Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][C:8](=[O:13])[CH2:9][CH2:10][CH2:11][Cl:12])=[C:4]([I:16])[CH:3]=1.[CH:17]([Mg]Br)=[CH2:18]>C1COCC1>[Br:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][C:8]([OH:13])([CH2:9][CH2:10][CH2:11][Cl:12])[CH:17]=[CH2:18])=[C:4]([I:16])[CH:3]=1
Reactant: O=C(CCCCl)COc1ccc(Br)cc1I
Reactant: C=C[Mg]Br
Solvent: C1CCOC1
Product: C=CC(O)(CCCCl)COc1ccc(Br)cc1I
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(4-bromo-2-iodophenoxy)-5-chloropentan-2-one (1.61 g, 3.86 mmol) in THF (35 mL) was added vinylmagnesium bromide (1M solution in THF, 4.3 mL) at −78° C. under an argon atmosphere. After stirring for 1 hour at −78° C., the mixture was gradually warmed up to −30° C. over 1 hour. The reaction was quenched by adding saturated aqueous NH4Cl solution and extracted with EtOAc. The combined organic layer were washed with brine, dried over Na2SO4, filtered, and the filtrate was evaporated. The residue was purified by silicagel column chromatography (EtOAc-hexane, a linear gradient of EtOAc from 0 to 20%) afforded 3-[(4-bromo-2-iodophenoxy)methyl]-6-chlorohex-1-en-3-ol (1.35 g).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][C@H:10]([CH3:22])[C:11]2=[O:21])[CH2:3]1.[H][H]>C(O)C.[Pd]>[CH3:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][C@H:10]([CH3:22])[C:11]2=[O:21])[CH2:3]1
Reactant: [H][H]
Reactant: C[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)[C@@H](C)C[C@@H]32)C1
Agent: [Pd]
Solvent: CCO
Product: C[C@H]1CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)[C@@H](C)C[C@@H]32)C1

Procedure:
To a solution of 3β,16β-dimethylandrost-5-en-17-one prepared in Example I in 500 ml of ethanol is added 5% Pd on C and the mixture is exposed to a hydrogen atmosphere while stirring. The catalyst is filtered off and the above-identified product is isolated.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][C@@H:15]2[CH2:17][C@@H:16]2[CH:18]2[CH2:23][CH2:22][N:21]([CH2:24][C:25]([F:28])([F:27])[F:26])[CH2:20][CH2:19]2)[CH:9]=[C:8]([F:29])[C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+].Cl>CO.CCOC(C)=O>[F:29][C:8]1[CH:9]=[C:10]([O:12][CH2:13][CH2:14][C@@H:15]2[CH2:17][C@@H:16]2[CH:18]2[CH2:23][CH2:22][N:21]([CH2:24][C:25]([F:28])([F:26])[F:27])[CH2:20][CH2:19]2)[CH:11]=[C:2]([F:1])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1c(F)cc(OCC[C@@H]2C[C@@H]2C2CCN(CC(F)(F)F)CC2)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(O)c1c(F)cc(OCC[C@@H]2C[C@@H]2C2CCN(CC(F)(F)F)CC2)cc1F
Temperature: 60 °C

Procedure:
A solution of methyl 2,6-difluoro-4-(2-{(1S,2R)-2-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]cyclopropyl}ethoxy)benzoate (16.0 mg, 0.038 mmol) in MeOH (0.75 mL) was treated with NaOH aqueous solution (0.076 mL, 5 M, 0.38 mmol). It was heated at 60° C. for 4 hours. The mixture was cooled to RT, acidified with 2N HCl, diluted with EtOAc, washed with water, brine, dried with sodium sulfate. The solvent was removed under reduced pressure to yield Example 2. LCMS calc: 407.37; obs: 408.01 (M+1).
Reaction SMILES: [CH2:1]([N:3]([CH2:16][CH3:17])[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=1)[CH3:2]>CO.[Pd]>[CH2:16]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([NH2:13])=[CH:11][CH:12]=1)[CH3:17]
Reactant: CCN(CC)CCOc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: CCN(CC)CCOc1ccc(N)cc1
Reaction time: 2 h

Procedure:
To a solution of diethyl-[2-(4-nitro-phenoxy)-ethyl]-amine 2 (14.0 mmol) in MeOH (20 mL), in a Parr pressure bottle, is added Pd (10% on carbon, 50% wet, 10% weight). The suspension is shaken at 50 psi of H2 for 2 h. The reaction mixture is filtered through celite. The solvent is removed and the residue is dissolved in MeOH (20 mL) and treated with HCl (1 eq of a 4N solution in dioxane) to afford 4-(2-diethylamino-ethoxy)-phenylamine 3 as hydrochloride salt. 1H NMR (400 MHz, d6-DMSO) δ 6.98-6.91 (m, 4H), 4.30 (t, J=4.0 Hz, 2H), 3.47 (t, J=4.0 Hz), 3.20 (m, 4H), 1.24 (t, J=8.0 Hz, 6H). MS (m/z) (M+1)+: 209.3.
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18](OC)=[O:19])[CH2:12][CH2:11]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:28]([OH:31])([CH3:30])[CH3:29]>>[C:3]1([CH:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][C:18]([O:31][CH:28]([CH3:30])[CH3:29])=[O:19])[CH2:14][CH2:15]2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)CCN1CCC(C(c2ccccc2)c2ccccc2)CC1
Reactant: CC(C)O
Agent: [H-]
Agent: [Na+]
Product: CC(C)OC(=O)CCN1CCC(C(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A dispersion of NaH (˜20 mg of a 60% oil dispersion) was added to a solution of 13b (799 mg, 2.37 mmol) in isopropyl alcohol (10 mL). The resulting mixture was immediately stoppered tightly and stirred at RT for 2 h. The reaction mixture was evaporated to dryness and chromatographed over silica gel using 3:1 heptane/EtOAc to give 0.75 g of 13d as a colorless viscous oil. The structure was confirmed by 1H NMR. (Propanoate esters 13e and 13f were similarly prepared using isobutanol and cyclopentanol, respectively (as mentioned above, 13e was also prepared by the previous method using isobutyl acrylate).)
Reaction SMILES: C([O:8][C:9]1[C:14]2[NH:15][C:16](=[O:19])[CH2:17][O:18][C:13]=2[C:12]([C:20](=[O:24])[CH:21](O)O)=[CH:11][CH:10]=1)C1C=CC=CC=1.[CH2:25]([C:32]1([NH2:35])[CH2:34][CH2:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.FC(F)(F)C([O-])=O>>[CH2:25]([C:32]1([NH:35][CH2:21][CH:20]([C:12]2[C:13]3[O:18][CH2:17][C:16](=[O:19])[NH:15][C:14]=3[C:9]([OH:8])=[CH:10][CH:11]=2)[OH:24])[CH2:34][CH2:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: NC1(Cc2ccccc2)CC1
Reactant: O=C1COc2c(C(=O)C(O)O)ccc(OCc3ccccc3)c2N1
Agent: O=C([O-])C(F)(F)F
Product: O=C1COc2c(C(O)CNC3(Cc4ccccc4)CC3)ccc(O)c2N1

Procedure:
Prepared according to general method 3 from 329 mg (1 mmol) 5-benzyloxy-8-(2,2-dihydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and 147 mg (1 mmol) 1-benzyl-cyclopropylamine. Yield: 56 mg (12%, trifluoroacetate); mass spectroscopy: [M+H]+=355.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[Cl:8].C([Mg]Cl)(C)C.[C:14]1(=[O:18])[CH2:17][CH2:16][CH2:15]1>C1COCC1>[Cl:8][C:7]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:14]1([OH:18])[CH2:17][CH2:16][CH2:15]1
Reactant: O=C1CCC1
Reactant: Clc1ccncc1Br
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: OC1(c2cnccc2Cl)CCC1
Temperature: -15 °C
Reaction time: 1 h
Yield: 87.1 %

Procedure:
To a solution of 3-bromo-4-chloropyridine (CAN 36953-42-1, 1 g, 5.2 mmol) in dry THF (25.0 ml) cooled down to −15° C. under an argon atmosphere was added isopropyl magnesium chloride, lithium chloride complex 1.3M solution in THF (4.2 ml, 5.46 mmol) and the reaction mixture was stirred at −15° C. for 1 hour. To the reaction mixture at −15° C. was slowly added cyclobutanone (CAN 1191-95-3, 401 mg, 428 μl, 5.72 mmol) and the reaction was stirred at −15° C. for 2 hours. The reaction was then let to warm up to 0° C. and stirred at 0° C. for 2 hours. Reaction was quenched by addition of water and the reaction mixture was concentrated in vacuo. The residue was dissolved in ethylacetate and extraction with an 3.0M aqueous solution of ammonium chloride. The organic phase was dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a heptane/ethylacetate gradient to yield the title compound (832 mg, 78%) as a yellow oil. MS (ESI, m/z): 184.3 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:5]=1)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: CCOC(=O)/C=C/c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CCc1ccc(N)cc1
Yield: 69 %

Procedure:
A mixture of (E)-ethyl 3-(4-nitrophenyl)acrylate (commercially available from Aldrich, 5.00 g, 26.0 mmol) and 2.8 g of 10% Pd/C (wet, 50% water) in MeOH (26 mL) was shaken under 20 psi of hydrogen at room temperature for 20 hours. The mixture was then filtered through a pad of celite, the filtrate was concentrated, and the residue was purified through a short column of silica gel using 20% EtOAc/hexane as the eluent to give 3.48 g (69%) of the desired product ethyl 3-(4-aminophenyl)propanoate 47.2. MS ESI (pos.) m/e: 194 (M+H)+.
Reaction SMILES: CN(C1C=CC=CN=1)C.[C:10]1([N:16]=[C:17]=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[NH2:19][C@@H:20]1[C:56]([CH3:58])([CH3:57])[C@H:55]2[C@@:23]3([O:51][C:27]4[C:28]5[CH2:29][N:30]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C:31](=[O:43])[C:32]=5[CH:33]=[C:34]([O:35][CH2:36][C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)[C:26]=4[CH2:25][C@:24]3([CH3:60])[C@@H:52]([CH3:59])[CH2:53][CH2:54]2)[CH2:22][CH2:21]1>C1COCC1>[CH2:36]([O:35][C:34]1[C:26]2[CH2:25][C@:24]3([CH3:60])[C@@H:52]([CH3:59])[CH2:53][CH2:54][C@H:55]4[C:56]([CH3:58])([CH3:57])[C@@H:20]([NH:19][C:17]([NH:16][C:10]5[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=5)=[O:18])[CH2:21][CH2:22][C@@:23]34[O:51][C:27]=2[C:28]2[CH2:29][N:30]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C:31](=[O:43])[C:32]=2[CH:33]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C=Nc1ccccc1
Reactant: C[C@H]1CC[C@H]2C(C)(C)[C@@H](N)CC[C@]23Oc2c(c(OCc4ccccc4)cc4c2CN(C(=O)OC(C)(C)C)C4=O)C[C@]13C
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Product: C[C@H]1CC[C@H]2C(C)(C)[C@@H](NC(=O)Nc3ccccc3)CC[C@]23Oc2c(c(OCc4ccccc4)cc4c2CN(C(=O)OC(C)(C)C)C4=O)C[C@]13C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.2 %

Procedure:
Under nitrogen, 2 mg (0.017 mmol) of dimethylaminopyridine and 12 μl (0.11 mmol) of phenyl isocyanate were added to a solution of Compound (45a) (50 mg, 0.087 mmol) in 2.0 ml of dry THF, and the mixture stirred at room temperature for 30 min. The reaction mixture was then concentrated under reduced pressure. The residue was purified by a preparative thin layer chromatography (Merck, Kieselgel 60 F254, 0.5 mm; chloroform:methanol=40:1) to give 49 mg (81%) of Compound (45e).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH:21]=O)=[CH:17][C:16]=2[F:23])=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.[NH2:25][OH:26]>>[Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH:21]=[N:25][OH:26])=[CH:17][C:16]=2[F:23])=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2ccc(C=O)cc2F)cc1
Reactant: NO
Agent: Cl
Product: CC(C)(C)[Si](C)(C)Oc1ccc(-c2ccc(C=NO)cc2F)cc1

Procedure:
The title compound was prepared by reacting 4′-{[tert-butyl(dimethyl)silyl]oxy}-2-fluoro-1,1′-biphenyl-4-carbaldehyde (450 mg, 1.36 mmol) with hydroxylamine hydrochloride (190 mg, 2.73 mmol) according to Method C to yield a white solid which was used in the next step without purification: MS (ESI) m/z 344 (M−H)−, 346 (M+H)+.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[F:5][C:6]1[C:11](OCCF)=[CH:10][C:9]([O:16][CH3:17])=[CH:8][C:7]=1[C@H:18]([NH:31][C:32]1[CH:40]=[CH:39][C:35]([C:36]([NH2:38])=[NH:37])=[CH:34][CH:33]=1)[C:19]1[NH:23][C:22](=[O:24])[N:21]([C:25]2[N:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[N:20]=1.[CH3:41][O:42]C(=O)N=C(SC)C(C1C=C(OC)C=C(O[C@@H](C)CO[Si](C(C)(C)C)(C)C)C=1F)=NC1C=CC(C2N=C(C)ON=2)=CC=1>>[C:1]([OH:4])(=[O:3])[CH3:2].[F:5][C:6]1[C:11]([O:4][C@@H:1]([CH3:2])[CH2:41][OH:42])=[CH:10][C:9]([O:16][CH3:17])=[CH:8][C:7]=1[CH:18]([NH:31][C:32]1[CH:33]=[CH:34][C:35]([C:36]([NH2:38])=[NH:37])=[CH:39][CH:40]=1)[C:19]1[NH:23][C:22](=[O:24])[N:21]([C:25]2[N:26]=[CH:27][CH:28]=[CH:29][N:30]=2)[N:20]=1
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)c1F
Reactant: COc1cc(OCCF)c(F)c([C@H](Nc2ccc(C(=N)N)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c1
Solvent: CC(=O)O
Product: COc1cc(O[C@@H](C)CO)c(F)c(C(Nc2ccc(C(=N)N)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c1

Procedure:
The same procedure was carried out as in Examples (3e) to (3h), except that {2-{3-[(S)-2-(t-butyldimethylsilanyloxy)-1-methylethoxy]-2-fluoro-5-methoxyphenyl}-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester was used instead of [2-(2-fluoro-3-hydroxy-5-methoxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene]carbamic acid methyl ester in Example (3e), to give the first eluting enantiomer of the title compound.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[CH3:5][N:6]([CH2:8][C:9]1[O:13][C:12]([CH2:14][S:15][CH2:16][CH2:17][NH2:18])=[CH:11][CH:10]=1)[CH3:7]>C(#N)C>[CH3:7][N:6]([CH2:8][C:9]1[O:13][C:12]([CH2:14][S:15][CH2:16][CH2:17][NH:18][C:3]([NH:2][CH3:1])=[O:4])=[CH:11][CH:10]=1)[CH3:5]
Reactant: CN=C=O
Reactant: CN(C)Cc1ccc(CSCCN)o1
Solvent: CC#N
Product: CNC(=O)NCCSCc1ccc(CN(C)C)o1

Procedure:
Methylisocyanate (0.33 g) was added to a suspension of 2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethanamine, phthalhydrazine complex (2 g) in acetonitrile (50 ml). After 2 hr the solution was filtered and the filtrate evaporated to give an oil which was purified by column chromatography (silica/methanol) to give N-[2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethyl]-N'-methylurea. Analysis Found: C, 52.38; H, 7.61; N, 15.25. C12H21N3O2S.1/4H2O requires: C, 52.24; H, 7.76; N, 15.32%.
Reaction SMILES: ClCCl.[C:4]1([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(N(CC)CC)C>[CH3:22][S:23]([O:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCCCCCCCCCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCCCCCCCCCc1ccccc1

Procedure:
To a mixture of 750 ml. of dichloromethane, 37.2 g. of 11-phenyl-1-undecanol (prepared as described in Example 6) and 32 ml. of triethylamine cooled in an ice-salt bath to -10° C. is added dropwise, over 15 minutes, 13.2 ml. of methanesulfonyl chloride. The mixture is cooled at -10° C. to -15° C. for 30 minutes and then washed with 300 ml. of cold water, 300 ml. of cold 10% hydrochloric acid, 300 ml. of cold 5% sodium carbonate and with 200 ml. of cold, saturated, sodium chloride solution. The organic layer is dried over magnesium sulfate and concentrated in vacuo to give a pale yellow oil.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:22]=[C:21]2[C:12]([N:13]3[C:18]([CH2:19][O:20]2)=[N:17][NH:16][C:15](=[O:23])[C@H:14]3[CH3:24])=[CH:11][C:10]=1[C@H:25]1[CH2:30][CH2:29][NH:28][CH2:27][C@H:26]1[CH3:31].C=O.[B-][C:35]#N.[Na+]>CO.CC(O)=O>[CH3:35][N:28]1[CH2:29][CH2:30][C@H:25]([C:10]2[CH:11]=[C:12]3[C:21](=[CH:22][C:9]=2[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[F:2])[O:20][CH2:19][C:18]2[N:13]3[C@H:14]([CH3:24])[C:15](=[O:23])[NH:16][N:17]=2)[C@H:26]([CH3:31])[CH2:27]1
Reactant: C[C@@H]1CNCC[C@@H]1c1cc2c(cc1-c1ccccc1F)OCC1=NNC(=O)[C@@H](C)N12
Reactant: [B-]C#N
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: C[C@@H]1CN(C)CC[C@@H]1c1cc2c(cc1-c1ccccc1F)OCC1=NNC(=O)[C@@H](C)N12
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.2 %

Procedure:
A mixture of (R)-7-(2-fluoro-phenyl)-4-methyl-6-((3S,4S)-3-methyl-piperidin-4-yl)-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one hydrochloride acid (3.0 g, 6.74 mmol) and paraformaldehyde (0.506 g, 16.86 mmol) in MeOH (100 mL) and AcOH (10 mL) was stirred at ambient temperature for 2 h. Then, sodium cyanotrihydroborate (0.847 g, 13.49 mmol) was added and the reaction mixture was stirred at ambient temperature for 0.5 h. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography on basified silica gel (eluting with 10% MeOH in EA) to give (R)-6-((3S,4S)-1,3-dimethyl-piperidin-4-yl)-7-(2-fluoro-phenyl)-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (2.0 g, 65%) as a white solid. The white solid was stirred in HCl/EtOAc (4 M, 15 mL) for 30 min and the reaction mixture was concentrated in vacuo to give (R)-6-((3S,4S)-1,3-dimethyl-piperidin-4-yl)-7-(2-fluoro-phenyl)-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one hydrochloride acid (1.65 g, 53%) as a white solid. 1H NMR (400 MHz, methanol-d4) δ 7.49-7.40 (m, 1H), 7.33-7.17 (m, 3H), 6.91 (s, 1H), 6.85 (s, 1H), 4.99-4.93 (m, 1H), 4.70-4.65 (m, 2H), 3.60-3.50 (m, 1H), 3.25-3.00 (m, 3H), 2.90-2.85 (m, 1H), 2.80 (s, 3H), 2.55-2.45 (m, 1H), 2.01-1.84 (m, 2H), 1.49 (d, J=6.4 Hz, 3H), 1.00-0.90 (m, 3H). LC/MS (Table 1, Method 4) Rt=1.654 min.; MS m/z: 423 [M+H]+. SFC (Table 1, Method 48), Rt=3.206 min.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=O.[C:12](OC)(=[O:15])[CH2:13][CH3:14].CC(C)([O-])C.[Na+]>C1COCC1>[CH3:14][C:13]1[C:12]([OH:15])=[N:1][C:2]2[C:3]([C:4]=1[OH:6])=[CH:8][CH:9]=[CH:10][N:11]=2
Reactant: CCC(=O)OC
Reactant: COC(=O)c1cccnc1N
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c(O)nc2ncccc2c1O
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a stirred solution of methyl 2-aminonicotinate (1.3 g, 8.54 mmol) and methyl propionate (20.08 mL, 214 mmol) in THF (20 mL) was added sodium tert-butoxide (2.053 g, 21.36 mmol) portion wise over 1 min. The reaction was stirred at rt for 40 min and then at 100° C. for 4 h. After this time the reaction was cooled to rt and evaporated in vacuo. The resulting solid was dissolved in water (20 mL) and neutralized to pH 7 with 1.0M aqueous HCl. The resulting solid was filtered and dried under vacuum overnight to give 3-methyl-1,8-naphthyridine-2,4-diol as a tan solid. Mass Spectrum (ESI) m/e=177.2 (M+1).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH:10]([C:13]1[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=1)([CH3:12])[CH3:11].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH:10]([C:13]1[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=1)[O:19][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])([CH3:12])[CH3:11]
Reactant: O=Cc1ccccc1F
Reactant: CC(C)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1cccc(Oc2ccccc2C=O)c1
Yield: 56.5 %

Procedure:
2-Fluorobenzaldehyde (1.0 mg, 8.1 mmol) was dissolved in DMF (20 mL), 3-isopropylphenol (1.1 g, 8.9 mmol) and potassium carbonate (1.1 g, 8.1 mmol) were added thereto, and then microwave was irradiated at 180° C. for 5 minutes. To the reaction solution was added water, and the reaction mixture was extracted with ethyl acetate. The extract was dried, and then concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane/ethyl acetate=100:0 to 70:30) to give the title compound (1.1 g, yield 57%).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH2:7][NH:8][C:9]([N:14]([CH3:16])[CH3:15])=[N:10][N+:11]([O-:13])=[O:12])=[CH:5][N:6]=1.C([O-])([O-])=O.[K+].[K+].CC#N.[CH:26]1[CH:31]=[CH:30][C:29]([O:32][C:33](Cl)=[S:34])=[CH:28][CH:27]=1>O>[Cl:1][C:2]1[S:3][C:4]([CH2:7][N:8]([C:33]([O:32][C:29]2[CH:30]=[CH:31][CH:26]=[CH:27][CH:28]=2)=[S:34])[C:9]([N:14]([CH3:16])[CH3:15])=[N:10][N+:11]([O-:13])=[O:12])=[CH:5][N:6]=1
Reactant: CN(C)C(=N[N+](=O)[O-])NCc1cnc(Cl)s1
Reactant: S=C(Cl)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CN(C)C(=N[N+](=O)[O-])N(Cc1cnc(Cl)s1)C(=S)Oc1ccccc1
Yield: 75.8 %

Procedure:
To a mixture of 1-(2-chloro-5-thiazolylmethyl)-3,3-dimethyl-2-nitroguanidine (200 mg), K2CO3 (420 mg) and CH3CN (13 ml) was added phenyl chlorothionoformate (260 mg) dropwise in 3 minutes at 3° C. under stirring. After stirring at room temperature for 4 hours, water (10 ml) was added to the mixture which was extracted with CHCl3 (20 ml). The organic layer was dried over MgSO4 and evaporated in vacuo. The residue was crystallized from AcOEt-Et2O to afford 230 mg of 1-(2-chloro-5-thiazolylmethyl)-3,3-dimethyl-2-nitro-1-phenoxythiocarbonylguanidine (Compound No. 44) as a white crystal, m.p. 161°-162° C.
Reaction SMILES: [Cl-].[NH4+].[Cl:3][C:4]1[N:9]=[C:8]([O:10][CH3:11])[C:7]([N+:12]([O-])=O)=[CH:6][CH:5]=1.[CH2:15]([OH:17])C>O.[Fe]>[Cl:3][C:4]1[N:9]=[C:8]([O:10][CH3:11])[C:7]([NH:12][CH:15]=[O:17])=[CH:6][CH:5]=1
Reactant: CCO
Reactant: COc1nc(Cl)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: COc1nc(Cl)ccc1NC=O
Temperature: 85 °C
Reaction time: 0.33 h

Procedure:
Iron (11.9 g) and ammonium chloride (22.7 g) were added to a solution of 6-chloro-2-methoxy-3-nitropyridine (10.0 g, CAS: 40851-91-0) in ethanol (130 mL) and water (52 mL). The reaction solution was stirred at 80 to 90° C. for one hour and 20 minutes and then left to cool to room temperature. The reaction solution was filtered through celite and washed with ethanol. Then, the filtrate was concentrated under reduced pressure. The residue was diluted with ethyl acetate and water, and the organic layer was separated. The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was diluted with THF (26 mL). The THF solution was added dropwise to a mixed solution of formic acid (20.1 mL) and acetic anhydride (20.1 mL) at room temperature. Then, the reaction solution was stirred for one hour. Ice water (120 mL) was added to the reaction solution, and the precipitated crystals were collected by filtration. The crystals were washed with water and then air-dried to obtain 5.85 g of the title compound. The property value of the compound is as follows.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][S:7]([CH2:10][C:11](O)=O)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[Br:16][C:17]1[CH:24]=[CH:23][C:20](C=O)=[CH:19][CH:18]=1>>[F:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][S:7](/[CH:10]=[CH:11]/[C:20]2[CH:23]=[CH:24][C:17]([Br:16])=[CH:18][CH:19]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(O)CS(=O)(=O)Cc1ccc(F)cc1
Reactant: O=Cc1ccc(Br)cc1
Product: O=S(=O)(/C=C/c1ccc(Br)cc1)Cc1ccc(F)cc1
Yield: 82 %

Procedure:
A solution of 4-fluorobenzyl sulfonylacetic acid (0.01 mol) and 4-bromobenzaldehyde (0.01 mol) was subjected to Procedure 1. The title compound was obtained in 82% yield.
Reaction SMILES: C([O:3][C:4](=[O:33])[C:5]1[CH:10]=[C:9]([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]([CH2:27][CH2:28][O:29][CH3:30])[CH:19]=3)[CH2:14][CH2:13]2)[CH:8]=[CH:7][C:6]=1[O:31][CH3:32])C.[OH-].[Na+].Cl>CO.O1CCCC1>[CH3:32][O:31][C:6]1[CH:7]=[CH:8][C:9]([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]([CH2:27][CH2:28][O:29][CH3:30])[CH:19]=3)[CH2:14][CH2:13]2)=[CH:10][C:5]=1[C:4]([OH:33])=[O:3]
Reactant: CCOC(=O)c1cc(CN2CCC(c3cn(CCOC)c4ccccc34)CC2)ccc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COCCn1cc(C2CCN(Cc3ccc(OC)c(C(=O)O)c3)CC2)c2ccccc21
Yield: 65.1 %

Procedure:
Over a solution of 0.9 g (0.002 mol) of 2-methoxy-5-{4-[1-(2-methoxyethyl)-1H-indol-3-yl]piperidin-1-ylmethy}-benzoic acid ethyl ester in 9 ml of methanol and 5 ml of tetrahydrofuran, 5 ml of a 1N aqueous sodium hydroxide were added. The crude mixture was stirred at room temperature for 20 hours and then neutralised with 1 N aqueous HCl. The product precipitated from the mixture. The solid obtained was filtrated and washed with ethanol and ethyl ether. 0.55 g (65% of yield) of 2-methoxy-5-{4-[1-(2-methoxyethyl)-1H-indol-3-yl]piperidin-1-ylmethyl}-benzoic acid were obtained.