Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][NH:11]3)=[CH:4][C:3]=2[O:2]1.Cl.[N:24]1[CH:29]=[CH:28][C:27]([CH2:30]Cl)=[CH:26][CH:25]=1.C1CCN2C(=NCCC2)CC1.O>CN(C=O)C.C(OCC)(=O)C>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][N:11]3[CH2:30][C:27]3[CH:28]=[CH:29][N:24]=[CH:25][CH:26]=3)=[CH:4][C:3]=2[O:2]1
Reactant: c1ccc2c3c([nH]c2c1)C(c1ccc2c(c1)OCO2)NCC3
Reactant: ClCc1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc2c3c([nH]c2c1)C(c1ccc2c(c1)OCO2)N(Cc1ccncc1)CC3
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 1-(3,4-methylenedioxyphenyl)-2,3,4,9-tetrahydro-1H-β-carboline (2.92 g, 10 mmol) (prepared according to the process as disclosed in WO97/43287, Intermediate 7, page 24), 4-picolylchloride hydrochloride (1.64 g, 10 mmol) and DBU (3.1 g, 20 mmol) in DMF (50 mL) was stirred at room temperature for 16 h. Water (100 mL) and ethyl acetate (100 mL) were added to the reaction mixture. The solute, present in the organic phase, was purified by column chromatography (silica gel, ethyl acetate) to yield the product as an off-white solid.
Reaction SMILES: O[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH2:10])=O)[CH:3]=1.P(Cl)(Cl)([Cl:13])=O>>[Cl:13][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]#[N:10])[CH:3]=1
Reactant: NC(=O)c1cc(O)ncn1
Reactant: O=P(Cl)(Cl)Cl
Product: N#Cc1cc(Cl)ncn1
Temperature: 25 °C
Yield: 61.2 %

Procedure:
6-Hydroxy-4-pyrimidinecarboxamide (Intermediate 7, 563 mg, 4.05 mmol) was taken up in phosphorus oxychloride (3.9 mL, 41.8 mmol) and the resulting mixture was heated under reflux for 18 hours. The reaction mixture was allowed to cool to room temperature and evaporated under reduced pressure. The residue was poured into ice cooled water, neutralised with 0.88 ammonia solution and extracted with ethyl acetate (×3). The ethyl acetate layers were combined, dried under magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (Biotage SP4) eluting with a gradient of 0-20% ethyl acetate and iso-hexane. Product containing fractions were combined and evaporated under reduced pressure to give the title compound as a colourless oil (346 mg);
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH:25]=O)[C:5]1=[O:29])[CH:2]=[CH2:3].[N:31]1([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[CH2:1]([C@@:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH2:25][N:34]2[CH2:35][CH2:36][N:31]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:32][CH2:33]2)[C:5]1=[O:29])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](C=O)CC)C1=O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CN2CCN(C(=O)OC(C)(C)C)CC2)C1=O

Procedure:
The title compound was prepared from (S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butanal (Example 91, Step C) and tert-butyl piperazine-1-carboxylate according to the procedure described in Example 91 Step D.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[CH2:13]([O:15][C:16](=[O:38])[CH:17]([O:35][CH2:36][CH3:37])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=2)=[CH:21][CH:20]=1)[CH3:14].Cl>ClCCl>[CH2:13]([O:15][C:16](=[O:38])[CH:17]([O:35][CH2:36][CH3:37])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][C:28]2[CH:29]=[CH:30][C:31]([NH:34][S:9]([CH3:8])(=[O:11])=[O:10])=[CH:32][CH:33]=2)=[CH:21][CH:20]=1)[CH3:14]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)C(Cc1ccc(OCCc2ccc(N)cc2)cc1)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(Cc1ccc(OCCc2ccc(NS(C)(=O)=O)cc2)cc1)OCC
Temperature: 25 °C
Reaction time: 20 h
Yield: 71.9 %

Procedure:
Triethylamine (0.544 g; 2.99 mmole) and thereafter methanesulfonyl chloride (0.392 g; 2.99 mmole) were added to a solution of 3-{4-[2-(4-aminophenyl)ethoxy]phenyl}-2-ethoxypropanoic acid ethyl ester (0.89 g; 2.49 mmole) in dichloromethane (8.9 ml) at 0° C. After stirring at room temperature for 20 hours the reaction mixture was poured onto a mixture of hydrochloric acid and ice. Dichloromethane was added, the phases were separated and the organic phase was washed with water, dried (sodium sulfate), filtered and the solvent was evaporated in vacuo. Purification by chromatography on silica gel using heptane:ethyl acetate (3:2) as eluant gave 0.78 g (yield 72%) of 2-ethoxy-3-{4-[2-(4-methanesulfonylaminophenyl)ethoxy]phenyl}propanoic acid ethyl ester.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[C:8]#[N:9].C(N(C(C)C)CC)(C)C.[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[S:32](Cl)(=[O:34])=[O:33].C(OCC)(=O)C>CN(C)C=O>[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[S:32]([NH:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[C:8]#[N:9])(=[O:33])=[O:34]
Reactant: N#Cc1cccc(OCCN)c1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: N#Cc1cccc(OCCNS(=O)(=O)c2ccc3ccccc3c2)c1

Procedure:
163 mg of 3-(2-aminoethoxy)benzonitrile and 0.5 ml of diisopropylethylamine were dissolved in 10 ml of dimethylformamide. A solution of 250 mg (1.1 mmol) of 2-naphthalenesulfonyl chloride in dimethylformamide was added to the obtained solution under cooling with ice, and they were stirred under cooling with ice for 2 hours. The title compound was obtained by the same isolation process as that of step 1 in Example 1 with ethyl acetate as the extractant.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([C:15]1[C:20]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)=[CH:19][CH:18]=[C:17]([C:28]([N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)=[O:29])[CH:16]=1)[CH:9]=[CH:8]2)=[O:4].[OH-].[Na+]>CO>[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([C:20]2[C:15]([C:10]3[CH:9]=[CH:8][C:7]4[C:12](=[CH:13][CH:14]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=4)[N:11]=3)=[CH:16][C:17]([C:28]([N:30]3[CH2:31][CH2:32][CH2:33][CH2:34]3)=[O:29])=[CH:18][CH:19]=2)=[CH:26][CH:25]=1
Reactant: COC(=O)c1ccc2nc(-c3cc(C(=O)N4CCCC4)ccc3-c3ccc(Cl)cc3)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc2nc(-c3cc(C(=O)N4CCCC4)ccc3-c3ccc(Cl)cc3)ccc2c1
Yield: 96 %

Procedure:
Compound 23 from the previous step (0.63 mmol) was dissolved in 15 mL methanol, and 5 mL of 1M NaOH were added. The solution was refluxed for 2 hours, then evaporated. The residue was then dissolved in water, acidified with 5 mL of 1M HCl, and the precipitate was filtered off, washed three times with water and dried to yield 276 mg (96%) of Compound 24.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:38]=[C:39]([F:41])[CH:40]=1)[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[NH:15][C:16](=[O:37])[C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][C:18]=1[N:24]([CH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)[C:25](=[O:30])[C:26]([F:29])([F:28])[F:27].[CH:42]([CH:44]1[CH2:47][N:46]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:45]1)=O.FC(F)(F)C(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.C[N+](C)(C)C>ClCCl>[F:41][C:39]1[CH:38]=[C:4]([CH:3]=[C:2]([F:1])[CH:40]=1)[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[NH:15][C:16]([C:17]1[CH:22]=[CH:21][C:20]([NH:23][CH2:42][CH:44]2[CH2:47][N:46]([C:48]([O:50][C:51]([CH3:52])([CH3:54])[CH3:53])=[O:49])[CH2:45]2)=[CH:19][C:18]=1[N:24]([CH:31]1[CH2:32][CH2:33][O:34][CH2:35][CH2:36]1)[C:25](=[O:30])[C:26]([F:29])([F:27])[F:28])=[O:37]
Reactant: Nc1ccc(C(=O)Nc2n[nH]c3ccc(Cc4cc(F)cc(F)c4)cc23)c(N(C(=O)C(F)(F)F)C2CCOCC2)c1
Reactant: CC(C)(C)OC(=O)N1CC(C=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C[N+](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N1CC(CNc2ccc(C(=O)Nc3n[nH]c4ccc(Cc5cc(F)cc(F)c5)cc34)c(N(C(=O)C(F)(F)F)C3CCOCC3)c2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-amino-2-[tetrahydro-2H-pyran-4-yl(trifluoroacetyl)amino]benzamide (240 mg, 0.42 mmol) in dichloromethane (20 mL) were added tert-butyl 3-formylazetidine-1-carboxylate (116 mg, 0.63 mmol), trifluoroacetic acid (0.32 mL) and tetramethylammonium triacetoxyborohydride (165 mg g, 0.63 mmol). The mixture was stirred at room temperature overnight, then diluted with dichloromethane, washed with NaHCO3 sat.sol. and brine, dried over sodium sulfate and evaporated to dryness.
Reaction SMILES: C([C:3]1[CH:4]=[N:5][C:6](N2CCC(S(N3CCC(OC4C=CC(C(F)(F)F)=CC=4)CC3)(=O)=O)(C(OC)=O)CC2)=[N:7][CH:8]=1)C.[N:39]1([S:45]([NH2:48])(=[O:47])=[O:46])[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1.C([O-])=O.[NH4+].C(=O)([O-])[O-].[K+].[K+].ClC1N=CC(CC)=CN=1>CO.CN(C)C=O>[N:5]1[CH:4]=[CH:3][CH:8]=[N:7][C:6]=1[NH:48][S:45]([N:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1)(=[O:47])=[O:46]
Reactant: NS(=O)(=O)N1CCCCC1
Reactant: CCc1cnc(N2CCC(C(=O)OC)(S(=O)(=O)N3CCC(Oc4ccc(C(F)(F)F)cc4)CC3)CC2)nc1
Agent: CCc1cnc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: O=C[O-]
Solvent: CO
Solvent: CN(C)C=O
Product: O=S(=O)(Nc1ncccn1)N1CCCCC1
Temperature: 80 °C
Reaction time: 4 h
Yield: 60 %

Procedure:
Part G: Preparation of methyl 1-(5-ethyl-2-pyrimidinyl)-4-[[4-[4-(trifluoromethyl)-phenoxy]-1-piperidinyl]sulfonyl]-4-piperidinecarboxylate. To a slurry of the piperidine sulfonamide from part F (6.3 g, 12.0 mmol) in methanol (25 mL) was added ammonium formate (2.2 g, 34.5 mmol). The system was purged with nitrogen for 10 min. The nitrogen stream was removed and palladium on carbon (1.2 g of 10 weight % on activated carbon, 50% water) was added. The reaction was refluxed for forty five min, cooled, filtered through Celite under N2, and concentrated in vacuo. The residue (4.5 g, 10 mmol) was dissolved in dry dimethylformamide (20 mL) and potassium carbonate (3.45 g, 325 mmol) and 2-chloro-5-ethylpyrimidine (1.82 mL, 15 mmol) were added. The reaction was stirred at 80° C. for four hr and then concentrated in vacuo. The residue was taken up in ethyl acetate and filtered through Celite. The filtrate washed with water two times, saturated sodium chloride solution, dried over Na2SO4, filtered, and concentrated in vacuo. The product was recrystallized (methanol) to give the N-pyrimidinyl piperidine sulfonamide as a white solid (3.33 g, 60%).
Reaction SMILES: [C:1]([OH:13])(=O)[CH2:2][CH:3]1[CH:11]=[CH:10][CH2:9][CH2:8][CH:4]1[C:5]([OH:7])=O.Cl.[CH3:15][O:16][NH2:17].C1(C)C(C)=CC=CC=1>O>[CH3:15][O:16][N:17]1[C:1](=[O:13])[CH2:2][C:3]2[CH2:11][CH2:10][CH2:9][CH2:8][C:4]=2[C:5]1=[O:7]
Reactant: O=C(O)CC1C=CCCC1C(=O)O
Reactant: CON
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1C
Product: CON1C(=O)CC2=C(CCCC2)C1=O

Procedure:
A mixture of tetrahydrohomophthalic acid (9.2 g., 0.05 mole) and methoxyamine hydrochloride (4.25 g., 0.05 mole) in 125 ml. of xylene is refluxed for 90 minutes, with water collected in Dean Stark trap as it formed. The reaction mixture is cooled and concentrated by vacuum to one-half its original volume, then diluted with ethyl acetate, washed with water and dried over sodium sulfate. Recrystallization from isopropanol and ethanol, followed by drying at 100° C. for 4 hours yields 2-methoxy-5,6,7,8-tetrahydroisoquinoline-1,3(2H,4H)-dione.
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(O)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[F:33][C:34]1[CH:35]=[C:36]([CH:64]=[CH:65][C:66]=1[F:67])[C:37]([NH:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]2[CH:54]=[C:53]3[C:49]([CH2:50][N:51]([C@@H:56]([CH:61]([CH3:63])[CH3:62])[C:57]([O:59]C)=[O:58])[C:52]3=[O:55])=[CH:48][CH:47]=2)=[CH:42][CH:41]=1)=[O:38]>>[F:33][C:34]1[CH:35]=[C:36]([CH:64]=[CH:65][C:66]=1[F:67])[C:37]([NH:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]2[CH:54]=[C:53]3[C:49]([CH2:50][N:51]([C@@H:56]([CH:61]([CH3:62])[CH3:63])[C:57]([OH:59])=[O:58])[C:52]3=[O:55])=[CH:48][CH:47]=2)=[CH:42][CH:41]=1)=[O:38]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(F)c(F)c4)cc3)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(F)c(F)c4)cc3)cc2C1=O
Yield: 71 %

Procedure:
The compound of example 140 was prepared analogous to compound of example 98 by hydrolysis of compound of example 139.
Reaction SMILES: O[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[N:3]=1.O=P(Cl)(Cl)[Cl:25]>>[Cl:25][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[N:3]=1
Reactant: CCOC(=O)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1O
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1Cl
Yield: 97 %

Procedure:
The title compound was prepared by (a) of diethyl ethoxymethylenemalonate (6.3 g, 29 mmol) with 4-trifluoromethylphenylbenzamidine (5.5 g, 29 mmol) to afford 50% of ethyl 4-hydroxy-2-(4'-trifluoromethylphenyl)pyrimidine-5-carboxylate in analogy to Example 15, (b) reaction of ethyl 4-hydroxy-2-(4'-trifluoromethylphenyl)pyrimidine-5-carboxylate (3 g, 9.6 mmol) with POCl3 (49 g, 322 mmol) to afford 97% of ethyl 4-chloro-2-(4'-trifluoromethylphenyl)pyrimidine-5-carboxylate in analogy to Example 7, (c) reaction of ethyl 4-chloro-2-(4'-trifluoromethylphenyl)pyrimidine-5-carboxylate (2 g, 6 mmol) with hydrazine (0.6 g, 18 mmol) to afford 60% of ethyl 4-hydrazino-2-(4'trifluoromethylphenyl)pyrimidine-5-carboxylate in analogy to Example 18, (d) reaction of ethyl 4-hydrazino-2-(4'-trifluoromethylphenyl)pyrimidine-5-carboxylate (1 g, 3 mmol) with citraconic anhydride (1 g, 9 mmol) to afford 40% (0.5 g) of the title compound (m.p. 148-150° C.) in analogy to Example 21.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([O:18][CH3:19])=[C:13]([CH:17]=2)[C:14]([OH:16])=O)[S:3]1.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][NH2:27].Cl.CN(C)CCCN=C=NCC.CN(C)C=O>O>[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][NH:27][C:14](=[O:16])[C:13]1[CH:17]=[C:9]([CH2:8][CH:4]2[S:3][C:2](=[O:1])[NH:6][C:5]2=[O:7])[CH:10]=[CH:11][C:12]=1[O:18][CH3:19]
Reactant: NCc1ccccn1
Reactant: COc1ccc(CC2SC(=O)NC2=O)cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CC2SC(=O)NC2=O)cc1C(=O)NCc1ccccn1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 19.8 %

Procedure:
5-[(2,4-Dioxothiazolidin-5-yl)methyl]-2-methoxybenzoic acid (282 mg, 1.00 mmol), 2-picolylamine (114 mg, 1.05 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (230 mg, 1.20 mmol) and N,N-dimethylformamide (5 mL) were mixed and stirred for 5.5 hours at room temperature, which was then allowed to stand overnight. After water was added to the reaction mixture, this was made acidic and extracted with ethyl acetate. The extracted solution was dried and then concentrated. The residue was recrystallized from acetonitrile to obtain 73.7 mg (20%) of the title compound as colorless crystals.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1Cl.C(N1C=CN=C1)([N:15]1C=CN=C1)=O>C(Cl)Cl>[C:4]1([CH2:9][C:10]([NH2:15])=[O:12])[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=1
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: NC(=O)Cc1ccccc1
Reaction time: 0.67 h
Yield: 176.8 %

Procedure:
A solution of 4.23 g of 3,4-dichlorophenylacetic acid in 200 ml of methylene chloride was treated at 0° with 3.35 g of carbonyldiimidazole. The mixture was stirred for 40 min. Then, 2.86 g (0.0159 mol) of the (+) amine from the resolution which was previously described in Part D, above, was added. The mixture was stirred for 24 hr and partitioned with saturated aqueous sodium bicarbonate. The organic phase was dried and concentrated to yield 4.93 g of the named (-)-benzeneacetamide product which had an [α]D25 -24° (6.75 mg/ml in methanol). The product was dissolved in a minimum volume of methanol and treated with 1.48 g of maleic acid which had been dissolved in a minimum volume of methanol and the mixture was diluted with diethyl ether. The resultant crystals were filtered to yield 5.02 g of the named salt product, mp 167°-169°, [α]D25 -29.7° (10.0 mg/ml in methanol).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:46])[C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:9]=[C:8]([O:31][CH2:32][CH2:33][CH2:34][O:35][C:36]2[CH:41]=[CH:40][C:39]([S:42]([CH3:45])(=[O:44])=[O:43])=[CH:38][CH:37]=2)[CH:7]=1>>[CH3:45][S:42]([C:39]1[CH:38]=[CH:37][C:36]([O:35][CH2:34][CH2:33][CH2:32][O:31][C:8]2[CH:7]=[C:6]([CH:11]=[C:10]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:9]=2)[C:5]([OH:46])=[O:4])=[CH:41][CH:40]=1)(=[O:43])=[O:44]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(OCCCOc2ccc(S(C)(=O)=O)cc2)cc(C(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCCCCCCCCCCCOc1cc(OCCCOc2ccc(S(C)(=O)=O)cc2)cc(C(=O)O)c1
Yield: 77 %

Procedure:
Sodium hydroxide hydrolysis of 3-[3-[4-(methylsulfonyl) phenoxy]propoxy]-5-(octadecyloxy)benzoic acid methyl ester as in earlier Examples gave 3-[3-[4-(methylsulfonyl)phenoxy]propoxy]-5-(octadecyloxy)benzoic acid (77% yield, mp 110°-111°).
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([C:28](O)=[O:29])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl>[CH2:1]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:28]([CH:25]2[CH2:26][CH2:27][N:22]([C:20]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:21])[CH2:23][CH2:24]2)=[O:29])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CCCNCC2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C(=O)N2CCCN(Cc3ccccc3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
1-Benzyl-[1,4]-diazepane (3.78 g) and 1-tert-butoxycarbonyl-piperidine-4-carboxylic acid (5.0 g) were dissolved in DCM (150 ml) and TEA (3.6 ml) was added followed by HOBT (1.34 g) and finally EDC (4.90 g). The reaction was stirred at rt overnight. The reaction mixture was then evaporated to a minimum, re-dissolved in DCM (50 ml) and washed with saturated sodium hydrogen carbonate solution (3×50 ml) and brine (50 ml). The organic layer was dried (MgSO4) and evaporated to a crude which was purified by column chromatography [silica gel, step gradient 0-10% MeOH (containing 10% 0.880 ammonia solution) in DCM]. Fractions containing pure desired product were combined and evaporated to give the subtitled compound as a pale brown solid (7.1 g).
Reaction SMILES: [C:1]([N:5]([CH2:10][CH2:11][C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:6](=[O:9])[O:7][CH3:8])([CH3:4])([CH3:3])[CH3:2].[Br-].[CH2:21]1[CH2:25]OC[CH2:22]1>>[C:1]([N:5]([CH2:10][CH2:11][C:12]([OH:19])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:25][CH:21]=[CH2:22])[C:6](=[O:9])[O:7][CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)N(CCC(=O)c1ccccc1)C(C)(C)C
Reactant: C1CCOC1
Agent: [Br-]
Product: C=CCC(O)(CCN(C(=O)OC)C(C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
To a solution of methyl tert-butyl(3-oxo-3-phenylpropyl)carbamate (2.0 g, 7.6 mmol) in THF (200 mL) was added allymagnesium bromide (1 M, 23 mL, 23 mmol) dropwise at −78° C. under N2. After adding completely, the reaction mixture was stirred at rt overnight. The reaction was quenched with saturated aqueous NH4Cl solution, and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by preparative TLC to afford methyl tert-butyl(3-hydroxy-3-phenylhex-5-enyl)carbamate (1.05 g, 46%). 1H NMR (CDCl3): 1.12-1.31 (s, 9H), 1.83-1.91 (m, 1H), 2.05-2.11 (m, 1H), 2.38-2.48 (m, 1H), 2.58-2.63 (m, 1H), 2.93-3.01 (m, 1H), 3.21-3.31 (m, 1H), 3.56 (s, 3H), 5.01-5.12 (m, 2H), 5.45-5.56 (m, 1H), 7.15-7.19 (m, 1H), 7.21-7.36 (m, 4H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[CH:18]=[C:17]([O:19][CH2:20][O:21][CH3:22])[CH:16]=[C:15]([O:23][CH2:24][O:25][CH3:26])[C:11]=1[C:12]([OH:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][Si](C=[N+]=[N-])(C)C.CCCCCC.C(O)(=O)C>CO>[CH3:27][O:13][C:12](=[O:14])[C:11]1[C:15]([O:23][CH2:24][O:25][CH3:26])=[CH:16][C:17]([O:19][CH2:20][O:21][CH3:22])=[CH:18][C:10]=1[CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCOc1cc(COCc2ccccc2)c(C(=O)O)c(OCOC)c1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCCCCC
Solvent: CC(=O)O
Solvent: CO
Product: COCOc1cc(COCc2ccccc2)c(C(=O)OC)c(OCOC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
The above-obtained 2-(benzyloxymethyl)-4,6-bis(methoxymethoxy)benzoic acid (20 mg, 0.054 mmol) was dissolved in methanol (2 mL) and the obtained solution was added with 2.0 mol/L trimethylsilyldiazomethane-hexane solution (0.30 mL, 0.60 mmol), followed by stirring at a room temperature for 1 hour. The reaction mixture was added with acetic acid (0.050 mL) and the solvent was evaporated under reduced pressure. The residue was purified by preparative thin-layer chromatography (chloroform/methanol=100/1) to obtain 2-(benzyloxymethyl)-4,6-bis(methoxymethoxy)benzoic acid methyl ester (12 mg, 57%).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH:11]([OH:21])[C:12]1[O:13][C:14]2[C:15]([N:20]=1)=[N:16][CH:17]=[CH:18][CH:19]=2)[CH2:9][CH3:10])(C)(C)C.[C:23]([OH:29])([C:25]([F:28])([F:27])[F:26])=[O:24]>C(Cl)Cl>[OH:29][C:23]([C:25]([F:28])([F:27])[F:26])=[O:24].[NH2:7][CH:8]([CH2:9][CH3:10])[CH:11]([C:12]1[O:13][C:14]2[C:15]([N:20]=1)=[N:16][CH:17]=[CH:18][CH:19]=2)[OH:21]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(O)c1nc2ncccc2o1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(N)C(O)c1nc2ncccc2o1
Reaction time: 1 h

Procedure:
(S)-[1-(Hydroxy-oxazolo[4,5-b]pyridin-2-yl-methyl)-propyl]-carbamic acid tert-butyl ester (311 mg, 1 mmol) and MeCl2 (5 ml) were mixed and TFA (1 ml) was added at room temperature. After stirring for 1 hour, the solvent and excess TFA were removed under vacuum to produce 355 mg of 2-Amino-1-oxazolo[4,5-b]pyridin-2-yl-butan-1-ol TFA salt.
Reaction SMILES: [OH:1][C:2]([CH3:16])([CH3:15])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:9]=[N:10][C:11](Cl)=[CH:12][CH:13]=1)=[O:7].[N:17]1([C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]([F:34])([F:33])[F:32])=[O:24])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>>[OH:1][C:2]([CH3:16])([CH3:15])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:9]=[N:10][C:11]([N:20]2[CH2:21][CH2:22][N:17]([C:23](=[O:24])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([F:34])([F:32])[F:33])[CH2:18][CH2:19]2)=[CH:12][CH:13]=1)=[O:7]
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Reactant: CC(C)(O)CCNC(=O)c1ccc(Cl)nn1
Product: CC(C)(O)CCNC(=O)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 15, making variations only as required to use 6-chloropyridazine-3-carboxylic acid (3-hydroxy-3-methylbutyl)amide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide to react with piperazin-1-yl-(2-trifluoromethylphenyl)methanone, the title compound was obtained as a white powder (46.4% yield). 1H NMR (500 MHz, CDCl3) δ 8.30, 8.05, 7.75, 7.65, 7.57, 7.37, 6.98, 4.06, 3.88, 3.81-3.69, 3.64, 3.40-3.32, 1.80, 1.64, 1.30. MS (ES+) m/z 466 (M+1).