Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(C)=O.C[O-].[Na+].[C:8]([O:16]C)(=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:20])[CH3:19]>CO.COCCOCCOC>[C:21]1([C:18](=[O:20])[CH2:19][C:8]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[O:16])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)c1ccccc1
Reactant: CC(=O)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CS(C)=O
Solvent: COCCOCCOC
Product: O=C(CC(=O)c1ccccc1)c1ccccc1
Temperature: 30 °C
Reaction time: 2 h

Procedure:
100 g of anhydrous dimethyl sulfoxide, 100 g of diethylene glycol dimethyl ether, 6 g of absolute methanol and 18 g of sodium methylate (97%) are charged to an apparatus as described in Example 1. A mixture of 45 g of methyl benzoate and 36 g of acetophenone are added dropwise to this mixture at 25 ° C. over 45 minutes. After this addition, the reaction mixture is stirred for 2 hours at 30° C. and the solvent is removed by vacuum distillation at a temperature of <60 ° C. The residue is diluted with 150 g of methyl tert-butyl ether, cooled to 0° C. and filtered. The filter cake is washed twice with methyl tert-butyl ether. The pale grey solid is thereafter taken up in dilute hydrochloric acid and stirred.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][N:6]=[C:5]2[Cl:13].[CH3:14][N:15]([CH2:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21][NH2:22])[CH3:16].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>CC(N(C)C)=O.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:13][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:22][CH2:21][C:20]3[CH:23]=[CH:24][CH:25]=[C:18]([CH2:17][N:15]([CH3:16])[CH3:14])[CH:19]=3)[CH:3]=2)[C:8](=[O:12])[NH:7][N:6]=1
Reactant: O=c1[nH]nc(Cl)c2cc(Br)ccc12
Reactant: CN(C)Cc1cccc(CN)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CN(C)Cc1cccc(CNc2ccc3c(=O)[nH]nc(Cl)c3c2)c1
Yield: 24.3 %

Procedure:
A mixture 6-bromo-4-chloro-2H-phthalazin-1-one (156 mg, 0.601 mmol), 3-dimethylaminomethylbenzylamine (110 mg, 0.67 mmol), Pd2(dba)3 (49 mg, 0.0535 mmol), rac-BINAP (108 mg, 0.173 mmol) and NaOtBu (143 mg, 1.488 mmol) in DMA (5 mL) was heated at 85° C. for 1 h. The mixture was allowed to cool, diluted with EtOAc and washed with water. The organic layer was washed with sat.aq. NaHCO3, brine and dried (Na2SO4). Preparatory HPLC afforded 4-chloro-6-(3-dimethylaminomethyl-benzylamino)-2H-phthalazin-1-one hydroformate (50 mg) as a pale brown solid. 1H (400 MHz, d6-DMSO) δ: 2.21 (s, 6H), 3.46 (s, 2H), 4.51 (d, 2H), 6.90 (s, 1H), 7.25 (m, 2H), 7.36 (m, 2H), 7.40 (s, 1H), 7.77 (t, 1H), 8.02 (s, 1H), 8.27 (s, 1H), 12.42 (s, 1H), ppm; m/z (M+1) 343.05.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([O:21][CH2:22][CH:23]=[C:24]([Cl:26])[Cl:25])[CH:18]=[C:17]([Cl:27])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=O.Cl.[CH2:29]([O:31][NH2:32])[CH3:30].Cl>N1C=CC=CC=1>[CH2:29]([O:31][N:32]=[CH:12][C:11]1[CH:14]=[CH:15][CH:16]=[C:9]([O:8][CH2:7][CH2:6][CH2:5][O:4][C:3]2[C:2]([Cl:1])=[CH:20][C:19]([O:21][CH2:22][CH:23]=[C:24]([Cl:26])[Cl:25])=[CH:18][C:17]=2[Cl:27])[CH:10]=1)[CH3:30]
Reactant: O=Cc1cccc(OCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)c1
Reactant: CCON
Agent: Cl
Solvent: c1ccncc1
Product: CCON=Cc1cccc(OCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 91.3 %

Procedure:
To a mixture of 0.21 g of 3-(3-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)propyloxy)benzaldehyde and 10 ml of pyridine was added 0.09 g of O-ethylhydroxylamine hydrochloride. After stirring at room temperature for 24 hours, the reaction mixture was poured into diluted hydrochloric acid, and extracted twice with diethyl ether. The diethyl ether layers were combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated to give a crude product. This crude product was subjected to silica gel chromatography, which afforded 0.21 g (yield, 92%) of 3-(3-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)propyloxy)benzaldehyde O-ethyloxime, m.p., 42.6° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.O[CH2:10][C:11]([CH3:20])([CH3:19])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([O:8][CH2:10][C:11]([CH3:20])([CH3:19])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)CO
Reactant: Oc1cnc(Cl)cn1
Product: CC(C)(C)OC(=O)C(C)(C)COc1cnc(Cl)cn1
Yield: 84.2 %

Procedure:
By using 5-chloropyrazin-2-ol (700 mg) and tert-butyl hydroxypivalate (1402 mg), the procedure was carried out in the same manner as in Example 1-1) to obtain tert-butyl 3-[(5-chloropyrazin-2-yl)oxy]-2,2-dimethylpropanoate (1294.5 mg).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[CH2:10]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:17]1([CH2:22][CH2:23][NH:24][C:25]([C:27]2[C:31]([CH3:32])=[C:30]([CH:33]=O)[NH:29][C:28]=2[CH3:35])=[O:26])[CH2:21][CH2:20][CH2:19][CH2:18]1>>[N:17]1([CH2:22][CH2:23][NH:24][C:25]([C:27]2[C:31]([CH3:32])=[C:30]([CH:33]=[C:10]3[C:9]4[C:13](=[CH:14][CH:15]=[C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[CH:8]=4)[NH:12][C:11]3=[O:16])[NH:29][C:28]=2[CH3:35])=[O:26])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCN1CCCC1
Reactant: O=C1Cc2cc(-c3ccccc3)ccc2N1
Product: Cc1[nH]c(C=C2C(=O)Nc3ccc(-c4ccccc4)cc32)c(C)c1C(=O)NCCN1CCCC1

Procedure:
5-Phenyl-1,3-dihydroindol-2-one (0.04 g, 0.2 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-ylethyl)amide (0.04 g) to give the title compound as a yellow-orange solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:16][CH2:15][N:14]([C:17](OC(C)(C)C)=O)[CH2:13][CH2:12]1)[CH2:10][C:9]2=[O:28].C(Cl)Cl.[C:33]1([CH2:39]C=O)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[Na]>C([O-])([O-])=O.[K+].[K+]>[CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:12][CH2:13][N:14]([CH2:17][CH2:39][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:15][CH2:16]1)[CH2:10][C:9]2=[O:28]
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(C(=O)OC(C)(C)C)CC1)O2
Reactant: O=CCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na]
Solvent: ClCCl
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(CCc3ccccc3)CC1)O2
Reaction time: 0.17 h
Yield: 71.9 %

Procedure:
A suspension of (E)-3-{4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (2.0 g, 5.9 mmol, Intermediate 1, hydrochloride salt) in 1 M K2CO3 solution (30 ml) was stirred for 10 minutes, then DCM (3×30 ml) was added to extract the corresponding free base. The organic phase was dried and concentrated to 50 ml, then phenylacetaldehyde (0.79 ml, 7.10 mmol) and sodium triacethoxyborohydride (1.88 g, 8.88 mmol) were subsequently added. The mixture was stirred for 3 h, washed with water, and the pH value was adjusted to 8 with aqueous ammonia. The product was extracted with DCM and the organic solution was dried and concentrated. The crude residue was purified by column chromatography (eluent: DCM/MeOH 99:1 to 97:3) to give (E)-3-{1′-(2-phenyl-ethyl)-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (1.72 g) as a light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH:9][C:10](=[S:18])OC2C=CC=CC=2)=[CH:7][C:6]([CH3:19])=[C:5]([CH2:20][CH2:21][CH3:22])[N:4]=1.[OH:23][C:24]1[CH:25]=[C:26]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:27]=[CH:28][CH:29]=1>>[CH3:1][O:2][C:3]1[C:8]([NH:9][C:10]([N:33]2[CH2:32][CH2:31][N:30]([C:26]3[CH:27]=[CH:28][CH:29]=[C:24]([OH:23])[CH:25]=3)[CH2:35][CH2:34]2)=[S:18])=[CH:7][C:6]([CH3:19])=[C:5]([CH2:20][CH2:21][CH3:22])[N:4]=1
Reactant: Oc1cccc(N2CCNCC2)c1
Reactant: CCCc1nc(OC)c(NC(=S)Oc2ccccc2)cc1C
Product: CCCc1nc(OC)c(NC(=S)N2CCN(c3cccc(O)c3)CC2)cc1C
Yield: 48 %

Procedure:
Phenyl N-(2-methoxy-5-methyl-6-propylpyridin-3-yl)thiocarbamate and 1-(3-hydroxyphenyl)piperazine were reacted by the same way with the example 22 to obtain the titled compound.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH3:8])[CH:3]1[O:9][C:10]1[CH:11]=[CH:12][C:13]2[CH2:14][N:15](C(OC(C)(C)C)=O)[CH2:16][CH2:17][O:18][C:19]=2[N:20]=1.[ClH:28].C(OCC)(=O)C>>[ClH:28].[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH3:8])[CH:3]1[O:9][C:10]1[CH:11]=[CH:12][C:13]2[CH2:14][NH:15][CH2:16][CH2:17][O:18][C:19]=2[N:20]=1
Reactant: CC1CCCC(C)C1Oc1ccc2c(n1)OCCN(C(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: CCOC(C)=O
Product: CC1CCCC(C)C1Oc1ccc2c(n1)OCCNC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 51 %

Procedure:
A mixture of the compound obtained in step 1 (0.51 g) and 4N hydrogen chloride/ethyl acetate (3 mL) was stirred at room temperature for 3 hr. The precipitate was collected by filtration, and the aqueous layer was basified and extracted with ethyl acetate and aqueous sodium hydroxide solution. The organic layer was washed with saturated brine and dried, and the solvent was evaporated under reduced pressure. Ethyl acetate was added to the residue, and 4N hydrogen chloride/ethyl acetate was added. The precipitate was collected by filtration and recrystallized from ethanol-diisopropyl ether to give the title compound (0.22 g, 51%) as a white powder.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:6][OH:7])[CH2:5][CH2:4]1.[H-].[Na+].[O:10]([C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20]Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O>O1CCCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[OH:1][CH2:2][C:3]1([CH2:6][O:7][CH2:20][C:19]2[CH:22]=[CH:23][CH:24]=[C:17]([O:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:18]=2)[CH2:5][CH2:4]1
Reactant: BrCc1cccc(Oc2ccccc2)c1
Reactant: OCC1(CO)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: O
Solvent: C1CCOC1
Product: OCC1(COCc2cccc(Oc3ccccc3)c2)CC1
Reaction time: 2 h
Yield: 40.5 %

Procedure:
A solution of 1,1-dihydroxymethylcyclopropane (3 g) in tetrahydrofuran (20 cm3) was added dropwise to a suspension of sodium hydride (0.35 g) in tetrahydrofuran (30 cm3). After effervescence has ceased, tetrabutylammonium iodide (1 g) was added to the grey suspension followed by a solution of 3-phenoxybenzyl bromide (3.88 g) in tetrahydrofuran (15 cm3) at the ambient temperature and the mixture stirred for a further 2 hours. The mixture was poured into water and extracted with ethylacetate. The extracts were combined, dried over magnesium sulphate and concentrated by evaporation of the solvent, and the residual oil purified by column chromatography using a silica gel column eluting first with dichloromethane, followed then by ethylacetate, to give 1-hydroxymethyl-1-(3-phenoxybenzyloxymethyl)cyclopropane (1.7 g).
Reaction SMILES: CC1C=CC(S(O)(=O)=O)=CC=1.[F:12][C@H:13]1[CH2:17][CH2:16][NH:15][CH2:14]1.C(N(CC)CC)C.[Cl:25][CH2:26][C:27](Cl)=[O:28]>ClCCl.O>[Cl:25][CH2:26][C:27]([N:15]1[CH2:16][CH2:17][C@H:13]([F:12])[CH2:14]1)=[O:28]
Reactant: F[C@H]1CCNC1
Reactant: O=C(Cl)CCl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C(CCl)N1CC[C@H](F)C1

Procedure:
A mixture of Step 3 intermediate (563 mg, 1.48 mmol) and triethylamine (196 mg, 1.93 mmol) in dry dichloromethane (20 ml) was added drop wise (10 min) to a stirred and cooled (0° C.) solution of chloroacetyl chloride (186 mg, 1.63 mmol) in dry dichloromethane (5 ml) over 20 min. The resulting mixture was stirred at 0° C. for 2 h and diluted with water (50 ml). The organic layer was separated, washed with water (2×50 ml), brine and dried (Na2SO4). The solvent was evaporated under reduced pressure to give 124 mg of the desired compound as an off white solid; 1H NMR (CDCl3, 300 MHz) δ 1.35 (brs, 2H), 1.20-2.41 (m, 2H), 3.52-4.11 (m, 4H), 5.19-5.43 (m, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH2:17][CH2:16][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([C:13](=[O:15])[CH3:14])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[H-].[Na+].[O:20]1[CH2:22][CH:21]1[C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1>CN(C=O)C>[OH:20][CH:21]([C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1)[CH2:22][N:6]1[C:7]2[CH:8]=[CH:9][C:10]([C:13](=[O:15])[CH3:14])=[CH:11][C:12]=2[C:4]2[CH2:3][N:2]([CH3:1])[CH2:17][CH2:16][C:5]1=2
Reactant: c1cc(C2CO2)ccn1
Reactant: CC(=O)c1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc2c(c1)c1c(n2CC(O)c2ccncc2)CCN(C)C1
Reaction time: 0.17 h
Yield: 4.9 %

Procedure:
To a stirred solution of 1-(2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indol-8-yl)ethanone (80 mg, 0.35 mmol) in DMF (2 mL) was added sodium hydride (60%, 42 mg, 1.05 mmol). After stirring for 10 min, a solution of 4-(oxiran-2-yl)pyridine (62 mg, 0.51 mmol) in DMF (1 mL) was added into the reaction mixture, and stirred at RT for 4 h. The reaction mixture was quenched with ice water and extracted with EtOAc. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue obtain was purified by crystallization with ether to yield 1-(2,3,4,5-tetrahydro-5-(2-hydroxy-2-(pyridin-4-yl)ethyl)-2-methyl-1H-pyrido[4,3-b]indol-8-yl)ethanone (6 mg). 1H NMR (CDCl3, freebase) δ (ppm): 8.5 (d, 2H), 7.95 (s, 1H), 7.73 (d, 1H), 7.26 (d, 2H), 7.12 (d, 1H), 4.78 (t, 1H), 4.8 (d, 2H), 3.49 (m, 2H), 2.90 (m, 1H), 2.8 (q, 2H), 2.79 (s, 3H), 2.6 (m, 1H), 2.37 (s, 3H). Separation by chiral HPLC provided enantiomers 49a and 49b.
Reaction SMILES: [Cl:1][C:2]1[S:10][C:9]2[S:8](=[O:12])(=[O:11])[NH:7][CH2:6][C@@H:5]([OH:13])[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][CH2:22][CH2:23][O:24][CH3:25].[Cl-].[Na+]>CS(C)=O>[Cl:1][C:2]1[S:10][C:9]2[S:8](=[O:11])(=[O:12])[N:7]([CH2:21][CH2:22][CH2:23][O:24][CH3:25])[CH2:6][C@@H:5]([OH:13])[C:4]=2[CH:3]=1
Reactant: COCCCBr
Reactant: O=S1(=O)NC[C@@H](O)c2cc(Cl)sc21
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CS(C)=O
Product: COCCCN1C[C@@H](O)c2cc(Cl)sc2S1(=O)=O
Reaction time: 1 h
Yield: 93.8 %

Procedure:
A 5-L, 4-necked flask equipped with a mechanical stirrer, a thermometer, and a 250-mL addition funnel was charged with (S)-3,4-dihydro-6-chloro-4-hydroxy-2H-thieno[3,2-e]-1,2-thiazine-1,1-dioxide (5, 350 g, 1.46 mol), dimethylsulfoxide (1.75 L), and potassium carbonate (605 g, 4.38 mol). 1-Bromo-3-methoxypropane (268 g, 1.75 mol, 1.2 eq) was added via the addition funnel in eight equal portions spaced 1 hour apart. Each addition caused a small rise in temperature, amounting to a 10° C. increase over 8 hours. TLC analysis 1.5 hours after the final addition indicated complete reaction. The reaction mixture was poured into a 50-L flask equipped with a mechanical stirrer containing saturated aqueous sodium chloride (18 L). The original reaction vessel was rinsed with both water and t-butyl methyl ether. The aqueous solution was extracted with t-butyl methyl ether (2×4 L) and the combined extracts were washed with 1M aqueous sodium hydroxide (2 L), 1:1 bleach/water (2 L), and saturated aqueous sodium chloride (2 L). The t-butyl methyl ether solution was dried over sodium sulfate (500 g), filtered, and stripped of solvent by rotary evaporation. The residual oil was transferred to a 2-L flask and trace solvent was removed by rotary evaporation at 50° C., first under water aspirator, then under high vacuum for 6 hours to provide 427 grams (94%) of (S)-3,4-dihydro-6-chloro-4-hydroxy-2-(3-methoxypropyl)-2H-thieno[3,2-e]-1,2-thiazine-1,1-dioxide as a light yellow syrup: IR (film) 3500, 2931, 2878, 1422, 1336, 1167, 1114, 1071, 1028, 690 cm-1 ; 1H NMR (CDCl3) δ6.96 (s, 1H), 4.64 (br s, 1H), 4.08 (dd, 1H, J=4 and 15 Hz), 3.81-3.28 (m, 6H), 3.25 (s, 3H), 2.04-1.83 (m, 2H); [α]25D +11.4° (c=1, CH3OH); Analysis for C10H14ClNO4S2 : Calcd: C, 38.52; H, 4.53; N, 4.49. Found: C, 38.65; H, 4.54; N, 4.47.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[S:4][CH:3]=1.O1CCC[CH2:12]1.C(NC(C)C)(C)C.[Li].CI>C1COCC1.C1CCCCC1>[Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[S:4][C:3]=1[CH3:12]
Reactant: Brc1csc2ncccc12
Reactant: C1CCOC1
Agent: [Li]
Solvent: CC(C)NC(C)C
Solvent: CI
Solvent: C1CCCCC1
Product: Cc1sc2ncccc2c1Br
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 45 %

Procedure:
500 mg of 3-Bromo-thieno[2,3-b]pyridine (3.70 mmol) is dissolved in 3 ml of dry THF and cooled to −78° C. 2.71 ml of lithium diisopropylamine mono (tetrahydrofuran) 1.5 M solution in cyclohexane (4.07) is added to the mixture at −78° C. and stirred at −78° C. for 20 min. 0.25 ml of methyl iodide (43.7 mmol) is added to the mixture and stirred at −78° C.→room temperature for 1 h. The reaction mixture is quenched with sat. NH4Cl and extracted with CH2Cl2. The separated CH2Cl2 is dried over Na2SO4 and evaporated. The crude product is applied onto a silica-gel chromatography column (Hexane:AcOEt=3:1) to give 382 mg of the title compound. Yield 45%. mass spectrum (m/e): 230 (M+1); 1H-NMR (CDCl3): 8.56 (dd, 1H, J=4.7 Hz, 1.5 Hz), 7.97 (dd, 1H, J=8.5 Hz, 1.5 Hz), 7.37 (dd, 1H, J=8.5 Hz, 4.7 Hz), 2.62 (s, 3H) ppm.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:7][CH:8]=[C:9]([CH2:11]O)[N:10]=1.S(Cl)([Cl:15])=O>>[Cl:15][CH2:11][C:9]1[N:10]=[C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[S:7][CH:8]=1
Reactant: OCc1csc(-c2cccs2)n1
Reactant: O=S(Cl)Cl
Product: ClCc1csc(-c2cccs2)n1
Yield: 65 %

Procedure:
In substantially the same manner as in Reference Example 73, 2-(2-thienyl)-4-thiazolylmethanol was allowed to react with thionylchloride to give 4-chloromethyl-2-(2-thienyl)thiazole. The yield was 65%. Recrystallization from ethyl acetate-hexane gave colorless needles, mp 54-55° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([NH:18][CH2:19][CH2:20][CH:21]([OH:39])[CH2:22][O:23][C:24]2[CH:29]=[C:28]([N+:30]([O-])=O)[CH:27]=[CH:26][C:25]=2[N:33]2[CH:37]=[N:36][C:35]([CH3:38])=[N:34]2)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[Cl-].[NH4+]>CO.O.[Fe]>[NH2:30][C:28]1[CH:27]=[CH:26][C:25]([N:33]2[CH:37]=[N:36][C:35]([CH3:38])=[N:34]2)=[C:24]([CH:29]=1)[O:23][CH2:22][CH:21]([OH:39])[CH2:20][CH2:19][NH:18][C:4]1[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=[C:2]([Cl:1])[N:3]=1
Reactant: Cc1ncn(-c2ccc([N+](=O)[O-])cc2OCC(O)CCNc2nc(Cl)nc3c2CCC3c2ccc(F)cc2)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: Cc1ncn(-c2ccc(N)cc2OCC(O)CCNc2nc(Cl)nc3c2CCC3c2ccc(F)cc2)n1
Temperature: 80 °C
Yield: 80.3 %

Procedure:
The mixture of 4-(2-chloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ylamino)-1-(2-(3-methyl-1H-1,2,4-triazol-1-yl)-5-nitrophenoxy)butan-2-ol (70 mg, 0.126 mmol), iron (42.3 mg, 0.758 mmol) and ammonium chloride (67.6 mg, 1.264 mmol) in MeOH (842 μL) and water (421 μL) was heated at 80° C. for 1 h. The crude product was purified by Prep-HPLC to obtain 1-(5-amino-2-(3-methyl-1H-1,2,4-triazol-1-yl)phenoxy)-4-(2-chloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ylamino)butan-2-ol (53 mg, 80% yield). LC-MS (M+H)+=524.3. 1H NMR (500 MHz, methanol-d4) δ 9.30 (s, 1H), 7.70 (d, J=8.5 Hz, 1H), 7.23-7.15 (m, 2H), 7.10-7.04 (m, 2H), 6.98 (s, 1H), 6.84 (dd, J=8.9, 1.8 Hz, 1H), 4.38-4.32 (m, 1H), 4.24-4.20 (m, 1H), 4.19-4.07 (m, 2H), 3.77-3.67 (m, 2H), 2.88-2.80 (m, 1H), 2.76-2.70 (m, 2H), 2.50 (d, J=1.5 Hz, 3H), 2.09-2.03 (m, 1H), 2.01-1.94 (m, 1H), 1.87 (d, J=5.5 Hz, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.[NH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:13]1>O1CCOCC1.C(N(C(C)C)CC)(C)C>[Cl:9][C:4]1[N:3]=[C:2]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[O:19])[CH2:13]2)[CH:7]=[C:6]([I:8])[CH:5]=1
Reactant: Clc1cc(I)cc(Cl)n1
Reactant: NCC1CCCN(C(=O)OCc2ccccc2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: O=C(OCc1ccccc1)N1CCCC(CNc2cc(I)cc(Cl)n2)C1
Temperature: 150 °C

Procedure:
To a mixture of 2,6-dichloro-4-iodopyridine (1.5 g, 5.5 mmol) and benzyl 3-(aminomethyl)piperidine-1-carboxylate (2.7 g, 11 mmol) in dioxane (10 mL) in a microwave tube was added ten drops of diisopropylethyl amine and sealed. The tube was heated at 150° C. for 72 hours. The reaction mixture was cooled to room temperature and concentrated, the residue was purified by flash chromatography eluting with EtOAc/hexane=1:3 to 1:2 to give the title compound. Yield: 1.0 g (38%). MS (DCI/NH3) m/z 486 (M+H)+.
Reaction SMILES: CSC.Cl[C:5]1[CH:10]=[C:9](Cl)[CH:8]=[CH:7][C:6]=1/[CH:12]=[C:13](/[N:20]1[CH:24]=[N:23][CH:22]=[N:21]1)\[C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16].C1(/C=C(/N2C=NC=N2)\C(=O)C(C)(C)C)CCCCC1>>[CH:6]1(/[CH:12]=[C:13](/[N:20]2[CH:24]=[N:23][CH:22]=[N:21]2)\[CH:14]([OH:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:5][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CC(C)(C)C(=O)/C(=C\c1ccc(Cl)cc1Cl)n1cncn1
Agent: CC(C)(C)C(=O)/C(=C\C1CCCCC1)n1cncn1
Solvent: CSC
Product: CC(C)(C)C(O)/C(=C\C1CCCCC1)n1cncn1
Reaction time: 24 h

Procedure:
The same procedure as in Example 1 was repeated except that dimethyl sulfide was used in an amount of 0.081 g (1.3 mmoles), (E)-1-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-one was replaced by 0.484 g (1.85 mmoles) of (E)-1-cyclohexyl-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-one, and the reduction reaction was effected for 24 hours, to obtain 0.489 g of crude (+)-(E)-1-cyclohexyl-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-ol.
Reaction SMILES: Br[C:2]1[S:6][CH:5]=[C:4]([C:7]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:8])[CH:3]=1.[CH2:16]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:17]#[CH:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O.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)I>[O:19]([CH2:16][C:17]#[C:18][C:2]1[S:6][CH:5]=[C:4]([C:7]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:8])[CH:3]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Oc1ccccc1)c1csc(Br)c1
Reactant: C#CCOc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Oc1ccccc1)c1csc(C#CCOc2ccccc2)c1
Temperature: 120 °C
Reaction time: 0.42 h

Procedure:
A mixture of phenyl 5-bromothiophene-3-carboxylate, Example 113 (100 mg, 0.35 mmol), (prop-2-ynyloxy)benzene (93 mg, 0.71 mmol), triphenylphosphine (19 mg, 0.071 mmol), dichlorobis(triphenylphosphine)palladium(II) (12 mg, 0.018 mmol), copper iodide (1 mg, 0.006 mmol) and triethylamine (0.74 mL, 5.30 mmol) in N,N-dimethylformamide (1 mL) was stirred under nitrogen in a heavy walled process vial in a microwave synthesizer at about 120° C. for about 25 minutes. The reaction mixture was concentrated under vacuum and the residue was purified by flash column chromatography on silica gel using hexane/ethyl acetate (2:1) as the mobile phase to provide the desired product. MS (DCI-NH3): m/z 352 (M+NH4)+.