Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([NH:13][C:14]1[S:15][C:16]([NH:24][C:25]([C:27]3[CH:31]=[CH:30][S:29][CH:28]=3)=[O:26])=[C:17]([C:19]([O:21]CC)=O)[N:18]=1)=[CH:8]2.[NH3:32].CO>C1COCC1>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([NH:13][C:14]1[S:15][C:16]([NH:24][C:25]([C:27]3[CH:31]=[CH:30][S:29][CH:28]=3)=[O:26])=[C:17]([C:19]([NH2:32])=[O:21])[N:18]=1)=[CH:8]2
Reactant: N
Reactant: CCOC(=O)c1nc(Nc2ccc3c(OC)cccc3c2)sc1NC(=O)c1ccsc1
Solvent: CO
Solvent: C1CCOC1
Product: COc1cccc2cc(Nc3nc(C(N)=O)c(NC(=O)c4ccsc4)s3)ccc12
Temperature: 80 °C
Yield: 92 %

Procedure:
To a solution of ethyl 2-[(5-methoxynaphthalen-2-yl)amino]-5-(thiophene-3-carboxamido)-thiazole-4-carboxylate (0.105 g, 0.23 mmol) in THF (5 mL) was added 7N NH3—MeOH (5 mL), and the mixture was heated at 80° C. for 16 hrs in a sealed tube. The solvent was evaporated in vacuo, and the resulting solids were collected by filtration and washed with MeOH to give 90 mg (92% yield) of the titled compound.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:15]=[C:14]([CH3:16])[NH:13][C:12](=[O:17])[C:11]=1[C:18]#[N:19])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H][H]>CO.N.[Ni]>[NH2:19][CH2:18][C:11]1[C:12](=[O:17])[NH:13][C:14]([CH3:16])=[CH:15][C:10]=1[CH2:9][O:8][Si:1]([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: Cc1cc(CO[Si](C)(C)C(C)(C)C)c(C#N)c(=O)[nH]1
Agent: [Ni]
Agent: N
Solvent: CO
Product: Cc1cc(CO[Si](C)(C)C(C)(C)C)c(CN)c(=O)[nH]1
Yield: 62.9 %

Procedure:
To a stirred solution of 4-(((tert-butyldimethylsilyl)oxy)methyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (5.5 g, 19.7 mmol) in methanol (100 mL) and ammonia (30 mL) was added Raney nickel (quantitative) and the reaction mixture was stirred in presence of hydrogen under balloon pressure for 14 h. On completion, reaction mixture was filtered through celite and washed with methanol. Removal of the solvent under reduced pressure afforded the desired compound (3.5 g, 63%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([N+:22]([O-:24])=[O:23])[NH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.C1C[O:35][CH2:34][CH2:33]1.C(Cl)(=O)C>C(OCC)(=O)C>[C:34]([N:10]1[C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[C:13]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:12]=[C:11]1[N+:22]([O-:24])=[O:23])(=[O:35])[CH3:33]
Reactant: COc1ccc(-c2nc([N+](=O)[O-])[nH]c2-c2ccc(OC)cc2)cc1
Reactant: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CC(=O)Cl
Solvent: CCOC(C)=O
Product: COc1ccc(-c2nc([N+](=O)[O-])n(C(C)=O)c2-c2ccc(OC)cc2)cc1
Reaction time: 2 h

Procedure:
To a solution of 4,5-bis(4-methoxyphenyl)-2-nitroimidazole (3.0 g, 9.22 mmole) and triethylamine (7 ml., 51 mmole) in 30 ml. THF at 0° C. under N2 was dropwise added a solution of acetyl chloride (1.3 ml., 18.4 mmole) in 5 ml. THF. After 2 hours at 0° C., the reaction mixture was diluted with ethyl acetate washed with 1 N HCl, saturated aqueous NaHCO3 and brine, dried and concentrated on a rotary evaporator. Crystallization from ether gave approximately 600 mg. of starting material. HPLC of the mother liquor and crystallization from ether gave 1-acetyl 4,5-bis(4-methoxyphenyl)-2-nitroimidazole, mp. 146°-151° C. H-NMR indicates purity >95%. H-NMR: 2.41δ(s, 3H), 3.8δ(s, 3H), 6.73-7.56 δ(2 AB quartets, J=9 Hz, 8H).
Reaction SMILES: [Pd:1](Cl)Cl.[P:4]([O-:12])([O:9][CH2:10][CH3:11])([O:6][CH2:7][CH3:8])=[O:5]>C(OCC)(=O)C>[Pd:1].[P:4]([O-:12])([O:9][CH2:10][CH3:11])([O:6][CH2:7][CH3:8])=[O:5]
Reactant: Cl[Pd]Cl
Agent: CCOP(=O)([O-])OCC
Solvent: CCOC(C)=O
Product: [Pd]
Reaction time: 3 h

Procedure:
Palladium black is prepared from 13 g of palladium chloride in the manner described in Example 1. A solution of 30.0 g of diethyl phosphate and 2R,3S 3',4',5,7-tetrabenzyloxy-flavan-3-yl phosphate in 1.3 l of ethyl acetate are added. The hydrogenation is carried out for 3 hours and 3.9 l of hydrogen are consumed. The palladium is filtered off and washed twice with 200 ml of ethyl acetate. The combined solutions are evaporated to dryness. 750 ml of water are added to the residue and evaporated under reduced pressure to a volume of approximately 100 ml. This operation is repeated twice then the product is lyophilised. Diethyl phosphate and 2R,3S 3',4',5,7-tetrahydroxy-flavan-3-yl phosphate are obtained. Mp.: 121°-123°.
Reaction SMILES: O=P(Cl)(Cl)Cl.[Cl:6][C:7]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:8]=1[O:9][CH2:10][CH:11]1[CH2:16][CH2:15][CH:14]=[CH:13][O:12]1.[Cl:22][CH2:23][CH:24]([OH:35])[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=1[Cl:34]>C(OCC)C.C(N(CC)CC)C>[Cl:6][C:7]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:8]=1[O:9][CH2:10][C@@H:11]1[O:12][C@@H:13]([O:35][CH:24]([CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[Cl:34])[CH2:23][Cl:22])[CH2:14][CH2:15][CH2:16]1
Reactant: OC(CCl)CCc1ccc(Cl)cc1Cl
Reactant: Clc1ccc(OCC2CCC=CO2)c(Cl)c1
Solvent: CCOCC
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: ClCC(CCc1ccc(Cl)cc1Cl)O[C@H]1CCC[C@H](COc2ccc(Cl)cc2Cl)O1

Procedure:
2 Drops of phosphorus oxytrichloride were added to a solution of 388 mg of 2-(2,4-dichlorophenoxymethyl)-3,4-dihydro-2H-pyran and 418 mg of 1-chloro-4-(2,4-dichlorophenyl)-2-butanol in 8 ml of diethyl ether, and the mixture was allowed to react at room temperature for 2 days. At the the end of this time, 3 drops of triethylamine were added and the solvent was evaporated off. The residue was purified by column chromatography through silica gel eluted with a 50:5:1 by volume mixture of hexane, benzene and ethyl acetate, to give 185 mg of the isomer of lesser polarity of trans-6-(2,4-dichlorphenoxymethyl)-2-[1-chloro-4-(2,4-dichlorophenyl)-2-butoxy]tetrahydropyran and 153 mg of the isomer of greater polarity.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].[CH3:12][S:13](Cl)(=[O:15])=[O:14]>C(Cl)Cl>[CH3:12][S:13]([O:1][C:2]1[CH:3]=[C:4]([CH:5]=[O:6])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])(=[O:15])=[O:14]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(C=O)cc1O
Solvent: ClCCl
Product: COc1ccc(C=O)cc1OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 87.4 %

Procedure:
3-hydroxy-4-methoxybenzaldehyde (2.5 g, 16.4 mmol) was dissolved in DCM (50 ml), then methanesulfonyl chloride (2 g, 17.5 mmol) and TEA (4 ml, 28.6 mmol) were added, and the reaction was stirred at RT for 12 hours. DCM was evaporated, and the mixture was dissolved in ethyl acetate and extracted with HCl 1M, dried over Na2SO4 and evaporated under vacuum to yield 3.3 g of the desired product. (Yield: 87%).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:9]([C:11]1[CH:33]=[CH:32][C:14]2[N:15]([CH3:31])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][C:21]=3[O:29][CH3:30])=[N:17][C:13]=2[CH:12]=1)=[O:10].Cl[C:42]([O:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])=[O:43]>ClCCl.C(O)C>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:9]([C:11]1[CH:33]=[CH:32][C:14]2[N:15]([CH3:31])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:42]([O:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])=[O:43])=[CH:22][C:21]=3[O:29][CH3:30])=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1OC)n2C)c1ccccn1
Reactant: CCCCCOC(=O)Cl
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: CCCCCOC(=O)NC(=N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OCC)c4ccccn4)ccc3n2C)c(OC)c1
Yield: 72 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidino-2-methoxy-phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and n-pentyl chloroformate. Yield: 72% of theory, C34H41N7O6 (643.7) Rf value: 0.49 (silica gel; dichloromethane/ethanol=9:1) ##EQU143##
Reaction SMILES: Cl.C([N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([CH2:22][C:23]3[C:31]4[C:26](=[CH:27][CH:28]=[C:29]([F:32])[CH:30]=4)[NH:25][CH:24]=3)[CH2:18][CH2:17]2)[C:6]1=[O:33])(C)=C.ClCCl>C(O)C>[F:32][C:29]1[CH:30]=[C:31]2[C:26](=[CH:27][CH:28]=1)[NH:25][CH:24]=[C:23]2[CH2:22][CH:19]1[CH2:18][CH2:17][N:16]([CH2:15][CH2:14][N:7]2[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[NH:5][C:6]2=[O:33])[CH2:21][CH2:20]1
Reactant: C=C(C)n1c(=O)n(CCN2CCC(Cc3c[nH]c4ccc(F)cc34)CC2)c2ccccc21
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: O=c1[nH]c2ccccc2n1CCN1CCC(Cc2c[nH]c3ccc(F)cc23)CC1
Temperature: 20 °C
Reaction time: 1 h
Yield: 11 %

Procedure:
6N hydrochloric acid (9.3 cc) is introduced at a temperature in the region of 20° C. into a solution of 3-isopropenyl-1-{2-[4-((5-fluoro-3-indolyl)methyl)piperidino]ethyl}-2H-benzimidazol-2-one (4 g) in ethanol (50 cc). The solution is heated to boiling for 1 hour and then cooled to a temperature in the vicinity of 20° C. The reaction medium is taken up with dichloromethane (100 cc) and distilled water (30 cc) and alkalinized to pH 9 with 5N sodium hydroxide. The organic phase is extracted with dichloromethane (3×30 cc), washed with distilled water (90 cc), dried over anhydrous magnesium sulphate, treated with vegetable charcoal, filtered and concentrated to dryness at 40° C. under reduced pressure (20 mm Hg; 2.7 kPa). The residue is recrystallized in methyl ethyl ketone (15 cc). 1-{2-[4-((5-Fluoro-3-indolyl)methyl)piperidino]ethyl}-2H-benzimidazolin-2-one (0.4 g), m.p. 220° C., is obtained.
Reaction SMILES: [Na].[O-]CC.[Na+].Cl.[N:7]1[CH:12]=[CH:11][C:10]([CH2:13]Cl)=[CH:9][CH:8]=1.[SH:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].[Cl-]>C(O)C>[N:7]1[CH:12]=[CH:11][C:10]([CH2:13][S:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:9][CH:8]=1
Reactant: CCOC(=O)CS
Reactant: ClCc1ccncc1
Agent: CC[O-]
Agent: Cl
Agent: [Cl-]
Solvent: CCO
Product: CCOC(=O)CSCc1ccncc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.6 %

Procedure:
Under nitrogen, absolute ethanol (120 ml.) was warmed to 40° C. Sodium metal (5.18 g., 0.225 mole) was added portionwise at such a rate as to maintain gentle reflux. After one hour, the resulting clear solution of sodium ethoxide was cooled in an ice-water bath. 4-Picolyl chloride hydrochloride (16.4 g., 0.10 mole) was slurried in 60 ml. of ethanol and ethyl mercaptoacetate (13.2 g., 0.11 mole) in 30 ml. of ethanol were placed in separate additional funnels. After 10% of the organic chloride was added, the remaining chloride and the mercaptan were added simultaneously and dropwise. The reaction mixture was warmed to room temperature, stirred for 16 hours and filtered over diatomaceous earth with ethanol wash. The combined filtrate and wash was evaporated to an oil (26 g.). The oil was chromatographed on 500 g. of silica gel, eluting with chloroform and monitoring by tlc. Clean fractions were combined and evaporated to yield title product as an oil [16.4 g.; Rf (9:1 chloroform:methanol) 0.75; ir (film) 3390, 2976, 1730, 1600, 1410, 1280, 1160, 1120, 1030, 813, 750 cm-1 ].
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:16])=[C:4]([CH:12]=[CH:13][C:14]=1F)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[N:17]1[CH:18]=[N:19][N:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][C:21]=12.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[N:17]1[CH:18]=[N:19][N:20]2[CH:25]=[CH:24][C:23]([O:26][C:14]3[CH:13]=[CH:12][C:4]([C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])=[C:3]([F:16])[C:2]=3[Cl:1])=[CH:22][C:21]=12
Reactant: CC(C)(C)OC(=O)c1ccc(F)c(Cl)c1F
Reactant: Oc1ccn2ncnc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccc(Oc2ccn3ncnc3c2)c(Cl)c1F
Temperature: 80 °C

Procedure:
A vial charged with tert-butyl 3-chloro-2,4-difluorobenzoate (0.210 g, 0.845 mmol), [1,2,4]triazolo[1,5-a]pyridin-7-ol (0.114 g, 0.845 mmol), cesium carbonate (0.413 g, 1.27 mmol), and DMF (1.7 ml). The reaction was heated to 80° C. for 12 hours, then poured into ice water. The resulting solids were collected by filtration and purified by flash chromatography, eluting with gradient of 10% EtOAc/Hexanes to 50% EtOAc/Hexanes to provide the desired product.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C@H:4]([OH:13])[C@@H:5]([OH:12])[C@@H:6]([OH:11])[C@H:7]([OH:10])[CH2:8][OH:9].[C:14]([C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([CH2:25][CH2:26][NH:27][C:28](=[O:42])[C:29]3[CH:34]=[CH:33][C:32]([C:35]4[CH:40]=[CH:39][N:38]=[C:37](Cl)[N:36]=4)=[CH:31][CH:30]=3)[CH:23]=2)[NH:18][CH:17]=1)#[N:15]>>[C:14]([C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([CH2:25][CH2:26][NH:27][C:28](=[O:42])[C:29]3[CH:34]=[CH:33][C:32]([C:35]4[CH:40]=[CH:39][N:38]=[C:37]([N:2]([CH3:1])[CH2:3][C@H:4]([OH:13])[C@@H:5]([OH:12])[C@@H:6]([OH:11])[C@H:7]([OH:10])[CH2:8][OH:9])[N:36]=4)=[CH:31][CH:30]=3)[CH:23]=2)[NH:18][CH:17]=1)#[N:15]
Reactant: CNC[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Reactant: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(Cl)n4)cc3)cc12
Product: CN(C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO)c1nccc(-c2ccc(C(=O)NCCc3ccc4[nH]cc(C#N)c4c3)cc2)n1

Procedure:
Using N-methyl-(2 (S),3 (R),4 (S),5 (R),6-pentahydroxy-hexyl)-amine and N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide (reference example 1az) as substrates.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]1[C:11]2[O:12][CH2:13][O:14][CH2:15][C:10]=2[CH:9]=[C:8]([NH:16][C:17](=[O:22])[O:18][CH:19]([CH3:21])[CH3:20])[CH:7]=1)[CH3:4].[C:23]1([S:29]Cl)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C)C=O>[C:23]1([S:29][N:16]([C:8]2[CH:7]=[C:6]([O:5][CH2:3][CH3:4])[C:11]3[O:12][CH2:13][O:14][CH2:15][C:10]=3[CH:9]=2)[C:17](=[O:22])[O:18][CH:19]([CH3:21])[CH3:20])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: ClSc1ccccc1
Reactant: CCOc1cc(NC(=O)OC(C)C)cc2c1OCOC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1cc(N(Sc2ccccc2)C(=O)OC(C)C)cc2c1OCOC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.6 %

Procedure:
Sodium hydride (0.107 g; 60% dispersion in mineral oil) was dispersed in N,N-dimethylformamide (20 ml). To this solution was added isopropyl N-(8-ethoxy-1,3-benzodioxan-6-yl)carbamate (0.75 g) under ice-cooling. After being stirred at room temperature for 1 hour, phenylsulfenyl chloride (0.39 g) was added thereto under ice-cooling, and stirring was continued at room temperature overnight. The resulting mixture was poured into ice-water and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a mixture of toluene and ethyl acetate as the eluent to give isopropyl N-phenylthio-N-(8-ethoxy-1,3-benzodioxan-6-yl)carbamate (Compound 25) (0.91 g) in a yield of 87.5%. M.P., 120°-123° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[N:5][N:4]=[C:3]1[C@H:7]([C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[CH:29]=[CH:28][C:27]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=3[CH:21]=2)=[CH:15][CH:14]=1)[CH2:8][C:9]([O:11]C)=[O:10].[OH-].[Na+].Cl>C1COCC1.CO>[CH3:1][N:2]1[CH:6]=[N:5][N:4]=[C:3]1[C@H:7]([C:13]1[CH:14]=[CH:15][C:16]([O:19][C:20]2[CH:29]=[CH:28][C:27]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=3[CH:21]=2)=[CH:17][CH:18]=1)[CH2:8][C:9]([OH:11])=[O:10]
Reactant: COC(=O)C[C@@H](c1ccc(Oc2ccc3c(c2)CCCC3)cc1)c1nncn1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cn1cnnc1[C@@H](CC(=O)O)c1ccc(Oc2ccc3c(c2)CCCC3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 44.2 in THF/MeOH (1:1, 2 mL), is treated with 2N NaOH aqueous solution (1 mL) and stirred overnight at room temperature. The reaction mixture is acidified with aqueous 2N HCl and extracted with EtOAc to obtain 44, which is purified by preparative HPLC, eluting with 5˜95% ACN in water containing 0.1% TFA.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11]O)=[CH:5][CH:4]=1.[I-:13].[Na+].ClC(OC(Cl)C)=O.C1(C)C=CC=CC=1>CC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][I:13])=[CH:5][CH:4]=1
Reactant: [I-]
Reactant: COc1ccc(CCCO)cc1
Agent: CC(Cl)OC(=O)Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Product: COc1ccc(CCCI)cc1
Reaction time: 4 h
Yield: 32.4 %

Procedure:
Under a nitrogen atmosphere, a solution of 8.0 grams (0.048 mole) of 3-(4-methoxyphenyl)propanol and 7.9 grams (0.053 mole) of sodium iodide in 50 mL of acetone was stirred, and 5.7 mL (0.053 mole) of 1-chloroethyl chloroformate was slowly added. Upon completion of addition, the reaction mixture was heated to reflux where it was stirred for four hours. After this time the reaction mixture was cooled, and 50 mL of toluene was added. The acetone was removed by distillation after which the reaction mixture was heated for one hour at reflux in the toluene. The reaction mixture was then cooled and poured into 300 mL of water. The mixture was extracted with 200 mL of diethyl ether. The ether extract was washed with 100 mL of an aqueous 5% sodium thiosulfate solution and then with water. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual oil, and the oil was dissolved in methylene chloride and filtered through a pad of silica gel. The filtrate was concentrated under reduced pressure to a residual oil. The oil was subjected to column chromatography on silica gel. Elution was accomplished with 40:1 petroleum ether and diethyl ether. The appropriate fractions were combined and concentrated under reduced pressure, yielding 4.3 grams of 3-(4-methoxyphenyl)propyl iodide. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][C@H:14]([C:18]2[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=2)[CH2:13]1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:32][CH2:33][OH:34]>CC#N>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][C@H:14]([C:18]2[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=2)[O:24][CH2:32][CH2:33][OH:34])[CH2:13]1
Reactant: OCCCl
Reactant: Oc1cccc([C@H]2CCCN(C[C@H]3COc4ccccc4O3)C2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: OCCOc1cccc([C@H]2CCCN(C[C@H]3COc4ccccc4O3)C2)c1

Procedure:
(R*)-3-{1-[(S)-1-(2,3-Dihydrobenzo[1,4]dioxin-2-yl)methyl]piperidin-3-yl}phenol (51 mg), K2CO3 (28 mg, 0.20 mmol), 2-chloroethanol and MeCN (2 ml) were heated under microwaves at 80-105° C. for 6 h. The solvent was removed and the residue was taken up in DCM. This solution was washed with water and 1 M NaOH and evaporated to dryness. Flash chromatography (heptane/EtOAc) gave 3 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:6][N:5]([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:25]([OH:27])=O)[CH2:10]2)=[O:8])[CH2:4]1.O[N:29]=[C:30]([NH2:35])[CH2:31][CH2:32][O:33][CH3:34]>>[CH3:1][O:2][CH:3]1[CH2:6][N:5]([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:22])[F:24])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:25]3[O:27][N:35]=[C:30]([CH2:31][CH2:32][O:33][CH3:34])[N:29]=3)[CH2:10]2)=[O:8])[CH2:4]1
Reactant: COC1CN(C(=O)N2CC(C(=O)O)CC(c3ccc(C(F)(F)F)cc3)C2)C1
Reactant: COCCC(N)=NO
Product: COCCc1noc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CC(OC)C3)C2)n1
Yield: 22.1 %

Procedure:
250 mg (0.647 mmol) of 1-[(3-methoxyazetidin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 103A) and 112 mg (0.712 mmol, 75% pure) of N′-hydroxy-3-methoxypropanimidamide (Example 64A) were reacted according to the General Method 1. Enantiomer separation of the racemate according to Method 16D gave 67.0 mg of the title compound from Example 313 and 67.0 mg of the title compound from Example 314 (44% of theory).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.[OH:18][C:19]1([C:29]#[C:30][C:31]([C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=2)=O)[CH2:28][CH2:27][C:22]2([O:26][CH2:25][CH2:24][O:23]2)[CH2:21][CH2:20]1>C(O)C>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:31]([C:33]3[CH:34]=[CH:35][C:36]([CH3:39])=[CH:37][CH:38]=3)=[CH:30][C:29]([C:19]3([OH:18])[CH2:28][CH2:27][C:22]4([O:23][CH2:24][CH2:25][O:26]4)[CH2:21][CH2:20]3)=[N:10]2)=[CH:5][CH:4]=1
Reactant: NNc1ccc(Cl)cc1
Reactant: Cc1ccc(C(=O)C#CC2(O)CCC3(CC2)OCCO3)cc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1ccc(-c2cc(C3(O)CCC4(CC3)OCCO4)nn2-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.1 %

Procedure:
To a solution of 4-chlorophenylhydrazine hydrochloride (418 mg, 2.33 mmol) in ethanol (4.8 mL), triethylamine (5.87 mL, 42.1 mmol) was added dropwise, and the obtained solution was stirred at room temperature for 30 minutes. To the reaction solution, a solution of 3-(8-hydroxy-1,4-dioxaspiro[4.5]decan-8-yl)-1-(p-tolyl)-2-propyn-1-one (Reference Example 15) (698 mg, 2.32 mmol) in ethanol (4.7 mL) was added dropwise, and the obtained solution was stirred at room temperature for 14 hours. Thereafter, the reaction solution was concentrated under reduced pressure. Water was added to the residue and the resultant was extracted with ethyl acetate. The organic layer was washed with distilled water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, n-hexane/ethyl acetate) to obtain the captioned compound (948 mg, 2.23 mmol, yield: 96%) as an amorphous product.
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:18]2[C:17]([NH2:19])=[N:16][C:15]([CH2:20][CH2:21][CH2:22][CH3:23])=[N:14][C:13]=2[C:12]([C:24]#[C:25][CH2:26][CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][N:32]([CH:35](C)[CH3:36])[CH2:31][CH2:30]2)=[C:11]1[CH3:38])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCN1C2C(N)=NC(CCCC)=NC=2C(I)=C1C)C1C=CC=CC=1.C(N1CCN(CCCC#C)CC1)C>>[CH2:1]([O:8][CH2:9][N:10]1[C:18]2[C:17]([NH2:19])=[N:16][C:15]([CH2:20][CH2:21][CH2:22][CH3:23])=[N:14][C:13]=2[C:12]([C:24]#[C:25][CH2:26][CH2:27][CH2:28][N:29]2[CH2:30][CH2:31][N:32]([CH2:35][CH3:36])[CH2:33][CH2:34]2)=[C:11]1[CH3:38])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCc1nc(N)c2c(n1)c(C#CCCCN1CCN(C(C)C)CC1)c(C)n2COCc1ccccc1
Agent: C#CCCCN1CCN(CC)CC1
Agent: CCCCc1nc(N)c2c(n1)c(I)c(C)n2COCc1ccccc1
Product: CCCCc1nc(N)c2c(n1)c(C#CCCCN1CCN(CC)CC1)c(C)n2COCc1ccccc1

Procedure:
Prepared similarly to Intermediate 17 from 5-((benzyloxy)methyl)-2-butyl-7-iodo-6-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-amine and 1-ethyl-4-(pent-4-yn-1-yl)piperazine (Bioorg. Med. Chem. Lett. 2011, 21(6), 1601; WO2006/105372).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[N:28]1([CH2:34][C:35]([N:37]([CH:45]([CH3:47])[CH3:46])[C:38]2[CH:43]=[CH:42][C:41]([NH2:44])=[CH:40][CH:39]=2)=[O:36])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[N:28]1([CH2:34][C:35]([N:37]([C:38]2[CH:39]=[CH:40][C:41]([NH:44]/[C:17](=[C:6]3\[C:5](=[O:27])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=4)/[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:42][CH:43]=2)[CH:45]([CH3:47])[CH3:46])=[O:36])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: CC(C)N(C(=O)CN1CCCCC1)c1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(N(C(=O)CN2CCCCC2)C(C)C)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and N-(piperidin-1-yl-methylcarbonyl)-N-isopropyl-p-phenylenediamine Rf value: 0.5 (silica gel, methylene chloride/methanol=9:1) C33H36N4O4