Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([O:21][CH3:22])=[O:20])[CH:14]=2)[C:8]=1[C:23]([O:25][CH3:26])=[O:24])(=O)=O.[Li+].[Cl-].[CH2:31](N(CC)CC)[CH3:32].C([Sn](CCCC)(CCCC)C=C)CCC>O1CCOCC1.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>[CH:31]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([O:21][CH3:22])=[O:20])[CH:14]=2)[C:8]=1[C:23]([O:25][CH3:26])=[O:24])=[CH2:32]
Reactant: COC(=O)c1cccc(-c2cccc(OS(=O)(=O)C(F)(F)F)c2C(=O)OC)c1
Reactant: CCN(CC)CC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C=C[Sn](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: C1COCCO1
Product: C=Cc1cccc(-c2cccc(C(=O)OC)c2)c1C(=O)OC
Temperature: 25 °C
Yield: 99.1 %

Procedure:
A mixture of 3-trifluoromethanesulfonyloxy-[1,1′-biphenyl]-2,3′-dicarboxylic acid, dimethyl ester (1.3 g, 3.1 mmol), tetrakis(triphenylphosphine)palladium (0.36 g, 0.31 mmol), LiCl (0.94 g, 22.2 mmol), triethylamine (0.6 mL, 4.3 mmol) and tri-n-butyl(vinyl)tin (1.0 mL, 3.4 mmol) in 1,4-dioxane (30 mL) was heated at reflux under N2 for 4 h. After cooling to rt, the mixture was filtered through a plug of silica gel and the filtrate was concentrated. Purification by flash chromatography (1:10 EtOAc/hexanes) provided 3-ethenyl-[1,1′-biphenyl]-2,3′-dicarboxylic acid, dimethyl ester (0.91 g, 99%) as a white solid: 1H NMR (CDCl3) 3.61 (s, 3H), 3.92 (s, 3H), 5.40 (d, J=11.1 Hz, 1H), 5.79 (d, J=17.5 Hz, 1H), 6.87 (dd, J=17.4, 11.0 Hz, 1H), 7.31 (d, J=7.5 Hz, 1H), 7.44-7.49 (m, 2H), 7.56 (dm, J=7.5 Hz, 1H), 7.62 (d, J=8.0 Hz, 1H), 8.03 (dm, J=7.5 Hz, 1H), 8.08 (t, 1, J=1.5 Hz, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>C(OCC)(=O)C.[Ni]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]2)=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(C2CCNCC2)cc1
Agent: [Ni]
Solvent: CCOC(C)=O
Product: Nc1ccc(C2CCNCC2)cc1
Yield: 72.9 %

Procedure:
A solution of the 4-(4-nitrophenyl) piperidine (29.3 g, 0.144 mol) obtained in (i) in ethyl acetate (150 ml) was hydrogenated at 3 atmospheres over Raney Nickel (5 g) until uptake of hydrogen ceased. Evaporation afforded a brown oil which was crystallised from ether to give the desired product as light yellow crystals (18.5 g, 74% yield), M.pt. 85°-87° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[CH2:11][CH2:12][CH2:13][C:14]#[N:15].[NH4+].[Cl-]>O.CO.[Fe]>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([CH2:11][CH2:12][CH2:13][C:14]#[N:15])=[C:2]([F:1])[CH:7]=1
Reactant: N#CCCCc1ccc([N+](=O)[O-])cc1F
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: N#CCCCc1ccc(N)cc1F
Temperature: 90 °C
Reaction time: 1 h
Yield: 95.3 %

Procedure:
A mixture of compound 67 (1.32 g, 6.3 mmol), NH4Cl (5.08 g, 95 mmol) and iron powder (3.52 g, 63 mmol) in water (30 mL) and CH3OH (50 mL) was stirred at 90° C. for 1 h. After cooling, the reaction mixture was filtered and the solid was washed by DCM. The filtrates were separated, the organic layer was washed with brine, dried over Na2SO4 and concentrated to dryness to give compound 68 (1.07 g, 96%) as a light yellow oil. 1H NMR (400 MHz, CDCl3) δ6.88-6.97 (m, 1H), 6.30-6.44 (m, 1H), 3.65 (br s, 2H), 2.67 (t, 2H, J=7.3 Hz), 2.31 (t, 2H, J=7.2 Hz), 1.86-1.96 (m, 2H).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.Cl[C:15]1[C:16]2[S:33][C:32]([NH2:34])=[N:31][C:17]=2[N:18]=[C:19]([S:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=2[F:30])[N:20]=1>>[NH2:34][C:32]1[S:33][C:16]2[C:15]([NH:1][C@@H:2]3[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]3)=[N:20][C:19]([S:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=3[F:30])=[N:18][C:17]=2[N:31]=1
Reactant: Nc1nc2nc(SCc3cccc(F)c3F)nc(Cl)c2s1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Product: CC(C)(C)OC(=O)N1CC[C@@H](Nc2nc(SCc3cccc(F)c3F)nc3nc(N)sc23)C1

Procedure:
Prepared by the method of example 18 step a) using (R)-3-amino-1-pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester and the product of example 4 step b).
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:6]=[C:7]([C:11]2[N:12]=[C:13]([NH2:16])[S:14][CH:15]=2)[CH:8]=[CH:9][CH:10]=1)([O-:4])=[O:3].[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.Cl>N1C=CC=CC=1>[CH3:27][C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH:16][C:13]2[S:14][CH:15]=[C:11]([C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([N+:2]([O-:4])=[O:3])[CH:6]=3)[N:12]=2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1nc(-c2cccc([N+](=O)[O-])c2)cs1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2nc(-c3cccc([N+](=O)[O-])c3)cs2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48 %

Procedure:
A mixture of 0.5 g of 4-(3-nitro-phenyl)-thiazol-2-ylamine hydrochloride with 0.42 g of p-toluenesulfonyl chloride was stirred overnight with 2 ml of pyridine. The resulting, red colored suspension was poured into 50 ml of 1N hydrochloric acid and the solid which thereby separated was filtered off and dissolved in a mixture of 10 ml of ethanol and 10 ml of 2N sodium hydroxide solution. After the addition of 0.4 g of active charcoal the mixture was stirred at room temperature for 30 minutes and subsequently the active charcoal was filtered off. The product separated upon neutralization with concentrated hydrochloric acid. Recrystallization from 40 ml of 50% ethanol yielded 0.35 g of 4-methyl-N-[4-(3-nitro-phenyl)-thiazol-2-yl]-benzenesulfonamide as yellowish crystals.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(C(C)C)C(C)C)C.[NH:66]1[CH2:71][CH2:70][O:69][CH2:68][CH2:67]1>O.C(=O)(O)[O-].[Na+].CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([N:66]5[CH2:71][CH2:70][O:69][CH2:68][CH2:67]5)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(=O)N2CCOCC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 0.08 h
Yield: 87.1 %

Procedure:
A mixture of 0.045 g (0.1 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid (I-22), 0.042 g (0.110 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 0.052 ml (0.300 mmole) of ethyldiisopropyl amine and 1.0 mL of dimethylformamide was stirred for 5 minutes and then 0.013 g (0.15 mmole) morpholine was added. The mixture was stirred for 3 hours, then diluted with 10 mL of water plus 2 mL of saturated aqueous sodium bicarbonate and then extracted 3 times with 10 mL of ethyl acetate. The combined extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase silica gel chromatography, eluting with water-acetonitrile (gradient, 0:100-80:20) to give 0.045 g of 9-cyclopentyl-7,7-difluoro-2-[2-methoxy-4-(morpholine-4-carbonyl)-phenylamino]-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (I-127) as a white solid.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Br.[CH:10]1([NH2:13])[CH2:12][CH2:11]1>C(O)C>[CH:10]1([NH:13][CH2:5][C:4]2[CH:7]=[CH:8][CH:9]=[C:2]([I:1])[CH:3]=2)[CH2:12][CH2:11]1
Reactant: NC1CC1
Reactant: BrCc1cccc(I)c1
Solvent: CCO
Product: Ic1cccc(CNC2CC2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 81.6 %

Procedure:
A solution of 3-iodobenzyl bromide (Aldrich, 3.2 g, 10.77 mmol) in ethanol (20 mL) was treated with cyclopropyl amine (7 mL, 101.5 mmol) and the resulting reaction mixture was stirred over 3 days at ambient temperature. The volatiles were evaporated in vacuo, the residue was diluted with ethyl acetate and washed with saturated, aqueous sodium bicarbonate solution, water and brine, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to an oil that was subjected to flash column chromatography over silica gel (230–400 mesh) using 10–20% ethyl acetate in hexane as the eluent afford the title product (2.4 g, 81%).
Reaction SMILES: [N+:1]([C:4](=[C:8]1[NH:13][CH2:12][CH2:11][CH2:10][S:9]1)[C:5](=[O:7])[CH3:6])([O-:3])=[O:2].[Br:14]N1C(=O)CCC1=O.C(OCC)C>C(Cl)(Cl)(Cl)Cl>[Br:14][N:13]1[CH2:12][CH2:11][CH2:10][S:9][C:8]1=[C:4]([N+:1]([O-:3])=[O:2])[C:5](=[O:7])[CH3:6]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)C(=C1NCCCS1)[N+](=O)[O-]
Solvent: CCOCC
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)C(=C1SCCCN1Br)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 10.1 g of 2 and 10.0 g of N-bromosuccinimide in 150 ml of carbon tetrachloride was stirred at room temperature for 18 hours. The resulting mixture was filtered and the filtrate stripped of solvent under reduced pressure to leave a slightly gummy yellow solid. The solid was treated with ethyl ether and the remaining solid collected (bright yellow solid, m.p.: 101°-104°), then dissolved in methylene chloride. The solution was treated with Norite, filtered and the solvent stripped under reduced pressure to leave a solid which on recrystallization from ethyl acetate gave 12 as a yellow solid, m.p.: 105°-109°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:34][CH3:35])=[C:6]([S:8]([N:11]2[C:19]3[C:14](=[C:15]([O:32][CH3:33])[CH:16]=[C:17]([C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=4)=[O:21])[CH:18]=3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:7]=1.Cl[C:37]1C=CC(OC)=C(S(Cl)(=O)=O)[CH:42]=1>>[CH2:37]([O:28][C:27](=[O:29])[C:26]1[CH:30]=[CH:31][C:23]([NH:22][C:20]([C:17]2[CH:18]=[C:19]3[C:14]([CH2:13][CH2:12][N:11]3[S:8]([C:6]3[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:34][CH3:35])(=[O:10])=[O:9])=[C:15]([O:32][CH3:33])[CH:16]=2)=[O:21])=[CH:24][CH:25]=1)[CH3:42]
Reactant: COc1ccc(Cl)cc1S(=O)(=O)N1CCc2c(OC)cc(C(=O)Nc3ccc(C(=O)O)cc3)cc21
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Cl
Product: CCOC(=O)c1ccc(NC(=O)c2cc(OC)c3c(c2)N(S(=O)(=O)c2cc(Cl)ccc2OC)CC3)cc1

Procedure:
4-{[1-(5-Chloro-2-methoxy-benzenesulfonyl)-4-methoxy-2,3-dihydro-1H-indole-6-carbonyl]-amino}benzoic acid, m/z (ES+): 517.32 (M+H+.), was prepared in analogy to example 26, steps 1 to 6. Step 5 was performed using 5-chloro-2-methoxy-benzenesulfonyl chloride, yielding 4-{[1-(5-chloro-2-methoxy-benzenesulfonyl)-4-methoxy-2,3-dihydro-1H-indole-6-carbonyl]-amino}-benzoic acid ethyl ester, which was hydrolyzed in step 6.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(CC)CC.[NH2:30][C:31]1[C:32]([C:38]([OH:40])=O)=[N:33][C:34]([Br:37])=[CH:35][N:36]=1.[C:41]([NH:49][NH2:50])(=[O:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>CN(C=O)C.O>[NH2:30][C:31]1[C:32]([C:38]([N:49]([C:41]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:48])[NH2:50])=[O:40])=[N:33][C:34]([Br:37])=[CH:35][N:36]=1
Reactant: Nc1ncc(Br)nc1C(=O)O
Reactant: NNC(=O)c1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1ncc(Br)nc1C(=O)N(N)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
TBTU (22.09 g, 68.80 mmol) and Et3N (4.642 g, 6.394 mL, 45.87 mmol) were added to a solution of 3-amino-6-bromo-pyrazine-2-carboxylic acid (10 g, 45.87 mmol) and benzohydrazide (7.494 g, 55.04 mmol) in DMF (100.0 mL) and the resulting solution stirred at ambient temperature overnight. The reaction mixture was poured into water and the resultant precipitate was filtered and dried under vacuum. This was triturated with hot EtOAc and the resulting precipitate filtered and dried to give the desired product (13.11 g, 85% Yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].[BH4-].[Na+]>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].CO>[CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:26][CH:27]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][N:18]([CH:12]([C:22]3[CH:23]=[CH:24][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:26][CH:27]=3)[CH3:11])[CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2]
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCNC2)c1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: CO
Product: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCN(C(C)c3ccc(C(F)(F)F)cc3)C2)c1
Reaction time: 3 h

Procedure:
To compound 33b, 4-Methyl-2-(5-piperidin-3-yl-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (75 mg, 0.17 mmol), was added 4-Trifluoromethylacetophenonne (34 mg, 0.18 mmol), and titanium isopropoxide (76 mg), 0.27 mmol) under argon at room temperature. After 3 hours, add methanol ((0.76 ml), followed by sodium borohydride (10 mg, 0.27 mmol). After 5 minutes, the reaction was quenched with 0.1 N NaOH, filtered through celite and washed with dichloromethane. The solution was concentrated in vacuo, then diluted with dichloromethane, and washed with NaHCO3, and brine, and dried over magnesium sulfate. The reaction was concentrated in vacuo, and purified by silica gel chromatography to give two diastereomeric mixtures (S* and R*, tentative assignments); Calcd for C35H39F6NO2 (M+H) 619.68, Found 520.4
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH:12]=O)[CH2:11][CH2:10]1.C(OC(=O)C)(=O)C.Cl[C:22](Cl)([F:27])[C:23]([O:25][CH3:26])=[O:24]>[Zn].[Cu]Cl.O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH:12]=[C:22]([F:27])[C:23]([O:25][CH3:26])=[O:24])[CH2:10][CH2:11]1
Reactant: O=CC1(c2ccc(F)cc2F)CC1
Reactant: COC(=O)C(F)(Cl)Cl
Agent: Cl[Cu]
Agent: [Zn]
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C(F)=CC1(c2ccc(F)cc2F)CC1
Yield: 38.8 %

Procedure:
The method of Example 1 was repeated using zinc powder (1 g), copper (I) chloride (0.12 g), molecular sieve 4A (1 g), tetrahydrofuran (18 ml), 1-(2,4-difluorophenyl)-1-formylcyclopropane (0.44 g), acetic anhydride (0.4 ml) and methyl dichlorofluoroacetate (0.62 g) to yield the title compound (0.24 g, 39%).
Reaction SMILES: [CH:1]1([C:4]2[CH:8]=[C:7]([N:9]3[CH2:46][CH2:45][C:12]4[N:13]=[C:14]([C:24]5[C:32]([CH3:33])=[CH:31][CH:30]=[C:29]6[C:25]=5[C:26]([CH3:44])=[N:27][N:28]6[S:34]([C:37]5[CH:43]=[CH:42][C:40]([CH3:41])=[CH:39][CH:38]=5)(=[O:36])=[O:35])[N:15]=[C:16]([N:17]5[CH2:22][CH2:21][O:20][CH2:19][C@H:18]5[CH3:23])[C:11]=4[CH2:10]3)[N:6]([CH2:47][CH3:48])[N:5]=2)[CH2:3][CH2:2]1.C1C(=O)N([Cl:56])C(=O)C1>C(Cl)Cl>[Cl:56][C:8]1[C:4]([CH:1]2[CH2:3][CH2:2]2)=[N:5][N:6]([CH2:47][CH3:48])[C:7]=1[N:9]1[CH2:46][CH2:45][C:12]2[N:13]=[C:14]([C:24]3[C:32]([CH3:33])=[CH:31][CH:30]=[C:29]4[C:25]=3[C:26]([CH3:44])=[N:27][N:28]4[S:34]([C:37]3[CH:38]=[CH:39][C:40]([CH3:41])=[CH:42][CH:43]=3)(=[O:35])=[O:36])[N:15]=[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][C@H:18]3[CH3:23])[C:11]=2[CH2:10]1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCn1nc(C2CC2)cc1N1CCc2nc(-c3c(C)ccc4c3c(C)nn4S(=O)(=O)c3ccc(C)cc3)nc(N3CCOC[C@H]3C)c2C1
Solvent: ClCCl
Product: CCn1nc(C2CC2)c(Cl)c1N1CCc2nc(-c3c(C)ccc4c3c(C)nn4S(=O)(=O)c3ccc(C)cc3)nc(N3CCOC[C@H]3C)c2C1

Procedure:
To a solution of (R)-4-(6-(3-cyclopropyl-1-ethyl-1H-pyrazol-5-yl)-2-(3,5-dimethyl-1-tosyl-1H-indazol-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)-3-methylmorpholine (0.075 g, 0.112 mmol) in DCM (2.2 mL) was added NCS (0.016 g, 0.124 mmol). After 1 h the solvent was removed under reduced pressure and the residue purified directly by FCC (20-80% EtOAc/heptanes) to provide the title compound (R)-4-(6-(4-chloro-3-cyclopropyl-1-ethyl-1H-pyrazol-5-yl)-2-(3,5-dimethyl-1-tosyl-1H-indazol-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)-3-methylmorpholine. MS (ESI+) m/z 701.1 (M+H)+.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:20]3[O:21][CH:22]=[CH:23][CH:24]=3)=[N:10][C:11]([NH2:19])=[N:12][C:13]=2[C:14]2[O:15][CH:16]=[CH:17][CH:18]=2)[CH:5]=[CH:4][N:3]=1.[CH2:25]([NH2:28])[CH2:26][CH3:27]>>[O:21]1[CH:22]=[CH:23][CH:24]=[C:20]1[C:9]1[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:28][CH2:25][CH2:26][CH3:27])[CH:7]=2)=[C:13]([C:14]2[O:15][CH:16]=[CH:17][CH:18]=2)[N:12]=[C:11]([NH2:19])[N:10]=1
Reactant: Nc1nc(-c2ccco2)c(-c2ccnc(F)c2)c(-c2ccco2)n1
Reactant: CCCN
Product: CCCNc1cc(-c2c(-c3ccco3)nc(N)nc2-c2ccco2)ccn1
Temperature: 120 °C
Reaction time: 18 h
Yield: 64 %

Procedure:
In a reaction vessel, 5-(2-fluoro-4-pyridyl)-4,6-di(2-furyl)-2-pyrimidinamine (200 mg, 0.621 mmol) and n-propylamine (5 ml) were mixed together and the mixture was stirred at 120° C. After 18 hours, the reaction mixture was extracted with ethyl acetate, and the extract was washed with water and brine, dried over anhydrous sodium sulfate and then the filtrate was concentrated. The resulting solid was suspended in ethanol, collected by filtration and washed with ethanol, to give the title compound (64%,72 mg) as a pale yellow solid.
Reaction SMILES: Cl.[CH2:2]([C:9]1([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH2:18][CH2:17][C:12]2(OCC[O:13]2)[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:2]([C:9]1([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH2:18][CH2:17][C:12](=[O:13])[CH2:11][CH2:10]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: c1ccc(CC2(N3CCOCC3)CCC3(CC2)OCCO3)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C1CCC(Cc2ccccc2)(N2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
6 M hydrochloric acid (5 ml) was added to a solution of 4-(8-benzyl-1,4-dioxaspiro[4.5]dec-8-yl)morpholine (1.00 g, 3.15 mmole) in acetone (5 ml). After 24 hours further 6 M hydrochloric acid (2.5 ml) was added to the reaction solution, which was stirred for a further 3 days at room temperature, following which it was made alkaline (pH ˜9) with 25% potassium carbonate solution and extracted with diethyl ether (3×20 ml). The combined organic phases were dried with sodium sulfate and concentrated by evaporation in vacuo.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:18]3[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:25])[C:10]([Cl:17])=[C:11]([C:13]([OH:16])([CH3:15])[CH3:14])[N:12]=2)=[C:4]([Cl:26])[CH:3]=1.[CH3:27][S:28]([C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1)(=[O:30])=[O:29].C([O-])([O-])=O.[K+].[K+]>>[Cl:17][C:10]1[N:9]([C:18]2[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:25])[C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:35]3[CH:34]=[CH:33][CH:32]=[C:31]([S:28]([CH3:27])(=[O:30])=[O:29])[CH:36]=3)=[CH:3][C:4]=2[Cl:26])=[N:12][C:11]=1[C:13]([OH:16])([CH3:15])[CH3:14]
Reactant: CC(C)(O)c1nc(-c2ccc(Br)cc2Cl)n(-c2c(Cl)cccc2Cl)c1Cl
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(O)c1nc(-c2ccc(-c3cccc(S(C)(=O)=O)c3)cc2Cl)n(-c2c(Cl)cccc2Cl)c1Cl
Temperature: 60 °C
Reaction time: 1.17 h
Yield: 78.2 %

Procedure:
A mixture of 2-[2-(4-bromo-2-chlorophenyl)-5-chloro-1-(2,6-dichlorophenyl)-1H-imidazol-4-yl]-propan-2-ol (184 mg, 0.37 mmol), 3-methanesulfonyl-phenylboronic acid (90 mg, 0.45 mmol), K2CO3 (0.15 g, 1.1 mmol), Cl2Pd(dppf).DCM (15 mg, 5 mol %) and H2O (0.2 mL) in DME (2 mL) was sparged with Argon for 5 min and then heated at 60° C. as a sealed flask. After 70 min the reaction mixture was allowed to cool to ambient temperature, filtered (Celite™) and the filter agent rinsed with EtOAc. The combined filtrates were concentrated under reduced pressure and purified by chromatography (silica, EtOAc/Hex, 20:80 to 60:40) to give the title compound (165 mg, 78%) as a white solid. 1H-NMR (DCM-d2): δ 8.08 (m, 1H), 7.93 (m, 1H), 7.84 (m, 1H), 7.73 (d, 1H), 7.67 (m, 1H), 7.33-7.47 (m, 5H), 3.42 (br s, 1H), 3.06 (s, 3H), 1.68 (s, 61-1); MS (ES): 591, 593, 595 [M+Na]+.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[N:13]2[CH:14]=[CH:15][N:16]=[C:12]2[CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.C(#N)C.[C:27]1([S:33](Cl)(=[O:35])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(Cl)Cl>[C:27]1([S:33]([NH:3][CH2:4][CH2:5][CH2:6][O:7][C:8]2[N:13]3[CH:14]=[CH:15][N:16]=[C:12]3[CH:11]=[CH:10][CH:9]=2)(=[O:35])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: NCCCOc1cccc2nccn12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Solvent: CC#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(NCCCOc1cccc2nccn12)c1ccccc1
Yield: 59.4 %

Procedure:
To a suspension of 5-[3-(amino)propyloxy]imidazo[1,2-a]pyridine dihydrochloride (2.64 g, 10 mmoles) and triethylamine (4.88 ml, 35 mmoles) in methylene chloride (100 ml)-acetonitrile (30 ml) was added benzenesulfonyl chloride (1.53 ml, 12 mmoles) under ice-cooling with stirring and the mixture was stirred at room temperature for 1 hour. The reaction mixture was washed in turn with an aqueous sodium bicarbonate solution and saturated saline and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the crude product thus obtained was recrystallized from methylene-ethanol to obtain 1.97 g of the desired product (59.5%, light brown crystals).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[N:22]2[C:30]3[CH:29]=[CH:28][N:27]=[C:26](Cl)[C:25]=3[N:24]=[N:23]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH3:32]>CCO>[NH2:32][C:26]1[C:25]2[N:24]=[N:23][N:22]([C:16]3[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=3[NH:14][S:11]([C:8]3[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:6][CH:7]=3)(=[O:12])=[O:13])[C:30]=2[CH:29]=[CH:28][N:27]=1
Reactant: N
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2-n2nnc3c(Cl)nccc32)cc1
Solvent: CCO
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2-n2nnc3c(N)nccc32)cc1
Temperature: 120 °C

Procedure:
A 4 mL scintillation vial was charged with 4-tert-butyl-N-[4-chloro-2-(4-chloro-[1,2,3]triazolo[4,5-c]pyridin-1-yl)-phenyl]-benzenesulfonamide (synthesized according to general procedure G, 20 mg, 0.042 mmol) and 2 M NH3 in EtOH (2 mL). The reaction was sealed and heated to 120° C. for 18 hours. The EtOH was then removed in vacuo and the resultant residue was purified by preparative TLC to afford N-[2-(4-amino-[1,2,3]triazolo[4,5-c]pyridin-1-yl)-4-chloro-phenyl]-4-tert-butyl-benzenesulfonamide: MS (ES) M+H expected 457.1, found 457.0.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[C:16]2[C:11](=[N:12][CH:13]=[N:14][CH:15]=2)[NH:10][C:9](=O)[CH:8]1[CH3:18])=[O:6])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:28])=CC=1>>[CH:1]([O:4][C:5]([N:7]1[C:16]2[C:11](=[N:12][CH:13]=[N:14][CH:15]=2)[NH:10][C:9](=[S:28])[CH:8]1[CH3:18])=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N1c2cncnc2NC(=O)C1C
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: CC(C)OC(=O)N1c2cncnc2NC(=S)C1C
Yield: 28 %

Procedure:
100 mg of (2RS)-1-(isopropoxycarbonyl)-2-methyl-1,2-dihydro-1,4,5,7-tetraazanaphthalen-3(4H)-one from Example 24 were reacted with Lawesson's reagent in analogy to Example 20. The crude product after concentration was chromatographed (silica gel; ethyl acetate/heptane=1:1). 30 mg (28%) of the desired compound, of melting point 203°-204° C., were obtained.