-N-(1-methylethyl)-2-propanamine (0.056 mL, 0.00032 mol) in DCM (2 mL) was stirred at rt for 3 h. The mixture was diluted with DCM and washed with water (3×) and satd. aq. NaCl. The separated organic layer was dried and concentrated. The residue was purified by FCC [7 N NH3/MeOH)/DCM] to give 0.010 g (16%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:37]=[CH:36][C:17]([O:18][CH2:19][C:20]([C:28]4[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=4[Cl:35])([OH:27])[CH2:21][N:22]4[CH:26]=[N:25][CH:24]=[N:23]4)=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:45](Cl)(=[O:47])[CH3:46]>C(Cl)Cl>[C:45]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:37]=[CH:36][C:17]([O:18][CH2:19][C:20]([C:28]4[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=4[Cl:35])([OH:27])[CH2:21][N:22]4[CH:26]=[N:25][CH:24]=[N:23]4)=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1)(=[O:47])[CH3:46]
Reactant: CC(=O)Cl
Reactant: Nc1ccc(N2CCN(c3ccc(OCC(O)(Cn4cncn4)c4ccc(Cl)cc4Cl)cc3)CC2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1ccc(N2CCN(c3ccc(OCC(O)(Cn4cncn4)c4ccc(Cl)cc4Cl)cc3)CC2)cc1
Reaction time: 1 h

Procedure:
To a solution of 3-(4-[4-(4-aminophenyl)piperazin-1-yl]phenoxy)-2-(2,4-dichlorophenyl)-1-(1H-1,2,4-triazol-1-yl)propan-2-ol (see Preparation 1) (0.2 g, 0.37 mmole) and triethylamine (0.1 g, 1 mmole) in methylene chloride (20 ml) at 0° was added, dropwise, a solution of acetyl chloride (0.1 g, 1.2 mmole) in methylene chloride (1 ml). After completion of the addition the mixture was stirred at 0° for a further 1 hour and then partitioned between ethyl acetate and sodium bicarbonate solution. The separated organic phase was dried over magnesium sulphate and concentrated under reduced pressure to give a gum which on trituration with ethyl acetate yielded the desired product as a pale yellow solid, m.p. 169°-171° (0.098 g, 45%).
Reaction SMILES: Cl[CH:2]([C:5](=[O:9])[CH2:6][CH2:7][CH3:8])[CH2:3][CH3:4].[CH3:10][OH:11].C[O-].[Na+]>>[CH3:10][O:11][CH:2]([C:5](=[O:9])[CH2:6][CH2:7][CH3:8])[CH2:3][CH3:4]
Reactant: CCCC(=O)C(Cl)CC
Reactant: CO
Agent: C[O-]
Agent: [Na+]
Product: CCCC(=O)C(CC)OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1.5 grams of 3-chloro-4-heptanone in 3 ml anhydrous methanol (0.01 moles 3-chloro-4-heptanone) is placed into a 25 ml, three-necked, round bottom flask equipped with magnetic stirrer, pot thermometer, reflux condenser (with drying tube), 10 ml addition funnel with nitrogen inlet at top, an ice water-salt bath, and nitrogen bubbler. The 3-chloro-4-heptanone solution is cooled to a temperature of between 0° and 1° C. Into the 10 ml addition funnel is placed a solution of 0.54 grams of sodium methoxide dissolved in 7 ml anhydrous methanol (0.01 moles sodium methoxide). Over a period of one hour, while maintaining the reaction mass at a temperature of between 0° and 1° C, the sodium methoxide solution is added to the 3-chloro-4-heptanone. The reaction mass is then permitted to warm up to room temperature. It is then vacuum filtered thereby separating the white precipitate from the filtrate. The white solid precipitate is washed with 25 ml methylene chloride, and the washings are combined with the filtrate prior to concentration. After concentration of the filtrate, the concentrate is dried over anhydrous sodium sulfate and further concentrated to a weight of 1.0 grams (white oil). The major peak is isolated by GLC trapping (8 feet × 1/4 inch SE-30 column). NMR, IR and mass spectral analyses confirm that the resulting material has the structure: ##STR89##
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([NH2:16])=[O:15])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:17][CH2:18][O:19][C:20]([CH:22]1[C:26](=O)[CH2:25][CH2:24][CH2:23]1)=[O:21].O>C1C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:1][C:2]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([NH:16][C:23]2[CH2:24][CH2:25][CH2:26][C:22]=2[C:20]([O:19][CH2:18][CH3:17])=[O:21])=[O:15])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C1CCCC1=O
Reactant: CCOC(=O)c1cc(NC(N)=O)ccc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)C1=C(NC(=O)Nc2ccc(Cl)c(C(=O)OCC)c2)CCC1

Procedure:
48.4 g of ethyl 2-chloro-5-ureido-benzoate and 31.2 g of ethyl cyclopentanone-2-carboxylate are heated under reflux for 6 hours in 500 ml of benzene and 2 g of toluene-4-sulphonic acid monohydrate. The water formed is removed by means of a water separator. The reaction mixture is subsequently evaporated to dryness, the residue is dissolved in 700 ml of diethyl ether and the solution is filtered. The filtrate is evaporated to dryness and the residue is purified by chromatography on 1.5 g of silica gel using diethyl ether/n-hexane (1:2) as the eluent. There is obtained ethyl 2-chloro-5-{3-[2-(ethoxycarbonyl)-1-cyclopenten-1-yl]ureido}-benzoate as colourless crystals. The product is recrystallized from diethyl ether/n-hexane, m.p. 110°-112° C.
Reaction SMILES: [OH:1][C:2]([CH3:6])([CH3:5])[C:3]#[CH:4].N1C=CN=C1.[C:12]([Si:16](Cl)([CH3:18])[CH3:17])([CH3:15])([CH3:14])[CH3:13].CN(C1C=CC=CN=1)C>O.CN(C)C=O>[C:12]([Si:16]([CH3:18])([CH3:17])[O:1][C:2]([CH3:6])([CH3:5])[C:3]#[CH:4])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C#CC(C)(C)O
Agent: CN(C)c1ccccn1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: C#CC(C)(C)O[Si](C)(C)C(C)(C)C
Temperature: 70 °C
Reaction time: 0.25 h

Procedure:
To the stirred mixture of 25 g (0.29M) of 3-hydroxy-3-methyl-butyne, 50 ml of anhydrous N,N-dimethyl-formamide and 44.5 g (0.65M) imidazole cooled in an ice-bath was added 50 g (0.33M) tert.butyldimethylsilyl chloride. Stirring in the ice-bath was continued for 15 minutes and then at room temperate overnight. After addition of 250 mg of dimethylaminopyridine, the reaction mixture was heated at 70° C. for two hours and then poured into one liter of cold water. It was then extracted with 5×150 ml of ether. The organic extract was washed with brine, dried over MgSO4 and evaporated to dryness. The crude product was purified by vacuum distillation yielding 3-(tert.butyldimethylsilyl)oxy-3-methyl-butyne.
Reaction SMILES: [NH:1]([C:13]([O:15]CC1C=CC=CC=1)=O)[C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH:23]1[CH:27]=[N:26][N:25]=[N:24]1.[NH:28]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C@H:29](C(O)=O)[CH2:30][NH2:31].CCOC(OC(OCC)=O)=O.CCN(C(C)C)C(C)C>C(O)C.[Pd]>[NH:28]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C@H:29]([C:13]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)=[O:15])[CH2:30][NH2:31].[NH:23]1[CH:27]=[N:26][N:25]=[N:24]1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CN)C(=O)O
Agent: [Pd]
Agent: CCOC(=O)OC(=O)OCC
Agent: c1nnn[nH]1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H](CN)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reaction time: 2 h
Yield: 26.7 %

Procedure:
Cbz-Phe-Tetrazole (2.25 g, 6.25 mmole) was then dissolved in ethanol (100 ml) and treated with Pd/C 10% (500 mg, 0.3125 mmole) and stirred under hydrogen for 2 hr. The reaction mixture was filtered through a celite pad and concentrated to dryness. This material was reconstituted in dichloromethane (80 ml) and treated with Boc-Dap (1.88 g, 6.54 mmole), DEPC (1.42 ml, 9.38 mmole) and DIEA (3.8 ml, 21.88 mmole). After 16 hr volatiles were removed to afford crude Boc-Dap-Phe-Tetrazole which was purified by preparative HPLC to give 704 mg (20%) of 1001 as a white powder. Reverse-phase HPLC analysis: 99% at 6.3 min; LCMS (ESI): m/z 458.905 (MH)+, 480.874 (M+Na)+, eluted at 12.95 min.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=O)=[CH:6][CH:5]=[CH:4][N:3]=1.Cl.[NH2:11][OH:12]>N1C=CC=CC=1>[NH2:1][C:2]1[C:7]([CH:8]=[N:11][OH:12])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: NO
Reactant: Nc1ncccc1C=O
Agent: Cl
Solvent: c1ccncc1
Product: Nc1ncccc1C=NO
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 84.7 %

Procedure:
To a solution of 2-amino-3-formylpyridine (1.00 g, 8.19 mmol) in pyridine (20 mL) was added hydroxylamine hydrochloride (854 mg, 12.3 mmol) at room temperature, which was stirred for 1 hour and 40 minutes at room temperature. The reaction solution was partitioned into water and ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:methanol=10:1) to obtain the title compound (951 mg, 85%).
Reaction SMILES: [OH-:1].[Na+].Br[CH:4]([CH3:23])[C:5]([C:7]1[CH:12]=[CH:11][C:10]([C@H:13]2[CH2:18][CH2:17][C@H:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)=[O:6]>O.CN(C=O)C>[C:5]([C:7]1[CH:12]=[CH:11][C:10]([C@H:13]2[CH2:18][CH2:17][C@H:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH:4]([CH3:23])[OH:1]
Reactant: [OH-]
Reactant: COC(=O)[C@H]1CC[C@H](c2ccc(C(=O)C(C)Br)cc2)CC1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1CC[C@H](c2ccc(C(=O)C(C)O)cc2)CC1
Reaction time: 0.67 h

Procedure:
Sodium hydroxide (370 mg, 9.25 mmol) in water (2 mL) was added to a stirred solution of methyl trans-4-[4-(2-bromopropanoyl)phenyl]cyclohexanecarboxylate (prepared as described in Patent Application WO2004/047755) (3.264 g, 9.25 mmol) in DMF (10 mL). The mixture was stirred for 40 minutes then extracted with ether (5×20 mL). The extracts were combined, dried and concentrated. The crude product was purified by flash column chromatography eluting with 20-40% EtOAc/hexanes to give the title compound (1.76 g, 66%) as a solid; 1H NMR δ 7.94 (2H, d), 7.39 (2H, d), 5.29 (1H, d), 5.08-4.98 (1H, m), 3.62 (3H, s), 2.68-2.54 (1H, m), 2.48-2.35 (1H, m), 2.08-1.94 (2H, m), 1.90-1.79 (2H, m), 1.60-1.40 (4H, m), 1.28 (3H, s); MS 313 (M+Na)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:25]([O:29][C:30](=[O:35])[C:31](Br)([CH3:33])[CH3:32])([CH3:28])([CH3:27])[CH3:26].CN(C)C=O>O>[C:25]([O:29][C:30](=[O:35])[C:31]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:6][CH:7]=1)([CH3:33])[CH3:32])([CH3:28])([CH3:27])[CH3:26]
Reactant: CCCCCCC(=O)NCCc1ccc(N)cc1
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCC(=O)NCCc1ccc(NC(C)(C)C(=O)OC(C)(C)C)cc1
Temperature: 80 °C
Yield: 58.1 %

Procedure:
1H NMR (400 MHz, CDCl3) δ6.94 (d, 2H), 6.61 (d, 2H), 5.35 (s, 1H), 3.57 (s, 2H), 3.43 (m, 2H), 2.66 (t, 3H), 2.07 (t, 2H), 1.55 (m, 3H), 1.24 (m, 5H), 0.84 (t, 3H). A mixture of heptanoic acid [2-(4-amino-phenyl)-ethyl]-amide (1.50 g, 6.04 mmol), cesium carbonate (7.87 g, 24.2 mmol), tert butyl-2-bromoisobutyrate (10.78 g, 48.3 mmol) and dimethylformamide (14.6 mL) was heated at 80° C. for 4 days. The reaction mixture was cooled to ambient temperature, diluted with water and extracted with ether (2×). The combined organics were washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by flash column chromatography (2:3 ethyl acetate/hexanes) to provide 1.37 g (58%) of 2-[4-(2-heptanoylamino-ethyl)-phenylamino]-2-methyl-propionic acid tert-butyl ester as a colorless oil.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=2)=[CH:10][CH:11]=1)[CH:2]([CH3:4])[CH3:3].[CH3:22][S:23](Cl)(=[O:25])=[O:24].C(N(CC)C(C)C)(C)C>ClCCl>[CH2:1]([N:5]([CH2:6][C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=2)=[CH:10][CH:11]=1)[S:23]([CH3:22])(=[O:25])=[O:24])[CH:2]([CH3:4])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)CNCc1ccc(-c2cccc(S(C)(=O)=O)c2)s1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)CN(Cc1ccc(-c2cccc(S(C)(=O)=O)c2)s1)S(C)(=O)=O

Procedure:
In analogy to example 13, step 2, isobutyl-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-amine was reacted with methanesulfonyl chloride in presence of N,N-diisopropyl ethyl amine in dichloromethane to give N-isobutyl-N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-methanesulfonamide as a colorless solid. MS: 419.3 ([M+NH4]+)
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([Cl:26])[CH:19]=2)[C:8]([O:11][CH:12]2[CH2:15][C:14]([F:17])([F:16])[CH2:13]2)=[CH:9][CH:10]=1)=[O:4].[Li+].[OH-].CO>O>[Cl:26][C:20]1[CH:19]=[C:18]([C:7]2[C:8]([O:11][CH:12]3[CH2:13][C:14]([F:17])([F:16])[CH2:15]3)=[CH:9][CH:10]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=2)[CH:23]=[CH:22][C:21]=1[O:24][CH3:25]
Reactant: COC(=O)c1ccc(OC2CC(F)(F)C2)c(-c2ccc(OC)c(Cl)c2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(-c2cc(C(=O)O)ccc2OC2CC(F)(F)C2)cc1Cl
Temperature: 25 °C
Reaction time: 15 h
Yield: 79.4 %

Procedure:
85 mg of 3′-Chloro-6-(3,3-difluoro-cyclobutoxy)-4′-methoxy-biphenyl-3-carboxylic acid methyl ester and 14 mg of LiOH (monohydrate) were dissolved using 5 ml of methanol and 0.5 ml of water. The mixture was stirred for 15 h at room temperature. Then, 14 mg of LiOH (monohydrate) were added and the reaction mixture stirred for 24 h at room temperature. Then, 10 ml of water were added and the methanol evaporated. The mixture was then acidified to pH=2 using aqueous NaHSO4-solution. The mixture was stirred for 30 minutes at room temperature. The product was then collected by filtration and dried in vacuo to yield 65 mg of the title compound that was used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18](Br)=[CH:17][C:15]=3[N:16]=2)[C:7]([O:10][CH3:11])=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH3:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1>>[N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([C:26]4[CH:27]=[CH:28][C:23]([CH3:22])=[CH:24][CH:25]=4)=[CH:17][C:15]=3[N:16]=2)[C:7]([O:10][CH3:11])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: COc1ccc([N+](=O)[O-])cc1-c1nc2cc(Br)ccc2o1
Reactant: Cc1ccc(B(O)O)cc1
Product: COc1ccc([N+](=O)[O-])cc1-c1nc2cc(-c3ccc(C)cc3)ccc2o1

Procedure:
Prepared by the method of Example 15d), from 2-(3-nitro-6-methoxyphenyl)-5-bromobenzoxazole (400 mg, 1.14 mmol) and 4-methylphenylboronic acid (234 mg, 1.71 mmol) the subtitle compound was obtained (273 mg, 53%). The product was used directly in the next step without purification.
Reaction SMILES: [CH3:1][OH:2].[H-].[Na+].[CH2:5]([C@@H:7]1[CH2:12][O:11][CH2:10][CH2:9][N:8]1[C:13]1[N:18]=[C:17]([NH:19][CH3:20])[N:16]=[C:15]([C:21]2[CH:28]=[C:27](F)[C:24]([C:25]#[N:26])=[C:23]([F:30])[CH:22]=2)[CH:14]=1)[CH3:6].C[O-].[Na+]>CCOC(C)=O.CN(C=O)C>[CH2:5]([C@@H:7]1[CH2:12][O:11][CH2:10][CH2:9][N:8]1[C:13]1[N:18]=[C:17]([NH:19][CH3:20])[N:16]=[C:15]([C:21]2[CH:28]=[C:27]([O:2][CH3:1])[C:24]([C:25]#[N:26])=[C:23]([F:30])[CH:22]=2)[CH:14]=1)[CH3:6]
Reactant: CO
Reactant: CC[C@@H]1COCCN1c1cc(-c2cc(F)c(C#N)c(F)c2)nc(NC)n1
Agent: C[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC[C@@H]1COCCN1c1cc(-c2cc(F)c(C#N)c(OC)c2)nc(NC)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
CH3OH (10 mL) was added dropwise to a 100 mL RBF at 0° C. charged with sodium hydride (66.8 mg, 2.78 mmol). The mixture was stirred for 10 minutes and then allowed to warm to room temperature for 10 minutes. To a 4 mL vial were added 4-[6-[(3R)-3-ethyl-4-morpholinyl]-2-(methylamino)-4-pyrimidinyl]-2,6-difluorobenzonitrile (100 mg, 0.278 mmol), DMF (1 mL) and 1.2 mL of sodium methoxide solution (1.2 eq). The reaction was stirred at room temperature overnight. An extra 0.5 eq of sodium methoxide was added to the reaction and it was heated to 40° C. for 3 hours. The reaction mixture was then poured into EtOAc (10 mL). The organics were washed with H2O (2×) and then dried over Na2SO4 and concentrated to afford 4-[6-[(3R)-3-ethyl-4-morpholinyl]-2-(methylamino)-4-pyrimidinyl]-2-fluoro-6-(methyloxy)benzonitrile. This material was taken up in CH3CN (1 mL) and added to a 5 mL microwave vial followed by the addition of hydrazine (0.035 mL, 1.113 mmol) and Hunig's base (0.39 mL, 2.23 mmol). The reaction was irradiated at 150° C. for 90 minutes. The reaction mixture was then concentrated and purified via reverse phase HPLC (10-30% CH3CN/H2O, 0.1% TFA). Fractions were combined and diluted with EtOAc. The organics were washed with saturated NaHCO3 solution that was back extracted with EtOAc (×1). The organics were combined and dried over Na2SO4. The product was taken up in 2 mL H2O and lyophilized to afford the title compound (34.8 mg) as a white fluffy powder. LC-MS (ES) m/z=384 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 0.88 (t, 3H), 1.59-1.82 (m, 2H), 2.82 (d, J=3.8 Hz, 3H), 3.07-3.18 (m, 1H), 3.39-3.49 (m, 1H), 3.50-3.56 (m, 1H), 3.82-3.87 (m, 1H), 3.87-3.92 (m, 1H), 3.94 (s, 3H), 4.10-4.23 (m, 1H), 4.27-4.39 (m, 1H), 5.02 (s, 2H), 6.45-6.57 (m, 1H), 6.94 (bs, 1H), 7.52 (bs, 1H), 8.30-8.34 (bs, 1H), 11.53 (bs, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=O.[Cl:17][C:18]1[CH:19]=[C:20]([NH2:33])[CH:21]=[CH:22][C:23]=1[O:24][CH2:25][CH:26]([O:30][CH2:31][CH3:32])[O:27][CH2:28][CH3:29]>C1COCC1>[Cl:17][C:18]1[CH:19]=[C:20]([NH:33][C:6](=[O:8])[CH2:5][O:4][C:3]2[CH:9]=[CH:10][C:11]([C:13]([F:16])([F:15])[F:14])=[CH:12][C:2]=2[Cl:1])[CH:21]=[CH:22][C:23]=1[O:24][CH2:25][CH:26]([O:30][CH2:31][CH3:32])[O:27][CH2:28][CH3:29]
Reactant: O=C(O)COc1ccc(C(F)(F)F)cc1Cl
Reactant: CCOC(COc1ccc(N)cc1Cl)OCC
Solvent: C1CCOC1
Product: CCOC(COc1ccc(NC(=O)COc2ccc(C(F)(F)F)cc2Cl)cc1Cl)OCC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4.495 g (0.028 mol) of CDl was added to a solution of 6.365 g (0.025 mol) of (2-chloro-4-trifluoromethyl-phenoxy)-acetic acid (intermediate product 2b) in 100 mL abs. THF and the mixture was stirred for 30 minutes at 50° C. 6.494 g (0.025 mol) of 3-chloro-4-(2,2-diethoxy-ethoxy)-phenylamine was added and the mixture was stirred for 16 hours at RT. The reaction mixture was poured into ice water and stirred for 1 hour. The precipitate formed was filtered off, washed with water and dried at 50° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][S:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([O:13]C)=[O:12])[CH:2]=1.[Li+].[OH-].O>CO.O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][S:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([OH:13])=[O:12])[CH:2]=1
Reactant: COC(=O)c1ccccc1SCc1cccnc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccccc1SCc1cccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.3 %

Procedure:
To a solution of compound 3 (55.0 g, 0.212 mol) in MeOH/H2O (300 mL/50 mL) was added LiOH. H2O (17.8 g, 0.425 mol) in portions at 0° C. The reaction mixture was stirred at room temperature overnight and TLC showed the starting material was consumed. The solvent was removed under reduced pressure. The residue was diluted with water, and extracted with Et2O (2×1 L) to remove neutral impurities. The aqueous layer was adjusted to pH 3-4 with 1 N aq. HCl (50 mL) and extracted with EtOAc (2×1 L). The combined organic phases were washed with water (2×200 mL), brine (300 mL), dried over Na2SO4 and concentrated to afford compound 4 (35.0 g, 67%). This was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:17])=[C:6]([CH:8]=[N:9][C:10]([O:12][Si](C)(C)C)=[CH2:11])[CH:7]=1.C(OC([N:25]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([Cl:34])[CH:32]=2)[C:27](=[CH:35][C:36]2[CH:41]=[C:40]([Cl:42])[CH:39]=[CH:38][C:37]=2[O:43][C:44]2([C:48]([O:50][CH3:51])=[O:49])[CH2:47][CH2:46][CH2:45]2)[C:26]1=[O:52])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C1(C)C=CC=CC=1>[Cl:34][C:31]1[CH:32]=[C:33]2[NH:25][C:26](=[O:52])[C:27]3([CH:35]([C:36]4[CH:41]=[C:40]([Cl:42])[CH:39]=[CH:38][C:37]=4[O:43][C:44]4([C:48]([O:50][CH3:51])=[O:49])[CH2:45][CH2:46][CH2:47]4)[CH2:12][C:10](=[O:11])[NH:9][CH:8]3[C:6]3[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[CH3:17])[C:28]2=[CH:29][CH:30]=1
Reactant: C=C(N=Cc1cc(F)ccc1C)O[Si](C)(C)C
Reactant: COC(=O)C1(Oc2ccc(Cl)cc2C=C2C(=O)N(C(=O)OC(C)(C)C)c3cc(Cl)ccc32)CCC1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: COC(=O)C1(Oc2ccc(Cl)cc2C2CC(=O)NC(c3cc(F)ccc3C)C23C(=O)Nc2cc(Cl)ccc23)CCC1
Temperature: 80 °C
Reaction time: 0.33 h

Procedure:
To a toluene solution of 1-(5-fluoro-2-methylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene in toluene (2 M, 5 mL, 10 mmol) was added E/Z 6-chloro-3-[5-chloro-2-(1-methoxycarbonyl-cyclobutoxy)-benzylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (1.5 g, 2.9 mmol). The reaction mixture was heated at 80° C. overnight under argon protection, then TFA (5 mL) was added, and the resulting mixture was stirred at room temperature for 20 min, evaporated in vacuo. The residue was partitioned between ethyl acetate and NaOH aq. (1 M). The organic layer was washed with water, dried over anhydrous Na2SO4, concentrated and purified by column chromatography to give the title compound as a white solid (340 mg).
Reaction SMILES: [CH2:1]([C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11]([CH3:16])([CH3:15])[CH2:10][CH2:9][C:8]2([CH3:18])[CH3:17])=O)[CH3:2].[CH2:19]([Mg]Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Mg].C(Cl)C1C=CC=CC=1.[Cl-].[NH4+]>CCOCC>[CH2:1]([C:3]([C:5]1[CH2:6][CH:7]2[C:12](=[CH:13][CH:14]=1)[C:11]([CH3:16])([CH3:15])[CH2:10][CH2:9][C:8]2([CH3:18])[CH3:17])=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:2]
Reactant: CCC(=O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: Cl[Mg]Cc1ccccc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: ClCc1ccccc1
Solvent: CCOCC
Product: CCC(=Cc1ccccc1)C1=CC=C2C(C1)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6.1 g of (1,2,3,4-tetrahydro-1,1,4,4-tetramethyl-6naphthyl) ethyl ketone are dissolved in 25 ml of abs. ether and added dropwise at 0° to a benzylmagnesium chloride solution prepared from 0.6 g of magnesium and 4.3 g of benzyl chloride in 30 ml of abs. ether. After stirring at room temperature for 2 hours the reaction mixture is poured into a saturated ammonium chloride solution, extracted with ether, dried over sodium sulphate and evaporated. The thus-obtained oil is dissolved in 100 ml of toluene and, after the addition of 0.5 g of p-toluenesulphonic acid, boiled at reflux overnight. After cooling the mixture is treated with 10% sodium bicarbonate solution. extracted with ether, dried and evaporated. The residue is purified by filtration over a short column (silica gel, elution agent hexane) and recrystallized from methylene chloride/methanol. There are obtained 3 g of 6-(α-ethylstyryl)-1,2,3,5-tetrahydro-1,1,4,4-tetramethylnaphthalene in colourless crystals, melting point 65°.