Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH:16]([CH3:18])[CH3:17])[CH3:15])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH2:23])([CH3:4])([CH3:3])[CH3:2].C([O:29][C:30](=O)[CH2:31][C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]2[O:44][N:43]=[C:42]([CH3:45])[CH:41]=2)[CH:35]=1)=[O:33])(C)(C)C>>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH:16]([CH3:17])[CH3:18])[CH3:15])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH:23][C:30](=[O:29])[CH2:31][C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]2[O:44][N:43]=[C:42]([CH3:45])[CH:41]=2)[CH:35]=1)=[O:33])([CH3:3])([CH3:4])[CH3:2]
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)on1
Reactant: CC(C)N(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(N(C)C(C)C)cc3NC(=O)OC(C)(C)C)c2)on1

Procedure:
The title compound was prepared from [2-amino-5-(isopropyl-methyl-amino)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J37) (350 mg, 1.01 mmol) and 3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K4) (304 mg, 1.01 mmol) according to the general procedure M. Obtained as a light brown foam (380 mg, 66%).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[OH:27][CH2:28][CH2:29][NH:30][S:31]([C:34]1[S:35][C:36]([Cl:40])=[C:37]([NH2:39])[CH:38]=1)(=[O:33])=[O:32]>>[Cl:40][C:36]1[S:35][C:34]([S:31](=[O:33])(=[O:32])[NH:30][CH2:29][CH2:28][OH:27])=[CH:38][C:37]=1[NH:39][C:12]([C:11]1[CH:10]=[N:9][N:8]2[C:3]([C:2]([F:26])([F:25])[F:1])=[CH:4][C:5]([C:15]3[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:19][CH:20]=3)=[N:6][C:7]=12)=[O:14]
Reactant: Nc1cc(S(=O)(=O)NCCO)sc1Cl
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: O=C(Nc1cc(S(=O)(=O)NCCO)sc1Cl)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C. 1) and 4-amino-5-chloro-thiophene-2-sulfonic acid (2-hydroxy-ethyl)-amide (example B.6) according to general procedure II. Yellow solid. MS (ISP) 612.0 [(M−H)−]; mp 191° C.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1(=[O:12])[O:11][C:9](=[O:10])[CH2:8][CH2:7][CH2:6]1.C[O:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:18]=[CH:19][CH:20]=1.Cl>ClC(Cl)C.O>[OH:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:18]=[CH:19][C:20]=1[C:9](=[O:10])[CH2:8][CH2:7][CH2:6][C:5]([OH:11])=[O:12]
Reactant: O=C1CCCC(=O)O1
Reactant: COc1cccc(-c2ccccc2)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: CC(Cl)Cl
Product: O=C(O)CCCC(=O)c1ccc(-c2ccccc2)cc1O
Reaction time: 0.25 h

Procedure:
24 g aluminium chloride are added at 0° C. to a solution of 10 g glutaric acid anhydride in 300 ml dichloroethane. After stirring for 15 mins. at 0° to 5° C., 15 g 3-methoxy-biphenyl in 50 ml dichloroethane are added rapidly at ca. 0° C. The reaction mixture is stirred for 24 hours at room temperature, poured onto a mixture of ice and conc. HCl and diluted with water. The organic phase is separated off and the aqueous phase extracted 3×with methylene chloride. The combined organic phases are washed thoroughly with water, dried over MgSO4 and clarified with activated charcoal. The solvent is evaporated off and the obtained oil crystallised from ether to yield the title compound: m.p.=168°-170° C.
Reaction SMILES: [Si]([O:18][C:19]1[CH:56]=[CH:55][C:22]([O:23][CH2:24][C@@H:25]([OH:54])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:53]=[CH:52][C:33]([NH:34][CH:35]3[CH2:40][CH2:39][N:38]([C:41]([C:43]4[C:51]5[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=5)[NH:45][CH:44]=4)=[O:42])[CH2:37][CH2:36]3)=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[OH:54][C@H:25]([CH2:24][O:23][C:22]1[CH:21]=[CH:20][C:19]([OH:18])=[CH:56][CH:55]=1)[CH2:26][NH:27][CH2:28][CH2:29][C:30]1[CH:53]=[CH:52][C:33]([NH:34][CH:35]2[CH2:40][CH2:39][N:38]([C:41]([C:43]3[C:51]4[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=4)[NH:45][CH:44]=3)=[O:42])[CH2:37][CH2:36]2)=[CH:32][CH:31]=1
Reactant: CC(C)(C)[Si](Oc1ccc(OC[C@@H](O)CNCCc2ccc(NC3CCN(C(=O)c4c[nH]c5ccccc45)CC3)cc2)cc1)(c1ccccc1)c1ccccc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C(c1c[nH]c2ccccc12)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 83 %

Procedure:
(4-[4-(2-{[(2S)-3-(4-([tert-Butyl(diphenyl)silyl]oxy}phenoxy)-2-hydroxy-propyl]amino}ethyl)anilino]-1-piperidinyl}(1H-indol-3-yl)methanone (0.148 g, 0.182 mmol) was reacted according to Procedure H (eluant: 5:1 chloroform-methanol) to give the title compound (0.087 g, 0.151 mmol).
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]2[CH:11]=[CH:12][C:13]([NH:15][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:14][C:8]=2[CH:7]=1)=O)C.[NH2:24][OH:25].Cl.C[O-].[Na+]>CO>[OH:25][NH:24][C:4]([C:6]1[S:10][C:9]2[CH:11]=[CH:12][C:13]([NH:15][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:14][C:8]=2[CH:7]=1)=[O:3]
Reactant: NO
Reactant: CCOC(=O)c1cc2cc(NC(=O)c3ccccc3)ccc2s1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=C(Nc1ccc2sc(C(=O)NO)cc2c1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To 5-benzoylamino -benzo[b]thiophene-2-carboxylic acid ethyl ester (102.9 mg, 0.32 mmol) were added NH2OH.HCl (76.2 mg, 0.97 mmol) and 5 mL of anhydrous MeOH. A solution of NaOMe (4.37 M in MeOH, 0.50 mL, 2.18 mmol) was added. The resulting mixture was allowed to stir at rt for 2 days. The reaction mixture was concentrated and the residue was dissolved in a minimal amount of water. After extracted with 5 mL of hexanes/EtOAc (4:1), the aqueous layer was acidified with 2N aqueous HCl to pH≈7. The precipitate was filtered, collected and dried to give 5-benzoylamino-benzo[b]thiophene-2-carboxylic acid hydroxyamide as a pale solid. 1H NMR (DMSO-d6, 200 MHz) δ 10.41 (s, 1H), 8.44 (s, 1H), 8.10-7.82 (m, 4H), 7.76 (dd, J=8.7, 2.1 Hz, 1H), 7.68-7.35 (m, 4H). MS (EI): cal'd 313.1 (MH+), exp 313.2 (MH+).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].CC[O-].[Na+].[F:16][C:17]([F:27])([F:26])[C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20]Br>C(O)C>[F:16][C:17]([F:26])([F:27])[C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: FC(F)(F)c1ccccc1CBr
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(Cc1ccccc1C(F)(F)F)C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
40 ml of diethyl malonate in 350 ml of ethyl alcohol were treated portionwise with 18.6 g of sodium ethylate at room temperature and the mixture was then treated with 12 g of o-trifluoromethylbenzyl bromide within 30 minutes. The reaction mixture was stirred at room temperature overnight. The alcohol was distilled under reduced pressure and the residue was dissolved in ethyl acetate. The solution was washed twice with water and once with NaCl solution, dried under reduced pressure and evaporated. The residue was chromatographed over 300 g of SiO2 with CH2Cl2 /AcOEt 95:5 and yielded 11 g of diethyl [o-(trifluoromethyl)benzyl]malonate as a colourless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=3)[NH2:23])[CH2:14][CH2:13]2)[N:3]=1.[S:27]1[CH:31]=[C:30]([C:32](O)=[O:33])[N:29]=[N:28]1>>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([NH:23][C:32]([C:30]4[N:29]=[N:28][S:27][CH:31]=4)=[O:33])[CH:24]=[CH:25][CH:26]=3)[CH2:16][CH2:17]2)[N:3]=1
Reactant: O=C(O)c1csnn1
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Product: Cc1ccc2c(N3CCN(CCc4cccc(NC(=O)c5csnn5)c4)CC3)cccc2n1
Yield: 75 %

Procedure:
The title compound was prepared in 75% yield according to the general procedure for the preparation of the amides (Method C) starting from 3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and 1,2,3-thiadiazole-4-carboxylic acid.
Reaction SMILES: [O-]S(C(F)(F)F)(=O)=O.[Na+].[CH2:10]=[CH:11][C:12](=[CH2:14])[CH3:13].[C:15]([O:18][CH:19]=[CH2:20])(=[O:17])[CH3:16].O>CO>[C:15]([O:18][CH:19]=[CH:20][CH2:13][CH:12]([CH3:14])[CH:11]=[CH2:10])(=[O:17])[CH3:16]
Reactant: C=CC(=C)C
Reactant: C=COC(C)=O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C=CC(C)CC=COC(C)=O
Temperature: 100 °C

Procedure:
(p-Cymene)ruthenium dichloride dimer (27.8 mg, 0.091 mmol Ru) and sodium triflate (80 mg, 0.464 mmol) were dissolved in 10 ml of methanol. To the mixed solution were added isoprene (3 ml) and vinyl acetate (5 ml) and the mixture was stirred under heat at 100° C. for 14 hours. The resulting product was poured into water and extracted using toluene and the extract was subjected to a GLC analysis. As a result, it was confirmed that a co-dimer was produced with the conversion rate being 10% and the ratio of an isomer being 17:3.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([S:29][CH3:30])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22](O)=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:31].[NH2:32][C:33]1[S:34][CH:35]=[CH:36][N:37]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([S:29][CH3:30])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22]([NH:32][C:33]3[S:34][CH:35]=[CH:36][N:37]=3)=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:31]
Reactant: Nc1nccs1
Reactant: CSc1nc(-c2cc(C(=O)O)ccc2C)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CSc1nc(-c2cc(C(=O)Nc3nccs3)ccc2C)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.2 %

Procedure:
To the solution of 3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylbenzoic acid (1.41 g, 3.19 mmol) in DMF (50 mL) was added 2-aminothiazole (479 mg, 4.78 mmol), HBTU (1.33 g, 3.51 mmol) and Et3N (0.90 mL, 6.38 mmol). The reaction mixture was stirred at room temperature for 18 hours before was concentrated and applied to flash chromatography to afford the titled compound 0.99 g (60%). LC-MS m/z 525 (M+H)+.
Reaction SMILES: [Cr+6].[Cr:2](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[K+].[K+].[C:13]([OH:16])(=[O:15])[CH3:14]>O>[C:13]([O-:16])(=[O:15])[CH3:14].[Cr+6:2].[C:13]([O-:16])(=[O:15])[CH3:14].[C:13]([O-:16])(=[O:15])[CH3:14].[C:13]([O-:16])(=[O:15])[CH3:14].[C:13]([O-:16])(=[O:15])[CH3:14].[C:13]([O-:16])(=[O:15])[CH3:14]
Reactant: CC(=O)O
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: [Cr+6]
Agent: [K+]
Solvent: O
Product: CC(=O)[O-]

Procedure:
Chromium (VI) Micelle: Weighed 17 grams of potassium dichromate (K2CrO4), and added to a 4 liter beaker. Dissolved the contents of the beaker in 200 ml of distilled water and added 25 ml of glacial acetic acid to produce chromium (VI) acetate in solution. Added 100 grams of chrysotile asbestos (Union Carbide, high purity, grade 7), and diluted to 3.5 liters with distilled water. Added 400 ml of 1 N sodium hydroxide. Heated at 100° C. for 30 minutes. Allowed to cool and collected by the vacuum filtration using a Whatman #1 filter. A pale green product was obtained and allowed to air dry for 16 hours. The filter cake was dried at 330° F. for 90 minutes. The dry cake was fiberized by use of a blender at high speed for 1 minute. A sample of the product was completely dissolved for analysis by treatment with 20% by weight sodium peroxide at 850° C. Elemental analysis of the product is shown in Table I. HF insoluble matter increased to 45% compared to 8.6% for an untreated chrysotile sample as shown in Table II.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:10]([N:13]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=2[O:28][CH3:29])[C:14]2[S:18][N:17]=[CH:16][N:15]=2)(=[O:12])=[O:11])[CH:6]=[CH:7][C:8]=1F)#[N:2].[Cl:30][C:31]1[C:32]([F:39])=[CH:33][C:34]([I:38])=[C:35]([OH:37])[CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Cl:30][C:31]1[C:32]([F:39])=[CH:33][C:34]([I:38])=[C:35]([CH:36]=1)[O:37][C:8]1[CH:7]=[CH:6][C:5]([S:10]([N:13]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=2[O:28][CH3:29])[C:14]2[S:18][N:17]=[CH:16][N:15]=2)(=[O:12])=[O:11])=[CH:4][C:3]=1[C:1]#[N:2]
Reactant: Oc1cc(Cl)c(F)cc1I
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(F)c(C#N)c2)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(Oc3cc(Cl)c(F)cc3I)c(C#N)c2)c(OC)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3-cyano-N-(2,4-dimethoxybenzyl)-4-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (Preparation 68, 335 mg, 0.77 mmol) in dimethylsulfoxide (10 ml), was added 5-chloro-4-fluoro-2-iodophenol (Preparation 734, 200 mg, 0.73 mmol) and potassium carbonate (229 mg, 1.47 mmol). The flask was purged with nitrogen (3×). The resulting suspension was allowed to stir at room temperature for 18 hours. The reaction was poured into a 1M aqueous solution of sodium hydroxide, and extracted with dichloromethane (3×). The combined organic phase was then dried over anhydrous magnesium sulfate, filtered and the solvent removed in vacuo to leave the desired product as an off white solid (504 mg, 100%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:9]2[N:10]=[C:11]([C:13]3[NH:22][C:16]4[CH2:17][CH2:18][NH:19][CH2:20][CH2:21][C:15]=4[N:14]=3)[S:12][C:8]=2[C:7]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:6][CH:5]=1.C(N(C(C)C)C(C)C)C.Cl.[CH3:39][C:40]1[CH:41]=[C:42]([CH:46]=[CH:47][N:48]=1)[C:43](Cl)=[O:44]>O1CCCC1>[CH3:2][O:3][C:4]1[C:9]2[N:10]=[C:11]([C:13]3[NH:22][C:16]4[CH2:17][CH2:18][N:19]([C:43]([C:42]5[CH:46]=[CH:47][N:48]=[C:40]([CH3:39])[CH:41]=5)=[O:44])[CH2:20][CH2:21][C:15]=4[N:14]=3)[S:12][C:8]=2[C:7]([N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)=[CH:6][CH:5]=1
Reactant: Cc1cc(C(=O)Cl)ccn1
Reactant: COc1ccc(N2CCOCC2)c2sc(-c3nc4c([nH]3)CCNCC4)nc12
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(N2CCOCC2)c2sc(-c3nc4c([nH]3)CCN(C(=O)c3ccnc(C)c3)CC4)nc12
Yield: 5007.6 %

Procedure:
To a suspension of 0.04 g 2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-1,4,5,6,7,8-hexahydro-imidazo[4,5-d]azepine hydrochloride in 3.5 ml tetrahydrofurane were added at 0–4° C. 0.37 ml N-ethyldiisopropylamine and 0.19 mg 2-methyl-isonicotinoyl chloride hydrochloride. The mixture was refluxed for 17 hours, silicagel was added and the solvent was distilled off. The residue was transferred to a column prefilled with silicagel and was chromatographed with ethylacetate/methanol 9:1 to yield 0.025 g (50%) [2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4,5,7,8-tetrahydro-1H-imidazo[4,5-d]azepin-6-yl]-(2-methyl-pyridin-4-yl)-methanone as yellow solid; MS (ISP): m/e=505 (M+H+).
Reaction SMILES: Br[C:2]1[N:3]([CH3:23])[C:4]([C:13]2[S:14][C:15]3[N:16]=[CH:17][N:18]=[C:19]([NH2:22])[C:20]=3[N:21]=2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.C[S-:25].[Na+]>CN(C=O)C>[NH2:22][C:19]1[C:20]2[N:21]=[C:13]([C:4]3[N:3]([CH3:23])[C:2]([SH:25])=[N:6][C:5]=3[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[S:14][C:15]=2[N:16]=[CH:17][N:18]=1
Reactant: Cn1c(Br)nc(-c2ccccc2)c1-c1nc2c(N)ncnc2s1
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(S)nc(-c2ccccc2)c1-c1nc2c(N)ncnc2s1
Temperature: 25 °C
Yield: 62.6 %

Procedure:
2-(2-Bromo-1-methyl-4-phenyl-1H-imidazol-5-yl)[1,3]thiazolo[5,4-d]pyrimidin-7-amine (Example 26) (80 mg) and sodium thiomethoxide (58 mg) in DMF (5 mL) were heated at 80° C. for 2 hours under an inert atmosphere. After cooling to ambient temperature the reaction mixture was concentrated in vacuo, then dissolved in 2M NaOH (5 mL) and washed with DCM (5 mL). The aqueous layer was acidified to pH 4 with 2M HCl, the solid precipitate washed with water (5 mL) then diethyl ether (10 mL) and dried under high vacuum to give the title compound as a yellow solid (44 mg, 65%);
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:20][CH2:19][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:21][C@H:22]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2N2C=CC(C)=N2)[C:23]([F:26])([F:25])[F:24])[N:3]=1.BrC1C=CC([C@@H](O)C(F)(F)F)=[C:43]([O:53][CH2:54][CH2:55][O:56]C)C=1>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:9][CH2:10][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:19][CH2:20]2)[CH:5]=[C:4]([O:21][C@H:22]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[O:56][CH2:55][CH2:54][O:53][CH3:43])[C:23]([F:24])([F:26])[F:25])[N:3]=1
Reactant: COCCOc1cc(Br)ccc1[C@@H](O)C(F)(F)F
Reactant: Cc1ccn(-c2cc(Cl)ccc2[C@@H](Oc2cc(N3CCC4(CC3)CN[C@H](C(=O)O)C4)nc(N)n2)C(F)(F)F)n1
Product: COCCOc1cc(Cl)ccc1[C@@H](Oc1cc(N2CCC3(CC2)CN[C@H](C(=O)O)C3)nc(N)n1)C(F)(F)F

Procedure:
The title compound was prepared as described for (S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 10d) starting with (R)-1-(4-bromo-2-(2-methoxyethoxy)phenyl)-2,2,2-trifluoroethanol and obtained as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8](Cl)=[O:9])[C:4](=[O:11])[O:3]1.[CH2:13]([NH:20][O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([N:20]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:8](=[O:9])[CH:7]=[C:5]1[C:4](=[O:11])[O:3][C:2]([CH3:12])([CH3:1])[O:6]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Reactant: c1ccc(CNOCc2ccccc2)cc1
Product: CC1(C)OC(=O)C(=CC(=O)N(Cc2ccccc2)OCc2ccccc2)O1
Yield: 92 %

Procedure:
Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride with N,O-dibenzyl-hydroxylamine (Bhat, J. I., Clegg, W.; Maskill, H.; Elsegood, M. R. J.; Menner, I. D.; Miatt, P. C. J. Chem. Soc. Perkin Trans. 2, 2000, 1435-1446) as described in the preparation of compound 1-A gave the title amide as white crystals (92% yield): mp 107-108° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.72 (6H, s), 4.76 (2H, s), 4.84 (2H, s), 6.36 (1H, s), 7.28-7.38 (10H, m). HRMS (MAB N2) calculated for C21H21NO5[M+]: 367.141973: Found: 367.140292.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]([OH:17])[C:11]#[C:12][C:13]([CH3:16])([OH:15])[CH3:14])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]>C(Cl)Cl.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:10](=[O:17])[C:11]#[C:12][C:13]([OH:15])([CH3:14])[CH3:16])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(C(O)C#CC(C)(C)O)cc1Cl
Solvent: O
Solvent: ClCCl
Product: COc1ccc(C(=O)C#CC(C)(C)O)cc1Cl
Reaction time: 1 h
Yield: 65.6 %

Procedure:
To a stirred solution of 1-(3-chloro-4-methoxyphenyl)-4-methylpent-2-yne-1,4-diol (0.69 g, 2.716 mmol) in DCM (20 mL) was added DMP (2.36 g, 5.430 mmol) at RT. The reaction mixture was stirred for 1 h and diluted with water (10 mL). The combined organic layers were washed with a saturated NaHCO3 solution and water, dried over Na2SO4, filtered, and then concentrated in vacuo to afford 1-(3-chloro4-methoxyphenyl)-4-hydroxy-4-methylpent-2-yn-1-one (0.45 g, 65%) as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10](OCC)[CH2:9][N:8]=[C:7]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:6]=2[CH:23]=1.CO.O.[NH2:27][NH2:28]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:27][NH2:28])[CH2:9][N:8]=[C:7]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:6]=2[CH:23]=1
Reactant: NN
Reactant: CCOC1=Nc2ccc(Cl)cc2C(c2ccc(OC)cc2)=NC1
Solvent: O
Solvent: CO
Product: COc1ccc(C2=NCC(NN)=Nc3ccc(Cl)cc32)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 0.11 part of 7-chloro-2-ethoxy-5-(4-methoxyphenyl)-3H-1,4-benzodiazepine in 5 parts by volume of methanol is added 0.2 part by volume of hydrazine hydrate (100%). The mixture is stirred at room temperature for 1.5 hours, and poured into 20 parts by volume of water. The mixture is extracted with chloroform. Chloroform layer is washed with water and dried over anhydrous sodium sulfate. The solvent is distilled off. Treatment of the residue with benzene gives 7-chloro-2-hydrazino-5-(4-methoxyphenyl)-3H-1,4-benzodiazepine as crystals melting at 213°-215° C.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([NH:18][C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[C:10]([F:17])=[C:11](F)[C:12]=3[O:14][CH3:15])[C:7](=[O:25])[C:6]([C:26]#[N:27])=[CH:5]2)[CH2:3][CH2:2]1.[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[NH:34][CH2:35][CH2:36][NH2:37].C(N(CC)CC)C>CS(C)=O>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([NH:18][C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[C:10]([F:17])=[C:11]([NH:37][CH2:36][CH2:35][NH:34][C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][N:28]=4)[C:12]=3[O:14][CH3:15])[C:7](=[O:25])[C:6]([C:26]#[N:27])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: NCCNc1ccccn1
Reactant: COc1c(F)c(F)c(NC(=O)C(F)(F)F)c2c(=O)c(C#N)cn(C3CC3)c12
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COc1c(NCCNc2ccccn2)c(F)c(NC(=O)C(F)(F)F)c2c(=O)c(C#N)cn(C3CC3)c12
Temperature: 60 °C
Reaction time: 16 h
Yield: 42.4 %

Procedure:
A mixture of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-5-(trifluoroacetamido) quinoline-3-carbonitrile (500 mg, 1.29 mmol), N-2-pyridyl-1,2-ethanediamine (354 mg, 2.58 mmol) and triethylamine (0.36 mL, 2.58 mmol) in anhydrous DMSO (8 mL) was stirred at 60° C. for 16 h. After cooling, the reaction mixture was poured into ice-water (50 mL). The resulting precipitate was collected by filtration, washed with water and then dried. The crude product was purified by column chromatography (Hexane:EtOAc 1:1→2:3→EtOAc→CH2Cl2: MeOH 8:1) to give 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-7-[2-(2-pyridylamino)ethylamino]-5-(trifluoroacetamido)quinoline-3-carbonitrile (276 mg, 42%) as a brown solid.
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:30])[CH2:14][NH:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=3)[N:18]([CH3:29])[N:17]=2)[CH2:9]1.[OH:31][C:32]1([C:39]2[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=2)[CH2:37][CH2:36][C:35](=O)[CH2:34][CH2:33]1>>[OH:31][C:32]1([C:39]2[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=2)[CH2:33][CH2:34][CH:35]([N:8]2[CH2:9][CH:10]([NH:12][C:13](=[O:30])[CH2:14][NH:15][C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:27])([F:26])[F:28])[CH:23]=4)[N:18]([CH3:29])[N:17]=3)[CH2:11]2)[CH2:36][CH2:37]1
Reactant: Cn1nc(NCC(=O)NC2CNC2)c2cc(C(F)(F)F)ccc21
Reactant: O=C1CCC(O)(c2cccnc2)CC1
Solvent: O=C(O)C(F)(F)F
Product: Cn1nc(NCC(=O)NC2CN(C3CCC(O)(c4cccnc4)CC3)C2)c2cc(C(F)(F)F)ccc21

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-(1-methyl-5-trifluoromethyl-1H-indazol-3-ylamino)-acetamide TFA salt (as prepared in Example 18, Step D) and 4-hydroxy-4-pyridin-3-yl-cyclohexanone using the procedure described in Step E of Example 1.