Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([N:10]2[CH2:14][CH2:13][N:12]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][C:20]=3[CH3:21])[C:11]2=[O:22])[CH:7]=[CH:6][C:5]=1F.O.[NH2:26][NH2:27].CO>C(Cl)(Cl)Cl.C(Cl)Cl>[CH3:21][C:20]1[CH:19]=[CH:18][N:17]=[CH:16][C:15]=1[N:12]1[CH2:13][CH2:14][N:10]([C:8]2[CH:9]=[C:4]3[C:5](=[CH:6][CH:7]=2)[NH:27][NH:26][C:3]3=[O:2])[C:11]1=[O:22]
Reactant: NN
Reactant: COC(=O)c1cc(N2CCN(c3cnccc3C)C2=O)ccc1F
Solvent: CO
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1ccncc1N1CCN(c2ccc3[nH][nH]c(=O)c3c2)C1=O
Temperature: 120 °C
Yield: 37.6 %

Procedure:
2-Fluoro-5-[3-(4-methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-benzoic acid methyl ester (I-117a: 510 mg, 1.55 mmol) and hydrazine hydrate were taken in a reaction flask and the flask was heated to 120° C. for 18 hours with stirring. The reaction was monitored by TLC (10% MeOH in CHCl3). The reaction mixture was partitioned between ice water and ethylacetate. The aqueous layer was concentrated to afford the solid residue which was dissolved in 1:1 DCM: MeOH and filtered. The filtrate was concentrated and purified by column chromatography on silica gel (10-15% MeOH in CHCl3). The residue was washed with DCM and dried to afford 180 mg of the product (37.6% yield).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[C:6](OC)=[O:7])#[N:2].O1CCCC1.[BH4-].[Na+].[Cl-].[NH4+]>CO>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[CH2:6][OH:7])#[N:2]
Reactant: COC(=O)c1ccc(OC)c(C#N)c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(CO)cc1C#N
Temperature: 45 °C

Procedure:
A mixture of methyl 3-cyano-4-methoxybenzoate (5g), tetrahydrofuran (25 mL) and sodium borohydride (1.98 g) was heated at 45° C. The mixture was dropwise added with methanol (6.36 mL) at 45-55° C. over 15 minutes and then refluxed for 3.5 hours. After cooling to 0° C., the mixture was added with an aqueous saturated ammonium chloride solution at the same temperature. The mixture was stirred at room temperature for an hour, and extracted with ethyl acetate. The organic layer was washed successively with water, an aqueous saturated sodium bicarbonate solution and brine. The organic layer was dried over magnesium sulfate and evaporated in vacuo. The residual solid was triturated with diisopropyl ether to give 3-cyano-4-methoxybenzyl alcohol (3.75 g) as a pale brown solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[CH:4][CH:3]=1.Cl[CH2:18][C:19]1[N:20]=[C:21]([C:24]2[O:25][C:26]([CH3:29])=[CH:27][CH:28]=2)[O:22][CH:23]=1>>[N:12]1([CH2:11][CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:18][C:19]3[N:20]=[C:21]([C:24]4[O:25][C:26]([CH3:29])=[CH:27][CH:28]=4)[O:22][CH:23]=3)=[CH:3][CH:4]=2)[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: Cc1ccc(-c2nc(CCl)co2)o1
Reactant: Oc1ccc(CCCCn2ccnc2)cc1
Product: Cc1ccc(-c2nc(COc3ccc(CCCCn4ccnc4)cc3)co2)o1
Yield: 99 %

Procedure:
In substantially the same manner as in Working Example 72, 1-[4-(4-hydroxyphenyl)butyl]imidazole was allowed to react with 4-chloromethyl-2-(5-methyl-2-furyl)oxazole to give 4-[4-[4-(1-imidazolyl)butyl]phenoxymethyl]-2-(5-methyl-2-furyl)oxazole. The yield was 99%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 91-92° C.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:11][CH2:12][OH:13].[Br:14]Br>C(O[Na])(C)=O.CC(O)=O>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([Br:14])[N:6]2[CH2:11][CH2:12][OH:13]
Reactant: BrBr
Reactant: Nc1ncnc2c1ncn2CCO
Agent: CC(=O)O[Na]
Solvent: CC(=O)O
Product: Nc1ncnc2c1nc(Br)n2CCO
Temperature: 25 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
To a solution of 10 g 2-(6-amino-purin-9-yl)ethanol in 200 ml 0.5M AcONa/AcOH buffer pH 4 were added 4 ml of Br2. The resulting mixture was stirred at room temperature for 8 hours. The precipitated product was isolated, washed with water and crystallized from ethanol to give 6.13 g (43%) of the desired compound.
Reaction SMILES: C([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH2:23][O:24][C:25](=[O:27])[CH3:26])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[OH:28])[CH2:6]1)(=O)C.C(=O)(O)[O-].[K+]>CO>[C:25]([O:24][CH2:23][C@@:20]12[C@@H:19]3[C@H:10]([C@H:11]4[C@@:15]([CH2:17][CH2:18]3)([CH3:16])[C@@H:14]([OH:28])[CH2:13][CH2:12]4)[CH2:9][CH:8]=[C:7]1[CH2:6][C@@H:5]([OH:4])[CH2:22][CH2:21]2)(=[O:27])[CH3:26]
Reactant: CC(=O)OC[C@]12CC[C@H](OC(C)=O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Agent: O=C([O-])O
Agent: [K+]
Solvent: CO
Product: CC(=O)OC[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12

Procedure:
To a solution of 5-androstene-3β,17β,19-triol 3,19-diacetate in methanol is added one equivalent of an aqueous 2% solution of potassium bicarbonate. The mixture is heated at its reflux temperature for a period of about 2 hours, concentrated to a small volume under reduced pressure and ether added thereto. The ethereal solution is separated, washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue so obtained is crystallized from an acetone-hexane solution to furnish the desired 5-androstene-3β,17β,19-triol 19-acetate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:13][N:14]3[CH:18]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:16]=[N:15]3)[S:11][CH:12]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:31](Cl)(=[O:35])[O:32][CH2:33][CH3:34]>O1CCCC1>[CH2:33]([O:32][C:31]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:13][N:14]3[CH:18]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:16]=[N:15]3)[S:11][CH:12]=2)=[CH:4][CH:3]=1)=[O:35])[CH3:34]
Reactant: CCOC(=O)Cl
Reactant: CCOC(=O)c1cnn(Cc2nc(-c3ccc(N)cc3)cs2)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)Nc1ccc(-c2csc(Cn3cc(C(=O)OCC)cn3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.5 %

Procedure:
In an ice-bath, to a solution (4 mL) of the crude compound (0.84 mmol) obtained in Example 36b in tetrahydrofuran were added triethylamine (0.15 ml, 1.1 mmol) and ethyl chlorocarbonate (79 ml, 1.0 mmol), and the mixture was stirred at room temperature overnight. After confirmation of the termination of the reaction by TLC, the resulting salt was removed. The solvent was evaporated under reduced pressure. The resulting crude title compound was recrystallized (hexane-ethyl acetate) to give the title compound (180 mg, 54% in 2 steps) as colorless crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][C:18]=1[N+:19]([O-])=O)[NH:7][C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([O-])=O.[N:22]1([C:28]2[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=2)[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>>[O:25]1[CH2:26][CH2:27][N:22]([C:28]2[CH:35]=[CH:34][C:31]([C:32]3[NH:19][C:18]4[CH:17]=[CH:16][C:6]([NH:7][C:8](=[O:15])[C:9]5[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=5)=[CH:5][C:4]=4[N:1]=3)=[CH:30][CH:29]=2)[CH2:23][CH2:24]1
Reactant: O=Cc1ccc(N2CCOCC2)cc1
Reactant: O=C(Nc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)c1ccccc1
Product: O=C(Nc1ccc2[nH]c(-c3ccc(N4CCOCC4)cc3)nc2c1)c1ccccc1

Procedure:
Compound 259 was prepared according to the procedure similar to that described in Scheme III from 3,4-dinitro-N-benzoylaniline and 4-morpholinylbenzaldehyde. [M+H]+ calcd for C24H22N4O2: 399.18; found: 398.99.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1.[CH:28]([C@@H:31]1[CH2:35][O:34][C:33](=[O:36])[NH:32]1)([CH3:30])[CH3:29]>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:32]4[C@H:31]([CH:28]([CH3:30])[CH3:29])[CH2:35][O:34][C:33]4=[O:36])=[CH:3][C:4]=3[S:24]([CH3:27])(=[O:26])=[O:25])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Reactant: CC(C)[C@@H]1COC(=O)N1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4C(C)C)cc3S(C)(=O)=O)CC2)c(C)c1
Yield: 4 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (4-bromo-2-methanesulfonylphenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (451 mg) described in Preparation Example 61 and (R)-4-isopropyloxazolidin-2-one (155 mg), the title compound (20 mg) was obtained.
Reaction SMILES: [CH2:1]([C:3]1[S:42][C:6]2[N:7]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[C:36]4[NH:40][C:39](=[O:41])[O:38][N:37]=4)=[CH:26][CH:25]=3)[C:8](=[O:22])[N:9]([CH2:12][C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[O:14])[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].[BH4-].[Na+]>C(Cl)(Cl)Cl.CO>[CH2:1]([C:3]1[S:42][C:6]2[N:7]([CH2:23][C:24]3[CH:25]=[CH:26][C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[C:36]4[NH:40][C:39](=[O:41])[O:38][N:37]=4)=[CH:28][CH:29]=3)[C:8](=[O:22])[N:9]([CH2:12][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[OH:14])[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1cc2c(=O)n(CC(=O)c3ccc(F)cc3)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCc1cc2c(=O)n(CC(O)c3ccc(F)cc3)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Reaction time: 8 h
Yield: 99.7 %

Procedure:
To a solution of 6-ethyl-3-[2-(4-fluorophenyl)-2-oxoethyl]-1-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (0.5 g) in CHCl3-methanol (1:1, 30 mL) was added NaBH4 (0.039 g) at room temperature, and the mixture was stirred overnight. The reaction mixture was concentrated, water was added and the mixture was adjusted to pH 5-6 with 1N hydrochloric acid and water, extracted with ethyl acetate, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the object compound (0.50 g, 100%).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[N:7]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH2:31])=[O:30])[CH:24]=2)[C:8](=[O:22])[CH:9]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])[CH:11]=1)(=[O:3])[CH3:2].[Cl:32]N1C(=O)CCC1=O.ClC(Cl)C(O)=O>ClCCl.C(OCC)C>[C:1]([O:4][CH2:5][C:6]1[N:7]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH2:31])=[O:30])[CH:24]=2)[C:8](=[O:22])[C:9]([Cl:32])=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])[CH:11]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1cc(OCc2ccc(F)cc2F)cc(=O)n1-c1cccc(C(N)=O)c1
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C(O)C(Cl)Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CC(=O)OCc1cc(OCc2ccc(F)cc2F)c(Cl)c(=O)n1-c1cccc(C(N)=O)c1
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 85 %

Procedure:
{1-[3-(aminocarbonyl)phenyl]-4-[(2,4-difluorobenzyl)oxy]-6-oxo-1,6-dihydropyridin-2-yl}methyl acetate (from step 2) (1.02 g, 2.39 mmol) was suspended in dichloromethane (15 mL) and N-chlorosuccinimide (0.37 g, 2.75 mmol) was added. Dichloroacetic acid (0.10 ml, 1.22 mmol) was added and the reaction mixture was stirred at 40° C. for 1.5 hours. The reaction was cooled to room temperature and a precipitate formed. The reaction mixture was diluted with diethyl ether and the precipitate was collected by filtration and washed with diethyl ether (3×15 mL) to afford a tan solid (0.940 g, 85%). 1H NMR (400 MHz, DMF-d6) δ 8.21 (br s, 1H), 8.11 (app dt, J=1.48, 7.52 Hz, 1H), 7.95 (app t, J=1.61 Hz, 1H), 7.80 (app dt, J=6.72, 8.59 Hz, 1H) 7.69-7.60 (m, 2H), 7.48 (br s, 1H), 7.35 (ddd, J=2.55, 9.53, 10.61 Hz, 1H), 7.24-7.19 (m, 1H), 6.97 (s, 1H), 5.49 (s, 2H), 4.71 (AB q, JAB=15.04 Hz, 2H), 198 (s, 3H). ES-HRMS m/z 463.0883 (M+H calcd for C22H17ClF2N2O5 requires 463.0867).
Reaction SMILES: COCC(N[C:7]([C:9]1[CH:10]=[C:11]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)[CH:12]=[C:13]([N:15]2[C:19]([C:20]([F:23])([F:22])[F:21])=[N:18][N:17]=[N:16]2)[CH:14]=1)=[O:8])C.C[O:32]CC(N)C>>[CH3:30][C:27]1[CH:26]=[CH:25][C:24]([C:11]2[CH:12]=[C:13]([N:15]3[C:19]([C:20]([F:23])([F:22])[F:21])=[N:18][N:17]=[N:16]3)[CH:14]=[C:9]([C:7]([OH:8])=[O:32])[CH:10]=2)=[CH:29][CH:28]=1
Reactant: COCC(C)N
Reactant: COCC(C)NC(=O)c1cc(-c2ccc(C)cc2)cc(-n2nnnc2C(F)(F)F)c1
Product: Cc1ccc(-c2cc(C(=O)O)cc(-n3nnnc3C(F)(F)F)c2)cc1

Procedure:
4′-Methyl-5-(5-trifluoromethyl-tetrazol-1-yl)-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide was reacted with 2-methoxy-1-methyl-ethylamine using the procedure of step 4 of Example 3 to give 4′-methyl-5-(5-trifluoromethyl-tetrazol-1-yl)-biphenyl-3-carboxylic acid. MS (M+H)=420.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[I-].[C:8]1([CH2:14][C:15]([NH:17][CH:18]2[C:61](=[O:62])[N:20]3[C:21]([C:45]([O:47][CH:48]([C:55]4[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=4)[C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)=[O:46])=[C:22]([CH2:25][P+:26]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)([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)[CH2:23][S:24][C@H:19]23)=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O.C(Cl)Cl>[C:8]1([CH2:14][C:15]([NH:17][CH:18]2[C:61](=[O:62])[N:20]3[C:21]([C:45]([O:47][CH:48]([C:55]4[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=4)[C:49]4[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=4)=[O:46])=[C:22]([CH:25]=[P:26]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[CH2:23][S:24][C@H:19]23)=[O:16])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@H]12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=P(c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@H]12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
14.0 g (0.132 mol) of Na2CO3, dissolved in 150 ml of water, are added to a suspension of 78.0 g (0.088 mol) of benzhydryl 7-phenylacetamido-3-(triphenylphosphonio)methyl-3-cephem-4-carboxylate iodide (Example 7) in 400 ml of methylene chloride and the mixture is stirred vigorously at room temperature for 15 minutes. The CH2Cl2 layer is separated off, the aqueous phase is extracted again with 200 ml of CH2Cl2 and the combined organic phases are dried over sodium sulphate. The methylene chloride phase is concentrated to dryness and the residue is stirred in about 600 ml of acetone for 1 hour. The product is filtered off with suction and rinsed thoroughly with acetone.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2([CH2:28][O:29][CH2:30][CH:31]=[CH2:32])[C:13](=[O:14])[N:12]([C:15]3[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([C:23]([F:26])([F:25])[F:24])[CH:16]=3)[C:11](=[O:27])[NH:10]2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[C:33](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]([C:9]2([CH2:28][O:29][CH2:30][CH:31]=[CH2:32])[C:13](=[O:14])[N:12]([C:15]3[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([C:23]([F:26])([F:24])[F:25])[CH:16]=3)[C:11](=[O:27])[N:10]2[CH3:33])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: C=CCOCC1(c2cccc(C#N)c2)NC(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: C=CCOCC1(c2cccc(C#N)c2)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1C
Temperature: 25 °C

Procedure:
To a solution of 358 mg of 4-[4-(3-cyanophenyl)-2,5-dioxo-4-[(2-propenyloxy)methyl]imidazolidin-1-yl]-2-trifluoromethylbenzonitrile in DMF (1.5 mL) 135 mg of potassium carbonate and 101 μL of methyl iodide are added. The mixture is stirred during the night at room temperature, evaporated, washed with brine, extracted with ethyl acetate, dried over magnesium sulfate and concentrated to give the desired compound.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:15]([C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=O)#[N:16].[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1.CO>ClCCCl>[N:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[NH:25][CH2:20][C:19]1[CH:18]=[C:17]([CH:24]=[CH:23][CH:22]=1)[C:15]#[N:16]
Reactant: Nc1ccccn1
Reactant: N#Cc1cccc(C=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCCl
Product: N#Cc1cccc(CNc2ccccn2)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Sodium triacetoxyborohydride (23 g; 108 mmol) is added in small portions to a solution, stirred under an argon atmosphere, of 3-cyanobenzaldehyde (10 g; 63.7 mmol) and 2-aminopyridine (6 g; 63.7 mmol) in 300 ml of 1,2-dichloroethane. After stirring for 12 hours at ambient temperature, the reaction mixture is hydrolysed with methanol and concentrated. The residue obtained is purified by chromotography on silica gel (eluant petroleum ether/ethyl acetate, 3/1 then 2/1 and 1/1) to yield the expected product.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[S:3](Cl)(=[O:5])=[O:4].[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:21]2[C:20]([CH3:22])=[C:19]([CH3:23])[N:18]=[C:17]([NH2:24])[C:16]=2[N:15]=[CH:14]1>>[NH2:24][C:17]1[C:16]2[N:15]=[CH:14][N:13]([CH2:12][CH2:11][CH2:10][CH2:9][NH:8][S:3]([N:2]([CH3:7])[CH3:1])(=[O:5])=[O:4])[C:21]=2[C:20]([CH3:22])=[C:19]([CH3:23])[N:18]=1
Reactant: Cc1nc(N)c2ncn(CCCCN)c2c1C
Reactant: CN(C)S(=O)(=O)Cl
Product: Cc1nc(N)c2ncn(CCCCNS(=O)(=O)N(C)C)c2c1C

Procedure:
Using the method of Examples 15-29, dimethylsulfamoyl chloride was reacted with 1-(4-aminobutyl)-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-4-amine to provide the desired product. The observed accurate mass was 341.1770.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2.[C:16](OC(=O)C)(=[O:18])[CH3:17]>CN(C)C1C=CN=CC=1>[C:16]([O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2)(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)c1cc2cc(O)ccc2[nH]1
Agent: CN(C)c1ccncc1
Product: CCOC(=O)c1cc2cc(OC(C)=O)ccc2[nH]1
Yield: 100 %

Procedure:
A stirred solution of ethyl 5-hydroxyindole-2-carboxylate (7.79 g) and 4-dimethylaminopyridine (20 mg) in acetic anhydride (80 ml) was heated at 80° C. for 4 hours. The reaction was concentrated in vacuo and the residue was dissolved in ethyl acetate. Combined organic extracts were washed with hydrochloric acid (2 M), saturated aqueous sodium hydrogen carbonate solution, water, aqueous saturated sodium chloride solution and dried. The solution was concentrated in vacuo to yield the product as a yellow solid (9.39 g, 100%). NMR: 1.20 (t, 3H), 2.10 (s, 3H), 4.19 (q, 2), 6.86 (dd, 1H), 6.97 (d, 1H), 7.20 (s, 1H), 7.29 (d, 1H); m/z 248 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9](=[O:14])N(OC)C)([CH3:4])([CH3:3])[CH3:2].[Br:24][C:25]1[CH:30]=[CH:29][C:28](I)=[C:27]([O:32][CH3:33])[CH:26]=1>>[C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9]([C:28]1[CH:29]=[CH:30][C:25]([Br:24])=[CH:26][C:27]=1[O:32][CH3:33])=[O:14])([CH3:2])([CH3:3])[CH3:4]
Reactant: CON(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1
Reactant: COc1cc(Br)ccc1I
Product: COc1cc(Br)ccc1C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared from rac-[(3,4-dichloro-phenyl)-(methoxy-methyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester (Intermediate 9) and 4-bromo-1-iodo-2-methoxy-benzene in analogy to Example 1a): MS (ISP): 490.0 (M+H)+ and 390.0 ((M-Boc)+H)+ (100%).
Reaction SMILES: [C:1]([C:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]2=[N:5][CH:4]=1)#[CH:2].[CH3:12][N:13]([CH2:15][C:16]1[N:17]([C:21]2[CH:22]=[C:23]([NH:31][C:32](=[O:51])[C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[C:35](C#CC4N5C=CN=CC5=NC=4)[CH:34]=3)[CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=2)[CH:18]=[CH:19][N:20]=1)[CH3:14].CCN(C(C)C)C(C)C>CN(C=O)C.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>[CH3:14][N:13]([CH2:15][C:16]1[N:17]([C:21]2[CH:22]=[C:23]([NH:31][C:32](=[O:51])[C:33]3[CH:34]=[CH:35][C:36]([CH3:39])=[C:37]([C:2]#[C:1][C:3]4[N:7]5[CH:8]=[CH:9][CH:10]=[CH:11][C:6]5=[N:5][CH:4]=4)[CH:38]=3)[CH:24]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:26]=2)[CH:18]=[CH:19][N:20]=1)[CH3:12]
Reactant: C#Cc1cnc2ccccn12
Reactant: Cc1ccc(C(=O)Nc2cc(-n3ccnc3CN(C)C)cc(C(F)(F)F)c2)cc1C#Cc1cnc2cnccn12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)Nc2cc(-n3ccnc3CN(C)C)cc(C(F)(F)F)c2)cc1C#Cc1cnc2ccccn12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 3-ethynylimidazo[1,2-a]pyridine (0.032 g, 0.22 mmol) in anhydrous DMF (1.26 mL) was added N-(3-(2-((dimethylamino)methyl)-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-iodo-4-methylbenzamide (prepared as in Example 3), Pd(PPh3)4 (0.013 g, 0.011 mmol), Cul (0.0032 mg, 0.0165 mmol) and DIPEA (0.064 mL, 0.44 mmol). The solution was degassed with argon for 15 minutes then stirred overnight at rt. The solvent was removed and the resultant residue was chromatographed over silica gel eluting initially with EtOAc and then with methanol/methylene chloride (5:95) to furnish the desired product: (0.07 g, 59%) MS (M+H)+ 542.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5](I)=[C:6]([CH3:8])[CH:7]=1.Br[C:12]([F:19])([F:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14]>CS(C)=O.[Cu]>[Br:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([C:12]([F:19])([F:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(Br)cc(C)c1I
Reactant: CCOC(=O)C(F)(F)Br
Agent: [Cu]
Solvent: CS(C)=O
Product: CCOC(=O)C(F)(F)c1c(C)cc(Br)cc1C
Temperature: 60 °C
Reaction time: 3 h
Yield: 88.3 %

Procedure:
To a degassed solution of 5-bromo-2-iodo-1,3-dimethylbenzene (3.9 g, 12.54 mmol) and ethyl 2-bromo-2,2-difluoroacetate (3.22 ml, 25.08 mmol) in DMSO (30 ml) was added copper (3.19 g, 50.2 mmol). The reaction mixture was stirred at 60° C. for 3 h, then cooled to r.t. and filtered. The filtrate was diluted with EtOAc and water, extracted with EtOAc (3×). The combined organic layer was washed with brine, dried with MgSO4, filtered and concentrated. The crude product was purified by flash chromatography to give Intermediate 7A (3.4 g, 11.07 mmol, 88% yield) as a colorless oil. 1H NMR (400 MHz, chloroform-d) δ ppm 1.32 (t, J=7.03 Hz, 3H) 2.44 (t, J=4.17 Hz, 6H) 4.32 (q, J=7.18 Hz, 2H) 7.23 (s, 2H). 19F NMR (376 MHz, chloroform-d) δ ppm −95.28 (br. s., 2F).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[Br:11]N1C(=O)CCC1=O>C(#N)C.C(O)C>[Br:11][C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][C:2](=[O:10])[CH2:3]2
Reactant: O=C1Cc2ccccc2N1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Solvent: CCO
Product: O=C1Cc2cc(Br)ccc2N1
Temperature: 7 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
2-Oxindole (53.3 g) was suspended in 640 mL acetonitrile and the mixture cooled to 7° C. in an ice bath with mechanical stirring. Solid N-bromosuccinimide (74.8 g) was added in portions over 20 minutes. After about one-third of the N-bromosuccinimide had been added (over 5 minutes), the temperature had increased to 12° C. The addition was halted until the temperature of the mixture had dropped to 10° C. The addition was resumed keeping the temperature below 12° C. After the addition was complete, the mixture was stirred for 1 hour at 10° C. and then for 1 additional hour during which the mixture was allowed to warm to ambient temperature. The precipitate was collected by vacuum filtration, washed with 80 mL of ethanol and sucked dry for 20 minutes in the filtration funnel to give product containing 6.4% of 2-oxindole by HPLC. The solid was suspended in 1440 mL of denatured ethanol and slurry-washed by stirring and refluxing for 5 minutes at which time most of the solid had dissolved. The mixture was cooled in an ice bath to 13° C. The solid product was collected by vacuum filtration, washed with 80 mL of ethanol and dried under vacuum to give 57.7 g (68.0%) of 5-bromo-2-oxindole containing 1.13% 2-oxindole by HPLC. Slurry-washing with 30% less ethanol gave a better yield (88%) but contained more 2-oxindole (1.76%).