Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:32])[CH2:14][NH:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([CH:25]([OH:30])[C:26]([F:29])([F:28])[F:27])[CH:23]=3)[N:18]([CH3:31])[N:17]=2)[CH2:9]1.[OH:33][C:34]1([C:41]2[CH:42]=[N:43][C:44]([CH3:47])=[CH:45][CH:46]=2)[CH2:39][CH2:38][C:37](=O)[CH2:36][CH2:35]1>>[OH:33][C:34]1([C:41]2[CH:42]=[N:43][C:44]([CH3:47])=[CH:45][CH:46]=2)[CH2:35][CH2:36][CH:37]([N:8]2[CH2:11][CH:10]([NH:12][C:13](=[O:32])[CH2:14][NH:15][C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([CH:25]([OH:30])[C:26]([F:29])([F:28])[F:27])[CH:23]=4)[N:18]([CH3:31])[N:17]=3)[CH2:9]2)[CH2:38][CH2:39]1
Reactant: Cn1nc(NCC(=O)NC2CNC2)c2cc(C(O)C(F)(F)F)ccc21
Reactant: Cc1ccc(C2(O)CCC(=O)CC2)cn1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C2(O)CCC(N3CC(NC(=O)CNc4nn(C)c5ccc(C(O)C(F)(F)F)cc45)C3)CC2)cn1

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-[1-methyl-5-(2,2,2-trifluoro-1-hydroxy-ethyl)-1H-indazol-3-ylamino]-acetamide TFA salt (as prepared in Example 60, Step B) and 4-hydroxy-4-(6-methyl-pyridin-3-yl)-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:15]2[NH:20][C:19](=O)[N:18]=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:16]=2)[CH:8]=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12].O=P(Cl)(Cl)[Cl:30]>>[Cl:30][C:19]1[N:20]=[C:15]([C:7]2[CH:8]=[CH:9][C:10]([C:11]([F:14])([F:13])[F:12])=[C:5]([O:4][CH2:3][C:2]([F:27])([F:26])[F:1])[CH:6]=2)[CH:16]=[C:17]([C:22]([F:25])([F:24])[F:23])[N:18]=1
Reactant: O=c1nc(C(F)(F)F)cc(-c2ccc(C(F)(F)F)c(OCC(F)(F)F)c2)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: FC(F)(F)COc1cc(-c2cc(C(F)(F)F)nc(Cl)n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 6-[3-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-4-trifluoromethyl-1H-pyrimidin-2-one (3.74 g, 9.21 mmol) and phosphoroxychloride (30 mL) according to the general procedure I. Obtained as a brown solid (3.75 g, 96%). MS (EI) 424.0 [(M)+]; mp 44° C.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]3[C:23]4[CH2:24][CH2:25][CH2:26][C:22]=4[N:21]=[C:20]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[N:19]=3)=[CH:13][CH:12]=2)[CH2:10][CH2:9][CH2:8]1)=[O:6]>O.CO>[N:27]1([C:20]2[N:19]=[C:18]([NH:17][C:14]3[CH:13]=[CH:12][C:11]([C:7]4([C:5]([OH:6])=[O:4])[CH2:10][CH2:9][CH2:8]4)=[CH:16][CH:15]=3)[C:23]3[CH2:24][CH2:25][CH2:26][C:22]=3[N:21]=2)[CH2:28][CH2:29][O:30][CH2:31][CH2:32]1
Reactant: COC(=O)C1(c2ccc(Nc3nc(N4CCOCC4)nc4c3CCC4)cc2)CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C1(c2ccc(Nc3nc(N4CCOCC4)nc4c3CCC4)cc2)CCC1
Reaction time: 3 h
Yield: 93.1 %

Procedure:
A solution of sodium hydroxide (0.588 g, 14.7 mmol) in water (15 mL) was added to a solution of 1-[4-(2-morpholin-4-yl-6,7-dihydro-5H-cyclopentapyrimidin-4-ylamino)-phenyl]-cyclobutanecarboxylic acid methyl ester (1.0 g, 2.45 mmol) in MeOH (15 mL) and stirred at a temperature in the range of 15° C. to 40° C. for 3 hours. Thereafter, MeOH was evaporated under reduced pressure and pH of the solution was adjusted to ˜4 by adding concentrated hydrochloric acid. The precipitated solid was filtered, washed with water and dried in vacuo to afford the title compound as a white solid (0.9 g, 93.2% yield).
Reaction SMILES: [F:1][C:2]1(F)[CH2:4][CH:3]1[C:5]1[NH:9][N:8]=[C:7]([NH2:10])[CH:6]=1.F[C@H]1C[C@H]1C(OCC)=O>>[F:1][C@H:2]1[CH2:4][C@H:3]1[C:5]1[NH:9][N:8]=[C:7]([NH2:10])[CH:6]=1
Reactant: Nc1cc(C2CC2(F)F)[nH]n1
Agent: CCOC(=O)[C@@H]1C[C@@H]1F
Product: Nc1cc([C@@H]2C[C@@H]2F)[nH]n1

Procedure:
Racemic cis-5-(2-fluorocyclopropyl)-1H-pyrazol-3-amine (49) was prepared analogously using the procedure as described for 5-(2,2-difluorocyclopropyl)-1H-pyrazol-3-amine, using ethyl cis-2-fluorocyclopropane-1-carboxylate in place of butyl 2,2-difluorocyclopropanecarboxylate as the starting material: 1H NMR (300 MHz, DMSO-d6) δ 5.16 (s, 1H), 4.67-4.95 (m, 1H), 4.50 (br, 2H), 3.40 (br s, 1H), 1.95-1.84 (m, 1H), 1.20-1.12 (m, 2H); MS (ESI+) m/z=142 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH2:12])=[C:10]2[C:5]([C:6](=[O:23])[C:7]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[C:8]([CH:13]([CH3:15])[CH3:14])[O:9]2)=[CH:4][CH:3]=1.Cl.CCCCCC.C(OCC)C.[F:36][C:37]([F:42])([CH3:41])[C:38](O)=O>O>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([C:7]2[C:6](=[O:23])[C:5]3[CH:4]=[CH:3][C:2]4[NH:1][C:38]([C:37]([F:42])([F:36])[CH3:41])=[N:12][C:11]=4[C:10]=3[O:9][C:8]=2[CH:13]([CH3:14])[CH3:15])=[CH:21][CH:20]=1
Reactant: CC(F)(F)C(=O)O
Reactant: CC(C)c1oc2c(N)c(N)ccc2c(=O)c1-c1ccc(Cl)cc1
Agent: Cl
Solvent: O
Solvent: CCCCCC
Solvent: CCOCC
Product: CC(C)c1oc2c(ccc3[nH]c(C(C)(F)F)nc32)c(=O)c1-c1ccc(Cl)cc1
Temperature: 110 °C

Procedure:
7,8-Diamino-3-(4-chlorophenyl)-2-isopropyl-chromen-4-one (168 mg, 0.511 mmol) is dissolved in 2,2-difluoropropionic acid (562 mg), dilute hydrochloric acid (2M, 0.1 ml) is added, and the mixture is heated at 110° C. for 4 h. The reaction mixture is cooled to room temperature, diluted with water (10 ml) and extracted with ethyl acetate (3×30 ml). The ethyl acetate extracts are combined and washed with saturated sodium bicarbonate solution (2×40 ml) and saturated brine (40 ml). The organic layer is dried (MgSO4), treated with decolourising charcoal (50 mg), filtered and evaporated to give a colourless solid. This is sonicated with n-hexane/diethyl ether and filtered to give a cream-coloured powder.
Reaction SMILES: [CH3:1][CH:2]([NH:32][CH3:33])[CH:3]1[O:8][CH:7]([O:9][CH:10]2[CH:15]([OH:16])[CH:14]([O:17][CH:18]3[O:23][CH2:22][C:21]([OH:25])([CH3:24])[CH:20]([NH:26][CH3:27])[CH:19]3[OH:28])[CH:13]([NH2:29])[CH2:12][CH:11]2[NH2:30])[CH:6]([NH2:31])[CH2:5][CH2:4]1.O.[S:35](=[O:39])(=[O:38])([OH:37])[OH:36]>CO>[CH3:1][CH:2]([NH:32][CH3:33])[CH:3]1[O:8][CH:7]([O:9][CH:10]2[CH:15]([OH:16])[CH:14]([O:17][CH:18]3[O:23][CH2:22][C:21]([OH:25])([CH3:24])[CH:20]([NH:26][CH3:27])[CH:19]3[OH:28])[CH:13]([NH2:29])[CH2:12][CH:11]2[NH2:30])[CH:6]([NH2:31])[CH2:5][CH2:4]1.[S:35]([O-:39])([O-:38])(=[O:37])=[O:36]
Reactant: O=S(=O)(O)O
Agent: CNC(C)C1CCC(N)C(OC2C(N)CC(N)C(OC3OCC(C)(O)C(NC)C3O)C2O)O1
Solvent: O
Solvent: CO
Product: O=S(=O)([O-])[O-]

Procedure:
Dissolve 5.0 gm. of 5-epigentamicin C1 in 25 ml. of water and adjust the pH of the solution to 4.5 with 1 N sulfuric acid. Pour into about 300 ml. of methanol with vigorous agitation, continue the agitation for about 10-20 minutes and filter. Wash the precipitate with methanol and dry at about 60° C in vacuo to obtain 5-epigentamicin C1 sulfate.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:26])[C:4](=[O:25])[C:5]([C:17]2[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=2)[CH:20]=O)([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH:14]([F:16])[F:15])=[CH:9][CH:8]=2)[N:6]=1.[CH2:27]([NH2:30])[CH2:28][CH3:29].[BH4-].[Na+].[OH-].[Na+]>CO>[NH2:1][C:2]1[N:3]([CH3:26])[C:4](=[O:25])[C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH:14]([F:16])[F:15])=[CH:9][CH:8]=2)([C:17]2[CH:24]=[CH:23][CH:22]=[C:19]([CH2:20][NH:30][CH2:27][CH2:28][CH3:29])[CH:18]=2)[N:6]=1
Reactant: CCCN
Reactant: CN1C(=O)C(c2ccc(OC(F)F)cc2)(c2cccc(C=O)c2)N=C1N
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCNCc1cccc(C2(c3ccc(OC(F)F)cc3)N=C(N)N(C)C2=O)c1
Yield: 79.2 %

Procedure:
A small vial (2 ml) was charged with 3-[2-Amino-4-(4-difluoromethoxy-phenyl)-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl]-benzaldehyde (32.7 mg, 91.0 μmol). To this was added one-fifth of a solution of propylamine (31 mg, 0.524 mmol) in methanol (2.50 ml). After stirring for two hours sodium borohydride (8.7 mg) was added, then after another hour 1N sodium hydroxide (1 ml) was added and the mixture extracted with diethyl ether. The ethereal layer was concentrated by rotary evaporation, diluted with methanol and re-concentrated (repeated three times). Finally the oily residue was redissolved in diethylether/hexanes and concentrated, twice then placed under vacuum to give a white foam 29 mg (78%) 1H NMR (400 MHz, DMSO-d6) δ ppm 0.79 (t, J=7.3 Hz, 3H) 1.29-1.39 (m, 2H) 2.36 (t, J=7.1 Hz, 2H) 2.93 (s, 3H) 3.57 (s, 2H) 6.62 (br. s., 2H) 6.67 (br. s., 1H) 7.06 (d, J=8.8 Hz, 2H) 7.13 (t, J=74.12 Hz, 1H) 7.14-7.25 (m, 3H) 7.35 (s, 1H) 7.43 (d, J=8.8 Hz, 2H); MS (APPI) m/z 403 [M+H]+
Reaction SMILES: [C:1]([C:5]1[C:6]([O:13][CH2:14][CH2:15][CH3:16])=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].[CH3:17][NH2:18].[BH4-].[Na+].O>CO>[C:1]([C:5]1[C:6]([O:13][CH2:14][CH2:15][CH3:16])=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH2:8][NH:18][CH3:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCOc1c(C=O)cccc1C(C)(C)C
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCOc1c(CNC)cccc1C(C)(C)C
Reaction time: 3 h
Yield: 96.2 %

Procedure:
3-tert-Butyl-2-propoxy-benzaldehyde (1.15 g, 5.21 mmol) was dissolved in anhydrous methanol (25 ml). Methylamine (2.00 ml of 33% solution in ethanol, 16.1 mmol) was added and the reaction was stirred for 3 h. The solution was concentrated to a yellow oil and then dissolved in anhydrous methanol (25 ml). Sodium borohydride (198 mg, 5.23 mmol) was added and the mixture was stirred overnight at room temperature. Water (10 ml) was added and the solution was concentrated. Sodium hydroxide (30 ml, 1N) was added and the aqueous layer was extracted with ethyl acetate (3×50 ml). Combined organic layers were dried over MgSO4, filtered and concentrated to afford (3-tert-butyl-2-propoxy-benzyl)-methyl-amine (1.18 g, 96%) as a clear oil: 1H NMR (400 MHz, DMSO-d6) δ 7.28 (d, J=8.0 Hz, 1H), 7.15 (d, J=8.0 Hz, 1H), 6.97 (y J=8.0, y1H), 3.79 (t, J=4.0 Hz, 2H), 3.61 (s, 2H), 2.28 (s, 3H), 1.80-1.75 (m, 2H), 1.33 (s, 9H), 1.03 (t, J=8.0 Hz, 3H).
Reaction SMILES: [C:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:11][CH:10]=2)[CH2:5][CH2:4]1)#[CH:2].C([Li])CCC.C1(O[C:32]#[N:33])C=CC=CC=1.O>O1CCCC1.CCCCCC>[CH2:15]([C:12]1[CH:13]=[CH:14][C:9]([C@H:6]2[CH2:5][CH2:4][C@H:3]([C:1]#[C:2][C:32]#[N:33])[CH2:8][CH2:7]2)=[CH:10][CH:11]=1)[CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: N#COc1ccccc1
Reactant: C#C[C@H]1CC[C@H](c2ccc(CCCCC)cc2)CC1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCc1ccc([C@H]2CC[C@H](C#CC#N)CC2)cc1
Temperature: -45 °C
Reaction time: 0.25 h

Procedure:
A solution of 254 mg of 1-(trans-4-ethynylcyclohexyl)-4-pentylbenzene (prepared according to Example 12) in 60 ml of absolute tetrahydrofuran was placed at -45° C. in a 100 ml sulphonation flask under argon gasification and treated within 1 minute with 1.2 ml of a 1.0N solution of butyl lithium in hexane. After completion of the addition, the mixture was stirred at -45° C. for a further 15 minutes, then cooled to -78° C. and treated with 182 μl of phenyl cyanate. The mixture was stirred at -78° C. for a further 90 minutes, then poured into 200 ml of water and extracted three times with 100 ml of diethyl ether each time. The organic phases were washed a further twice with 100 ml of water each time and once with 100 ml of saturated sodium chloride solution, dried over magnesium sulphate and concentrated. Low-pressure chromatography (0.5 bar) of the residue (380 mg) on silica gel with 2% ethyl acetate/petroleum ether gave 186 mg (66.6%) of trans-4-(p-pentylphenyl)cyclohexanepropiolonitrile as colourless crystals (purity 97.3%) which were recrystallized further from hexane (purity 99.3%); m.p. (C-I) 46.9° C., cl.p. (N-I) 45.4° C.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([CH2:15][C:16](=[O:37])[CH:17]=P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[NH:13][C:12]1=[O:38])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:39]([O:42][C:43]([N:45]1[CH2:49][CH2:48][CH2:47][C@H:46]1[CH:50]=O)=[O:44])[CH:40]=[CH2:41].C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH2:39]([O:42][C:43]([N:45]1[CH2:49][CH2:48][CH2:47][C@H:46]1/[CH:50]=[CH:17]/[C:16](=[O:37])[CH2:15][C@H:14]1[NH:13][C:12](=[O:38])[C@@H:11]1[C@H:9]([O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3])[CH3:10])=[O:44])[CH:40]=[CH2:41]
Reactant: C=CCOC(=O)N1CCC[C@H]1C=O
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N1CCC[C@H]1/C=C/C(=O)C[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Reaction time: 3 h
Yield: 63 %

Procedure:
A solution of (3S,4R)-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-4-(3-triphenylphosphoranylidene-2-oxopropyl)-2-oxoazetidine (572 mg) and (2S)-1-allyloxycarbonyl-2-formylpyrrolidine (201.5 mg) in toluene (5 ml) was heated to reflex for three hours. Evaporation of the solvent gave a residue, which was taken up into ethyl acetate. The resultant precipitate was filtered off and washed with ethyl acetate. The filtrate and the washings were combined and evaporated in vacuo. The residue was chromatographed on silica gel (50 ml) eluting with a mixture of n-hexane and ethyl acetate (2:1-1:1-1:3 V/V) to give (3S,4R)-4-[(E)-4-{(2S)-1-allyloxycarbonylpyrrolidin-2-yl}-2-oxo-3-butenyl]-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-2-oxoazetidine (297.7 mg).
Reaction SMILES: [CH:1]([CH:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:4]#[N:5])=O.Cl.[NH2:13][NH:14][C:15]([NH2:17])=[O:16].[OH-].[Na+]>CO.O>[NH2:5][C:4]1[N:14]([C:15](=[O:16])[NH2:17])[N:13]=[CH:1][C:3]=1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: N#CC(C=O)c1ccccc1
Reactant: NNC(N)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: NC(=O)n1ncc(-c2ccccc2)c1N
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
The α-formylphenylacetonitrile obtained above is dissolved in methanol-water (1:1-10:1, 200 ml), and to the solution is added with stirring semicarbazide hydrochloride (9.95 g) under ice cooling. After taking off the ice bath, the mixture is reacted for 12 hours. The reaction mixture is neturalized with 5N sodium hydroxide solution. The mixture is stirred for 20 minutes, and the resulting precipitate is separated by filtration, washed with water and dried to give 3-amino-2-carbamoyl-4-phenylpyrazole (16.82 g). This product is used in the subsequent procedure without further purification.
Reaction SMILES: [C:1]([N:5]1[CH2:8][CH:7]([OH:9])[CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[C:10]1([OH:18])[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:11]=1[CH3:17].FC(F)(F)C(O)=O>CCOCC>[CH3:17][C:11]1[C:12]([CH3:16])=[CH:13][CH:14]=[CH:15][C:10]=1[O:18][CH2:6][CH:7]([OH:9])[CH2:8][NH:5][C:1]([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)N1CC(O)C1
Reactant: Cc1cccc(O)c1C
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: Cc1cccc(OCC(O)CNC(C)(C)C)c1C
Temperature: 130 °C

Procedure:
A mixture of 4.8 parts of 1-(tert.-butyl)-3-azetidinol, 6.1 parts of 2,3-xylenol and 1.4 parts of trifluoroacetic acid was heated at 130° C. for 12 hours. The reaction mixture was cooled and dissolved in 100 parts of ether, and the solution was washed three times with 50 parts of 2N-sodium hydroxide aqueous solution and extracted three times with 2N-hydrochloric acid aqueous solution. The extract was washed twice with 50 parts of ether and made alkaline by addition of 2N-sodium hydroxide solution. The extraction was conducted three times with 50 parts of ether, and the extract was condensed and distilled under reduced pressure to yield 3.2 parts of 1-(2',3'-dimethylphenyloxy)-3-(tert.-butylamino)-2-propanol having a melting point of 57° C. and a boiling point of 134°-136° C. under 0.7 mm Hg.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[S:9])[S:5][C:6]=1[CH3:7].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:64][O:65][C:66]1[CH:71]=[CH:70][C:69]([NH2:72])=[CH:68][CH:67]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:64][O:65][C:66]1[CH:71]=[CH:70][C:69]([NH:72][C:2]2[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[S:9])[S:5][C:6]=2[CH3:7])=[CH:68][CH:67]=1
Reactant: COc1ccc(N)cc1
Reactant: COC(=S)c1cc(Br)c(C)s1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Product: COC(=S)c1cc(Nc2ccc(OC)cc2)c(C)s1
Temperature: 100 °C
Yield: 63 %

Procedure:
To an oven-dried glass vial with stir bar was added a mixture of 120 mg (0.449 mmol) of methyl 4-bromo-5-methylthiothiophene-2-carboxylate (as prepared in Example 241, step (a)), 7.1 mg (7 mol %) of palladium (II) acetate, 29.4 mg (10.5 mol %) of racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, 205 mg (0.629 mmol) of cesium carbonate and 69.1 mg (0.561 mmol) of p-anisidine. The vial was transferred to a glove bag, flushed with dry argon and anhydrous toluene (0.9 mL) was added. The vial was capped with a Teflon-lined screw cap and heated at 100° C. for 48 h. To the cooled suspension was added ethyl acetate (4 mL), the mixture filtered (Celite) washing with ethyl acetate (2×2 mL), and the solvents removed in vacuo. The resulting residue was purified by silica gel preparative thin layer chromatography (40% CH2Cl2 in hexane) to afford 83 mg (60%) of the title compound as a yellow oil. 1H-NMR (CDCl3, 400 MHz) δ2.39 (s, 3H), 3.82 (s, 3H), 3.87 (s, 3H), 6.03 (s, 1H), 6.89 (m, 2H), 7.03 (m, 2H), 7.58 (s, 1H).
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]([NH:15][CH2:16][C:17]([N:19]([C:21]2[C:22]([Cl:30])=[C:23]([CH2:28]O)[C:24]([Cl:27])=[CH:25][CH:26]=2)[CH3:20])=[O:18])=[O:14])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.CS([Cl:42])(=O)=O.O>CN(C)C=O>[C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]([NH:15][CH2:16][C:17]([N:19]([C:21]2[C:22]([Cl:30])=[C:23]([C:24]([Cl:27])=[CH:25][CH:26]=2)[CH2:28][Cl:42])[CH3:20])=[O:18])=[O:14])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)Nc1ccc(/C=C/C(=O)NCC(=O)N(C)c2ccc(Cl)c(CO)c2Cl)cn1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Nc1ccc(/C=C/C(=O)NCC(=O)N(C)c2ccc(Cl)c(CCl)c2Cl)cn1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
3-[N-[(E)-3-(6-Acetamidopyridin-3-yl)acryloylglycyl]-N-methylamino]-1-hydroxymethyl-2,6-dichlorobenzene (5.36 g) was dissolved in N,N-dimethylformamide (30 ml) under nitrogen atmosphere, triethylamine (2.4 g) and methanesulfonyl chloride (1.3 ml) were added to the mixture at 0° C., and the mixture was stirred at 0° C. for 1 hour and at ambient temperature for 18 hours. The reaction mixture was poured into water and extracted with chloroform. The organic layer was separated, washed with saturated aqueous solution of sodium hydrogen carbonate and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was washed with ethyl acetate to give 3-[N-[(E)-3-(6-acetamidopyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dichlorobenzyl chloride (5.1 g) as a powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13](SCC)[N:12]2[CH:18]=[CH:19][N:20]=[C:11]2[CH:10]=1.[OH-:21].[K+].Cl.[Cl-].[NH4+]>CO.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([OH:21])[N:12]2[CH:18]=[CH:19][N:20]=[C:11]2[CH:10]=1
Reactant: CCSc1nc(-c2ccc(Cl)cc2Cl)cc2nccn12
Reactant: [OH-]
Agent: Cl
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Oc1nc(-c2ccc(Cl)cc2Cl)cc2nccn12
Reaction time: 2 h

Procedure:
16.6 g (51.19 mmol) of 7-(2,4-dichlorophenyl)-5-(ethylthio)imidazo[1,2-c]pyrimidine are dissolved in 330 ml of methanol, and 77 ml of a 2 molar aqueous potassium hydroxide solution are added. The mixture is stirred at the reflux temperature for 2 h. After cooling, 300 ml of water are added and then, while cooling in ice, 140 ml of 0.1 molar hydrochloric acid. The mixture is then neutralized with saturated aqueous ammonium chloride solution and stirred for 10 min, and the solid is filtered off with suction. It is thoroughly washed with water and dried under high vacuum. 13.6 g (92% of theory) of the product are obtained as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][CH:13]([CH:17]([CH3:19])[CH3:18])[C:14]([OH:16])=[O:15].[F:20][C:21]1[CH:28]=[CH:27][C:26]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:25][C:22]=1[CH2:23]O>>[F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][CH:13]([CH:17]([CH3:19])[CH3:18])[C:14]([O:16][CH2:23][C:22]1[CH:25]=[C:26]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:27]=[CH:28][C:21]=1[F:20])=[O:15]
Reactant: CC(C)C(Nc1ccc(C(F)(F)F)cc1F)C(=O)O
Reactant: OCc1cc(Oc2ccccc2)ccc1F
Product: CC(C)C(Nc1ccc(C(F)(F)F)cc1F)C(=O)OCc1cc(Oc2ccccc2)ccc1F

Procedure:
The acid chloride of 2(2-fluoro-4-trifluoromethylphenylamino)-3-methylbutanoic acid is reacted with 2-fluoro-5-phenoxybenzyl alcohol using the procedure of Example 1 to give 2-fluoro-5-phenoxybenzyl 2-(2-fluoro-4-trifluoromethylphenylamino)-3-methylbutanoate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]2([CH2:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][CH:16]=[C:17](/[CH:23]=[CH:24]/[C:25]([OH:27])=O)[CH:18]=3)[O:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:42][O:43][CH:44]1[CH2:49][CH2:48][CH2:47][CH2:46][O:45]1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]2([CH2:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][CH:16]=[C:17](/[CH:23]=[CH:24]/[C:25]([NH:42][O:43][CH:44]4[CH2:49][CH2:48][CH2:47][CH2:46][O:45]4)=[O:27])[CH:18]=3)[O:13]2)[CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC(=O)c3cc(/C=C/C(=O)O)ccc3O2)C1
Reactant: NOC1CCCCO1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC2(CC(=O)c3cc(/C=C/C(=O)NOC4CCCCO4)ccc3O2)C1
Temperature: 0 °C
Reaction time: 3 h
Yield: 81.9 %

Procedure:
TEA (0.271 ml, 1.95 mmol) was added to solution of (±)-(E)-3-[1′-tert-butoxycarbonyl-4-oxo-spiro(chromane-2,3′-pyrrolidine)-6-yl]-acrylic acid (484 mg, 1.29 mmol) in DCM (10 ml). The mixture was cooled down to 0° C., and EDC (372 mg, 1.95 mmol) and HOBt (263 mg, 1.95 mmol) were added. The mixture was stirred at 0° C. for 3 h, then NH2OTHP (182 mg, 1.56 mmol) was added and the mixture was stirred at RT overnight. The solution was washed with aqueous 5% NaHCO3 solution and brine. The organic layer was then dried over Na2SO4 and evaporated. The crude residue was purified by column chromatography (eluent: DCM/MeOH 98:2) to give (±)-(E)-3-[1′-tert-butoxycarbonyl-4-oxo-spiro(chromane-2,3′-pyrrolidine)-6-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide (499 mg) as a light yellow solid.
Reaction SMILES: [CH:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)=[O:2].ClCCCl.[Cl:16][S:17](O)(=[O:19])=[O:18].S(Cl)(Cl)=O>>[CH:1]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([S:17]([Cl:16])(=[O:19])=[O:18])=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)=[O:2]
Reactant: O=CN1CCc2ccccc21
Reactant: O=S(=O)(O)Cl
Solvent: O=S(Cl)Cl
Solvent: ClCCCl
Product: O=CN1CCc2cc(S(=O)(=O)Cl)ccc21
Temperature: 70 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
A 17% (w/w) solution of N-formylindoline in 1,2-dichloroethane (100 g, 680 mmol) was cooled to 5° C., treated with chlorosulfonic acid (90.4 mmol, 1.35 mol) at a rate which kept the internal temperature <25° C., heated to 70° C., treated with thionyl chloride (99.2 mL, 1.35 mol), and stirred for 2 hours. The mixture was cooled to 5° C., quenched with water (1.0 L) at a rate which kept the internal temperature <25° C., warmed to 10° C., diluted with heptane (1.0 L), and stirred for 30 minutes. The resulting precipitate was filtered, washed with water (6×1 L) until the filtrate pH was 4.5, washed with heptane, and partially dried under vacuum at 40° C. to provide the desired product (solid assay for 157 g (94%) of 1-formyl-5-indolinesulfonyl chloride. The product was used directly in the next step without further purification.