Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]=[C:10]=[O:11].[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11]
Reactant: C1CCNC1
Reactant: O=C=Nc1ccc(Cl)cc1Cl
Solvent: c1ccccc1
Product: O=C(Nc1ccc(Cl)cc1Cl)N1CCCC1
Yield: 100.1 %

Procedure:
3.76 g of 2,4-dichlorophenyl isocyanate was dissolved in 100 ml of benzene and 1.44 g of pyrrolidine was added to this resulting solution and reacted for 8 hours at room temperature. After completing the reaction, benzene was evaporated under reduced pressure to obtain 5.19 g of N-(2,4-dichlorophenyl)pyrrolidine-1-carboxamide. 0.50 g of the obtained N-(2,4-dichlorophenyl)pyrrolidine-1-carboxamide was dissolved in the mixed solvent composed of 10 ml of acetonitrile and 0.4 ml of carbon tetrachloride and 0.69 g of triphenylphosphine was then added to this resulting solution and the entire mixture was stirred for 1 hour at room temperature. 0.55 g of cuprous cyanide was added to this reaction solution and the entire mixture was refluxed for 2.5 hours. After cooling the reaction solution, insolubles were removed by filtration and the concentrate obtained by evaporating the filtrate under reduced pressure was purified by silica gel column chromatography to obtain 0.39 g of N′-(2,4-dichlorophenyl)-N,N-(butane-1,4-di-yl)cyanoformamidine (1-1) (yield: 72%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][N:5]2[C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].[CH:16]1[C:21]([OH:22])=[CH:20][CH:19]=[C:18]([Br:23])[CH:17]=1.[H-].[Na+]>CN(C=O)C.CO>[Br:23][C:18]1[CH:19]=[CH:20][C:21]([O:22][C:2]2[N:3]=[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][N:5]3[C:10]=2[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:16][CH:17]=1.[Br:23][C:18]1[CH:19]=[CH:20][C:21]([O:22][C:2]2[N:3]=[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][N:5]3[CH:10]=2)=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1c(Cl)nc2ccccn12
Reactant: Oc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: Brc1ccc(Oc2cn3ccccc3n2)cc1
Product: CCOC(=O)c1c(Oc2ccc(Br)cc2)nc2ccccn12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Ethyl 2-chloroimidazo[1,2-a]pyridine-3-carboxylate (2.00 g) was added to a solution of p-bromophenol (1.617 g) and NaH (0.427 g) in DMF (dry) (10 mL) at 100° C. The mixture was stirred at 100° C. under a dry atmosphere overnight. The reaction mixture was diluted with MeOH, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0%-30% EtOAc in hexane) to give ethyl 2-(4-bromophenoxy)imidazo[1,2-a]pyridine-3-carboxylate (1.5 g) as a colorless solid and 2-(4-bromophenoxy)imidazo[1,2-a]pyridine (530 mg) as a colorless solid. The mixture of 2-(4-bromophenoxy)imidazo[1,2-a]pyridine (410 mg), 1,3-dihydro-2H-pyrrolo[2,3-b]pyridine-2-one (164 mg), trans-N,N′-dimethylcyclohexane-1,2-diamine (174 mg), copper(I) iodide (116 mg), K2CO3 (338 mg) and THF (dry) (5 mL) was heated at 180° C. for 3 h under microwave irradiation. The solid was removed by filtration, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, EtOAc/hexane) to give the title compound (72 mg) as an orange solid (mixture with 1,3-dihydro-2H-pyrrolo[2,3-b]pyridine-2-one, ca. 20% purity).
Reaction SMILES: O(CC([NH:11][CH:12]1[C:23](=[O:24])[N:14]2[C:15]([C:20]([OH:22])=[O:21])=[C:16]([CH3:19])[CH2:17][S:18][C@H:13]12)=O)C1C=CC=CC=1.C1(NC2CCCCC2)CCCCC1.C(NC(C)C)(C)C.Cl[Si](Cl)(C)C.P(Cl)(Cl)(Cl)(Cl)Cl>C(Cl)Cl>[CH3:19][C:16]1[CH2:17][S:18][C@@H:13]2[C@H:12]([NH2:11])[C:23](=[O:24])[N:14]2[C:15]=1[C:20]([OH:22])=[O:21]
Reactant: CC1=C(C(=O)O)N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SC1
Agent: C1CCC(NC2CCCCC2)CC1
Agent: C[Si](C)(Cl)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: CC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Temperature: -45 °C

Procedure:
7-(Phenoxyacetamido)-3-methyl-3-cephem-4-carboxylic acid (11.38 mmoles) is dissolved in 80 ml of methylene chloride. Dicyclohexylamine or diisopropylamine (13 mmoles) is added with stirring and 1.75 ml of dichlorodimethylsilane is added. After stirring for 30 minutes, the mixture is cooled to -45° C and an additional 27.77 mmoles of the same amine as used above is added followed by 3 g of finely powdered PCl5.
Reaction SMILES: CCO[CH2:4][CH3:5].CN(C)P(=O)(N(C)C)N(C)C.[C:17](=[O:20])([O-])[O-:18].[K+].[K+].O([C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33]Br)C1C=CC=CC=1>O.CCCCCC>[CH:32]([CH:31]([CH:30]=[C:37]([C:5]1[CH:4]=[CH:36][CH:37]=[CH:30][CH:31]=1)[CH3:36])[C:17]([OH:18])=[O:20])([CH3:33])[CH3:35]
Reactant: BrCc1cccc(Oc2ccccc2)c1
Reactant: O=C([O-])[O-]
Reactant: CCOCC
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCCCCC
Solvent: O
Product: CC(=CC(C(=O)O)C(C)C)c1ccccc1
Reaction time: 16 h

Procedure:
To 2.14 g (10 mmole) of the thus-obtained acid, 10 ml ether and 10 ml hexamethylphosphorictriamide (HMPT), under nitrogen, is added 1.45 g (10.5 mmole) potassium carbonate and 2.76 g (10.5 mmole) m-phenoxybenzyl bromide. The reaction is stirred about 16 hr and then poured into hexane and water. The organic phase is washed with water, saturated sodium chloride, and dried over calcium sulfate. Solvent is removed by rotoevaporation to yield the m-phenoxybenzyl ester of 2-isopropyl-4-phenyl-3-pentenoic acid, which can be further purified by preparatory thin layer chromatography (prep. TLC) eluting with 2.5% ethyl acetate/hexane, MS m/e 400 (M+, 15), 183 (100).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]2[C:11]([C:16]([OH:18])=O)=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:4][CH:3]=1.[CH2:20]([NH2:23])[CH2:21][NH2:22]>ClCCCl.CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]23[NH:23][CH2:20][CH2:21][N:22]2[C:16](=[O:18])[C:11]2[N:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9]3)=[CH:6][CH:7]=1
Reactant: O=C(Cc1cccnc1C(=O)O)c1ccc(F)cc1
Reactant: NCCN
Solvent: ClCCCl
Solvent: CO
Product: O=C1c2ncccc2CC2(c3ccc(F)cc3)NCCN12
Temperature: 25 °C
Yield: 66.9 %

Procedure:
To a suspension of 3-[2-(4-fluorophenyl)-2-oxoethyl]pyridine-2-carboxylic acid (1.5 g, 5.8 mmol) in 1,2-dichloroethane (100 mL) was added ethylenediamine (8 mL, 120 mmol) and the resulting solution heated at reflux for 1 hour. The resulting suspension was then allowed to cool to room temperature before being concentrated in vacuo to yield a thick, orange gum. The gum was suspended in methanol with the aid of sonication and filtered. The filtrate was adsorbed onto silica and purified by flash chromatography (5 to 7.5% methanol-dichloromethane) to yield 10a-(4-fluorophenyl)-2,3,10,10a-tetrahydroimidazo[2,1-g][1,7]naphthyridin-5(1H)-one as a pale yellow solid (1.1 g, 67% yield). ESI-MI m/z [M+H]+ 284.04. 1H NMR (400 MHz, CDCl3) δ 8.66 (brd, J=4.7 Hz, 1H), 7.36 (brd, J=7.7 Hz, 1H), 7.30 (dd, J=8.9, 5.2 Hz, 2H), 7.23 (dd, J=7.7, 4.7 Hz, 1H), 6.89 (t, J=8.7 Hz, 2H), 4.02-3.89 (m, 1H), 3.70-3.60 (m, 1H), 3.47 (d, J=15.2 Hz, 1H), 3.42 (d, J=15.2 Hz, 1H), 3.35 (ddd, J=12.4, 7.9, 2.8 Hz, 1H), 2.86-2.74 (m, 1H), 2.49 (brs, 1H).
Reaction SMILES: N[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([C:11]=1[C:12]([OH:14])=[O:13])=[CH:9][C:8]([F:15])=[CH:7][CH:6]=2.[CH2:28]=O.[C:30]([BH3-])#[N:31].[Na+].[BH4-].[Na+]>C(#N)C.C(O)(=O)C.O>[C:19]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:21][C:16]([C:3]2[C:2]([N:31]([CH3:30])[CH3:28])=[C:11]([C:12]([OH:14])=[O:13])[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([F:15])[CH:9]=3)[N:4]=2)=[CH:17][CH:18]=1
Reactant: C=O
Reactant: Nc1c(-c2ccc(-c3ccccc3)cc2)nc2ccc(F)cc2c1C(=O)O
Reactant: [BH3-]C#N
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Solvent: O
Product: CN(C)c1c(-c2ccc(-c3ccccc3)cc2)nc2ccc(F)cc2c1C(=O)O
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A 4 g portion of 3-amino-2-[1,1'biphenyl]-4-yl-6-fluoro-4-quinolinecarboxylic acid was dissolved in 250 ml of acetonitrile. To this was added 2.7 ml of 40% aqueous formaldehyde and the mixture was heated at 80° C. until solution was complete. A 2.1 g portion of sodium cyanoborohydride was added and the solution stirred at 20° C. for 8 hours. Glacial acetic acid was added to pH 6, then 0.69 g of sodium borohydride was added and stirring continued at 20° C. for 72 hours. The reaction mixture was poured into 1 liter of water and adjusted to pH 4 with glacial acetic acid. The solid was collected, washed with water, dried and then twice suspended in 200 ml of hot ethanol and filtered. The solid was collected, giving 2.5 g of the desired product as a yellow powder, mp 235°-239° C. (gas solution).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]3=[N:13][CH:14]=[N:15][C:16]([NH2:17])=[C:11]3[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[S:23](Cl)(=[O:25])=[O:24].C(N(C(C)C)CC)(C)C.CN(C=O)C>CO>[NH2:17][C:16]1[N:15]=[CH:14][N:13]=[C:12]2[N:8]([C:4]3[CH:3]=[C:2]([NH:1][S:23]([C:19]4[S:18][CH:22]=[CH:21][CH:20]=4)(=[O:25])=[O:24])[CH:7]=[CH:6][CH:5]=3)[N:9]=[CH:10][C:11]=12
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: Nc1cccc(-n2ncc3c(N)ncnc32)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CN(C)C=O
Product: Nc1ncnc2c1cnn2-c1cccc(NS(=O)(=O)c2cccs2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 18.8 %

Procedure:
Title compound 11B, 1-(3-amino-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (36 mg, 1.1 eq, 0.16 mmol), 2-thiophenesulphonylchloride (29 mg, 1.0 eq, 0.16 mmol) and diisopropylethylamine (28 μl, 1.0 eq, 0.16 mmol) were added to DMF (1 ml) and the mixture was stirred for 15 hours at room temperature under an inert atmosphere. Methanol was then added (1 ml) and the solvents were removed in vacuo. The resultant residue was purified by semi-preparative HPLC to yield the title compound as a white solid (10 mg, 0.03 mmol, 16%). LCMS: [M+H]+=373, Rt=1.63 min, 100% purity.
Reaction SMILES: [C:1]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:13])[CH2:2][C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].[Br:22]Br>C(Cl)(Cl)(Cl)Cl>[CH2:6]([O:5][C:3](=[O:4])[CH:2]([Br:22])[C:1]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: BrBr
Reactant: O=C(CC(=O)OCc1ccccc1)OCc1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(OCc1ccccc1)C(Br)C(=O)OCc1ccccc1

Procedure:
To a solution of dibenzyl malonate (9.8 g, 34.46 mmole) in carbon tetrachloride (25 mL), bromine (10.14 g, 63.4 mmole) was added dropwise at room temperature over 4 h. The reaction mixture was irradiated with a 150 W lamp during the addition. The reaction mixture was quenched with water. The organic layer was separated and the aqueous layer was further extracted with dichloromethane (3 ×30 mL). The organic extracts were combined, washed with sodium hydrogen carbonate solution (3×50 mL) and brine solution 3×50 mL). The organic layer was dried over magnesium sulphate and concentrated. The residue was purified by column chromatography (9:1 Hex:EtOAc) to afford intermediate 2 as an orange oil. Yield 3.8 g, 30%
Reaction SMILES: [O:1]=[C:2]([N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[C:16]([OH:18])=[O:17])[C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH2:5][CH3:6].[C:19]1([CH2:25][CH2:26][CH2:27]O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1(N=C=NC2CCCCC2)CCCCC1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C(Cl)Cl>[O:1]=[C:2]([N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[C:16]([O:18][CH2:27][CH2:26][CH2:25][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:17])[C:3](=[O:9])[C:4]([CH3:7])([CH3:8])[CH2:5][CH3:6]
Reactant: OCCCc1ccccc1
Reactant: CCC(C)(C)C(=O)C(=O)N1CCCCC1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: ClCCl
Product: CCC(C)(C)C(=O)C(=O)N1CCCCC1C(=O)OCCCc1ccccc1
Reaction time: 8 h
Yield: 92.7 %

Procedure:
A mixture of 1-(1,2-dioxo-3,3-dimethylpentyl)-2-piperidinecarboxylic acid (590 mg; 2.31 mmol), 3-phenylpropanol (520 mg; 3.71 mmol), dicyclohexylcarbodiimide (815 mg; 3.95 mmol), camphorsulphonic acid (180 mg; 0.77 mmol) and 4-dimethyl aminopyridine (95 mg; 0.77 mmol) in methylene chloride (15 mL) was stirred overnight under a nitrogen atmosphere. The reaction mixture was filtered through Celite to remove solids and concentrated in vacuo. The crude material was triturated with several portions of ether, and the ether portions were filtered through Celite to remove solids and concentrated in vacuo. The concentrated filtrate was purified on a flash column (20% ethyl acetate in hexane) to obtain 800 mg (93%) of the product as an oil, 1H NMR (CDCl3, 300 MHz): δ 0.85 (t, 3H); 1.23,1.26 (s, 3H each); 1.63–1.94 (m, 9H); 2.32 (m, 1H); 2.69 (m, 2H); 3.21 (m, 1H); 3.35 (m, 1H); 4.17 (m, 2H); 5.24 (m, 1H); 7.14 (m, 3H); 7.7.23 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:28]([N:29]([C:31](=[O:49])[CH2:32][NH:33][C:34](=[O:48])/[CH:35]=[CH:36]/[C:37]2[CH:38]=[N:39][C:40]([C:43]([O:45]CC)=[O:44])=[CH:41][CH:42]=2)[CH3:30])=[CH:27][CH:26]=[C:25]([Cl:50])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[C:11]2[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1.[OH-].[Na+]>C(O)C>[C:43]([C:40]1[N:39]=[CH:38][C:37](/[CH:36]=[CH:35]/[C:34]([NH:33][CH2:32][C:31]([N:29]([C:28]2[C:2]([Cl:1])=[C:3]([C:25]([Cl:50])=[CH:26][CH:27]=2)[CH2:4][O:5][C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:15]=2[N:14]=[C:13]([CH3:16])[CH:12]=[C:11]3[O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH3:30])=[O:49])=[O:48])=[CH:42][CH:41]=1)([OH:45])=[O:44]
Reactant: CCOC(=O)c1ccc(/C=C/C(=O)NCC(=O)N(C)c2ccc(Cl)c(COc3cccc4c(OCc5ccccn5)cc(C)nc34)c2Cl)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(OCc2ccccn2)c2cccc(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)/C=C/c4ccc(C(=O)O)nc4)c3Cl)c2n1
Temperature: 50 °C
Reaction time: 6 h
Yield: 97.1 %

Procedure:
To a solution of 8-[2,6-dichloro-3-[N-[(E)-3-(6-ethoxycarbonylpyridin-3-yl)acryloylglycyl]-N-methylamino]benzyloxy]-2-methyl-4-(2-pyridylmethoxy)quinoline (30 mg) in ethanol (0.5 ml) was added 1N aqueous sodium hydroxide solution (0.1 ml) at ambient temperature, and the mixture was stirred at 50° C. for 6 hours. The reaction mixture was evaporated in vacuo, and the residue was dissolved in water. The aqueous layer was washed with diethyl ether and adjusted to pH 5 with 1N hydrochloric acid. The precipitate was collected by filtration to give 8-[3-[N-[(E)-3-(6-carboxypyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-2-methyl-4-(2-pyridylmethoxy)quinoline (28 mg) as powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([S:12]([Cl:15])(=[O:14])=[O:13])[CH:9]=[CH:8][C:4]=1[C:5](O)=O.[NH2:16][C:17]1[C:22]([NH2:23])=[CH:21][N:20]=[CH:19][N:18]=1>>[ClH:15].[CH3:1][O:2][C:3]1[CH:11]=[C:10]([S:12]([Cl:15])(=[O:14])=[O:13])[CH:9]=[CH:8][C:4]=1[C:5]1[N:16]=[C:17]2[C:22]([NH:23][CH:19]=[N:18]2)=[CH:21][N:20]=1
Reactant: Nc1cncnc1N
Reactant: COc1cc(S(=O)(=O)Cl)ccc1C(=O)O
Product: COc1cc(S(=O)(=O)Cl)ccc1-c1ncc2[nH]cnc2n1
Product: Cl

Procedure:
Prepared analogously to Example C from 2.5 gm of 2-methoxy-4-chlorosulfonyl benzoic acid and 2.4 gm of 4,5-diamino-pyrimidine (crystalline product obtained from dihydorchloride and 1 mol of common salt) by refluxing for eight hours. The solid crude product was processed further without any purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][N:8]([CH:12]3[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(O)(=O)C.COC(OC)OC.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][N:8]([C@H:12]3[CH2:17][CH2:16][C@H:15]([N:23]4[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]4)[CH2:14][CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=C1CCC(n2cc(I)c3c(Cl)ncnc32)CC1
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: COC(OC)OC
Solvent: CC(Cl)Cl
Product: CN1CCN([C@H]2CC[C@H](n3cc(I)c4c(Cl)ncnc43)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 4-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-cyclohexanone (5.6 g, 14.9 mmol), N-methylpiperazine (3.3 mL, 29.8 mmol), acetic acid (2.6 mL, 44.7 mmol), and trimethylorthoformate (9.9 mL, 89.4 mmol) in dichloroethane (100 mL) was stirred at ambient temperature under an atmosphere of nitrogen for 1 hr. Sodium triacetoxyborohydride (14.2 g, 67.05 mmol) was added into the mixture and stirred at ambient temperature under an atmosphere of nitrogen for 18 hours. The solvent was removed under reduced pressure. The residue was partitioned between saturated aqueous sodium bicarbonate solution and ethyl acetate. The water phase was further extracted with ethyl acetate and the combined organic extracts were dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel using triethylamine/dichloromethane (2:98) followed by methanol/triethylamine/dichloromethane (2:3:95) as mobile phase to yield trans-4-chloro-5-iodo-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidine (1.7 g, 3.7 mmol). 1H NMR (DMSO-d6, 400 MHz) 8.63 (s, 1H), 8.12 (s, 1H), 4.63 (br, 1H), 2.15 (s, 3H), 1.94 (br, 6H), 1.45 (br, 2H) RP-20 HPLC (Hypersil C18, 5 μm, 250×4.6 mm; 25%-100% over 15 min with 0.05 M ammonium acetate, 1 mL/min) Rt 6.17 min.
Reaction SMILES: [Se-2:1].[Na+].[Na+].Cl[C:5]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[CH:7][N:6]=1.Cl[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C[O-].[Na+]>CN(C=O)C.CO.O>[NH2:12][C:11]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[Se:1][C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: [Se-2]
Reactant: N#Cc1cccnc1Cl
Reactant: CCOC(=O)CCl
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: CCOC(=O)c1[se]c2ncccc2c1N
Temperature: 65 °C
Reaction time: 2 h
Yield: 77.4 %

Procedure:
To a suspension of sodium selenide (0.9 g, 7.2 mmol, prepared from 0.75 g of selenium as described above) in DMF (7 mL) was added a solution of 2-chloropyridine-3-carbonitrile (1 g, 7.2 mmol) in DMF (3 mL) at rt for 5 min and stirred the mixture at 60-70° C. for 2 h. Then ethyl chloroacetate (0.78 mL, 7.22 mmol) was added dropwise to the reaction mixture and again stirred at 60-70° C. for 2 h. Then, a solution of sodium methoxide (0.39 g, 7.2 mmol) in methanol (7 mL) was added dropwise and stirring was continued for 1 h at the same temperature. The mixture was allowed to room temperature (rt) and poured into cold water and stirred for 15 min. The precipitated solid was filtered, washed with water and dried to give the product as a yellow color solid (1.5 g, 77%), mp 194-196° C. 1H NMR (400 MHz, CDCl3): δ 8.65 (1H, dd, J=4.6, 1.4 Hz, H-6), 7.86 (1H, dd, J=8.2, 1.4 Hz, H-4), 7.33 (1H, dd, J=8.2, 4.6 Hz, H-5), 6.04 (2H, br s, —NH2), 4.34 (2H, q, J=7.1 Hz, —COOCH2CH3), 1.38 (3H, t, J=7.1 Hz, —COOCH2CH3); LC-MS (positive ion mode): m/z 269, 271 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1([CH2:6][CH3:7])[CH2:5][O:4]1)[CH3:2].[NH2:8][C:9]1[CH:10]=[C:11]([CH:15]([OH:19])[CH2:16][C:17]#[N:18])[CH:12]=[CH:13][CH:14]=1>>[CH2:1]([C:3]([OH:4])([CH2:6][CH3:7])[CH2:5][NH:8][C:9]1[CH:10]=[C:11]([CH:15]([OH:19])[CH2:16][C:17]#[N:18])[CH:12]=[CH:13][CH:14]=1)[CH3:2]
Reactant: N#CCC(O)c1cccc(N)c1
Reactant: CCC1(CC)CO1
Product: CCC(O)(CC)CNc1cccc(C(O)CC#N)c1

Procedure:
Reaction between 2,2-diethyloxirane and aniline 12 gives 3-(3-(2-ethyl-2-hydroxybutylamino)phenyl)-3-hydroxypropanenitrile.
Reaction SMILES: [N+:1]([C:4]1[C:9]([C:10]#[N:11])=[C:8]([I:12])[C:7]([O:13][CH3:14])=[C:6]([O:15][CH3:16])[CH:5]=1)([O-])=O.S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(O)C.O>[NH2:1][C:4]1[C:9]([C:10]#[N:11])=[C:8]([I:12])[C:7]([O:13][CH3:14])=[C:6]([O:15][CH3:16])[CH:5]=1
Reactant: COc1cc([N+](=O)[O-])c(C#N)c(I)c1OC
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1cc(N)c(C#N)c(I)c1OC
Temperature: 85 °C
Reaction time: 5 h
Yield: 91.7 %

Procedure:
In a reactor vessel, a suspension of 6-nitro-2-iodo-3,4-dimethoxybenzonitrile (see Example 1(d) of WO 98/30560, 10 kg) in ethanol (60 l) at room temperature was charged with a solution of sodium dithionite (15.6 kg of technical grade material) in water (67.5 l) over 45 mins maintaining the temperature below 35° C. The addition vessel was washed with water (10 l). The resulting mixture was warmed to reflux (ca. 85° C.) for ca. 90 mins and then the temperature adjusted to 65° C. A solution of 6M aqueous hydrochloric acid (12.5 l) was added over ca. 10 mins and the resulting mixture stirred at 65° C. for ca. 5 hours before being cooled to room temperature. The pH was adjusted to the range 7–8 using 40% sodium hydroxide (2 l), the resulting mixture left to stir for 3 hours, filtered and washed with water (50 l). The damp cake was slurried in water (90 l) overnight at room temperature, filtered, washed with water (100 l) and dried in vacuo to give 8.35 kg (92%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7]([OH:9])=O)[NH:5][CH:6]=1.[NH2:10][C:11]1[CH:22]=[CH:21][C:14]([O:15][CH2:16][C:17]([CH3:20])([OH:19])[CH3:18])=[C:13]([O:23][CH3:24])[CH:12]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>ClC(Cl)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([C:7]([NH:10][C:11]2[CH:22]=[CH:21][C:14]([O:15][CH2:16][C:17]([OH:19])([CH3:20])[CH3:18])=[C:13]([O:23][CH3:24])[CH:12]=2)=[O:9])[NH:5][CH:6]=1
Reactant: O=C(O)c1cc(Br)c[nH]1
Reactant: COc1cc(N)ccc1OCC(C)(C)O
Agent: On1nnc2ccccc21
Solvent: CC(Cl)Cl
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: COc1cc(NC(=O)c2cc(Br)c[nH]2)ccc1OCC(C)(C)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.6 %

Procedure:
To a solution of 4-bromo-1H-pyrrole-2-carboxylic acid (1.00 g, 5.30 mmol), preparation described in step A of Example 2, and 1-(4-amino-2-methoxyphenoxy)-2-methylpropan-2-ol (1.12 g, 5.30 mmol), preparation described in step A of Example 4. in dichloroethane (46.0 mL) was added EDC (2.03 g, 10.6 mmol) and HOBT (1.62 g, 10.6 mmol) and the reaction was allowed to stir at rt for 16 h. The reaction mixture was diluted with EtOAc (100 mL), washed with sat. NaHCO3 (3×100 mL), water, brine, dried over anhydrous Na2SO4 and concentrated to give 1.84 g of the title compound as a brown oil which was used in the next step without purification: HPLC a) column: Phenomenex Luna 5μ 4.6×50 mm, 4 min gradient, 10% MeOH/90% H2O/0.1% H3PO4 to 90% MeOH/10% H2O/0.1% H3PO4; 1 min hold, 4 mL/min UV detection at 220 nm, 3.058 min retention time, (91%); HPLC b) column: Phenomenex Luna C18 4.6×50 mm, 4 min gradient, 10% MeOH/90% H2O/0.1% TFA to 90% MeOH/10% H2O/0.1% TFA, 1 min hold; 4 mL/min, UV detection at 220 nm, 3.051 min retention time; MS (ES) 385 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7]O)=[CH:3][CH:2]=1.P(Br)(Br)(Br)(Br)[Br:10]>C(Cl)(Cl)Cl>[BrH:10].[Br:10][CH2:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1
Reactant: OCc1ccncc1
Reactant: BrP(Br)(Br)(Br)Br
Solvent: ClC(Cl)Cl
Product: Br
Product: BrCc1ccncc1
Yield: 233.8 %

Procedure:
To a solution of 4-pyridylcarbinol (3 g, 27.5 mmol) in 30 mL of CHCl3 was added phosphorus pentabromide (5.93 g, 13.7 mmol). The solution was refluxed for 1 hour. The solvent was removed in vacuo and recrystallized in ethanol to afford the title compound as a white solid (4.05 g, 58.1%). ES (+) MS m/e=173 (M+H).