Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10])[CH2:3][CH2:4]Br.[Mg].C(Br)CBr.[Cl-:17].[Zn+2:18].[Cl-].CC(CCCC(C)C)CC[Mg]Br>O1CCCC1>[Cl-:17].[CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10])[CH2:3][CH2:4][Zn+:18]
Reactant: CC(C)CCCC(C)CCBr
Reactant: [Zn+2]
Agent: CC(C)CCCC(C)CC[Mg]Br
Agent: [Cl-]
Agent: [Mg]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: CC(C)CCCC(C)CC[Zn+]
Reaction time: 1 h

Procedure:
A Grignard reagent was prepared from 3.63 g (0.016 mol) of 3,7-dimethyloctyl bromide, 0.363 g (0.015 mol) of metallic magnesium, 40 ml of tetrahydrofuran and 3 droplets of ethylene dibromide as a reaction initiator. 2.09 g (0.015 mol) of anhydrous zinc chloride was added to the tetrahydrofuran solution of 3,7-dimethyloctylmagnesium bromide, while keeping the solution at 20° C. The obtained mixture was stirred at that temperature for one hour to give a cloudy tetrahydrofuran solution of 3,7-dimethyloctylzinc chloride. 0.3 g (0.0007 mol) of CuI·(C6H5)3P was added to this solution, followed by stirring for 5 minutes. 20 ml of a solution of 1.0 g (0.0024 mol) of 2,5,7,8-tetramethyl-2-(3'-chloro-4'-methylenepentyl)-6-yl benzyl ether having a purity of 98% in tetrahydrofuran was dropped into the obtained mixture at 20° C. over a period of 5 minutes. After the completion of the dropping, the obtained mixture was stirred at that temperature for 2 hours and subjected to TLC and HPLC to confirm the disappearance of the chlorine-containing raw material. The ratio of the γ-adduct to the α-adduct (γ:α) was 98:2 (conversion: 95%).
Reaction SMILES: [NH2:1][C@H:2]1[C@@H:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])[C:10]2[CH:9]=[C:8]([O:20][CH2:21][CH2:22][NH:23][S:24]([C:27]3[N:28]=[CH:29][N:30]([CH3:32])[CH:31]=3)(=[O:26])=[O:25])[CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1.[CH:33]12[CH2:38][CH:37]1[C:36](=[O:39])[O:35][C:34]2=[O:40]>CN(C)C=O>[F:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH2:12][CH:11]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:20][CH2:21][CH2:22][NH:23][S:24]([C:27]3[N:28]=[CH:29][N:30]([CH3:32])[CH:31]=3)(=[O:26])=[O:25])[CH:9]=2)[CH2:4][CH2:3][CH:2]1[NH:1][C:36]([C@H:37]1[CH2:38][C@H:33]1[C:34]([OH:40])=[O:35])=[O:39]
Reactant: O=C1OC(=O)C2CC12
Reactant: Cn1cnc(S(=O)(=O)NCCOc2ccc3c(c2)[C@H](Cc2ccccc2F)[C@H](N)CC3)c1
Solvent: CN(C)C=O
Product: Cn1cnc(S(=O)(=O)NCCOc2ccc3c(c2)C(Cc2ccccc2F)C(NC(=O)[C@H]2C[C@H]2C(=O)O)CC3)c1
Temperature: 110 °C

Procedure:
cis-N-(2-{[7-Amino-8-(2-fluorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)-1-methyl-1H-imidazole-4-sulfonamide (50 mg, 0.109 mmol) was dissolved in dimethylformamide (2 mL), 3-oxabicyclo[3.1.0]hexane-2,4-dione (13.4 mg 0.12 mmol) was added and the reaction mixture was heated to 110° C. for 2 h. The solvent was removed in vacuo and the crude product was taken up in dichloromethane and washed successively with water (2×) and saturated sodium chloride solution (1×) and dried (magnesium sulfate). The solvent was evaporated in vacuo and the crude product was used for the next step without further purification. Yield: 63 mg (colorless foam).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]([CH2:16][C:17]1[CH:18]=[C:19]([CH:24]=[C:25]([CH2:27][N:28]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=2)[CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[CH:26]=1)[C:20]([O:22]C)=[O:21])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[OH-].[Na+].CO.CCOC(C)=O.Cl>CO.O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]([CH2:16][C:17]1[CH:18]=[C:19]([CH:24]=[C:25]([CH2:27][N:28]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=2)[CH:26]=1)[C:20]([OH:22])=[O:21])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: COC(=O)c1cc(CN(Cc2ccccn2)Cc2ccccn2)cc(CN(Cc2ccccn2)Cc2ccccn2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(O)c1cc(CN(Cc2ccccn2)Cc2ccccn2)cc(CN(Cc2ccccn2)Cc2ccccn2)c1
Temperature: 0 °C

Procedure:
Methyl 3,5-bis[[bis(2-pyridylmethyl)amino]methyl]benzoate (1 g, 1.8 mmol) was dissolved in MeOH (50 mL) and 10% solution of NaOH (5 mL) was added. The reaction mixture was refluxed for 2 h (reaction progress was monitored by TLC, Al2O3, MeOH/AcOEt 1:9 (v/v)). The reaction mixture was cooled to 0° C. followed by the addition of 10M HCl until pH=2 was reached followed by solvent evaporation under reduced pressure. Obtained yellow oily suspension was redissolved in water (50 mL) and TEA (3.6 g, 36 mmol) was added dropwise. Aqueous solution was extracted with DCM (2×50 mL) and organic layers were combined, evaporated and dried under high vacuum to obtain a product as a viscous oil. Yield: 1.1 g (95%). 1H NMR (500 MHz, CDCl3) δ 8.50 (m, 3H), 7.99 (d, J=1.3 Hz, 2H), 7.66 (d, J=8.7 Hz, 1H), 7.59 (m, 8H), 7.11 (m, 4H), 3.82 (s, 8H), 3.70 (s, 4H), 3.06 (q, J=7.3 Hz, 6H), 1.29 (t, J=7.3 Hz, 9H). 13C NMR (101 MHz, CDCl3) δ 170.2, 159.4, 148.9, 148.6, 138.8, 136.6, 136.5, 133.4, 132.7, 129.1, 122.9, 122.0, 77.3, 76.7, 60.1, 59.8, 58.5, 45.0, 8.5.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:4]([NH2:18])[N:3]=1.[Br:19]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([Br:19])[N:8]2[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:4]([NH2:18])[N:3]=1
Reactant: Nc1nc(N)c2ncn(Cc3ccccc3)c2n1
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: Nc1nc(N)c2nc(Br)n(Cc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 47 %

Procedure:
2,6-Diamino-9-benzylpurine (1.00 g, 4.16 mmol) and bromine (1 ml) were dissolved in 100 ml of methylene chloride and the solution was stirred at room temperature for 5 hours. Aqueous sodium thiosulfate was added to the reaction mixture. The organic layer was separated, dried on sodium sulfate and filtered. The solvent in the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (1% methanol/chloroform) to give the subject compound (0.62 g, yield 47%).
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][C:5]2[CH2:6][C:7](=[O:11])[NH:8][CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:15]1[N:20]=[C:19]([NH:21][C:22]2[C:31]([CH3:32])=[CH:30][C:29]([CH3:33])=[CH:28][C:23]=2[C:24]([NH:26][CH3:27])=[O:25])[C:18]([Cl:34])=[CH:17][N:16]=1>>[Cl:34][C:18]1[C:19]([NH:21][C:22]2[C:31]([CH3:32])=[CH:30][C:29]([CH3:33])=[CH:28][C:23]=2[C:24]([NH:26][CH3:27])=[O:25])=[N:20][C:15]([NH:1][C:2]2[CH:13]=[CH:12][C:5]3[CH2:6][C:7](=[O:11])[NH:8][CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:16][CH:17]=1
Reactant: CNC(=O)c1cc(C)cc(C)c1Nc1nc(Cl)ncc1Cl
Reactant: Nc1ccc2c(c1)CCNC(=O)C2
Product: CNC(=O)c1cc(C)cc(C)c1Nc1nc(Nc2ccc3c(c2)CCNC(=O)C3)ncc1Cl

Procedure:
Following a procedure analogous to Example 1742a, 7-amino-1,3,4,5-tetrahydro-benzo[d]azepin-2-one and 2-(2,5-dichloro-pyrimidin-4-ylamino)-3,5,N-trimethyl-benzamide were converted to 2-[5-chloro-2-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino)-pyrimidin-4-ylamino]-3,5,N-trimethyl-benzamide. TFA salt: 1H NMR (300 MHz, 5% CD3OD in CDCl3) δ 8.00 (s, 1H), 7.43 (s, 1H), 7.31 (s, 1H), 7.25 (s, 1H), 6.94 (s, 2H), 3.58 (bs, 2H), 3.12 (s, 2H), 3.06 (t, 2H), 2.90 (s, 3H), 2.44 (s, 3H), 2.21 (s, 3H); MS (m/e) 465 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:12]([O:18][CH2:19][CH2:20][C:21]#[N:22])(=[O:17])[CH2:13][C:14]([CH3:16])=[O:15]>CC(O)C.N1CCCCC1.C(O)(=O)C>[C:21]([CH2:20][CH2:19][O:18][C:12](=[O:17])[C:13](=[CH:8][C:7]1[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[C:14](=[O:15])[CH3:16])#[N:22]
Reactant: CC(=O)CC(=O)OCCC#N
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Solvent: CC(C)O
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: CC(=O)C(=Cc1ccc([N+](=O)[O-])cc1)C(=O)OCCC#N
Temperature: 25 °C
Reaction time: 48 h
Yield: 0.1 %

Procedure:
A suspension of 4-nitrobenzaldehyde (10.00 g, 66.2 mol), 2-cyanoethyl acetoacetate (10.27 g, 66.2 mol), piperidine (281 mg, 3.31 mmol) and acetic acid (198 mg, 3.31 mmol) in 250 ml of 2-propanol was stirred at room temperature for 48 hrs. Reaction mixture was filtered, the solid collected and dried in air to give 2-[(4-nitrophenyl)methylene]-3-oxobutanoic acid 2-cyanoethyl ester as a white powder (11.24 g, 59%).
Reaction SMILES: BrCCCCC(C)(C1C=CC(C)=CC=1)CO.[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([CH3:35])([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:24](OCC)=[O:25].[Li+].[BH4-].CO>C(Cl)Cl>[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([CH3:35])([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[CH2:24][OH:25]
Reactant: CCOC(=O)C(C)(CCCCCBr)c1ccccc1
Agent: Cc1ccc(C(C)(CO)CCCCBr)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: ClCCl
Solvent: CO
Product: CC(CO)(CCCCCBr)c1ccccc1
Yield: 97.7 %

Procedure:
According to the procedure given for the synthesis of 206e, 205h (60.0 g, 183 mmol) was reduced with LiBH4 (5.96 g, 274 mmol) and methanol (8.55 g, 269 mmol) in anhydrous CH2Cl2 (390 mL). After the typical workup, crude 206h (51.0 g, 98%) was obtained as a yellowish oil, which was used without further purification for the next step. 1H NMR (CDCl3): δ 7.25-7.08 (m, 5 H), 3.64 (d, 1 H, J=7.2), 3.50 (d, 1 H, J=7.2), 3.35 (t, 2 H, J=6 Hz), 1.92-0.95 (m, 9 H), 1.28 (s, 3 H). 13C NMR (CDCl3): δ 144.77, 128.51, 126.76, 126.21, 72.63, 43.45, 38.37, 34.06, 32.73, 28.96, 23.12, 21.59. HRMS (EI): Calcd for C14H21BrO (M+); 284.0776, found: 284.0787.
Reaction SMILES: [C:1](=[N:14][C:15]1[CH:24]=[C:23](Cl)[C:22]2[C:17](=[CH:18][C:19]([S:26][C:27]3[CH:28]=[C:29]([C:33]4([C:39]#[N:40])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)[CH:30]=[CH:31][CH:32]=3)=[CH:20][CH:21]=2)[N:16]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:41][C:42]1[CH:47]=[CH:46][C:45](B(O)O)=[CH:44][CH:43]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.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>[C:1](=[N:14][C:15]1[CH:24]=[C:23]([C:45]2[CH:46]=[CH:47][C:42]([F:41])=[CH:43][CH:44]=2)[C:22]2[C:17](=[CH:18][C:19]([S:26][C:27]3[CH:28]=[C:29]([C:33]4([C:39]#[N:40])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)[CH:30]=[CH:31][CH:32]=3)=[CH:20][CH:21]=2)[N:16]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CC1(c2cccc(Sc3ccc4c(Cl)cc(N=C(c5ccccc5)c5ccccc5)nc4c3)c2)CCOCC1
Reactant: OB(O)c1ccc(F)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: [K+]
Solvent: COCCOC
Product: N#CC1(c2cccc(Sc3ccc4c(-c5ccc(F)cc5)cc(N=C(c5ccccc5)c5ccccc5)nc4c3)c2)CCOCC1
Temperature: 80 °C

Procedure:
3c (400 mg, 0.72 mmol), 4-fluorobenzeneboronic acid (150 mg, 1.07 mmol), potassium carbonate (247 mg, 1.79 mmol), and Pd(PPh3)4 (82 mg, 0.07 mmol) were dissolved in 2:1 DME:H2O (10 mL) at degassed for 5 minutes with N2. The reaction was then sealed and heated to 80° C. overnight. After cooling to room temperature, the reaction was concentrated and purified by silica gel chromatography (10% MeOH in CH2Cl2) to give the desired product, 3d.
Reaction SMILES: [CH:1]1([C:7]2[CH:13]=[CH:12][C:10](N)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[BrH:14].N([O-])=O.[Na+].[C:19]([O:23][CH3:24])(=[O:22])[CH:20]=[CH2:21]>CC(C)=O.O>[Br:14][CH:20]([CH2:21][C:10]1[CH:12]=[CH:13][C:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:8][CH:9]=1)[C:19]([O:23][CH3:24])=[O:22]
Reactant: Br
Reactant: C=CC(=O)OC
Reactant: Nc1ccc(C2CCCCC2)cc1
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)C(Br)Cc1ccc(C2CCCCC2)cc1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
In acetone (400 ml) was dissolved 4-cyclohexylaniline (50 g) followed by addition of 47% aqueous HBr (147 g). Then, a solution of NaNO2 (21.6 g) in water (30 ml) was added dropwise at 0°-5° C. and the mixture was stirred at 5° C. for an additional 30 minutes. Thereafter, the reaction mixture was warmed to 15° C. and methyl acrylate (147 g) was added. With vigorous stirring, Cu2O (1 g) was added in small portions, whereupon an exothermic reaction took place to liberate a nitrogen gas. After the evolution of nitrogen gas had subsided, the reaction mixture was further stirred for 2 hours and, then, concentrated. The residue was diluted with water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and the solvent was distilled off to give methyl 2-bromo-3-(4-cyclohexylphenyl)propionate as a crude oil (91 g, yield 98%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([S:12]([OH:15])(=[O:14])=[O:13])[C:6]=2[CH:5]=[CH:4][C:3]=1[NH2:16].O.O.[C:19](O)(=[O:23])[C:20](O)=[O:21]>Cl>[OH:21][C:20]1[C:19]([OH:23])=[N:16][C:3]2[CH:4]=[CH:5][C:6]3[C:7]([S:12]([OH:15])(=[O:13])=[O:14])=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[N:1]=1
Reactant: Nc1ccc2c(S(=O)(=O)O)cccc2c1N
Reactant: O=C(O)C(=O)O
Agent: Cl
Solvent: O
Product: O=S(=O)(O)c1cccc2c1ccc1nc(O)c(O)nc12
Temperature: 25 °C
Yield: 57 %

Procedure:
A mixture of 0,5 g (2,1 mmol) 1,2-diaminonaphthalene-5-sulphonic acid and 0,75 g (5,8 mmol) oxalic acid dihydrate in 25 ml 4N hydrochloric acid was refluxed for 4 h. After cooling to 25° C., the precipitate was filtered off and washed with 5 ml 4N hydrochloric acid and 5 ml ice-cooled water. The crude product was dissolved in 15 ml 4N sodium hydroxide, and then reprecipitated with 4N hydrochlorid acid to give 0,35 g (57%) of 2,3-dihydroxy-benzo(f)quinoxaline-7-sulphonic acid, m.p. > 300° C. IR (KBr): 3450 (m), 1690 (s), 1190 (s), 1055 (s), 1020 (s) cm-1.1H NMR (DMSO-d6): 12,2 (2H,s), 8,7 (1H,d), 8,6 (1H,d), 8,0 (1H,d), 7,5 (1H,t), 7,4 (1H,d).
Reaction SMILES: [CH:1]([CH:4]1[CH2:12][C:11]2[C:6](=[C:7]([Cl:16])[C:8]([Cl:15])=[C:9]([O:13][CH3:14])[CH:10]=2)[C:5]1=[O:17])([CH3:3])[CH3:2].[H-].[Na+].[CH3:20]I>COCCOC>[CH3:20][C:4]1([CH:1]([CH3:3])[CH3:2])[CH2:12][C:11]2[C:6](=[C:7]([Cl:16])[C:8]([Cl:15])=[C:9]([O:13][CH3:14])[CH:10]=2)[C:5]1=[O:17]
Reactant: COc1cc2c(c(Cl)c1Cl)C(=O)C(C(C)C)C2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cc2c(c(Cl)c1Cl)C(=O)C(C)(C(C)C)C2
Temperature: 30 °C

Procedure:
A stirred suspension of 2-isopropyl-5-methoxy-6,7-dichloro-1-indanone (7.3 g., 0.025 mole) and sodium hydride (810 mg., 0.028 mole) in anhydrous 1,2-dimethoxyethane (250 ml.) is heated in an inert atmosphere at 80°-85° C. for 1 hour, cooled to 30° C. and treated with methyl iodide (6 ml.). The reaction mixture is heated to 80° C., then the solvent is distilled at reduced pressure and the residue poured into ice water. The 2-methyl-2-isopropyl-5-methoxy-6,7-dichloro-1-indanone which separates (7.0 g.) melts at 143° C. after recrystallization from ethanol-water.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([C:18]3[CH:19]=[N:20][C:21]([N:24]4[CH2:29][CH2:28][C:27]([CH3:35])([C:30]([O:32]CC)=[O:31])[CH2:26][CH2:25]4)=[N:22][CH:23]=3)=[CH:12][C:10]=2[N:11]=1)=[O:5])[CH3:2].[OH-].[Na+].Cl.C(Cl)Cl>C(O)C.O>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([C:18]3[CH:19]=[N:20][C:21]([N:24]4[CH2:25][CH2:26][C:27]([CH3:35])([C:30]([OH:32])=[O:31])[CH2:28][CH2:29]4)=[N:22][CH:23]=3)=[CH:12][C:10]=2[N:11]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)c(OC)cc2s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)O)CC4)nc3)c(OC)cc2s1
Temperature: 60 °C

Procedure:
Ethyl 1-[5-[2-(ethylcarbamoylamino)-6-methoxy-1,3-benzothiazol-5-yl]pyrimidin-2-yl]-4-methyl-piperidine-4-carboxylate (101 mg, 0.20 mmol) was suspended in ethanol (2 mL) and sodium hydroxide solution (2 mL, 1 M, aq) was added to give a pale yellow solution and the mixture heated to 60° C. for 1 h 40 minutes then left to cool to rt overnight. The mixture was acidified to pH 3 with HCl solution (1 M, aq) and diluted with water. DCM was added but the material did not dissolve so the mixture was concentrated under reduced pressure to remove the DCM then filtered through a PTFE filter (the filter was treated with ˜2 mL DCM to make it more permeable to aqueous suspensions) and rinsed with water (2 mL). A white solid was obtained which was dried in a vacuum oven at 40° C. to give Compound 198, 75 mg (79%). 1H NMR (DMSO): δ 1.11 (3H, t, J=7.1 Hz), 1.21 (3H, s), 1.40 (2H, ddd, J=13.8, 9.9 and 3.8 Hz), 2.02 (2H, dt, J=13.8 and 3.8 Hz), 3.20 (2H, dt, J=12.8 and 7.1 Hz), 3.33 (2H, m), 3.83 (3H, s), 4.28 (2H, dt, J=13.8 and 4.5 Hz), 6.71 (1H, br t, J=5.7 Hz), 7.56 (1H, s), 7.65 (1H, s), 8.53 (2H, s), 10.56 (1H, br s), 12.44 (1H, br s). MS: 471.13 [M+H]+.
Reaction SMILES: C([O:5][C:6](=[O:35])[CH:7]([CH:32]1[CH2:34][CH2:33]1)[CH2:8][NH:9][C:10]([C:12]1[N:13]=[C:14]([C:30]#[N:31])[C:15]2[C:20]([C:21]=1[OH:22])=[CH:19][CH:18]=[C:17]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:16]=2)=[O:11])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl.CCOC(C)=O>[C:30]([C:14]1[C:15]2[C:20](=[CH:19][CH:18]=[C:17]([O:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:16]=2)[C:21]([OH:22])=[C:12]([C:10]([NH:9][CH2:8][CH:7]([CH:32]2[CH2:34][CH2:33]2)[C:6]([OH:35])=[O:5])=[O:11])[N:13]=1)#[N:31]
Reactant: CC(C)(C)OC(=O)C(CNC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O)C1CC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: N#Cc1nc(C(=O)NCC(C(=O)O)C2CC2)c(O)c2ccc(Oc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3-[(1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carbonyl)-amino]-2-cyclopropyl-propionic acid tert-butyl ester (65 mg) and TFA (2 mL) in DCM (2 mL) was stirred at rt for 2 h. The mixture was subsequently concentrated and resulting residue was dissolved in EtOAc, washed with water, diluted NaCl solution and dried over anhydrous sodium sulfate, filtered, concentrated and solids were treated with hot DCM/hexanes (1:1 by volume); solids after cooling were collected via filtration, giving desired product after air-drying as white solids (40 mg). LC-MS ESI+: 418 (M+1)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][CH2:10][C:11]2[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:18])[C:5]([NH2:8])=[N:6][CH:7]=1.[C:19]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)([OH:21])=[O:20].C(=O)([O-])[O-].[K+].[K+].CN(C)C=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.O>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([C:25]2[CH:26]=[CH:27][C:22]([C:19]([OH:21])=[O:20])=[CH:23][CH:24]=2)=[CH:3][C:4]=1[O:9][CH2:10][C:11]1[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:18]
Reactant: Nc1ncc(Br)cc1OCc1c(F)cccc1Cl
Reactant: O=C(O)c1ccc(B(O)O)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: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ncc(-c2ccc(C(=O)O)cc2)cc1OCc1c(F)cccc1Cl
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 24.8 %

Procedure:
5-Bromo-3-(2-chloro-6-fluoro-benzyloxy)-pyridin-2-ylamine (Example I(e), 9.00 g, 27.0 mmol), 4-carboxybenzeneboronic acid (4.41 g, 27.0 mmol), tetrakis(triphenylphosphine)palladium(0) (0.99 g, 0.9 mmol), potassium carbonate (13.1 g, 95.0 mmol), dimethylformamide (72 mL) and water (36 mL) were charged to a 250 mL three neck round bottom flask equipped with a thermometer, a reflux condenser and magnetic stirring. The mixture was purged with nitrogen and gradually heated from 81° C. to 98° C. over a period of 4 hr. Thin layer chromatography (ethyl acetate:hexane:acetic acid 4:6:0.5) showed a trace of starting material at Rf 0.7, product at Rf 0.4 and many small impurities. The mixture was cooled to 45° C. The solids were collected by vacuum filtration, washed with 30 mL of ethanol:water 1:1 and discarded. The filtrate was diluted with 432 mL of water and 8 mL of 9 N potassium hydroxide solution (to pH 12–13), cooled in an ice bath and stirred for 30 minutes. The solids were collected by vacuum filtration and washed with 5 mL of water. The filtrate was cooled in an ice bath and acidified to pH 7.5 with acetic acid using a pH meter. The solids were collected by vacuum filtration, washed with 10 mL of ethanol:water 1:1 and dried under vacuum to give 2.5 g of 4-[6-amino-5-(2-chloro-6-fluoro-benzyloxy)-pyridin-3-yl]-benzoic acid and a second compound as a brown solid in a ratio of about 1:1 by 1H-NMR. This material was discarded. The filtrate was acidified to pH 6.5 with acetic acid using a pH meter. The solids were collected by vacuum filtration, washed with 10 mL of ethanol:water 1:1 and dried under vacuum to give 3.6 g (36% yield) of 4-[6-amino-5-(2-chloro-6-fluoro-benzyloxy)-pyridin-3-yl]-benzoic acid as a brown solid containing a 5–10% impurity by 1H-NMR.
Reaction SMILES: [C:1]1([CH3:17])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.CCCCCC.C(OCC)(=O)C>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[C:1]1([CH3:17])[CH:2]=[CH:3][C:4]([S:7]([N:10]2[CH:14]=[CH:13][C:12]([CH:15]=[O:16])=[CH:11]2)(=[O:9])=[O:8])=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc(CO)c2)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)n2ccc(C=O)c2)cc1
Yield: 50.7 %

Procedure:
Manganese dioxide (100 g) was added to the solution of 11 (14.3 g, 0.057 mol) in 250 mL chloroform and the mixture was refluxed for 12 h. The mixture was then filtered and the filtrate was concentrated under vacuum to afford a yellow oil which subjected to flash chromatography (silica gel, hexane:ethyl acetate=2:1) to afford 12 as a white solid (7.2 g, 51%). 1H NMR (CDCl3, δ/ppm), 9.97 (s, 1H), 7.81 (m, 2H), 7.63 (m, 1H), 7.34 (d, 2H), 7.16 (m, 1H), 6.40 (t, 1H), 2.42 (s, 3H).
Reaction SMILES: [C:1]1([C:7]2[C:19]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:18][C:17]3[C:16]4[C:11](=[CH:12][C:13]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)=[C:14]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:15]=4)[CH2:10][C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39].C1([C:46]2[C:50](=C)[CH:49]=[CH:48][CH:47]=2)CCCCC1.Cl>O1CCCC1.C(OCC)C>[C:36]1(=[C:15]2[C:16]3[C:11]([CH:10]=[C:9]4[C:17]=3[CH:18]=[C:19]([C:20]([CH3:21])([CH3:22])[CH3:23])[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:8]4)=[C:12]([CH:49]3[CH:48]=[CH:47][CH:46]=[CH:50]3)[C:13]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[C:14]2[C:24]([CH3:26])([CH3:27])[CH3:25])[CH2:35][CH2:34][CH2:39][CH2:38][CH2:37]1
Reactant: CC(C)(C)c1cc2c(cc1-c1ccccc1)Cc1cc(-c3ccccc3)c(C(C)(C)C)cc1-2
Reactant: CCCCCC
Reactant: C=C1C=CC=C1C1CCCCC1
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)c1cc2c(cc1-c1ccccc1)=Cc1c(C3C=CC=C3)c(-c3ccccc3)c(C(C)(C)C)c(=C3CCCCC3)c1=2
Temperature: -78 °C
Yield: 64 %

Procedure:
Under a nitrogen atmosphere, 30 mL of dehydrated tetrahydrofuran was added to 1.14 g (2.65 mmol) of 2,7-diphenyl-3,6-ditert-butyl-fluorene synthesized in Synthesis Example 1-1 (ii), and the mixture was stirred. This solution was cooled in an ice bath, and 1.90 mL (2.96 mmol) of a 1.56 mol/L hexane solution n-butyllithium was added. The mixture was stirred at room temperature for 2 hours. The resulting dark red solution was cooled to −78° C. in a dry ice/methanol bath, and a solution prepared by dissolving 0.49 g (3.35 mmol) of cyclohexylfulvene, which was synthesized according to a method described in JP-A No. 2000-26490, in 20 mL of tetrahydrofuran was added dropwise over 15 minutes. Subsequently, the mixture was stirred for 19 hours while gradually warming to room temperature. 30 mL of 1 N hydrochloric acid was added to the resulting dark red solution to terminate the reaction. 100 mL of diethyl ether was added to perform liquid-liquid phase separation, and the soluble fraction was extracted. This organic layer was washed two times with a saturated aqueous solution of sodium hydrogen carbonate, two times with water, and once with saturated brine, and dried over magnesium sulfate. The solvent was distilled off, and the residue was recrystallized with diethylether and methanol to obtain a target product as a pale yellow powder (yield 0.98 g (64%)). The target product was identified by 1H-NMR and FD-MS spectroscopy.