Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.N1C=CC=CC=1.F.[Si]([O:21][CH:22]([CH2:50][CH2:51][CH2:52][O:53][Si](C(C)(C)C)(C)C)/[CH:23]=[CH:24]\[CH:25]=[C:26]1[C:30](=[O:31])[C:29]([S:32][CH3:33])=[CH:28][C:27]1([CH2:39][CH2:40][CH2:41][CH2:42][O:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[O:34][Si](C)(C)C)(C(C)(C)C)(C)C.C(=O)([O-])O.[Na+]>C(#N)C>[OH:21][CH:22]([CH2:50][CH2:51][CH2:52][OH:53])/[CH:23]=[CH:24]\[CH:25]=[C:26]1[C:30](=[O:31])[C:29]([S:32][CH3:33])=[CH:28][C:27]1=[CH:39][CH2:40][CH2:41][CH2:42][O:43][C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1.[OH:21][CH:22]([CH2:50][CH2:51][CH2:52][OH:53])/[CH:23]=[CH:24]\[CH:25]=[C:26]1[C:30](=[O:31])[C:29]([S:32][CH3:33])=[CH:28][C:27]1([OH:34])[CH2:39][CH2:40][CH2:41][CH2:42][O:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: CSC1=CC(CCCCOc2ccccc2)(O[Si](C)(C)C)C(=C/C=C\C(CCCO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C)C1=O
Agent: F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CC#N
Product: CSC1=CC(=CCCCOc2ccccc2)C(=C/C=C\C(O)CCCO)C1=O
Product: CSC1=CC(O)(CCCCOc2ccccc2)C(=C/C=C\C(O)CCCO)C1=O
Reaction time: 8 h
Yield: 43 %
Yield: 20 %

Procedure:
To a solution of 9 ml of pyridine dissolved in 50 ml of acetonitrile was added, 4.5 ml of hydrogen fluoride-pyridine solution, under ice-cooling and stirring. A solution of 1.41 g of 5-[(Z)-4,7-bis-(t-butyldimethylsilyloxy)-2-heptenylidene]-2-methylthio-4-(4-phenoxybutyl)-4-trimethylsilyloxy-2-cyclopentenone obtained in Example 570 in 15 ml of acetonitrile was added, and the mixture was stirred at 0° C. for 10 minutes, an at room temperature for 8 hours. The reaction mixture was poured onto saturated aqueous sodium hydrogencarbonate, and the mixture was extracted for 3 times with ethyl acetate. The organic layers were combined, washed once with saturated aqueous sodium hydrogencarbonate and twice with saturated aqueous sodium chloride. The product was dried over anhydrous magnesium sulfate, filtered and concentrated. The oily product obtained was subject to silica gel column chromatography to obtain 158 mg (yield 20%) of 5-[(Z)-4,7-dihydroxy-2-heptenylidene]-2-methylthio-4-(4-phenoxybutylidene)-2-cyclopentenone and 353 mg (yield 43%) of 5-[(Z)-4,7-dihydroxy-2-heptenylidene]-4-hydroxy-2-methylthio-4-(4-phenoxybutyl)-2-cyclopentenone.
Reaction SMILES: OC[CH2:3][C:4]1[C:9]([OH:10])=[C:8]([O:11][CH3:12])[C:7]([O:13][CH3:14])=[C:6](O)[C:5]=1C.[H-].[Na+].[CH3:19]I.Cl.[CH2:22]([CH2:25][O:26][CH3:27])[O:23][CH3:24]>>[CH3:24][O:23][C:22]1[C:5]([CH2:6][CH2:7][O:13][CH3:14])=[C:4]([CH3:3])[C:9]([O:10][CH3:19])=[C:8]([O:11][CH3:12])[C:25]=1[O:26][CH3:27]
Reactant: COc1c(O)c(C)c(CCO)c(O)c1OC
Reactant: CI
Reactant: COCCOC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: COCCc1c(C)c(OC)c(OC)c(OC)c1OC

Procedure:
6-(2-Hydroxyethyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone (350 mg) which was obtained in Example 3 was treated with sodium hydrosulfite to give 6-(2-hydroxyethyl)-2,3-dimethoxy-5-methylhydroquinone (313 mg). A solution of the hydroquinone (290 mg) in dimethoxyethane (DME, 4 ml) was added dropwise to a suspension of 60% sodium hydride (450 mg) and methyl iodide (2.7 ml) in DME (3 ml) within 90 minutes at 45°-60° C. After cooling, the reaction mixture was treated with diluted hydrochloric acid. The aqueous layer was separated and extracted with ethyl ether. The combined ethereal layer was worked up in the usual manner. The resulting residue (240 mg) was purified by a silica gel column chromatography to give 1,2,3,4-tetramethoxy-5-methyl-6-(2-methoxyethyl)benzene (330 mg). To a solution of this compound (210 mg) in tetrahydrofuran (14 ml), silver (II) oxide (490 mg) and 6N nitric acid (1 ml) were added. After being stirred for 5 minutes at 0° C., silver (II) oxide (2 g) and 6N nitric acid (2 ml) were further added. The reaction mixture was worked up in the usual manner and purified by column chromatography to give 2,3-dimethoxy-5-methyl-6-(2-methoxyethyl)-1,4-benzoquinone as an orange oil. NMR spectrum (δ value in CDCl3): 2.05 (3H, s, CH3 on ring), 2.73 (2H, t, J=6 Hz, CH2 on ring), 3.32 (3H, s, OCH3), 3.47 (2H, t, J=6 Hz, CH2O), 4.00 (6H, s, OCH3 on ring).
Reaction SMILES: C(Cl)Cl.[NH2:4][CH:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[O:9][CH2:8][CH2:7][CH2:6]1.[Br:16][CH2:17][C:18](Br)=[O:19].[Cl-].[NH4+]>C(N(CC)CC)C>[Br:16][CH2:17][C:18]([NH:4][CH:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[O:9][CH2:8][CH2:7][CH2:6]1)=[O:19]
Reactant: NC1CCCOc2ccccc21
Reactant: O=C(Br)CBr
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CBr)NC1CCCOc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
To a 5 ml methylene chloride solution of 150 mg of 5-amino-2,3,4,5-tetrahydro-1-benzoxepine (Japanese Unexamined Patent Publication (Kokai) No. 4-178381) and 0.15 ml of triethylamine was added dropwise, under ice cooling, 0.08 ml of bromoacetyl bromide. This was then stirred at room temperature for 1 hour. To the reaction was added 5 ml of a saturated aqueous solution of ammonium chloride, then extraction was performed with methylene chloride. The extract was washed with saturated saline, dried, filtered, then concentrated under reduced pressure to obtain a residue which was then purified by silica gel column chromatography (methylene chloride:methanol=25:1) to obtain the above-referenced compound (8) in an amount of 165 mg (yield of 65%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][C:2]=1[CH3:10].[C:11]([C:13]1([NH:16][C:17]([C@H:19]2[CH2:23][C@H:22]([S:24]([C:27]3[CH:32]=[CH:31][C:30](Br)=[CH:29][C:28]=3[C:34]([F:37])([F:36])[F:35])(=[O:26])=[O:25])[CH2:21][C@@H:20]2[O:38][CH:39]([CH3:41])[CH3:40])=[O:18])[CH2:15][CH2:14]1)#[N:12].C(C1(NC([C@H]2C[C@H](S(C3C=CC(Br)=CC=3C(F)(F)F)(=O)=O)C[C@@H]2OC)=O)CC1)#N>>[C:11]([C:13]1([NH:16][C:17]([C@H:19]2[CH2:23][C@H:22]([S:24]([C:27]3[CH:32]=[CH:31][C:30]([C:4]4[CH:5]=[CH:6][N:1]=[C:2]([CH3:10])[CH:3]=4)=[CH:29][C:28]=3[C:34]([F:37])([F:35])[F:36])(=[O:26])=[O:25])[CH2:21][C@@H:20]2[O:38][CH:39]([CH3:41])[CH3:40])=[O:18])[CH2:15][CH2:14]1)#[N:12]
Reactant: CC(C)O[C@H]1C[C@@H](S(=O)(=O)c2ccc(Br)cc2C(F)(F)F)C[C@@H]1C(=O)NC1(C#N)CC1
Reactant: Cc1cc(B(O)O)ccn1
Agent: CO[C@H]1C[C@@H](S(=O)(=O)c2ccc(Br)cc2C(F)(F)F)C[C@@H]1C(=O)NC1(C#N)CC1
Product: Cc1cc(-c2ccc(S(=O)(=O)[C@@H]3C[C@H](OC(C)C)[C@@H](C(=O)NC4(C#N)CC4)C3)c(C(F)(F)F)c2)ccn1

Procedure:
The title compound was prepared in analogy to example 62 using 2-picoline-4-boronic acid instead of 2.4-difluorophenylboronic acid and (1R,2R,4R) and (1S,2S,4S)-4-(4-bromo-2-trifluoromethyl-benzenesulfonyl)-2-isopropoxy-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide instead of (1R,2R,4R) and (1S,2S,4S)-4-(4-bromo-2-trifluoromethyl-benzenesulfonyl)-2-methoxy-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide. White solid. MS (EI): 536.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH:16][CH:17]=[CH:18][C:19]([OH:21])=O)=[CH:11][C:10]=1[O:22][CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(OCC)(OCC)=O.C(N(CC)CC)C.[CH3:40][N:41]([CH3:52])[CH2:42][CH2:43][NH:44][C@H:45]1[CH2:50][CH2:49][C@H:48]([CH3:51])[CH2:47][CH2:46]1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:40][N:41]([CH3:52])[CH2:42][CH2:43][N:44]([C@H:45]1[CH2:46][CH2:47][C@H:48]([CH3:51])[CH2:49][CH2:50]1)[C:19]([CH:18]=[CH:17][CH:16]=[CH:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:10]([O:22][CH3:23])[CH:11]=1)=[O:21]
Reactant: CN(C)CCN[C@H]1CC[C@H](C)CC1
Reactant: COc1cc(C=CC=CC(=O)O)ccc1OCc1ccccc1
Agent: CCOP(=O)(Cl)OCC
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(C=CC=CC(=O)N(CCN(C)C)[C@H]2CC[C@H](C)CC2)ccc1OCc1ccccc1

Procedure:
Using 4g of 4-(4-benzyloxy-3-methoxyphenyl)-1,3-butadiene-1-carboxylic acid disclosed in the literature [R. Backstrom, E. Honkanen, A. Pippuri, P. Kairisalo, J. Pystynen, K. Heinola, E. Nissinen, I. Linden, P. T. Mannisto, S. Kaakkola, and P. Pohto, J. Med. Chem., 32, 841-848 (1989)], 3 ml of diethyl chlorophosphate, 3.5 ml of triethylamine, 150 ml of methylene chloride, 4 ml of N-(2-dimethylaminoethyl)-trans-4-methylcyclohexylamine (Example 78), and 0.5 g of 4-dimethylaminopyridine, a reaction similar to that conducted in Example 81 was carried out. As a result, 3.81 g of N-(2-dimethylaminoethyl)-N-(trans-4-methylcyclohexyl)-4-(4-benzyloxy-3-methoxyphenyl)-1,3-butadiene-1-carboxamide (a compound of the present invention) was obtained as a pale yellow oil, which had following physiochemical properties:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:14]([F:15])=[CH:13][CH:12]=[C:11]([CH3:16])[N:10]=1.[O-:17][Mn](=O)(=O)=O.[K+].[OH2:23]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:10]=[C:11]([C:16]([OH:17])=[O:23])[CH:12]=[CH:13][C:14]=1[F:15]
Reactant: Cc1ccc(F)c(-c2c(F)cccc2F)n1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: O
Agent: [K+]
Product: O=C(O)c1ccc(F)c(-c2c(F)cccc2F)n1
Temperature: 25 °C
Yield: 32 %

Procedure:
To a solution of 2-(2,6-difluorophenyl)-3-fluoro-6-methylpyridine (1.0 equiv.) in water (0.05 M) was added KMnO4 (2.0 equiv.) and the reaction was heated to reflux overnight. Another 2.0 equiv. of KMnO4 were added and stirred at reflux for another 8 hours. The solution was cooled to room temperature, filtered through Celite and washed with water. The filtrate was acidified with 6N HCl to pH=3, the white precipitate was filtered. The filtrate was further acidified to pH=1 and filtered again. The filtrate was extracted with ethyl acetate until no more product in the aqueous layer. The organic phase was washed with brine and dried over magnesium sulfate, filtered, and concentrated. The residue was dissolved in ethyl acetate, washed with 1N NaOH, the aqueous layer was acidified to pH=1 and the white crystals were filtered. The combined products yielded 6-(2,6-difluorophenyl)-5-fluoropicolinic acid in 32% yield as a white solid. LC/MS=254.0 (M+H), Rt=0.71 min.
Reaction SMILES: [CH2:1]([C:5]1[C:6]2[N:7]([C:17]([CH:20](CC3C=NC=CC=3)[C:21]([O-:23])=O)=[N:18][N:19]=2)[CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=C[CH:12]=2)[N:10]=1)[CH:2]([CH3:4])C.[Na+].[NH2:32][C@@H:33]([CH2:48][CH:49]1[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]1)[C@@H:34]([OH:47])[CH2:35][C@@H:36]([CH:44]([CH3:46])[CH3:45])[C:37]([NH:39][CH2:40][CH2:41][CH2:42][CH3:43])=[O:38].C1C=CC2N(O)N=[N:61]C=2C=1.CCN=C=NCCCN(C)C>O.CN(C=O)C>[CH2:40]([NH:39][C:37](=[O:38])[C@H:36]([CH:44]([CH3:45])[CH3:46])[CH2:35][C@H:34]([OH:47])[C@@H:33]([NH:32][C:21](=[O:23])[CH2:20][C:17]1[N:7]2[CH:8]=[C:9]([C:11]3[CH:12]=[N:61][CH:14]=[CH:15][CH:16]=3)[N:10]=[C:5]([CH2:1][CH2:2][CH3:4])[C:6]2=[N:19][N:18]=1)[CH2:48][CH:49]1[CH2:50][CH2:51][CH2:52][CH2:53][CH2:54]1)[CH2:41][CH2:42][CH3:43]
Reactant: On1nnc2ccccc21
Reactant: CC(C)Cc1nc(-c2ccccc2)cn2c(C(Cc3cccnc3)C(=O)[O-])nnc12
Reactant: CCCCNC(=O)[C@@H](C[C@H](O)[C@@H](N)CC1CCCCC1)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCNC(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)Cc1nnc2c(CCC)nc(-c3cccnc3)cn12)C(C)C
Reaction time: 8 h

Procedure:
A solution of sodium 8-propyl-6-(3-pyridyl)-1,2,4-triazolo[4,3-a]pyrazin-3-ylacetate (A) (112 mg) in water (1.5 ml) was added to a solution of (2S,4S,5S)-5-amino-N-butyl-6-cyclohexyl-4-hydroxy-2-isopropylhexanamide (114 mg) in DMF (13.5 ml). HOBT (47 mg) and EDAC (67 mg) were added, and the solution was allowed to stand overnight. A further quantity of EDAC (67 mg) was added and the solution was again allowed to stand overnight. The reaction mixture was worked up using a similar procedure to that described in Example 1, and purified by flash chromatography eluting with methanol/ dichloromethane (6:94 v/v) to give (2S,4S,5S)-N-butyl-6-cyclohexyl-4-hydroxy-2-isopropyl-5-[8-propyl-6-(3-pyridyl)-1,2,4-triazolo[4,3-a]pyrazin-3-yl]acetamidohexanamide, as a foam (60 mg); NMR (d6 -DMSO/d4 -acetic acid): 0.8-1.8 (complex m, 32H), 2.1 (m, 3H), 2.8-3.5 (m, 5H0, 3.8 (m, 1H), 4.4 (m, partially exchanged with d4 -acetic acid), 7.7 (dd, 1H), 8.6 (m, 1H), 8.7 (d, 1H), 8.9 (s, 1H), 9.3 (s, 1H); mass spectrum (+ve FAB, methanol/glycerol: 606 (M+H)+, 533, 327, 297, 290; microanalysis, found: C, 6.34; H, 8.1; N, 14.8%; C34H51N7O3,2H2O requires C, 63.7; H, 8.6; N, 15.3%.
Reaction SMILES: C1C2C(=CC=CC=2)CC1.[CH:10]([C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1[CH2:14][CH2:15][CH2:16]2)=O.[CH:21]([C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[CH2:28][CH2:27][CH2:26]2)=O>O>[CH3:10][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1[CH2:14][CH2:15][CH2:16]2.[CH3:21][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[CH2:28][CH2:27][CH2:26]2
Reactant: O=Cc1cccc2c1CCC2
Reactant: O=Cc1ccc2c(c1)CCC2
Solvent: O
Solvent: c1ccc2c(c1)CCC2
Product: Cc1ccc2c(c1)CCC2
Product: Cc1cccc2c1CCC2

Procedure:
Indane is reacted with an α,α-dichloromethyl lower alkyl ether, the reaction mixture is treated with water to produce a mixture of 4-formylindane and 5-formylindane, the aldehyde isomers are separated and the aldehydes are catalytically hydrogenated to produce 4-methylindane and 5-methylindane.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:20][C:21](OC2C=CC=CC=2)=[O:22])=[N+:4]([O-:19])[C:5]([NH:8][CH2:9][C:10]([F:18])([F:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:6][CH:7]=1.Cl.Cl.[C:32]([NH:35][O:36][CH2:37][CH2:38][NH2:39])(=N)[NH2:33].CC[N:42](C(C)C)C(C)C.N>C(Cl)Cl.CO.CO>[Cl:1][C:2]1[C:3]([CH2:20][C:21]([NH:39][CH2:38][CH2:37][O:36][NH:35][CH:32]=[N:33][NH2:42])=[O:22])=[N+:4]([O-:19])[C:5]([NH:8][CH2:9][C:10]([F:17])([F:18])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:6][CH:7]=1
Reactant: O=C(Cc1c(Cl)ccc(NCC(F)(F)c2ccccc2)[n+]1[O-])Oc1ccccc1
Reactant: N=C(N)NOCCN
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Agent: N
Solvent: ClCCl
Solvent: CO
Product: NN=CNOCCNC(=O)Cc1c(Cl)ccc(NCC(F)(F)c2ccccc2)[n+]1[O-]
Temperature: 70 °C
Reaction time: 0.67 h
Yield: 14.9 %

Procedure:
A mixture of 3-chloro-6-(2,2-difluoro-2-phenyl-ethylamino)-2-phenoxycarbonylmethyl-pyridine 1-oxide (41.2 mg, 98.4 μmol), as prepared in Example 2d, N-[2-(amidinoaminooxy)ethylamine dihydrochloride (32.9 mg, 172 μmol), as prepared in the previous step, MeOH (0.50 mL), and DIPEA (66 μL, 379 μmol) were stirred at 70° C. for 40 min. The homogeneous dark amber solution yielded a heavy white precipitate. Application of this crude reaction mixture to a silica flash column (95:5 DCM/MeOH with saturated NH3 as eluent) yielded the title compound as an off-white solid (6.5 mg, 15%). 1H-NMR (300 MHz, CD3OD) δ 7.58-7.42 (m, 5H), 7.35 (d, 1H), 6.83 (d, 1H), 4.06 (t, J=13.7 Hz, 2H), 4.08 (s, 2H), 3.79 (t, 2H), 3.41 (t, 2H). LC/MS (ESI): calcd mass 442.1. found 443.3 (MH)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.S(=O)(=O)(O)O.[CH2:17](O)[CH3:18]>>[NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([O:9][CH2:17][CH3:18])=[O:8])=[CH:10][CH:11]=1
Reactant: NCc1ccc(C(=O)O)cc1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(CN)cc1

Procedure:
A mixture of 4-aminomethylbenzoic acid (25 g) and concentrated sulphuric acid (25 ml) in ethanol (250 ml) was heated at reflux for 18 hours. The volume of solvent was reduced to a third by evaporation. The residue was poured onto ice (500 g) and basified with concentrated aqueous ammonia. The product was extracted with ethyl acetate (3×200 ml) and the extracts dried and evaporated to give ethyl 4-aminomethylbenzoate.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=O.[N+:8]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])#[C-:9].C1CCN2C(=NCCC2)CC1.CC(O)=O>O1CCOCC1>[N:3]1[CH:4]=[CH:5][N:1]2[C:2]=1[CH:6]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:8]=[CH:9]2
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: O=Cc1ncc[nH]1
Solvent: C1COCCO1
Solvent: CC(=O)O
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1cc2nccn2cn1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
To a suspension of imidazole-2-carboxaldehyde (2.3 g, 23.4 mmol) in 50 mL dioxane is added to ethyl isocyanoacetate (2.9 g, 25.8 mmol) and DBU (3.9 g, 25.8 mmol). After stirring at RT for 5 days, the reaction is neutralized with 10% AcOH. The solvent is removed in vacuo. The residue is taken up in EtOAc/H2O, the aqueous layer is extracted with CHCl3, dried (MgSO4), filtered and concentrated. The residue is purified by chromatography (Biotage 40M, eluting with 5% MeOH/EtOAc). Ethyl imidazo[1,2-c]pyrimidine-7-carboxylate is obtained (1.4 g, 32%) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ9.14, 8.43, 7.88, 7.81, 4.54-4.48, 1.49-1.44.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:9]2[CH2:10][CH2:11][CH2:12][CH:8]2[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: Fc1ccc(C2CCCN2)cc1
Product: O=S(=O)(c1ccc(Cl)cc1)N1CCCC1c1ccc(F)cc1

Procedure:
The title compound, white solid, m.p. 118° C. and MS: m/e=339 (M+) was prepared in accordance with the general method of example 1e from (RS)-2-(4-fluoro-phenyl)-pyrrolidine and 4-chloro-benzenesulfonyl chloride.
Reaction SMILES: [Si]([O:8][CH2:9][C@H:10]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[CH2:20][CH2:21][C:22]([OH:25])([CH3:24])[CH3:23])[C@H:12]([CH3:26])[N:11]1[C:27](=[O:38])[CH2:28][C:29]1[C:34]([O:35][CH3:36])=[CH:33][CH:32]=[CH:31][C:30]=1[Cl:37])(C(C)(C)C)(C)C.C(O)(=O)C.O>C1COCC1>[Cl:37][C:30]1[CH:31]=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:29]=1[CH2:28][C:27]([N:11]1[C@@H:10]([CH2:9][OH:8])[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[CH2:20][CH2:21][C:22]([OH:25])([CH3:23])[CH3:24])[C@@H:12]1[CH3:26])=[O:38]
Reactant: COc1cccc(Cl)c1CC(=O)N1[C@@H](CO[Si](C)(C)C(C)(C)C)Cc2c(CCC(C)(C)O)cccc2[C@@H]1C
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: COc1cccc(Cl)c1CC(=O)N1[C@@H](CO)Cc2c(CCC(C)(C)O)cccc2[C@@H]1C
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 73.1 %

Procedure:
Dissolve 1-[(1S,3R)-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-5-(3-hydroxy-3-methyl-butyl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-(2-chloro-6-methoxy-phenyl)ethanone (0.58 g, 1.04 mmol) in THF (5.3 mL). Add acetic acid (16 mL, 279 mmol) and water (5.3 mL). Stir at 50° C. for 1.5 hours. Concentrate under reduced pressure. Dissolve the residue in ethyl acetate and wash with saturated sodium bicarbonate solution, water, and brine. Dry over sodium sulfate, filter, and concentrate under reduced pressure. Purify the residue by silica gel chromatography, eluting with acetone: hexanes (gradient, 0-30%) to give the title compound as a white foam (0.34 g, 0.76 mmol). MS (m/z): 446.0 (M+1).
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([C:28]5[CH:29]=[N:30][C:31]6[C:36]([CH:37]=5)=[CH:35][CH:34]=[CH:33][CH:32]=6)[CH:26]=4)[N:21]=[CH:20][C:19]=3[C:38]([O:40]CC)=[O:39])=[CH:13][C:12]=2[C:43]([F:46])([F:45])[F:44])[CH2:7][CH2:6]1)(=[O:4])[CH2:2][CH3:3].[OH-].[Na+].Cl>C1COCC1.CO.O>[C:1]([N:5]1[CH2:6][CH2:7][N:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([C:28]5[CH:29]=[N:30][C:31]6[C:36]([CH:37]=5)=[CH:35][CH:34]=[CH:33][CH:32]=6)[CH:26]=4)[N:21]=[CH:20][C:19]=3[C:38]([OH:40])=[O:39])=[CH:13][C:12]=2[C:43]([F:44])([F:45])[F:46])[CH2:9][CH2:10]1)(=[O:4])[CH2:2][CH3:3]
Reactant: CCOC(=O)c1cnc2ccc(-c3cnc4ccccc4c3)cc2c1Nc1ccc(N2CCN(C(=O)CC)CC2)c(C(F)(F)F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCC(=O)N1CCN(c2ccc(Nc3c(C(=O)O)cnc4ccc(-c5cnc6ccccc6c5)cc34)cc2C(F)(F)F)CC1
Reaction time: 8 h

Procedure:
To a solution of compound 5.4 ethyl 4′-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)phenylamino)-3,6′-biquinoline-3′-carboxylate in THF/MeOH/H2O (1:1:1, 6 mL) at room temperature was added NaOH (76 mg, 1.9 mmol, 5 equiv.). The resulting solution was stirred overnight. To the mixture was added HCl (1N) to adjust the pH to 4, and EtOAC (20 mL) to extract the product. The organic layer was concentrated to afford the desired product 5.5 4′-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)phenylamino)-3,6′-biquinoline-3′-carboxylic acid. LC-MS (M+H): 622.21
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].O(C(C)(C)C)[K]>C(COC)OC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([NH:25][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[CH:4][N:3]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: Clc1nccc2ccccc12
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)O[K]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC(Nc2nccc3ccccc23)CC1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
To a degassed solution of 1-chloro-isoquinoline (1.00 g, 6.11 mmol, 1.0 equiv; commercially available) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (1.47 g, 7.34 mmol, 1.2 equiv; commercially available) in dimethoxyethane (15 mL) was added KOtert-Bu (0.96 g, 8.56 mmol, 1.4 equiv), (R)-(−)-1-[(S)-2-(dicyclohexyl-phosphino)-ferrocenyl]ethyl-di-tert-butylphosphine (3.39 mg, 0.0061 mmol, 0.1 mol %; Josiphos ligand [CAS RN 158923-11-6]; commercially available from Strem Chemicals, USA) and palladium(II) acetate (1.37 mg, 0.0061 mmol, 0.1 mol %). The reaction mixture was stirred at 90° C. for 4 h, concentrated by evaporation under reduced pressure and the residue purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane (+1% triethylamine)/ethyl acetate providing 0.83 g (42%) of the title compound. 1H NMR (300 MHz, DMSO): δ1.42-1.54 (m, 2H), 1.43 (s, 9H), 1.92-1.93 (m, 2H), 2.89 (br s, 2H), 3.97-4.03 (m, 2H), 4.29-4.35 (m, 1H), 6.88 (d, J=5.8 Hz, 1H), 7.04 (d, J=7.6 Hz, 1H), 7.47 (t, J=7.0 Hz, 1H), 7.63 (t, J=7.0 Hz, 1H), 7.68 (d, J=7.6 Hz, 1H), 7.86 (d, J=5.8 Hz, 1H), 8.27 (d, J=8.6 Hz, 1H). 13C NMR (75 MHz, DMSO): δ28.09, 31.42, 42.99, 47.39, 78.50, 109.41, 117.77, 123.10, 125.29, 126.38, 129.60, 136.67, 141.31, 153.91, 154.49. MS (ISP): 328.5 [M+H]−.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:52]([CH3:54])[CH3:53])[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]1[NH:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:26]=[C:27]4[C:49](=[CH:50][CH:51]=3)[C:31]3[NH:32][C:33]([C@@H:35]5[C@@H:40]6[CH2:41][C@@H:37]([CH2:38][CH2:39]6)[N:36]5C(OC(C)(C)C)=O)=[N:34][C:30]=3[CH:29]=[CH:28]4)=[CH:21][CH:20]=2)=[CH:17][N:18]=1)=[O:8])=[O:4].Cl.[CH3:56][O:57][C:58]([NH:60][C@@H:61]([CH:65]([CH3:67])[CH3:66])[C:62](O)=[O:63])=[O:59].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[CH3:66][CH:65]([CH3:67])[C@H:61]([NH:60][C:58](=[O:59])[O:57][CH3:56])[C:62]([N:36]1[C@H:35]([C:33]2[NH:32][C:31]3[C:49]4[C:27]([CH:28]=[CH:29][C:30]=3[N:34]=2)=[CH:26][C:25]([C:22]2[CH:21]=[CH:20][C:19]([C:16]3[NH:15][C:14]([C@@H:10]5[CH2:11][CH2:12][CH2:13][N:9]5[C:7](=[O:8])[C@@H:6]([NH:5][C:3]([O:2][CH3:1])=[O:4])[CH:52]([CH3:54])[CH3:53])=[N:18][CH:17]=3)=[CH:24][CH:23]=2)=[CH:51][CH:50]=4)[C@@H:40]2[CH2:41][C@H:37]1[CH2:38][CH2:39]2)=[O:63]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc(-c3ccc4c(ccc5nc([C@@H]6[C@H]7CC[C@H](C7)N6C(=O)OC(C)(C)C)[nH]c54)c3)cc2)[nH]1)C(C)C
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc(-c3ccc4c(ccc5nc([C@@H]6[C@H]7CC[C@H](C7)N6C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]c54)c3)cc2)[nH]1)C(C)C
Reaction time: 2 h
Yield: 50.5 %

Procedure:
To (1R,3S,4S)-tert-butyl 3-(7-(4-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl) pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (280 mg, 0.38 mmol) in DCM (5 mL) was added HCl (4M in dioxane, 1 mL). The solution stirred for 2 h, and the solvent was removed. The intermediate (80 mg, 0.13 mmol) was dissolved in DMF (2 mL). (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (22 mg, 0.13 mmol), HATU (48 mg, 0.13 mmol), and DIPEA (0.11 mL, 0.64 mmol) were added sequentially. The solution stirred o/n and the mixture was purified by HPLC to yield product (51.8 mg). LCMS-ESI+: calc'd for C44H54N8O5: 786.96 (M+); Found: 789.23 (M+H+).