Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH:2]([N:5]([C@@H:32]1[CH2:37][CH2:36][CH2:35][NH:34][CH2:33]1)[C:6]([C:8]1[C:9]([C:28]([F:31])([F:30])[F:29])=[CH:10][C:11]2[O:16][C:15]([CH3:18])([CH3:17])[C:14](=[O:19])[N:13]([CH2:20][CH2:21][NH:22][C:23](=[O:26])[CH2:24][CH3:25])[C:12]=2[CH:27]=1)=[O:7])([CH3:4])[CH3:3].[C:38]([NH:45][C@H:46]([C:50](O)=[O:51])[CH:47]([CH3:49])[CH3:48])([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH3:18][C:15]1([CH3:17])[C:14](=[O:19])[N:13]([CH2:20][CH2:21][NH:22][C:23](=[O:26])[CH2:24][CH3:25])[C:12]2[CH:27]=[C:8]([C:6]([N:5]([CH:2]([CH3:3])[CH3:4])[C@@H:32]3[CH2:37][CH2:36][CH2:35][N:34]([C:50]([C@@H:46]([NH:45][C:38](=[O:39])[O:40][C:41]([CH3:42])([CH3:44])[CH3:43])[CH:47]([CH3:49])[CH3:48])=[O:51])[CH2:33]3)=[O:7])[C:9]([C:28]([F:30])([F:29])[F:31])=[CH:10][C:11]=2[O:16]1
Reactant: CCC(=O)NCCN1C(=O)C(C)(C)Oc2cc(C(F)(F)F)c(C(=O)N(C(C)C)[C@@H]3CCCNC3)cc21
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCC(=O)NCCN1C(=O)C(C)(C)Oc2cc(C(F)(F)F)c(C(=O)N(C(C)C)[C@@H]3CCCN(C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)C3)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 113.1 %

Procedure:
To N-isopropyl-2,2-dimethyl-3-oxo-N-[(3R)-piperidin-3-yl]-4-[2-(propionylamino)ethyl]-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazine-6-carboxamide hydrochloride (300 mg) were added N-Boc valine (158 mg), WSC (210 mg), HOBt (150 mg), triethylamine (0.30 ml) and chloroform (5 ml), and the mixture was stirred at room temperature overnight. After the reaction is completed, the solvent was concentrated, and the obtained residue was purified by column chromatography (hexane:ethyl acetate=1:2) to give the desired title compound (440 mg) as white amorphous.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([C:10]3[C:19]4[C:14](=[CH:15][C:16]5[O:22][CH2:21][O:20][C:17]=5[CH:18]=4)[NH:13][C:12](=O)[N:11]=3)=[CH:4][C:3]=2[O:2]1.P(Cl)(Cl)([Cl:26])=O.[OH-].[Na+]>CN(C=O)C>[Cl:26][C:12]1[N:11]=[C:10]([C:5]2[CH:6]=[CH:7][C:8]3[O:9][CH2:1][O:2][C:3]=3[CH:4]=2)[C:19]2[C:14](=[CH:15][C:16]3[O:22][CH2:21][O:20][C:17]=3[CH:18]=2)[N:13]=1
Reactant: O=c1nc(-c2ccc3c(c2)OCO3)c2cc3c(cc2[nH]1)OCO3
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Clc1nc(-c2ccc3c(c2)OCO3)c2cc3c(cc2n1)OCO3
Temperature: 25 °C
Yield: 111.1 %

Procedure:
4-(3,4-Methylenedioxyphenyl)-6,7-methylenedioxyquinazolin-2(1H)-one (1 g, 3.23 mmol) was treated with DMF (one drop) and phosphorous oxychloride (7 mL, 75 mmol) and the suspension was heated to reflux for 4 h. Upon cooling to rt, the reaction mixture was poured into ice and the pH was adjusted to ˜8 with 3N NaOH solution. The precipitate was vacuum filtered and dried to give the title compound as a brown granular solid (1.18 g). 1H NMR (DMSO-d6) 6.16 (s, 2H), 6.32 (s,2H), 6.85-7.41 (m, 5H).
Reaction SMILES: C(O[C:6]1[C:7](=[O:17])[C:8](=[O:16])[C:9]=1[NH:10][CH:11]([CH3:15])[CH:12]([CH3:14])C)CCC.[Cl:18][C:19]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:20]=1[CH2:21][NH2:22].O1CCC[CH2:29]1>>[Cl:18][C:19]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:20]=1[CH2:21][NH:22][C:6]1[C:7](=[O:17])[C:8](=[O:16])[C:9]=1[NH:10][C:11]([CH3:15])([CH3:29])[CH2:12][CH3:14]
Reactant: CCCCOc1c(NC(C)C(C)C)c(=O)c1=O
Reactant: NCc1ccc(Cl)cc1Cl
Reactant: C1CCOC1
Product: CCC(C)(C)Nc1c(NCc2ccc(Cl)cc2Cl)c(=O)c1=O
Yield: 40 %

Procedure:
A solution of 3-butoxy-4-(1,1-dimethyl-propylamino)-cyclobut-3-ene-1,2-dione (7.18 g, 30 mmol, Example 5) and 2,4-dichlorobenzylamine (5.28 g, 30 mmol) in tetrahydrofuran (40 mL) was stirred at room temperature for 16 hours. The solvent was removed and the residue was triturated thoroughly with diethyl ether and dried to give 8.94 g of a crude product. Successive recrystallizations of this material from acetonitrile (charcoal), acetonitrile (twice), acetone (charcoal) and acetone (twice) afforded 4.08 g (40%) of the title compound as a white, electrostatic solid: mp 196°-197° C. (softens 188° C.); 1H NMR (DMSO-d6): δ 7.81 (m, 1H), 7.68 (m, 1H), 7.48 (m, 3H), 4.81 (d, 2H), 1.67 (m, 2H), 1.31 (s, 6H), 0.82 (t, 3H) ppm. IR (KBr): 3210, 1790, 1645 cm-1 ; MS (m/z) 340/342/344 (M+). HPLC indicates a major component (99% ). Differential scanning calorimetry studies indicate that this material is a mixture of crystal forms.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:7]([CH2:8][N:9]2[CH:13]=[C:12]([NH2:14])[CH:11]=[N:10]2)=[C:6]([CH3:15])[O:5][N:4]=1.C(N(CC)CC)C.[Cl:23][C:24]1[C:28]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][S:26][C:25]=1[C:33](Cl)=[O:34]>C(Cl)Cl.CC#N>[Cl:23][C:24]1[C:28]([S:29]([CH3:32])(=[O:30])=[O:31])=[CH:27][S:26][C:25]=1[C:33]([NH:14][C:12]1[CH:11]=[N:10][N:9]([CH2:8][C:7]2[C:3]([CH3:2])=[N:4][O:5][C:6]=2[CH3:15])[CH:13]=1)=[O:34]
Reactant: Cc1noc(C)c1Cn1cc(N)cn1
Reactant: CS(=O)(=O)c1csc(C(=O)Cl)c1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: ClCCl
Product: Cc1noc(C)c1Cn1cc(NC(=O)c2scc(S(C)(=O)=O)c2Cl)cn1
Temperature: 0 °C
Yield: 45.2 %

Procedure:
To a stirring mixture of ((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-amine hydrochloride (Example 4-1a) (500 mg, 2 mmol) in DCM (20 mL), cooled to 0° C. via an ice water bath, was added triethylamine (600 mg, 6 mmol). The mixture was stirred until all solids were in solution (˜10 minutes). 3-Chloro-4-(methylsulfonyl)thiophene-2-carbonyl chloride (543 mg, 2.1 mmol), in 2 mL CH3CN, was added via syringe to the free amine at 0° C. The ice bath was removed and the mixture was stirred for 2 hours. The reaction was diluted with dichloromethane (100 mL) and the organic phase was washed with H2O (200 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The solid was triturated with ethyl acetate/hexanes (1/5) to afford 3-chloro-N-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-4 (methylsulfonyl)thiophene-2-carboxamide (375 mg, 45%) as a white solid. 1H NMR (CDCl3, 400 MHz):2.20 (s, 3H), 2.43 (s, 4H), 3.22 (s, 3H), 5.05 (s, 2H), 7.57 (s, 1H), 7.94 (s, 1H), 8.41 (s, 1H), 8.59 (bs, 1H). LC/MS; [M+H] 415.5. Melting point: 202-204° C.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[CH:24]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:36]=[C:35]([C:37]([NH2:39])=[O:38])[O:34][N:33]=2)=[CH:28][CH:27]=1)=O.C([O-])([O-])=O.[Na+].[Na+]>ClC(Cl)C.CC(O)=O>[NH:2]1[C:1]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:4][CH:3]1[CH2:24][C:26]1[CH:27]=[CH:28][C:29]([C:32]2[CH:36]=[C:35]([C:37]([NH2:39])=[O:38])[O:34][N:33]=2)=[CH:30][CH:31]=1
Reactant: NC(=O)c1cc(-c2ccc(C=O)cc2)no1
Reactant: c1ccc2c(c1)CNC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: NC(=O)c1cc(-c2ccc(CC3Cc4ccccc4N3)cc2)no1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 33.7 %

Procedure:
To a solution of isoindoline (11 μL, 0.097 mmol) in dichloroethane (1 mL) was added Na(OAc)3BH (59 mg, 0.278 mmol). The mixture was stirred at room temperature under argon for 20 min. A slurry of 3-(4-formyl-phenyl)-isoxazole-5-carboxylic acid amide (which may be prepared as described in Preparation of Intermediate 20; 20 mg, 0.093 mmol) in dichloroethane (1 mL) was added, followed by AcOH (20 μL). The reaction mixture was stirred at room temperature overnight. 1 M Na2CO3 solution was added and the mixture was extracted with CHCl3 (3×25 mL). The organic layer was washed with brine, dried (Na2SO4), evaporated, and purified by chromatography (20-25% acetone/CH2Cl2) to give 3-[4-(1,3-dihydro-indol-2-ylmethyl)-phenyl]-isoxazole-5-carboxylic acid amide (10 mg, 32%) as an off-white powder. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.36 (br. s., 1H), 7.99 (br. s., 1H), 7.88 (d, J=8.2 Hz, 2H), 7.48-7.61 (m, 3H), 7.09-7.26 (m, 4H), 5.74 (s, 2H), 4.07 (br. s., 1H), 3.92 (s, 1H), 3.30 (d, J=3.0 Hz, 2H), 3.15 (d, J=4.8 Hz, 2H).
Reaction SMILES: Cl.C([N:9]1[CH2:13][C@@H:12]([S:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C@H:11]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:10]1)(OC(C)(C)C)=O.C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.O.[C:53]([O:57][C:58]([NH:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][C:66](O)=[O:67])=[O:59])([CH3:56])([CH3:55])[CH3:54].C1CCC(N=C=NC2CCCCC2)CC1>C(OCC)(=O)C>[C:53]([O:57][C:58]([NH:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][C:66]([N:9]1[CH2:13][C@@H:12]([S:14][C:15]([CH3:17])([CH3:18])[CH3:16])[C@H:11]([NH:19][S:20]([C:23]2[CH:24]=[CH:25][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:27][CH:28]=2)(=[O:22])=[O:21])[CH2:10]1)=[O:67])=[O:59])([CH3:56])([CH3:55])[CH3:54]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](NS(=O)(=O)c2ccc(-c3ccccc3)cc2)[C@H](SC(C)(C)C)C1
Reactant: CC(C)(C)OC(=O)NCCCCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCCCCC(=O)N1C[C@@H](NS(=O)(=O)c2ccc(-c3ccccc3)cc2)[C@H](SC(C)(C)C)C1
Temperature: 0 °C
Yield: 93.4 %

Procedure:
To a solution of 1.5 M HCl in ethyl acetate (1 mL) was added (±)-N-Boc-trans-3-(4-phenylbenzenesulfonamido)-4-tert-butylmercaptopyrrolidine (220 mg, 0.45 mmol) and the mixture was stirred until no starting material could be detected by TLC (50% ethyl acetate). The solvent was evaporated under reduced pressure and the residue was dissolved in CH2Cl2 (2 mL) and cooled to 0° C. To the solution was added triethylamine (69 μL, 0.50 mmol), HOBt.H2O (61 mg, 0.45 mmol), and 6-(tert-butoxy-carbonylamino)hexanoic acid (104 mg, 0.39 mmol) and DCC (92 mg, 0.45 mmol). The mixture was stirred overnight, then it was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (10 mL) and the organic layer was washed with 10% citric acid and sat. aq NaHCO3, then it was dried over Na2SO4 and evaporated. The residue was purified by flash chromatography (50% ethyl acetate in hexane) to give (±)-N-(6-(tert-butoxycarbonylamino)hexanoyl)-trans-3-(4-phenylbenzenesulfonamido)-4-tert-butylmercaptopyrrolidine (220 mg, 81%): 1H NMR (300 MHz, CDCl3) δ 7.94 (dd, J=9, 4, 2H), 7.75 (t, J=8, 2H), 7.61 (m, 2H), 7.46 (m, 3H), 5.21 (br s, 1H, NH), 4.56 (br s, 1H, NH), 3.77-4.11 (m, 2H), 3.02-3.49 (m, 6H), 2.22 (t, J=7, 2H), 1.63 (m, 2H), 1.49 (m, 2H), 1.44 (s, 9H), 1.36 & 1.29 (s, 9H), 1.25 (m, 2H); HRMS (ESI) calculated for C31H45N3O5S2Na+ 626.2698. found 626.2699.
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20](F)[C:21]=3[Cl:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([F:30])=[CH:9][C:8]=1[F:31].Cl.Cl.[CH3:34][NH:35][CH:36]1[CH2:39][NH:38][CH2:37]1.CN1CCCC1>C(O)C>[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20]([N:38]4[CH2:39][CH:36]([NH:35][CH3:34])[CH2:37]4)[C:21]=3[Cl:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([F:30])=[CH:9][C:8]=1[F:31]
Reactant: CNC1CNC1
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Agent: CN1CCCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCO
Product: CNC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(-c4nc(N)c(F)cc4F)c3c2Cl)C1
Temperature: 90 °C
Reaction time: 1 h
Yield: 87.3 %

Procedure:
To 400 mg of N,N-dimethylformamide were added 90 mg of 1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 80 mg of 3-methylaminoazetidine dihydrochloride, and 160 mg of N-methylpyrrolidine, and the mixture was stirred at 90° C. for 1 hour. After adding 0.5 ml of ethanol, the mixture-was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 92 mg of the title compound as a colorless powder.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:14]([OH:17])(=O)[CH3:15].C1(NC2C3[S:45][CH2:44][CH2:43][C:27]=3[N:28]=[C:29](N3CCN(C4C=CC=CC=4)CC3)[N:30]=2)CCCCC1>O>[OH:13][C:10]1[CH:9]=[CH:8][C:7]([N:1]2[CH2:2][CH2:3][N:4]([C:29]3[N:30]=[C:14]([OH:17])[C:15]4[S:45][CH2:44][CH2:43][C:27]=4[N:28]=3)[CH2:5][CH2:6]2)=[CH:12][CH:11]=1
Reactant: CC(=O)O
Reactant: Oc1ccc(N2CCNCC2)cc1
Reactant: c1ccc(N2CCN(c3nc4c(c(NC5CCCCC5)n3)SCC4)CC2)cc1
Solvent: O
Product: Oc1ccc(N2CCN(c3nc(O)c4c(n3)CCS4)CC2)cc1
Temperature: 180 °C
Reaction time: 16 h
Yield: 89.3 %

Procedure:
1.70 g (9.54 mmol) of 4-piperazin-1-ylphenol is placed in 0.55 mL (9.62 mmol) of glacial acetic acid and heated to 180° C. in the heating block. 0.800 g (3.73 mmol) of 2-ethylsulfanyl-6,7-dihydrothieno[3,2-d]pyrimidin-4-ol (I) is added, then the mixture is left to stand for 1.5 hours at 180° C. and 16 hours at ambient temperature. Then the reaction mixture is combined with water and treated in the ultrasound bath. The precipitate is suction filtered, washed, and dried. 1.1 g of product II is obtained as a powder.
Reaction SMILES: [Si:1]([O:18][CH:19]1[CH2:24][CH:23]2[CH:21]([CH:22]2[C:25](=O)[CH2:26][C:27](=O)[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH:36]([NH:39][NH2:40])([CH3:38])[CH3:37].C(N(CC)CC)C>C(O)C>[Si:1]([O:18][CH:19]1[CH2:24][CH:23]2[CH:21]([CH:22]2[C:25]2[N:39]([CH:36]([CH3:38])[CH3:37])[N:40]=[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:26]=2)[CH2:20]1)([C:14]([CH3:15])([CH3:17])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)CC(=O)C1C2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)CC21
Reactant: CC(C)NN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1cc(C2C3CC(O[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)CC32)n(C(C)C)n1
Reaction time: 16 h
Yield: 44.9 %

Procedure:
To a solution of ethyl 4-(3-((tert-butyldiphenylsilyl)oxy)bicyclo[3.1.0]hexan-6-yl)-2,4-dioxobutanoate (0.40 kg, 84 mmol) in ethanol (500 mL) was added N-isopropylhydrazine hydrochloride (9.7 g, 84 mmol) at room temperature. After 16 h, triethylamine was added, and the resulting mixture was concentrated in vacuo. Purification of the residue by flash column chromatography (9% ethyl acetate in petroleum ether) afforded ethyl 5-(3-((tert-butyldiphenylsilyl)oxy)bicyclo[3.1.0]hexan-6-yl)-1-isopropyl-1H-pyrazole-3-carboxylate (19.5 g, 45%) as a colorless oil. LRMS: [M+H]+=517.1.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH:12]=[CH:11][C:10]=2[CH:14]=1.C([Li])CCC.C([C:22]([O:24][CH3:25])=[O:23])#N.O>C1COCC1.C(OCC)(=O)C>[CH3:25][O:24][C:22]([C:12]1[O:13][C:9]2[CH:8]=[CH:7][C:6]([CH:2]3[O:3][CH2:4][CH2:5][O:1]3)=[CH:14][C:10]=2[CH:11]=1)=[O:23]
Reactant: c1cc2cc(C3OCCO3)ccc2o1
Reactant: COC(=O)C#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2cc(C3OCCO3)ccc2o1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 44 %

Procedure:
5-[1,3]Dioxolan-2-yl-benzofuran (50 mg, 0.26 mmol) was dissolved in THF (2 mL) and the solution was cooled down to −78° C. Butyl lithium (180 uL, 1.1 eq.) was added dropwise. This mixture was stirred 30 min at 25° C. Then the reaction mixture was cooled down to −78° C. and methyl cyanoformate (23 uL, 1.1 eq.) dissolved in 1 mL THF was added dropwise to the reaction mixture. After 1 h30 only small amount of starting material was detected and two major compounds were formed (expected product/dimer 73:27). The temperature was increased slowly to room temperature overnight. Water and ethyl acetate were added to the mixture and the aqueous layer was extracted 3 times. Combined organic phases was dried over MgSO4, filtrated and evaporated to give the 5-[1,3]Dioxolan-2-yl-benzofuran-2-carboxylic acid methyl ester (31.9 mg, 44%) mixed with the dimer (expected product/dimer 46:54). The mixture was used directly in the next step.
Reaction SMILES: [CH2:1]([O:3][C@@H:4]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][S:34]([CH3:37])(=[O:36])=[O:35])=[CH:29][CH:28]=2)=[CH:20][CH:19]=1)[C:5](N[C@H](C1C=CC=CC=1)CO)=[O:6])[CH3:2].S(=O)(=O)(O)[OH:39].O1CCOCC1>O>[CH2:1]([O:3][C@@H:4]([CH2:17][C:18]1[CH:19]=[CH:20][C:21]([O:24][CH2:25][CH2:26][C:27]2[CH:28]=[CH:29][C:30]([O:33][S:34]([CH3:37])(=[O:35])=[O:36])=[CH:31][CH:32]=2)=[CH:22][CH:23]=1)[C:5]([OH:6])=[O:39])[CH3:2]
Reactant: O=S(=O)(O)O
Reactant: CCO[C@@H](Cc1ccc(OCCc2ccc(OS(C)(=O)=O)cc2)cc1)C(=O)N[C@@H](CO)c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CCO[C@@H](Cc1ccc(OCCc2ccc(OS(C)(=O)=O)cc2)cc1)C(=O)O
Yield: 79 %

Procedure:
(S)-2-Ethoxy-N-(2-hydroxy(R)-1-phenylethyl)-3-[4-(2-{4-methanesulfonyloxyphenyl}ethoxy)phenyl]propanoic amide (4.49 g; 8.59 mmole), concentrated sulfuric acid (12.5 Ml), dioxan (50 ml) and water (50 ml) were stirred at 80° C. for 6 hours. After cooling, water (100 ml) was added and the product was extracted with dichloromethane (2×100 ml). The organic phases were combined and washed with brine (60 ml), dried (sodium sulfate), filtered and evaporated in vacuo. Purification by chromatography on silica gel using heptan:ethyl acetate:acetic acid (10:10:1) as gradient and azeotropic destillation with toluen gave 2.78 g (yield 79%) of (S)-2-ethoxy-3-[4-(2-{4-methanesulfonyloxyphenyl}ethoxy)phenyl]propanoic acid.
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][C:5]([O:6][CH:7]([CH3:16])[CH2:8][NH:9][S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])=[CH:4][CH:3]=1.[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOC>[CH3:14][CH:13]([S:10]([NH:9][CH2:8][CH:7]([O:6][C:5]1[CH:17]=[CH:18][C:2]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH3:19])=[CH:3][CH:4]=1)[CH3:16])(=[O:12])=[O:11])[CH3:15]
Reactant: CC(CNS(=O)(=O)C(C)C)Oc1ccc(Br)cc1
Reactant: Cc1ccccc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1ccccc1-c1ccc(OC(C)CNS(=O)(=O)C(C)C)cc1
Yield: 33.9 %

Procedure:
The title compound (120 mg, 34%, yellow foam) was prepared from [2-(4-bromophenoxy)propyl][(methylethyl)sulfonyl]amine (343 mg, 1.02 mmol, prepared in example 1), 2-methylbenzeneboronic acid (165 mg, 1.21 mmol), dichlorobis(triphenylphosphine)palladium(II) (30 mg, 0.043 mmol), 2 M sodium carbonate (370 mg in 1.75 mL water), and 1,2-dimethoxyethane (6.8 mL) in a manner analogous to the procedure described in Example 8.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:19])[CH:15]=2)[N:10]=[C:9]1[CH3:20].C(OC(=O)C)(=O)C.[CH3:28][C:29]1[S:30][CH:31]=[C:32]([CH:34]=O)[N:33]=1>O.[Cl-].[Zn+2].[Cl-]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:19])[CH:15]=2)[N:10]=[C:9]1[CH:20]=[CH:34][C:32]1[N:33]=[C:29]([CH3:28])[S:30][CH:31]=1
Reactant: Cc1nc2ccc(F)cc2c(=O)n1-c1ccccc1Cl
Reactant: Cc1nc(C=O)cs1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: Cc1nc(C=Cc2nc3ccc(F)cc3c(=O)n2-c2ccccc2Cl)cs1
Temperature: 25 °C
Yield: 82.1 %

Procedure:
Anhydrous zinc chloride (0.133 g, 0.98 mmol) was fused with a nitrogen purge in a round bottom flask with an open flame. The reaction vessel was allowed to return to ambient temperature, at which time dioxane (7 mL) was then added. To this mixture was added 3-(2-chloro-phenyl)-6-fluoro-2-methyl-3H-quinazolin-4-one (0.14 g, 0.49 mmol), acetic anhydride (0.138 mL, 1.46 mmol), and 2-methylthiazole-4-carboxaldehyde (0.185 g, 1.46 mmol in 4 mL of dioxane). The reaction was refluxed for 4 hours, at which time it was allowed to cool to ambient temperature. Once the reaction had cooled to ambient temperature it was diluted with water. The mixture was repeatedly extracted with chloroform. The chloroform extracts were combined to form a chloroform layer which was washed with water and brine, dried over sodium sulfate and concentrated to yield a dark residue. This residue was triturated with ether, filtered and dried to afford 0.16 g (57%) of 3-(2-chloro-phenyl)-6-fluoro-2-[2-(2-methyl-thiazol-4-yl)-vinyl]-3H-quinazolin-4-one as tan solid.
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][C:5]([O:8][CH3:9])=[C:4]2[N:10]([C:18]3[CH:19]=[C:20]([C:23]([NH2:25])=[O:24])[S:21][CH:22]=3)[N:11]=[C:12]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:3]=12.C(O)C>[Pd].CN(C=O)C>[CH:13]1([C:12]2[C:3]3[C:4](=[C:5]([O:8][CH3:9])[N:6]=[CH:7][CH:2]=3)[N:10]([C:18]3[CH:19]=[C:20]([C:23]([NH2:25])=[O:24])[S:21][CH:22]=3)[N:11]=2)[CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: COc1ncc(Br)c2c(C3CCCC3)nn(-c3csc(C(N)=O)c3)c12
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCO
Product: COc1nccc2c(C3CCCC3)nn(-c3csc(C(N)=O)c3)c12
Temperature: 25 °C
Reaction time: 15 h
Yield: 123 %

Procedure:
A mixture of 4-(4-bromo-3-cyclopentyl-7-methoxy-1H-pyrazolo[3,4-c]pyridin-1-yl)thiophene-2-carboxamide (60 mg) obtained in Step A of Example 67 and 10% palladium/carbon (50% wet, 15 mg) in a mixed solvent of ethanol (10 mL) and DMF (3 mL) was stirred under hydrogen atmosphere at room temperature for 15 hr. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title compound (60 mg).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[CH:5][C:4]([C:8]([OH:10])=O)=[N:3]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.[Cl:43][C:44]1[CH:45]=[C:46]([C:51]2[O:55][C:54]([CH2:56][CH2:57][NH2:58])=[CH:53][CH:52]=2)[CH:47]=[CH:48][C:49]=1[Cl:50]>CN(C=O)C.O>[Cl:43][C:44]1[CH:45]=[C:46]([C:51]2[O:55][C:54]([CH2:56][CH2:57][NH:58][C:8]([C:4]3[CH:5]=[C:6]([CH3:7])[N:2]([CH3:1])[N:3]=3)=[O:10])=[CH:53][CH:52]=2)[CH:47]=[CH:48][C:49]=1[Cl:50]
Reactant: Cc1cc(C(=O)O)nn1C
Reactant: NCCc1ccc(-c2ccc(Cl)c(Cl)c2)o1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C(=O)NCCc2ccc(-c3ccc(Cl)c(Cl)c3)o2)nn1C
Reaction time: 0.5 h

Procedure:
1,5-Dimethyl-1H-pyrazole-3-carboxylic acid (100 mg, 0.71 mmol) was dissolved in dry DMF (2 ml). EDCl (205 mg, 1.1 mmol), HOBt (145 mg, 1.1 mmol) and DIPEA (0.19 ml, 141 mg, 1.1 mmol) were added at RT. The solution was stirred for 30 min. Then, 2-[5-(3,4-dichlorophenyl)furan-2-yl]ethylamine hydrochloride (313 mg, 1.1 mmol) dissolved in the mixture of dry DMF (4 ml) and DIPEA (0.19 ml, 141 mg, 1.1 mmol) was added to the solution at RT. After stirring overnight water was added. The product was extracted into ethyl acetate. The organic phase was washed with water, dried and evaporated. The crude product was purified by flash chromatography using CH2Cl2-MeOH as a gradient eluent (100:0-95:5). Another purification was done also by flash chromatography using CH2Cl2-MeOH as a gradient eluent (100:0-99.7:0.3). The product was triturated in heptane-CH2Cl2 at RT. 1H NMR (400 MHz, DMSO-d6): 2.26 (3H, s), 2.92 (2H, t), 3.52 (2H, m), 3.76 (3H, s), 6.31 (1H, d), 6.38 (1H, s), 7.01 (1H, d), 7.60 (1H, distorted dd), 7.64 (1H, distorted d), 7.83 (1H, d), 8.09 (1H, t).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17](=[O:18])[C:16]3[C:11](=[C:12]([CH:21]=[O:22])[C:13]([OH:20])=[C:14]([Cl:19])[CH:15]=3)[O:10][CH:9]=2)=[CH:4][CH:3]=1.Cl.[NH2:24]O>CCO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:24][O:18][C:17]=2[C:16]2[C:11]([OH:10])=[C:12]([C:13]([OH:20])=[C:14]([Cl:19])[CH:15]=2)[CH:21]=[O:22])=[CH:4][CH:3]=1
Reactant: O=Cc1c(O)c(Cl)cc2c(=O)c(-c3ccc(Br)cc3)coc12
Reactant: NO
Agent: Cl
Solvent: CCO
Product: O=Cc1c(O)c(Cl)cc(-c2oncc2-c2ccc(Br)cc2)c1O
Yield: 59.7 %

Procedure:
To a solution of 3-(4-bromo-phenyl)-6-chloro-7-hydroxy-4-oxo-4H-chromene-8-carbaldehyde 53.5 mg, 0.14 mmol) in EtOH (6 ml), hydroxylamine hydrochloride (100 mg, 1.4 mmol) was added. The resulting mixture was heated at reflux for 16 hours. EtOH was evaporated and EtOAc (20 ml) was added. The organic layer was washed with sat. NaHCO3 and dried. Solids (33 mg) were obtained when the resulting oil was triturated with ether. 1H NMR (d6-DMSO) δ=9.83 (1H, s); 8.70 (1H, s); 8.21 (1H, s); 7.78 (2H, d) and 7.68 (2H, s). LCMS: (M+1)+=394.1 (RT=8.60 min.)