Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:8]=[CH:9][C:10]([C:13]2[S:21][C:20]3[C:15](=[N:16][CH:17]=[CH:18][C:19]=3Cl)[CH:14]=2)=[N:11][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+].[N+:29]([C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([F:39])[CH:33]=1)([O-:31])=[O:30]>C1(OC2C=CC=CC=2)C=CC=CC=1.C(Cl)Cl>[O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:8]=[CH:9][C:10]([C:13]2[S:21][C:20]3[C:15](=[N:16][CH:17]=[CH:18][C:19]=3[O:38][C:35]3[CH:36]=[CH:37][C:32]([N+:29]([O-:31])=[O:30])=[CH:33][C:34]=3[F:39])[CH:14]=2)=[N:11][CH:12]=1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Reactant: Clc1ccnc2cc(-c3ccc(C4OCCCO4)cn3)sc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccc(Oc2ccccc2)cc1
Product: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4ccc(C5OCCCO5)cn4)sc23)c(F)c1
Temperature: 180 °C
Reaction time: 0.25 h
Yield: 82.4 %

Procedure:
To a suspension of 29 (22.48 g, 67.5 mmol) in phenyl ether (65 mL) was added sodium carbonate (14.32 g, 135 mmol) and 2-fluoro-4-nitrophenol (3) (15.92 g, 101 mmol). The reaction mixture was heated at 180° C. for 2 h, cooled down to 40° C., diluted with DCM (300 mL), stirred at r.t. for 15 min and filtered. The filtrate was collected and concentrated to a minimal volume; Et2O (200 mL) was added and the formed suspension was stirred for 30 min. The solid material was collected by filtration, to afford intermediate 30 (25.20 g, 55.6 mmol, 82% yield) as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.63-8.62 (m, 2H), 8.48 (dd, J=10.6, 2.6 Hz, 1H), 8.43 (s, 1H), 8.31 (d, J=8.0 Hz, 1H), 8.21 (dt, J=8.8, 1.2 Hz, 1H), 7.94 (dd, J=8.4, 2.0 Hz, 1H), 7.71 (t, J=8.6 Hz, 1H), 6.98 (d, J=5.2 Hz, 1H), 5.67 (s, 1H), 4.19 (dd, J=10.8, 5.2 Hz, 2H), 3.98 (td, J=12.0, 2.0 Hz, 2H), 2.08-1.99 (m, 1H), 1.46 (d, J=13.6 Hz, 1H). MS (m/z): 454.2 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][C:6]([C:12]([NH2:14])=[O:13])=[CH:5][CH:4]=1.[Cl:15][C:16]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:17]=1[NH2:18]>>[Cl:15][C:16]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:17]=1[NH:18][C:9](=[O:11])[C:8]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[O:2][CH3:1])[C:12]([NH2:14])=[O:13]
Reactant: COc1ccc(C(N)=O)cc1C(=O)O
Reactant: Cc1ccc(Cl)c(N)c1
Product: COc1ccc(C(N)=O)cc1C(=O)Nc1cc(C)ccc1Cl

Procedure:
The captioned compound was synthesized from 6-methoxyisophthalamic acid and 2-chloro-5-methylaniline by the same procedure as in the manufacturing method described in step C of Example 1-3-1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:12][CH3:13])[C:10]=1[OH:11])[CH:6]=O.[Br:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:12][CH3:13])[C:10]=1[OH:11])[CH:6]=[N:19][C:18]1[CH:20]=[CH:21][C:15]([Br:14])=[CH:16][CH:17]=1
Reactant: Nc1ccc(Br)cc1
Reactant: COc1cc(C=O)cc(OC)c1O
Solvent: CO
Product: COc1cc(C=Nc2ccc(Br)cc2)cc(OC)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.9 %

Procedure:
3,5-Dimethoxy-4-hydroxybenzaldehyde (1 g, 5.46 mmol) was dissolved in methanol (50 ml) and 4-bromoaniline (939 mg, 5.46 mmol) was added. The resultant reaction solution was stirred overnight at room temperature under nitrogen to give a precipitate that was collected by filtration to yield light yellow fine crystals (860 mg) of the title product: 1H NMR (300 MHz, CDCl3); δ 8.30 (S, 1H), 7.49 (d, J=9 Hz, 2H), 7.16 (S, 2H), 7.07 (d, J=9 Hz, 2H), 5.86 (S, 1H), 3.98 (S, 6H).
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].[Cl:8][C:9]1[CH:21]=[CH:20][C:12]2[O:13][CH:14]([CH2:17][NH:18][CH3:19])[CH2:15][O:16][C:11]=2[CH:10]=1>>[CH2:6]([O:5][C:1](=[O:4])[CH2:2][CH2:3][N:18]([CH2:17][CH:14]1[O:13][C:12]2[CH:20]=[CH:21][C:9]([Cl:8])=[CH:10][C:11]=2[O:16][CH2:15]1)[CH3:19])[CH3:7]
Reactant: C=CC(=O)OCC
Reactant: CNCC1COc2cc(Cl)ccc2O1
Product: CCOC(=O)CCN(C)CC1COc2cc(Cl)ccc2O1
Reaction time: 60 h

Procedure:
3.3 ml (0.03 mol) of ethyl acrylate are added to 5.0 g (0.023 mol) of 6-chloro-2-methylaminomethylbenzo-1,4-dioxane and the reaction mixture is allowed to stand for 60 hours at room temperature, yielding crude 3-[N-(6-chlorobenzo-1,4-dioxan-2-ylmethyl)-N-methylamino]-propionic acid ethyl ester which can be used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:13]([C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:20]([CH:23]([CH3:25])[CH3:24])=[N:21][N:22]=3)[N:19]=2)=[CH:12][N:11]([CH:26]2[CH2:30][CH2:29][NH:28][CH2:27]2)[N:10]=1.CCN(C(C)C)C(C)C.[C:40](Cl)(=[O:42])[CH3:41]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:13]([C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:20]([CH:23]([CH3:24])[CH3:25])=[N:21][N:22]=3)[N:19]=2)=[CH:12][N:11]([CH:26]2[CH2:30][CH2:29][N:28]([C:40](=[O:42])[CH3:41])[CH2:27]2)[N:10]=1
Reactant: CC(C)c1nnc2ccc(-c3cn(C4CCNC4)nc3-c3ccc(F)cc3F)nn12
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1CCC(n2cc(-c3ccc4nnc(C(C)C)n4n3)c(-c3ccc(F)cc3F)n2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 84.7 %

Procedure:
To a round bottom flask was added 6-(3-(2,4-difluorophenyl)-1-(pyrrolidin-3-yl)-1H-pyrazol-4-yl)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine (0.150 g, 0.366 mmol, Example #Q.1.1.1), DCM (10 mL), DIPEA (0.077 mL, 0.440 mmol) and acetyl chloride (0.029 mL, 0.403 mmol). The reaction mixture was stirred at ambient temperature for about 10 min. The reaction mixture was diluted with DCM (50 mL) and washed with saturated aqueous NaHCO3 (50 mL), dried with MgSO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (40 g RediSep® silica gel; DCM/MeOH gradient from 1:0 to 9:1) to give the title compound (0.140 g, 84%): LC/MS (Table 1, Method g) Rt=2.07 min; MS m/z: 452.4 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)=O.[CH3:21][C:22](=O)[CH2:23][C:24](=[O:26])[CH3:25]>C(O)(=O)C.S(=O)(=O)(O)O>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]2[C:23]([C:24](=[O:26])[CH3:25])=[C:22]([CH3:21])[N:1]=[C:2]3[S:6][C:5]4[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=4[C:3]=23)=[CH:14][CH:15]=1
Reactant: COc1ccc(C(=O)c2c(N)sc3c2CCCC3)cc1
Reactant: CC(=O)CC(C)=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: COc1ccc(-c2c(C(C)=O)c(C)nc3sc4c(c23)CCCC4)cc1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 63.6 %

Procedure:
To a stirred solution of 50 mg (0.17 mmol) (2-amino-4,5,6,7-tetrahydro-benzo[b]thiophen-3-yl)-(4-methoxy-phenyl)-methanone in 1.5 ml acetic acid was added 0.018 ml (0.18 mmol) of pentane-2,4-dione and one drop of sulfuric acid. The mixture was then stirred at 100° C. for 10 minutes in a microwave and then concentrated in vacuo. Flash chromatography (heptane/ethyl acetate 9:1) afforded 38 mg (62%) 1-[4-(4-methoxy-phenyl)-2-methyl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-b]pyridin-3-yl)-ethanone as a light yellow solid. ES-MS m/e (%): 352 (M+H+, 100).
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:3]=1[O:4][CH2:5][C:6]([N:8]1[CH2:13][C@H:12]([CH3:14])[N:11]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH2:10][C@H:9]1[CH3:23])=[O:7].N1C=CC=CC=1.Cl[C:36]([O:38][C:39]1[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=1)=[O:37]>ClCCl>[N+:45]([C:42]1[CH:41]=[CH:40][C:39]([O:38][C:36](=[O:37])[NH:1][C:2]2[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:3]=2[O:4][CH2:5][C:6]([N:8]2[CH2:13][C@H:12]([CH3:14])[N:11]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[CH2:10][C@H:9]2[CH3:23])=[O:7])=[CH:44][CH:43]=1)([O-:47])=[O:46]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1NC(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 72.4 %

Procedure:
To a solution of (2R, 5S)-2-(2-amino-4-chloro-phenoxy)-1-[4-(4-fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-ethanone (0.150 g, 0.37 mmol) in dichloromethane (7 ml) was added pyridine (0.066 ml, 0.82 mmol) followed by 4-nitrophenyl chloroformate (0.075 g, 0.41 mmol). The reaction was stirred at ambient temperature for 3½ hours. The reaction mixture was concentrated followed by chromatography on silica gel to give the title compound (0.153 g, 74% yield).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[Br:11]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:11][CH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Cc1nc2ccccc2s1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1nc2ccccc2s1
Yield: 71.6 %

Procedure:
A mixture of 2-methylbenzothiazole (2.0 g, 13.40 mmol), N-bromosuccinimide (2.39 g, 13.40 mmol), and AIBN (0.5 g, 3.04 mmol) in CCl4 (40 mL) was refluxed for 12 h, then the mixture was cooled and filtered. The filtrate was concentrated and purified by silica gel chromatography (5% EtOAc/hexane) to give the title compound (2.19 g, 72%) as a yellow oil: 1H NMR (250 MHz, DMSO-d6): δ 5.12 (s, 2H), 7.5 (m, 2H), 8.01 (dd, J=7.9, 1.8 Hz, 1H), 8.15 (dd, J=7.9, 1.8 Hz 1H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].ClCCl.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH:20]([CH2:21][OH:22])[CH2:19][O:18][C:17]2=[O:23])=[CH:12][CH:11]=1>C(N(CC)CC)C>[CH3:1][S:2]([O:22][CH2:21][CH:20]1[CH2:19][O:18][C:17](=[O:23])[N:16]1[C:13]1[CH:12]=[CH:11][C:10]([Cl:9])=[CH:15][CH:14]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1OCC(CO)N1c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC1COC(=O)N1c1ccc(Cl)cc1
Reaction time: 2 h
Yield: 91.3 %

Procedure:
Methanesulfonyl chloride (3.0 g) was added dropwise to a dichloromethane (50 ml) solution of 5.30 g of 3-(4-chlorophenyl)-2-oxooxazolidin-4-ylmethyl alcohol obtained in Reference Example 17 and 8.5 ml of triethylamine with ice-cooling, and the mixture was stirred at the same temperature for 2 hours. The reaction mixture was washed with water, dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and purified by chloroform-ethanol gradient elution to give 6.50 g of the title compound (yield 91%).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][NH:11]3)=[CH:4][C:3]=2[O:2]1.Cl[C:24]1[N:29]=[CH:28][C:27]([Br:30])=[CH:26][N:25]=1.C(N(CC)C(C)C)(C)C>C(OCC)(=O)C>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][N:11]3[C:24]3[N:29]=[CH:28][C:27]([Br:30])=[CH:26][N:25]=3)=[CH:4][C:3]=2[O:2]1
Reactant: Clc1ncc(Br)cn1
Reactant: c1ccc2c3c([nH]c2c1)C(c1ccc2c(c1)OCO2)NCC3
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Brc1cnc(N2CCc3c([nH]c4ccccc34)C2c2ccc3c(c2)OCO3)nc1
Temperature: 125 °C

Procedure:
To the solution of 1-(3,4-methylenedioxyphenyl)-2,3,4,9-tetrahydro-1H-β-carboline (4.38 g, 15.0 mmol) (prepared according to the process as disclosed in WO97/43287, Intermediate 7, page 24) and 2-chloro-5-bromopyrimidine (2.90 g, 15.0 mmol) (prepared as in Example 51) in dry degassed DMF (30 ml) was added N,N-diisopropylethylamine (4.2 ml, 30 mmol). The mixture was heated at 120-130° C. overnight. The mixture was then cooled and diluted with ethyl acetate. The solution was washed with 0.5 N citric acid, water and brine, then dried over Na2SO4 and concentrated in vacuo. Purification by flash column (silical gel, hexane:ethyl acetate=6:1, v/v, followed by hexane:ethyl acetate=4:1, v/v) yielded the product as a white solid.
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:9]=[CH:8][C:7]([C:10]([OH:19])([C:15]([F:18])([F:17])[F:16])[C:11]([F:14])([F:13])[F:12])=[CH:6][CH:5]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:12][C:11]([F:13])([F:14])[C:10]([C:7]1[CH:8]=[CH:9][C:4]([CH:3]=[O:2])=[CH:5][CH:6]=1)([OH:19])[C:15]([F:16])([F:18])[F:17]
Reactant: COC(OC)c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=Cc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Reaction time: 2 h
Yield: 100 %

Procedure:
2-(4-Dimethoxymethyl-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol (350 mg, 1.1 mmol) was dissolved in DCM (5 ml). A 50% aqueous TFA (5 ml) was added and the solution was allowed to stir for 2h. The solvent was removed under vacuum, and the reaction mixture was partitioned between ethyl acetate and a 1M sodium carbonate solution. The organic layer was washed with carbonate two additional times, and then it was washed with brine. It was dried over MgSO4, and the solvent was removed to yield the title product (300 mg (100%), 1.1 mmol) as a white solid. 1H NMR (DMSO-d6) δ=10.1 (s, 1H), 9.05 (s, 1H), 8.12 (d, J=8.5 Hz, 2H), 7.96 (d, J=8.2 Hz, 2H).
Reaction SMILES: [CH:1]([C:3]1[C:4]([O:14][CH2:15][C:16]2[CH:40]=[CH:39][C:19]([O:20][CH2:21][C:22]3[N:23]=[C:24]([C:28]4[CH:29]=[CH:30][C:31]([CH3:38])=[C:32]([CH:37]=4)[C:33]([O:35][CH3:36])=[O:34])[O:25][C:26]=3[CH3:27])=[C:18]([O:41][CH3:42])[CH:17]=2)=[N:5][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1)=O.[CH2:43]([P:52](=[O:59])([O:56][CH2:57][CH3:58])[O:53][CH2:54][CH3:55])P(=O)(OCC)OCC.CN(C)C=O.[H-].[Na+]>O>[CH2:57]([O:56][P:52](/[CH:43]=[CH:1]/[C:3]1[C:4]([O:14][CH2:15][C:16]2[CH:40]=[CH:39][C:19]([O:20][CH2:21][C:22]3[N:23]=[C:24]([C:28]4[CH:29]=[CH:30][C:31]([CH3:38])=[C:32]([CH:37]=4)[C:33]([O:35][CH3:36])=[O:34])[O:25][C:26]=3[CH3:27])=[C:18]([O:41][CH3:42])[CH:17]=2)=[N:5][N:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:7]=1)([O:53][CH2:54][CH3:55])=[O:59])[CH3:58]
Reactant: COC(=O)c1cc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4C=O)cc3OC)c(C)o2)ccc1C
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccc(C)c(C(=O)OC)c3)oc2C)c(OC)c1)OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.8 %

Procedure:
To a mixture of methyl 5-{4-[(4-{[(4-formyl-1-phenyl-1H-pyrazol-3-yl)oxy]methyl}-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}-2-methylbenzoate (1.13 g), tetraethyl methylenediphosphonate (0.63 g) and N,N-dimethylformamide (30 mL) was added sodium hydride (60% in oil, 0.10 g) at room temperature. The mixture was stirred at room temperature for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give methyl 5-[4-({4-[({4-[(E)-2-(diethoxyphosphoryl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]-2-methylbenzoate as colorless crystals (0.57 g, yield 41%) from a fraction eluted with ethyl acetate-hexane (4:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 121-122° C.
Reaction SMILES: C(O[C:6](=O)[N:7](C)[CH:8]([CH3:42])[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]3=[N:20][C:19]=2[CH3:27])=[C:14]([C:28]#[C:29][C:30]2[CH:31]=[C:32]3[C:37](=[CH:38][CH:39]=2)[N:36]([CH3:40])[C:35](=[O:41])[CH:34]=[CH:33]3)[N:13]=1)=[O:10])(C)(C)C.C(Cl)Cl.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:6][NH:7][CH:8]([CH3:42])[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]3=[N:20][C:19]=2[CH3:27])=[C:14]([C:28]#[C:29][C:30]2[CH:31]=[C:32]3[C:37](=[CH:38][CH:39]=2)[N:36]([CH3:40])[C:35](=[O:41])[CH:34]=[CH:33]3)[N:13]=1)=[O:10]
Reactant: Cc1nc2ccccn2c1-c1ccc(NC(=O)C(C)N(C)C(=O)OC(C)(C)C)nc1C#Cc1ccc2c(ccc(=O)n2C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(C)C(=O)Nc1ccc(-c2c(C)nc3ccccn23)c(C#Cc2ccc3c(ccc(=O)n3C)c2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of tert-butyl-N-methyl-N-[1-[[5-(2-methylimidazo[1,2-a]pyridin-3-yl)-6-[2-(1-methyl-2-oxoquinolin-6-yl)ethynyl]pyridin-2-yl]amino]-1-oxopropan-2-yl]carbamate G1b (17 mg, 0.03 mmol) and DCM:TFA (9:1, 2 ml) is stirred at RT for 2 h. The mixture is diluted with DCM and a saturated aqueous solution of NaHCO3 is added. The mixture is extracted with DCM. The combined organic layers are dried over MgSO4 and concentrated in vacuo. The product is purified by RP HPLC. Yield: 14 mg (99%). HPLC-MS: M+H=491; tR=0.97 min (*Method—1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C@@H:9]2[CH2:13][N:12]([C@H](C3C=CC=CC=3)C)[CH2:11][C:10]2([F:23])[F:22])[CH2:8][CH2:7]1)=[O:5])[CH3:2].Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>ClCCl>[CH2:28]([O:27][C:25]([N:12]1[CH2:13][C@@H:9]([C:6]2([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:8][CH2:7]2)[C:10]([F:22])([F:23])[CH2:11]1)=[O:26])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)C1([C@@H]2CN([C@@H](C)c3ccccc3)CC2(F)F)CC1
Solvent: ClCCl
Product: CCOC(=O)C1([C@@H]2CN(C(=O)OCc3ccccc3)CC2(F)F)CC1
Temperature: 25 °C
Reaction time: 44 h
Yield: 82.8 %

Procedure:
4-(R)-(1-Ethoxycarbonylcyclopropyl)-3,3-difluoro-1-[1-(S)-phenylethyl]pyrrolidine(2.536 g, 7.842 mmol) was dissolved in dry dichloromethane (80 ml), and benzyl chloroformate (2.80 ml, 19.6 mmol) was added dropwise to the thus prepared solution which was cooled in an ice bath. The reaction solution was stirred at room temperature for 44 hours and then dichloromethane was evaporated under reduced pressure. Thereafter, the resulting residue was subjected to flash silica gel chromatography and eluted with an eluant of n-hexane:ethyl acetate=4:1, to thereby obtain 2.294 g (82.8%) of the title compound as a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]([CH3:16])[CH:13]=[CH:14][N:15]=3)[S:10][C:3]=12.[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23][C:24]([C:26]1[C:34]2[C:29](=[CH:30][C:31]([OH:35])=[CH:32][CH:33]=2)[N:28]([CH3:36])[C:27]=1[CH3:37])=[O:25].C([O-])([O-])=O.[Cs+].[Cs+]>>[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23][C:24]([C:26]1[C:34]2[C:29](=[CH:30][C:31]([O:35][C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[CH:8]=[C:9]([C:11]5[N:12]([CH3:16])[CH:13]=[CH:14][N:15]=5)[S:10][C:3]=34)=[CH:32][CH:33]=2)[N:28]([CH3:36])[C:27]=1[CH3:37])=[O:25]
Reactant: Cn1ccnc1-c1cc2nccc(Cl)c2s1
Reactant: Cc1c(C(=O)Nc2ccccn2)c2ccc(O)cc2n1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1c(C(=O)Nc2ccccn2)c2ccc(Oc3ccnc4cc(-c5nccn5C)sc34)cc2n1C

Procedure:
This material was prepared by the reaction of 7-chloro-2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridine 1e with 6-hydroxy-1,2-dimethyl-1H-indole-3-carboxylic acid pyridin-2-ylamide 69b and Cs2CO3 in a manner as previously described for example 1. 1H NMR (300 MHz, DMSO-d6) δ 8.43 (1H, d, J=5.5 Hz), 8.33 (1H, s), 8.20 (1H, d, J=3.8 Hz), 7.75–7.95 (3H, m), 7.61 (1H, s), 7.40 (1H, s), 7.11 (2H, m), 7.03 (1H, s), 6.60 (1H, d, J=5.5 Hz), 4.05 (3H, s), 3.73 (3H, s), 2.68 (3H, s). LCMS (ESI+) [M+H]/z Calc'd 495, found 495.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.[Cl:21][C:22]1[S:26][C:25]([CH2:27][N:28]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30](=[O:37])[C:29]2=[O:38])=[CH:24][CH:23]=1>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([OH:15])=[C:13]([C:30]2([OH:37])[C:31]3[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=3)[N:28]([CH2:27][C:25]3[S:26][C:22]([Cl:21])=[CH:23][CH:24]=3)[C:29]2=[O:38])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: O=C1C(=O)N(Cc2ccc(Cl)s2)c2ccccc21
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: O=C1N(Cc2ccc(Cl)s2)c2ccccc2C1(O)c1cc(OCc2ccccc2)ccc1O
Reaction time: 0.5 h
Yield: 34.2 %

Procedure:
To a pale yellow solution of 4-(benzyloxy)phenol (9.01 g, 45.0 mmol) in anhydrous tetrahydrofuran (100.0 mL) was added isopropylmagnesium chloride (26.3 mL, 52.5 mmol, 2.0 M solution in tetrahydrofuran) at 0° C. The reaction solution was stirred for 0.5 h followed by the addition of 1-((5-chlorothiophen-2-yl)methyl)indoline-2,3-dione (8.31 g, 30.0 mmol) in portions. The reaction mixture was stirred for 16 h at ambient temperature. The reaction was quenched by the addition of saturated ammonium chloride solution (50.0 mL) and concentrated in vacuo to dryness. The residue was diluted with ethyl acetate (100 mL), washed with saturated ammonium chloride solution (2×25.0 mL), brine (2×25 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was purified by column chromatography with ethyl acetate to afford 3-[5-(benzyloxy)-2-hydroxyphenyl]-1-[(5-chlorothiophen-2-yl)methyl]-3-hydroxy-1,3-dihydro-2H-indol-2-one (4.90 g, 28%) as a colourless solid: mp 174-175° C.; 1H NMR (300 MHz, CDCl3) δ8.45 (br, 1H), 7.40-7.27 (m, 7H), 7.14 (dd, J=7.5, 7.5 Hz, 1H), 6.92 (d, J=2.9 Hz, 1H), 6.89 (s, 1H), 6.83 (d, J=2.9 Hz, 1H), 6.79 (d, J=3.7 Hz, 1H), 6.70 (d, J=3.7 Hz, 1H), 6.43 (d, J=2.9 Hz, 1H), 4.86 (ABq, 2H), 4.84 (s, 2H); 13C NMR (75 MHz, CDCl3) δ178.3, 152.6, 149.790, 141.7, 136.8, 135.8, 130.4, 130.1, 129.1, 128.6, 127.9, 127.6, 126.3, 126.2, 126.0, 125.9, 124.3, 120.2, 116.3, 114.4, 109.6, 79.1, 70.6, 39.2; MS (ES+) m/z 478.2 (M−1), 476.2 (M−1).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C1C(=O)N([Cl:18])C(=O)C1>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([Cl:18])=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Brc1ccc2cc[nH]c2c1
Solvent: ClCCl
Product: Clc1c[nH]c2cc(Br)ccc12
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 89.4 %

Procedure:
A mixture of 6-bromo-1H-indole (850 mg, 4.34 mmol) and NCS (593 mg, 4.44 mmol) in DCM (17 mL) was stirred at 0° C. for 1.5 hour. The mixture was partitioned between saturated aqueous ammonium chloride (25 mL) and ethyl acetate (150 mL). The organic phase was separated, washed with brine (25 mL), dried with anhydrous magnesium sulfate, filtered and evaporated to dryness to give the title compound (894 mg). LCMS (A): m/z (M+H)+ 230/232, C8H5BrClN requires 229/231 (acidic).
Reaction SMILES: Cl[C:2]1[N:22]=[C:5]2[C:6]([NH:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[S:18]([CH3:21])(=[O:20])=[O:19])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=2)[CH2:26][CH2:25]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:21][S:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][NH:10][C:6]1[C:5]2[N:4]([N:3]=[C:2]([NH:36][C:33]3[CH:32]=[CH:31][C:30]([N:27]4[CH2:26][CH2:25][N:24]([CH3:23])[CH2:29][CH2:28]4)=[CH:35][CH:34]=3)[N:22]=2)[CH:9]=[CH:8][CH:7]=1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)c1ccccc1CNc1cccn2nc(Cl)nc12
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(c2ccc(Nc3nc4c(NCc5ccccc5S(C)(=O)=O)cccn4n3)cc2)CC1

Procedure:
(2-Chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(2-methanesulfonyl-benzyl)-amine was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (470.0 mg, 2.022 mmol) and 2-methanesulfonyl-benzylamine; hydrochloride (500.0 mg, 2.255 mmol) in a manner analogous to Example 2d. Product isolated as a yellow solid (0.45 g, 66%). MP=161-163° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.11 (d, J=7.6 Hz, 1H), 7.92 (d, J=6.6 Hz, 1H), 7.64-7.60 (m, 2H), 7.56-7.51 (m, 1H), 6.88 (t, J=7.5 Hz, 1H), 6.53 (d, J=7.8 Hz, 1H), 5.43 (t, J=5.9 Hz, 1H), 4.98 (d, J=6.1 Hz, 2H), 3.15 (s, 3H). MS=337, 339 (MH)+. 138b) N(8)-(2-Methanesulfonyl-benzyl)-N(2)-[4-(4-methyl-piperazin-1-yl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridine-2,8-diamine was prepared from (2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(2-methanesulfonyl-benzyl)-amine (75.0 mg, 0.223 mmol) and 4-(4-methyl-piperazin-1-yl)-phenylamine (47.0 mg, 0.246 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a tan foam (0.035 g, 32%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.11 (d, J=7.9 Hz, 1H), 7.84 (d, J=6.5 Hz, 1H), 7.67-7.59 (m, 2H), 7.55-7.50 (m, 1H), 7.47 (d, J=8.8 Hz, 2H), 6.96 (d, J=8.9 Hz, 2H), 6.68 (t, J=7.3 Hz, 1H), 6.55 (s, 1H), 6.41 (d, J=7.7 Hz, 1H), 5.19 9t, J=6.1 Hz, 1H), 4.96 (d, J=6.1 Hz, 2H), 3.20-3.14 (m, 7H), 2.69-2.58 (m, 4H), 2.39 (s, 3H). MS=492 (MH)+.