Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(COC2N=C(C(O)=O)C=CC=2C2CCOC2)CC1.[CH:20]1([CH2:23][O:24][C:25]2[N:30]=[C:29]([C:31]([OH:33])=O)[CH:28]=[CH:27][C:26]=2[CH:34]2[CH2:38][CH2:37][CH2:36][O:35]2)[CH2:22][CH2:21]1.[CH3:39][C:40]([CH3:48])([C:42]1[N:46]=[C:45]([CH3:47])[O:44][N:43]=1)[NH2:41]>>[CH3:39][C:40]([NH:41][C:31]([C:29]1[CH:28]=[CH:27][C:26]([CH:34]2[CH2:38][CH2:37][CH2:36][O:35]2)=[C:25]([O:24][CH2:23][CH:20]2[CH2:21][CH2:22]2)[N:30]=1)=[O:33])([C:42]1[N:46]=[C:45]([CH3:47])[O:44][N:43]=1)[CH3:48]
Reactant: O=C(O)c1ccc(C2CCCO2)c(OCC2CC2)n1
Reactant: Cc1nc(C(C)(C)N)no1
Agent: O=C(O)c1ccc(C2CCOC2)c(OCC2CC2)n1
Product: Cc1nc(C(C)(C)NC(=O)c2ccc(C3CCCO3)c(OCC3CC3)n2)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using the mixture of 6-(cyclopropylmethoxy)-5-(tetrahydrofuran-3-yl)-pyridine-2-carboxylic acid and 6-(cyclopropylmethoxy)-5-(tetrahydrofuran-2-yl)-pyridine-2-carboxylic acid (mixture from Example 114 d) and α,α,5-trimethyl-1,2,4-oxadiazole-3-methanamine (CAN 1153831-97-0) as starting materials, MS (EI): m/e=387.2 [M+H]+.
Reaction SMILES: [C:1]1([C:7]([SH:20])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[C:24]([CH3:28])([CH3:27])[CH:25]=[O:26]>C1COCC1.C1(C)C=CC=CC=1>[CH3:27][C:24]([S:20][C:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH3:28])[CH:25]=[O:26]
Reactant: CC(C)(Br)C=O
Reactant: SC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C=O)SC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 59 %

Procedure:
Triphenylmethylmercaptan (362.94 g, 1.31 mol, 100 mol %) dissolved in anhydrous THF (2 L)was cooled in an ice bath under argon. Sodium hydride (60% in oil; 54.39 g, 1.35 mol, 104 mol %) was added in portions over 20 min. 2-bromo-2-methylpropanal (206.06 g, 1.36 mol, 104 mol %; see Stevens & Gillis, 1957, J. Amer. Chem. Soc. 79: 3448-51) was then added slowly over 20 min. The reaction mixture was allowed to warm to room temperature and stirred for 12 hours. The reaction was quenched with water (1 L) and extracted with diethyl ether (3×1 L). The ether extracts were combined, washed with saturated NaCl solution (500 mL), dried over Na2SO4 and filtered. The solvent was removed under reduced pressure to afford a thick orange oil. The crude oil was dissolved in toluene (200 mL)and diluted to 2 L with hot hexanes. The mixture was filtered through a sintered glass funnel and cooled at -5° C. for 12 hours. The white crystalline solid which formed was removed by filtration to afford 266.36 g (59% yield of the title compound. The melting point of the resulting compound was determined to be 83°-85° C. Nuclear magnetic resonance characterization experiments yielded the following molecular signature: 1H NMR(300 MHz, CDCl3): δ1.24(s, 6H, 2CH3), 7.2-7.35 (m, 9H), 7.59-7.62 (m,6H), 8.69 (s, H, --COH) 13C NMR (75 MHz, CDCl3): δ22.86, 55.66, 67.48, 126.85, 127.75, 129.72, 144.79, 197.31.
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH2:7][C:8]2[S:9][CH:10]=[CH:11][C:12]=2[S:13](N2C=CC=C2)(=[O:15])=[O:14])=[CH:4][CH:3]=1.[K].S(Cl)([Cl:27])(=O)=O>>[CH3:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH2:7][C:8]2[S:9][CH:10]=[CH:11][C:12]=2[S:13]([Cl:27])(=[O:15])=[O:14])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: Cc1ccc(CCc2sccc2S(=O)(=O)n2cccc2)cc1
Agent: [K]
Product: Cc1ccc(CCc2sccc2S(=O)(=O)Cl)cc1
Yield: 51 %

Procedure:
2-[(4-Methyl)phenethyl]thiophene-3-sulfonyl chloride was prepared, as described in Example 15E, using N-{2-[(4-methyl)phenethyl]thiophene-3-sulfonyl}pyrrole by basic hydrolysis (KOH/ethanol) of the sulfonamide to the corresponding potassium salt followed by conversion of the salt to the corresponding sulfonyl chloride in 51% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:50]=[CH:49][C:6]([CH2:7][N:8]([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][C:31]=5[F:39])[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[NH2:51][C:52]1[S:53][CH:54]=[CH:55][N:56]=1>>[CH3:1][O:2][C:3]1[CH:50]=[CH:49][C:6]([CH2:7][N:8]([CH2:40][C:41]2[CH:42]=[CH:43][C:44]([O:47][CH3:48])=[CH:45][CH:46]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:38]=[CH:37][C:33]([C:34]([NH:51][C:52]6[S:53][CH:54]=[CH:55][N:56]=6)=[O:35])=[CH:32][C:31]=5[F:39])[C:17]=4[N:18]=[C:19]([N:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)O)cc3F)cn2)cc1
Reactant: Nc1nccs1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)Nc4nccs4)cc3F)cn2)cc1
Yield: 147.2 %

Procedure:
Using 4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-3-fluoro-benzoic acid (80.0 mg, 0.118 mmol) obtained in Step A in Example 1-D-21 and 2-aminothiazole (23.6 mg, 0.236 mmol) instead of 1-pyridine-3-yl-piperazine, amidation was carried out in the same manner as Step B in Example 1-D-21, to obtain a crude product of 4-[4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl]-3-fluoro-N-thiazol-2-yl-benzamide as a yellow solid (132 mg), and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-270) as a yellow powder (37.8 mg, 62%).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[OH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([N:15]([CH3:17])[CH3:16])(=[O:14])=[O:13].O>C(O)(=O)C.[Cl-].[Na+].O>[OH:5][C:6]1[C:11]([N+:1]([O-:4])=[O:2])=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([N:15]([CH3:17])[CH3:16])(=[O:14])=[O:13]
Reactant: O=[N+]([O-])O
Reactant: CN(C)S(=O)(=O)c1ccccc1O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CN(C)S(=O)(=O)c1cccc([N+](=O)[O-])c1O
Temperature: 25 °C
Yield: 22 %

Procedure:
2.24 ml (47.4 mmol, 1.3 eq) of fuming nitric acid at 90% were added, over the course of 15 minutes, to a mixture of 7.17 g (35.6 mmol, 1 eq) of 2-hydroxy-N,N-dimethylbenzenesulfonamide in 35.5 ml of acetic acid in a bath at 5° C. The reaction medium was then stirred at ambient temperature. After one and a half hours, the reaction medium was hydrolyzed with water and brine. The reaction medium was then extracted with a 4/1 ethyl acetate/heptane mixture (2×100 ml). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The solid obtained (8.66 g) was combined with GUL1537-178 and was chromatographed on silica gel (prepacked column, eluent heptane/(ethyl acetate+1% methanol), from 20% to 65% of (ethyl acetate+1% methanol)). A fraction enriched in ortho isomer was isolated, that is to say 3.7 g of a yellow solid. This solid was recrystallized from 40 ml of ethanol. 1.93 g of product were obtained in the form of a pale yellow solid. Yield=20%.
Reaction SMILES: Br[C:2]1[CH:6]=[C:5]([Cl:7])[S:4][C:3]=1[Cl:8].[CH3:9][O:10][C:11]([C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[CH:18]=1)=[O:12].[Cl-].[Li+].C(=O)([O-])[O-].[Na+].[Na+]>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(OCC)(=O)C>[Cl:8][C:3]1[S:4][C:5]([Cl:7])=[CH:6][C:2]=1[C:15]1[CH:14]=[C:13]([C:11]([O:10][CH3:9])=[O:12])[CH:18]=[C:17]([CH:16]=1)[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)c1cc(B(O)O)cc(C(=O)OC)c1
Reactant: Clc1cc(Br)c(Cl)s1
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: [Cl-]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(C(=O)OC)cc(-c2cc(Cl)sc2Cl)c1
Temperature: 85 °C
Reaction time: 4 h
Yield: 58.2 %

Procedure:
A mixture of 3-bromo-2,5-dichlorothiophene (0.30 g), [3,5-bis(methoxycarbonyl)phenyl]-dihydroxyborane (0.37 g), lithium chloride (0.164 g), tetrakis(triphenylphosphine)palladium(0) (0.0747 g) and 2M aqueous sodium carbonate solution (1.55 ml) in 1,2-dimethoxyethane (3.6 ml) was heated at 85° C. and stirred vigorously for 4 hours under nitrogen. The reaction mixture was cooled to room temperature and to the mixture was added ethyl acetate (20 ml) and 2M sodium carbonate solution (20 ml). The layers were separated, and the organic layer was washed successively with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a mixture of hexane and ethyl acetate (20:1). The fractions containing the desired product were collected and evaporated in vacuo to give dimethyl 5-(2,5-dichlorothiophen-3-yl)isophthalate (0.26 g).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[CH:2]1.[NH2:9][C@@H:10]([CH3:26])[CH2:11][N:12]1[CH:16]=[CH:15][C:14]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([Cl:25])[CH:18]=2)=[N:13]1>>[Cl:25][C:19]1[CH:18]=[C:17]([C:14]2[CH:15]=[CH:16][N:12]([CH2:11][C@H:10]([NH:9][C:6]([C:4]3[N:3]=[CH:2][S:1][CH:5]=3)=[O:8])[CH3:26])[N:13]=2)[CH:24]=[CH:23][C:20]=1[C:21]#[N:22]
Reactant: O=C(O)c1cscn1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Product: C[C@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cscn1
Yield: 15 %

Procedure:
The title compound was prepared using the method of Example 54 but starting from 1,3-thiazole-4-carboxylic acid (149 mg; 1.51 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (300 mg; 1.51 mmol). Crude product was purified by EtOH trituration to obtain 84 mg (20%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.12 (d, 3H), 4.30-4.53 (m, 3H), 6.95 (d, 1H), 7.86 (d, 1H), 7.95-8.04 (m, 2H), 8.15 (s, 1H), 8.28 (d, 1H), 8.77 (d, 1H), 9.23 (d, 1H).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH2:8][O:9][N:10]=[C:11]([C:18]2[N:22]([CH3:23])[N:21]=[N:20][N:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=[CH:4][CH:3]=1.[CH:24]1(/[CH:30]=[CH:31]/B(O)O)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.C([O-])([O-])=O.[Na+].[Na+]>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.C1(C)C=CC=CC=1.C(O)C.O>[CH:24]1(/[CH:30]=[CH:31]/[C:2]2[N:7]=[C:6]([CH2:8][O:9][N:10]=[C:11]([C:18]3[N:22]([CH3:23])[N:21]=[N:20][N:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:5]=[CH:4][CH:3]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: OB(O)/C=C/C1CCCCC1
Reactant: Cn1nnnc1C(=NOCc1cccc(Br)n1)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: Cn1nnnc1C(=NOCc1cccc(/C=C/C2CCCCC2)n1)c1ccccc1
Temperature: 90 °C
Yield: 71.8 %

Procedure:
In a dried and purged vessel were added N-[(6-bromopyridin-2-yl)methoxy]-1-(1-methyl-1H-tetrazol-5-yl)-1-phenylmethanimine (0.2 g, 0.536 mmol, 1 eq.), [(E)-2-cyclohexylvinyl]boronic acid (0.090 g, 0.58 mmol, 1.1 eq.), Na2CO3 (0.119 g, 1.12 mmol, 2.1 eq.) and Tetrakis(triphenylphosphine)palladium (0.030 g, 0.027 mmol, 0.05 eq.). A mixture of solvent was added toluene/ethanol/water (4/1/1) was added and the vessel purged with argon and sealed. The reaction was heated to 90° C. for 6 hrs. After cooling, 10 ml of EtOAc were added and the solids were filtered through a “Celite” plug and washed with EtOAc. The organics were separated, dried over MgSO4 and concentrated. The residue was purified by chromatography on silica gel to give N-({6-[(E)-2-cyclohexylvinyl]pyridin-2-yl}methoxy)-1-(1-methyl-1H-tetrazol-5-yl)-1-phenylmethanimine (0.155 g, 68% yield) as a colorless gum.
Reaction SMILES: N[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:15])([CH3:14])[CH2:7][N:8]2[C:11](=[O:13])[CH3:12])=[CH:4][CH:3]=1.Cl.N([O-])=O.[Na+].[I-:21].[K+]>O.C(Cl)Cl>[I:21][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:15])([CH3:14])[CH2:7][N:8]2[C:11](=[O:13])[CH3:12])=[CH:4][CH:3]=1
Reactant: [I-]
Reactant: CC(=O)N1CC(C)(C)c2ccc(N)cc21
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CC(=O)N1CC(C)(C)c2ccc(I)cc21
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a suspension of 1-(6-amino-3,3-dimethylindolin-1-yl)ethanone (2.000 g, 9.791 mmol) in concentrated hydrochloric acid (20.00 ml, 548.5 mmol) at 0° was added ice (15 g) followed by a solution of sodium nitrite (0.7769 g, 11.26 mmol) in water (15 mL). After 45 min, a solution of potassium iodide (3.251 g, 19.58 mmol) in water (15 mL) was added dropwise. After 5 min, the mixture was allowed to warm to RT. After 1 hr, CH2Cl2 (ca. 100 mL) and water (ca. 25 mL) were added. The aqueous fraction was extracted 2× with CH2Cl2. The combined organic fractions were washed with saturated NaHCO3 followed by 10% NaS2O3 and brine. After drying with Na2SO4, the deep red solution was concentrated in vacuo and purified by silica gel chromatography using 10-60% hexanes:EtOAc to afford 1-(6-iodo-3,3-dimethylindolin-1-yl)ethanone as an orange oil that solidified upon standing. M+H+=316.0.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][C:19]1[C:20](=[O:30])[N:21]([CH2:27][CH2:28][CH3:29])[C:22](=[O:26])[NH:23][C:24]=1[NH2:25].CCN=C=NCCCN(C)C>CO>[NH2:25][C:24]1[NH:23][C:22](=[O:26])[N:21]([CH2:27][CH2:28][CH3:29])[C:20](=[O:30])[C:19]=1[NH:18][C:13](=[O:15])[C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:17][CH:16]=1
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1
Reactant: CCCn1c(=O)[nH]c(N)c(N)c1=O
Agent: CCN=C=NCCCN(C)C
Solvent: CO
Product: CCCn1c(=O)[nH]c(N)c(NC(=O)c2ccc(OCc3ccccc3)cc2)c1=O
Temperature: 22.5 °C
Reaction time: 20 h
Yield: 37.6 %

Procedure:
A mixture of 4-benzyloxy-benzoic acid (7.44 g, 0.033 mol), 5,6-diamino-3-propyl-1H-pyrimidine-2,4-dione (5.0 g, 0.027 mol), methanol (60 ml), EDCI (10.0 g, 0.052 mol), were taken and stirred for 20 hours at 20-25° C. The reaction mixture was concentrated and water (50 ml) was added to obtain solid precipitate. The compound was purified by column chromatography to obtain N-(6-Amino-2,4-dioxo-3-propyl-1,2,3,4-tetrahydro-pyrimidin-5-yl)-4-benzyloxy-benzamide as light yellow solid (4.0 g, 38%).
Reaction SMILES: [ClH:1].[NH2:2][C@H:3]1[C@H:8]([C:9]([OH:11])=[O:10])[C@@H:7]([CH3:12])[O:6][C:4]1=[O:5].Cl.[CH3:14]O>>[ClH:1].[NH2:2][C@H:3]1[C@H:8]([C:9]([O:11][CH3:14])=[O:10])[C@@H:7]([CH3:12])[O:6][C:4]1=[O:5]
Reactant: C[C@H]1OC(=O)[C@@H](N)[C@@H]1C(=O)O
Reactant: CO
Agent: Cl
Product: COC(=O)[C@H]1[C@H](N)C(=O)O[C@@H]1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
19.56 g of 2(S)-amino-3(S)-carboxy-4(R)-pentanolide hydrochloride are suspended in methanol, the whole is gassed with hydrogen chloride for 15 minutes and stirred overnight at room temperature. The solvent is distilled off in a rotary evaporator and the residue is crystallised from chloroform: [α]D20 =-27.3° (1% in DMSO), m.p. 170°-172° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([O:16]C)=[O:15])[C:5]2[CH:6]=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[CH3:18][S:19]([O-:21])=[O:20].[Na+].CNCCNC>CS(C)=O>[CH:11]([N:8]1[C:9]2[CH:10]=[C:2]([S:19]([CH3:18])(=[O:21])=[O:20])[CH:3]=[C:4]([C:14]([OH:16])=[O:15])[C:5]=2[CH:6]=[CH:7]1)([CH3:13])[CH3:12]
Reactant: COC(=O)c1cc(Br)cc2c1ccn2C(C)C
Reactant: CS(=O)[O-]
Agent: CNCCNC
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)n1ccc2c(C(=O)O)cc(S(C)(=O)=O)cc21
Temperature: 165 °C
Yield: 9.2 %

Procedure:
To a 10-mL microwave tube were added methyl 6-bromo-1-(1-methylethyl)-1H-indole-4-carboxylate (160 mg, 0.540 mmol), sodium methanesulfinate (80 mg, 0.702 mmol), DMSO (2 mL), and N,N′-dimethyl-1,2-ethanediamine (6.19 mg, 0.070 mmol), and the mixture was degassed for 5 min by bubbling N2. Copper(I) trifluoromethanesulfonate benzene complex (25.6 mg, 0.043 mmol) was added and the mixture was heated to 165° C. for 2 h with stirring. The mixture was filtered and the DMSO solution was purified using reverse-phase HPLC to give 14 mg of product as white solid. 1H NMR (400 MHz, DMSO-d6) ppm 1.51 (d, J=4.00 Hz, 6 H), 4.90-5.11 (m, 1 H), 7.13 (d, J=3.03 Hz, 1 H), 7.98-8.08 (m, 1 H), 8.15-8.23 (m, 1 H), 8.32-8.46 (m, 1 H), 13.19 (br. s., 1 H). MS: (M+H)+=281.9.
Reaction SMILES: C([O:3][C:4](=[O:26])[CH:5]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:6][C:7]1[C:8](=[O:18])[O:9][C:10]2[C:15]([C:16]=1[OH:17])=[CH:14][CH:13]=[CH:12][CH:11]=2)C.[OH-].[Na+]>CCO>[CH2:19]([CH:5]([CH2:6][C:7]1[C:8](=[O:18])[O:9][C:10]2[C:15]([C:16]=1[OH:17])=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:4]([OH:26])=[O:3])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCOC(=O)C(Cc1ccccc1)Cc1c(O)c2ccccc2oc1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C(Cc1ccccc1)Cc1c(O)c2ccccc2oc1=O
Temperature: 50 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
2-Benzyl-3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-propionic acid ethyl ester (160 mg) in EtOH (1 mL) was added 1N NaOH (1.36 mL). The resulting mixture was heated to 50° C. and stirred for 2 hours, cooled to room temperature, acidified with Conc. HCl/ice and extracted with ether. The organic layer was dried over MgSO4 and conc. in vacuo to give 2-Benzyl-3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-propionic acid as a pale yellow solid (120mg). MS: 323[M-H].
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6]4=[C:7]([C:17](=[O:27])[C:18]([CH2:20][C:21]5[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=5)=[CH:19][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([OH:16])[CH:10]=3.Br[CH2:29][CH2:30][CH2:31][OH:32]>>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6]4=[C:7]([C:17](=[O:27])[C:18]([CH2:20][C:21]5[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=5)=[CH:19][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([O:16][CH2:29][CH2:30][CH2:31][OH:32])[CH:10]=3
Reactant: OCCCBr
Reactant: O=c1c(Cc2cccnc2)cn2c3c(cc(O)cc13)Sc1ccc(Br)cc1-2
Product: O=c1c(Cc2cccnc2)cn2c3c(cc(OCCCO)cc13)Sc1ccc(Br)cc1-2
Yield: 73 %

Procedure:
According to Example 34, the compound (300 mg) produced in Example 37 was reacted with 3-bromopropanol (78 μL) to obtain the title compound (210 mg; 73%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][C:25]1[C:30]([OH:31])=[CH:29][CH:28]=[C:27]([CH3:32])[N:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:31][C:30]4[C:25]([CH3:24])=[N:26][C:27]([CH3:32])=[CH:28][CH:29]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Reactant: Cc1ccc(O)c(C)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ncnc3c2cnn3C2CCN(C(=O)OC(C)(C)C)CC2)c(C)n1
Yield: 74.3 %

Procedure:
4-[4-(2,6-Dimethyl-pyridin-3-yloxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (41 mg, 65%) was prepared using the procedure described for the preparation of Example 96, by the reaction of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19; 50 mg, 0.15 mmol) with 2,6-dimethyl-3-hydroxypyridine (Apollo Scientific Ltd., Stockport, Cheshire, UK; 16 mg) in the presence of potassium carbonate (27 mg, 0.19 mmol) in dimethylformamide (2 mL). Mass spectrum (ES) MH+=425. HRMS Calcd. for C22H29N6O3 (MH+): 425.2296. Found: 425.2294.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([CH3:13])([CH3:12])[CH2:6][C:5]2=O.Cl.[NH2:16][OH:17]>CO.N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([CH3:13])([CH3:12])[CH2:6][C:5]2=[N:16][OH:17]
Reactant: NO
Reactant: CC1(C)CC(=O)c2cc(F)ccc2O1
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: CC1(C)CC(=NO)c2cc(F)ccc2O1

Procedure:
By heating 10 mmol of 6-fluoro-2,2-dimethyl-4-chromanone with 12 mmol of hydroxylamine hydrochloride in 5 ml of methanol and 5 ml of pyridine for 2 hours to 80° C., after distilling off the solvent and precipitating with water, 6-fluoro-2,2-dimethyl-4-chromanone oxime is obtained; m.p. 108-110° C.
Reaction SMILES: [CH2:1]([S:3][C:4]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[CH:16][CH:15]=2)[C:12](=[O:26])[C:11]2[C:6](=[N:7][C:8]([O:27]C)=[CH:9][N:10]=2)[N:5]=1)[CH3:2].Cl.N1C=CC=CC=1>CN(C)C=O>[CH2:1]([S:3][C:4]1[N:13]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][C:22]([F:23])([F:25])[F:24])=[CH:18][CH:19]=2)[C:12](=[O:26])[C:11]2[N:10]=[CH:9][C:8](=[O:27])[NH:7][C:6]=2[N:5]=1)[CH3:2]
Reactant: CCSc1nc2nc(OC)cnc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCSc1nc2[nH]c(=O)cnc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Temperature: 120 °C
Reaction time: 10 h
Yield: 56.3 %

Procedure:
A mixture of 2-(ethylsulfanyl)-7-methoxy-3-[4-(2,2,2-trifluoroethoxy)phenyl]pteridin-4(3H)-one (92 mg), pyridine hydrochloride (640 mg) and N,N-dimethylformamide (3 ml) was stirred at 120° C. for 10 hr, and in the same manner as in Example 6, the title compound (50 mg) was obtained as a white powder.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5](I)[CH:6]=[CH:7][CH:8]=1.[N+:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1Br)([O-:12])=[O:11]>[Cu]>[CH3:1][S:2][C:3]1[CH:4]=[C:5]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N+:10]([O-:12])=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: CSc1cccc(I)c1
Reactant: O=[N+]([O-])c1ccccc1Br
Agent: [Cu]
Product: CSc1cccc(-c2ccccc2[N+](=O)[O-])c1
Temperature: 120 °C

Procedure:
A mixture of 3-methylthioiodobenzene (30 g), 2-nitrobromobenzene (24 g) and copper powder (23 g) was heated at 120° C. for 34 hours to yield a residue which was purified by chromatography on a silica column eluted with hexane to give 3'-methylthio-2-nitrobiphenyl (m.p. 42°-43° C.).
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][N:15](C(=O)C(F)(F)F)[CH2:16]2)=[CH:11][CH:10]=1)(=[O:8])=[O:7])(C)(C)C>C(O)(C(F)(F)F)=O>[CH2:16]1[C:17]2[C:12](=[CH:11][CH:10]=[C:9]([S:6]([NH2:5])(=[O:7])=[O:8])[CH:18]=2)[CH2:13][CH2:14][NH:15]1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc2c(c1)CN(C(=O)C(F)(F)F)CC2
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1ccc2c(c1)CNCC2
Temperature: 25 °C
Reaction time: 96 h

Procedure:
N-(tert-Butyl)-2-(trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide (the product from step i), 1.78 g) was dissolved in TFA and stirred at room temperature for 96 h. The reaction was reduced in vacuo and the residue purified by column chromatography on silica gel 50% EtOAc/50% iso-hexane to give the subtitle compound as a white solid. Yield: 0.65 g
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:11]/[O:12][CH3:13])/[C:8](O)=[O:9])[N:3]=1.P(Cl)(Cl)([Cl:16])=O.CN(C)C=O>COCCOC>[NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:11]/[O:12][CH3:13])/[C:8]([Cl:16])=[O:9])[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CO/N=C(\C(=O)O)c1nsc(N)n1
Solvent: CN(C)C=O
Solvent: COCCOC
Product: CO/N=C(\C(=O)Cl)c1nsc(N)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In 50.0 ml of 1,2-dimethoxyethane (DME), 10.0 g of 2- (5-amino-1,2,4-thiadiazol-3-yl)-2(Z)-methoxyiminoacetic acid were stirred at -20° C., followed by the dropwise addition of a chlorinating reagent, which had been prepared beforehand by gradually adding 8.4 g of phosphorus oxychloride at 5° C. to a mixture of 20 ml of DME and 4.0 g of N,N-dimethylformamide (DMF) and then reacting them for 30 minutes. After they were reacted for 5 minutes, the reaction mixture was poured into 160 ml of ice water to precipitate crystals. The resulting crystals were collected by filtration, washed with 200 ml of ice water and then stirred for 30 minutes in 120 ml of n-hexane. After filtration, the resulting crystals were dried under reduced pressure, whereby the title compound was obtained. Yield: 8.43 g (76.6%). Purity: 97.2%.