Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19](Br)[CH3:20])[CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]21[O:18]CCO2.[Mg].[C:23](=[O:25])=[O:24].Cl>O1CCCC1.O.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]([CH3:20])[C:23]([OH:25])=[O:24])[CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=[O:18]
Reactant: CC(Br)c1ccc(CC2CCCCC23OCCO3)c(Cl)c1
Reactant: O=C=O
Agent: Cl
Agent: [Mg]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C(=O)O)c1ccc(CC2CCCCC2=O)c(Cl)c1
Reaction time: 4 h
Yield: 61 %

Procedure:
5.6 g of 1-[3-chloro-4-(2,2-ethylenedioxycyclohexane-1-yl methyl)phenyl]ethyl bromide were dissolved in 50 ml of tetrahydrofuran and added dropwise over one hour to 0.55 g of magnesium suspended in 10 ml of tetrahydrofuran, after which the whole was refluxed under agitation for three hours and cooled to produce a Grignard's reagent. The Grignard's reagent so produced was poured onto an excessive amount of solid carbon dioxide and allowed to stand still for 4 hours, after which the whole was acidified with diluted hydrochloric acid and extracted with 100 ml of ether. The extract obtained was concentrated to obtain a residue which was then incorporated with 25 ml of acetic acid and 10 ml of water and refluxed under agitation for two hours. After the end of the reaction, the reaction mixture was incorporated with 100 ml of water and extracted with 50 ml of ether. The extract obtained was washed with water, dried and freed of the solvent to obtain a residue which was then recrystallized from isopropyl ether thereby to obtain 2.7 g (yield 61%) of 2-[3-chloro-4-(2-oxocyclohexane-1-yl methyl)phenyl] propionic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([NH:14][C:15]1[CH:36]=[CH:35][C:18]([CH2:19][N:20]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:22]([CH2:29][C:30]([O:32]CC)=[O:31])=[N:21]3)=[CH:17][CH:16]=1)=[O:13])[CH:6]=[CH:5]2.O.[OH-].[Li+].O.Cl>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([NH:14][C:15]1[CH:36]=[CH:35][C:18]([CH2:19][N:20]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:22]([CH2:29][C:30]([OH:32])=[O:31])=[N:21]3)=[CH:17][CH:16]=1)=[O:13])[CH:6]=[CH:5]2
Reactant: CCOC(=O)Cc1nn(Cc2ccc(NC(=O)c3ccc4cc(F)ccc4c3)cc2)c2ccccc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)Cc1nn(Cc2ccc(NC(=O)c3ccc4cc(F)ccc4c3)cc2)c2ccccc12
Yield: 92.4 %

Procedure:
Ethyl 2-[1-[4-(6-fluoro-2-naphthamido)benzyl]-1H-indazol-3-yl]acetate (262 mg, 0.544 mmol) was dissolved in tetrahydrofuran (10 mL), and in an ice bath 10 mL aqueous solution dissolving lithium hydroxide monohydrate (114 mg, 2.71 mmol) was added. It was reacted at room temperature for 3 h, and the reaction was monitored to be complete by TLC. Water was added into the system, and adjusted to pH≈3-4 with diluted hydrochloric acid. A solid precipitated, which was filtered and dried to obtain a white solid 228 mg, at a yield of 92.5%.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:16][CH2:17][CH:18]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:20][C:21]1[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:22]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:16][CH2:17][CH2:18][N:31]2[CH2:32][CH2:33][N:28]([C:22]3[CH:23]=[CH:24][CH:25]=[C:26]([CH3:27])[C:21]=3[CH3:20])[CH2:29][CH2:30]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)n1nc(CCC=O)cc1-c1ccccc1
Reactant: Cc1cccc(N2CCNCC2)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(N2CCN(CCCc3cc(-c4ccccc4)n(C(C)(C)C)n3)CC2)c1C

Procedure:
39 mg (45%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-phenyl-1H-pyrazol-3-yl)propanal (50 mg, 0.195 mmol), 1-(2,3-dimethylphenyl)piperazine (35.4 mg, 0.186 mmol), DIPEA (49 mL, 0.279 mmol) and NaBH(OAc)3 (118 mg, 0.558 mmol).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=[CH:4][C:3]=1[CH2:13]O.P(Br)(Br)[Br:16].C([O-])(O)=O.[Na+]>ClCCl>[Br:16][CH2:13][C:3]1[CH:4]=[CH:5][C:6]([N+:10]([O-:12])=[O:11])=[C:7]([O:8][CH3:9])[C:2]=1[Cl:1]
Reactant: BrP(Br)Br
Reactant: COc1c([N+](=O)[O-])ccc(CO)c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1c([N+](=O)[O-])ccc(CBr)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 126.8 %

Procedure:
To a solution of (2-Chloro-3-methoxy-4-nitrophenyl)methanol (Compound 54H, 1.1 g, 5.06 mmol) in dichloromethane (10 mL) at 0° C. was added phosphorous tribromide (684 mg, 2.53 mmol). After the addition was over, the reaction mixture was allowed to stir at RT overnight. The reaction mixture was neutralized with NaHCO3, extracted with ethyl acetate (30 mL) and the solvent was removed under reduced pressure to get the compound 900 mg (64%). 1H NMR (300 MHz, CDCl3) δ 7.72 (d, J=8.4 Hz, 1H), 7.34 (d, J=8.4 Hz, 1H), 4.58 (s, 2H), 4.04 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.C(O)(=O)[CH2:20][C:21]([OH:23])=[O:22].N1CCCCC1>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[C:10]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[CH:20][C:21]([OH:23])=[O:22]
Reactant: COc1c(C=O)cccc1Oc1ccccc1C
Reactant: O=C(O)CC(=O)O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: COc1c(C=CC(=O)O)cccc1Oc1ccccc1C
Yield: 53.3 %

Procedure:
2-Methoxy-3-(o-tolyloxy)benzaldehyde (28 g), malonic acid (24 g), pyridine (200 ml) and piperidine (2 ml) were treated in a similar manner to that of Example 4-(4), and the resultant crude product was crystallized with a mixture of benzene and n-hexane to give 3-[2-methoxy-3-(o-tolyloxy)phenyl]acrylic acid (17.5 g). mp 143°-146° C.
Reaction SMILES: C([Cl:4])(=O)C.Cl.C(OC([N:13]1[CH:18]([CH3:19])[CH:17]=[C:16]([CH3:20])[CH:15]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH3:29])=[CH:23][CH:22]=2)[O:14]1)=O)(C)(C)C>CO>[ClH:4].[CH3:19][CH:18]1[CH:17]=[C:16]([CH3:20])[CH:15]([C:21]2[CH:22]=[CH:23][C:24]([O:27][CH2:28][CH3:29])=[CH:25][CH:26]=2)[O:14][NH:13]1
Reactant: CCOc1ccc(C2ON(C(=O)OC(C)(C)C)C(C)C=C2C)cc1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CO
Product: CCOc1ccc(C2ONC(C)C=C2C)cc1

Procedure:
Acetyl chloride (30 ml) was added dropwise over 10 mins to a cooled solution of methanol (300 ml) The resulting solution of hydrogen chloride in methanol was added to a stirred solution of 2-t-butoxycarbonyl-3, 6-dihydro-3,5-dimethyl-6-(4-ethoxyphenyl)-2H-1, 2-oxazine (11.6 g, 34.8 mmol) in methanol (50 ml). After 4 h at room temperature the mixture was evaporated to a solid (8.35 g), triturated with diethyl ether and the solid filtered to give 3,6-dihydro-3,5-dimethyl-6-(4-ethoxyphenyl)-2H-1,2-oxazine hydrochloride.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].C(N(CC)CC)C.ClC1C=CC(C2C(C3C=CC(Cl)=CC=3)NC(C3C=CC(OC)=CC=3OC)=N2)=CC=1.[CH3:41][N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1.C(=O)(O)[O-].[Na+]>C1COCC1.C(Cl)Cl>[CH3:41][N:42]1[CH2:47][CH2:46][N:45]([CH:1]=[O:2])[CH2:44][CH2:43]1
Reactant: O=C(Cl)Cl
Reactant: CN1CCNCC1
Agent: COc1ccc(C2=NC(c3ccc(Cl)cc3)C(c3ccc(Cl)cc3)N2)c(OC)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCN(C=O)CC1
Reaction time: 2.5 h

Procedure:
Phosgene (1.31 mL, 2.53 mmol, 1.93 M in toluene) was added dropwise to a cooled (0° C.) mixture of triethylamine (0.37 mL, 2.64 mmol) and 4,5-bis-(4-chloro-phenyl)-2-(2,4-dimethoxy phenyl)-4,5-dihydro-1H-imidazole (225 mg, 0.53 mmol, example 1) in THF (5 mL). The reaction mixture was stirred for 2.5 h and evaporated. The residue was kept under high vacuum for 30 min and was redissovled in methylene chloride (10 mL). The slurry was added dropwise to a solution of N-methylpiperazine (1.05 g, 10.48 mmol) in methylene chloride (5 mL). After 1 h, the reaction was worked up with aqueous sodium bicarbonate and extracted with methylene chloride. The organic extracts were washed with water and brine, and dried over sodium sulfate. Evaporation of the solvents and chromatography of the residue over silica gel using 1-4% methanol in methylene chloride gave 4,5-bis-(4-chloro-phenyl)-2-(2,4-dimethoxy-phenyl)-4,5-dihydro-imidazol-1-yl]-(4-methyl-piperazin-1-yl)-methanone. HR-MS (ES, m/z) calculated for C29H31N4O3Cl2[(M+H)+]553.1768, observed 553.1773.
Reaction SMILES: I[C:2]1[C:3](=[O:12])[C:4]([CH3:11])([CH3:10])[CH2:5][C:6]([CH3:9])([CH3:8])[CH:7]=1.[N+:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O)([O-:15])=[O:14].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-]>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]>[CH3:8][C:6]1([CH3:9])[CH2:5][C:4]([CH3:11])([CH3:10])[C:3](=[O:12])[C:2]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N+:13]([O-:15])=[O:14])=[CH:7]1
Reactant: O=[N+]([O-])c1ccccc1B(O)O
Reactant: CC1(C)C=C(I)C(=O)C(C)(C)C1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: CC1(C)C=C(c2ccccc2[N+](=O)[O-])C(=O)C(C)(C)C1
Temperature: 38 °C
Reaction time: 1.5 h
Yield: 69.9 %

Procedure:
A 250-mL modified Schlenk-type flask was charged with 2-iodo-4,4,6,6-tetramethyl-cyclohex-2-en-1-one (3, 1.06 g, 3.96 mmol, 1 equiv), 2-nitrophenyl boronic acid (661 mg, 3.95 mmol, 1.0 equiv), Pd2(dba)3 (181 mg, 0.198 mmol, 0.05 equiv), 2-(di-t-butylphosphino)-biphenyl (236 mg, 0.791 mmol, 0.20 equiv), and barium hydroxide octahydrate (3.73 g, 11.8 mmol, 3.0 equiv). Tetrahydrofuran (64 mL) and distilled water (13 mL) were added sequentially to the flask, and the resulting red, heterogeneous mixture was heated to 38° C. The progress of the reaction was monitored by thin-layer chromatography (20% ethyl acetate-hexanes, Rf=0.37, 0.61 for product, starting material, respectively; UV, CAM). After 1.5 h, the reaction was allowed to cool to 23° C., then was quenched by the addition of saturated aqueous ammonium chloride solution (30 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with brine (20 mL), and then were dried over sodium sulfate. Filtration and concentration of the dried organic layers afforded a brown oil which was purified by flash column chromatography (10% ethyl acetate-hexanes), to afford 4,4,6,6-tetramethyl-2-(o-nitrophenyl)-cyclohex-2-en-1-one (4, 755 mg, 70%) as a white solid. 4,4,6,6-Tetramethyl-2-(o-nitrophenyl)-cyclohex-2-en-1-one (4) could be further purified by re-crystallization from hot 10% ethyl acetate-hexanes solution (white crystals, mp 101-102° C.).
Reaction SMILES: C(N1C=CN=C1)([N:3]1C=CN=C1)=O.[O:13]=[C:14]1[N:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:18]2[S:26][C:27]([C:35]([OH:37])=O)=[C:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:17]=2[CH:16]=[CH:15]1.N>CN(C=O)C>[O:13]=[C:14]1[N:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:18]2[S:26][C:27]([C:35]([NH2:3])=[O:37])=[C:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:17]=2[CH:16]=[CH:15]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1sc2c(ccc(=O)n2-c2ccccc2)c1-c1ccccc1
Agent: N
Solvent: CN(C)C=O
Product: NC(=O)c1sc2c(ccc(=O)n2-c2ccccc2)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.7 %

Procedure:
1,1′-Carbonyidiimidazole (51 mg, 0.32 mmol) was added to the compound of Example 59 (100 mg, 0.29 mmol) in DMF (2 mL). After 15 min aq. ammonia (0.190 mL, 25% solution, 3.0 mmol) was added and the solution stirred at r.t. overnight. The mixture was concentrated in vacuo and azeotroped twice with heptane. The crude product was purified by column chromatography on silica (3% MeOH in DCM) to give the title compound as a white solid (74 mg, 74%). δH (DMSO-d6) 7.87–7.76 (3H, m), 7.75–7.68 (5H, m), 7.64–7.61 (2H, m), 7.54 (1H, d, J 9.6 Hz), 6.69 (1H, d, J 9.6 Hz), 6.25 (2H, br s). LCMS (ES+) RT 2.95 minutes, 347.0 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[C@@H:11]([NH:12][CH2:13][CH2:14][CH:15]2[CH2:17][CH2:16]2)[C@H:10]2[CH2:18][C@@H:7]1[CH2:8][CH2:9]2)=[O:5])[CH3:2].[CH3:19][S:20]([NH:23][C:24]1[CH:39]=[CH:38][C:27]2[NH:28][C:29]([CH2:34][C:35](O)=[O:36])=[N:30][S:31](=[O:33])(=[O:32])[C:26]=2[CH:25]=1)(=[O:22])=[O:21].CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.Cl>CN(C)C=O>[CH2:1]([O:3][C:4]([C@H:6]1[C@@H:11]([N:12]([CH2:13][CH2:14][CH:15]2[CH2:16][CH2:17]2)[C:35](=[O:36])[CH2:34][C:29]2[NH:28][C:27]3[CH:38]=[CH:39][C:24]([NH:23][S:20]([CH3:19])(=[O:22])=[O:21])=[CH:25][C:26]=3[S:31](=[O:32])(=[O:33])[N:30]=2)[C@H:10]2[CH2:18][C@@H:7]1[CH2:8][CH2:9]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1NCCC1CC1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1N(CCC1CC1)C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
To a stirred solution of (1S,2R,3S,4R)-3-(2-cyclopropyl-ethylamino)-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (338.2 mg, 1.35 mmol) in anhydrous N,N-dimethylformamide (10 mL) under a nitrogen atmosphere, (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1g, 493 mg, 1.48 mmol), N-methylmorpholine (0.33 mL, 2.96 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (284 mg, 1.48 mmol) were added sequentially. After shaking at 25° C. for 21 h, additional (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1g, 150 mg, 0.45 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (85 mg, 0.44 mmol) were added. After another 26 h, a 1.0M aqueous hydrochloric acid solution (12 mL) was added and the mixture was extracted with ethyl acetate (3×60 mL). The combined organic layers were washed with saturated aqueous brine solution (15 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to afford the crude product, (1S,2R,3S,4R)-3-{(2-cyclopropyl-ethyl)-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-amino}-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester, as a red oil, which was used in the next step without any further purification. LC-MS (ESI) calcd for C25H34N4O7S2 566.19, found 567.4 [M+H+].
Reaction SMILES: [CH2:1]([C:8]1[O:12][N:11]=[C:10]([CH2:13][S:14]([C:16]2[CH:31]=[CH:30][C:19]([CH2:20][CH2:21][NH:22]C(=O)OC(C)(C)C)=[CH:18][CH:17]=2)=[O:15])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl.CO>[CH2:1]([C:8]1[O:12][N:11]=[C:10]([CH2:13][S:14]([C:16]2[CH:17]=[CH:18][C:19]([CH2:20][CH2:21][NH2:22])=[CH:30][CH:31]=2)=[O:15])[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(S(=O)Cc2noc(Cc3ccccc3)n2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: NCCc1ccc(S(=O)Cc2noc(Cc3ccccc3)n2)cc1
Reaction time: 4 h
Yield: 101.9 %

Procedure:
To a solution of the sulfoxide of Example 21 (0.92 g, 2.04 mmol) in dichloromethane (14 mL) and methanol (2 drops) was added trifluoroacetic acid (3.5 mL). This mixture was stirred for 4 h, and TLC indicated the absence of starting material. The volatile components were removed in vacuo and the residue was taken up into dichloromethane (50 mL) and washed with dilute aqueous sodium bicarbonate (2×). The organic phase was dried (Na2SO4), filtered and completely evaporated to leave 0.71 g of pure title compound.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[SH:9].Br[CH2:11][CH2:12][CH2:13][Cl:14].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:14][CH2:13][CH2:12][CH2:11][S:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][OH:1]
Reactant: ClCCCBr
Reactant: OCc1ccccc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCc1ccccc1SCCCCl
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.3 %

Procedure:
A mixture of 11.9 g of 2-(hydroxymethyl)thiophenol, 35.44 g of 1-bromo-3-chloropropane, 11.58 g of potassium carbonate and 150 ml of dimethylformamide is stirred at room temperature for 2 hours. Insoluble materials are filtered off, and the filtrate is concentrated under reduced pressure to remove solvent. Water is added to the residue, and the aqueous mixture is extracted with ethyl acetate. The extract is wahsed with water, dried and concentrated under reduced pressure to remove solvent. The residue is distilled under reduced pressure. 16.8 g of 2-(3-chloropropylthio)benzylalcohol are obtained as colorless oil. Yield: 93%.
Reaction SMILES: C([N:14]1[CH2:17][CH:16]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1>C(O)C.[Pd]>[O:18]([CH:16]1[CH2:17][NH:14][CH2:15]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: c1ccc(OC2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Agent: [Pd]
Solvent: CCO
Product: c1ccc(OC2CNC2)cc1
Temperature: 70 °C
Yield: 37.1 %

Procedure:
1-benzhydryl-3-phenoxyazetidine (D20) (2.28 g, 7.23 mmol) was dissolved in ethanol (50 ml) and Pd/C (400 mg, w/w 10%) was added. The mixture was heated at 70° C. under hydrogen atmosphere (50 psi) for 18 hours then filtered off. The filtrate was concentrated to obtain a residue which was recrystallized from diethylether to provide the title compound (D48) (400 mg) as a white solid.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH:6]([C:12](=[O:14])[CH3:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:3])[CH3:2]>C(Cl)Cl>[C:1]([NH:4][CH2:5][C@@H:6]([C@H:12]([OH:14])[CH3:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(CNC(C)=O)C(C)=O
Solvent: ClCCl
Product: CCOC(=O)[C@@H](CNC(C)=O)[C@@H](C)O
Yield: 95.9 %

Procedure:
In a 100 ml-volume stainless steel autoclave whose atmosphere had been displaced with nitrogen was added a solution of 2.01 g (10 mmole) of ethyl 2-(N-acetylamino)methyl-3-oxobutanoate and 84.5 mg (0.05 mmole) of Ru2Cl4 ((+)-BINAP)2NEt3 in 18 ml of methylene chloride, and a reaction was conducted at 35° C. under a hydrogen pressure of 70 kg/cm2 for 17 hours. The reaction mixture was taken out, concentrated under reduced pressure of 20 mmHg, and purified by silica gel column chromatography using a 7/3 (by volume) mixed solvent of hexane and isopropanol as an eluent to obtain 1.95 g (yield: 96.5%) of ethyl (2S, 3R)-2-(N-acetylamino)methyl-3-hydroxybutanoate having an optical purity of 98 %ee. The optical purity of the product was determined by HPLC in the same manner as in Example 1, except for using A-002-3 S-3 120A produced by Yamamura Kagaku Kenkyusho K.K. as a column and a 800/200/1 (by volume) mixture of hexane, tetrahydrofuran and methanol as an eluent.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]=[C:13]([CH3:21])[N:14]([CH:15]4[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]4)[C:5]=3[C:4]=2[N:3]=1.CCN(CC)CC.[CH:29]1([C:32](Cl)=[O:33])[CH2:31][CH2:30]1>C1COCC1>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]=[C:13]([CH3:21])[N:14]([CH:15]4[CH2:20][CH2:19][N:18]([C:32]([CH:29]5[CH2:31][CH2:30]5)=[O:33])[CH2:17][CH2:16]4)[C:5]=3[C:4]=2[N:3]=1
Reactant: Cc1nc2cnc3ccc(Cl)nc3c2n1C1CCNCC1
Reactant: O=C(Cl)C1CC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1nc2cnc3ccc(Cl)nc3c2n1C1CCN(C(=O)C2CC2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78 %

Procedure:
To a solution of 8-chloro-2-methyl-1-(piperidin-4-yl)-1H-imidazo[4,5-c][1,5]naphthyridine (110 mg, 0.364 mmol) and Et3N (101 μL, 0.728 mmol) in THF (15 mL) was added cyclopropanecarbonyl chloride (36 μL, 0.401 mmol) while cooling with an ice-water bath. The reaction mixture was stirred at r.t. for 3 h, and was then concentrated under vacuum. The residue was dissolved in a mixture of CH2Cl2 (10 mL) and H2O (10 mL). The resulting solution was then extracted with EA (2×10 mL). The combined organic layers were concentrated to give crude (4-(8-chloro-2-methyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl) piperidin-1-yl)(cyclopropyl)methanone as a yellow solid (105 mg, yield 80%) which was used in the next step without further purification. MS (m/z): 370 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([CH:11]([N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH3:23]OC(OC)OC>C(O)=O>[N:18]1([CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[CH:10]=[C:2]3[C:3]([C:4](=[O:5])[NH:6][CH:23]=[N:1]3)=[CH:7][CH:8]=2)[CH:22]=[CH:21][N:20]=[CH:19]1
Reactant: COC(OC)OC
Reactant: NC(=O)c1ccc(C(c2ccccc2)n2ccnc2)cc1N
Solvent: O=CO
Product: O=c1[nH]cnc2cc(C(c3ccccc3)n3ccnc3)ccc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 23.6 %

Procedure:
A mixture of 4.2 parts of 2-amino-4-[(1H-imidazol-1-yl)phenylmethyl]benzamide, 97 parts of trimethoxymethane and 1.3 parts of formic acid was stirred for 5 hours at reflux temperature and overnight at room temperature. The solvent was evaporated and the residue was dissolved in methanol. The solution was basified with ammonious methanol and then evaporated. The residue was purified twice by column chromatography (silica gel; CHCl3 /CH3OH 95:5; CHCl3 /CH3OH 90:10). The eluent of the desired fraction was evaporated and the residue was crystallized from acetonitrile. The product was filtered off, washed with 2,2'-oxybispropane and dried, yielding 1 part (23.6%) of 7-[(1H-imidazol-1-yl)phenylmethyl]-4(3H)-quinazolinone; mp. 205.0° C. (comp. 47).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:5]([O:24][CH3:25])=[C:6]([CH2:8][C:9]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])=[CH:15][CH:14]=2)([CH:11]=[O:12])[CH3:10])[CH:7]=1.[BH4-].[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:5]([O:24][CH3:25])=[C:6]([CH2:8][C:9]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])=[CH:15][CH:14]=2)([CH2:11][OH:12])[CH3:10])[CH:7]=1
Reactant: COc1c(CC(C)(C=O)c2ccc(NS(C)(=O)=O)cc2)cc(Br)cc1C(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1c(CC(C)(CO)c2ccc(NS(C)(=O)=O)cc2)cc(Br)cc1C(C)(C)C
Temperature: 25 °C
Yield: 94.3 %

Procedure:
step 2—To a solution of 292 (117 mg, 0.243 mmol) in MeOH (5 mL) at 0° C. was added sodium borohydride (44 mg, 1.163 mmol). The solution was gradually warmed to RT over 3 h. The reaction was quenched with NH4Cl solution and extracted with EtOAc. The combined extracts were dried (Na2SO4), filtered and concentrated in vacuo to afford 111 mg of N-{4-[2-(5-bromo-3-tert-butyl-2-methoxy-phenyl)-1-hydroxymethyl-1-methyl-ethyl]-phenyl}-methanesulfonamide (294) a white foam (94%).
Reaction SMILES: [N:1]1[N:9]2[C:4]([CH2:5][O:6][CH2:7][CH2:8]2)=[CH:3][C:2]=1[NH2:10].Br[C:12]1[C:13](=[O:20])[N:14]([CH3:19])[N:15]=[C:16]([Cl:18])[CH:17]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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:18][C:16]1[CH:17]=[C:12]([NH:10][C:2]2[CH:3]=[C:4]3[CH2:5][O:6][CH2:7][CH2:8][N:9]3[N:1]=2)[C:13](=[O:20])[N:14]([CH3:19])[N:15]=1
Reactant: Nc1cc2n(n1)CCOC2
Reactant: Cn1nc(Cl)cc(Br)c1=O
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cn1nc(Cl)cc(Nc2cc3n(n2)CCOC3)c1=O
Yield: 80.1 %

Procedure:
A mixture of 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-amine 129b (0.8 g, 5.76 mmol), xantophos (360 mg, 0.623 mmol), Pd2dba3 (384 mg, 0.42 mmol), 4-bromo-6-chloro-2-methylpyridazin-3(2H)-one (1.28 g, 5.76 mmol) and Cs2CO3 (5.05 g. 17.3 mmol) in 1,4-dioxane (40 mL) was heated at reflux for 2 h. After the completion of the reaction, the mixture was filtered off, and washed with MeOH (60 mL). The filtrate was evaporated in vacuo. The residue was purified on reverse phase Combi-flash to give 132a (1.3 g, 81%). MS: [M+H]+ 282.