Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C:4]1[C:14]([F:15])=[C:13]([NH:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)[C:5]=1[F:30])=[N+]=[N-].[BH4-].[Na+].O>CO>[NH2:1][C:4]1[C:14]([F:15])=[C:13]([NH:16][C:17](=[O:22])[C:18]([CH3:20])([CH3:21])[CH3:19])[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)[C:5]=1[F:30]
Reactant: CCOC(=O)c1c(NC(=O)C(C)(C)C)c(F)c(N=[N+]=[N-])c(F)c1OC1CCCCO1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCOC(=O)c1c(NC(=O)C(C)(C)C)c(F)c(N)c(F)c1OC1CCCCO1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 93.7 %

Procedure:
4.64 g (10.9 mmol) of the above ethyl 4-azido-3,5-difluoro-6-pivaloylamino-2-(2-tetrahydropyranyloxy)benzoate was dissolved in 100 mL of methanol, 2.90 g (76.7 mmol) of sodium borohydride was added in several portions under ice-cooling, 10 mL of water was further added and the mixture was stirred at room temperature for 4.5 hours. The solvent was distilled off under reduced pressure, water was added and the mixture was extracted once with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol=100:1) to give 4.09 g of ethyl 4-amino-3,5-difluoro-6-pivaloylamino-2-(2-tetrahydropyranyloxy)benzoate (yield: 94%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][N:12]=2)=[N:6][CH:7]=1.[C:17]([C:19]1[CH:20]=[C:21]([CH:43]=[CH:44][C:45]=1[CH3:46])[C:22]([NH:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][N:32]2[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]2)=[C:27]([C:39]([F:42])([F:41])[F:40])[CH:26]=1)=[O:23])#[CH:18]>>[CH3:46][C:45]1[CH:44]=[CH:43][C:21]([C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([CH2:31][N:32]3[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]3)=[C:27]([C:39]([F:40])([F:42])[F:41])[CH:26]=2)=[O:23])=[CH:20][C:19]=1[C:17]#[C:18][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][N:12]=2)=[N:6][CH:7]=1
Reactant: C#Cc1cc(C(=O)Nc2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)ccc1C
Reactant: FC(F)(F)c1cnc(-c2ccc(Br)cn2)[nH]1
Product: Cc1ccc(C(=O)Nc2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1C#Cc1ccc(-c2ncc(C(F)(F)F)[nH]2)nc1

Procedure:
The title compound was prepared using 5-bromo-2-(5-trifluoromethyl-1H-imidazol-2-yl)pyridine and 3-ethynyl-4-methyl-N-[4-((4-methylpiperazin-1-yl)methyl)-3-trifluoromethylphenyl]benzamide as raw materials, according to the method described in Step 4 of Example 3.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([CH2:11][CH2:12][CH2:13]C)[NH:7][C:8]=1[C:9]#[N:10])(=[O:3])[CH3:2].[CH2:15](C1NC(C#N)=C(C#N)N=1)[CH2:16]C.C([Mg]Br)CC>>[C:1]([C:4]1[N:5]=[C:6]([CH2:11][CH2:12][CH3:13])[NH:7][C:8]=1[C:9]#[N:10])(=[O:3])[CH2:2][CH2:15][CH3:16]
Reactant: CCCc1nc(C#N)c(C#N)[nH]1
Reactant: CCCCc1nc(C(C)=O)c(C#N)[nH]1
Agent: CCC[Mg]Br
Product: CCCC(=O)c1nc(CCC)[nH]c1C#N
Yield: 49.8 %

Procedure:
Following a procedure similar to that described in Preparation 24(i), but using 2-propylimidazole-4,5-dicarbonitrile (prepared as described in Preparation 10) and propylmagnesium bromide, the title compound, melting at 94°-95° C., was obtained in a 49.8% yield.
Reaction SMILES: [CH:1]([C:4]1[C:9]([C:10](OCC)=[O:11])=[C:8]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH3:22])=[CH:17][CH:16]=2)[C:7]([CH:23]=[CH:24][CH2:25][CH2:26][CH3:27])=[C:6]([CH:28]([CH3:30])[CH3:29])[N:5]=1)([CH3:3])[CH3:2]>C(OCC)(=O)C.CCCCCC>[CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:15]2[CH:16]=[CH:17][C:18]([CH2:21][CH3:22])=[CH:19][CH:20]=2)[C:7]([CH:23]=[CH:24][CH2:25][CH2:26][CH3:27])=[C:6]([CH:28]([CH3:29])[CH3:30])[N:5]=1)([CH3:3])[CH3:2]
Reactant: CCCC=Cc1c(C(C)C)nc(C(C)C)c(C(=O)OCC)c1-c1ccc(CC)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCC=Cc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(CC)cc1

Procedure:
The title compound was prepared from the intermediate obtained in Step A by the procedure described in Example 125, Step F. 1H NMR (300 MHz, CDCl3) (reported as a mixture of olefin isomers): δ 0.73 (t, J=7.0 Hz, 3 H), 1.10-1.40 (m, 18 H), 1.91 (tdd, J=7.0, 7.0, 1.0, 2 H), 2.68 (q, J=7.4 Hz, 2 H), 3.3-3.5 (m, 2 H), 4.41 (d, J=5.5 Hz, 2 H), 5.20-5.40 (m, 1 H), 6.0 (dt, J=16.0, 1.0 Hz, 1 H), 7.0 (d, J=8.5 Hz, 2 H), 7.23 (d, J=8.5 Hz, 2 H). FAB-MS: calculated for C25H35NO 366; found 366 (M+H, 100%). Rf=0.31 (10% ethyl acetate/n-hexane).
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:29])/[CH:14]=[C:15](\[C:20]2[CH:25]=[C:24]([Cl:26])[C:23]([Cl:27])=[C:22]([Cl:28])[CH:21]=2)/[C:16]([F:19])([F:18])[F:17])=[CH:9][C:8]=1[CH3:30])([CH3:4])([CH3:3])[CH3:2].C(O)(=[S:34])C.C(N(CC)CC)C>C(N(CC)CC)C.ClCCl>[C:1]([O:5][C:6](=[O:31])[C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:29])[CH2:14][C:15]([SH:34])([C:20]2[CH:25]=[C:24]([Cl:26])[C:23]([Cl:27])=[C:22]([Cl:28])[CH:21]=2)[C:16]([F:17])([F:19])[F:18])=[CH:9][C:8]=1[CH3:30])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C(=O)/C=C(\c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)ccc1C(=O)OC(C)(C)C
Reactant: CC(O)=S
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)CC(S)(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)ccc1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To 2-Methyl-4-[(E)-4,4,4-trifluoro-3-(3,4,5-trichloro-phenyl)-but-2-enoyl]-benzoic acid tert-butyl ester (1.29 g) was added thioacetic acid (6 eq.) and triethylamine (12 μL). The solution was stirred under argon at room temperature for 24 hours. More thioacetic acid (1 mL) and triethylamine (1 drop) were added and the solution was stirred under argon at room temperature for 72 hours. To this mixture was added a minimum of dichloromethane and then isolute. The suspension was evaporated under vacuo. The residue was purified by chromatography on silica gel (eluent: cyclohexane/dichloromethane) to give 2-Methyl-4-[4,4,4-trifluoro-3-mercapto-3-(3,4,5-trichloro-phenyl)-butyryl]-benzoic acid tert-butyl ester (573 mg).
Reaction SMILES: [CH2:1]([C:5]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:9][CH2:8][CH2:7][CH:6]1[OH:10])[CH2:2][CH2:3][CH3:4].N1C=CC=CC=1.[CH3:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1>C(Cl)Cl>[CH2:1]([C:5]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:9][CH2:8][CH2:7][CH:6]1[O:10][C:27](=[O:28])[C:26]1[CH:30]=[CH:31][C:23]([CH3:22])=[CH:24][CH:25]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: CCCCC1(C(=O)OCC)CCCC1O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCC1(C(=O)OCC)CCCC1OC(=O)c1ccc(C)cc1

Procedure:
6.42 grams of ethyl 1-n-butyl-2-hydroxy-cyclopentane carboxylate obtained in Example 16 were diluted with 60 ml of methylene chloride. At room temperature and with magnetic stirring, 3.66 ml of pyridine was slowly added, then 6.12 ml of 4-methyl-benzoyl chloride was dropwise added. Then the procedure as described in Example 23 was followed, to give 11.77 g of brown liquid. MS: m/e 332(M+′), 287(M+—OCH2CH3), 213(M+—CH3C6H4CO), 197(M+—CH3C6H4CO2), 119 (base), 91.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[CH:4][CH:3]=1.[N:10]1([C:15]2[CH:16]=[C:17]([C:21]3[N:26]=[C:25]([N:27]4[CH2:32][CH2:31][CH:30]([CH2:33][NH:34][C:35](=[O:45])[C:36]5[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[C:38]([OH:44])[CH:37]=5)[CH2:29][CH2:28]4)[CH:24]=[CH:23][N:22]=3)[CH:18]=[CH:19][CH:20]=2)[CH:14]=[CH:13][CH:12]=[N:11]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[N:10]1([C:15]2[CH:16]=[C:17]([C:21]3[N:26]=[C:25]([N:27]4[CH2:28][CH2:29][CH:30]([CH2:33][NH:34][C:35](=[O:45])[C:36]5[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[C:38]([O:44][CH2:6][C:5]6[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=6)[CH:37]=5)[CH2:31][CH2:32]4)[CH:24]=[CH:23][N:22]=3)[CH:18]=[CH:19][CH:20]=2)[CH:14]=[CH:13][CH:12]=[N:11]1
Reactant: Fc1ccc(CCl)cc1
Reactant: COc1cc(O)cc(C(=O)NCC2CCN(c3ccnc(-c4cccc(-n5cccn5)c4)n3)CC2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cc(OCc2ccc(F)cc2)cc(C(=O)NCC2CCN(c3ccnc(-c4cccc(-n5cccn5)c4)n3)CC2)c1
Temperature: 40 °C
Yield: 65.2 %

Procedure:
4-Fluorobenzyl chloride (15 μl, 0.12 mmol) was added to a solution of N-((1-(2-(3-(1H-pyrazol-1-yl)phenyl)pyrimidin-4-yl)piperidin-4-yl)methyl)-3-hydroxy-5-methoxybenzamide (Example 13, 55 mg, 0.11 mmol) and cesium carbonate (80 mg, 0.24 mmol) in DMF (1 ml). The reaction mixture was heated to 40° C. for 5 hours. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate and the combined organics were filtered through a hydrophobic frit and concentrated under reduced pressure. The crude residue was purified by normal phase chromatography, eluting with iso-hexane and increasing amounts of ethyl acetate to give the title compound N-((1-(2-(3-(1H-pyrazol-1-yl)phenyl)pyrimidin-4-yl)piperidin-4-yl)methyl)-3-(4-fluorobenzoxy)-5-methoxybenzamide as a white solid (42.5 mg). 1H NMR (CDCl3): δ 8.64 (1H, t, J=1.88 Hz), 8.34-8.29 (2H, m), 8.06 (1H, d, J=2.48 Hz), 7.86 (1H, ddd, J=8.02, 2.33, 1.07 Hz), 7.74 (1H, d, J=1.74 Hz), 7.54 (1H, t, J=7.90 Hz), 7.43-7.37 (2H, m), 7.11-7.05 (2H, m), 6.96 (1H, t, J=1.75 Hz), 6.91 (1H, t, J=1.74 Hz), 6.65 (1H, t, J=2.25 Hz), 6.49-6.44 (2H, m), 6.21 (1H, t, J=6.08 Hz), 5.04 (2H, s), 4.60 (2H, s), 3.82 (3H, s), 3.39 (2H, t, J=6.43 Hz), 3.01-2.92 (2H, m), 2.04-1.88 (3H, m), 1.33 (2H, qd, J=12.28, 4.12 Hz).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.[CH3:10][C:11]1([CH3:18])[NH:15][C:14](=[S:16])[NH:13][C:12]1=[S:17].[OH-].[Na+]>>[N:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH2:3][S:16][C:14]1[NH:15][C:11]([CH3:18])([CH3:10])[C:12](=[S:17])[N:13]=1
Reactant: CC1(C)NC(=S)NC1=S
Reactant: ClCc1ccccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC1(C)NC(SCc2ccccn2)=NC1=S
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Initially, 2.7 g of 2-chloromethylpyridine hydrochloride was added to a solution of 2.4g of 5,5-dimethyl-2,4-dithiohydantoin in 17 mL of 2N aqueous solution of NaOH. The reaction mixture was stirred for one hour at the room temperature, and extracted with 100 mL of chloroform (CHCl3). The CHCl3 layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (using CHCl3 as a developing solvent). As a result, 2-(2-pyridylmethylthio) was initially obtained. From the earlier fractions, the desired compound of 2-(2-pyridylmethylthio)-5,5-dimethylimidazolin-4-thione was isolated in the form of a syrup. The yield of this compound was 1.02 g with a yield ratio of 27.1%.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[Cl:10][CH2:11][CH:12]([OH:15])[CH2:13]O.O>CC1C=CC(S(O)(=O)=O)=CC=1.CCCCCC>[CH3:5][C:3]1([CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6])[O:15][CH:12]([CH2:11][Cl:10])[CH2:13][O:4]1
Reactant: CCOC(=O)CC(C)=O
Reactant: OCC(O)CCl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCCCCC
Product: CCOC(=O)CC1(C)OCC(CCl)O1
Yield: 71.9 %

Procedure:
In a similar manner to the preceding Examples, 65 g (0.5 mol) of ethyl acetoacetate are heated together with 55 g (0.5 mol) of 3-chloro-1,2-propanediol and 0.2 g of p-TSA in a water separator. 100 ml of hexane act as entraining agent. Once 9 ml of water have separated, the reaction mixture is washed with 100 ml of water, to which 1 g of NaOH is added, dried over Na2SO4 and fractionated. 80 g (72%) of 2-methyl-2-ethoxycarbonylmethyl-4-chloromethyl-1,3-dioxolane are obtained. Bp.: 124° C. (1500 Pa); IR: 1736 cm−1 (C═O, ester); MS: m/e=207 (M−15), 181, 173, 157, 144, 135, 115, 99, 75, 57, 43.
Reaction SMILES: C(OC([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([NH:18][C:19]([C:21]3[C:30](=[O:31])[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[NH:23][CH:22]=3)=[O:20])[CH:16]=2)[C:11]([CH3:33])([CH3:32])[CH2:10][CH2:9]1)=O)(C)(C)C>CC#N>[CH3:32][C:11]1([CH3:33])[C:12]2[C:17](=[CH:16][C:15]([NH:18][C:19]([C:21]3[C:30](=[O:31])[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[NH:23][CH:22]=3)=[O:20])=[CH:14][CH:13]=2)[NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(C)(C)c2ccc(NC(=O)c3c[nH]c4ccccc4c3=O)cc21
Solvent: CC#N
Product: CC1(C)CCNc2cc(NC(=O)c3c[nH]c4ccccc4c3=O)ccc21

Procedure:
N-(4,4-Dimethyl-1,2,3,4-tetrahydroquinolin-7-yl)-4-oxo-1H-quinoline-3-carboxamide (300) was synthesized following the general scheme above starting from 4,4-dimethyl-7-[(4-oxo-1H-quinolin-3-yl)carbonylamino]-1,2,3,4-tetrahydroquinoline-1-carboxylic acid tert-butyl ester (108). Yield (33%). 1H NMR (400 MHz, DMSO-d6) δ 13.23 (d, J=6.6 Hz, 1H), 12.59 (s, 1H), 8.87 (d, J=6.8 Hz, 1H), 8.33 (d, J=7.7 Hz, 1H), 7.86-7.79 (m, 3H), 7.58-7.42 (m, 3H), 3.38 (m, 2H), 1.88 (m, 2H), 1.30 (s, 6H); HPLC ret. time 2.40 min, 10-99% CH3CN, 5 min run; ESI-MS 348.2 m/z (MH+).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[N:5][N:6]=1.[Cl:7][CH2:8][CH2:9][NH:10][C:11](N[N+]([O-])=O)=[O:12].C(=O)([O-])O.[Na+]>C(O)C>[Cl:7][CH2:8][CH2:9][NH:10][C:11](=[O:12])[NH:1][C:2]1[S:3][CH:4]=[N:5][N:6]=1
Reactant: O=C(NCCCl)N[N+](=O)[O-]
Reactant: Nc1nncs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: O=C(NCCCl)Nc1nncs1
Yield: 71.9 %

Procedure:
Ten grams of 2-amino-1,3,4-thiadiazole, 16.6 g of 1-(2-chloroethyl)-3-nitrourea and 84 g of sodium hydrogencarbonate were stirred in 100 ml of diluted ethanol at a temperature of 80° C. for 2 hours. While being still hot after the reaction, the precipitated inorganic matters were removed by filtration, and the filtrate was cooled. The precipitated crystals were collected by filtration and washed with water, to obtain 14.7 g (Yield 71%) of 2-{3-(2-chloroethyl)ureido}-1,3,4-thiadiazole. The product was then treated in the same manner as in Example 1 (2), to obtain 2-{3-(2-chloroethyl)-3-nitrosoureido}-1,3,4-thiadiazole.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]([C:11]1[CH:15]=[CH:14][NH:13][CH:12]=1)=[O:10].Cl[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=[CH:19][CH:18]=1.O>CS(C)=O>[CH3:7][O:8][C:9]([C:11]1[CH:15]=[CH:14][N:13]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:12]=1)=[O:10]
Reactant: COC(=O)c1cc[nH]c1
Reactant: Clc1ccnc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1ccn(-c2ccnc3ccccc23)c1
Temperature: 100 °C
Reaction time: 23 h
Yield: 59.5 %

Procedure:
1.73 g (12.5 mmol) of potassium carbonate are added at 20° C. under an argon atmosphere to 0.625 g (5 mmol) of 3-methoxycarbonyl-1H-pyrrole and 0.82 g (5 mmol) of 4-chloroquinoline dissolved in 10 mL of dimethyl sulphoxide. After stirring at 100° C. for 23 hours, the reaction mixture is poured into 30 mL of water and then allowed to crystallise at 20° C. for 1 hour. After filtering off and air-drying the solid residue, 0.75 g of 3-methoxycarbonyl-1-(quinol-4-yl)-1H-pyrrole is obtained in the form of a beige-coloured solid melting at 156° C.
Reaction SMILES: [CH3:1][CH:2]([CH2:22][CH3:23])[CH2:3][C:4]1[CH:21]=[CH:20][C:7]([C:8]([O:10][C:11]2[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=2)=[O:9])=[CH:6][CH:5]=1.S(Cl)([Cl:26])=O>>[CH3:1][CH:2]([CH2:22][CH3:23])[CH2:3][C:4]1[CH:21]=[CH:20][C:7]([C:8]([O:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([Cl:26])=[O:16])=[CH:13][CH:12]=2)=[O:9])=[CH:6][CH:5]=1
Reactant: CCC(C)Cc1ccc(C(=O)Oc2ccc(C(=O)O)cc2)cc1
Reactant: O=S(Cl)Cl
Product: CCC(C)Cc1ccc(C(=O)Oc2ccc(C(=O)Cl)cc2)cc1

Procedure:
A mixture of (+)-4-(4'-β-methylbutylbenzoyloxy)-benzoic acid (5.7g, 0.0182m) and thionyl chloride (20ml) was refluxed for four hours. The excess thionyl chloride was distilled and the residue was used in the following reaction without purification.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:15][CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH2:10][CH2:9]1)C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[C:25]([O:24][C:22]([N:19]1[CH2:20][CH2:21][CH:16]([CH2:15][O:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH2:17][CH2:18]1)=[O:23])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CCC(COC2CCN(Cc3ccccc3)CC2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(COC2CCNCC2)CC1

Procedure:
8.04 g (21 mmol) of 1-benzyl-4-[(1-tert-butyloxycarbonylpiperidin-4-yl)methyloxy]piperidine are exhaustively hydrogenated analogously to Example 5 over palladium hydroxide on carbon in methanol.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:20])[CH2:10][C:11]1([O:19][CH2:18][CH2:17][O:16]1)[CH2:12][C:13](O)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC=CC=1.CC(C)=O.[BH4-].[Cu+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:18]1[CH2:17][O:16][C:11]([CH2:12][CH:13]=[O:14])([CH2:10][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:20])[O:19]1
Reactant: O=C(O)CC1(CC(=O)OCc2ccccc2)OCCO1
Agent: [Cu+]
Agent: O=C(Cl)C(=O)Cl
Agent: [BH4-]
Solvent: CC(C)=O
Solvent: c1ccccc1
Product: O=CCC1(CC(=O)OCc2ccccc2)OCCO1
Yield: 70 %

Procedure:
By following the procedure employed in Preparation 1, E. and F., 3,3-(ethylenedioxy)glutaric acid mono benzyl ester prepared as described above in step A. (2.937 g, 10.48 mmole) was converted to the corresponding acid chloride with oxalyl chloride (3.0 ml, 34.39 mmole) in 30 ml of benzene. The acid chloride was reduced with bis(triphenylphosphine) copper (I) tetrahydroborate (6.32 g, 10.48 mmole) and triphenylphosphine (5.5 g, 20.97 mmole) in 50 ml of acetone. There was obtained 1.930 g, 70% yield of benzyl 3,3-(ethylenedioxy)-4-formylbutyrate, as a colorless syrup.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][NH2:10].[BrH:11]>C(O)(=O)C>[BrH:11].[NH2:10][CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[OH:2]
Reactant: COc1ccccc1CN
Agent: Br
Solvent: CC(=O)O
Product: NCc1ccccc1O

Procedure:
A solution of 3.0 mL (0.023 mol) {[2-(methoxy)phenyl]methyl}amine was refluxed in 50 mL 33% HBr in glacial acetic acid until the full deprotection of the starting material. The solvent was evaporated to obtain 4.7 g 2-(aminomethyl)phenol hydrobromide: MS (EI) for C7H9NO: 124.1 (MH+).
Reaction SMILES: [CH2:1]([NH2:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].CCN(C(C)C)C(C)C.[Cl:23][CH2:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1>C(Cl)Cl>[Cl:23][CH2:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([NH:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:30])=[CH:27][CH:26]=1
Reactant: O=C(Cl)c1ccc(CCl)cc1
Reactant: CCCCCCCCCCCCN
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCCCCCCNC(=O)c1ccc(CCl)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
The resin-bound dodecylamine (described in step a, 0.0426 mmol) was swelled in DCM (1.0 mL) for 15 min at rt. DIEA (28 mg, 0.213 mmol) and 4-chloromethylbenzoyl chloride (40 mg, 0.213 mmol) were added and the reaction mixture was shaken at 0° C. for 2 h then 14 h at rt. The resin was washed successively with THF (1×15 min), MeOH (1×15 min), THF (1×15 min), MeOH (3×10 min), DMF (3×10 min), MeOH (1×5 min), THF (3×10 min), MeOH (1×5 min), DCM (3×10 min) and with Et2O (1×10 min). The resin was then dried under vacuum to afford the resin-bound 4-chloromethyl-N-dodecyl-benzamide which was used directly in the next step.
Reaction SMILES: [N:1]([C:4]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:21])[CH:5]([O:10][C:11]1[N:16]=[C:15]([O:17][CH3:18])[CH:14]=[C:13]([O:19][CH3:20])[N:12]=1)[C:6]([O:8]C)=[O:7])=[N+:2]=[N-:3].[OH-].[Na+]>CO.C1COCC1>[N:1]([C:4]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)([CH3:21])[CH:5]([O:10][C:11]1[N:12]=[C:13]([O:19][CH3:20])[CH:14]=[C:15]([O:17][CH3:18])[N:16]=1)[C:6]([OH:8])=[O:7])=[N+:2]=[N-:3]
Reactant: COC(=O)C(Oc1nc(OC)cc(OC)n1)C(C)(N=[N+]=[N-])c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(OC)nc(OC(C(=O)O)C(C)(N=[N+]=[N-])c2ccccc2)n1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
4.1 g (11 mmol) of methyl 3-azido-3-phenyl-2-(4,6-dimethoxypyrimidin-2-yl)oxybutyrate (Ex. 2) are dissolved in 100 ml of methanol/THF (1:1) and treated with 13.2 g (33 mmol) of 10% strength sodium hydroxide solution. The mixture is stirred for 6 hours at 50° C. and for 12 hours at room temperature and concentrated on a rotary evaporator. The residue is taken up in 100 ml of water and acidified to pH 2 using 10% strength hydrochloric acid. The resulting precipitate is filtered off with suction, washed with diethyl ether and dried.
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([NH2:13])[CH2:9]1)=[O:7])(C)(C)C.Cl[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][N:16]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[N+:21]([C:18]1[CH:19]=[CH:20][C:15]([NH:13][C@H:10]2[CH2:11][CH2:12][N:8]([C:6]([OH:5])=[O:7])[CH2:9]2)=[N:16][CH:17]=1)([O-:23])=[O:22]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(O)N1CC[C@H](Nc2ccc([N+](=O)[O-])cn2)C1
Reaction time: 48 h

Procedure:
To a solution of (S)-3-aminopyrrolidine-1-carboxylic acid-tert-butyl ester (5 g, 26.88 mmol) and 2-chloro-5-nitropyridine (4.26 g, 26.88 mmol) in THF (100 mL) was added potassium carbonate (7.42 g, 53.76 mmol). The mixture was refluxed for 72 hrs. The mixture was filtered and the filtrate was concentrated. The residue was extracted with ethyl acetate and water. The organic layer was dried over sodium sulfate and solvents were evaporated. The oily residue was diluted with ether (50 mL) to give a clear solution which was kept at room temperature for 48 hrs. The crystalline material was filtered to give (S)-3-(5-nitro-pyridin-2-ylamino)-pyrrolidine-1-carboxylic acid test-butyl ester (6.66 g, 80.5% yield). LCMS for C14H20N4O4 calcd (m/e) 308, obsd 307 (M−H).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)[CH:9]=[CH:8][C:7]=1[NH:19][C:20](=[O:22])[CH3:21])C.[NH4+:24].[OH-]>>[C:20]([NH:19][C:7]1[CH:8]=[CH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[CH:11][C:6]=1[CH2:5][C:4]([NH2:24])=[O:3])(=[O:22])[CH3:21]
Reactant: CCOC(=O)Cc1cc(N2CCN(C)CC2)ccc1NC(C)=O
Reactant: [NH4+]
Agent: [OH-]
Product: CC(=O)Nc1ccc(N2CCN(C)CC2)cc1CC(N)=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
[2-Acetylamino-5-(4-methyl-piperazin-1-yl)-phenyl]-acetic acid ethyl ester (450 mg, 1.41 mmol) is suspended in a 33% aqueous NH4OH solution (200 mL), and stirred for 16 h at RT. The volume is carefully reduced under vacuum until the title compound remains as a brown solid, which is further dried under high vacuum. ES+-MS: 291 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][C:10](O)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].S(Cl)(Cl)=O.[NH3:19]>C(O)C>[N+:1]([C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][C:10]([NH2:19])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: N
Reactant: O=C(O)COc1ccc([N+](=O)[O-])cc1
Solvent: O=S(Cl)Cl
Solvent: CCO
Product: NC(=O)COc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
4-Nitrophenoxyacetic acid (10.2 g) was added to thionyl chloride (50 ml) and the mixture was boiled under reflux for 1.5 hours. Excess thionyl chloride was distilled off and the residue was heated with toluene (2×50 ml) and the toluene removed by distillation to leave an oil which solidified on cooling. The acid chloride was added in portions to a stirred mixture of absolute ethanol (50 ml) and concentrated aqueous ammonia (50 ml, SG 0.880) at 10°-15° C. The mixture was stirred for 45 minutes at 10°-15° C. and then allowed to warm up to ambient temperature. The mixture was filtered to give 4-nitrophenoxyacetamide, m.p. 153°-155° C.