Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([CH2:13][CH3:14])[C:10]([NH2:12])=[O:11])[CH:5]=[N:4][C:3]=1[C:15]#[N:16].[NH2:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23](=[O:28])[CH2:22][CH2:21]2.C([O-])([O-])=O.[K+].[K+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:15]([C:3]1[N:4]=[CH:5][C:6]([NH:8][C@H:9]([CH2:13][CH3:14])[C:10]([NH2:12])=[O:11])=[N:7][C:2]=1[NH:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23](=[O:28])[CH2:22][CH2:21]2)#[N:16]
Reactant: CC[C@@H](Nc1cnc(C#N)c(Cl)n1)C(N)=O
Reactant: Nc1ccc2c(c1)CCC(=O)N2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC[C@@H](Nc1cnc(C#N)c(Nc2ccc3c(c2)CCC(=O)N3)n1)C(N)=O
Reaction time: 4 h
Yield: 59 %

Procedure:
A mixture of (R)-2-(6-chloro-5-cyanopyrazin-2-ylamino)butanamide (80 mg, 0.334 mmol), 6-amino-3,4-dihydroquinolin-2(1H)-one (60 mg, 0.370 mmol), K2CO3 (100 mg, 0.724 mmol), BINAP (25 mg, 0.040 mmol) and Pd(OAc)2 (10 mg, 0.044 mmol) in dioxane (2 mL) was degassed with Ar, then was stirred at 110 C for 4 h. The mixture was concentrated in vacuo. The residue was purified by HPLC to give (R)-2-(5-cyano-6-(2-oxo-1,2,3,4-tetrahydroquinolin-6-ylamino)pyrazin-2-ylamino)butanamide (72 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[C:12](=[O:13])[C:11]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[CH:10][NH:9]2)[CH:3]=1.[NH:20]1[CH2:23][CH:22]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:21]1>C(O)C>[O:13]=[C:12]1[N:8]([C:4]2[N:5]=[CH:6][N:7]=[C:2]([N:20]3[CH2:23][CH:22]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])[CH2:21]3)[CH:3]=2)[NH:9][CH:10]=[C:11]1[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=c1c(-c2cccnc2)c[nH]n1-c1cc(Cl)ncn1
Reactant: CC(C)(C)OC(=O)NC1CNC1
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1CN(c2cc(-n3[nH]cc(-c4cccnc4)c3=O)ncn2)C1

Procedure:
200 mg (0.7 mmol) of the compound from Example 23 and 252 mg (1.5 mmol) of tert-butyl azetidin-3-ylcarbamate are suspended in 6 ml of ethanol and reacted at 120° C. in a single-mode microwave oven (CEM Explorer) for 40 min. The solid formed is filtered off, washed twice with in each case 0.5 ml of ethanol and dried under high vacuum.
Reaction SMILES: [CH3:1][N:2]1[C:7]([NH:8][CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][C:19]=3[O:27][CH3:28])[CH2:14][CH2:13]2)=[C:6]([CH3:29])[C:5](=[O:30])[N:4]([CH3:31])[C:3]1=[O:32]>C(O)C.O.O.NN.[Ni]>[CH3:1][N:2]1[C:7]([NH:8][CH2:9][CH2:10][CH2:11][N:12]2[CH2:13][CH2:14][N:15]([C:18]3[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=3[O:27][CH3:28])[CH2:16][CH2:17]2)=[C:6]([CH3:29])[C:5](=[O:30])[N:4]([CH3:31])[C:3]1=[O:32]
Reactant: COc1cc([N+](=O)[O-])ccc1N1CCN(CCCNc2c(C)c(=O)n(C)c(=O)n2C)CC1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CCO
Product: COc1cc(N)ccc1N1CCN(CCCNc2c(C)c(=O)n(C)c(=O)n2C)CC1

Procedure:
50 mmol of 1,3,5-trimethyl-6-[(3-[4-(2-methoxy-4-nitrophenyl)-1-piperazinyl]propyl)amino]-2,4(1H,3H)-pyrimidinedione are reduced using hydrazine hydrate/Raney-Nickel in ethanol/water according to a known method. After purification by column chromatography and recrystallization from ethyl acetate, 73% of the title compound of m.p. 146-148° C. is obtained. The starting substance is the product of Example 14.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[N:12]1([CH2:18][CH2:19][CH2:20][OH:21])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C(N(CC)CC)C>ClCCl>[N:12]1([CH2:18][CH2:19][CH2:20][O:21][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCCN1CCCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCCN2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Add p-toluenesulfonyl-chloride (1.33 g, 6.98 mmol), portionwise, to a mixture of 3-piperidin-1-yl-propan-1-ol (1 g, 6.98 mmol), triethylamine (1.41 g, 13.9 mmol) and dichloromethane (6 mL). Stir the resulting suspension vigorously overnight at room temperature. Add water, separate the organic layer, and extract the aqueous layer with dichloromethane, twice. Combine the organic layers and wash with water, dry with sodium sulfate and evaporate the solvent to give the final, desired compound. The final compound may be purified by chromatography.
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][C:10]#[N:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:13]1[C:14]2[S:25][CH:24]=[CH:23][C:15]=2[N:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[N:18]=1.O>CN(C=O)C.C1(C)C=CC=CC=1>[C:3]1([CH:9]([C:13]2[C:14]3[S:25][CH:24]=[CH:23][C:15]=3[N:16]=[C:17]([C:19]([F:21])([F:22])[F:20])[N:18]=2)[C:10]#[N:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: N#CCc1ccccc1
Reactant: FC(F)(F)c1nc(Cl)c2sccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: N#CC(c1ccccc1)c1nc(C(F)(F)F)nc2ccsc12
Reaction time: 0.17 h
Yield: 22.9 %

Procedure:
A suspension of NaH (60% dispersion in oil, 60 mg, 1.5 mmol) in DMF (5 mL) and toluene (15 mL) at room temperature was treated with phenylacetonitrile (0.16 g, 1.37 mmol), stirred for 10 min, treated with a solution of 4-chloro-2-trifluoromethylthieno[3,2-d]pyrimidine (0.3 g, 126 mmol) in DMF (2 mL), stirred for 15 min, treated with water (5 mL) and the phases separated. The aqueous phase was extracted with EtOAc (2×50 mL), the combined organic phase washed with water (3×10 mL), brine (10 mL), dried (MgSO4), concentrated in vacuo and the resulting orange oily solid crystallised from heptane to give the title compound (0.1 g, 25%) as a gold solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([C@H:10]2[C@@H:15]([O:16]COC)[C@H:14]([O:20]COC)[C@H:13]([O:24]COC)[CH:12]([CH2:28][O:29]COC)[O:11]2)[CH:6]=[CH:7][C:8]=1[Cl:9].[CH2:33]([N:35]1[C:39](=[O:40])[CH2:38][N:37]([C:41]2[CH:46]=[CH:45][C:44](B3OC(C)(C)C(C)(C)O3)=[CH:43][CH:42]=2)[C:36]1=[O:56])[CH3:34].C(=O)([O-])[O-].[Na+].[Na+].Cl.CO>[Pd].CN(C)C=O.O>[Cl:9][C:8]1[CH:7]=[CH:6][C:5]([C@H:10]2[C@H:15]([OH:16])[C@@H:14]([OH:20])[C@H:13]([OH:24])[C@@H:12]([CH2:28][OH:29])[O:11]2)=[CH:4][C:3]=1[CH2:2][C:44]1[CH:43]=[CH:42][C:41]([N:37]2[CH2:38][C:39](=[O:40])[N:35]([CH2:33][CH3:34])[C:36]2=[O:56])=[CH:46][CH:45]=1
Reactant: COCOCC1O[C@@H](c2ccc(Cl)c(CBr)c2)[C@@H](OCOC)[C@H](OCOC)[C@@H]1OCOC
Reactant: CCN1C(=O)CN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)C1=O
Agent: [Pd]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: CCN1C(=O)CN(c2ccc(Cc3cc([C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)ccc3Cl)cc2)C1=O
Yield: 63.8 %

Procedure:
A mixture of the product from step C (82 mg, 0.15 mmol), 3-ethyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)imidazolidine-2,4-dione (which compound) (59 mg, 0.18 mmol, 1.2 equiv), sodium carbonate (48 mg, 0.45 mmol), and the palladium catalyst (0.12 mg, 0.015 mmol) in N,N-dimethylformamide/water (2:1, 2.1 mL) was heated at 80° C. under nitrogen for 4 h. The reaction was quenched with water (10 mL) and extracted with ethyl acetate (4×). The combined extracts were dried over sodium sulfate, passed through a short pad of silica gel, and concentrated. The coupling product obtained was then stirred overnight with 6 N HCl/methanol (20:1 v/v) at room temperature. The reaction mixture was concentrated to dryness and the residual material was purified by flash column chromatography (eluent: dichloromethane/methanol 100:0 to 90:10) to provide 1-(4-(2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)benzyl)phenyl)-3-ethylimidazolidine-2,4-dione (47 mg, 47%).
Reaction SMILES: CN(C)[CH:3]=[C:4]([C:10](=O)[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[N+]([O-])(O)=O.[N+]([O-])(O)=O.[CH3:31][O:32][C:33]1[CH:34]=[C:35]([NH:45][C:46]([NH2:48])=[NH:47])[CH:36]=[CH:37][C:38]=1[N:39]1[CH:43]=[C:42]([CH3:44])[N:41]=[CH:40]1>>[CH3:31][O:32][C:33]1[CH:34]=[C:35]([NH:45][C:46]2[N:48]=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:15][CH:16]=3)[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:3][N:47]=2)[CH:36]=[CH:37][C:38]=1[N:39]1[CH:43]=[C:42]([CH3:44])[N:41]=[CH:40]1
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1ccc(C(F)(F)F)cc1
Solvent: O=[N+]([O-])O
Product: CCOC(=O)c1cnc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)nc1-c1ccc(C(F)(F)F)cc1

Procedure:
The title compound was prepared from ethyl 3-dimethylamino-2-(4-trifluoromethyl-benzoyl)-acrylate (151 mg, 0.48 mmol) and N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (133 mg, 0.36 mmol) using in analogous manner the procedure described in example 28b). Obtained as a pale-yellow solid (14 mg, 6%).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[CH2:13][CH2:14][C:15](=[O:18])[NH:16][N:17]=3)=[CH:8][N:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1>O1CCOCC1>[N:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[CH:13]=[CH:14][C:15](=[O:18])[NH:16][N:17]=3)=[CH:8][N:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C1CCC(c2ccc(-n3ccnc3)nc2)=NN1
Solvent: C1COCCO1
Product: O=c1ccc(-c2ccc(-n3ccnc3)nc2)n[nH]1

Procedure:
2 g. (8.3 mmole) of the compound prepared in Example 2 were boiled in 250 ml. dioxan with 50 g. pyrolusite for 5 hours, filtered off with suction and the filtrate concentrated until it crystallised. After recrystallisation from ethanol, there was obtained 1 g. of the title compound; m.p. 300° C.
Reaction SMILES: C(O[C:4]([C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH:23]=[CH:22][C:21](=[O:24])[CH2:20][CH2:19]3)=[CH:14][CH:13]=2)[CH2:7]1)=[O:5])C.C(N(CC)CC)C.Cl.[F:33][CH2:34][CH2:35][NH2:36]>CO>[F:33][CH2:34][CH2:35][NH:36][C:4]([C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH:23]=[CH:22][C:21](=[O:24])[CH2:20][CH2:19]3)=[CH:14][CH:13]=2)[CH2:7]1)=[O:5]
Reactant: CCOC(=O)[C@H]1CN(c2ccc(N3C=CC(=O)CC3)cc2)C(=O)O1
Reactant: NCCF
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C1C=CN(c2ccc(N3C[C@H](C(=O)NCCF)OC3=O)cc2)CC1
Temperature: 55 °C
Reaction time: 8 h

Procedure:
To a stirred solution of (5R)-3-[4-(4-oxo-3,4-dihydro-2H-pyridin-1-yl)phenyl]-2-oxo-5-oxazolidinecarboxylic acid ethyl ester (EXAMPLE 72, Step 5, 226 mg, 0.68 mmol) in MeOH (2 mL) is added triethylamine (0.48 mL, 5.0 equiv.). Then 2-fluoroethylamine hydrochloride (136 mg, 2.0 equiv.) is added to the solution. The reaction mixture is heated at 50-60° C. for 5 h, followed by stirring overnight at room temperature. Solvent is removed and the residue is dissolved in 20% MeOH/CH2Cl2 and purified by column chromatography (10% MeOH/CH2Cl2). The title compound is obtained as a yellow solid (100 mg, 42%), 1H NMR (300 MHz, DMSO) δ 8.69 (t, 1H), 7.75-7.27 (m, 5H), 5.09 (dd, 1H), 4.98 (d, 1H), 4.55 (t, 1H), 4.39 (t, 1H), 4.29 (t, 1H), 4.02-3.93 (m, 3H), 3.51-3.37 (m, 2H), 2.50-2.45 (m, 2H); MS for C17H18FN3O4 m/z 348.5 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[C:18](B2OC(C)(C)C(C)(C)O2)[CH:17]=[CH:16][N:15]=1>>[CH3:12][O:13][C:14]1[CH:19]=[C:18]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=2)[CH:17]=[CH:16][N:15]=1
Reactant: FC(F)(F)c1ccc(Br)nc1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Product: COc1cc(-c2ccc(C(F)(F)F)cn2)ccn1
Yield: 73.2 %

Procedure:
2-Bromo-5-trifluoromethylpyridine (410 mg, 2.13 mmol) and 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (500 mg, 1.81 mmol) were reacted according to Example 3 (step a) to provide the title compound (337 mg, 62%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 8.96 (s, 1H), 8.31 (d, J=5.4 Hz, 1H), 8.04 (dd, J=8.3, 2.1 Hz, 1H), 7.87 (d, J=8.3 Hz, 1H), 7.51 (dd, J=5.4, 1.4 Hz, 1H), 7.36 (s, 1H), 3.52 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13](=O)[C:14]([CH3:20])([CH3:19])[C:15](OC)=[O:16])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].O.[NH2:23][NH2:24]>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[C:14]([CH3:20])([CH3:19])[C:15](=[O:16])[NH:23][N:24]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: NN
Reactant: CCOc1ccc(C(=O)C(C)(C)C(=O)OC)cc1OCC
Solvent: O
Product: CCOc1ccc(C2=NNC(=O)C2(C)C)cc1OCC

Procedure:
Prepared analogously as described for example C1 using methyl 3-(3,4-diethoxyphenyl)-2,2-dimethyl-3-oxopropanoate (compound D2) and hydrazine hydrate as starting compounds.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[CH3:6][S:7]([N:10]1[CH2:15][CH2:14][CH2:13][S:12][C:11]1=[CH:16][N+:17]([O-:19])=[O:18])(=[O:9])=[O:8]>C(Cl)Cl>[CH3:6][S:7]([N:10]1[CH2:15][CH2:14][CH2:13][S:12][C:11]1=[C:16]([Cl:4])[N+:17]([O-:19])=[O:18])(=[O:8])=[O:9]
Reactant: O=S(=O)(Cl)Cl
Reactant: CS(=O)(=O)N1CCCSC1=C[N+](=O)[O-]
Solvent: ClCCl
Product: CS(=O)(=O)N1CCCSC1=C(Cl)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 1.25 g of redistilled sulfuryl chloride in 5 ml of methylene chloride was added drop-by-drop over a 5-minute period to a slurry of (1A) in 50 ml of methylene chloride in a nitrogen atmosphere at 0-5° C. The mixture was stirred for 30 minutes more, then allowed to warm to room temperature. Two drops more of sulfuryl chloride were added and the mixture was stirred for 5 minutes. The resulting mixture was washed with water, then with brine, dried (MgSO4), and stripped of solvent to give a yellow solid. The solid was triturated with ether to give (2), as a yellow solid, m.p. 149°-151° C. (with decomposition).
Reaction SMILES: CO.C[O-].[Na+].C[O:7][C:8]([C:10]1[N:15]=C(C2C=CC=C(OC)C=2)C2N=C(C3C=CC=CC=3)OC=2C=1OC(=O)C(C)(C)C)=[O:9].CO[C:42]([C:44]1[N:49]=[C:48]([C:50]2[CH:55]=[CH:54][CH:53]=[C:52]([O:56][CH3:57])[CH:51]=2)[C:47]2[N:58]=[C:59]([C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)[O:60][C:46]=2[C:45]=1[OH:67])=[O:43].NCC(O)=O>CO>[OH:67][C:45]1[C:46]2[O:60][C:59]([C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)=[N:58][C:47]=2[C:48]([C:50]2[CH:55]=[CH:54][CH:53]=[C:52]([O:56][CH3:57])[CH:51]=2)=[N:49][C:44]=1[C:42]([NH:15][CH2:10][C:8]([OH:9])=[O:7])=[O:43]
Reactant: COC(=O)c1nc(-c2cccc(OC)c2)c2nc(-c3ccccc3)oc2c1OC(=O)C(C)(C)C
Reactant: COC(=O)c1nc(-c2cccc(OC)c2)c2nc(-c3ccccc3)oc2c1O
Agent: C[O-]
Agent: NCC(=O)O
Agent: [Na+]
Solvent: CO
Product: COc1cccc(-c2nc(C(=O)NCC(=O)O)c(O)c3oc(-c4ccccc4)nc23)c1
Yield: 350.2 %

Procedure:
Sodium methoxide methanol solution (0.5 N, 0.4 mL, 0.2 mmol) was added to a solution of 7-(2,2-dimethyl-propionyloxy)-4-(3-methoxy-phenyl)-2-phenyl-oxazolo[4,5-c]pyridine-6-carboxylic acid methyl ester (7.5 mg, 0.016 mmol), and 7-hydroxy-4-(3-methoxy-phenyl)-2-phenyl-oxazolo[4,5-c]pyridine-6-carboxylic acid methyl ester (24.7 mg, 0.066 mmol) in methanol (2 mL) at room temperature. After the reaction mixture was refluxed for 1 hour, the mixture was concentrated. To the residue glycine (0.129 g, 1.72 mmol) and sodium methoxide methanol solution (0.5 N, 2.88 mL, 1.44 mmol) were then added. The mixture was then refluxed overnight, cooled, and concentrated. The residue was dissolved in water (30 mL), and the solution was washed with ethyl acetate (3×20 mL). After the solution was acidified to pH 1-2 with 2N HCl, a light yellow solid precipitated, that was collected by filtration and then dried in vacuo to give 23.5 mg of the title compound. MS: (−) m/z 417.9 (M−1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([C:8]2[NH:17][C:16](=[O:18])[C:15]3[C:10](=[N:11][CH:12]=[CH:13][N:14]=3)[N:9]=2)[CH:7]=1.[NH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[C:6]([C:8]2[NH:17][C:16](=[O:18])[C:15]3[C:10](=[N:11][CH:12]=[CH:13][N:14]=3)[N:9]=2)[CH:7]=1
Reactant: O=c1[nH]c(-c2cc(Br)ccc2F)nc2nccnc12
Reactant: C1CCNC1
Product: O=c1[nH]c(-c2cc(Br)ccc2N2CCCC2)nc2nccnc12

Procedure:
A solution of 2-(5-bromo-2-fluorophenyl)pteridin-4-one 104 in pyrrolidine was heated in a microwave cavity (Power=270 W, Temp=110° C.) for 12 min. The pyrrolidine was evaporated, then residue partitioned between NaHCO3 0.5 N and CH2Cl2, dried (Na2SO4) and evaporated. Trituration in Et2O afforded the title product 110 as a yellow powder (LCMS analysis).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6](=[O:24])[CH:5]2[C:25]1[C:34]([OH:35])=[CH:33][C:28]2[O:29][CH2:30][CH2:31][O:32][C:27]=2[CH:26]=1.[C:36]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6](=[O:24])[C:5]12[C:25]2[C:34](=[CH:33][C:28]3[O:29][CH2:30][CH2:31][O:32][C:27]=3[CH:26]=2)[O:35][CH2:36]1
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Reactant: O=C1C(c2cc3c(cc2O)OCCO3)c2cc(Br)ccc2N1C(c1ccccc1)c1ccccc1
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccc(Br)cc2C12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 5-bromo-1-(diphenylmethyl)-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 5′-bromo-1′-(diphenylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (76%) as a colorless solid: MS (ES+) m/z 539.9 (M+1), 541.1 (M+1).
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=3)[N:12]([CH:22]([CH3:24])[CH3:23])[C:11]2=[O:25])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B([C:29]1[CH:30]=[C:31]([S:35]([NH2:38])(=[O:37])=[O:36])[CH:32]=[CH:33][CH:34]=1)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15]3[CH:16]=[C:17]([C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([S:35]([NH2:38])(=[O:37])=[O:36])[CH:30]=4)[CH:18]=[CH:19][CH:20]=3)[N:12]([CH:22]([CH3:24])[CH3:23])[C:11]2=[O:25])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NS(=O)(=O)c1cccc(B(O)O)c1
Reactant: CC(C)N1C(=O)N(S(=O)(=O)c2ccccc2)CC1c1cccc(Br)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: CC(C)N1C(=O)N(S(=O)(=O)c2ccccc2)CC1c1cccc(-c2cccc(S(N)(=O)=O)c2)c1

Procedure:
In analogy to example 1, step 3,1-benzenesulfonyl-4-(3-bromo-phenyl)-3-isopropyl-imidazolidin-2-one (example 12, step 1) was reacted with 3-boronobenzenesulfonamide in the presence of dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium dichloromethane adduct and sodium carbonate in dioxane/water to give 3′-(1-benzenesulfonyl-3-isopropyl-2-oxo-imidazolidin-4-yl)-biphenyl-3-sulfonic acid amide as a colorless solid. MS: 499.9 ([M+H]+)
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]#[C:17][CH2:18][CH2:19]O)=[CH:13][CH:14]=2)[CH:9]=[N:8]1.O=P(Cl)(Cl)[Cl:23]>N1C=CC=CC=1>[Cl:23][CH2:19][CH2:18][C:17]#[C:16][C:12]1[CH:11]=[C:10]2[C:15](=[CH:14][CH:13]=1)[N:7]([CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)[N:8]=[CH:9]2
Reactant: OCCC#Cc1ccc2c(cnn2C2CCCCO2)c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: ClCCC#Cc1ccc2c(cnn2C2CCCCO2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 37.4 %

Procedure:
To a solution of 4-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-3-yn-1-ol (1.0 g, 3.7 mmol; Intermediate 17) in dry pyridine (10 mL) was added dropwise POCl3 (2.4 g, 14.7 mmol) under N2 atmosphere. The resulting solution was stirred at room temperature for 16 hours. Upon completion, the reaction mixture was concentrated in vacuo. The residue was poured into ice-water and extracted with EtOAc (2×10 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was further purified on silica gel column (0˜20% EtOAc in petroleum ether) affording the title compound (400 mg). 1H NMR (400 MHz, DMSO-d6): δ 8.11 (s, 1H), 7.86 (s, 1H), 7.72 (d, 1H), 7.42 (dd, 1H), 5.86 (dd, 1H), 3.90-3.86 (m, 1H), 3.81 (t, 2H), 3.77-3.70 (m, 1H), 2.93 (t, 2H), 2.41-2.34 (m, 1H), 2.05-1.94 (m, 2H), 1.75-1.71 (m, 1H), 1.60-1.55 (m, 2H); LCMS: 289 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:7][C:8]([CH3:13])([CH3:12])[O:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:26]([CH:28]1[O:30][CH2:29]1)Cl>CC(C)=O>[O:30]1[CH2:29][CH:28]1[CH2:26][O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:7][C:8]([CH3:13])([CH3:12])[O:9]2)=[CH:4][CH:3]=1
Reactant: CC1(C)CC(c2ccccc2)c2ccc(O)cc2O1
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC1(C)CC(c2ccccc2)c2ccc(OCC3CO3)cc2O1
Yield: 95 %

Procedure:
A mixture of 7-hydroxy-2,2-dimethyl-4-phenylchroman (11.8 g, 0.046 mole), anhydrous potassium carbonate (11.7 g, 0.093 mole), epichlorohydrin (50 ml) and dry acetone (50 ml) was stirred and boiled under reflux for 6 hours, then cooled and filtered. The filtrate was evaporated in vacuo and the residual brown oil dissolved in ether, washed with water and dried (magnesium sulphate). Removal of the solvent gave 7-(2,3-epoxypropoxy)-2,2-dimethyl-4-phenylchroman as a pale brown solid (13.56 g, 95%), m.p. 82°-85°, after crystallisation from ethanol.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][CH:25]=[C:26]([C:28](OC)=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12].[CH3:40][C:41]([O-:44])([CH3:43])[CH3:42].[K+]>C(OC(C)(C)C)(=O)C.C1COCC1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][CH:25]=[C:26]([C:28]([O:44][C:41]([CH3:43])([CH3:42])[CH3:40])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: COC(=O)c1csc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)n1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1csc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)n1

Procedure:
To a stirring solution of methyl 2-(8-(benzo[d]thiazol-2-yl((2-(trimethylsilyl)ethoxy)methyl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)thiazole-4-carboxylate (38A) (14 g, 24.1 mmol) in t-butyl acetate (200 mL) was added 2 mL of t-BuOK in THF (2M) under vacuum. 3×2 mL t-BuOK were added to the stirring solution under vacuum to drive the reaction to complete. The mixture was then acidified to neutrality and washed with water, brine, dried over Na2SO4, and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel eluting with 5% EtOAc in hexanes to provide 3.5 g of the desired product 38B: 1H NMR (300 MHz, CDCl3) δ ppm 8.29 (1H, m), 7.71 (1H, d), 7.62 (2H, m), 7.49 (2H, t), 7.34 (3H, m), 6.02 (2H, s), 5.20 (2H, s), 4.02 (2H, m), 3.71 (3H, m), 3.08 (2H, m), 1.59 (9H, t), 0.97 (2H, m), −0.09 (9H, m). MS (ESI(+)): m/z 623.0 (M+H).