Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20]3)=[CH:15][CH:14]=2)[N:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:49]([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=1[C:57]1([C:60]([O:62][CH3:63])=[O:61])[CH2:59][CH2:58]1)#[CH:50].CCN(CC)CC>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:63][O:62][C:60]([C:57]1([C:52]2[CH:53]=[CH:54][CH:55]=[CH:56][C:51]=2[C:49]#[C:50][C:2]2[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([CH:19]4[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20]4)=[CH:15][CH:14]=3)[N:3]=2)[CH2:59][CH2:58]1)=[O:61]
Reactant: C#Cc1ccccc1C1(C(=O)OC)CC1
Reactant: CC(C)(C)OC(=O)N1CC(c2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)cc2)C1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)C1(c2ccccc2C#Cc2nc(Nc3ccc(C4CN(C(=O)OC(C)(C)C)C4)cc3)ncc2C(F)(F)F)CC1
Temperature: 120 °C
Yield: 100 %

Procedure:
A solution of tert-butyl 3-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)azetidine-1-carboxylate (K4) (260 mg, 0.606 mmol), PdCl2(PPh3)2 (21 mg, 0.030 mmol), PPh3 (16 mg, 0.061 mmol), CuI (12 mg, 0.061 mmol) and methyl 1-(2-ethynylphenyl)cyclopropanecarboxylate (K2) (146 mg, 0.728 mmol) in DMF (3.0 mL) was degassed with nitrogen for 10 minutes. Et3N (1.0 mL) was added and the resulting mixture heated under microwave irradiation at 120° C. for 20 minutes. The resulting mixture was adsorbed onto silica and purified by silica gel column chromatography (Biotage Isolera, 40 g SiO2 cartridge, 0-25% EtOAc in petroleum benzine 40-60° C.) to give the title compound A7 as an orange oil (359 mg, >95%); 1H NMR (400 MHz, d6-DMSO) δ 10.45 (s, 1H), 8.82 (s, 1H), 7.75 (d, J=8.4 Hz, 2H), 7.61 (dd, J=7.5, 1.0 Hz, 1H), 7.55-7.38 (m, 3H), 7.32 (d, J=8.6 Hz, 2H), 4.32-4.17 (m, 2H), 3.89-3.74 (m, 3H), 3.52 (s, 3H), 1.64 (q, J=4.0 Hz, 2H), 1.40 (s, 9H), 1.29 (q, J=4.2 Hz, 2H). LCMS-A: rt 6.550 min; m/z 593 [M+H]+.
Reaction SMILES: [CH:1]1[C:6]([CH2:7][CH2:8][OH:9])=[CH:5][CH:4]=[C:3]([OH:10])[CH:2]=1.N1C=CC=CC=1.ClC(Cl)([O:20][C:21](=[O:27])[O:22]C(Cl)(Cl)Cl)Cl>C(Cl)Cl>[CH:1]1[C:6]([CH2:7][CH2:8][OH:9])=[CH:5][CH:4]=[C:3]([OH:10])[CH:2]=1.[C:21](=[O:20])([O-:27])[O-:22]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: OCCc1ccc(O)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C([O-])[O-]
Reaction time: 0.25 h

Procedure:
In a 1 L 3-necked round-bottomed flask equipped with a mechanical stirrer, and a liquid addition device were placed 45 g (0.084 mol) of I2DTy, 5 g (0.036 mol) of tyrosol, 35.5 g (0.45 mol) of pyridine, and 300 mL of DCM and stirred for 15 min to get a clear solution. Triphosgene (12.3 g, 0.125 mol of phosgene) was dissolved in 32 ml of DCM and the solution was introduced into the reaction flask over 2-3 hours. After the addition was complete, the reaction mixture was quenched with a mixture of 135 mL of THF and 15 mL of water. 350 mL of water was added to the reaction mixture and stirred for 5 min. After allowing the layers to separate, the top aqueous layer was removed and discarded. The washing, was repeated with two additional 350 mL portions of DI water. The reaction mixture was then precipitated with 600 mL of IPA. The resulting gel was ground twice in a 4 L high speed blender. The precipitate obtained was isolated by filtration and dried in a vacuum oven at 80° C. The polymer had a Mw of 318 Kda and a glass transition temperature (Tg) of 100° C. 1H NMR spectrum of the polymer was in agreement with the structure. Compression molding at 190° C. gave a uniform transparent film. Using similar procedures a copolymer with 15% tyrosol was prepared. The properties of the polymers are set forth below:
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH2:8][CH2:9][CH2:10][C:11](=[O:12])[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[Cl:20][C:21]1[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24]>ClCCl>[Cl:20][C:21]1[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[CH:27]=[CH:26][C:22]=1[C:23]([N:7]1[CH2:8][CH2:9][CH2:10][C:11](=[O:12])[C:5]2[CH:4]=[CH:3][CH:2]=[N:1][C:6]1=2)=[O:24]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1Cl
Reactant: O=C1CCCNc2ncccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCCN(C(=O)c2ccc([N+](=O)[O-])cc2Cl)c2ncccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-5-one and 0.234 g of triethylamine in 6 ml of dichloromethane is added 0.506 g of 2-chloro-4-nitrobenzoyl chloride in 2 ml of dichloromethane. The mixture is stirred at room temperature overnight under argon. The solution is washed with H2O, 10% NaHCO3 and dried (MgSO4). The solvent is removed to give a brown oil which crystallizes. The mixture is chromatographed on silica with a waters Prep-500 instrument with ethyl acetate-hexane (1:1) as solvent to give 2.4 g of off-white crystals, m.p. 162°-164° C. (identified as O-2-chloro-4-nitrobenzoyl derivative (2-chloro-4-nitrobenzoyl enolate of product) and 0.80 g of product as crystals, m.p. slowly decomposes 160°-220° C.
Reaction SMILES: Cl.C[CH:3]1[O:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[O:4]1.[CH2:12]=O.[CH2:14]([Cl:16])Cl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:16][CH2:14][C:9]1[C:10]([CH3:12])=[CH:11][C:5]2[O:4][CH2:3][O:7][C:6]=2[CH:8]=1
Reactant: C=O
Reactant: CC1Oc2ccccc2O1
Reactant: ClCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Br-]
Product: Cc1cc2c(cc1CCl)OCO2
Reaction time: 8 h

Procedure:
To a mixture of methylene chloride (130 L), concentrated HCl (130 L), and tetrabutylammonium bromide (1.61 Kg) was added 5 methylbenzo[d][1,3]dioxole (10 Kg) followed by the slow addition of formaldehyde (14 L, 37 wt % in water). The mixture was stirred overnight. The organic layer was separated, dried with magnesium sulfate and concentrated to an oil. Hexane (180 L) was added and the mixture heated to boiling. The hot hexane solution was decanted from a heavy oily residue and evaporated to give almost pure 5-chloromethyl-6-methylbenzo[d][1,3]dioxole as a white solid. Recrystallization from hexane (50 L) gave 5-chloromethyl-6-methylbenzo[d][1,3]dioxole (80% recovery after recrystallization).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH2:23]([C:30]1[N:31]=[C:32]([CH2:37][CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)[O:33][C:34]=1[CH2:35]Cl)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CC(C)=O>[CH2:23]([C:30]1[N:31]=[C:32]([CH2:37][CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)[O:33][C:34]=1[CH2:35][N:12]1[CH2:13][CH2:14][N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:10][CH2:11]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COc1ccccc1N1CCNCC1
Reactant: ClCc1oc(CC2CCCCC2)nc1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccccc1N1CCN(Cc2oc(CC3CCCCC3)nc2Cc2ccccc2)CC1
Yield: 81 %

Procedure:
A suspension containing 2-methoxyphenylpiperazine (2.0 mmole), potassium carbonate (4.0 mmole), potassium iodide (1.0 mmole) and 4-benzyl-5-chloromethyl-2-cyclohexylmethyl oxazole (2.0 mmole) from example 8, was stirred in acetone (20 ml) at ambient temperature for 18 hr. The solvent was removed in vacuo, water (50 ml) added and the product extracted into ethyl acetate (3×50 ml). The combined organics were washed with water (50 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The product was purified by “flash” chromatography over silica gel to afford the titled compound as an off-white crystalline powder (1.62 mmole, 81% yield). This was transformed into its mono-fumarate salt, an off-white crystalline powder, using the procedure outlined in example 10 above.
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([N:25]3[CH2:30][CH2:29][CH:28]([CH2:31][CH2:32][O:33][Si:34]([CH:41]([CH3:43])[CH3:42])([CH:38]([CH3:40])[CH3:39])[CH:35]([CH3:37])[CH3:36])[CH2:27][CH2:26]3)=[N:23][N:24]=2)[CH:21]=1>CN(C=O)C.O>[CH:38]([Si:34]([CH:35]([CH3:37])[CH3:36])([CH:41]([CH3:43])[CH3:42])[O:33][CH2:32][CH2:31][CH:28]1[CH2:29][CH2:30][N:25]([C:22]2[N:20]3[CH:21]=[C:16]([O:12][C@H:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C@@H:2]([NH2:1])[CH2:3][CH2:4]4)[CH:17]=[CH:18][C:19]3=[N:24][N:23]=2)[CH2:26][CH2:27]1)([CH3:39])[CH3:40]
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Reactant: CC(C)[Si](OCCC1CCN(c2nnc3ccc(F)cn23)CC1)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)[Si](OCCC1CCN(c2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)CC1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 42.6 %

Procedure:
To a solution of Intermediate A (122 mg, 0.75 mmol) in DMF (3 mL) was added NaH (60% dispersion in oil, 60 mg, 1.5 mmol) and the mixture stirred at RT for 25 min. A solution of Intermediate 66b (315 mg, 0.75 mmol) in DMF (2.5 mL) was added and the mixture stirred at 60° C. for 1.5 h. The cooled mixture was diluted with water and extracted with DCM (5×25 mL). The combined organics were dried and concentrated in vacuo. The residue was purified by FCC, using 0-14% [2M NH3 in MeOH] in DCM, to give the title compound as a dark brown gum (180 mg, 42%). LCMS (Method 3): Rt 3.35 min, m/z 564 [MH+].
Reaction SMILES: [C:1]([C:4]1[NH:8][C:7]([CH3:9])=[N:6][C:5]=1[CH3:10])(=[O:3])[CH3:2].[Br:11]Br>Br>[CH3:9][C:7]1[NH:8][C:4]([C:1](=[O:3])[CH2:2][Br:11])=[C:5]([CH3:10])[N:6]=1
Reactant: BrBr
Reactant: CC(=O)c1[nH]c(C)nc1C
Agent: Br
Product: Cc1nc(C)c(C(=O)CBr)[nH]1
Yield: 71.3 %

Procedure:
A solution of 1.0 g (7.24 mmol) of 5-acetyl-2,4-dimethylimidazole in 15 ml of concentrated hydrobromic acid was warmed to 50° and 1.16 g (7.25 mmol) of bromine was added dropwise over 1 minute. The mixture was then heated at 50°-60° for 1 hour. The mixture was concentraed and the solid residue was triturated with 30 ml of saturated sodium bicarbonate solution. The insoluble material was collected by filtration, washed with water, and dried in vacuo to give 1.12 g (71%) of 1-(2,4-dimethyl-5-imidazolyl)-2bromoethanone as a white solid, mp 128°-132° . nmr (D6DMSO) (δ): 4.40 (s, 2H); 2.27 (s, 3H); 2.13 (s, 3H).
Reaction SMILES: C([NH:3][C:4]1[N:9]=[C:8]([C:10](=[N:41][O:42][CH2:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C:11]([NH:13][CH:14]2[C:39](=[O:40])[N:16]3[C:17]([C:23]([O:25][CH:26]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[O:24])=[C:18]([CH:21]=[CH2:22])[CH2:19][S:20][C@H:15]23)=[O:12])[CH:7]=[CH:6][CH:5]=1)=O.Cl.C(=O)(O)[O-].[Na+]>CO>[NH2:3][C:4]1[N:9]=[C:8]([C:10](=[N:41][O:42][CH2:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C:11]([NH:13][CH:14]2[C:39](=[O:40])[N:16]3[C:17]([C:23]([O:25][CH:26]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[O:24])=[C:18]([CH:21]=[CH2:22])[CH2:19][S:20][C@H:15]23)=[O:12])[CH:7]=[CH:6][CH:5]=1
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(C)(C)C)c3cccc(NC=O)n3)[C@H]2SC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(C)(C)C)c3cccc(N)n3)[C@H]2SC1
Temperature: 35 °C
Yield: 97.7 %

Procedure:
To a suspension of benzhydryl 7-[2-(6-formamidopyridin-2-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (4.8 g) in methanol (300 ml) was added conc. hydrochloric acid (2.88 ml), and the mixture was stirred at 35° C. for an hour. The reaction mixture was adjusted to pH 5.5 with 5% aqueous sodium bicarbonate, and the methanol was removed by distillation under reduced pressure, followed by extraction with ethyl acetate (300 ml). The extract was washed with a saturated aqueous sodium chloride and then dried over magnesium sulfate. Removal of the solvent gave benzhydryl 7-[2-(6-aminopyridin-2-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (4.5 g), mp 125°-129° C. IR (Nujol): 3350, 1778, 1721, 1682, 1615 cm-1.
Reaction SMILES: C(OC1C=CC(N2CCN(CCCC3CCCCC3)CC2)=CC=1[Cl:30])C1C=CC=CC=1.C([O:38][C:39]1[CH:44]=[CH:43][C:42]([N:45]2[CH2:50][CH2:49][N:48]([CH2:51][CH2:52][CH2:53][CH:54]3[CH2:59][CH2:58][CH2:57][CH2:56][CH2:55]3)[CH2:47][CH2:46]2)=[CH:41][C:40]=1[F:60])C1C=CC=CC=1>>[ClH:30].[CH:54]1([CH2:53][CH2:52][CH2:51][N:48]2[CH2:49][CH2:50][N:45]([C:42]3[CH:43]=[CH:44][C:39]([OH:38])=[C:40]([F:60])[CH:41]=3)[CH2:46][CH2:47]2)[CH2:59][CH2:58][CH2:57][CH2:56][CH2:55]1
Reactant: Fc1cc(N2CCN(CCCC3CCCCC3)CC2)ccc1OCc1ccccc1
Reactant: Clc1cc(N2CCN(CCCC3CCCCC3)CC2)ccc1OCc1ccccc1
Product: Cl
Product: Oc1ccc(N2CCN(CCCC3CCCCC3)CC2)cc1F

Procedure:
Production Example 30 was repeated except that 1-(4-benzyloxy-3-chlorophenyl)-4-(3-cyclohexylpropyl)piperazine was replaced with 1-(4-benzyloxy-3-fluorophenyl)-4-(3-cyclohexylpropyl)-piperazine (1.45 g), to provide 4-[4-(3-cyclohexylpropyl)piperazin-1-yl]-2-fluorophenol hydrochloride (1.17 g).
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:31])=[C:7]2[C:12](=[C:13]([C:15]#[N:16])[N:14]=1)[N:11]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:10](=[O:24])[C:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH:8]2)=[O:4].[NH2:32][CH2:33][C:34]([OH:36])=[O:35].C[O-].[Na+]>>[CH2:17]([N:11]1[C:12]2[C:7](=[C:6]([OH:31])[C:5]([C:3]([NH:32][CH2:33][C:34]([OH:36])=[O:35])=[O:4])=[N:14][C:13]=2[C:15]#[N:16])[CH:8]=[C:9]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:10]1=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)c1nc(C#N)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2cc(-c3ccccc3)c(=O)n(Cc3ccccc3)c12
Temperature: 25 °C
Yield: 80.3 %

Procedure:
A mixture of 1-benzyl-8-cyano-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (70 mg, 0.17 mmol), glycine (3.07 g, 41 mmol) and NaOMe solution (61 mL, 31 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was dissolved in saturated NaHCO3 and washed with ether. The aqueous layer was acidified with 4 M HCl to pH about 3, and the resulting mixture was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated to give 62 mg of the title compound. MS: (+) m/z 455.11 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[C@@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]1[O:13][C:14](=[O:16])[CH3:15].[Br:34][C:35]1[S:39][C:38]([C:40](Cl)=[O:41])=[CH:37][CH:36]=1>>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([C:40]([C:38]1[S:39][C:35]([Br:34])=[CH:36][CH:37]=1)=[O:41])=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[C@@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]1[O:13][C:14](=[O:16])[CH3:15]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2ccc3c(C)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: O=C(Cl)c1ccc(Br)s1
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(C(=O)c3ccc(Br)s3)c3c(C)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
4-Methyl-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-indole obtained in Example 23-(1) and 5-bromothiophene-2-carbonyl chloride were treated in a manner similar to Example 21-(1) to give 5-bromo-2-thienyl 4-methyl-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)indol-3-yl ketone as a yellow powder. APCI-Mass m/Z 650/652 (M+H).
Reaction SMILES: Cl.[OH:2][CH:3]1[CH2:6][NH:5][CH2:4]1.CCN(C(C)C)C(C)C.Cl[C:17]1[C:36]([C:37]2[NH:41][N:40]=[CH:39][CH:38]=2)=[CH:35][C:20]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]([Cl:34])([F:33])[F:32])=[CH:26][CH:25]=2)=[O:22])=[CH:19][N:18]=1.O>CC(O)C>[Cl:34][C:31]([F:32])([F:33])[O:30][C:27]1[CH:26]=[CH:25][C:24]([NH:23][C:21](=[O:22])[C:20]2[CH:35]=[C:36]([C:37]3[NH:41][N:40]=[CH:39][CH:38]=3)[C:17]([N:5]3[CH2:6][CH:3]([OH:2])[CH2:4]3)=[N:18][CH:19]=2)=[CH:29][CH:28]=1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(-c2ccn[nH]2)c1
Reactant: OC1CNC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CC(C)O
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC(O)C2)c(-c2ccn[nH]2)c1
Temperature: 140 °C

Procedure:
3-Hydroxyazetidine hydrochloride (53.2 mg, 0.486 mmol) and DIPEA (0.170 mL, 0.972 mmol) were added to a suspension of 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(1H-pyrazol-5-yl)nicotinamide (Stage 48.1, 100 mg, 0.243 mmol) in iPrOH (0.5 mL) and the RM was heated at 140° C. for 3 h. The RM was treated with water, extracted with EtOAc, and the combined extracts were dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give. the crude product which was purified by flash chromatography (RediSep® Silica gel column, 24 g, DCM/MeOH 9:1) to give the title product as a yellow foam. HPLC (Condition 7) tR=5.518 min, UPLC-MS (Condition 3) tR=0.89 min, m/z=436 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 3.49-3.57 (m, 2H) 3.87-3.99 (m, 2H) 4.32-4.44 (m, 1H) 5.53 (br.s, 1H) 6.40 (br.s, 1H) 7.33 (d, J=8.60 Hz, 2H) 7.81-7.91 (m, 3H) 8.06 (d, J=2.35 Hz, 1H) 8.70 (br.s, 1H) 10.23 (s, 1H) 13.01 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH:17]([NH:19][C:20](=[O:22])[CH3:21])[CH3:18])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=1.[CH2:23]([OH:25])[CH3:24].[H-].[Na+]>O1CCOCC1>[CH2:23]([O:25][C:2]1[N:7]=[C:6]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH:17]([NH:19][C:20](=[O:22])[CH3:21])[CH3:18])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=1)[CH3:24]
Reactant: CCO
Reactant: CC(=O)NC(C)Cc1ccc(C#Cc2ccnc(Cl)n2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOc1nccc(C#Cc2ccc(CC(C)NC(C)=O)cc2)n1
Temperature: 0 °C

Procedure:
25 mg (0.08 mmol) N-(1-(4-((2-chloropyrimidin-4-yl)ethynyl)phenyl)propan-2-yl)acetamide (170) in 1.0 mL dioxane are added to 9.3 μl (0.16 mmol) ethanol in 0.5 ml dioxane and cooled down to 0° C. 10 mg (0.24 mmol) NaH are added and the mixture is stirred at r.t. over night. The reaction is quenched with water and the solvent is evaporated in vacuo. The residue is purified by HPLC (MeOH/H2O/TFA).
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:10](Br)=[CH:9][N:8]=[C:7]([Cl:12])[N:6]=1)[CH:2]=[CH2:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:12][C:7]1[N:8]=[CH:9][C:10]2[C:2]([CH3:3])=[CH:1][NH:4][C:5]=2[N:6]=1
Reactant: C=CCNc1nc(Cl)ncc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1c[nH]c2nc(Cl)ncc12
Temperature: 100 °C
Yield: 40 %

Procedure:
A mixture of Allyl-(5-bromo-2-chloro-pyrimidin-4-yl)-amine (1 g, 4 mmol), palladium(II) acetate, (90 mg, 0.40 mmol), triphenylphosphine (211 mg, 0.80 mmol) and triethylamine (1.1 mL, 8.0 mmol) in DMF (10 mL) is heated at 100° C. overnight. After cooling to room temperature the reaction mixture is diluted with ethyl acetate and washed with brine. The organic phase is dried (anhydrous Na2SO4) and the solvent is evaporated. The crude product is purified by flash chromatography (gradient elution EtOAC:Heptanes 0:0 to 1:1) on silicagel to afford 2-Chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine as a white solid (40%).
Reaction SMILES: [C:1]([N:3]=[C:4]1[NH:8][CH2:7][CH2:6][N:5]1[C@@H:9]1[C:14]2[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:13]=2[O:12][C:11]([CH3:22])([CH3:21])[C@H:10]1[OH:23])#[N:2].[C:24](OC(=O)C)(=[O:26])[CH3:25]>N1C=CC=CC=1.C(OCC)(=O)C>[C:24]([O:23][C@H:10]1[C@H:9]([N:5]2[CH2:6][CH2:7][NH:8][C:4]2=[N:3][C:1]#[N:2])[C:14]2[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:13]=2[O:12][C:11]1([CH3:21])[CH3:22])(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](N2CCNC2=NC#N)[C@@H]1O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1[C@H](N2CCNC2=NC#N)c2cc(C#N)ccc2OC1(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of trans-4-(2-cyanoiminoimidazolidin-1-yl)-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (0.62 g) and acetic anhydride (0.47 ml) in dry pyridine (3.1 ml) was stirred at room temperature for 3 days. The mixture was diluted with ethyl acetate (30 ml) and washed with 5% hydrochloric acid (20 ml×2), brine (20 ml), saturated aqueous sodium bicarbonate (20 ml) and brine (20 ml), successively. The organic layer was dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was subjected to column chromatography on silica gel (50 g) and eluted with a mixture of chloroform and methanol (50:1). The fractions containing the object compound were combined and concentrated under reduced pressure. The residue was recrystallized from a mixture of dichloromethane and n-hexane to give trans-3-acetoxy-4-(2-cyanoiminoimidazolidin-1-yl)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (0.44 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]([OH:14])=O)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:15][CH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:26]=[C:27]([NH:31][C:32](=[O:36])[CH2:33][CH2:34][CH3:35])[CH:28]=[CH:29][CH:30]=2)[CH2:21][CH2:20]1>>[C:32]([NH:31][C:27]1[CH:26]=[C:25]([CH:22]2[CH2:23][CH2:24][N:19]([CH2:18][CH2:17][CH2:16][NH:15][C:12]([C:8]3([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[CH2:9][CH2:10][CH2:11]3)=[O:14])[CH2:20][CH2:21]2)[CH:30]=[CH:29][CH:28]=1)(=[O:36])[CH2:33][CH2:34][CH3:35]
Reactant: CCCC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CCC1
Product: CCCC(=O)Nc1cccc(C2CCN(CCCNC(=O)C3(c4ccc(Cl)cc4)CCC3)CC2)c1

Procedure:
Example 106 was prepared from 1-(4-chlorophenyl)cyclobutanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}butanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 7.53 (s, 2H), 7.32–7.23 (m, 6H), 6.95 (d, 1H, J=7.6 Hz), 6.53 (br s, 1H), 3.29 (dd, 2H, J=6.0, 12.4 Hz), 2.93 (d, 2H, J=10.8 Hz), 2.86–2.79 (m, 2H), 2.48–2.41 (m, 3H), 2.37–2.30 (m, 4H), 2.07 (m, 1H), 1.98–1.61 (m, 11H), 1.01 (t, 3H, J=7.6 Hz); ESMS m/e: 496.3 (M+H)+.
Reaction SMILES: FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[F:16][C:17]1[CH:42]=[CH:41][C:20]([CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([N:29]3[C:37]4[C:32](=[CH:33][CH:34]=[C:35]([CH:38]=[N:39]O)[CH:36]=4)[CH2:31][CH2:30]3)[CH2:25][CH2:24]2)=[CH:19][CH:18]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(Cl)(Cl)Cl>[F:16][C:17]1[CH:42]=[CH:41][C:20]([CH2:21][CH2:22][N:23]2[CH2:24][CH2:25][CH:26]([N:29]3[C:37]4[C:32](=[CH:33][CH:34]=[C:35]([C:38]#[N:39])[CH:36]=4)[CH2:31][CH2:30]3)[CH2:27][CH2:28]2)=[CH:19][CH:18]=1
Reactant: ON=Cc1ccc2c(c1)N(C1CCN(CCc3ccc(F)cc3)CC1)CC2
Agent: O=C([O-])O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1ccc2c(c1)N(C1CCN(CCc3ccc(F)cc3)CC1)CC2
Yield: 70.1 %

Procedure:
Trifluoromethanesulfonic anhydride (0.72 ml) was added dropwise at −78° C. into a solution of 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-hydroxyiminomethylindoline (1.5 g) and triethylamine (1.2 ml) in methylene chloride (1 l) and the resultant mixture was warmed to room temperature. Next, a saturated aqueous solution of sodium bicarbonate and chloroform were added thereto and the layers were separated. The organic layer was dried over anhydrous magnesium sulfate and the residue was purified by NH-silica gel column chromatography (hexane/ethyl acetate system) to give the title compound (1.0 g) as a white powder (yield: 67%).