Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]([CH:15]([CH3:17])[CH3:16])=[C:5]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([OH:14])[CH:9]=1)[O:6][CH3:7])([CH3:3])[CH3:2].[C:18](Cl)(=[O:20])[CH3:19].C(OCC)(=O)C.CCCCCC>C(Cl)Cl.N1C=CC=CC=1>[C:18]([O:14][C:10]1[CH:9]=[C:8]([C:5]([O:6][CH3:7])=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:15]([CH3:17])[CH3:16])[CH:13]=[CH:12][CH:11]=1)(=[O:20])[CH3:19]
Reactant: COC(=C(C(C)C)C(C)C)c1cccc(O)c1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=C(C(C)C)C(C)C)c1cccc(OC(C)=O)c1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
Alkene 1b (200 mg, 0.85 mmol) was dissolved in 20 mL of dry methylene chloride with 0.3 mL of anhydrous pyridine. The flask was purged with argon and cooled in an ice bath. Acetyl chloride (0.115 g, 1.47 mmol) in 5 mL of dry methylene chloride was added dropwise over one hour. TLC analysis (silica, 20% ethyl acetate/hexane) indicated the reaction to be complete after 2.5 hours of stirring at 0° C. The solvents were evaporated and the residue dissolved in ethyl acetate. The solution was washed four times with water, dried over MgSO4 and evaporated. The residue was purified by column chromatography on silica gel, eluting with 10-20% ethyl acetate/hexane yielding 220 mg (93%) of 1c: 1H NMR (CDCl3) δ 7.37-6.99 (m, 4H), 3.19 (s, 3H), 2.47 (sept, 1H, J=6.9 Hz), 2.33 (sept, 1H, J=6.9 Hz), 2.29 (s, 3H), 1.24 (d, 6H, J=6.9 Hz), 0.93 (d, 6H, J=6.9 Hz); 13C NMR (CDCl3) δ 169.46, 150.62, 149.03, 139.02, 133.64, 128.95, 127.24, 122.89, 120.72, 56.50, 30.49, 26.98, 22.06, 21.25, 21.05.
Reaction SMILES: C([O:3][C:4](=[O:23])[CH:5]([C:15]1[CH:20]=[CH:19][N:18]=[C:17]([S:21][CH3:22])[N:16]=1)[C:6]([C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)=O)C.C(O)C.[N:27]1C=CC=CC=1>>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[NH:27][O:3][C:4](=[O:23])[C:5]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]([S:21][CH3:22])[N:16]=2)=[CH:9][CH:10]=1
Reactant: CCOC(=O)C(C(=O)c1ccc(F)cc1)c1ccnc(SC)n1
Reactant: c1ccncc1
Solvent: CCO
Product: CSc1nccc(-c2c(-c3ccc(F)cc3)[nH]oc2=O)n1

Procedure:
Using the procedure from Example 1k set forth above, substitute 3-(4-fluorophenyl)-3-oxo-2-(2-methylsulfanyl-pyrimidin-4-yl)-propionic acid ethyl ester for 2-(4-fluorophenyl)-3-oxo-3-pyridin4-yl-propiornc acid methyl ester and ethanol for pyridine to produce the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:16]=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)[CH:7]=[N:8]O)[CH3:2]>C(O)(=O)C.C(OCC)(=O)C.[Zn]>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH2:7][NH2:8])[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:16]=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)[CH3:2]
Reactant: CCOc1cc(C=NO)ccc1OCc1ccc(OC)nc1
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOc1cc(CN)ccc1OCc1ccc(OC)nc1
Temperature: 65 °C
Reaction time: 2 h
Yield: 94.5 %

Procedure:
To a stirred solution of 3-ethoxy-4-((6-methoxypyridin-3-yl)methoxy)benzaldehyde oxime (3.05 g, 10.09 mmol) in acetic acid (25 mL) was added zinc (3.30 g, 50.44 mmol). The resulting mixture was heated to 65° C. After 2 h, the gray suspension was allowed to cool to room temperature and was diluted with ethyl acetate (150 mL). The mixture was filtered through Celite with the aid of additional ethyl acetate (50 mL). The filtrate was diluted with water (50 mL) and made basic by the addition of concentrated ammonium hydroxide solution (˜30 mL). The phases were separated, and the aqueous phase was extracted with ethyl acetate (50 mL). The combined organic phases were dried over magnesium sulfate, filtered, and concentrated to provide 2.75 g (95%) of (3-ethoxy-4-((6-methoxypyridin-3-yl)methoxy)phenyl)methanamine as a yellow oil.
Reaction SMILES: [Br-].[Br:2][C:3]1[CH:4]=[C:5]([O:20][CH3:21])[C:6]2[C:15]([CH:16]=1)=[S+:14][C:13]1[C:8](=[C:9]([O:18][CH3:19])[CH:10]=[C:11](Br)[CH:12]=1)[N:7]=2.[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>C(Cl)(Cl)Cl>[Br-:2].[CH3:21][O:20][C:5]1[C:6]2[C:15](=[S+:14][C:13]3[C:8]([N:7]=2)=[C:9]([O:18][CH3:19])[CH:10]=[C:11]([N:26]2[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]2)[CH:12]=3)[CH:16]=[C:3]([N:26]2[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]2)[CH:4]=1
Reactant: COc1cc(Br)cc2[s+]c3cc(Br)cc(OC)c3nc12
Reactant: CN1CCNCC1
Agent: [Br-]
Solvent: ClC(Cl)Cl
Product: COc1cc(N2CCN(C)CC2)cc2[s+]c3cc(N4CCN(C)CC4)cc(OC)c3nc12
Yield: 42.2 %

Procedure:
Performed the reaction as described in the literature starting with 3,7-dibromo-1,9-dimethoxyphenothiazin-5-ium bromide (750 mg, 1.54 mmol), N-methylpiperazine (0.848 mL, 7.7 mmol) and chloroform (35 mL). Purified using flash silica gel chromatography to obtain product as a dark blue residue (35 mg, 0.65 mmol, 4% yield).
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Cl:13][C:14]1[S:15][C:16]([Cl:49])=[C:17]([CH:34]([C:42]2[CH:47]=[CH:46][CH:45]=[C:44]([Cl:48])[CH:43]=2)[O:35]C2CCCCO2)[C:18]=1[C:19]([NH:21][C@H:22]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1)[CH3:23])=[O:20]>CO>[Cl:13][C:14]1[S:15][C:16]([Cl:49])=[C:17]([CH:34]([C:42]2[CH:47]=[CH:46][CH:45]=[C:44]([Cl:48])[CH:43]=2)[OH:35])[C:18]=1[C:19]([NH:21][C@H:22]([C:24]1[CH:25]=[CH:26][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:32][CH:33]=1)[CH3:23])=[O:20]
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)c2c(Cl)sc(Cl)c2C(OC2CCCCO2)c2cccc(Cl)c2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2c(Cl)sc(Cl)c2C(O)c2cccc(Cl)c2)cc1
Reaction time: 1.5 h

Procedure:
p-Toluenesulfonic acid monohydrate (6.00 mg, 0.0338 mmol) was added to methyl 4-{(1S)-1-[({2,5-dichloro-4-[(3-chlorophenyl)(tetrahydro-2H-pyran-2-yloxy)methyl]-3-thienyl}carbonyl)amino]ethyl}benzoate from Example 8, Step 4 (197 mg, 0.338 mmol) in MeOH (2 mL). After 1.5 h, the reaction mixture was quenched with 5% aq. NaHCO3 and extracted with EtOAc. The combined organics were washed with 5% aq. NaHCO3, water and brine, dried (Na2SO4) and concentrated. The crude product was purified by Combi Flash chromatography system (2-8% EtOAc/toluene in 20 min.) to afford the desired product as a colorless gum.
Reaction SMILES: [OH:1][C@H:2]1[CH2:23][CH2:22][C@@:21]2([CH3:24])[CH:4]([CH2:5][CH2:6][C:7]3[C:8]4[C@:17]([CH3:25])([CH2:18][CH2:19][C:20]=32)[C@@H:11]([C@@H:12]([CH3:16])[CH2:13][CH:14]=O)[CH2:10][CH:9]=4)[C:3]1([CH3:27])[CH3:26].[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[N:28]1([CH2:14][CH2:13][C@@H:12]([C@@H:11]2[C@:17]3([CH3:25])[C:8]([C:7]4[CH2:6][CH2:5][C@@H:4]5[C@:21]([C:20]=4[CH2:19][CH2:18]3)([CH3:24])[CH2:22][CH2:23][C@H:2]([OH:1])[C:3]5([CH3:26])[CH3:27])=[CH:9][CH2:10]2)[CH3:16])[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: C1CCNC1
Reactant: C[C@@H](CC=O)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)C1CC3
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: C[C@@H](CCN1CCCC1)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)[C@@H]1CC3

Procedure:
(20S)-3β-hydroxy-4,4,20-trimethyl-pregna-8,14-dien-21-carbaldehyde was treated with pyrrolidine and sodium tris(acetoxy)borohydride as described in Example 9d). (20S)-20-[(pyrrolidin-1-yl)ethyl]-4,4-dimethyl-5α-pregna-8,14-dien-3β-ol was isolated as a white solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][CH2:15][C:16]2[CH:25]=[C:24]3[C:19]([CH2:20][CH2:21][C:22]([F:27])([F:26])[CH2:23]3)=[CH:18][C:17]=2[O:28][CH3:29])[C@@H:9]1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=O)(C)(C)C.[ClH:36].Cl.CC(C1C=CC(OC)=C(C=1)CN[C@H]1CCCN[C@H]1C1C=CC=CC=1)(C)C#CC(F)(F)F>>[ClH:36].[ClH:36].[F:27][C:22]1([F:26])[CH2:21][CH2:20][C:19]2[C:24](=[CH:25][C:16]([CH2:15][NH:14][C@H:10]3[CH2:11][CH2:12][CH2:13][NH:8][C@H:9]3[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[C:17]([O:28][CH3:29])[CH:18]=2)[CH2:23]1
Reactant: COc1cc2c(cc1CN[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1)CC(F)(F)CC2
Agent: COc1ccc(C(C)(C)C#CC(F)(F)F)cc1CN[C@H]1CCCN[C@H]1c1ccccc1
Agent: Cl
Product: COc1cc2c(cc1CN[C@H]1CCCN[C@H]1c1ccccc1)CC(F)(F)CC2

Procedure:
This compound was prepared from Compound 97 in the same manner of Compound 60.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:7]2[O:11][CH:10]=[CH:9][C:8]=2[CH:12]=1)([O-])=O>CCOC(C)=O.O=[Pt]=O>[N:13]1([C:6]2[C:7]3[O:11][CH:10]=[CH:9][C:8]=3[CH:12]=[C:4]([NH2:1])[CH:5]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=[N+]([O-])c1cc(N2CCCCC2)c2occc2c1
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: Nc1cc(N2CCCCC2)c2occc2c1
Reaction time: 36 h

Procedure:
1-(5-Nitro-1-benzofuran-7-yl)piperidine (630 mg, 2.56 mmol; Intermediate 4) was dissolved in EtOAc (50 mL), PtO2 added and the mixture stirred under H2 for 36 h. Filtration through Celite and concentration of the filtrate furnished 7-piperidin-1-yl-1-benzofuran-5-amine. Yield: 540 mg (98%). 1H NMR (400 MHz, CDCl3) δ ppm 1.59-1.65 (m, 2H), 1.71-1.83 (m, 4H), 3.21-3.26 (m, 4H), 3.55 (br s, 2H), 6.19 (d, 1H), 6.45 (d, 1H), 6.56 (d, 1H), 7.51 (d, 1H); GC-MS (EI+) for C13H16N2O m/z 216 M+.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([CH:14]([OH:17])[C:15]#[CH:16])[CH:5]=[C:4]([O:18][CH2:19][CH2:20][O:21][CH2:22][CH3:23])[C:3]1=2.Cl>CCCCCCC.C(OC=C)(=O)C.C([O-])([O-])=O.[K+].[K+].CO>[CH3:1][C:2]1([CH3:24])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C@H:14]([OH:17])[C:15]#[CH:16])[CH:5]=[C:4]([O:18][CH2:19][CH2:20][O:21][CH2:22][CH3:23])[C:3]1=2
Reactant: C#CC(O)c1cc(OCCOCC)c2c(c1)C(C)(C)CCC2(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCCC
Solvent: CO
Solvent: C=COC(C)=O
Product: C#C[C@@H](O)c1cc(OCCOCC)c2c(c1)C(C)(C)CCC2(C)C
Temperature: 38 °C
Reaction time: 72 h
Yield: 41 %

Procedure:
36 g (110 mmol) of 1-[5,5,8,8-tetramethyl-4-(2-ethoxyethoxy)-5,6,7,8-tetrahydronaphth-2-yl]prop-2-yn-1-ol (Example 2b) are dissolved in 75 mL of heptane and 10.2 ml of vinyl acetate. 7.26 g of enzyme PS30 are added, and the reaction medium is stirred and heated to 38° C. After 72 hours, the reaction medium is filtered and concentrated under reduced pressure. Two products are separated out by chromatography: 1-[5,5,8,8-tetramethyl-4-(2-ethoxyethoxy)-5,6,7,8-tetrahydronaphth-2-yl]prop-2-yn-1-ol (R)-acetate and (S)-1-[5,5,8,8-tetramethyl-4-(2-ethoxyethoxy)-5,6,7,8-tetrahydronaphth-2-yl]prop-2-yn-1-ol, which will be used for Example 5.18 g (48 mmol) of 1-[5,5,8,8-tetramethyl-4-(2-ethoxyethoxy)-5,6,7,8-tetrahydronaphth-2-yl]prop-2-yn-1-ol (R)-acetate are thus dissolved in 500 mL of a 2% solution of K2CO3 in methanol and the medium is stirred for 3 hours. The reaction medium is then treated with 0.01N hydrochloric acid solution and extracted with ethyl acetate. The residue obtained is purified by chromatography (eluent: 8/2 heptane/EtOAc). A colorless oil is obtained (m=15 g, yield=41%).
Reaction SMILES: Cl.[CH2:2]1[C:4]2([CH2:9][O:8][CH2:7][CH2:6][NH:5]2)[CH2:3]1.Br[CH2:11][CH2:12][OH:13].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.[Cl-].[Na+].O>[OH:13][CH2:12][CH2:11][N:5]1[CH2:6][CH2:7][O:8][CH2:9][C:4]21[CH2:3][CH2:2]2
Reactant: OCCBr
Reactant: C1COCC2(CC2)N1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Product: OCCN1CCOCC12CC2
Temperature: 90 °C
Reaction time: 48 h

Procedure:
A mixture of 7-oxa-4-azaspiro[2.5]octane hydrochloride (200 mg), 2-bromoethanol (0.28 ml) and potassium carbonate (550 mg) in N,N-dimethylformamide (2 ml) was stirred at 90° C. for 48 hours and cooled. The mixture was poured into brine and extracted with dichloromethane. The extract was dried over magnesium sulfate and evaporated under reduced pressure, and purified by column chromatography on silica gel using a mixture of methanol and chloroform (2:98) to give 4-(2-hydroxyethyl)-7-oxa-4-azaspiro[2.5]octane as an oil. This oil was dissolved in ethyl acetate (5 ml) and the solution was added methanesulfonyl chloride (0.16 ml) and triethylamine (0.3 ml). After 30 minutes of stirring at room temperature, the mixture was filtered, evaporated, and purified by column chromatography on silica gel using a mixture of ethyl acetate and n-hexane (20:80˜30:70) to give 4-(2-chloroethyl)-7-oxa-4-azaspiro[2.5]octane (140 mg) as an oil.
Reaction SMILES: C(O)(=O)CC(CC(O)=O)(C(O)=O)O.ClC1C=C([C@H](CC[N:42]2[CH2:47][CH2:46][CH:45]([C:48]3[CH:53]=[CH:52][C:51]([O:54][CH3:55])=[CH:50][C:49]=3[S@:56]([CH3:58])=O)[CH2:44][CH2:43]2)CN(C)C(C2C3C(=CC=CC=3)C=C(C#N)C=2)=O)C=CC=1Cl.FC(F)(F)C(O)=O>>[CH3:55][O:54][C:51]1[CH:52]=[CH:53][C:48]([CH:45]2[CH2:46][CH2:47][NH:42][CH2:43][CH2:44]2)=[C:49]([S:56][CH3:58])[CH:50]=1
Reactant: COc1ccc(C2CCN(CC[C@H](CN(C)C(=O)c3cc(C#N)cc4ccccc34)c3ccc(Cl)c(Cl)c3)CC2)c([S@](C)=O)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C2CCNCC2)c(SC)c1

Procedure:
1-Benzyloxycarbonyl-4-[4-methoxy-2-methylthiophenyl]piperidine (Example 2) was N-deprotected using trifluoroacetic acid under standard conditions to give 4-[4-methoxy-2-methylthiophenyl]piperidine; 1H NMR (CDCl3) δ 7.15 (d, 1H), 6.76 (d, 1H), 6.69 (dd, 1H), 3.80 (s, 3H), 3.18 (dm, 2H), 3.01 (tt, 1H), 2.78 (td, 2H), 2.45 (s, 3H), 1.82 (dm, 2H), 1.66 (s, 1H), 1.58 (qd, 2H); MS m/z 238 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=2[O:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].CO[CH:18](OC)[N:19]([CH3:21])[CH3:20]>>[CH2:10]([O:9][C:7]([C:6]1[O:5][C:4]2[CH:12]=[CH:13][CH:14]=[CH:15][C:3]=2[C:2]=1[N:1]=[CH:18][N:19]([CH3:21])[CH3:20])=[O:8])[CH3:11]
Reactant: COC(OC)N(C)C
Reactant: CCOC(=O)c1oc2ccccc2c1N
Product: CCOC(=O)c1oc2ccccc2c1N=CN(C)C
Temperature: 25 °C
Yield: 75 %

Procedure:
A mixture of 4.2 g (20.0 mmol) of ethyl 3-amino -2-benzo[b]furancarboxylate (EP 187487 A1) in 10 mL of N,N-dimethylformamide dimethyl acetal is heated at reflux temperature for 1.5 hours, then cooled to room temperature and concentrated in vacuo. The residue is partitioned between ethyl acetate and water. The organic layer is washed with water, dried over sodium sulfate, passed through a pad of diatomaceous earth and concentrated in vacuo. The solid is collected by filtration to provide 3.90 g (75%) of a white solid, mp 89-90° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].[F:21][C:22]1[CH:28]=[CH:27][C:26](B2OC(C)(C)C(C)(C)O2)=[CH:25][C:23]=1[NH2:24]>>[NH2:24][C:23]1[CH:25]=[C:26]([C:2]2[CH:3]=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]3=[O:20])[CH:27]=[CH:28][C:22]=1[F:21]
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Reactant: CC1(C)OB(c2ccc(F)c(N)c2)OC1(C)C
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(F)c(N)c3)ccn2c1=O
Yield: 102.8 %

Procedure:
Methyl 8-(3-amino-4-fluoro-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A from methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (100 mg, 0.34 mmol) and 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-aniline (122 mg, 0.51 mmol). Purification by flash silica column chromatography (DCM:MeOH) (1:0 to 94:6) afforded the title compound as a yellow solid (128 mg, 98%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[N:7]([CH2:18][CH2:19][OH:20])[CH2:8][CH:9](O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:7]1[CH2:18][CH2:19][O:20][CH:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8]1)=[O:21])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(CCO)CC(O)Cc1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCOC(Cc2ccccc2)C1
Reaction time: 8 h

Procedure:
The above compound could be made in the following manner: 1 eq. of (2-Hydroxy-ethyl)-(2-hydroxy-3-phenyl-propyl)-carbamic acid tert-butyl ester and 1.2 eq. of triphenylphosphine could be dissolved in toluene. 1.2 eq. of diethylazodicarboxylate in toluene could be added dropwise to the resulting solution at room temperature under argon atmosphere and the mixture could be stirred overnight. The solvent could be removed in vacuo and the material purified by column chromatography.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[CH3:12].[CH:13](O)=O.Cl.[OH-].[NH4+]>O>[CH3:12][C:3]1[C:2]2[NH:1][CH:13]=[N:8][C:7]=2[CH:6]=[CH:5][C:4]=1[N+:9]([O-:11])=[O:10]
Reactant: Cc1c([N+](=O)[O-])ccc(N)c1N
Reactant: O=CO
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: Cc1c([N+](=O)[O-])ccc2nc[nH]c12
Temperature: 25 °C

Procedure:
A mixture of 11.8 g of 2,3-diamino-6-nitrotoluene, 390 mL of 88% formic acid and 38 mL of 12N hydrochloric acid is heated to reflux for 1 hour. The resulting mixture is cooled to room temperature and rotary evaporated. The residue is diluted with 200 mL of water, then basified with ammonium hydroxide (28-30%). The suspension is extracted with ethyl acetate (3×200 mL). The combined extracts are dried over magnesium sulfate and rotary evaporated to provide 4-methyl-5-nitrobenzimidazole as an orange solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C([Al](CC(C)C)CC(C)C)C(C)C.[C:20]1([C:26]2[C:27]([OH:47])=[C:28]([C:42](OCC)=[O:43])[C:29]([C:38]([F:41])([F:40])[F:39])=[N:30][C:31]=2[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl.C1(C)C=CC=CC=1>[C:20]1([C:26]2[C:27]([OH:47])=[C:28]([C:42]([NH:1][C:2]3[S:3][CH:4]=[CH:5][N:6]=3)=[O:43])[C:29]([C:38]([F:40])([F:41])[F:39])=[N:30][C:31]=2[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(-c2ccccc2)c(-c2ccccc2)c1O
Reactant: Nc1nccs1
Agent: CC(C)C[Al](CC(C)C)CC(C)C
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C(Nc1nccs1)c1c(C(F)(F)F)nc(-c2ccccc2)c(-c2ccccc2)c1O
Reaction time: 0.33 h
Yield: 72 %

Procedure:
3.22 g of 2-aminothiazole were cooled to +2° C. in 80 ml of methylene chloride, and while maintaining the temperature between +2° and +5° C. 17.9 ml of triisobutyl aluminium in toluene (0.9M) were added and stirred for 20 minutes. 2.5 g of the product of Step D were then introduced all at once into the mixture and the temperature was brought up progressively to reflux and kept there for 24 hours then lowered to the ambient. The mixture was concentrated to dryness under reduced pressure and 50 ml of water and 50 ml of 2N hydrochloric acid were added to the residue. The mixture was triturated and the precipitate was separated and washed abundantly with water. While still humid, the latter was dissolved in tetrahydrofuran and the solution was dried and concentrated under reduced pressure. The 2.6 g of residue were triturated in ether, separated and dried to obtain 2.05 g of product melting at 256° C. After crystallizing from acetonitrile, 1.48 g of the expected product melted at 256° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH:2]=1.[Li]C(C)(C)C.N1([CH:26]=[O:27])CCCCC1.[NH4+].[Cl-]>C1COCC1>[CH:26]([C:4]1[CH:5]=[CH:6][N:1]=[CH:2][C:3]=1[NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:27]
Reactant: CC(C)(C)OC(=O)Nc1cccnc1
Reactant: O=CN1CCCCC1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cnccc1C=O
Temperature: -20 °C
Reaction time: 8 h

Procedure:
At −78° C., to a solution of tert-butyl pyridin-3-ylcarbamate (2.98 g, 15.34 mmol) in THF (60 mL) is added t-BuLi (1.7 N, 21.65 mL, 36.8 mmol) dropwise while maintaining the internal temperature below −70° C. Then, the mixture is allowed to warm to −20° C. for 2 hr and piperidine-1-carbaldehyde (5.11 mL, 46.02 mmol) is added dropwise and the mixture is stirred at −20° C. to rt overnight. Saturated NH4Cl solution (30 mL) is added and the layers are separated. The aqueous layer is extracted with EtOAc (45 ml) and the combined extracts are dried and evaporated. The residue is purified by flash column with hexane/EtOAc (4:1) to give the title compound as a white solid. MS (M+1): 223.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][CH:11]=[C:12]([C:15]([CH3:17])=O)[C:13]=2[OH:14])[CH:5]=[CH:6][C:7]=1[Cl:8].O.[NH2:19][NH2:20]>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][CH:11]=[C:12]([C:15](=[N:19][NH2:20])[CH3:17])[C:13]=2[OH:14])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NN
Reactant: CC(=O)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Solvent: CC(C)O
Solvent: O
Product: CC(=NN)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Temperature: 25 °C
Yield: 70.3 %

Procedure:
2-(3,4-Dichlorophenyl)-3-hydroxy-4-(methylcarbonyl)thiophene (50 mg, 0.17 mmol) (prepared by the method disclosed in WO2004/108683) in isopropanol was stirred with hydrazine monohydrate (95 μL/0.19 mmol) at 90° C. for 1 hour, then allowed to cool to room temperature and stirred at 0° C. The precipitated solid was collected by filtration and dried to give 36 mg of the desired product (yield 69%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][N:8]([CH:17]1[CH2:22][CH2:21][N:20]([C:23](=[O:31])[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([NH2:30])[CH:25]=2)[CH2:19][CH2:18]1)[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Cl:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37](Cl)=[O:38]>CC(C)=O.O>[CH3:7][N:8]([CH:17]1[CH2:22][CH2:21][N:20]([C:23](=[O:31])[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][C:37](=[O:38])[CH2:36][CH2:35][CH2:34][CH2:33][Cl:32])[CH:25]=2)[CH2:19][CH2:18]1)[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CN(CCc1ccccc1)C1CCN(C(=O)c2cccc(N)c2)CC1
Reactant: O=C(Cl)CCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CN(CCc1ccccc1)C1CCN(C(=O)c2cccc(NC(=O)CCCCCl)c2)CC1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
1.3 g of potassium carbonate was added to a solution of 2.0 g of 4-[N-methyl-N-(2-phenylethyl)amino]-1-(3-aminobenzoyl)piperidine in 30 ml of acetone and 20 ml of water. Thereto was dropwise added 0.9 ml of 5-chlorovaleryl chloride with ice-cooling. The mixture was stirred at the same temperature for 20 minutes. The reaction mixture was poured into ice water. The mixture was extracted with methylene chloride. The extract was washed with a saturated aqueous sodium chloride solution, dried with magnesium sulfate, and concentrated under reduced pressure to obtain 2.2 g of 4-[N-methyl-N-(2-phenylethyl)amino]-1-[3-(5-chlorovalerylamino)benzoyl]piperidine as a colorless oil.