Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[NH:19][C:20](=O)[C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:14][C:13]=1[O:29][CH3:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:33])=O>>[CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:19]([Cl:33])[CH2:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:14][C:13]=1[O:29][CH3:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(-c2cc3ccccc3c(=O)[nH]2)ccc1OCCOCc1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1cc(C2=Cc3ccccc3CN2Cl)ccc1OCCOCc1ccccc1

Procedure:
The resulting 3-[4-(2-benzyloxyethoxy)-3-methoxyphenyl]isoquinolin-1-one (3.15 g) was reacted with phosphorus oxychioride (20 ml) according to the method of Example 10-2, to give 3-(4-(2-benzyloxyethoxy)-3-methoxyphenyl)-2-chloroisoquinoline. Then, N-ethylpiperazine (30 ml) and potassium carbonate (1.83 g) were added to the resulting compound as it was. The resulting mixture was reacted at 90° C. overnight. The reaction solution was evaporated, and to the resulting residue were added ethyl acetate and purified water. The ethyl acetate layer was washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated, to give 3-[4-(2-benzyloxyethoxy)-3-methoxyphenyl]-1-(4-ethylpiperazin-1-yl)isoquinoline.
Reaction SMILES: [CH2:1]([C@H:8]([NH2:25])[CH:9](C(OC(C)(C)C)=O)[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:26]>CO>[ClH:26].[CH2:1]([C@H:8]([NH2:25])[CH2:9][O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)C(OCc1ccccc1)[C@@H](N)Cc1ccccc1
Agent: Cl
Solvent: CO
Product: N[C@H](COCc1ccccc1)Cc1ccccc1
Reaction time: 1 h
Yield: 99 %

Procedure:
(1S)-1-Benzyl-2-(benzyloxy)-N-(t-butoxycarbonyl)ethylamine (205 mg) is dissolved in a 2.3 N solution of hydrogen chloride in methanol (3 ml), and the solution is stirred for one hour. The reaction mixture is concentrated under reduced pressure, ether is added to the concentrate, and the resulting precipitate is filtered off to give 143 mg (99%) of the titled compound (Reference compound No. 12-1) as crystals.
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[CH:12]=O)=[CH:3][CH:2]=1.[S:23]1[CH2:27][C:26](=[O:28])[NH:25][C:24]1=[O:29].N1CCCCC1>C(O)C>[C:1]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:2]=[CH:3][C:4]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[CH:12]=[C:27]2[S:23][C:24](=[O:29])[NH:25][C:26]2=[O:28])=[CH:5][CH:6]=1
Reactant: O=C1CSC(=O)N1
Reactant: O=Cc1cccc(OCc2ccc(-c3ccccc3)cc2)c1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1NC(=O)C(=Cc2cccc(OCc3ccc(-c4ccccc4)cc3)c2)S1
Yield: 28.5 %

Procedure:
A mixture of the above benzaldehyde (5.00 g, 17 mmol), 2,4-thiazolidinedione (3.03 g, 26 mmol) and piperidine (0.35 ml, 3.5 mmol) in ethanol (75 ml) was stirred at reflux temperature for 16 h. The reaction mixture was cooled and the precipitated was filtered off and washed thoroughly with ethanol and dried in vacuo at 50° C. The solid was first washed with a mixture of ethyl acetate, heptane and dichloromethane (1:1:6, 40 ml) and then washed with dichloromethane (20 ml). Drying in vacuo at 50° C. afforded 1.88 g (28%) of the title compound as a solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH2:15][NH2:16])[CH:6]=[N:7][C:8]=1[O:9][CH2:10][C:11]([F:14])([F:13])[F:12].[NH2:17][C:18]1[N:23]=[C:22]([C:24](O)=[O:25])[CH:21]=[CH:20][N:19]=1>>[NH2:17][C:18]1[N:23]=[C:22]([C:24]([NH:16][CH2:15][C:5]2[CH:6]=[N:7][C:8]([O:9][CH2:10][C:11]([F:12])([F:13])[F:14])=[C:3]([Cl:2])[CH:4]=2)=[O:25])[CH:21]=[CH:20][N:19]=1
Reactant: NCc1cnc(OCC(F)(F)F)c(Cl)c1
Reactant: Nc1nccc(C(=O)O)n1
Agent: Cl
Product: Nc1nccc(C(=O)NCc2cnc(OCC(F)(F)F)c(Cl)c2)n1
Yield: 17 %

Procedure:
The title compound is prepared in 17% yield (43 mg, pale yellow oil) from (5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanamine hydrochloride (199 mg, 0.72 mmol, Amine-19) and 2-aminopyrimidine-4-carboxylic acid (100 mg, 0.72 mmol) by the similar manner in Step-1 of Example 8.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:12]([CH3:13])=[CH:11][C:10]([N+:14]([O-:16])=[O:15])=[CH:9][C:8]=1[CH3:17])(=O)=O.[Li+].[Br-:21].C(OCC)(=O)C.C1CCCCC1.O>CN1CCCC1=O>[Br:21][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([N+:14]([O-:16])=[O:15])=[CH:9][C:8]=1[CH3:17]
Reactant: [Br-]
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1OS(=O)(=O)C(F)(F)F
Agent: [Li+]
Solvent: CN1CCCC1=O
Solvent: C1CCCCC1
Solvent: O
Product: Cc1cc([N+](=O)[O-])cc(C)c1Br
Yield: 87.8 %

Procedure:
10.7 g (35.8 mmol) of 2,6-dimethyl-4-nitrophenyl trifluoromethanesulphonate (Example I) and 4.84 g (55.8 mmol) of LiBr are stirred in 120 ml of N-methylpyrrolidinone at 120° C. for 41 h. (Solvent: ethyl acetate/cyclohexane 1:4). After cooling, 80 ml of water are slowly added, and the mixture is stirred while cooling in an icebath for 1 h. The precipitate is filtered off with suction and stirred with 200 ml of petroleum ether. The solvent is removed in vacuo. 7.23 g (85%) of solid are obtained.
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]([F:20])([O:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14](O)=[O:15])[CH:7]([F:9])[F:8]>ClCCCl>[F:5][C:6]([F:20])([O:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([Cl:3])=[O:15])[CH:7]([F:9])[F:8]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cccc(OC(F)(F)C(F)F)c1
Solvent: ClCCCl
Product: O=C(Cl)c1cccc(OC(F)(F)C(F)F)c1
Reaction time: 3 h

Procedure:
39.4 parts by weight of thionyl chloride are added to a suspension of 65 parts by weight of m-(1,1,2,2-tetrafluoroethoxy)-benzoic acid in 500 parts by volume of 1,2-dichloroethane and the mixture is stirred for 3 hours under reflux. It is then concentrated under reduced pressure, and after filtering off a small amount of starting material which has precipitated, m-(1,1,2,2-tetrafluoroethoxy)-benzoyl chloride is obtained as a yellowish oil. The IR spectrum shows C=O bands at 1,770 and 1,748 cm-1 and fluoroalkoxy bands at 1,225, 1,190 and 1,125 cm-1.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1.[S:18]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19]1>>[NH:15]1[CH:16]=[CH:17][C:13]([NH:12][C:4]2[N:3]=[C:2]([C:20]3[CH:21]=[CH:22][S:18][CH:19]=3)[C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)=[N:14]1
Reactant: Clc1nc(Nc2cc[nH]n2)cc2ccccc12
Reactant: OB(O)c1ccsc1
Product: c1ccc2c(-c3ccsc3)nc(Nc3cc[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 3-thiophene boronic acid to give (1H-pyrazol-3-yl)-(1-thiophen-3-yl-isoquinolin-3-yl)-amine. LC-MS m/e 293(MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[C:6](=[O:25])[N:7]=[C:8]([C:10]3[N:15]=[C:14]([CH2:16][CH2:17][C:18]([O:20]C(C)(C)C)=[O:19])[CH:13]=[CH:12][CH:11]=3)[S:9][C:4]=2[CH:3]=1>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[C:6](=[O:25])[N:7]=[C:8]([C:10]3[N:15]=[C:14]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH:13]=[CH:12][CH:11]=3)[S:9][C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)CCc1cccc(-c2nc(=O)c3ccc(Cl)cc3s2)n1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCc1cccc(-c2nc(=O)c3ccc(Cl)cc3s2)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
tert-Butyl 3-[6-(7-chloro-4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]propanoate (0.60 g, 1.5 mmol) was dissolved in trifluoroacetic acid (5 ml), and the mixture was stirred at 0° C. for 2 hrs. The solvent was evaporated and the residue was crystallized from diisopropyl ether to give the titled compound (0.49 g, 96%) as white crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C@@H:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH3:14])[CH:7]=1.[CH2:23]([O:25][C:26]([C:28]1[C:29]2[CH:30]=[CH:31][NH:32][C:33]=2[CH:34]=[CH:35][CH:36]=1)=[O:27])[CH3:24].C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1.[Cu](I)I>[CH2:23]([O:25][C:26]([C:28]1[C:29]2[CH:30]=[CH:31][N:32]([C:2]3[CH:3]=[N:4][CH:5]=[C:6]([C@@H:8]4[CH2:12][CH2:11][CH2:10][N:9]4[C@@H:13]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=4)[CH3:14])[CH:7]=3)[C:33]=2[CH:34]=[CH:35][CH:36]=1)=[O:27])[CH3:24]
Reactant: COc1ccc([C@@H](C)N2CCC[C@H]2c2cncc(Br)c2)cc1
Reactant: CCOC(=O)c1cccc2[nH]ccc12
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1cccc2c1ccn2-c1cncc([C@@H]2CCCN2[C@H](C)c2ccc(OC)cc2)c1
Temperature: 190 °C
Yield: 42.6 %

Procedure:
A mixture of 3-bromo-5-{(S)-1-[(R)-1-(4-methoxy-phenyl)-ethyl]-pyrrolidin-2-yl}-pyridine (4.0 g, 11 mmol), 1H-indole-4-carboxylic acid ethyl ester (6.3 g, 33 mmol), K2CO3 (2.3 g, 16.6 mmol), copper iodide (0.42 g, 2.2 mmol) in NMP (22 mL) was heated in a microwave tube at 190° C. for 30 minutes. The resulting mixture was cooled to room temperature filtered through celite and concentrated under reduced pressure to give an oil. This oil was purified by silica gel column chromatography (30% ethyl acetate/heptane) to give the titled compound as a yellow solid (2.2 g, 42%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[C:7]([Cl:12])[C:3]=1[C:4]([OH:6])=[O:5].[OH-].[Na+].[C:15](O)(=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(Cl)C1C=CC=CC=1>C(O)C.C1(C)C=CC=CC=1>[CH2:15]([O:11][C:10]1[C:2]([Cl:1])=[C:3]([C:7]([Cl:12])=[CH:8][CH:9]=1)[C:4]([OH:6])=[O:5])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(O)c1ccccc1
Reactant: O=C(O)c1c(Cl)ccc(O)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: ClCc1ccccc1
Product: O=C(O)c1c(Cl)ccc(OCc2ccccc2)c1Cl
Reaction time: 1 h

Procedure:
271.6 g of 2,6-dichloro-3-hydroxybenzoic acid are dissolved in ethanol (2 l). Aqueous sodium hydroxide (242 g of 50% aqueous NaOH solution in 550 ml H2O) is added to the benzoic acid solution, followed by the addition of benzyl chloride (368 g). The reaction mixture is heated to reflux with stirring, and after one hour, additional sodium hydroxide solution (45 g of a 50% aqueous NaOH) and benzyl chloride (30 g) are added. After one hour twenty-five minutes, another 20 g of 50% sodium hydroxide solution are added. After twenty minutes, the reaction mixture is cooled and evaporated to remove ethanol. The mixture is then partitioned between diethylether (2 l) and 5% aqueous sodium hydroxide (2 l). The layers are separated and the aqueous solution washed with diethylether. The aqueous extract is cooled in an ice bath and acidified just short of neutral with conc. HCl. Diethylether (2 l) is added and the solution made strongly acidic. The two layers are stirred for fifteen minutes and separated. The aqueous layer is washed with diethylether and the combined ether layers washed with H2O, saturated sodium chloride solution, and dried over Na2SO4. The ether is filtered and the filtrate evaporated in vacuo to a light yellow oil (338.2 g). 500 ml of toluene are added to the oil and partially evaporated, resulting in a precipitate. The suspension is allowed to stand and used without further treatment for the further reactions. The toluene suspension contains a large amount of heavy crystalline precipitate.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[C:7]([N:10]([C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][S:25]([N:28]2[CH2:49][CH2:48][C:31]3([N:35]=[C:34]([C:36]4[CH:41]=[CH:40][CH:39]=[C:38]([O:42][C:43]([F:46])([F:45])[F:44])[CH:37]=4)[NH:33][C:32]3=[O:47])[CH2:30][CH2:29]2)(=[O:27])=[O:26])=[C:19]([CH3:50])[CH:18]=1)[CH2:11][CH2:12][O:13]C(=O)C)(=[O:9])[CH3:8].O>CO.C(Cl)Cl>[OH:13][CH2:12][CH2:11][N:10]([C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][S:25]([N:28]2[CH2:49][CH2:48][C:31]3([N:35]=[C:34]([C:36]4[CH:41]=[CH:40][CH:39]=[C:38]([O:42][C:43]([F:45])([F:46])[F:44])[CH:37]=4)[NH:33][C:32]3=[O:47])[CH2:30][CH2:29]2)(=[O:27])=[O:26])=[C:19]([CH3:50])[CH:18]=1)[C:7](=[O:9])[CH3:8]
Reactant: CC(=O)OCCN(C(C)=O)c1ccc(CCS(=O)(=O)N2CCC3(CC2)N=C(c2cccc(OC(F)(F)F)c2)NC3=O)c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CC(=O)N(CCO)c1ccc(CCS(=O)(=O)N2CCC3(CC2)N=C(c2cccc(OC(F)(F)F)c2)NC3=O)c(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
K2CO3 (9.1 mg, 66.0 μmol) was added to a solution of acetic acid 2-[acetyl-(3-methyl-4-{2-[4-oxo-2-(3-trifluoromethoxy-phenyl)-1,3,8-triaza-spiro[4.5]dec-1-ene-8-sulfonyl]-ethyl}-phenyl)-amino]-ethyl ester (28.1 mg, 44.0 μmol) in MeOH (0.5 mL). The mixture was stirred at room temperature for two hours. H2O was then added and the mixture was diluted with CH2Cl2. The organic layer was washed with saturated brine, and then dried over MgSO4 and concentrated under reduced pressure. The resulting residue was purified by column chromatography (CH2Cl2/MeOH=15/1) to give N-(2-hydroxy-ethyl)-N-(3-methyl-4-{2-[4-oxo-2-(3-trifluoromethoxy-phenyl)-1,3,8-triaza-spiro[4.5]dec-1-ene-8-sulfonyl]-ethyl}-phenyl)-acetamide as a white amorphous (24.0 mg, 92%).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21](O)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=2)[CH:26]=1>>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21]([NH:37][C:34]4[CH:33]=[CH:32][C:31]([C:27]5[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=5)=[CH:36][CH:35]=4)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccc(-c2cccnc2)cc1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2ccc3cnc(O)nn23)c1
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2ccc3cnc(Nc4ccc(-c5cccnc5)cc4)nn23)c1

Procedure:
N-tert-Butyl-3-[2-(4-pyridin-3-yl-phenylamino)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-benzenesulfonamide was prepared from N-tert-butyl-3-(2-hydroxy-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-benzenesulfonamide and 4-pyridin-3-yl-phenylamine in an analogous manner to Example 1052a. Product isolated as a pale yellow solid (14 mg, 9%). m.p.=250-253° C.; LCMS (m/e) 499 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.90 (s, 1H), 8.80 (s, 1H), 8.78 (s, 1H), 8.57 (s, 1H), 8.26 (d, 1H, J=7.8 Hz), 7.95 (d, 1H, J=7.9 Hz), 7.89 (d, 1H, J=7.9 Hz), 7.75 (d, 1H, J=8.5 Hz), 7.69 (d, 1H, J=8.5 Hz), 7.65-7.57 (m, 1H), 7.44-7.32 (m, 1H), 7.10 (d, 1H, J=4.7 Hz), 6.97 (s, 1H), 6.89 (d, 1H, J=4.7 Hz), 1.18 (s, 9H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10])([O-:3])=[O:2].[CH3:11][N:12](C(N(C)C)COC)C>CN(C=O)C>[NH2:12][CH:11]=[CH:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: Cc1ccccc1[N+](=O)[O-]
Reactant: COCC(N(C)C)N(C)C
Solvent: CN(C)C=O
Product: NC=Cc1ccccc1[N+](=O)[O-]
Temperature: 120 °C

Procedure:
20.6 g of o-nitrotoluene of 24 g of bis-(dimethylamino) ethoxy methane in 50 ml of DMF were initially introduced into a distillation apparatus and the mixture was heated at 120° C. for 6 h to form the β-amino-2-nitrostyrene. The ethanol was then removed by briefly applying vacuum.
Reaction SMILES: [C:1]1([CH:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])C(O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B#B.[O:19]1CCC[CH2:20]1>>[C:1]1([CH2:7][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:20][OH:19])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCCCCC(C(=O)O)c1ccccc1
Reactant: C1CCOC1
Agent: B#B
Product: OCCCCCCCCc1ccccc1

Procedure:
A solution of 8 phenyloctanoic acid (19.8 mmoles in sieve dried tetrahydrofuran (5 ml) was reduced with diborane in tetrahydrofuran (30 ml, 29.1 mmoles) at 0° C. for 4 hours to give 8-phenyloctanol. To an ice cold solution of the octanol (ca. 19.8 mmoles) and carbon tetrabromide (21.98 mmoles) in methylene chloride (50 ml) was added triphenylphosphine (22.30 mmoles) in methylene chloride (50 ml) and the resulting solution was stirred for 2.5 hours. The volatiles were evaporated and the residue was taken up in ether (100 ml), cooled in ice, and filtered. The filtrate was evaporated and distilled to afford 8-phenyloctyl bromide as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH2:13][NH:14][C@H:15]1[CH2:20][CH2:19][CH2:18][NH:17][C@H:16]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[N:9]([CH3:27])[C:8](=[O:28])[CH2:7][CH2:6]2.I.CSC1NCCN=1.[CH2:37](O)[CH2:38][CH3:39]>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH2:13][NH:14][C@H:15]1[CH2:20][CH2:19][CH2:18][N:17]([CH2:37][CH2:38][CH3:39])[C@H:16]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[N:9]([CH3:27])[C:8](=[O:28])[CH2:7][CH2:6]2
Reactant: CCCO
Reactant: COc1cc2c(cc1CN[C@H]1CCCN[C@H]1c1ccccc1)N(C)C(=O)CC2
Agent: CSC1=NCCN1
Agent: I
Solvent: CCOC(C)=O
Product: CCCN1CCC[C@H](NCc2cc3c(cc2OC)CCC(=O)N3C)[C@@H]1c1ccccc1
Yield: 21 %

Procedure:
2-Imidazolidinethione (10 g, 97.89 mmol) and methyl iodide (6.70 mL, 107.67 mmol) were stirred in 20 mL of absolute ethanol at reflux for 2 hours. The reaction was cooled and an equal volume of diethyl ether was added. The suspension was filtered to give 22.9 g (96%) of 2-methylsulfanyl-4,5-dihydro-1H-imidazole hydrogen iodide as an off-white solid that was used in the next reaction. 6-Methoxy-1-methyl-7-[(2S,3S)-(2-phenyl-piperidin-3-ylamino)-methyl]-3,4-dihydro-1H-quinolin-2-one (500 mg, 1.32 mmol) and 2-methylsulfanyl-4,5-dihydro-1H-imidazole hydrogen iodide (402 mg, 1.65 mmol) were stirred in 5 mL of n-propanol at reflux for 2 days. The reaction was diluted with ethyl acetate, washed 1× with satd. K2CO3, dried over MgSO4, filtered, and concentrated. Silica gel chromatography using (95:5 ethyl acetate/methanol) gave 123 mg (21%) of the title compound, a pale yellow oil. Rf=0.12 (9:1 ethyl acetate/methanol). 1H NMR (400 MHz, CDCl3): δ 0.67–0.70 (t, J=7.4 Hz, 3H), 1.36–1.49 (m, 4H), 1.72–1.79 (m, 1H), 1.92–2.04 (m, 3H), 2.39–2.43 (m, 1H), 2.51–2.55 (t, J=7.3 Hz, 2H), 2.63 (s, 1H), 2.73–2.78 (t, J=7.3 Hz, 2H), 3.12 (s, 3H), 3.16–3.19 (m, 1H), 3.30 (s, 1H), 3.34–3.38 (d, J=14.4 Hz, 1H), 3.49 (s, 3H), 3.60–3.64 (d, J=14.4 Hz, 1H), 6.46 (s, 1H), 6.60 (s, 1H), 7.15–7.32 (m, 5H). 13C NMR (100 MHz, CDCl3): δ 11.8, 19.3, 20.3, 25.4, 27.5, 29.5, 31.7, 45.1, 53.4, 55.4, 56.2, 57.9, 72.1, 109.7, 115.9, 124.8, 126.5, 127.7, 128.7, 133.3, 141.7, 152.8, 169.9. The dihydrochloride salt was prepared by the addition of 2 M HCl in ether to a solution of the product in ethyl acetate. Concentration gave a white solid.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9]([OH:13])(=[O:12])[CH:10]=[CH2:11].[C:14]([OH:18])(=[O:17])[CH:15]=[CH2:16].[C:19]([OH:23])(=[O:22])[CH:20]=[CH2:21].[CH2:24]([C:26]([CH2:31][OH:32])([CH2:29][OH:30])[CH2:27][CH3:28])[OH:25].C([O-])(=O)C=C>C(O)(=O)C>[CH3:1][N:2]([CH2:11][CH2:10][C:9]([OH:13])=[O:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:1][N:2]([CH2:16][CH2:15][C:14]([OH:18])=[O:17])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:1][N:2]([CH2:21][CH2:20][C:19]([OH:23])=[O:22])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:24]([C:26]([CH2:31][OH:32])([CH2:29][OH:30])[CH2:27][CH3:28])[OH:25]
Reactant: CNc1ccccc1
Reactant: C=CC(=O)O
Agent: C=CC(=O)[O-]
Agent: CCC(CO)(CO)CO
Solvent: CC(=O)O
Product: CN(CCC(=O)O)c1ccccc1

Procedure:
N-methylaniline (14.81 g) was added to glacial acetic acid (25 ml) containing trimethylolpropane triacrylate (16.05 g) and the mixture heated under reflux for 12 hr. The acetic acid was removed by distillation in vacuo to give a viscous oil. An infrared spectrum of the product showed that very few acrylate residues were present. Strong absorptions due to an ester and an aromatic amine group were present (1740 and 1600 cm−1).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C@H:10]([C@H:15]([OH:17])[CH3:16])[C:11]([O:13]C)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>C1COCC1.CO>[C:1]1([CH2:7][CH2:8][CH2:9][C@H:10]([C@H:15]([OH:17])[CH3:16])[C:11]([OH:13])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)[C@H](CCCc1ccccc1)[C@@H](C)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@@H](O)[C@@H](CCCc1ccccc1)C(=O)O
Temperature: 23 °C
Reaction time: 20 h
Yield: 82.7 %

Procedure:
To a solution of methyl (2R,3R)-2-(3-phenyl-1-propyl)-3-hydroxybutanoate (42.2 g, 179.5 mmol) in THF-methanol (3:1, 535 mL) is added 2 N aqueous sodium hydroxide solution (135 mL, 269.3 mmol). The solution is stirred at 23° C. for 20 h, then concentrated and extracted with hexanes (100 mL). The aqueous layer is acidified to pH 3 with saturated aqueous sodium bisulfate and is extracted with two 500-mL portions of EtOAc. The combined organic layers are dried over magnesium sulfate and concentrated under reduced pressure to provide (2R,3R)-2-(3-phenyl-1-propyl)-3-hydroxybutanoic acid as an oil (33.0 g, 83% yield).
Reaction SMILES: C[O:2][C:3](=[O:32])[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24](=[O:26])[CH3:25])=[C:20]([OH:27])[C:19]=2[CH2:28][CH2:29][CH3:30])[C:8]=1[CH3:31])=[O:5]>C1(C)C=CC=CC=1>[C:24]([C:21]1[CH:22]=[CH:23][C:18]([O:17][CH2:16][CH2:15][CH2:14][O:13][C:9]2[C:8]([CH3:31])=[C:7]([NH:6][C:4](=[O:5])[C:3]([OH:32])=[O:2])[CH:12]=[CH:11][CH:10]=2)=[C:19]([CH2:28][CH2:29][CH3:30])[C:20]=1[OH:27])(=[O:26])[CH3:25]
Reactant: CCCc1c(OCCCOc2cccc(NC(=O)C(=O)OC)c2C)ccc(C(C)=O)c1O
Solvent: Cc1ccccc1
Product: CCCc1c(OCCCOc2cccc(NC(=O)C(=O)O)c2C)ccc(C(C)=O)c1O

Procedure:
In analogous manner, starting from N-{3-[3-(4-acetyl-3-hydroxy-2-n-propylphenoxy)-propoxy]-2-methylphenyl}-oxamic acid methyl ester there is obtained N-{3-[3-(4-acetyl-3-hydroxy-2-n-propylphenoxy)-propoxy]-2-methylphenyl}-oxamic acid having a melting point of 146°-148° (toluene) and the triethanolammonium salt thereof having a melting point of 114°-115°,
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[N:17][N:18]([CH2:20][CH2:21][CH2:22][OH:23])[CH:19]=2)=[CH:11][C:3]=1[C:4]([N:6](CC)[CH2:7]C)=[O:5].NC1C(C(NC)=O)=C([F:35])C(Br)=CC=1>>[NH2:1][C:2]1[C:3]([C:4]([NH:6][CH3:7])=[O:5])=[C:11]([F:35])[C:12]([C:15]2[CH:16]=[N:17][N:18]([CH2:20][CH2:21][CH2:22][OH:23])[CH:19]=2)=[CH:13][CH:14]=1
Reactant: CNC(=O)c1c(N)ccc(Br)c1F
Reactant: CCN(CC)C(=O)c1cc(-c2cnn(CCCO)c2)ccc1N
Product: CNC(=O)c1c(N)ccc(-c2cnn(CCCO)c2)c1F
Yield: 34 %

Procedure:
Prepared analogously to Compound 3C replacing Compound 3D with 6-amino-3-bromo-2-fluoro-N-methylbenzamide (Compound 27D, 700 mg, 2.83 mmol) to afford 281 mg of the title compound (34%). 1H NMR (400 MHz, CD3OD) δ=7.88 (d, J=1.8 Hz, 1H), 7.76 (d, J=1.0 Hz, 1H), 7.38 (t, J=8.6 Hz, 1H), 6.59 (d, J=8.6 Hz, 1H), 4.26 (t, J=7.0 Hz, 2H), 3.54 (t, J=6.2 Hz, 2H), 2.92 (s, 3H), 1.98-2.13 (m, 2H). MS (ESI): m/z=293.87 [M+H]+. UPLC: tR=0.60 min (UPLC-SQD: analytical—2 min).
Reaction SMILES: [CH:1]1([CH:4]([O:24][CH3:25])[CH:5]([N:7]2[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[C:9]([C:16]([O:18]C(C)(C)C)=[O:17])=[C:8]2[CH3:23])[CH3:6])[CH2:3][CH2:2]1.C(C(O)=O)(F)(F)F>C(Cl)Cl>[CH:1]1([CH:4]([O:24][CH3:25])[CH:5]([N:7]2[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[C:9]([C:16]([OH:18])=[O:17])=[C:8]2[CH3:23])[CH3:6])[CH2:3][CH2:2]1
Reactant: COC(C1CC1)C(C)n1c(C)c(C(=O)OC(C)(C)C)c2cccnc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(C1CC1)C(C)n1c(C)c(C(=O)O)c2cccnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a solution of tert-butyl 1-(1-cyclopropyl-1-methoxypropan-2-yl)-2-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylate (100 mg, 0.29 mmol) in CH2Cl2 (2 mL) were added CF3CO2H (2 mL). The solution was stirred at 25° C. for 2 h. After the reaction completed, the solution was concentrated under reduced pressure to obtain 1-(1-cyclopropyl-1-methoxypropan-2-yl)-2-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid as red oil. (87 mg, yield 99%).