Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=1[Cl:11].[Br:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([N:10]=[CH:17][C:16]2[CH:19]=[CH:20][CH:21]=[C:14]([Br:13])[CH:15]=2)[CH:7]=[CH:6][C:5]=1[Cl:11]
Reactant: COC(=O)c1cc(N)ccc1Cl
Reactant: O=Cc1cccc(Br)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(N=Cc2cccc(Br)c2)ccc1Cl
Temperature: 25 °C
Yield: 99.7 %

Procedure:
A mixture solution of 5-amino-2-chloro-benzoic acid methyl ester (21 g, 113.2 mmol), 3-bromo-benzaldehyde (21 g, 113.2 mmol) and p-toluenesulfonic acid (431 mg, 2.2 mmol) in toluene (200 mL) was heated to reflux for 12 hours. Then the reaction mixture was cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford 5-[(3-bromo-benzylidene)-amino]-2-chloro-benzoic acid methyl ester (39.8 g, quant.) as a pale-white solid: MS calcd. for C18H11BrClNO2 353.62, obsd. (ESI+) [(M+H)+]351.9 & 353.9.
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[O:4][C:5]1[C:18](=[O:19])[N:17]([CH2:20][C@H:21]([OH:23])[CH3:22])[C:8]2[N:9]=[C:10](S(C)(=O)=O)[N:11]=[CH:12][C:7]=2[CH:6]=1.[NH2:29][C@@H:30]([CH3:33])[CH2:31][OH:32]>C1COCC1>[F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[O:4][C:5]1[C:18](=[O:19])[N:17]([CH2:20][C@H:21]([OH:23])[CH3:22])[C:8]2[N:9]=[C:10]([NH:29][C@@H:30]([CH3:33])[CH2:31][OH:32])[N:11]=[CH:12][C:7]=2[CH:6]=1
Reactant: C[C@H](N)CO
Reactant: C[C@@H](O)Cn1c(=O)c(Oc2ccc(F)cc2F)cc2cnc(S(C)(=O)=O)nc21
Solvent: C1CCOC1
Product: C[C@@H](O)Cn1c(=O)c(Oc2ccc(F)cc2F)cc2cnc(N[C@@H](C)CO)nc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.4 %

Procedure:
To a THF (5 mL) solution of 6-(2,4-difluorophenoxy)-8-((R)-2-hydroxypropyl)-2-methanesulfonyl-8H-pyrido[2,3-d]pyrimidin-7-one (615 mg, 1.5 mmol) was added (S)-2-amino-1-propanol (1.2 mL, 15 mmol) and stirred overnight at RT. Concentrated under vacuum and chromatographed on silica gel eluding with 2% methanol in dichloromethane and converted to the hydrochloride salt to give 295 mg 6-(2,4-difluoro-phenoxy)-2-((S)-2-hydroxy-1-methyl-ethylamino)-8-((R)-2-hydroxy-propyl)-8H-pyrido[2,3-d]pyrimidin-7-one (mass spec. M+1=407, MP=186.0-189.1° C.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[CH:5]=[O:6].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]=1[C:19]([F:22])([F:21])[F:20]>>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:9]2[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=2[F:1])=[CH:14][C:13]=1[C:19]([F:20])([F:21])[F:22]
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: Oc1ccc(Cl)c(C(F)(F)F)c1
Product: O=Cc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)c(F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 3,4-difluorobenzaldehyde and 4-chloro-3-trifluoromethyl-phenol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:23]=2[N:22]([CH3:24])[C:21]([C:25](=[O:44])[NH:26][C:27]2[CH:32]=[C:31]([C:33]([CH3:36])([CH3:35])[CH3:34])[CH:30]=[C:29]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[C:28]=2[O:42][CH3:43])=[CH:20]3)[CH2:10][CH2:9]1)=[O:7])(C)(C)[CH3:2].FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:23]=2[N:22]([CH3:24])[C:21]([C:25](=[O:44])[NH:26][C:27]2[CH:32]=[C:31]([C:33]([CH3:35])([CH3:36])[CH3:34])[CH:30]=[C:29]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[C:28]=2[O:42][CH3:43])=[CH:20]3)[CH2:10][CH2:9]1)=[O:7])[CH3:2]
Reactant: COc1c(NC(=O)c2cc3cccc(OC4CCN(C(=O)OC(C)(C)C)CC4)c3n2C)cc(C(C)(C)C)cc1NS(C)(=O)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)N1CCC(Oc2cccc3cc(C(=O)Nc4cc(C(C)(C)C)cc(NS(C)(=O)=O)c4OC)n(C)c23)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-[2-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenylcarbamoyl)-1-methyl-1H-indol-7-yloxy]-piperidine-1-carboxylic acid tert-butyl ester (160 mg, 0.254 mmol) (Example 7) in dichloromethane (1 mL) was added trifluoroacetic acid (0.2 mL). The mixture was stirred at room temperature overnight and concentrated. The crude piperidine intermediate thus obtained was dried under vacuum and directly used in later reactions.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].C[Al](C)C.[CH3:9][C:10]1[N:11]=[C:12]([CH2:18][CH2:19][C:20]2[C:21]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:22][O:23][C:24]=2[CH3:25])[S:13][C:14]=1[C:15](O)=[O:16]>O1CCOCC1.C1(C)C=CC=CC=1>[CH:1]([NH:4][C:15]([C:14]1[S:13][C:12]([CH2:18][CH2:19][C:20]2[C:21]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:22][O:23][C:24]=2[CH3:25])=[N:11][C:10]=1[CH3:9])=[O:16])([CH3:3])[CH3:2]
Reactant: CC(C)N
Reactant: Cc1nc(CCc2c(-c3ccccc3)noc2C)sc1C(=O)O
Agent: C[Al](C)C
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: Cc1nc(CCc2c(-c3ccccc3)noc2C)sc1C(=O)NC(C)C
Temperature: 90 °C
Reaction time: 1 h
Yield: 54.1 %

Procedure:
To a stirred solution of isopropylamine (216 mg, 3.65 mmol) in dioxane (4 mL) under argon and at room temperature was added trimethylaluminium (1.83 mL of a 2M solution in toluene, 3.7 mmol). After 1 h, a solution of 4-methyl-2-[2-(5-methyl-3-phenyl-isoxazol-4-yl)-ethyl]-thiazole-5-carboxylic acid (300 mg, 0.91 mmol) in dioxane (4 mL) was added and the reaction mixture warmed to 90° C. After 4 h, the reaction mixture was cooled, quenched with ice water and extracted with dichloromethane. The combined extracts were washed with Seignette's salt solution then dried, filtered, and concentrated. Purification by chromatography (silica, 0 to 10% methanol in dichloromethane) gave the title compound (182 mg, 54%) as a light yellow gum. MS: m/e=370.1 [M+H]+.
Reaction SMILES: [Si:1]([O:8][C:9]1[C:17]([CH2:18]/C=C(\C)/CCC(OC)=O)=[C:16]([O:28][CH3:29])[C:15]([CH3:30])=[C:14]2[C:10]=1[C:11](=[O:31])[O:12][CH2:13]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].ClCCl.N1C=CC=CC=1.[CH3:41][OH:42]>>[Si:1]([O:8][C:9]1[C:17]([CH2:18][CH:41]=[O:42])=[C:16]([O:28][CH3:29])[C:15]([CH3:30])=[C:14]2[C:10]=1[C:11](=[O:31])[O:12][CH2:13]2)([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:3])[CH3:2]
Reactant: COC(=O)CC/C(C)=C/Cc1c(OC)c(C)c2c(c1O[Si](C)(C)C(C)(C)C)C(=O)OC2
Reactant: CO
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1c(C)c2c(c(O[Si](C)(C)C(C)(C)C)c1CC=O)C(=O)OC2
Reaction time: 0.75 h

Procedure:
A solution of methyl (E) 6-(4-t-butyldimethylsilyloxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate (11.0 g) in methanol 125 ml), dichloromethane (125 ml) and pyridine (2 ml) was cooled to -78° C. and a stream of ozonized oxygen was bubbled through. After 45 minutes a blue color developed indicating the presence of unreacted ozone. Dimethyl sulfide (5 ml) was added and the cooling bath was removed. After 16 hours the solution was washed with dilute hydrochloric acid, dilute aqueous sodium bicarbonate and then water, then dried and evaporated. The residue was chromatographed on silica gel, eluting with 2:1 hexane:ethyl acetate, so as to produce 2-(4-tert-butyldimethylsilyloxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)acetaldehyde, mp. 88°-92° C. (ether).
Reaction SMILES: C([Li])CCC.[CH:6]([C@H:9]1[N:14]=[C:13]([O:15][CH2:16][CH3:17])[CH2:12][N:11]=[C:10]1[O:18][CH2:19][CH3:20])([CH3:8])[CH3:7].[CH2:21]([C:24]1[CH:34]=[CH:33][C:27]([CH:28](Br)[SiH:29]([CH3:31])[CH3:30])=[CH:26][CH:25]=1)[CH:22]=[CH2:23].[NH4+].[Cl-]>C1COCC1>[CH2:21]([C:24]1[CH:34]=[CH:33][C:27]([CH:28]([SiH:29]([CH3:30])[CH3:31])[C@H:12]2[N:11]=[C:10]([O:18][CH2:19][CH3:20])[C@@H:9]([CH:6]([CH3:7])[CH3:8])[N:14]=[C:13]2[O:15][CH2:16][CH3:17])=[CH:26][CH:25]=1)[CH:22]=[CH2:23]
Reactant: CCOC1=N[C@H](C(C)C)C(OCC)=NC1
Reactant: C=CCc1ccc(C(Br)[SiH](C)C)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CCc1ccc(C([C@H]2N=C(OCC)[C@@H](C(C)C)N=C2OCC)[SiH](C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.1 %

Procedure:
n-Butyllithium (10.2 mL, 1.6 M solution in hexanes, 16.5 mmol) was injected into a solution of (3R)-3-isopropyl-2,5-diethoxy-3,6-dihydropyrazine (3.5 g, 16.5 mmol) in THF (70 mL) at −78° C. After 30 min of further stirring, 4-allyldimethylsilylbenzyl bromide (1 Scheme 2, 4.4 g, 16.5 mmol) in dry THF (30 mL) was added to the reaction mixture over a period of 1 h. After 1 h, saturated NH4Cl (1 mL) was added and the reaction mixture was allowed to warm to room temperature. The reaction mixture was concentrated, diluted with ethyl acetate (100 mL), and extracted with brine (20 mL×2). The organic layer was concentrated and the residue was purified by column chromatography (1:25 ethyl acetate/hexanes) to afford a colorless oil (4.7 g, 71%); 1H NMR (300 MHz, CDCl3) δ 0.28 (s; 6 H), 0.65 (d, J=6.75 Hz, 3 H), 0.96 (d, J=6.75 Hz, 3 H), 1.29 (t, J=7.05 Hz, 3 H), 1.35 (t) J=7.09 Hz, 3 H), 1.74 (d, J=8.05 Hz, 2 H), 2.19 (quintet of d, J=6.87, 3.21 Hz, 1 H), 3.10 (d, J=4.92 Hz, 2 H), 3.28 (m, 1 H), 4.07-4.24 (4 H), 4.31 (app q, J=4.50 Hz, 1 H), 4.83 (s, 1 H), 4.87 (m, 1 H), 5.77 (ddt, J=15.87, 11.13, 8.08 Hz, 1 H), 7.14 (d, J=7.98 Hz, 2 H), 7.38 (d, J=7.98 Hz, 2 H); 13C NMR (75 MHz, CDCl3) −3.4 −3.3, 14.5, 16.6, 19.1, 23.9, 31.3, 40.2, 56.7, 60.2, 60.4, 60.5, 113.3, 129.5 (2C), 133.2 (2C), 134.7, 135.9, 138.5, 162.2, 163.5; HRMS calcd for C23H36N2O2Si 400.2546, found 400.2543.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Na].[Cl:9][C:10]1[CH:11]=[CH:12][C:13]2[S:17][C:16](=[O:18])[N:15]([CH2:19][C:20](OC)=[O:21])[C:14]=2[CH:24]=1>C[O-].[Na+].CO>[OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:20]([CH2:19][N:15]2[C:14]3[CH:24]=[C:10]([Cl:9])[CH:11]=[CH:12][C:13]=3[S:17][C:16]2=[O:18])=[O:21])[CH2:4][CH2:3]1
Reactant: COC(=O)Cn1c(=O)sc2ccc(Cl)cc21
Reactant: OC1CCNCC1
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: O=C(Cn1c(=O)sc2ccc(Cl)cc21)N1CCC(O)CC1
Temperature: 0 °C
Yield: 80.8 %

Procedure:
4-Hydroxypiperidine (47.2 g) was added at room temperature to and dissolved in a methanolic sodium methoxide solution prepared from sodium metal (2.2 g) in dry methanol (100 ml). To the resultant solution was added methyl 5-chloro-2-oxo-3-benzothiazolineacetate (100 g), and the mixture was heated for 3 hours under reflux with stirring. The reaction mixture was left to cool, poured into ice water (500 ml) and stirred for 30 minutes. The precipitates were collected, washed with water and then dried to give 3-(4-hydroxypiperidino)carbonylmethyl-5-chloro-2-benzothiazolinone (102.5 g), which was recrystallized from 90% aqueous methanol to give colorless crystals, m.p. 180.1° C.
Reaction SMILES: [CH2:1]1[O:11][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:12]([NH2:16])[CH2:13][CH2:14][NH2:15]>CO>[CH2:12]([NH:16][CH2:1][CH:2]([OH:11])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:13][CH2:14][NH:15][CH2:1][CH:2]([OH:11])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCC1CO1
Reactant: NCCCN
Solvent: CO
Product: CCCCCCCCC(O)CNCCCNCC(O)CCCCCCCC

Procedure:
In a manner similar to that of Example 1, condensation of 1-decene oxide (58 g.) and 1,3-propanediamine (13.8 g.) and three recrystallizations of the resulting product from methanol gave N,N'-(1,3-propylene)-bis[2-hydroxydecylamine] (I: R = CH3 (CH2)7, R' = H, X = (CH2)3, Z = H) (8.5 g., m.p. 104.0°-107.6° C.).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:16]=[C:15]([NH2:17])[C:14]([N:18]=O)=[C:13]([NH2:20])[N:12]=1.[C:21](OCC)(=[O:28])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>>[CH2:26]([O:25][C:23]([C:22]1[C:21](=[O:28])[NH:17][C:15]2[N:16]=[C:11]([S:10][CH2:9][C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=3[F:1])[N:12]=[C:13]([NH2:20])[C:14]=2[N:18]=1)=[O:24])[CH3:27]
Reactant: Nc1nc(SCc2cccc(F)c2F)nc(N)c1N=O
Reactant: CCOC(=O)CC(=O)OCC
Product: CCOC(=O)c1nc2c(N)nc(SCc3cccc(F)c3F)nc2[nH]c1=O
Temperature: 120 °C

Procedure:
The product of Example 2, step (b) (5 g) was dissolved in diethyl malonate (100 ml) and heated to 120° C. for 10 hr, with stirring. The reaction mixture was allowed to cool and the solid that precipitated was filtered, washed with water and dried in the oven at 50° C. to yield the product as a yellow solid (3.2 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][C:15](=[O:17])O[C:13](=[O:18])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([O:23][C:24]([C@H:26]([C@@H:36]([CH2:41][CH:42]([CH3:44])[CH3:43])[C:37]([NH:39][NH2:40])=[O:38])[CH2:27]/[CH:28]=[CH:29]/[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:25])([CH3:22])([CH3:21])[CH3:20].Cl.C(N=C=NCCCN(C)C)C>ClCCl>[C:19]([O:23][C:24]([C@H:26]([C@@H:36]([CH2:41][CH:42]([CH3:44])[CH3:43])[C:37]([NH:39][N:40]1[C:13](=[O:18])[CH2:12][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:16][C:15]1=[O:17])=[O:38])[CH2:27][CH:28]=[CH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)C[C@@H](C(=O)NN)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Reactant: O=C1CN(C(=O)OCc2ccccc2)CC(=O)O1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)C[C@@H](C(=O)NN1C(=O)CN(C(=O)OCc2ccccc2)CC1=O)[C@H](CC=Cc1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.7 %

Procedure:
A solution of 0.7 g of 2,6-dioxo-4-morpholine carboxylic acid benzyl ester in 20 ml of dichloromethane was treated with 1.0 g of (E)-2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-4-methylvalerohydrazide (prepared as described in Example 1). The mixture was stirred for 1 hour at room temperature and then treated with 0.53 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride. The mixture was stirred for a further 3 hours at room temperature and then washed in sequence with 2M aqueous hydrogen chloride, 5% aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride. Drying of the organic phase over anhydrous magnesium sulphate and evaporation gave a residue which was purified by column chromatography on silica gel using ethyl acetate/ hexane (3:7) for the elution to give 1.16 g of 2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-4-methyl-N-(4-benzyloxycarbonyl-2,6-dioxo-1-piperazinyl)valeramide in the form of a white solid.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[Br:9][CH:10]([CH2:14][CH2:15][Br:16])[C:11](Cl)=[O:12].[OH-].[Na+]>ClCCl.O>[Br:9][CH:10]([CH2:14][CH2:15][Br:16])[C:11]([NH:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:12]
Reactant: O=C(Cl)C(Br)CCBr
Reactant: CCOC(=O)CN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)CNC(=O)C(Br)CCBr
Temperature: 0 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
To a stirred mixture of ethyl 2-aminoacetate hydrochloride (1.568 g, 11.24 mmol) in dichloromethane (9 mL) and water (2 mL) at 0° C. was added a solution of 2,4-dibromobutanoyl chloride (3.0 g, 10.21 mmol) in dichloromethane (2 mL). A solution of sodium hydroxide in water (11.5 M, 2 mL) was then added slowly. The reaction was stirred 1 hour at 0° C. and then 15 minutes at room temperature. The reaction was then treated with dichloromethane (40 mL) and water (25 mL). The layers were separated, and the organic layer was brine-washed, dried over sodium sulfate, filtered, concentrated down, and dried under vacuum to afford the crude title racemic compound (3.165 g in 90% purity, 84% yield) as a clear oil. 1H NMR (400 MHz, chloroform-d) δ ppm 6.81 (br s, 1H), 4.58 (dd, J=8.84, 4.80 Hz, 1H), 4.21-4.31 (m, 2H), 4.07 (d, J=5.56 Hz, 2H), 3.51-3.63 (m, 2H), 2.62-2.75 (m, 1H), 2.44-2.57 (m, 1H), 1.28-1.36 (m, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([N:19]=[N:20][C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27]CC)=[O:26])=[CH:23][CH:22]=3)[CH:5]=[CH:4][C:3]1=2.C(O)C.[OH-].[Na+].Cl>C1COCC1>[CH3:1][C:2]1([CH3:32])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([N:19]=[N:20][C:21]3[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:30][CH:31]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(N=Nc2ccc3c(c2)C(c2ccc(C)cc2)=CCC3(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1ccc(C2=CCC(C)(C)c3ccc(N=Nc4ccc(C(=O)O)cc4)cc32)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(4-methylphenyl)-2-naphthalenyl)azo]-benzoate (Compound 46a) 16.5 mg, 0.042 mmol) in THF (2 ml) and ethanol (1 ml) was added 80.0 mg (2.00 mmol) of NaOH (2.0 ml, 1M aqueous solution). The mixture was stirred for 12 hours at room temperature, acidified with 10% HCl, and extracted with EtOAc. The combined organic layers were washed with water, and saturated aqueous NaCl, then dried over MgSO4. Removal of the solvents under reduced pressure, and recrystallization of the residue from EtOAC/hexane, afforded the title compound as a red solid. 1H NMR (acetone-d6): δ 8.19 (2H, d, J=8.4 Hz), 7.92 (2H, d, J=8.5 hz), 7.88 (2H, dd, J=2.1, 6.1 Hz), 7.66 (1H, s), 7.64 (2H, d, J=2.3 Hz), 7.28 (4H, d, J=3.0 Hz), 6.09 (1H, t, J=2.5 Hz), 2.42 (2H, d, J=4.8 Hz), 2.39 (3H, s), 1.40 (6H, s).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH2:17])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(N(CC)CC)C.[CH2:25]([CH:32]1[CH2:37][CH2:36][N:35]([C:38](=[O:42])[C:39](Cl)=[O:40])[CH2:34][CH2:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(Cl)(Cl)Cl>[CH2:25]([CH:32]1[CH2:33][CH2:34][N:35]([C:38](=[O:42])[C:39]([NH:17][C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[NH:8][CH2:9][CH2:10]3)=[O:40])[CH2:36][CH2:37]1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(N)ccc21
Reactant: O=C(Cl)C(=O)N1CCC(Cc2ccccc2)CC1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(Nc1ccc2c(c1)CCN2)C(=O)N1CCC(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.7 %

Procedure:
To a stirred solution of 0.5 g (2.25 mmol) of 5-amino-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester and 0.4 ml (2.8 mmol) of triethylamine in 20 ml of chloroform 0.7 g (2.6 mmol) of (4-benzyl-piperidin-1-yl)-oxo-acetyl chloride in 10 ml of chloroform is added dropwise at 0° C. The reaction mixture is stirred at room temperature for 1 hour, then washed with water and the organic layer is concentrated. The residue is purified by column chromatography using Kieselgel 60 (Merck) as adsorbent and toluene:methanol=4:1 as eluent to yield 0.9 g (88.7%) of the title compound as solid. The crude product is used in the next step.
Reaction SMILES: [CH2:1]([CH:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]([OH:18])=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[NH2:19][C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[CH:22]=[CH:23][N:24]=[CH:25]2>>[CH:25]1[C:26]2[C:21](=[C:20]([NH:19][C:16]([CH:12]3[CH2:13][CH2:14][CH2:15][CH:11]3[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[O:18])[CH:29]=[CH:28][CH:27]=2)[CH:22]=[CH:23][N:24]=1
Reactant: CCCCCCCCCCC1CCCC1C(=O)O
Reactant: Nc1cccc2cnccc12
Product: CCCCCCCCCCC1CCCC1C(=O)Nc1cccc2cnccc12

Procedure:
2-(Decyl) cyclopentane carboxylic acid, prepared according to the procedure of Hoefle, et. al. (U.S. Pat. No. 4,715,175), was coupled with 5-aminoisoquinoline according to the procedure outlined in Example 47 to give the title compound.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:22]([CH2:23][C:24]([OH:26])=O)[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]=2)=[CH:10][CH:9]=1.[Cl:27][C:28]1[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=1[NH2:30].C(N(CC)CC)C>CN(C)C=O>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[N:22]([CH2:23][C:24]([NH:30][C:29]3[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=3[Cl:27])=[O:26])[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]=2)=[CH:12][CH:13]=1
Reactant: Nc1ccccc1Cl
Reactant: O=C(O)Cn1c(-c2ccc(Br)cc2)nc2cccnc21
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Cn1c(-c2ccc(Br)cc2)nc2cccnc21)Nc1ccccc1Cl
Temperature: 25 °C
Yield: 39.8 %

Procedure:
Under a nitrogen atmosphere, oxalyl chloride (3.2 g, 0.025 mole) was added dropwise (slowly) to a stirred and chilled (5°-10° C.) solution of 2-(4-bromophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (8.0 g, 0.024 mole) in anhydrous dimethylformamide (50 ml). The reaction mixture was heated at 55°-60° C. for 4 hrs, cooled to room temperature, and added dropwise to a stirred and chilled (10°-15° C.) solution of 2-chloroaniline (3.2 g, 0.25 mole) and triethylamine (2.5 g, 0.025 mole) in anhydrous dimethylformamide (100 ml). The reaction mixture was stirred at room temperature overnight, filtered, and poured into water (350 ml). The mixture was allowed to precipitate and filtered. The filter cake was twice suspended in water (250 ml) and filtered. The filter cake was air dried and twice recrystallized from tetrahydrofuran to give 4.22 g (40%) of a white solid, mp. 230.5°-232° C.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][N:15]=1.C([O:24][B:25](OCCC)[O:26]CCC)CC>C1COCC1>[F:13][C:14]1[C:19]([B:25]([OH:26])[OH:24])=[CH:18][C:17]([CH3:20])=[CH:16][N:15]=1
Reactant: CCCOB(OCCC)OCCC
Reactant: Cc1ccc(F)nc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Cc1cnc(F)c(B(O)O)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 94.3 %

Procedure:
n-Butyllithium (2.5M solution in hexane, 9.6 mL, 24 mmol) was added to a mixture of diisopropylamine (3.4 mL, 24 mmol) in THF (5.00 mL, 61 mmol) at 0° C. and the resulting pale yellow solution was stirred at the same temperature for 30 min and then cooled down to −78° C. A suspension of 2-fluoro-5-methylpyridine (Aldrich, St. Louis, Mo.) (2.22 g, mmol) in THF (5.00 mL, not complete dissolved) was slowly added. The resulting bright yellow solution was stirred at −78° C. for 1 h, treated with a solution of tri-1-propylborate (6.9 mL, 30 mmol) in THF (10.00 mL) and then allowed to warm up to room temperature. The yellow suspension was quenched with 1 N NaOH until basic (pH about 10) and the organic layer was separated. The aqueous layer was collected and carefully acidified with 6N aqueous HCl until slightly acidic, and then extracted with EtOAc(×3). The combined organic layers were dried (Na2SO4), filtered and concentrated. The resulting white solid was washed with ether to give 2-fluoro-5-methylpyridin-3-ylboronic acid (2.9196 g, 94% yield) as a white solid. LCMS (API-ES) m/z 156 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:20]=[CH:19][C:18]([C:29]2[CH:28]=[CH:27][CH:26]=[C:25]([O:24][CH3:23])[CH:30]=2)=[CH:17][CH:16]=1)=[O:22]
Reactant: COc1cccc(B(O)O)c1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(I)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1cccc(-c2ccc(C(=O)NCCc3c[nH]c4ccc(Cl)cc34)cc2)c1
Yield: 73 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-methoxybiphenyl-4-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-iodobenzamide (0.075 g; 0.176 mmol), 3-methoxyphenylboronic acid (0.028 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in dichloromethane) furnished 0.052 g (73%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-methoxybiphenyl-4-carboxamide as a white solid.