Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]=[O:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.C([O-])([O-])=O.[K+].[K+].[I:18]I.[O-]S(S([O-])=O)=O.[Na+].[Na+].S([O-])(O)(=O)=O.[Na+]>CN(C=O)C.O>[I:18][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([CH:10]=[O:11])[CH:5]=2)[NH:1][N:2]=1
Reactant: II
Reactant: O=Cc1ccc2[nH]ncc2c1
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Agent: O=S([O-])S(=O)[O-]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc2[nH]nc(I)c2c1
Reaction time: 3 h
Yield: 34.5 %

Procedure:
To a solution of 1H-indazole-5-carbaldehyde (315.2 mg, 2.16 mmol), K2CO3 (598.8 mg, 4.33 mmol) in DMF (2.5 mL) was added dropwise a solution of I2 (938 mg, 3.7 mmol) in DMF (2.5 mL) and the reaction allowed to stir for three hours. An aqueous solution consisting of Na2S2O4 (511 mg)/K2CO3 (35 mg)/H2O (3.5 mL) was then added and the solution stirred for two hours. Water (30 mL) and aqueous sodium hydrogen sulfate (1M, 10 mL) was added and the product was extracted with ethyl acetate (350 mL); this organic layer was washed with brine (3×25 mL). The aqueous layer was then extracted with dichloromethane (3×75 mL), this second organic layer was also washed with brine (25 mL). TLC indicated product present in both, so the residues were combined and purified by chromatography (10 g silica SPE tube, Silicycle, 5% ethyl acetate in dichloromethane) to yield a beige solid (203 mg, 35%). A precipitate that formed in the original aqueous layer was collected by vacuum filtration to give after drying a beige solid (first crop 135.6 mg, 23%; second crop 147 mg, 25%). 1H NMR (400 MHz, CDCl3 plus a drop of CD3OD) δ 10.03 (s, 1H), 8.00 (s, 1H), 7.95 (d, J=8.8 Hz, 1H), 7.54 (d, J=8.8 Hz, 1H).
Reaction SMILES: [Cl-].[NH4+].[N+:3]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:10][CH:11]=1)([O-])=O>O.C1COCC1.[Zn]>[C:12]1([C:9]2[N:10]=[CH:11][C:6]([NH2:3])=[CH:7][CH:8]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=[N+]([O-])c1ccc(-c2ccccc2)nc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc(-c2ccccc2)nc1
Yield: 82.3 %

Procedure:
Ammonium chloride (1.1 g, 0.020 mol) dissolved in water (15 mL) was added to a stirred solution of 5-nitro-2-phenyl-pyridine (0.5 g, 2.5 mmol) in THF (10 mL) Methanol (5 mL) was then added, affording a clear solution. Zinc powder (1.3 g, 0.020 mol) was then added portion wise at room temperature and the resulting mixture maintained for 1 hour, then filtered over celite. The filtrate was concentrated and the residue was extracted with ethyl acetate. The organics were washed with brine solution, dried over Na2SO4 and concentrated under reduced pressure to afford 0.35 g (82%) of 6-phenyl-pyridin-3-ylamine. LCMS purity: 171.08 (M+1)+, 87.9%, 1H NMR (DMSO-d6): δ 8.12 (d, 1H), 8.0 (d, 2H), 7.72 (d, 1H), 7.48 (t, 2H), 7.36 (t, 1H), 7.1 (dd, 1H), 5.6 (s, 2).
Reaction SMILES: [CH3:1][C:2]1[N:10]([C:11]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)=[O:12])[C:9]2[CH:8]=[CH:7][C:6]([O:20][CH3:21])=[CH:5][C:4]=2[C:3]=1[CH2:22][C:23]([OH:25])=[O:24].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:33][C:34]([O:36][CH2:37][CH:38]=[CH:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:35]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.CC(C)=O>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([C:11]([N:10]2[C:9]3[C:4](=[CH:5][C:6]([O:20][CH3:21])=[CH:7][CH:8]=3)[C:3]([CH2:22][C:23]([O:25][CH2:33][C:34]([O:36][CH2:37][CH:38]=[CH:39][C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)=[O:35])=[O:24])=[C:2]2[CH3:1])=[O:12])=[CH:18][CH:17]=1
Reactant: COc1ccc2c(c1)c(CC(=O)O)c(C)n2C(=O)c1ccc(Cl)cc1
Reactant: O=C(CCl)OCC=Cc1ccccc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CC(C)=O
Product: COc1ccc2c(c1)c(CC(=O)OCC(=O)OCC=Cc1ccccc1)c(C)n2C(=O)c1ccc(Cl)cc1
Reaction time: 3.5 h

Procedure:
10 g of indometacin, 4 g of potassium carbonate, 0.3 g of benzyltriethylammonium chloride and 50 ml of acetone are stirred for 30 minutes at 50°-60° C. After addition of 6.32 g of cinnamyl chloroacetate stirring is continued for 3 to 4 hours at 40° C. (check by thin layer chromatography). After filtration, and distilling off the solvent, the residue is recrystallized first from ether/petroleum ether and then from acetone/water.
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2.[CH3:13]I>CN(C=O)C>[CH3:13][O:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2
Reactant: Oc1cccc2[nH]ccc12
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COc1cccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
Potassium hydroxide (2.12 g) was added to 4-hydroxyindole (4.99 g) in DMF (100 ml) and the mixture was stirred at room temperature for 30 minutes. Methyl iodide (2.80 ml) was added to the mixture and the resultant was stirred at room temperature for 150 minutes. Since the reaction had not been completed, potassium hydroxide (0.64 g) was added and the mixture was stirred at room temperature for 5 hours. The solvent was removed under reduced pressure and water (20 ml) was added to the residue, followed by extraction with ether (3×30 ml). The organic layers were washed with saturated brine, and dried over sodium sulfate. After removing solids by filtration, the solvent was removed under reduced pressure and the obtained crude product was purified by silica gel column chromatography to obtain the desired product (3.38 g, yield: 61%).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]2[CH2:10][CH2:9][CH2:8][CH:7]([OH:11])[C:5]=2[CH:6]=1.N1C=CN=C1.[C:17]([Si:21]([CH3:24])([CH3:23])Cl)([CH3:20])([CH3:19])[CH3:18].O>CN(C)C=O>[Br:1][C:2]1[S:3][C:4]2[CH2:10][CH2:9][CH2:8][CH:7]([O:11][Si:21]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:24])[CH3:23])[C:5]=2[CH:6]=1
Reactant: OC1CCCc2sc(Br)cc21
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC1CCCc2sc(Br)cc21
Yield: 91 %

Procedure:
To a solution of 2-bromo-4,5,6,7-tetrahydro-1-benzothiophen-4-ol (5.0 g, 21 mmol) that was obtained in Example 8 (8a) in N,N-dimethylformamide (30 ml) were added successively imidazole (2.9 g, 43 mmol) and t-butyldimethylchlorosilane (3.5 g, 24 mmol) with stirring, and the resulting mixture was stirred for 2 hours. After stirring, the reaction mixture was poured into water (50 ml) to quench the reaction and extracted with ether. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo, and the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:9) as the eluent to afford the title compound (6.8 g) in a yield of 91% as a colourless oily product.
Reaction SMILES: [CH2:1]([Zn]CC)C.C(=O)=O.CC(C)=O.ICI.[CH2:16]=[C:17]1[CH2:20][CH:19]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:18]1>ClCCl.O>[CH2:1]1[C:17]2([CH2:18][CH:19]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:27])[CH3:26])[CH2:20]2)[CH2:16]1
Reactant: C=C1CC(NC(=O)OC(C)(C)C)C1
Reactant: CC[Zn]CC
Agent: O=C=O
Solvent: CC(C)=O
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CC2(CC2)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Diethyl zinc (40 mL, 1N hexane solution) was added to 100 mL of anhydrous dichloromethane under nitrogen. After the addition, cooled to −78° C. with dry ice-acetone, and diiodomethane (15 g, 56 mmol) was slowly added dropwise. After the addition stirring was continued for 30 minutes, and then changed into the ice-water bath. A solution of Compound 3-2 (1.7 g, 9.3 mmol) dissolved in 100 mL of dichloromethane was further added dropwise and stirred overnight, added 200 mL of water to quench the reaction, liquid separated, and the aqueous phase was extracted with 200 mL of dichloromethane three times. The organic phases were combined, rotary evaporated to remove solvents, and purified by silica gel column chromatography (petroleum ether/ethyl acetate=10:1) to give
Reaction SMILES: [CH:1](OCC)(OCC)OCC.[NH2:11][C:12]1[CH:13]=[N:14][C:15]2[C:20]([C:21]=1[NH:22][CH2:23][CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:19][CH:18]=[CH:17][CH:16]=2>C1(C)C=CC=CC=1>[N:22]1([CH2:23][CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:29])([CH3:31])[CH3:30])[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[CH:13][C:12]=2[N:11]=[CH:1]1
Reactant: CCOC(OCC)OCC
Reactant: CC(C)(C)OC(=O)NCCNc1c(N)cnc2ccccc12
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCCn1cnc2cnc3ccccc3c21
Temperature: 25 °C
Yield: 81.2 %

Procedure:
Triethyl orthoformate (11.3 g, 73.4 mmol) was added to a solution of tert-butyl N-[2-(3-aminoquinolin-4-yl)aminoethyl]carbamate (21 g, 69.4 mmol) in anhydrous toluene (250 mL). The reaction mixture was heated at reflux for 5 hours and then allowed to slowly cool to ambient temperature. The resulting precipitate was isolated by filtration and dried to provide 17.6 g of tert-butyl N-[2-(1H-imidazo[4,5-c]quinolin-1-yl)ethyl]carbamate as a light tan solid, m.p. 154-155° C.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:8]2[N:12]=[CH:11][N:10]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:9]=2)=[C:5]([Br:7])[N:6]=1.[Cl-].[Li+].O1CCOCC1.[CH2:29]([Sn](CCCC)(CCCC)C#CC)[CH2:30][CH2:31]C>C(Cl)Cl.[Cu]I.C1C=CC([P]([Pt]([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>[Br:7][C:5]1[N:6]=[C:2]([C:29]#[C:30][CH3:31])[S:3][C:4]=1[C:8]1[N:12]=[CH:11][N:10]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:9]=1
Reactant: CC#C[Sn](CCCC)(CCCC)CCCC
Reactant: C[Si](C)(C)CCOCn1cnc(-c2sc(Br)nc2Br)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pt]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC#Cc1nc(Br)c(-c2ncn(COCC[Si](C)(C)C)n2)s1
Temperature: 100 °C
Yield: 76.2 %

Procedure:
A mixture of 3-(2,4-dibromo-1,3-thiazol-5-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazole (6.00 g, 13.6 mmol), lithium chloride (1.73 g, 40.9 mmol), copper(I) iodide (0.779 g, 4.09 mmol) and tetrakis(triphenylphosphine)platinum (O) (0.848 g, 0.681 mmol) in anhydrous 1,4-dioxane (120 mL, 1500 mmol) was sonicated under an argon atmosphere for 2 minutes in a 250 mL RBF. Tributyl(1-propynyl)tin (4.80 mL, 15.0 mmol) was added. The mixture was heated to 100° C. for 1 hour under an argon atmosphere. The mixture was cooled to it, diluted with DCM (˜150 mL), filtered through celite, and washed with DCM. The filtrate was rotavaped to give a crude residue which was then purified by column chromatography (SiO2, elution with 0-100% EtOAc in hexane) to afford a pure solid product (4.14 g, 76% yield). LCMS: (FA) ES+ 399, 401. NMR (400 MHz, CDCl3) δ: 8.29 (s, 1H), 5.54 (s, 2H), 3.69-3.74 (m, 2H), 2.15 (s, 3H), 0.93-0.97 (m, 2H), 0.00 (s, 9H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][C:12]([F:15])([F:14])[F:13])(=[O:4])=[O:3].[N+:16]([O-])([OH:18])=[O:17]>S(=O)(=O)(O)O>[CH3:1][S:2]([C:5]1[CH:10]=[C:9]([N+:16]([O-:18])=[O:17])[CH:8]=[CH:7][C:6]=1[O:11][C:12]([F:13])([F:14])[F:15])(=[O:4])=[O:3]
Reactant: O=[N+]([O-])O
Reactant: CS(=O)(=O)c1ccccc1OC(F)(F)F
Agent: O=S(=O)(O)O
Product: CS(=O)(=O)c1cc([N+](=O)[O-])ccc1OC(F)(F)F
Temperature: 40 °C
Reaction time: 8 h

Procedure:
1-Methylsulfonyl-2-trifluoromethoxybenzene (15.7 g, 65 mmol) was dissolved in concentrated sulfuric acid (27 mL) and the solution was heated to 40° C. Nitric acid (100%, 27 mL) was added dropwise over 45 min. The reaction mixture was allowed to stand overnight at 60° C., cooled, and then poured on crushed ice (300 mL). The precipitated product was isolated by filtration, washed with water (10×50 mL) and dried (magnesium sulphate), affording 17.5 g of 3-methylsulfonyl-4-trifluoromethoxynitrobenzene.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:15][C@@H:14]([C:16]([OH:18])=O)[C:13]1([CH3:20])[CH3:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:21]1[CH:22]=[CH:23]C2N(O)N=[N:27][C:25]=2[CH:26]=1.N1CCCCC1.CCN(CC)CC>C(Cl)Cl>[CH3:19][C:13]1([CH3:20])[C@H:14]([C:16]([N:27]2[CH2:23][CH2:22][CH2:21][CH2:26][CH2:25]2)=[O:18])[CH2:15][C@@H:12]1[NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: On1nnc2ccccc21
Reactant: CC1(C)[C@@H](NC(=O)OCc2ccccc2)C[C@H]1C(=O)O
Solvent: ClCCl
Solvent: C1CCNCC1
Solvent: CCN(CC)CC
Product: CC1(C)[C@@H](NC(=O)OCc2ccccc2)C[C@H]1C(=O)N1CCCCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 48.6 %

Procedure:
To a stirred solution of (1R,3S)-3-(benzyloxycarbonylamino)-2,2-dimethylcyclobutanecarboxylic acid (Intermediate 1-Step 3, 0.650 g, 2.346 mmol) in DCM (5 ml) EDCI (0.674 g, 3.519 mmol) and HOBt (0.475 g, 3.519 mmol) were added at 0° C., after 10 minutes piperidine (0.46 ml, 4.692 mmol) and Et3N (0.65 ml, 4.692 mmol) were added drop wise and the reaction mixture was stirred at room temperature for about 12 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM and washed with water, saturated NaHCO3 solution, water, 1N HCl, water and saturated brine and the organic layer was concentrated under reduced pressure. The resulting crude was purified by a silica gel column (100-200 mesh, elution 20% EtOAC in hexane) to afford the title compound as an off white solid. Wt: 0.393 g; Yield: 48.6%; 1H NMR (300 MHz, CDCl3): δ 7.40-7.28 (m, 5H), 5.18-4.99 (m, 3H), 3.97-3.87 (m, 1H), 3.77-3.67 (m, 1H), 3.49-3.28 (m, 3H), 2.83 (t, 1H, J=8.4 Hz), 2.47-2.20 (m, 2H), 3.65-3.41 (m, 6H), 1.35 (s, 3H), 0.87 (s, 3H); Mass: [M+1]+ 345 (10%), [M+Na]+ 367 (100%); IR (KBr, cm−1): 3315, 3013, 2931, 2855, 1719, 1622, 1534, 1443, 1369, 1255, 1236, 1219, 1125, 1040, 853, 746, 697; M.R: 145.2° C.-150.8° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:22])[CH3:21])=[CH:16][CH:15]=2)=[CH:12][C:11]([CH:23]2[CH2:28][C:27]([CH3:30])([CH3:29])[O:26][C:25]([CH3:32])([CH3:31])[CH2:24]2)=[N:10]1.[BH4-].[Na+]>C(O)C.CC#N.C(O)(C(F)(F)F)=O.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]([OH:22])[CH3:21])=[CH:16][CH:15]=2)=[CH:12][C:11]([CH:23]2[CH2:28][C:27]([CH3:30])([CH3:29])[O:26][C:25]([CH3:31])([CH3:32])[CH2:24]2)=[N:10]1
Reactant: COc1ccccc1-n1nc(C2CC(C)(C)OC(C)(C)C2)cc1-c1ccc(C(C)=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: CCO
Product: COc1ccccc1-n1nc(C2CC(C)(C)OC(C)(C)C2)cc1-c1ccc(C(C)O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
To a solution of 1-{4-[1-(2-methoxyphenyl)-3-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-yl]-phenyl}-ethanone (Example 12) (20 mg, 0.05 mmol) in 1 mL of ethanol was added sodium borohydride (1.8 mg, 0.05 mmol) and the mixture stirred for 1 hr at RT. The solution was diluted with 5 mL of 50% CH3CN in 0.1% TFA/H2O and purified by RP-HPLC, eluting with a linear gradient of 50%-100% CH3CN in 0.1% TFA/H2O over 10 mins to give 20 mg (86%) of the title compound a white solid containing 0.5 eq of TFA.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([C:8]2[N:16]3[C:11]([CH:12]=[CH:13][C:14]([OH:17])=[CH:15]3)=[C:10]([C:18]([O:20][CH3:21])=[O:19])[C:9]=2[CH3:22])=[O:7])=[CH:4][C:3]=1[O:25][CH3:26].Br[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]>>[NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([C:8]2[N:16]3[C:11]([CH:12]=[CH:13][C:14]([O:17][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:15]3)=[C:10]([C:18]([O:20][CH3:21])=[O:19])[C:9]=2[CH3:22])=[O:7])=[CH:4][C:3]=1[O:25][CH3:26]
Reactant: COC(=O)c1c(C)c(C(=O)c2ccc(N)c(OC)c2)n2cc(O)ccc12
Reactant: CCOC(=O)CBr
Product: CCOC(=O)COc1ccc2c(C(=O)OC)c(C)c(C(=O)c3ccc(N)c(OC)c3)n2c1

Procedure:
This compound is obtained by carrying out the procedure according to the preparation described in the example above, by alkylating methyl [3-(4-amino-3-methoxybenzoyl)-6-hydroxy-2-methylindolizin-1-yl]carboxylate with ethyl bromoacetate.
Reaction SMILES: C(OC([NH:8][C:9]1[S:13][C:12]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[F:21])=[N:11][C:10]=1[C:22]([NH:24][C:25]1[CH:29]=[N:28][N:27]([CH3:30])[C:26]=1[N:31]1[CH2:46][C:35]2([CH2:38][N:37](C(OC(C)(C)C)=O)[CH2:36]2)[CH2:34][CH2:33][CH2:32]1)=[O:23])=O)(C)(C)C.ClCCl.Cl>CO.O1CCOCC1>[NH2:8][C:9]1[S:13][C:12]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[F:21])=[N:11][C:10]=1[C:22]([NH:24][C:25]1[CH:29]=[N:28][N:27]([CH3:30])[C:26]=1[N:31]1[CH2:32][CH2:33][CH2:34][C:35]2([CH2:36][NH:37][CH2:38]2)[CH2:46]1)=[O:23]
Reactant: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2NC(=O)OC(C)(C)C)c1N1CCCC2(CN(C(=O)OC(C)(C)C)C2)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1N1CCCC2(CNC2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 147.2 %

Procedure:
tert-butyl 8-[4-[[5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carbonyl]amino]-2-methyl-pyrazol-3-yl]-2,8-diazaspiro[3.5]nonane-2-carboxylate (336 mg, 0.51 mmol) was dissolved in methanol (2 mL) and dichloromethane (2 mL) before the addition of 4 M of hydrogen chloride in 1,4-Dioxane (2 mL). The solution was stirred at room temperature for 16 hr. After evaporation, a crude mixture as an off while solid (345 mg) was obtained. The crude mixture was purified by reverse phase HPLC to give 508 as a white solid (66 mg, 28%). 1H NMR (400 MHz, DMSO-d6) δ 8.70 (s, 1H), 7.55-7.45 (m, 4H), 7.26 (t, J=8.8 Hz, 2H), 3.66 (s, 3H), 3.54 (s, 1H), 3.22 (s, 4H), 3.12 (s, 2H), 2.94 (t, J=5.3 Hz, 2H), 1.68-1.60 (m, 2H), 1.58-1.50 (m, 2H). MS (ESI) m/z: 460.2 [M+H+].
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:14](=[O:38])[NH:15][C:16]1[C:17]([CH3:37])=[N:18][CH:19]=[C:20]([NH:22][C:23]2[N:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)=[CH:25][N:24]=2)[CH:21]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:36][O:35][C:32]1[CH:33]=[CH:34][C:29]([C:26]2[CH:25]=[N:24][C:23]([NH:22][C:20]3[CH:21]=[C:16]([NH:15][C:14]([CH:9]4[CH2:10][CH2:11][CH2:12][CH2:13][NH:8]4)=[O:38])[C:17]([CH3:37])=[N:18][CH:19]=3)=[N:28][CH:27]=2)=[CH:30][CH:31]=1
Reactant: COc1ccc(-c2cnc(Nc3cnc(C)c(NC(=O)C4CCCCN4C(=O)OC(C)(C)C)c3)nc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(-c2cnc(Nc3cnc(C)c(NC(=O)C4CCCCN4)c3)nc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-{5-[5-(4-Methoxy-phenyl)-pyrimidin-2-ylamino]-2-methyl-pyridin-3-ylcarbamoyl}-piperidine-1-carboxylic acid tert-butyl ester 20 is dissolved in DCM (1 mL) and TFA is added (2 mL). The yellow solution is stirred at rt for 2 h. The solvent and the excess of TFA are removed under vacuum and the residue is purified by preparative LCMS to afford piperidine-2-carboxylic acid {5-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-2-methyl-pyridin-3-yl}-amide C1. 1H NMR (400 MHz, d6-DMSO) δ 1H NMR (400 MHz, d4-CH3OH) δ 9.27 (d, J=4.0 Hz, 1H), 8.85 (d, J=4.0 Hz, 1H), 8.80 (s, 2H), 7.59-7.57 (m, 2H), 7.06-7.06 (m, 2H), 4.14 (dd, J=4.0 and 12.0 Hz, 1H), 3.86 (s, 3H), 3.52-3.48 (m, 1H), 3.15-3.12 (m, 1H), 2.62 (s, 3H), 2.45-2.44 (m, 1H), 2.07-2.06 (m, 1H), 1.98-1.95 (m, 1H), 1.89-1.85 (m, 1H), 1.79-1.75 (m, 2H). MS (m/z) (M+1)+: 419.2.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]2[C:7]3([O:20][CH2:21][C:22]([F:24])([F:23])[C:4]=2[CH:3]=1)[CH2:12][CH2:11][N:10]([CH2:13][C:14]1[C:15]([CH3:19])=[N:16][NH:17][CH:18]=1)[CH2:9][CH2:8]3.C(=O)([O-])[O-].[K+].[K+].Br[C:32]1[C:37]([CH2:38][O:39][CH3:40])=[CH:36][CH:35]=[CH:34][N:33]=1.CN[C@@H]1CCCC[C@H]1NC>C(OCC)(=O)C.[Cu]I.C1(C)C=CC=CC=1>[Cl:1][C:2]1[S:6][C:5]2[C:7]3([O:20][CH2:21][C:22]([F:23])([F:24])[C:4]=2[CH:3]=1)[CH2:12][CH2:11][N:10]([CH2:13][C:14]1[C:15]([CH3:19])=[N:16][N:17]([C:32]2[C:37]([CH2:38][O:39][CH3:40])=[CH:36][CH:35]=[CH:34][N:33]=2)[CH:18]=1)[CH2:9][CH2:8]3
Reactant: Cc1n[nH]cc1CN1CCC2(CC1)OCC(F)(F)c1cc(Cl)sc12
Reactant: COCc1cccnc1Br
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COCc1cccnc1-n1cc(CN2CCC3(CC2)OCC(F)(F)c2cc(Cl)sc23)c(C)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 65.5 %

Procedure:
To a screw-cap test tube is added copper (I) iodide (1.15 g, 6.02 mmol), 2-chloro-4,4-difluoro-1′-[(3-methyl-1H-pyrazol-4-yl)methyl]spiro[5H-thieno[2,3-c]pyran-7,4′-piperidine] (15 g, 40.12 mmol), potassium carbonate (11.76 g, 84.26 mmol), 15 mL of toluene (previously bubbled with nitrogen for 20 minutes) and a stir bar. The reaction mixture is bubbled with nitrogen for additional 10 min and then 2-bromo-3-methoxymethyl-pyridine (10.54 g, 52.16 mmol), and trans-N,N′-dimethylcyclohexane-1,2-diamine (1.90 mL, 12.04 mmol) are added. The reaction tube is quickly sealed (caution: build-up of pressure possible; use a safety shield), stirred at room temperature for 5 min and immersed in a preheated oil bath at 115° C. for 24 h. The sample is cooled down to room temperature, diluted with ethyl acetate and filtered through celite. The solvent is evaporated in vacuo. The residue is purified by normal phase Isco chromatography using hexane/ethyl acetate (30-70%). The desired fractions are collected and evaporated. Some impure fractions (<2 g) are repurified by normal phase Isco chromatography using hexane/ethyl acetate (20-60% in ethyl acetate) as eluent. All the fractions containing final compound are combined and evaporated to dryness in vacuo. The residue is dissolved in dichloromethane and washed with 10% aqueous solution of ammonium hydroxide to remove copper residues. The organic solvent is evaporated and the compound is dried overnight to yield 13 g of 2-chloro-4,4-difluoro-1′-[[1-[3-(methoxymethyl)-2-pyridyl]-3-methyl-pyrazol-4-yl]methyl]spiro[5H-thieno[2,3-c]pyran-7,4′-piperidine]. MS (m/z): 495 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[C:5]([N+:10]([O-])=O)[C:3]=1[NH2:4].Cl[Sn]Cl.Cl.[OH-].[K+]>>[NH2:10][C:5]1[CH:6]=[C:7]([Cl:9])[CH:8]=[C:2]([Cl:1])[C:3]=1[NH2:4]
Reactant: Nc1c(Cl)cc(Cl)cc1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [K+]
Product: Nc1cc(Cl)cc(Cl)c1N
Yield: 94.1 %

Procedure:
A mixture of 2,4-dichloro-6-nitroaniline (7.7 g, 37.2 mmol) and SnCl2 (21.6 g, 111.6 mmol) were mechanically stirred under a nitrogen atmosphere. Hydrochloric acid (38.5 ml) was added and the mixture was warmed at 75°-80° C. for 2 h. The mixture was cooled (ice bath) and neutralized (pH=9) with 50% potassium hydroxide solution followed by extraction with ether (3×150 ml). The combined organic extracts was dried over sodium hydroxide pellets and filtered. The solvent was evaporated leaving 6.2 g of intermediary 1,2-diamino-3,5-dichlorobenzene, which was dissolved in 200 ml of methanol and stirred under cooling in an ice bath. Hydrochloric acid (2.90 ml) was added followed by addition of glyoxylic acid monohydrate (3.9 g, 42.4 mmol). The ice bath was removed and stirring was continued for 16 h. The precipitate was filtered off, washed with cold methanol and dried to afford 6.0 g isomeric mixture (6:1, 1H-NMR) of 6,8-dichloroquinoxalin-2(1H)-one and 5,7-dichloroquinoxalin-2(1H)-one, respectively. The isomeric mixture was recrystallized from 2-methoxyethanol (100 ml) to afford 3.4 g of 6,8 -dichloroquinoxalin-2-(1H)-one. M.p. 228°-229° C. 1H-NMR (DMSO-d6):δ7.88 (m, 2H), 8.30 (s, 1H), 12.20 (s, 1H).