Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([N:16]3[CH:20]=[C:19]([CH2:21][OH:22])[CH:18]=[N:17]3)[CH:13]=[CH:12]2)=[C:4](Cl)[N:3]=1.[C:24]1([CH:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:31][NH2:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([N:16]3[CH:20]=[C:19]([CH2:21][OH:22])[CH:18]=[N:17]3)[CH:13]=[CH:12]2)=[C:4]([NH:32][CH2:31][CH:30]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:3]=1
Reactant: OCc1cnn([C@@H]2C=C[C@H](n3cnc4c(Cl)nc(Cl)nc43)C2)c1
Reactant: NCC(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: OCc1cnn([C@@H]2C=C[C@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(Cl)nc43)C2)c1

Procedure:
A mixture comprising {1-[(1S,4R)-4-(2,6-dichloro purin-9-yl)-cyclopent-2-enyl]-1H-pyrazol-4-yl}-methanol (0.675 g, 1.92 mmol), diphenylethylamine (0.398 g, 2.02 mmol) and DIPEA (0.298 g, 2.31 mmol) in dry THF (20 mL) is stirred at 35 C for 3 days. The solvent is removed in vacuo and the resulting crude residue is partitioned between DCM and 0.1 M HCl. The organic portion is separated, washed with water, brine, dried (MgSO4) and concentrated in vacuo to afford the title product.
Reaction SMILES: [C:1]([NH:24][CH:25]([CH2:39][CH:40]([CH3:42])[CH3:41])[C:26]([NH:28][C:29]1[CH:30]=[CH:31][C:32]([OH:38])=[C:33]([CH:37]=1)[C:34]([OH:36])=[O:35])=[O:27])(=[O:23])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6]/[CH:7]=[CH:8]\[CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH3:22].N[C@H:44]([C:52](O)=O)[CH2:45]C1C=CC=CC=1>>[C:1]([NH:24][CH:25]([CH2:39][C:40]1[CH:41]=[CH:52][CH:44]=[CH:45][CH:42]=1)[C:26]([NH:28][C:29]1[CH:30]=[CH:31][C:32]([OH:38])=[C:33]([CH:37]=1)[C:34]([OH:36])=[O:35])=[O:27])(=[O:23])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6]/[CH:7]=[CH:8]\[CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH3:22]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)NC(CC(C)C)C(=O)Nc1ccc(O)c(C(=O)O)c1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)NC(Cc1ccccc1)C(=O)Nc1ccc(O)c(C(=O)O)c1

Procedure:
5-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-Docosa-4,7,10,13,16,19-hexaenamido-3-phenylpropanamido)-2-hydroxybenzoic acid was prepared in a similar fashion as 5-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido-4-methylpentanamido)-2-hydroxybenzoic acid, using the appropriate phenylalanine starting material. Mass calculated for C38H46N2O5=610.78. found: [M−H]+=609.3.
Reaction SMILES: O[CH:2]([P:9](=[O:14])([O:12][CH3:13])[O:10][CH3:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.N1C=CC=CC=1.S(Br)([Br:23])=O>C(Cl)Cl>[Br:23][CH:2]([P:9](=[O:14])([O:12][CH3:13])[O:10][CH3:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=S(Br)Br
Reactant: COP(=O)(OC)C(O)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COP(=O)(OC)C(Br)c1ccccc1
Reaction time: 8 h
Yield: 88.2 %

Procedure:
In a round bottom flask 4 (1 g, 4.63 mmol, 1 eq) was dissolved in dry DCM (10 mL) and dry pyridine (0.47 mL, 5.78 mmol, 1.25 eq) was added. Thionyl bromide (0.45 mL, 5.78 mmol, 1.25 eq) was then added to the round bottom flask under inert atmosphere. The round bottom flask was sealed with a septum, cooled in an ice bath and slowly allowed to come to room temperature overnight. The solvent was then evaporated and the crude product was dissolved in ethyl acetate. The organic layer was washed with 1 M HCl, saturated NaHCO3, water, brine, then dried over Na2SO4 and filtered. The solvent was evaporated and the crude product was purified on a silica plug 1:4 (hexanes:ethyl acetate) followed by 3:7 (hexanes:ethyl acetate) to give 5 as a viscous oil (1.14 g, 88%). The product was dried under high vacuum over P2O5. 1H NMR (400 MHz, CDCl3) δ 7.56 (d, J=7.8 Hz, 2H), 7.34 (d, J=7.5 Hz, 3H), 7.26 (s, 1H), 4.88 (d, J=13.1 Hz, 1H), 3.85 (d, J=10.8 Hz, 3H), 3.60 (d, J=10.7 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 134.56 (d, JC-P=3.3 Hz), 129.70 (d, JC-P=6.7 Hz), 129.40 (d, JC-P=2.2 Hz), 129.04 (d, JC-P=1.3 Hz), 54.87 (dd, JC-P=22.1, 7.0 Hz), 41.11 (d, JC-P=159.9 Hz). 31P NMR (162 MHz, CDCl3) δ 20.55 (s). ESIMS calculated for C9H12BrO3PNa [M+Na]+300.96, found: 300.96.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:16][C@@H:17]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:18](Cl)=[O:19]>>[CH3:16][C@@H:17]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:18]([O:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1)=[O:19]
Reactant: CCCCCC[C@H](C)C(=O)Cl
Reactant: COc1ccc(-c2cccc(O)c2)cc1
Product: CCCCCC[C@H](C)C(=O)Oc1cccc(-c2ccc(OC)cc2)c1

Procedure:
Using 3'-hydroxy-4-methoxy-1,1'-biphenyl (4.2 g, 20.4 mmol) obtained in Example 1, (3) and (S)-2-methyloctanoylchloride (4.1 g, 21.5 mmol), the reaction was carried out in the same manner as described in Example 1, (5), to give the title compound as a pale yellow oil; yield: 5.4 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9](=O)[NH:8][C:7](=[O:12])[C:6]=2[CH:13]=1.C([O:16][C:17](=[O:26])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]CBr)C>CC(N(C)C)=O>[Cl:1][C:2]1[CH:13]=[C:6]([C:7]([NH:8][CH2:9][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][C:17]([OH:26])=[O:16])=[O:12])[C:5]([OH:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCCCCCCBr
Reactant: O=c1[nH]c(=O)c2cc(Cl)ccc2o1
Solvent: CC(=O)N(C)C
Product: O=C(O)CCCCCCCNC(=O)c1cc(Cl)ccc1O
Temperature: 45 °C
Reaction time: 7 h

Procedure:
222 L of dry dimethylacetamide is charged to a dry 200 gallon glass-lined reactor. The reactor agitator is set to 100–125 rpm. Cooling is applied to the condenser and valve reactor overheads are set for distillation. 41.6 kg of dry anhydrous sodium carbonate is charged to the reactor and the reactor charging port is closed. Caution is used due to some off-gassing and a slight exothermic reaction. 77.5 kg of dry 6-chloro-2H-1,3-benzoxazine-2,4(3H)-dione is charged to the reactor. Quickly, 88 kg of dry ethyl-8-bromooctanoate is charged to the reactor. The reaction is evacuated to 22–24 inches of vacuum and the reactor temperature is raised to 65–75° C. The reactor temperature is maintained and the contents are watched for foaming. The reactor mixture is sampled and monitored for conversion by monitoring for the disappearance of the bromo ester in the reaction mixture by gas chromatography. The reaction is complete after 7 hours. The vacuum is broken and the reactor contents are cooled to 45–50° C. The contents are centrifuged and the filtrate sent into a second 200 gallon glass-lined reactor. 119 L of ethanol (200 proof denatured with 0.5% toluene) is charged to the first 200 gallon reactor, warmed to about 45° C. and the filter cake washed with warm ethanol and this wash is charged to the reaction mixture in the second 200 gallon reactor.
Reaction SMILES: [OH:1][CH:2]1[C:6]2([CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]2)[O:5][CH2:4][CH2:3]1.[F:19][C:20]([F:25])([F:24])[C:21]([OH:23])=[O:22]>ClCCl>[F:19][C:20]([F:25])([F:24])[C:21]([OH:23])=[O:22].[OH:1][CH:2]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[O:5][CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)OCCC2O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: OC1CCOC12CCNCC2
Reaction time: 2 h

Procedure:
tert-Butyl 4-hydroxy-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (from step (iii) above; 300 mg) was dissolved in dichloromethane and trifluoroacetic acid (2 mL) was added. The solution was stirred for 2 h and was concentrated in vacuo to afford the product as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[N:12]1([CH:18]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[CH2:19][NH2:20])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>>[CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:20][CH2:19][CH:18]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[C:21]1[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=1)=[O:6]
Reactant: Cc1cccc(C(=O)O)c1C
Reactant: NCC(c1ccncc1)N1CCOCC1
Product: Cc1cccc(C(=O)NCC(c2ccncc2)N2CCOCC2)c1C

Procedure:
From 2,3-dimethylbenzoic acid and (2-morpholin-4-yl-2-pyridin-4-ylethyl)amine.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[S:10][C:11]([C:20]([O:22]CC)=[O:21])=[C:12]([CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19])[N:13]=2)[CH2:5][CH2:4]1.[Cl:25][C:26]1[C:30]([Cl:31])=[C:29]([CH3:32])[NH:28][C:27]=1[C:33](NC1CCN(C2SC(C3NN=NN=3)=CN=2)CC1)=[O:34].[Li+].[OH-].C1COCC1>>[Cl:25][C:26]1[C:30]([Cl:31])=[C:29]([CH3:32])[NH:28][C:27]=1[C:33]([NH:2][CH:3]1[CH2:4][CH2:5][N:6]([C:9]2[S:10][C:11]([C:20]([OH:22])=[O:21])=[C:12]([CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19])[N:13]=2)[CH2:7][CH2:8]1)=[O:34]
Reactant: CCOC(=O)c1sc(N2CCC(N)CC2)nc1COCCOC
Reactant: Cc1[nH]c(C(=O)NC2CCN(c3ncc(-c4nnn[nH]4)s3)CC2)c(Cl)c1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COCCOCc1nc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)sc1C(=O)O

Procedure:
Prepared in an analogous manner to Example 129 starting from ethyl 2-(4-aminopiperidin-1-yl)-4-[(2-methoxyethoxy)methyl]-1,3-thiazole-5-carboxylate hydrochloride (Intermediate 126) and 3,4-dichloro-5-methyl-1H-pyrrole-2-carboxylic acid (Intermediate 3). The ester product was submitted to hydrolysis using LiOH/THF at 65° C.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:14][CH:15]=2)[C:10]([CH:21]=O)=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:14][CH:15]=2)[CH:10]([CH3:21])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc2c(c1)c(C=O)cn2Cc1ccccc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc2c(c1)C(C)CN2Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A 500 mg portion of methyl 1-benzyl-3-formyl-1H-indole-5-carboxylate was dissolved in 17 ml of trifluoroacetic acid, and 2.70 ml of triethylsilane was added at 0° C., followed by stirring at room temperature for 3 hours. After evaporation of the solvent, ethyl acetate was added thereto, followed by washing with water, a saturated sodium bicarbonate aqueous solution and saturated brine and subsequent drying over anhydrous sodium sulfate. After evaporation of the solvent, the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:30 to 1:20) to obtain 433 mg of methyl 1-benzyl-3-methylindoline-5-carboxylate as a pale yellow liquid.
Reaction SMILES: [CH3:1][O:2][C@@H:3]([C@@H:12]([N:17]([CH3:25])[C:18](=[O:24])[C@H:19]([CH:21]([CH3:23])[CH3:22])[NH2:20])[C@@H:13]([CH3:16])[CH2:14][CH3:15])[CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[CH3:26][N:27]1[CH2:34][CH2:33][CH2:32][C@@:28]1([CH3:35])[C:29](O)=[O:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>ClCCl>[CH3:26][N:27]1[CH2:34][CH2:33][CH2:32][C@@:28]1([CH3:35])[C:29]([NH:20][C@H:19]([C:18]([N:17]([C@@H:12]([C@@H:13]([CH3:16])[CH2:14][CH3:15])[C@H:3]([O:2][CH3:1])[CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:9])[CH3:10])=[O:6])[CH3:25])=[O:24])[CH:21]([CH3:23])[CH3:22])=[O:30]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)OC(C)(C)C)OC)N(C)C(=O)[C@@H](N)C(C)C
Reactant: CN1CCC[C@@]1(C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)OC(C)(C)C)OC)N(C)C(=O)[C@@H](NC(=O)[C@]1(C)CCCN1C)C(C)C
Yield: 89.6 %

Procedure:
According to the general procedure D, from #6 (4.3 g, 12 mmol, 1 eq.), #150 (2.15 g, 12 mmol, 1 eq.), dichloromethane (50 mL), HATU (5.46 g, 14 mmol, 1.2 eq.), and diisopropylethylamine (8.17 mL) was synthesized the crude desired material, which was purified by silica gel chromatography (Gradient: 20 to 55% ethyl acetate in petroleum ether) to afford #202 (5.2 g, 89%) as a yellow oil. 1
Reaction SMILES: [CH3:1][O:2][Si:3](OC)([O:6][CH3:7])[O:4][CH3:5].O1[CH2:14][CH2:13][CH2:12][CH2:11]1>>[CH3:1][O:2][Si:3]([O:6][CH3:7])([O:4][CH3:5])[C:12]([CH:13]=[CH2:14])=[CH2:11]
Reactant: C1CCOC1
Reactant: CO[Si](OC)(OC)OC
Product: C=CC(=C)[Si](OC)(OC)OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
4.1 ml of the tetrahydrofuran solution of magnesium 2-(1,3-butadienyl)chloride and 6 ml of dried tetrahydrofuran were charged into a reactor in the stream of argon. Subsequently, the reactor was cooled down to 0° C., followed by gentle dropping of 1.2 ml (8 mmols) of tetramethoxysilane. While the reaction temperature was kept at 0° C., the reaction was continued for 30 minutes. After completion of the reaction, the solvent was distilled off to obtain 2-(trimethoxy)silyl-1,3-butadiene (yield: 65%).
Reaction SMILES: [CH2:1]([C:12]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[H][H]>[Pd].C(O)(=O)C>[CH2:12]([C:14]1[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=1)[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCCCC(=O)c1ccc(O)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: CCCCCCCCCCCCc1ccc(O)cc1

Procedure:
16.75 g of dodecyl chloride was dropwise added to 7.0 g of phenol and the resulting mixture was subjected to reaction at 90° C. for 30 minutes. And then, 12.0 g of AlCl3 powder was added thereto and the resulting mixture was further subjected to reaction at 100° C. for 4 hours. The reaction mixture was cooled and added to dilute hydrochloric acid. The resulting mixture was then subjected to extraction with two 50-ml portions of ethyl acetate. To the resulting solution of the reaction product in the ethyl acetate was added 80 ml of 3% aqueous sodium hydroxide solution, and the aqueous layer was then separated. To the aqueous layer was added conc hydrochloric acid to adjust the pH to 2, and the crystal, thus precipitated was filtered and washed with water to obtain 9.35 g of 4-hydroxyphenyl undecyl ketone. Subsequently, 8.0 g of the 4-hydroxyphenyl undecyl ketone thus obtained was mixed with 650 mg of a 5% active carbon-supported palladium and 100 ml of acetic acid, and the resulting mixture was subjected to reaction in a hydrogen gas stream at 50° C. for 15 hours to reduce the ketone. The reaction mixture was cooled and filtered, and acetic acid was distilled off to obtain 7.50 g of white, solid 4-dodecylphenol.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[N+:15]([O-:17])=[O:16])[CH2:10][OH:11])[CH2:5][CH2:4][CH2:3][CH2:2]1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[N+:15]([O-:17])=[O:16])[CH:10]=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=[N+]([O-])c1ccc(CO)cc1OC1CCCC1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1ccc([N+](=O)[O-])c(OC2CCCC2)c1
Temperature: 25 °C

Procedure:
To a stirred solution of 5.0 g (21.1 mmol) of 3-cyclopentoxy-4-nitrobenzyl alcohol in 200 mL of dry methylene chloride is added 19.0 g (218.5 mmol) of activated manganese dioxide in one portion. The brown suspension is warmed to reflux for 48 hours after which time the mixture is cooled to room temperature, filtered over Celite 545 and concentrated. Liquid chromatography over 200 g of silica gel eluting with 30% ethyl acetate in hexane provided the desired, analytically pure compound upon drying in vacuo.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Br:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>O1CCOCC1>[C:10]([O:9][C:7]([N:1]1[CH2:6][CH2:5][N:4]([S:28]([C:25]2[CH:26]=[CH:27][C:22]([Br:21])=[CH:23][CH:24]=2)(=[O:30])=[O:29])[CH2:3][CH2:2]1)=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.3 %

Procedure:
To a solution of tert-butyl 1-piperazine-carboxylate (932 mg, 5 mmol) and triethyl amine (836 μL, 6 mmol) in dioxane (10 mL) was added 4-bromo-benzenesulfonyl chloride (1.28 g, 5 mmol). A white precipitate begins to form almost immediately. The reaction mixture was stirred for 1 hour at room temperature and the filtered. The filtrate was concentrated in vacuo to yield the product as a shiny white solid (1.85 g, 91%). 1H NMR (CDCl3) δ 1.44 (s, 9H), 3.01 (t, 4H, J=5.1 Hz), 3.53 (t, 4H, J=5.1 Hz), 7.64 (dt, 2H, J=2.1, 8.7 Hz), 7.70 (dt, 2H, J=2.1, 8.7).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([N:11]2[CH2:16][CH2:15][C:14]([F:35])([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24](OCC4C=CC=CC=4)=O)=[CH:19][C:18]=3[F:34])[CH2:13][CH2:12]2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[C:41]([O:46][CH2:47][C@@H:48]1[O:50]C1)(=[O:45])CCC>O1CCCC1>[C:1]1([CH2:7][O:8][C:9]([N:11]2[CH2:16][CH2:15][C:14]([F:35])([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:24][C@H:47]([CH2:48][OH:50])[O:46][C:41]4=[O:45])=[CH:19][C:18]=3[F:34])[CH2:13][CH2:12]2)=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Nc1ccc(C2(F)CCN(C(=O)OCc3ccccc3)CC2)c(F)c1)OCc1ccccc1
Reactant: CCCC(=O)OC[C@H]1CO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCC(F)(c2ccc(N3C[C@H](CO)OC3=O)cc2F)CC1
Temperature: -78 °C
Reaction time: 1.25 h

Procedure:
A solution of 4-fluoro-4-[4-[[(phenylmethoxy)carbonyl]amino]-2-fluorophenyl]-1-piperidinecarboxylic acid phenylmethyl ester (EXAMPLE 74, Step 2, 2.03 g, contaminated with the elimination side product) in dry tetrahydrofuran (21 mL) at −78° C. under N2 is treated with n-butyllithium (2.80 mL, 1.6M in hexanes) dropwise over 5 mins. The resulting mixture is stirred at −78° C. for 1.25 hrs and is then treated with (R)-(−)-glycidyl butyrate (0.63 mL) dropwise. The resulting solution is stirred at −78° C. for 1 hr, warmed to ambient temperature and stirred for an additional 20 hrs, after which the reaction is quenched with saturated aqueous ammonium chloride (10 mL), diluted with water (10 mL), and the layers are separated. The organic phase is washed with saline (10 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the crude product which is chromatographed on silica gel (230-400 mesh, 250 g), eluting with methanol/methylene chloride (3/97). Pooling and concentration of those fractions with an Rf=0.51 by TLC (methanol/chloroform, 10/90) and repurification by silica gel chromatography (230-400 mesh, 100 g, methanol/methylene chloride (4/96) eluent) gives the title compound (contaminated with the elimination side product from the starting material). An analytical sample is prepared by radial chromatography (2000 m silica gel rotor, ethyl acetate/hexane (60/40) eluent), NMR (400 MHz, CDCl3) 7.45, 7.34, 7.18, 5.16, 4.74, 4.17, 3.97, 3.72, 3.22, 2.25 and 1.90δ and HRMS calculated for C23H24F2N2O5: 446.1653. Found: 446.1660.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]2[S:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:4]=2[CH:3]=1.[CH2:15]([N:17]([CH2:26][CH3:27])[C:18](=O)[CH2:19][C:20]1[S:21][CH:22]=[CH:23][CH:24]=1)[CH3:16]>>[CH:3]1[C:4]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[S:6][C:5]=2[CH:13]=[CH:14][C:2]=1[N:1]=[C:18]([N:17]([CH2:15][CH3:16])[CH2:26][CH3:27])[CH2:19][C:20]1[S:21][CH:22]=[CH:23][CH:24]=1
Reactant: Nc1ccc2sc3ccccc3c2c1
Reactant: CCN(CC)C(=O)Cc1cccs1
Product: CCN(CC)C(Cc1cccs1)=Nc1ccc2sc3ccccc3c2c1

Procedure:
The procedure of Example 28 was followed using 2-aminodibenzothiophene and N,N-diethyl-2-thiopheneacetamide giving the desired product as a solid, mp 114°-115° C. following purification on silica gel using methylene chloride.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@H:4]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH3:29])=[CH:23][CH:22]=2)[CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][C:19]=2[CH3:20])[CH2:8][CH2:7]1)[CH3:5].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl:51][C:52]1[N:60]=[CH:59][CH:58]=[C:57]([CH3:61])[C:53]=1[C:54](O)=[O:55].CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:51][C:52]1[N:60]=[CH:59][CH:58]=[C:57]([CH3:61])[C:53]=1[C:54]([NH:1][CH2:2][CH2:3][C@H:4]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH3:29])=[CH:23][CH:22]=2)[CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][C:19]=2[CH3:20])[CH2:8][CH2:7]1)[CH3:5])=[O:55]
Reactant: CCOc1ccc(N(Cc2cnccc2C)C2CCN([C@H](C)CCN)CC2)cc1
Reactant: Cc1ccnc(Cl)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccc(N(Cc2cnccc2C)C2CCN([C@H](C)CCNC(=O)c3c(C)ccnc3Cl)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.6 %

Procedure:
[1-((R)-3-Amino-1-methyl-propyl)-piperidin-4-yl]-(4-ethoxy-phenyl)-(4-methyl-pyridin-3-ylmethyl)-amine (58.0 mg, 0.15 mmol), EDCI (30.9 mg, 0.16 mmol) and HOBT (21.8 mg, 0.16 mmol) were combined in DMF (5 mL) to give a pale yellow solution. To this solution was added 2-chloro-4-methyl-nicotinic acid (27.5 mg, 0.16 mmol) followed by DIPEA (30.6 μL, 0.18 mmol) and the resulting mixture was stirred at room temperature for 16 h. Standard workup according to General Procedure C gave the crude product as a tan oil. Purification by preparative TLC (91:8:1, CH2Cl2/MeOH/NH4OH) afforded 2-chloro-N-((R)-3-{4-[(4-ethoxy-phenyl)-(4-methyl-pyridin-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-4-methyl-nicotinamide as a white foam (49.2 mg, 61%). 1H NMR (CDCl3) δ 1.02 (d, 3H, J=5 Hz), 1.25 (s, 1H), 1.35 (t, 4H, J=5 Hz), 1.58 (m, 1H), 1.84 (m, 4H), 2.15 (m, 1H), 2.35 (s, 6H), 2.54 (m, 1H), 2.86 (m, 3H), 3.31 (m, 2H), 3.78 (m, 1H), 3.93 (m, 4H), 6.66 (dd, 4H, J=9 Hz, 24 Hz), 7.00 (dd, 2H, J=6 Hz, 18 Hz), 8.01 (d, 1H, J=6 Hz), 8.35 (m, 2H). ES-MS m/z 550 (M+H). Anal. Calcd. For C31H40ClN5O2: C, 67.68; H, 7.33; Cl, 6.44; N, 12.73.
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[CH:7][N:6]=[C:5](O)[CH:4]=1)[CH3:2].[Cl:10]CCCl.P(Cl)(Cl)(Cl)=O>O>[Cl:10][C:5]1[CH:4]=[C:3]([CH2:1][CH3:2])[N:8]=[CH:7][N:6]=1
Reactant: CCc1cc(O)ncn1
Reactant: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CCc1cc(Cl)ncn1

Procedure:
To 12.4 g (0.1 mole) of 6-ethyl-4-hydroxypyrimidine was added 50 ml of 1,2-dichloroethane, and 18.4 g (0.12 mole) of phosphorus oxychloride was added thereto. The mixture was refluxed by heating for 3 hours. After cooling, water was added to the reaction mixture, and the mixture was extracted with chloroform. The chloroform layer was washed with water and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain 10.38 g of 4-chloro-6-ethylpyrimidine as slightly red liquid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([NH:16][C:17]2[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=2)[N:3]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1>>[CH3:23][O:24][C:25]1[CH:30]=[C:29]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[CH:5]=[C:4]([NH:16][C:17]3[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=3)[N:3]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: COc1cc2cc(Nc3cc(C)[nH]n3)nc(Cl)c2cc1OC
Product: COc1cccc(-c2nc(Nc3cc(C)[nH]n3)cc3cc(OC)c(OC)cc23)c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6,7-dimethoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 3-methoxy-phenylboronic acid to give [1-(3-Methoxy-phenyl)-6,7-dimethoxy-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 391(MH+).