Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]3[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:15][CH:16]=3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[N:25]1[CH:30]=[CH:29][C:28]([C:31](Cl)=[O:32])=[CH:27][CH:26]=1>>[N:25]1[CH:30]=[CH:29][C:28]([C:31]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([C:11]4[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C:19]5[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=5)[CH2:15][CH:16]=4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:32])=[CH:27][CH:26]=1
Reactant: Nc1ccc2[nH]cc(C3=CCN(CCc4ccccc4)CC3)c2n1
Reactant: O=C(Cl)c1ccncc1
Product: O=C(Nc1ccc2[nH]cc(C3=CCN(CCc4ccccc4)CC3)c2n1)c1ccncc1

Procedure:
Beginning with 0.015 gm (0.047 mmol) 5-amino-3-(1-(2-phenyleth-1-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo[3,2-b]pyridine and 0.011 mL (0.061 mMol) 4-pyridinecarbonyl chloride, the title compound was prepared essentially by the procedure described in Example 7.
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]2[N:6]=[C:7]([O:9][CH:10]3[CH2:15][CH2:14][N:13]([C:16]4[N:21]=[CH:20][C:19]([F:22])=[CH:18][N:17]=4)[CH2:12][CH2:11]3)[S:8][C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:33]2[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH:34]=2)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.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>[F:22][C:19]1[CH:18]=[N:17][C:16]([N:13]2[CH2:14][CH2:15][CH:10]([O:9][C:7]3[S:8][C:4]4[CH:3]=[C:2]([C:33]5[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH:34]=5)[CH:24]=[CH:23][C:5]=4[N:6]=3)[CH2:11][CH2:12]2)=[N:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Fc1cnc(N2CCC(Oc3nc4ccc(Br)cc4s3)CC2)nc1
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc3nc(OC4CCN(c5ncc(F)cn5)CC4)sc3c2)CC1
Temperature: 100 °C
Reaction time: 4 h
Yield: 91.2 %

Procedure:
To a degassed solution of 6-bromo-2-(1-(5-fluoropyrimidin-2-yl)piperidin-4-yloxy)benzo[d]thiazole (1.112 g, 2.72 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (1.26 g, 4.08 mmol), and potassium carbonate (1.127 g, 8.15 mmol) in dioxane (15 mL) and water (5 mL) was added Pd(Ph3P)4 (126 mg, 0.109 mmol). The mixture was stirred at 100° C. for 4 h. The reaction mixture was cooled to rt, diluted with water (40 mL), and extracted with CH2Cl2 (3×30 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The residue was purified by column chromatography (silica gel, hexanes-EtOAc gradient 0 to 45% EtOAc) to afford tert-butyl 4-(2-(1-(5-fluoropyrimidin-2-yl)piperidin-4-yloxy)benzo[d]thiazol-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate (1.27 g, 2.482 mmol, 91% yield) as a white solid. LCMS (m/z)=512 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:17]([C:19]3[O:20][C:21](=[O:35])[C:22]4[C:27]([C:28]=3[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH3:18])[N:9]=[C:10](C3C=NC=CN=3)[C:3]=12.NC1N=CN=C2N(C(C3OC(=O)C4C(C=3C3C=CC=CC=3)=CC=CC=4)C)N=C(I)C=12.C[Sn](C)(C)[C:68]1[CH:76]=[CH:75][CH:74]=[C:73]2[C:69]=1[CH:70]=[N:71][NH:72]2>>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:17]([C:19]3[O:20][C:21](=[O:35])[C:22]4[C:27]([C:28]=3[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH3:18])[N:9]=[C:10]([C:68]3[CH:76]=[CH:75][CH:74]=[C:73]4[C:69]=3[CH:70]=[N:71][NH:72]4)[C:3]=12
Reactant: C[Sn](C)(C)c1cccc2[nH]ncc12
Reactant: CC(c1oc(=O)c2ccccc2c1-c1ccccc1)n1nc(-c2cnccn2)c2c(N)ncnc21
Agent: CC(c1oc(=O)c2ccccc2c1-c1ccccc1)n1nc(I)c2c(N)ncnc21
Product: CC(c1oc(=O)c2ccccc2c1-c1ccccc1)n1nc(-c2cccc3[nH]ncc23)c2c(N)ncnc21
Yield: 39 %

Procedure:
The title compound was made in a similar way as that of the compound of example 52 from 3-(1-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-4-phenyl-1H-isochromen-1-one (intermediate D2a, 50 mg, 0.098 mmol), and 4-(trimethylstannyl)-1H-indazole (Intermediate G19, 41.4 mg, 0,147 mmol) to give the title compound (19 mg, 39%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][C:34]=1[Cl:35])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][C@@H:8]([CH2:12][NH:13][C:14](=[O:31])[CH2:15][S:16][C:17]2[S:18][CH:19]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-])=O)[CH:23]=3)[N:21]=2)[CH2:7]1.[Cl-].[NH4+]>O1CCCC1.CO.[Fe]>[NH2:28][C:24]1[CH:23]=[C:22]([C:20]2[N:21]=[C:17]([S:16][CH2:15][C:14]([NH:13][CH2:12][C@@H:8]3[O:9][CH2:10][CH2:11][N:6]([CH2:5][C:4]4[CH:32]=[CH:33][C:34]([Cl:35])=[C:2]([Cl:1])[CH:3]=4)[CH2:7]3)=[O:31])[S:18][CH:19]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: O=C(CSc1nc(-c2cccc([N+](=O)[O-])c2)cs1)NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1cccc(-c2csc(SCC(=O)NC[C@H]3CN(Cc4ccc(Cl)c(Cl)c4)CCO3)n2)c1

Procedure:
A solution of the resultant product (4.65 g) of (6-2) in tetrahydrofuran (24 mL) and methanol (16 mL) was added dropwise to an aqueous (16 mL) suspension of ammonium chloride (2.25 g) and iron powder (1.41 g) at 60° C. The reaction mixture was heated under reflux for 3.5 hrs. After allowing to cool, the reaction mixture was filtered through celite. A 1 mol/L aqueous sodium hydroxide solution was added to the filtrate, and the organic solvent alone was evaporated under reduced pressure. The residue was extracted with ethyl acetate, the extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography using a mixed solvent of chloroform and methanol as an eluent. The solvent was evaporated from the eluent to give the title compound (3.87 g) as a pale-yellow amorphous solid.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][N:10]1[C:14]2=[CH:15][N:16]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=[C:17]3[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:13]2[CH:12]=[N:11]1.O>CN(C)C=O>[Br:1][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]2[C:25]=1[CH:24]=[C:17]1[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:13]3[CH:12]=[N:11][N:10]([CH3:9])[C:14]3=[CH:15][N:16]12
Reactant: CN1N=CN2C1=Cn1c(cc3ccccc31)-c1ccccc12
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: CN1N=CN2C1=Cn1c(cc3c(Br)cccc31)-c1ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.6 %

Procedure:
A solution of 2.41 g N-bromosuccinimide in 50 ml dimethylformamide was added dropwise to 3.53 g 1-methyl-4H-indolo[1,2-d][1,2,4]triazolo[4,3-a][1,4]benzodiazepine in 108 ml dimethylformamide. After the addition was complete, the reaction mixture was stirred for one hour at room temperature. Upon addition of water, a solid precipitated, which was collected, washed with water and dried. Recrystallization from water/methanol yielded 2.55 g solid;
Reaction SMILES: [CH2:1](N(CC)CC)C.Br[CH:9]([CH2:15]Br)[C:10]([O:12][CH2:13][CH3:14])=[O:11].CN(C)[CH:19]=[CH:20][C:21]([NH2:23])=C>O1CCOCC1>[CH3:19][C:20]1[CH:1]=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:23][CH:21]=1
Reactant: CCN(CC)CC
Reactant: C=C(N)C=CN(C)C
Reactant: CCOC(=O)C(Br)CBr
Solvent: C1COCCO1
Product: CCOC(=O)c1ccc(C)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6.1 g of triethylamine are added at 0° C. to 13 g of ethyl 2,3-di-bromopropionate in 50 ml of dioxane. The mixture is stirred for 2 hours at room temperature and then a solution of 5.6 g of 1-dimethylamino-1-aza-3-methyl-1,3-butadiene and 6.1 g of triethylamine in 50 ml of dioxane is added dropwise. The reaction mixture is kept for 30 hours at 70° C. and then cooled and concentrated by evaporation. The residue is partitioned between water and ether and the organic phase is washed with brine, dried and concentrated by evaporation. The residue is distilled under reduced pressure, affording 3.2 g of the title compound as an oil with a boiling point of 69°-74° C. (at 0.08 mbar).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C@@H:7]([NH:12][S:13]([CH:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])[CH2:6]2.S(Cl)(Cl)=O.C(=O)([O-])[O-].[K+].[K+].[F:29][C:30]([F:42])([F:41])[C:31]1[C:35]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:34][NH:33][N:32]=1>C(Cl)Cl.CN(C=O)C>[CH3:17][CH:16]([S:13]([NH:12][C@H:7]1[CH2:6][C:5]2[C:9](=[CH:10][CH:11]=[C:3]([CH2:2][N:33]3[CH:34]=[C:35]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:31]([C:30]([F:29])([F:41])[F:42])=[N:32]3)[CH:4]=2)[CH2:8]1)(=[O:15])=[O:14])[CH3:18]
Reactant: CC(C)S(=O)(=O)N[C@@H]1Cc2ccc(CO)cc2C1
Reactant: CCOC(=O)c1c[nH]nc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(Cc2ccc3c(c2)C[C@H](NS(=O)(=O)C(C)C)C3)nc1C(F)(F)F
Temperature: 25 °C
Yield: 85.7 %

Procedure:
(R)—N-(5-(hydroxymethyl)-2,3-dihydro-1H-inden-2-yl)propane-2-sulfonamide (2.82 mmol, 760 mg) was dissolved in DCM (20 mL) and Thionyl Chloride (5.64 mmol, 0.409 mL, 671 mg) added and the solution stirred at room temperature. After 45 min the mixture was concentrated then azeotroped with DCM (4×10 mL) to give a yellow oil. To this oil was added DMF (10 mL) and potassium carbonate (8.46 mmol, 1170 mg) followed by ethyl 3-(trifluoromethyl)-1H-pyrazole-4-carboxylate (2.82 mmol, 587 mg). The mixture was heated to 60° C. with stirring for 1 h. The reaction was concentrated to remove DMF before partitioning between EtOAc/Water. The phases were mixed and separated and the aqueous phase further washed with EtOAc (×2). Combined organics were dried and concentrated to give a light yellow oil which was purified on silica eluting with 25% EtOAc/heptane. Desired fractions were collected and concentrated to give (R)-ethyl 1-((2-(1-methylethylsulfonamido)-2,3-dihydro-1H-inden-5-yl)methyl)-3-(trifluoromethyl)-1H-pyrazole-4-carboxylate as a colourless solid (1.11 g, 86%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]([O:15][CH2:16][C:17]([OH:19])=O)[C:12]2[C:7](=[CH:8][C:9]([CH3:20])=[CH:10][CH:11]=2)[N:6]=1)=[O:4].FC1C(O)=C(F)C(F)=C(F)C=1F.Cl.[F:34][C:35]1([F:40])[CH2:39][CH2:38][NH:37][CH2:36]1.C(N1CCOCC1)C>CN(C=O)C.C(Cl)Cl.C(Cl)CCl>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]([O:15][CH2:16][C:17]([N:37]2[CH2:38][CH2:39][C:35]([F:40])([F:34])[CH2:36]2)=[O:19])[C:12]2[C:7](=[CH:8][C:9]([CH3:20])=[CH:10][CH:11]=2)[N:6]=1)=[O:4]
Reactant: COC(=O)c1cc(OCC(=O)O)c2ccc(C)cc2n1
Reactant: FC1(F)CCNC1
Agent: CCN1CCOCC1
Agent: Cl
Agent: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OCC(=O)N2CCC(F)(F)C2)c2ccc(C)cc2n1

Procedure:
To a solution of 900 mg 4-Carboxymethoxy-7-methyl-quinoline-2-carboxylic acid methyl ester in 5 ml DMF were added 902 mg pentafluorophenol and 940 mg EDC. The mixture was stirred under exclusion of moisture until LCMS indicated complete conversion to the corresponding pentafluorophenolester. 3,3-Difluoropyrrolidine hydrochloride (455 mg) was mixed with 1.2 ml N-ethylmorpholine and 5 ml DMF and this mixture added dropwise to the solution of the pentafluorophenolester. After 12 h the reaction mixture was diluted with DCM and washed with aqueous LiCl (4%), saturated aqueous NaHCO3 and brine. The crude product obtained after evaporation of the solvent was purified by flash chromatography on silica eluting with ethyl acetate/heptane gradient. Yield: 815 mg.
Reaction SMILES: [Si]([O:8][CH2:9]/[C:10](=[CH:24]\[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]2[CH:37]=[CH:36][N:35]=[C:34]([C:38]3[NH:39][CH2:40][CH2:41][N:42]=3)[CH:33]=2)[CH:26]=1)/[C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:15]=1)=[O:12])(C(C)(C)C)(C)C.N1C=CC=CC=1>C1COCC1.N1C=CC=CC=1.CCOC(C)=O>[C:20]([C:16]1[CH:15]=[C:14]([NH:13][C:11](=[O:12])/[C:10](/[CH2:9][OH:8])=[CH:24]/[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]3[CH:37]=[CH:36][N:35]=[C:34]([C:38]4[NH:39][CH2:40][CH2:41][N:42]=4)[CH:33]=3)[CH:26]=2)[CH:19]=[CH:18][CH:17]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)c1cccc(NC(=O)/C(=C/c2cccc(Oc3ccnc(C4=NCCN4)c3)c2)CO[Si](C)(C)C(C)(C)C)c1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(C)(C)c1cccc(NC(=O)/C(=C/c2cccc(Oc3ccnc(C4=NCCN4)c3)c2)CO)c1
Temperature: 0 °C

Procedure:
(E)-2-((tert-butyldimethylsilyloxy)methyl)-N-(3-tert-butylphenyl)-3-(3-(2-(4,5-dihydro-1H-imidazol-2-yl)pyridin-4-yloxy)phenyl)acrylamide (107 mg, 0.18 mmol) was dissolved in a 1:1 mixture of THF/pyridine (3 mL). The reaction mixture was cooled to 0° C. and 20 drops of HF/pyridine were added. The reaction was sealed and allowed to warm to rt over 5 h. The mixture was diluted with EtOAc and washed with sat. NaHCO3, dried over Na2SO4, filtered, and concentrated. Purification by column chromatography (SiO2, 0-10% MeOH with 1% NH4OH in DCM) provided B-140 (32 mg). LCMS, FA: Rt=1.21 min, [MH+ 471.0]. 1H NMR (300 MHz, d4-MeOH): δ 8.48 (d, 1H), 7.68 (t, 1H), 7.56-7.51 (m, 3H), 7.48-7.44 (m, 1H), 7.41 (d, 1H), 7.31 (t, 1H), 7.25 (t, 1H), 7.19-7.15 (m, 2H), 7.08-7.05 (dd, 1H), 4.52 (s, 2H), 3.75 (s, 4H), and 1.32 (s, 9H).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]5)=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:40]2[N:41]=[CH:42][N:43]([CH2:45][CH2:46]OS(C)(=O)=O)[CH:44]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:52][NH:53][CH3:54]>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]5)=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:40]2[N:41]=[CH:42][N:43]([CH2:45][CH2:46][N:53]([CH3:54])[CH3:52])[CH:44]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC5)n4c3)c3ccccc32)n(-c2cn(CCOS(C)(=O)=O)cn2)n1
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)CCn1cnc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC5)n4c3)c3ccccc32)c1
Temperature: 50 °C
Reaction time: 24 h
Yield: 18 %

Procedure:
To a solution of Intermediate 119f (0.10 mmol) in THF (2 mL) was added dimethylamine (2M in MeOH, 0.4 mL, 0.8 mmol) and the reaction stirred at 50° C. for 24 h. The crude reaction mixture was cooled and partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by FCC on silica, using a gradient of 0-10% [2M NH3 in MeOH] in DCM followed by HPLC (XBridge C18 column, 30-98% MeCN in H2O, 0.1% NH4OH), to give the title compound (12 mg, 18%). LCMS (Method 5): Rt 3.43 min, m/z 666 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.21 (9H, s), 1.54-1.60 (2H, m), 1.65-1.71 (4H, m), 1.86-1.94 (2H, m), 1.95-2.05 (1H, m) 2.13 (6H, s), 2.13-2.16 (1H, m), 2.55 (2H, t, J=6.3 Hz), 3.10 (4H, t, J=5.2 Hz), 4.05 (2H, t, J=7.1 Hz), 4.86 (1H, td, J=8.4, 5.5 Hz), 5.51 (1H, t, J=4.5 Hz), 6.32 (1H, s), 7.12 (1H, dd, J=10.0, 1.9 Hz), 7.20-7.25 (2H, m), 7.28-7.36 (3H, m), 7.56-7.59 (2H, m), 7.63 (1H, d, J=1.4 Hz), 7.90 (1H, d, J=8.6 Hz), 9.63 (1H, br s).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][O:6][C:5]([O:14][CH3:15])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:4]1.C(N(CC)CC)C.[C:23](Cl)(=[O:26])[CH:24]=[CH2:25]>C(Cl)Cl>[C:23]([O:1][CH2:2][CH:3]1[CH2:7][O:6][C:5]([O:14][CH3:15])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:4]1)(=[O:26])[CH:24]=[CH2:25]
Reactant: COC1(c2ccccc2)OCC(CO)O1
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)OCC1COC(OC)(c2ccccc2)O1

Procedure:
The procedure of Example A was repeated, employing 21 grams (100 mmol.) of 4-hydroxymethyl-2-methoxy-2-phenyl-1,3-dioxolane, 25.3 grams (250 mmol.) of triethylamine, 9.5 grams (105 mmol.) of acryloyl chloride and 150 ml. of methylene chloride. The crude product was purified by column chromatography over basic alumina, using 15% (by volume) ethyl acetate in hexane as an eluant, to yield the desired 4-acryloyloxymethyl-2-methoxy-2-phenyl-1,3-dioxolane.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[CH:19]=[C:18]([C:20]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:21]=3[CH:22]=[CH:23][NH:24]4)[CH:17]=[C:16]3[C:12]=2[CH:13]=[N:14][NH:15]3)=[O:9])[CH:5]=[CH:4][CH:3]=1.[CH:29]1([NH2:32])[CH2:31][CH2:30]1.CCN(C(C)C)C(C)C>CS(C)=O.CS(C)=O.CO>[CH:29]1([NH:32][C:2]2[N:7]=[C:6]([C:8]([NH:10][C:11]3[CH:19]=[C:18]([C:20]4[CH:28]=[CH:27][CH:26]=[C:25]5[C:21]=4[CH:22]=[CH:23][NH:24]5)[CH:17]=[C:16]4[C:12]=3[CH:13]=[N:14][NH:15]4)=[O:9])[CH:5]=[CH:4][CH:3]=2)[CH2:31][CH2:30]1
Reactant: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1cccc(Cl)n1
Reactant: NC1CC1
Solvent: CS(C)=O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1cccc(NC2CC2)n1
Temperature: 160 °C
Yield: 1.8 %

Procedure:
To a microwave vial was added 2 ml of a solution of 6-chloro-N-[6-(1H-indol-4-yl)-1H-indazol-4-yl]-2-pyridinecarboxamide (350 mg, 0.90 mmol, prepared as described in Example 18) in DMSO (14 ml). Cyclopropylamine (0.018 ml, 0.26 mmol) and DIPEA (0.113 ml) were added and the mixture was heated at 160° C. for 2 h under microwave irradiation. Further cyclopropylamine (0.018 ml, 0.26 mmol) was added and the mixture was heated at 160° C. for 2 h under microwave irradiation. Again, cyclopropylamine (0.018 ml, 0.26 mmol) was added and the mixture was heated at 160° C. for 1 h under microwave irradiation. After this time, cyclopropylamine (0.018 ml, 0.26 mmol) and DIPEA (0.113 ml) were both added to the mixture and it was heated at 160° C. for 2 h under microwave irradiation. The crude reaction mixture was dissolved in DMSO/MeOH (1:1) and purified by Mass Directed Automated Preparative HPLC (Method E). The sample was re-purified by Mass Directed Automated Preparative HPLC (Method E, using Waters Atlantis column 100 mm×19 mm, 5 um). Product-containing fractions were dried under a stream of nitrogen to afford the title compound (1.9 mg).
Reaction SMILES: [CH2:1]=[C:2]1[CH:7]2[O:8]C(C)(C)[O:10][CH:6]2[CH:5]([O:13][Si:14]([C:27]([CH3:30])([CH3:29])[CH3:28])([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:4][C:3]1=[CH:31][C:32]([O:34][CH2:35][CH3:36])=[O:33].C1(C)C=CC(S(O)(=O)=O)=CC=1.O.C(OCC)C>C(O)C>[CH2:1]=[C:2]1[CH:7]([OH:8])[CH:6]([OH:10])[CH:5]([O:13][Si:14]([C:27]([CH3:30])([CH3:28])[CH3:29])([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:4][C:3]1=[CH:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]
Reactant: C=C1C(=CC(=O)OCC)CC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C2OC(C)(C)OC12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: CCOCC
Solvent: O
Product: C=C1C(=CC(=O)OCC)CC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C(O)C1O
Temperature: 25 °C
Reaction time: 5 h
Yield: 86.9 %

Procedure:
Ethyl (2-methylene-3,4-(dimethylmethylenedioxy)-5-(tert-butyldiphenylsilyloxy)cyclohexylidene)acetate (0.506 g) was dissolved in 10 ml of ethanol, and a catalytic amount of p-toluenesulfonic acid was added, followed by stirring the mixture at room temperature for 5 hours. Water was added to the reaction mixture, and extraction was conducted with diethyl ether. The extract was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 0.405 g of ethyl (2-methylene-3,4-dihydroxy-5-(tert-butyldiphenylsilyloxy)cyclohexylidene)acetate having the following property.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH2:19][C:20]([N:22]2[CH2:31][CH2:30][C:29]3[CH:28]=[N:27][C:26]([NH:32][CH:33]([CH3:35])[CH3:34])=[N:25][C:24]=3[CH2:23]2)=[O:21])[CH2:9][N:10](C)[C:11](=O)OC(C)(C)C)=[CH:4][CH:3]=1.Cl.O1CCOCC1>CO.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([CH2:9][NH:10][CH3:11])[CH2:19][C:20]([N:22]2[CH2:31][CH2:30][C:29]3[CH:28]=[N:27][C:26]([NH:32][CH:33]([CH3:35])[CH3:34])=[N:25][C:24]=3[CH2:23]2)=[O:21])=[CH:4][CH:3]=1
Reactant: CC(C)Nc1ncc2c(n1)CN(C(=O)C[C@H](CN(C)C(=O)OC(C)(C)C)c1ccc(Cl)cc1)CC2
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: ClCCl
Product: CNC[C@@H](CC(=O)N1CCc2cnc(NC(C)C)nc2C1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution 322 (28 mg, 0.056 mmol) in MeOH (2 mL) was added 4M HCl in dioxane (0.6 mL, 2.4 mmol) and the reaction stirred at RT 4 h. The reaction was diluted with DCM (25 mL) and satd. aq. NaHCO3 (25 mL), the phases separated and the aqueous phase extracted with 10% MeOH/DCM (25 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated. The crude product was purified on a preparative SiO2 TLC plate (0.5 mm) developed with MeOH/DCM/NH4OH (9/90/1) to afford 6 mg (25%) of I-113 as a pale yellow residue: 1H NMR (400 MHz, CDCl3) δ 8.04 (s, 0.6H), 8.02 (s, 0.4H), 7.15-7.30 (m, 4H), 4.80 (m, 1H), 4.52 (s, 1H), 4.34 (m, 1H), 4.09 (m, 1H), 3.74 (m, 1H), 3.59 (m, 1H), 3.47 (m, 1H), 2.79-2.92 (m, 3H), 2.51-2.73 (m, 3H), 2.42 (s, 1.2H), 2.39 (s, 2.8H), 1.87 (br s, 2H), 1.22 (m, 6H); LRMS (M+H) (APCI pos) m/e=402.1.
Reaction SMILES: [OH-:1].[K+].[CH3:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:8]=[CH:7][C:6]=1[C:19]1[NH:27][C:26]2[C:21](=[N:22][C:23](Cl)=[N:24][CH:25]=2)[N:20]=1>C(O)C1C=CC=CC=1>[CH3:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:8]=[CH:7][C:6]=1[C:19]1[NH:27][C:26]2[C:21](=[N:22][C:23]([O:1][CH2:19][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][CH:5]=3)=[N:24][CH:25]=2)[N:20]=1
Reactant: COc1cc(OCc2ccccc2)ccc1-c1nc2nc(Cl)ncc2[nH]1
Reactant: [OH-]
Agent: [K+]
Solvent: OCc1ccccc1
Product: COc1cc(OCc2ccccc2)ccc1-c1nc2nc(OCc3ccccc3)ncc2[nH]1
Temperature: 150 °C

Procedure:
An amount of 4.5 gm of powdered potassium hydroxide is dissolved in 70 ml of benzyl alcohol, and then 7.2 gm of 8-(2-methoxy-4-benzyloxy-phenyl)-2-chloro-purine are added. The mixture is heated to 150° C. for three hours, cooled, and filtered, the filtrate is mixed with ether, and the precipitate obtained is purified by chromatography on silica gel [eluant: methylene chloride/ethanol (100:2.5)].
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]#[CH:9])[CH2:3]1.[F:10][C:11]1[C:12](I)=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])/[C:14]/2=[CH:21]\[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28]>CN(C=O)C.CCN(CC)CC.CCOC(C)=O.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>[F:10][C:11]1[C:12]([C:9]#[C:8][CH2:7][N:4]2[CH2:5][CH2:6][C@H:2]([OH:1])[CH2:3]2)=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])/[C:14]/2=[CH:21]\[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28]
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Reactant: C#CCN1CC[C@H](O)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#CCN3CC[C@H](O)C3)c21

Procedure:
Using Method C above, (S)-3-hydroxy-1-prop-2-ynyl-pyrrolidine (60 mg, 0.48 mmol) (Example 96A) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (60 mg, 0.16 mmol) (Starting Material 6) using (Ph3P)4Pd (18 mg, 0.02 mmol) and a catalytic amount of Cul in a mixture of DMF (4 mL) and Et3N (4 mL) as solvent at 80° C. for 6 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with H2O. The organic layer was dried over Na2SO4 and concentrated. (S)-(Z)-1,3-Dihydro-5-fluoro-4-[3-(3-hydroxy-pyrrolidin-1-yl)-1-propynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one was obtained after silica gel column chromatography with a 0-20% MeOH in CH2Cl2 gradient and precipitation out of THF with excess of pentane. (Yield 42 mg, 71%).