Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[ClH:10].Cl.[C:12]([C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26]([NH2:28])=[NH:27])=[NH:24])=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13]>C(O)C>[ClH:10].[NH2:24][C:23]1[N:22]([C:19]2[CH:20]=[CH:21][C:16]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:17][CH:18]=2)[CH:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[N:27]=[C:26]([NH2:28])[N:25]=1
Reactant: CCCCCCCC=O
Reactant: CC(C)(C)c1ccc(NC(=N)NC(=N)N)cc1
Agent: Cl
Solvent: CCO
Product: CCCCCCCC1N=C(N)N=C(N)N1c1ccc(C(C)(C)C)cc1

Procedure:
100 ml of ethanol, 4.3 g (33.1 mmol) of 1-octanal and 0.9 ml of concentrated hydrochloric acid were added to 6.0 g (22.2 mmol) of N1-(4-tert-butylphenyl)-biguanide hydrochloride, and the mixture was refluxed for 20 hours. The solvent was concentrated under reduced pressure, and the residue was cooled. The resulting precipitated colorless crystals were collected by filtration, and recrystallized from 80% aqueous ethanol to obtain 4.2 g of colorless crystals having a melting point of 239 to 241° C.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:12]=3)=[C:6]2[CH:5]=[CH:4][C:3]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31].[CH3:35][Zn]C>O1CCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:18]1([NH:17][C:13]2[N:12]=[C:11]([C:10]3[C:9]([C:23]4[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=4)=[N:8][N:7]4[C:2]([CH3:35])=[C:3]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:4]=[CH:5][C:6]=34)[CH:16]=[CH:15][N:14]=2)[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: CCOC(=O)c1ccc2c(-c3ccnc(NC4CCCC4)n3)c(-c3ccc(F)cc3)nn2c1Cl
Reactant: C[Zn]C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc2c(-c3ccnc(NC4CCCC4)n3)c(-c3ccc(F)cc3)nn2c1C
Temperature: 60 °C
Reaction time: 16 h
Yield: 45.8 %

Procedure:
To a solution of ethyl 7-chloro-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine-6-carboxylate (90 mg, 0.19 mmol) in tetrahydrofuran (1 mL) was added dimethylzinc (281 μL 2.0 M in toluene, 0.56 mmol) and tetrakis(triphenylphosphine)palladium (21 mg, 0.018 mmol). The reaction mixture was stirred at 60° C. for 16 hours. The reaction mixture was quenched with ice water then extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over magnesium sulfate. Filtration and concentration, followed by flash chromatography (49:1 dichloromethane:methanol) provided ethyl 3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-7-methylpyrazolo[1,5-α]pyridine-6-carboxylate (40 mg, 45%). 1H NMR (300 MHz, CDCl3) δ 8.34 (d1H), 8.11 (d, 1H), 7.91 (d, 1H), 7.70 (m, 2H), 7.19 (t, 2H), 6.36 (d, 1H), 5.33 (br, 1H), 4.47 (q, 2H), 4.38 (m, 1H), 3.26 (s, 3H), 2.12 (m, 2H), 1.83–1.43 (m, 9H); MS m/z 460 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[NH:26]1[CH2:31][CH2:30][CH:29]([NH2:32])[CH2:28][CH2:27]1>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:32][CH:29]3[CH2:30][CH2:31][NH:26][CH2:27][CH2:28]3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Reactant: NC1CCNCC1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NC3CCNCC3)c2c1

Procedure:
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and piperidin-4-amine. MS obsd. (ESI+) [(M+H)+] 437, 1H NMR (400 MHz, CD3OD) δ ppm 8.05 (t, J=8 Hz, 2 H), 7.88 (d, J=8 Hz, 1 H), 7.73-7.69 (m, 2 H), 7.59-7.57 (m, 2 H), 6.04 (s, 1 H), 5.33 (s, 2 H), 4.52 (s, 2 H), 4.18-4.11 (m, 1 H), 3.74 (s, 2 H), 3.61-3.57 (m, 2 H), 3.33-3.26 (m, 2 H), 2.46 (s, 3 H), 2.24-2.19 (m, 2 H), 2.01-1.91 (m, 2 H).
Reaction SMILES: [OH:1][C:2]1[CH:38]=[CH:37][C:5]([C:6]([CH2:8][CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=2[CH:20]2[CH2:29][CH2:28][C:27]3[CH:26]=[C:25]([O:30]C(=O)C(C)(C)C)[CH:24]=[CH:23][C:22]=3[CH2:21]2)=O)=[CH:4][CH:3]=1.Cl[CH2:40][CH2:41][N:42]1[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1>>[N:42]1([CH2:41][CH2:40][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:6][CH2:8][CH2:9][CH2:10][NH:11][C:12]3[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=3[CH:20]3[CH2:29][CH2:28][C:27]4[CH:26]=[C:25]([OH:30])[CH:24]=[CH:23][C:22]=4[CH2:21]3)=[CH:37][CH:38]=2)[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1
Reactant: ClCCN1CCCCCC1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCCCC(=O)c2ccc(O)cc2)c1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(NCCCCc2ccc(OCCN3CCCCCC3)cc2)c1
Yield: 28.5 %

Procedure:
Synthesized from pivalic acid 6-{2-[(4-hydroxybenzoyl)propylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (30 mg) and 1-(2-chloroethyl)azepane (23 mg) according to an analogous synthetic method to Example 404 and purified by NH silica gel column chromatography (hexane-ethyl acetate system), the title compound (9 mg) was obtained.
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.N1C=CC=CC=1>O>[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14]([O:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: OC1CCCCC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC2CCCCC2)cc1
Reaction time: 8 h
Yield: 99.8 %

Procedure:
Cyclohexanol (5.01 g, 50.0 mmol) and p-toluenesulfonyl chloride (10.6 g, 55.6 mmol) were charged into a 100 cc round-bottom flask, and then pyridine (20 ml) was added dropwise thereto under ice-cooling. The mixture was stirred for 8 hours while gradually elevating the temperature to room temperature. After completion of the reaction, cold water (500 ml) was added to the reaction mixture, and the mixture was extracted with ether (100 ml×3). The organic layers were combined, washed successively with 2N hydrochloric acid, water and a saturated aqueous solution of sodium chloride, and dried with anhydrous magnesium sulfate. The drying agent was separated by filtration, and the solvent was distilled off under reduced pressure to obtain substantially pure cyclohexyl p-toluenesulfonate as a white solid (12.7 g, 49.9 mmol, 99% yield).
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([CH2:12][C:13]([N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]1[CH3:21])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[CH3:22][C:23]1[CH:24]=[C:25]([N:29]=[C:30]=[O:31])[CH:26]=[CH:27][CH:28]=1>>[CH3:21][CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][N:15]1[C:13](=[O:14])[CH2:12][N:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3](=[O:4])[CH2:2][NH:1][C:30]([NH:29][C:25]1[CH:26]=[CH:27][CH:28]=[C:23]([CH3:22])[CH:24]=1)=[O:31]
Reactant: CC1CCCCN1C(=O)CN(C(=O)CN)c1ccccc1
Reactant: Cc1cccc(N=C=O)c1
Product: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)N2CCCCC2C)c2ccccc2)c1
Yield: 37.8 %

Procedure:
The procedure is analogous to that described in Example 1, but 1.45 g of (RS)-2-amino-N-[2-(2-methylpiperidino)-2-oxoethyl]-N-phenylacetamide and 0.67 g of 3-methylphenyl isocyanate used as the starting material. After recrystallization from a mixture of ethanol and diisopropyl ether (50-50 by volume), 0.80 g of (RS)-N-[2-(2-methylpiperidino)-2-oxoethyl]-2-[3-(3-methylphenyl)ureido]-N-phenylacetamide melting at 188° C. is obtained.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Br:5][C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1>OS(O)(=O)=O.C(Cl)Cl>[Br:5][C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][C:7]=1[N+:1]([O-:4])=[O:2]
Reactant: Nc1ccc(Br)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: Nc1ccc(Br)c([N+](=O)[O-])c1
Temperature: 20 °C

Procedure:
Conc. nitric acid (15.8 mL, 376.9 mmol) was added to a solution of 4-bromoaniline (40 g, 232.5 mmol) in H2SO4/CH2Cl2 (400 mL, 1:1, v/v) dropwise at 0° C. under an atmosphere of N2. The cooling bath was removed and the mixture was stirred at 20° C. until the starting material was consumed (about 1 h). The reaction mixture was poured onto water and neutralized with NaOH solution to pH=9 and extracted with DCM. The organic layer was dried, filtered and evaporated in vacuo to afford the crude product 4-bromo-3-nitro-aniline, which was used directly in the next step.
Reaction SMILES: [I-].[C:2]1([CH2:8][C:9]([NH:11][CH:12]2[C:55](=[O:56])[N:14]3[C:15]([C:39]([O:41][CH:42]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)[C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)=[O:40])=[C:16]([CH2:19][P+](C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH2:17][S:18][C@H:13]23)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:57]1([CH:60]=O)[CH2:59][CH2:58]1.O.[OH-].[Na+]>C(Cl)Cl>[C:2]1([CH2:8][C:9]([NH:11][CH:12]2[C:55](=[O:56])[N:14]3[C:15]([C:39]([O:41][CH:42]([C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=4)[C:49]4[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=4)=[O:40])=[C:16](/[CH:19]=[CH:60]\[CH:57]4[CH2:58][CH2:59]4)[CH2:17][S:18][C@H:13]23)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CC1CC1
Reactant: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@H]12
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(/C=C\C3CC3)CS[C@H]12
Temperature: 0 °C
Reaction time: 8 h

Procedure:
15.9 g (17.9 mmol ) of benzhydryl 7-phenylacetamido-3-(triphenylphosphonio)methyl-3-cephem-4-carboxylate iodide (Example 7) are taken in 100 ml of methylene chloride and 17.56 g (250.6 mmol) of cyclopropanecarboxaldehyde in a 250 ml three-necked flask. The mixture is cooled to 0° C. and 100 ml of water are added. 16.3 ml of 1N NaOH are then added dropwise in the course of 4 hours, the pH being kept constant at 8.6. The reaction solution is diluted with methylene chloride and the organic phase is separated off, washed once with water and then dried over sodium sulphate. After the drying agent has been removed, a further 13 ml (233 mmol) of cyclopropanecarboxaldehyde are added to the methylene chloride solution and the mixture is stirred overnight. The reaction solution is then concentrated to dryness, the residue is again dissolved in a little methylene chloride and the mixture is introduced onto a column filled with 500 ml of silica gel (0.04-0.063 mm). 400 ml fractions are collected and all the fractions are investigated for the cis-isomer compound by means of analytical HPLC.
Reaction SMILES: Br[C:2]1[S:10][C:9]2[S:8](=[O:12])(=[O:11])[N:7]=[C:6]([NH:13][CH:14]([CH3:16])[CH3:15])[NH:5][C:4]=2[CH:3]=1.[Cu][C:18]#[N:19].O.[OH-].[Na+]>CN(C)C=O>[C:18]([C:2]1[S:10][C:9]2[S:8](=[O:12])(=[O:11])[N:7]=[C:6]([NH:13][CH:14]([CH3:16])[CH3:15])[NH:5][C:4]=2[CH:3]=1)#[N:19]
Reactant: CC(C)NC1=NS(=O)(=O)c2sc(Br)cc2N1
Reactant: N#C[Cu]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)NC1=NS(=O)(=O)c2sc(C#N)cc2N1
Temperature: 150 °C
Yield: 2 %

Procedure:
To a solution of 6-bromo-3-isopropylamino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (243 mg, 0.75 mmol) in dry N,N-dimethylformamide (2 ml) was added copper(I) cyanide (135 mg, 1.5 mmol) and the mixture was heated at 150° C. for 2 h under nitrogen. The dark mixture was allowed to cool to room temperature and water was added. The suspension was made basic by the addition of 1 N sodium hydroxide, filtered and the filtrate was acidified by the addition of 4 M hydrochloric acid. The resulting precipitate was purified by preparative hplc on a Source RPC 15 column using acetonitrile/water (20:80) with 0.1% TFA as eluent to afford 4 mg (2%) of the pure title compound; LC-MS: m/e 271 ((M+1)+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[C:10]([C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Cl-].[NH4+]>CCOCC>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:10]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[OH:17])=[CH:4][CH:3]=1
Reactant: Cc1ccc([Mg]Br)cc1
Reactant: O=C(c1ccccc1)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: Cc1ccc(C(O)(c2ccccc2)c2ccncc2)cc1
Reaction time: 1.5 h

Procedure:
A solution of 0.05 mole of 4-methylphenyl magnesium bromide in 500 ml of anhydrous ether was treated with 4-benzoylpyridine in 500 ml anhydrous ether. After stirring the resulting mixture for 1.5 hours at 25° , an aqueous solution of ammonium chloride was added causing a solid to form which was filtered. Recrystallization of this material from 95% ethanol afforded the desired α-(4-methylphenyl)-α-phenyl-4-pyridine methanol, m.p. 192°-195° C. The corresponding 4-chlorophenyl (m.p. 198°-202° C.) and 4-methoxyphenyl (m.p. 204°-206° C.) derivatives were also prepared by the same method, using equivalent amounts of the appropriate starting materials.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([CH:6]1[CH2:11][NH:10][CH:9]=[N:8][CH2:7]1)=[O:5].[H-].[Na+].[CH3:14]I>CN(C=O)C>[CH3:14][N:8]1[CH2:7][CH:6]([C:4]([O:3][CH3:2])=[O:5])[CH2:11][N:10]=[CH:9]1
Reactant: CI
Reactant: COC(=O)C1CN=CNC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C1CN=CN(C)C1
Reaction time: 3 h
Yield: 75.9 %

Procedure:
1,4,5,6-Tetrahydro-5-methoxycarbonylpyrimidine hydrochloride (300 mg, 1.35 mmol) and NaH (60% in mineral oil 107 mg, 1.35 mmol) were suspended in anhydrous DMF (5 ml) in an oven dried round bottom flask with stirring under nitrogen. After stirring 15 minutes CH3I 84μl, 1.35 mmol) was added via syringe and stirring continued 3 hours at room temperature. The solvents were evaporated in vacuo and the residue triturated with chloroform. The resulting suspension was filtered and evaporated in vacuo. Chromatography (silica, chloroform/methanol, 9:1) gave 160 mg (76%) crystals mp 93°-95° C. identified by 300 MHz nmr; ms m/z=156.
Reaction SMILES: O[CH2:2][C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[C:5]([NH:7][CH2:8][CH2:9][CH2:10][S:11][C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)=[O:6].C(N(CC)CC)C.CS(Cl)(=O)=O>C(Cl)Cl>[C:5]1(=[O:6])[C:4]2[C:3](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:2][N:7]1[CH2:8][CH2:9][CH2:10][S:11][C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1
Reactant: O=C(NCCCSc1ccncc1)c1ccccc1CO
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1c2ccccc2CN1CCCSc1ccncc1
Temperature: 25 °C
Yield: 78.8 %

Procedure:
To a solution of 1.51 g (5.0 mmol) of 4-[3-(2-hydroxymethylbenzoyl)aminopropylthio]pyridine and 2.09 ml (15.0 mmol) of triethylamine in 50 ml of methylene chloride, 0.77 ml (10.0 mmol) of methanesulfonyl chloride was added with stirring at room temperature, and the mixture was stirred at room temperature for 30 minutes. The mixture was washed with saturated aqueous sodium bicarbonate, water and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by column chromatography (eluent:ethyl acetate) to give 1.12 g of the desired compound (78.9% yield, pale brown crystals), mp. 73°-74.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=O.[CH3:11][C:12]([CH3:14])=[O:13].[OH-].[K+]>>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1/[CH:4]=[CH:11]/[C:12](=[O:13])/[CH:14]=[CH:4]/[C:3]1[C:2]([Cl:1])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:10]
Reactant: CC(C)=O
Reactant: O=Cc1c(Cl)cccc1Cl
Agent: [K+]
Agent: [OH-]
Product: O=C(/C=C/c1c(Cl)cccc1Cl)/C=C/c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
(73) To a 0.33 M solution of 2,6-dichlorobenzaldehyde (1.75 g, 10 mmol) and acetone (290 mg, 5 mmol) in 30 was added 5 ml of 40% potassium hydroxide at 10° C. After stirring for 18 hr at room temperature, a solid precipitated and was filtered. The precipitate was recrystallized from ethanol to afford 1.46 g (78.5%) of pale yellow, cotton-like flakes: mp 154.0-154.4° C. (lit. mp 145-146° C., Unterhalt, Arch. Pharm., 1978, 311, 262-267). 1H NMR (250 MHz) δ 7.85-7.79 (d, 2H), 7.40-7.36 (d, 4H), 7.26-7.19 (d, 2H), 7.24-7.18 (m, 2H); 13C NMR (62.7 MHz) 189.1, 137.6, 135.4, 133.3, 132.5, 130.2, 129.1 ppm.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[C:14]([C:18]1[N:22]([CH2:23][CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:21]2[CH:30]=[CH:31][C:32]([S:34]([N:37]3[CH:41]=[C:40]([C:42](O)=[O:43])[CH:39]=[N:38]3)(=[O:36])=[O:35])=[CH:33][C:20]=2[N:19]=1)([CH3:17])([CH3:16])[CH3:15].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:14]([C:18]1[N:22]([CH2:23][CH:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)[C:21]2[CH:30]=[CH:31][C:32]([S:34]([N:37]3[CH:41]=[C:40]([C:42]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:43])[CH:39]=[N:38]3)(=[O:36])=[O:35])=[CH:33][C:20]=2[N:19]=1)([CH3:15])([CH3:16])[CH3:17]
Reactant: CC(C)N
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)n3cc(C(=O)O)cn3)ccc2n1CC1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)NC(=O)c1cnn(S(=O)(=O)c2ccc3c(c2)nc(C(C)(C)C)n3CC2CCOCC2)c1
Yield: 70.2 %

Procedure:
Following the same procedure in Example 24, Step A, using iso-propylamine (9 mg, 0.15 mmol), DIPEA (28 uL, 21 mg, 0.16 mmol), 1-{[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]sulfonyl}-1H-pyrazole-4-carboxylic acid (0.073 mmol) and HATU (44 mg, 0.12 mmol) in DMF (2.5 mL). The crude product was purified by MPLC using Hex/EtOAc (1:2) on silica gel to give 25 mg (70%) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 1.17 (d, J=6.45 Hz, 6 H), 1.40-1.56 (m, 4 H), 1.59 (s, 9 H), 2.18-2.40 (m, 1 H), 3.23-3.39 (m, 2 H), 3.81-3.96 (m, 2 H), 4.02-4.18 (m, 1 H), 4.41 (d, J=7.42 Hz, 2 H), 7.91 (d, J=8.8 Hz, 1 H), 7.98 (dd, J=8.8, 1.8 Hz, 1 H), 8.04 (s, 1 H), 8.33 (d, J=1.76 Hz, 1 H), 8.77 (d, J=0.78 Hz, 1 H); MS (ESI) (M+H)+=488.0; Anal. Calcd for C24H33N5O4S+0.70 TFA+0.50 EtOAc+0.40H2O (624.71): C, 53.64; H, 6.21; N, 11.21. Found: C, 53.58; H, 6.23; N, 11.28.
Reaction SMILES: [F:1][C:2]1([F:28])[C:8]([CH3:10])([CH3:9])[O:7][CH2:6][C:5](=O)[NH:4][C@@:3]1([C:13]1[CH:18]=[C:17]([C:19]#[C:20][C:21]2[N:22]=[C:23]([CH3:26])[S:24][CH:25]=2)[CH:16]=[CH:15][C:14]=1[F:27])[CH3:12].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:38])=CC=1>O1CCOCC1>[F:1][C:2]1([F:28])[C:8]([CH3:10])([CH3:9])[O:7][CH2:6][C:5](=[S:38])[NH:4][C@@:3]1([C:13]1[CH:18]=[C:17]([C:19]#[C:20][C:21]2[N:22]=[C:23]([CH3:26])[S:24][CH:25]=2)[CH:16]=[CH:15][C:14]=1[F:27])[CH3:12]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1nc(C#Cc2ccc(F)c([C@@]3(C)NC(=O)COC(C)(C)C3(F)F)c2)cs1
Solvent: C1COCCO1
Product: Cc1nc(C#Cc2ccc(F)c([C@@]3(C)NC(=S)COC(C)(C)C3(F)F)c2)cs1
Yield: 94.6 %

Procedure:
The reaction of (R)-6,6-difluoro-5-[2-fluoro-5-(2-methyl-thiazol-4-ylethynyl)-phenyl]-5,7,7-trimethyl-[1,4]oxazepan-3-one (178 mg, 436 μmol) with Lawesson's reagent (182 mg, 436 μmol) in 1,4-dioxane (8 ml) yielded the (R)-6,6-difluoro-5-[2-fluoro-5-(2-methyl-thiazol-4-ylethynyl)-phenyl]-5,7,7-trimethyl-[1,4]oxazepan-3-thione (175 mg, 94% yield) as a light yellow foam. MS (ISP): m/z=425.1 [M+H]+ and 427.1 [M+2+H]+.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]2=[N:4][CH:3]=1.[F:15][C:16]1[C:21](B2OC(C)(C)C(C)(C)O2)=[CH:20][CH:19]=[C:18]([F:31])[C:17]=1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1>>[F:15][C:16]1[C:17]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)=[C:18]([F:31])[CH:19]=[CH:20][C:21]=1[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]2=[N:4][CH:3]=1
Reactant: FC(F)(F)c1ccn2c(Br)cnc2n1
Reactant: CC1(C)OB(c2ccc(F)c(-c3ccccn3)c2F)OC1(C)C
Product: Fc1ccc(-c2cnc3nc(C(F)(F)F)ccn23)c(F)c1-c1ccccn1

Procedure:
3-Bromo-7-trifluoromethylimidazo[1,2-α]pyrimidine was coupled with 2-[2,6-difluoro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]pyridine as described in Example 1 to give 3-[2,4-difluoro-3-(pyridin-2-yl)phenyl]-7-trifluoromethylimidazo[1,2-α]pyrimidine as a pale yellow solid. Bis-hydrochloride salt (from ethyl acetate/ethanol): δH (360 MHz, DMSO) 7.55 (1H, dd, J 9 and 9), 7.62-7.68 (2H, m), 7.86-7.96 (2H, m), 8.14 (1H, ddd, J 8, 8 and 2), 8.38 (1H, s), 8.84 (1H, d, J 5), 9.30 (1H, dd, J 7 and 3); m/z (ES+) 377 (M++H).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5]([NH:6][CH:7]=[N:8][C:9]=2[Cl:11])=[N:4][CH:3]=1.O[CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[Br:1][C:2]1[C:10]2[C:9]([Cl:11])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:13][CH2:14][CH:15]2[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])[CH2:19][CH2:20]2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Reactant: Clc1nc[nH]c2ncc(Br)c1-2
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CCn2cc(Br)c3c(Cl)ncnc32)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.4 %

Procedure:
To 5-bromo-4-chloro-1H-pyrrolo[2,3-d]pyrimidine (200 mg, 0.860 mmol) in Tetrahydrofuran (THF) (10 mL) was added 1,1-dimethylethyl 4-(2-hydroxyethyl)-1-piperidinecarboxylate (592 mg, 2.58 mmol) and polymer bound triphenylphosphine (574 mg, 1.721 mmol) resin. To the mixture was then added dropwise DEAD (0.272 mL, 1.721 mmol). The stir bar was then removed from the reaction and the reaction was then placed on to a horizontal shaker and the reaction was agitated at room temp overnight. The resin was filtered off and the filtrated was concentrated then loaded on to a 10 g Biotage SNAP column and eluded with 0 to 45% EtOAc in Hexane to give 1,1-dimethylethyl 4-[2-(5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethyl]-1-piperidinecarboxylate (326 mg, 85% yield) as a white solid. LC-MS (ES) m/z=443.4 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:13][C:12]2[CH:14]=[C:15]([CH:18]=O)[CH:16]=[CH:17][C:11]=2[O:10][CH2:9][CH2:8]1.[S:20]1[CH2:24][C:23](=[O:25])[NH:22][C:21]1=[O:26].C([O-])(=O)C.[NH2+]1CCCCC1>C1(C)C=CC=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:13][C:12]2[CH:14]=[C:15]([CH:18]=[C:24]3[S:20][C:21](=[O:26])[NH:22][C:23]3=[O:25])[CH:16]=[CH:17][C:11]=2[O:10][CH2:9][CH2:8]1
Reactant: O=C1CSC(=O)N1
Reactant: O=Cc1ccc2c(c1)CN(c1ccccn1)CCO2
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: O=C1NC(=O)C(=Cc2ccc3c(c2)CN(c2ccccn2)CCO3)S1

Procedure:
4-Pyridin-2-yl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepine-7-carbaldehyde [compound of Example 1-Step III] (0.868 g, 3.4 mmol) was dissolved in 100 mL dry toluene and to this solution, was added 2,4-thiazolidinedione (0.402 g, 3.4 mmol) and piperidinium acetate (46 mg, 0.32 mmol). The reaction mixture was refluxed in a Dean Stark apparatus for 4 hours. The reaction mixture was cooled and filtered. The residue was washed with petroleum ether (500 mL) and dried in air to give crude material A (0.6 g). The filtrate and petroleum ether wash were combined, cooled overnight and filtered. The filtrate was washed with petroleum ether (500 mL). The residue was dried in air to give crude material B (0.24 g). Both crude materials, A and B were combined and purified by silica chromatography using 1% CH2Cl2 in MeOH to give 5-(4-pridin-2-yl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-7-ylmethylene)-thiazolidine-2,4-dione.