Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:11]([F:16])([F:15])([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([OH:7])=[O:6].N([O-])=[O:18].[Na+].N([O-])=O>S(=O)(=O)(O)O.O>[OH:18][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:11]([F:16])([F:15])([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: Nc1cc(C(=O)O)cc(S(F)(F)(F)(F)F)c1
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cc(O)cc(S(F)(F)(F)(F)F)c1
Temperature: -5 °C
Reaction time: 0.67 h
Yield: 92 %

Procedure:
3-Amino-5-pentafluorosulfanylbenzoic acid (O6.007; 3.9 g) was dissolved in 35% sulfuric acid (120 ml) and cooled to −5° C., and a solution of sodium nitrite (1.1 g) in water (100 ml) was added dropwise within 10 min. After 40 min, further nitrite solution was added (2 ml), and another 2 ml and 1 ml after a further 20 min in each case. Then the cooling bath was removed and the mixture was heated to 100° C. After 5 h, the mixture was cooled and the solution was decanted. The clear, acidic solution was extracted five times with ethyl acetate. The combined extracts were dried over magnesium sulfate, filtered and concentrated. The crude product was recrystallized from ethyl acetate/heptane. 3.6 g of the desired compound were obtained.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]([CH3:14])[CH:3]=1.[CH3:15][C:16]1([CH3:25])[CH2:21][CH:20]([NH2:22])[CH2:19][C:18]([CH3:24])([CH3:23])[NH:17]1>>[CH3:13][C:6]1[N:5]=[C:4]([CH3:14])[CH:3]=[C:2]([NH:22][CH:20]2[CH2:21][C:16]([CH3:25])([CH3:15])[NH:17][C:18]([CH3:24])([CH3:23])[CH2:19]2)[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)c1c(Cl)cc(C)nc1C
Reactant: CC1(C)CC(N)CC(C)(C)N1
Product: CCOC(=O)c1c(NC2CC(C)(C)NC(C)(C)C2)cc(C)nc1C

Procedure:
was synthesized analogously to Example 8 using ethyl 4-chloro-2,6-dimethylnicotinate and 2,2,6,6-tetramethyl-4-aminopiperidine. M.p.: 89° to 90° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)=[O:5])[CH3:2].[H-].[Na+].[CH3:16][S:17](Cl)(=[O:19])=[O:18].O>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[N:7]([S:17]([CH3:16])(=[O:19])=[O:18])[CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c[nH]1
Reactant: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cc([N+](=O)[O-])cn1S(C)(=O)=O
Temperature: 25 °C
Yield: 84.3 %

Procedure:
To a solution of 4-nitro-1H-pyrrole-2-carboxylic acid ethyl ester (2.0 g, 10.86 mmol) in anhydrous THF (54 mL) was added NaH (650 mg, 60% dispersion, 16.25 mmol) at room temperature. The suspension was stirred at room temperature for 30 minutes before the addition of methanesulfonyl chloride (1.87 g, 16.32 mmol). The reaction mixture was stirred at room temperature over night. Water was carefully added to the reaction solution, and the resulting mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with aqueous NaHCO3 solution and brine, dried over MgSO4, filtered, and evaporated under reduced pressure to give a white solid (2.4 g, 84%). The crude product was used directly without purification. 1H NMR (500 MHz, DMSO-d6) δ8.36 (s, 1H), 7.60 (s, 1H), 4.33 (q, 2H), 4.02 (s, 3H), 2.51 (DMSO), 1.35 (t, 3H) ppm. MS (ES−): m/e=183.1 (M−Ms); LC/Method A/3.64 min.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH2:6]([NH2:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[CH2:6]([NH:13][C:3](=[O:4])[CH2:2][Cl:1])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NCc1ccccc1
Reactant: O=C(Cl)CCl
Product: O=C(CCl)NCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of chloroacetyl chloride (11.4 mL) was added drop-wise over 1 hour to a stirred solution of benzylamine (15 mL) and TEA (23 mL) in dry TFP (200 mL) previously cooled at 0–3° C. under a Nitrogen atmosphere. The dark suspension was allowed to warm gradually to r.t. and then stirred at r.t. for 3 hours. The inorganic salts were filtered and washed with AcOEt (300 mL). The filtrate was washed with 2N hydrochloric acid solution (2×250 mL), sodium hydrogen carbonate (2×200 mL) and water (200 mL). The organic layer was dried and concentrated in vacuo to give a dark solid, which was crystallized from Et2O/CH (1:1, 700 mL) to give N-benzyl-2-chloroacetamide (17.8 g) as a grey solid (T.l.c.: AcOEt 100%, Rf=0.47).
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][CH2:10][CH:11]([C:17]([CH3:19])=[O:18])[C:12](OCC)=[O:13])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([Li])CCC.[C:25]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1.O>[OH:18][C:17]1[CH2:19][C:25]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:32][C:12](=[O:13])[C:11]=1[CH2:10][CH2:9][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C(CCc1ccccc1)C(C)=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C1OC(c2ccccc2)(c2ccccc2)CC(O)=C1CCc1ccccc1
Temperature: 0 °C

Procedure:
Alternatively, the title compound could be prepared as follows. A suspension of 0.25 g (6.2 mmol) of sodium hydride in 5 mL of dry THF was cooled to 0° C. under nitrogen and treated with a solution of 1.40 g (6.0 mmol) of ethyl 2-(2-phenylethyl)acetoacetate in THF (2 mL). The solution was stirred at 0° C. for ten minutes, treated with 4.3 mL of 1.4 M n-butyllithium, and stirred for another fifteen minutes. A solution of 0.55 g (3.0 mmol) of benzophenone in THF (3 mL) was added all at once, and the reaction mixture was stirred at room temperature for two hours. Water (75 mL) was added, and the mixture was stirred overnight at room temperature. The solution was washed with ether. The aqueous layer was acidified to pH 2 with 6 N HCl and extracted with ethyl acetate; the extract was washed with brine, dried over magnesium sulfate, and concentrated. The residue was triturated with ether:hexane 1:1, and the solids were filtered and dried to give the title compound.
Reaction SMILES: O.[OH-].[Li+].O.[F:5][C:6]1[CH:14]=[C:13]2[C:9]([C:10]([C:25]([O:27]C)=[O:26])=[CH:11][N:12]2[C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[CH:8][CH:7]=1.Cl>O1CCCC1>[C:25]([C:10]1[C:9]2[C:13](=[CH:14][C:6]([F:5])=[CH:7][CH:8]=2)[N:12]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)[CH:11]=1)([OH:27])=[O:26]
Reactant: COC(=O)c1cn(-c2ccnc3ccccc23)c2cc(F)ccc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cn(-c2ccnc3ccccc23)c2cc(F)ccc12
Reaction time: 16 h
Yield: 97.3 %

Procedure:
0.57 g (13.6 mmol) of lithium hydroxide monohydrate and 70 cm3 of water are added at a temperature in the region of 20° C. to 1.45 g (4.53 mmol) of 6-fluoro-3-methoxycarbonyl-1-(quinol-4-yl)-1H-indole dissolved in 70 cm3 of tetrahydrofuran. After stirring at the reflux point of the solvent for 16 hours, the reaction mixture is concentrated under reduced pressure (2.7 kPa) to give a residue which is taken up with 13.6 cm3 of N hydrochloric acid. After filtering off and drying the solid residue at atmospheric pressure at 60° C., 1.35 g of 3-carboxy-6-fluoro-1-(quinol-4-yl)-1H-indole are obtained in the form of a yellow solid melting at 190° C.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[C:16](=[O:17])[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[N:9]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]4[CH:25]=[N:26][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][CH:29]=4)[CH:19]=3)[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.NC(N)=[O:36].OO.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:1]1([NH:4][C:5]([C:7]2[C:16](=[O:17])[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[N:9]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]4[CH:25]=[N+:26]([O-:36])[C:27]([S:30]([CH3:33])(=[O:31])=[O:32])=[CH:28][CH:29]=4)[CH:19]=3)[CH:8]=2)=[O:6])[CH2:2][CH2:3]1
Reactant: NC(N)=O
Reactant: CS(=O)(=O)c1ccc(-c2cccc(-n3cc(C(=O)NC4CC4)c(=O)c4cccnc43)c2)cn1
Agent: OO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(-c2cccc(-n3cc(C(=O)NC4CC4)c(=O)c4cccnc43)c2)c[n+]1[O-]
Temperature: 0 °C
Reaction time: 18 h

Procedure:
To a suspension of N-cyclopropyl-1-[3-(6-methylsulfonylpyridin-3-yl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide from Example 51 in methylene chloride (30 ml/mmol) was added urea-hydrogen peroxide (8 eq) and the resulting mixture was cooled to 0° C. Trifluoroacetic acid (4.7 eq) was added and the mixture was warmed to room temperature as a solution was obtained. After 18 hours, more urea-hydrogen peroxide (2.6 eq) and trifluoroacetic acid (2 eq) were added and stirring was continued for 2 hours. The mixture was quenched with saturated aqueous sodium metabisulfite, diluted with methylene chloride and the organic phase was washed with 1N aqueous HCl, then brine and water, dried and evaporated. The crude product was chromatographed on silica gel eluting with 40% toluene in acetone to afford the title compound as a solid.
Reaction SMILES: [CH2:1]([N:3]1[CH2:9][CH2:8][C:7]2[CH:10]=[C:11]([NH2:14])[CH:12]=[CH:13][C:6]=2[CH2:5][CH2:4]1)[CH3:2].Cl[C:16]1[N:21]=[C:20]([NH:22][CH2:23][CH2:24][NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[C:19]([Cl:30])=[CH:18][N:17]=1.Cl.O1CCOCC1>CC(O)C>[Cl:30][C:19]1[C:20]([NH:22][CH2:23][CH2:24][NH:25][S:26]([CH3:29])(=[O:28])=[O:27])=[N:21][C:16]([NH:14][C:11]2[CH:12]=[CH:13][C:6]3[CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:9][CH2:8][C:7]=3[CH:10]=2)=[N:17][CH:18]=1
Reactant: CCN1CCc2ccc(N)cc2CC1
Reactant: CS(=O)(=O)NCCNc1nc(Cl)ncc1Cl
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: CCN1CCc2ccc(Nc3ncc(Cl)c(NCCNS(C)(=O)=O)n3)cc2CC1
Temperature: 150 °C
Yield: 42.9 %

Procedure:
3-Ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (90.9 mg, 0.478 mmol) and N-[2-(2,5-dichloro-pyrimidin-4-ylamino)-ethyl]-methanesulfonamide (150 mg, 0.526 mmol, 1.1 eq) were dissolved in IPA (3 mL). 4.0 M HCl in dioxane (132 μL, 0.526 mmol, 1.1 eq) was added and the reaction was heated at 150° C. in a microwave for 6 hours. The reaction was then concentrated under reduced pressure and the residue was taken up in CH2Cl2 (20 mL) and washed with sat. NaHCO3 (20 mL). The organic layer was dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by basic alumina chromatography using a gradient of 0-10% MeOH/CH2Cl2 as the eluting solvent to obtain N-{2-[5-chloro-2-(3-ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino)-pyrimidin-4-ylamino]-ethyl}-methanesulfonamide as a white solid (90 mg, 43%). m.p.=146° C.; LCMS (m/e) 439 (M+1); 1H-NMR (d6-DMSO, 400 MHz) δ 9.06 (s, 1H), 7.93 (s, 1H), 7.45-7.40 (m, 2H), 7.18-7.08 (m, 2H), 6.97 (d, 1H, J=8.3 Hz), 3.58-3.50 (m, 2H), 3.25-3.14 (m, 2H), 2.89 (s, 3H), 2.82-2.73 (m, 4H), 2.57-2.40 (m, 6H) 1.00 (t, 3H, J=7.2 Hz).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].[Cl-].[Al+3].[Cl-].[Cl-].[NH2:11][C:12]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[S:14][N:13]=1.O>C1(C)C=CC=CC=1>[CH3:1][N:2]([CH3:6])[C:3]([NH:11][C:12]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[S:14][N:13]=1)=[O:4]
Reactant: Nc1cc(-c2ccccc2)sn1
Reactant: CN(C)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: O
Product: CN(C)C(=O)Nc1cc(-c2ccccc2)sn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.4 %

Procedure:
N,N-Dimethylcarbamoyl chloride (1.29 g) and aluminum chloride (1.60 g) are dissolved in toluene (40 ml), and the mixture is stirred at room temperature for 30 minutes. To this mixture is added 3-amino-5-phenylisothiazole (1.76 g), and the resulting mixture is refluxed for 6 hours with stirring. After cooling, the reaction mixture is mixed with water and shaken with toluene. The organic layer is separated, washed with water, dried, and concentrated to dryness to give 1,1-dimethyl-3-(5-phenyl-3-isothiazolyl)urea (2.38 g). Yield is 96.4%. Melting point of the colorless crystals is 129 to 130.5° C. (after recrystallization from benzene/petroleum benzin).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][CH2:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH:10]2[OH:15])=[CH:3][CH:2]=1.[CH3:16][C:17]1[CH:34]=[CH:33][C:20]([CH2:21][O:22][C:23](=O)[O:24]N2C(=O)CCC2=O)=[CH:19][CH:18]=1>CN(C=O)C>[CH3:16][C:17]1[CH:34]=[CH:33][C:20]([CH2:21][O:22][C:23]([N:12]2[CH2:13][CH2:14][C@H:9]([CH2:8][NH:7][C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)[C@H:10]([OH:15])[CH2:11]2)=[O:24])=[CH:19][CH:18]=1
Reactant: Cc1ccc(COC(=O)ON2C(=O)CCC2=O)cc1
Reactant: OC1CNCCC1CNc1ccncc1
Solvent: CN(C)C=O
Product: Cc1ccc(COC(=O)N2CC[C@H](CNc3ccncc3)[C@H](O)C2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A suspension of the 4-(pyridin-4-ylaminomethyl)-piperidin-3-ol from Step 2 above (0.076 g, 0.367 mmol) in DMF (1.5 mL) was treated with carbonic acid 2,5-dioxo-pyrrolidin-1-yl ester 4-methyl-benzyl ester (0.097 g, 0.37 mmol) (INTERMEDIATE 1A) and the resulting reaction mixture stirred at rt for 5 min. The mixture was then partitioned between dilute sodium carbonate solution and EtOAc. The organic layer was washed with saturated sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, and the solvent evaporated to give a crude product. Purification by flash column chromatography (DCM to 80/20/2 DCM MeOH NH4OH) afforded the cis 3-hydroxy-4-(pyridin-4-ylaminomethyl)-piperidine-1-carboxylic acid 4-methyl-benzyl ester compound. M.S (M+1): 356.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[CH2:8][C:7]2[CH:17]=[CH:18][CH:19]=[CH:20][C:6]1=2)=[O:4].[CH:21](OC)(OC)OC>CO.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][O:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9]([O:16][CH3:21])=[CH:8][C:7]2[CH:17]=[CH:18][CH:19]=[CH:20][C:6]1=2)=[O:4]
Reactant: COC(OC)OC
Reactant: COC(=O)N1c2ccccc2CC(=O)c2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC(=O)N1c2ccccc2C=C(OC)c2ccccc21
Temperature: 60 °C
Reaction time: 4 h
Yield: 98.4 %

Procedure:
A suspension of 10-oxo-10,11-dihydro-dibenzo[b,f]azepine-5-carboxylic acid methyl ester (15 g, 56 mmol) in methanol (75 ml) is heated to 60° C. and a catalytic amount of p-toluene sulfonic acid (0.213 g, 1.1 mmol) is added. After addition of trimethyl ortho-formate (6.25 g, 58.9 mmol) the solution is stirred at 60–70° C. for 4 hours. During this reaction the product precipitates as white crystals. The mixture is cooled to room temperature, filtered and dried to yield 15.5 g of pure title compound (98%).
Reaction SMILES: [ClH:1].Cl.[N+:3]([C:6]1[CH:18]=[CH:17][C:9]([CH2:10][N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:8][CH:7]=1)([O-:5])=[O:4].[Cl:19][CH2:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:32])[CH3:31])=[CH:25][CH:24]=1)=[O:22].C([O-])([O-])=O.[K+].[K+]>>[ClH:19].[ClH:1].[N+:3]([C:6]1[CH:18]=[CH:17][C:9]([CH2:10][N:11]2[CH2:16][CH2:15][N:14]([CH2:20][C:21]([C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:32])[CH3:31])=[CH:25][CH:24]=3)=[O:22])[CH2:13][CH2:12]2)=[CH:8][CH:7]=1)([O-:5])=[O:4]
Reactant: O=[N+]([O-])c1ccc(CN2CCNCC2)cc1
Reactant: CC(=O)Nc1ccc(C(=O)CCl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(=O)Nc1ccc(C(=O)CN2CCN(Cc3ccc([N+](=O)[O-])cc3)CC2)cc1
Yield: 74 %

Procedure:
A mixture of N-(4-nitrobenzyl)piperazine dihydrochloride (2.94 g, 10 mmol), N-[4-(2-chloroacetyl)phenyl]acetamide (2.37 g, 12 mmol) and anhydrous K2CO3 (4.83 g, 35 mmol) was treated according to general preparation 2 to give compound (IV-18), yield 74%, mp 228-230° C. M+ 396.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14](C1CCCCO1)[N:13]=[C:12]2[C:24]1[N:29]=[C:28]([O:30][C@H:31]2[CH2:38][N:37](C(OC(C)(C)C)=O)[CH2:36][CH2:35][C:32]32[CH2:34][CH2:33]3)[CH:27]=[N:26][CH:25]=1.[C:46]([OH:52])([C:48]([F:51])([F:50])[F:49])=[O:47]>C(Cl)Cl>[CH2:34]1[C:32]2([CH2:35][CH2:36][NH:37][CH2:38][C@@H:31]2[O:30][C:28]2[N:29]=[C:24]([C:12]3[C:11]4[C:15](=[CH:16][CH:17]=[C:9]([C:3]5[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=5[F:1])[CH:10]=4)[NH:14][N:13]=3)[CH:25]=[N:26][CH:27]=2)[CH2:33]1.[C:46]([OH:52])([C:48]([F:51])([F:50])[F:49])=[O:47]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC2)[C@@H](Oc2cncc(-c3nn(C4CCCCO4)c4ccc(-c5c(F)cccc5F)cc34)n2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1cccc(F)c1-c1ccc2[nH]nc(-c3cncc(O[C@H]4CNCCC45CC5)n3)c2c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of (4R)-tert-butyl 4-(6-(5-(2,6-difluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)-6-azaspiro[2.5]octane-6-carboxylate (0.983 g, 1.591 mmol) in 8 mL DCM was added TFA (3.68 mL, 47.7 mmol). After 6 h at RT, the orange reaction was placed in the freezer overnight, and in the morning was warmed and stirred at RT for 3 h. The reaction was concentrated in vacuo, then taken up in DMSO (6 mL total), filtered, and purified by RPHPLC, 20-70% ACN/H2O with 0.1% TFA; product-containing fractions were combined and concentrated in vacuo to give (R)-3-(6-(6-azaspiro[2.5]octan-4-yloxy)pyrazin-2-yl)-5-(2,6-difluorophenyl)-1H-indazole*1.5 TFA (0.530 g, 0.88 mmol, 55% yield) yellow solid: MS (ESI, pos. ion) m/z: 434 (M+1).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]2[CH:11]=[C:12]([CH2:16][OH:17])[CH:13]=[CH:14][CH:15]=2)=[CH:2]1.O[C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:21][CH:20]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.C(OCC)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]2[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=2)[CH2:16][O:17][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:21][CH:20]=2)=[CH:2]1
Reactant: COC(=O)CCc1ccc(O)cc1
Reactant: OCc1cccc(-c2csc3ccccc23)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)CCc1ccc(OCc2cccc(-c3csc4ccccc34)c2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.4 %

Procedure:
To a solution of [3-(1-benzothiophen-3-yl)phenyl]methanol (0.70 g, 2.91 mmol), methyl 3-(4-hydroxyphenyl)propanoate (0.58 g, 3.22 mmol) and tributylphosphine (0.95 mL, 3.81 mmol) in anhydrous tetrahydrofuran (40 mL) was added 1,1′-(azodicarbonyl)dipiperidine (0.96 g, 3.80 mmol) by small portions, and the mixture was stirred at room temperature for 18 hr. The reaction solution was diluted with diethyl ether (40 mL). The precipitate was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:5) to give the title compound (1.0 g, yield 85%) as a colorless oil. MS: m/z 403 (MH+).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:14]([O:16]C)=[O:15].[C:18](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[CH3:18][O:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:14]([OH:16])=[O:15]
Reactant: COC(=O)c1ccc2ccc(OC)cc2c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc2ccc(C(=O)O)c(OC)c2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 3.7 g (0.016 mole) of 1-hydroxy-7-methoxy-2-naphthalenecarboxylic acid, methyl ester and 2.9 g (0.021 mole) of anhydrous potassium carbonate in 20 ml of N,N-dimethylformamide under a nitrogen atmosphere was treated with 3.0 ml (6.8 g; 0.048 mole) of iodomethane. The mixture was stirred at room temperature for 24 hours, and then added to 150 g of ice/water. The crude intermediate ester was separated by extracting with dichloromethane (3×50 ml). The combined organic layers were washed with water (2×50 ml), dried (anhydrous magnesium sulfate) and evaporated (vacuum).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[CH2:4][C:5]([CH2:7][Cl:8])=[O:6].[CH3:10]OC(OC)OC>>[CH3:1][O:2][C:3](=[O:9])/[CH:4]=[C:5](/[O:6][CH3:10])\[CH2:7][Cl:8]
Reactant: COC(=O)CC(=O)CCl
Reactant: COC(OC)OC
Product: COC(=O)/C=C(\CCl)OC
Temperature: 150 °C
Yield: 75 %

Procedure:
31.0 g (0.2 mol) of 4-chloro aceto acetic acid methyl ester was mixed with 106.0 g (1.0 mol) of orthoformic acid trimethyl ester. 30.0 g of Amberlyst-15 ion exchange resin was added under argon with stirring. The reaction temperature rose to 40° C. with vigorous development of gas. After 5 hours of stirring, no educt could any longer be detected by thin-layer chromatography. The ion exchange resin was filtered off, and the residue was distilled in a water jet vacuum. The distillate was mixed with 1.0 g of p-toluenesulfonic acid monohydrate and slowly heated to 150° C., whereby methanol distilled off. The reaction mass was then distilled in a water jet vacuum. 24.7 g of a colorless liquid with a boiling point bp12 =93° C. was obtained.
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(Cl)(Cl)=O.[CH3:16]O>>[CH3:16][O:8][C:7](=[O:9])[C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH2:1])=[CH:11][CH:10]=1
Reactant: CO
Reactant: NCc1ccc(C(=O)O)cc1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(CN)cc1
Yield: 92 %

Procedure:
To a solution of 4-(aminomethyl)benzoic acid (300 g, 1.98 mol) in methanol (5 L) was added thionylchloride (473 g 3.97 mol). The reaction mixture was refluxed for 6 h, followed by the removal of the solvent under reduced pressure to obtain the crude product. The crude was purified by acid-base work up to afford methyl-4-(aminomethyl)benzoate (300 g, 92%) as a liquid.
Reaction SMILES: [OH-].[K+].N([CH2:5]NC(N)=O)=O.[CH2:10]([O:12][C:13]([N:15]1[C:23]2[C:18](=[C:19]([Br:24])[CH:20]=[CH:21][CH:22]=2)[C:17]([OH:25])=[N:16]1)=[O:14])[CH3:11]>CCOCC.C1COCC1>[CH2:10]([O:12][C:13]([N:15]1[C:23]2[C:18](=[C:19]([Br:24])[CH:20]=[CH:21][CH:22]=2)[C:17]([O:25][CH3:5])=[N:16]1)=[O:14])[CH3:11]
Reactant: CCOC(=O)n1nc(O)c2c(Br)cccc21
Reactant: NC(=O)NCN=O
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)n1nc(OC)c2c(Br)cccc21
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a 0° C. mixture of KOH (50% in H2O, 50 ml) and Et2O (150 ml), N-nitrosomethylurea (10.7 g, 103 mmol) was added portionwise over 40 minute period. After stirring for additional 20 minutes, the mixture was cooled to −78° C. and the upper bright yellow layer was poured into a 0° C. suspension of 4-Bromo-3-hydroxy-indazole-1-carboxylic acid ethyl ester CLXXXIV (2.96 g, 10.4 mmol) in a mixture of Et2O (100 ml) and THF (30 ml). After 2 hours, the yellow solution was warmed to room temperature and was left to stand at room temperature for 24 hours. The mixture was then washed with H2O and brine. The organic layer was dried over MgSO4, filtered, concentrated, and purified via flash chromatography (hexane/EtOAc) affording 4-Bromo-3-methoxy-indazole-1-carboxylic acid ethyl ester CLXXXV as an off-white solid (40% yield).