Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:13][CH3:14])=[CH:4][C:5]([Cl:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].CCN(CC)CC.[C:22](Cl)(=[O:24])[CH3:23]>C(Cl)Cl>[C:22]([NH:1][C:2]1[C:3]([O:13][CH3:14])=[CH:4][C:5]([Cl:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8])(=[O:24])[CH3:23]
Reactant: COC(=O)c1cc(N)c(OC)cc1Cl
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cc(NC(C)=O)c(OC)cc1Cl
Reaction time: 12 h
Yield: 62.7 %

Procedure:
To a mixture of methyl 5-amino-2-chloro-4-methoxybenzoate (3.6 g, 16.7 mmol), Et3N (6.7 g, 66.8 mmol) and DCM (100 mL) at RT, acetyl chloride (1.57 g, 20.1 mmol) was added dropwise and the resulting mixture was stirred for 12 h. The reaction mixture was partitioned between dichloromethane and water. The organic layer was washed with saturated NaHCO3 solution and brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (ethyl acetate/petroleum ether=1:1) to afford the desired product (2.7 g, 63% yield).
Reaction SMILES: Br[CH2:2][C:3]1[S:11][C:10]2[C:9]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:8][C:7]([Cl:18])=[N:6][C:5]=2[CH:4]=1.[CH3:19][S:20]([CH2:23][CH2:24][CH2:25][NH2:26])(=[O:22])=[O:21].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:18][C:7]1[N:8]=[C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:10]2[S:11][C:3]([CH2:2][NH:26][CH2:25][CH2:24][CH2:23][S:20]([CH3:19])(=[O:22])=[O:21])=[CH:4][C:5]=2[N:6]=1
Reactant: Clc1nc(N2CCOCC2)c2sc(CBr)cc2n1
Reactant: CS(=O)(=O)CCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CS(=O)(=O)CCCNCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Temperature: 80 °C

Procedure:
To a solution of 6-bromomethyl-2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (200 mg) in acetonitrile (10 mL) was added 3-methanesulfonyl-propylamine (86 mg) and potassium carbonate (317 mg) and the reaction heated at 80° C. for 16 h. After cooling to room temperature, the solvent was reduced in vacuo and the residue redissolved in dicholoromethane (20 mL). The solution was washed with saturated aqueous sodium hydrogen carbonate solution (20 mL), aqueous brine solution (2×20 mL), dried (MgSO4), reduced in vacuo and purified by column chromatography to give (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-(3-methanesulfonyl-propyl)-amine as a yellow solid.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[C:13](=[O:14])[O:12][CH2:11]2)(O)=[O:6]>CN(C)C=O>[Cl:3][C:5]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[C:13](=[O:14])[O:12][CH2:11]2)=[O:6]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc2c(c1)COC2=O
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc2c(c1)COC2=O
Temperature: 80 °C
Yield: 86 %

Procedure:
To a mixture of 1800 ml of thionyl chloride and 8.1 ml of N,N-dimethylformamide, 750 g (4.21 moles) of 5-carboxyphthalide are added under stirring. The mixture is heated slowly to reach an inner temperature of 60° C. in one hour, then it is kept at this temperature for another hour and finally it is brought to the reflux. After refluxing for 6 hours, about 600 ml of thionyl chloride are distilled off at a temperature of 80÷85° C., by replacing them by addition of toluene. Distillation is continued for a total of 2800 ml with concurrent replacement of the solvent by addition of 3800 ml of toluene. The mixture is slowly cooled and, at 80° C., the crystallization of the product begins. Cool to 10÷15° C. by continuing stirring for 15 hours. The hygroscopic product is filtered, washing with a total of 1500 ml of toluene, then it is dried under vacuum at 55° C. to give 710 g (86%) of 5-chlorocarbonylphthalide with a purity of 99% (HPLC).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH2:11][CH2:10][CH:9]([N:13]2[CH2:18][CH2:17][CH:16]([C:19]([OH:21])=O)[CH2:15][CH2:14]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:22]([NH2:26])[CH:23]([CH3:25])[CH3:24].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:24][CH:23]([CH3:25])[CH2:22][NH:26][C:19]([CH:16]1[CH2:15][CH2:14][N:13]([CH:9]2[CH2:10][CH2:11][CH2:12][N:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7][CH2:8]2)[CH2:18][CH2:17]1)=[O:21]
Reactant: CC(C)CN
Reactant: CCOC(=O)N1CCCC(N2CCC(C(=O)O)CC2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCCC(N2CCC(C(=O)NCC(C)C)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 5.4 %

Procedure:
1-(1-(ethoxycarbonyl)azepan-4-yl)piperidine-4-carboxylic acid (0.26 g assumed 0.89 mmol) was dissolved in DMF (4 mL) and isobutylamine (0.81 g, 1.1 mL, 11.0 mmol), HATU (0.51 g, 1.34 mmol) and DIPEA (0.46 g, 0.62 mL, 3.56 mmol) were added. The reaction mixture was stirred at rt overnight and the solvents were removed in vacuo. The residue was partitioned between DCM and sat. NaHCO3 sol., the organic layer was washed with sat. NaCl sol. and dried (MgSO4). The solvents were removed in vacuo, and the residue was purified by column chromatography (normal phase, [Biotage SNAP cartridge KP-sil 25 g, 40-63 μm, 60 Å, 25 mL per min, gradient 0% to 3% MeOH in DCM]) to give ethyl 4-(4-((2-methylpropyl)carbamoyl)piperidin-1-yl)azepane-1-carboxylate (17 mg, 2%) as a pale yellow gum.
Reaction SMILES: [OH:1][C@H:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:3][C:4]([O:6]C)=[O:5].O1CCOCC1.[OH-].[Na+]>CO>[OH:1][C@H:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: CCCCCCCCCCC[C@@H](O)CC(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: CCCCCCCCCCC[C@@H](O)CC(=O)O
Yield: 97.9 %

Procedure:
Under nitrogen and while stirring there were added dropwise to a solution of 129.2 g of methyl (R)-3-hydroxytetradecanoate, 1033 ml of dioxan and 122.9 g of 28 percent sodium hydroxide solution. 77.5 ml of methanol were added dropwise to the solution. After stirring for a further 1.5 hours the resulting suspension was filtered and the filter cake was washed with 1000 ml of dioxan and filtered off. The filter cake was adjusted to pH 0 by the addition of 650 ml of 1.5N hydrochloric acid. The suspension was stirred, filtered, the filter cake was washed with 3000 ml of water and the crystals were dried. 119.64 g (98%) of (R)-3-hydroxytetradecanoic acid, m.p. 70.6°-71.4°, were obtained.
Reaction SMILES: [CH3:1][O:2][C@@H:3]1[C:8](OC)([O:9]C)[CH2:7][CH2:6][O:5][CH2:4]1.C1COCC1.Cl>O>[CH3:1][O:2][C@@H:3]1[C:8](=[O:9])[CH2:7][CH2:6][O:5][CH2:4]1
Reactant: CO[C@H]1COCCC1(OC)OC
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CO[C@H]1COCCC1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
A 5-L 4-neck round bottom flask equipped with a overhead air stirrer, nitrogen inlet adapter, thermocouple, and septum was charged with (S)-3,4,4-trimethoxytetrahydro-2H-pyran (as prepared in the previous step, 83 g, 0.47 mol), THF (2.1 L), H2O (670 mL), and stirred in ice/acetone bath until <0° C., where upon a solution of HCl (conc., 350 mL, 4.24 mol) was added via addition funnel over 30 min while keeping temperature <2° C. After the addition was complete, the reaction was allowed to stir for 1 h at 0° C. The reaction was evaporated until ˜1.2 L of concentrate remained. The concentrate was transferred to a reparatory funnel and extracted with CH2Cl2 (3×750 mL). The combined organic fractions were washed with sat. NaHCO3 (500 mL), brine (500 mL), dried over MgSO4, filtered and evaporated to afford the title compound (46.9 g, 77%, Chiral GC 91% ee) as an oil which solidified upon sitting. Optical Rotation: [α]25(D)+3.65° (c=1.020, MeOH); Elemental Analysis calc for C6H10O3: C, 53.39; H, 7.57. Found: 53.59; H, 7.62.
Reaction SMILES: [C:1]1([O:7][C:8](=[O:26])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([B:16]3[O:20][C:19]([CH3:22])([CH3:21])[C:18]([CH3:24])([CH3:23])[O:17]3)=[C:12](F)[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC1(C)C(C)(C)OB(C2C=CC(N)=CC=2)O1>>[C:1]1([O:7][C:8](=[O:26])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([B:16]3[O:17][C:18]([CH3:23])([CH3:24])[C:19]([CH3:22])([CH3:21])[O:20]3)=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC1(C)OB(c2ccc(NC(=O)Oc3ccccc3)cc2F)OC1(C)C
Agent: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Product: CC1(C)OB(c2ccc(NC(=O)Oc3ccccc3)cc2)OC1(C)C

Procedure:
Method as described for intermediate 12 using 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline to afford a white solid (4.71 g) used without further purification.
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](Cl)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[NH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20].C(Cl)Cl.CO.[NH4+].[OH-]>>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:12][CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: Clc1ccc2ncc(Br)n2n1
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCNc1ccc2ncc(Br)n2n1

Procedure:
Prepared from 3-bromo-6-chloroimidazo[1,2-b]pyridazine and tert-butyl 3-aminopropylcarbamate according to general procedure 1 providing the intermediate (300 mg, 63%) as a yellow oil: Rf=0.65 (CH2Cl2/MeOH/NH4OH, 160:18:2); 1H NMR (500 MHz, CDCl3) δ 7.56 (d, J=9.6 Hz, 1H), 7.46 (s, 1H), 6.46 (d, J=9.6 Hz, 1H), 5.13-5.10 (m, 2H), 3.53 (quart, J=6.2 Hz, 2H), 3.27-3.23 (m, 2H), 1.84-1.79 (m, 2H), 1.46 (s, 9H); ES-MS: (M+H)=370, 372 m/z.
Reaction SMILES: [Br:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14]C)=[O:13])=[CH:7][CH:6]=1.CO.[OH-].[Na+]>O>[Br:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1
Reactant: COC(=O)Cc1ccc(OCCBr)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)Cc1ccc(OCCBr)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
4-Hydroxyphenylacetic acid (100 g, 0.6 mol) and cesium carbonate (250 g) were suspended in 300 mL of anhydrous acetonitrile followed by addition of 1,2-dibromoethane (300 mL). The suspension was brought to reflux for 24 hours in a 2L 3 neck round bottom flask fitted with a mechanical stirrer and reflux condenser then cooled to room temperature. The mixture was diluted to a volume of 2L by addition of ethyl ether and the suspension was filtered. Concentration of the filtrate in vacuo afforded a colorless oil which was purified by vacuum distillation (0.2 mm Hg, 140-145° C.) to give methyl 4-(2-bromoethoxy)-phenylacetate (93.14 g, 60% yield) as a colorless oil. The methyl 4-(2-bromoethoxy)-phenylacetate was taken into methanol (250 mL) and the resulting solution was cooled to 0° C. Sodium hydroxide (29 g) in a minimum of water was added to the methanol solution in portions and the mixture was stirred at 0° C. for an additional 30 minutes. The solution was warmed to room temperature then concentrated to a white solid. The residue was taken into water and the solution washed once with ethyl ether. The aqueous solution was then acidified to pH 1 by addition of concentrated aqueous hydrochloric acid to give a thick suspension. Filtration and drying afforded 4-(2-bromoethoxy)-phenylacetic acid (86 g, 97% yield) as a colorless solid. The 4-(2-bromoethoxy)-phenylacetic acid (50 g) was taken into thionyl chloride (70 mL) and brought to reflux under an atmosphere of nitrogen for 2 hours. Fractional vacuum distillation (0.2 mm Hg, 139-140° C.) afforded 4-(2-bromoethoxy)phenylacetyl chloride (46.0 g, 86% yield) as a colorless oil that quickly crystallized on cooling. 1H NMR (CDCl3) 6.95, 6.76, 6.60 (m, 11H, Ar—H), 4.68 (m, 1H), 4.24 (m, 2H), 3.80 (m, 1H), 3.41-3.63 (m, 3H), 3.07 (m, 1H), 2.87 (m, 2H), 2.61 (m, 1H); ES−MS (m/z) 458 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19].[Br:23][C:24]1[CH:29]=[C:28]([O:30][CH3:31])[C:27](I)=[CH:26][C:25]=1[F:33].C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1(C)C=CC=CC=1.ClCCl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:9]([S:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:27]2[CH:26]=[C:25]([F:33])[C:24]([Br:23])=[CH:29][C:28]=2[O:30][CH3:31])=[C:3](/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:4]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(=O)/C=C/c1cc(SCc2ccccc2)ccc1N
Reactant: COc1cc(Br)c(F)cc1I
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)/C=C/c1cc(SCc2ccccc2)ccc1Nc1cc(F)c(Br)cc1OC
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 70.7 %

Procedure:
To a solution of (E)-ethyl 3-(2-amino-5-(benzylthio)phenyl)acrylate (300 g, 958.1 mmol, 1.0 equiv) and 1-bromo-2-fluoro-4-iodo-5-methoxybenzene (348.0 g, 1051.6 mmol, 1.1 equiv) in toluene (2.5 L) was added Cs2CO3 (468 g, 1436.3 mmol, 1.5 equiv, Spectrochem) and the mixture was degassed with nitrogen for 20 mins. Pd2(dba)3 (35 g, 38.2 mmol, 0.04 equiv, Hindustan Platinum) and XantPhos (44.6 g, 76.4 mmol, 0.08 equiv, GLR) were added to the reaction mixture and the mixture was heated at 110° C. for 5 h. The reaction mixture was allowed to cool to room temperature, diluted with dichloromethane (2.0 L) and filtered through celite. The filtrate was concentrated under reduced pressure to obtain the crude material which was purified by stirring with 5% ethyl acetate in hexanes (3.0 L) for 30 min and filtered to obtain (E)-ethyl 3-(5-(benzylthio)-2-((4-bromo-5-fluoro-2-methoxyphenyl)amino)phenyl)acrylate (350 g, 71%) as yellow solid. TLC solvent system: 30% ethyl acetate in hexanes. Product's Rf: 0.5. MS (ESI, positive ion) m/z; 516.2 (M+1). 1H NMR (400 MHz, DMSO) δ 7.73-7.61 (m, 3H), 7.34-7.15 (m, 6H), 7.02 (d, J=11.4 Hz, 1H), 6.60 (d, J=21.2 Hz, 1H), 6.33 (d, J=14.1 Hz, 1H), 4.26 (s, 2H), 4.16-4.09 (m, 2H), 3.81 (s, 3H), 1.22 (t, J=7.2 Hz, 3H). Note: NH proton not observed.
Reaction SMILES: Cl[CH2:2][C:3](=O)[CH3:4].[F:6][C:7]1[CH:8]=[C:9]([CH:33]=[CH:34][CH:35]=1)[CH2:10][N:11]1[C:23]2[CH2:22][CH2:21][C@@H:20]([NH:24][C:25](=[O:29])[CH:26]([CH3:28])[CH3:27])[CH2:19][C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[C:15]([C:30](=[S:32])[NH2:31])[CH:16]=2>CN(C=O)C.O>[F:6][C:7]1[CH:8]=[C:9]([CH:33]=[CH:34][CH:35]=1)[CH2:10][N:11]1[C:23]2[CH2:22][CH2:21][C@@H:20]([NH:24][C:25](=[O:29])[CH:26]([CH3:27])[CH3:28])[CH2:19][C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[C:15]([C:30]1[S:32][CH:2]=[C:3]([CH3:4])[N:31]=1)[CH:16]=2
Reactant: CC(C)C(=O)N[C@@H]1CCc2c(c3cc(C(N)=S)ccc3n2Cc2cccc(F)c2)C1
Reactant: CC(=O)CCl
Solvent: O
Solvent: CN(C)C=O
Product: Cc1csc(-c2ccc3c(c2)c2c(n3Cc3cccc(F)c3)CC[C@@H](NC(=O)C(C)C)C2)n1
Yield: 85.1 %

Procedure:
Combine chloroacetone (0.197 g, 2.13 mmol) and (R)-N-(9-(3-fluorobenzyl)-6-thiocarbamoyl-2,3,4,9-tetrahydro-1H-carbazol-3-yl)isobutyramide (Preparation 22) (0.300 g, 0.708 mmol) and heat at 80° C. in DMF under nitrogen for 2.5 h. Upon cooling, dilute the mixture with water and collect the precipitate by filtration. Slurry the precipitate in hot EtOAc to give 0.278 g of a yellow solid. MS (ES): m/z 462 (M+1); HPLC: Rt=3.33 min (100%).
Reaction SMILES: [C:1]([O:5][C:6]([C@@:9]12[CH2:18][CH2:17][CH2:16][CH2:15][C@:14]1([O:19]COCCOC)[CH2:13][CH2:12][CH2:11][CH2:10]2)([CH3:8])[CH3:7])(=[O:4])[CH:2]=[CH2:3].Cl>CC(C)=O>[C:1]([O:5][C:6]([C@@:9]12[CH2:18][CH2:17][CH2:16][CH2:15][C@:14]1([OH:19])[CH2:13][CH2:12][CH2:11][CH2:10]2)([CH3:8])[CH3:7])(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)OC(C)(C)[C@]12CCCC[C@@]1(OCOCCOC)CCCC2
Agent: Cl
Solvent: CC(C)=O
Product: C=CC(=O)OC(C)(C)[C@]12CCCC[C@@]1(O)CCCC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 100 mmol of 4a-(1-acryloyloxy-1-methylethyl)-8a-(2-methoxyethoxymethoxy)-cis-decalin, 6 N-hydrochloric acid (150 mmol in terms of HCl), and 30 ml of acetone was stirred at room temperature for 1 hour. The resulting reaction mixture was concentrated to yield 4a-(1-acryloyloxy-1-methylethyl)-8a-hydroxy-cis-decalin represented by the following formula (yield: 98%). The conversion rate from 4a-(1-acryloyloxy-1-methylethyl)-8a-(2-methoxyethoxymethoxy)-cis-decalin was 99%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1(O)C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl.CN1CCOCC1.[CH3:47][S:48][C:49]1[C:57]2[C:52](=[CH:53][C:54]([NH2:58])=[CH:55][CH:56]=2)[N:51]([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[N:50]=1>ClCCl>[CH3:47][S:48][C:49]1[C:57]2[C:52](=[CH:53][C:54]([NH:58][C:15](=[O:17])[CH2:14][CH:9]3[CH2:10][CH2:11][CH2:12][CH2:13][N:8]3[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[CH:55][CH:56]=2)[N:51]([C:59]2[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=2)[N:50]=1
Reactant: CSc1nn(-c2ccccc2)c2cc(N)ccc12
Reactant: CC(C)(C)OC(=O)N1CCCCC1CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CSc1nn(-c2ccccc2)c2cc(NC(=O)CC3CCCCN3C(=O)OC(C)(C)C)ccc12
Temperature: 15 °C
Reaction time: 0.17 h

Procedure:
Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 2-(1-(tert-butoxycarbonyl)piperidin-2-yl)acetic acid (0.47 mg), 1H-benzo[d][1,2,3]triazol-1-ol (300 mg, 1.96 mmol), EDC.HCl (370 mg, 1.94 mmol), 4-methylmorpholine (590 mg, 5.84 mmol, 2.98 equiv) in dichloromethane (3 mL). The resulting solution was stirred for 10 min at 15° C. A solution of 3-(methylthio)-1-phenyl-1H-indazol-6-amine (500 mg, 1.96 mmol, 1.00 equiv) in dichloromethane (3 mL) was added. The resulting solution was stirred for an additional 2 h at 15° C. The resulting mixture was washed with aq. sodium bicarbonate (1×8 mL) and brine (2×8 mL). The resulting mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10˜1:3) to yield tert-butyl 2-(2-(3-(methylthio)-1-phenyl-1H-indazol-6-ylamino)-2-oxoethyl)piperidine-1-carboxylate as a white solid. MS: 481 (MH+).
Reaction SMILES: S([O-])([O-])(=O)=O.[Na+].[Na+].[OH-].[K+].[OH:10][CH2:11][C:12]1[CH:26]=[CH:25][C:15]([C:16](=[N:23][NH2:24])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:14][CH:13]=1>C(O)C.C1COCC1.[Hg]=O>[N+:23](=[C:16]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:15]1[CH:14]=[CH:13][C:12]([CH2:11][OH:10])=[CH:26][CH:25]=1)=[N-:24]
Reactant: NN=C(c1ccccc1)c1ccc(CO)cc1
Agent: O=S(=O)([O-])[O-]
Agent: O=[Hg]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCO
Product: [N-]=[N+]=C(c1ccccc1)c1ccc(CO)cc1
Reaction time: 2 h
Yield: 97.3 %

Procedure:
To a mixture of mercury (II) oxide (2.9 g, 13 mmol), sodium sulphate (2.2 g, 15 mmol) and sat potassium hydroxide in ethanol (4 ml) was added a solution of 4 (2.6 g, 11 mmol) in dry THF (20 ml). The mixture was stirred in the dark for 2 h. then filtered through a celite pad. Concentration of the filtrate in vacuo yielded 5 (2.4 g, 100%) as a dark red oil; δH (CDCl3) 4.69 (s, 2H, CH2OH), 7.29-7.31 (m, 4H, 3-, 3′-, 5-, 5′-H), 7.39-7.41 (m, 5H, 2-, 2′-, 4′-, 6-, 6′-H) ppm; δC (CDCl3) 64.8 (CH2OH), 125.1, 125.2 (3-, 3′-, 5-, 5′-C), 125.6 (4′-C), 127.9, 129.1 (2-, 2′-, 6-, 6′-C), 128.9, 129.4 (1-, 1′-C), 138.2 (4-C) ppm; νmax (thin film) 3346, 2872, 2038, 1511, 1493 cm−1; m/z (F14) 224 ([M]+, 100%); found (FT) 224.0949, C14H12N2O requires 224.0950.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.Br[CH2:10][CH2:11][CH2:12][CH2:13][Cl:14].C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[Cl:14][CH2:13][CH2:12][CH2:11][CH2:10][N:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[N:6][C:5]1=[O:8]
Reactant: ClCCCCBr
Reactant: Cc1cnc(=O)[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cnc(=O)n(CCCCCl)c1
Temperature: 0 °C

Procedure:
10.5 g (95.0 mmol) of 5-methylpyrimidin-2(1H)-one from Example 6.1, 16.3 g (95.0 mmol) of 1-bromo-4-chlorobutane and 39.4 g (285.0 mmol) of K2CO3 in 200 ml of dimethyl sulfoxide were stirred at room temperature for 12 hours. The reaction mixture was added to ice-water, and the aqueous mixture was extracted twice with diethyl ether. The aqueous phase was extracted twice with methylene chloride. The methylene chloride phase was dried over Na2SO4 and filtered to remove the desiccant, and the solvent was evaporated to dryness in vacuo. The resulting solid residue was stirred with diethyl ether, and the precipitate was filtered off with suction, washed with diethyl ether and dried. Yield: 5.0 g.
Reaction SMILES: Br[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].[CH2:11]([NH2:15])[CH:12]([CH3:14])[CH3:13]>C1COCC1>[CH2:11]([NH:15][CH2:2][C:3]([N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4])[CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)CN
Reactant: O=C(CBr)N1CCOCC1
Solvent: C1CCOC1
Product: CC(C)CNCC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 39.7 %

Procedure:
N-Bromoacetyl-morpholine (3.73 g, 18 mmol) was dissolved in 20 mL of THF. Isobutylamine (5.40 mL, 54.0 mmol) was added. The reaction mixture was stirred at room temperature for 24 h. Solvent and excess reagent were removed in vacuo. The residue was treated with ether. The resulting solid was removed by filtration and washed with ether. The filtrate was concentrated under reduced pressure to give 2-isobutylamino-1-morpholin-4-yl-ethanone (1.43 g, 40%) as a clear oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([C:15](=[O:17])[NH2:16])[CH:14]=1)[NH:11][C:10]1[CH:9]=[C:8]([N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)[CH:7]=[CH:6][C:5]2=1.[CH3:31][N:32]1[C:40]2[C:35](=[CH:36][C:37](B(O)O)=[CH:38][CH:39]=2)[CH:34]=[N:33]1.COCCOC.C([O-])([O-])=O.[Na+].[Na+]>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].C(Cl)Cl.O>[C:15]([C:13]1[CH:14]=[C:2]([C:37]2[CH:36]=[C:35]3[C:40](=[CH:39][CH:38]=2)[N:32]([CH3:31])[N:33]=[CH:34]3)[CH:3]=[C:4]2[C:12]=1[NH:11][C:10]1[CH:9]=[C:8]([N:18]3[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH2:22][CH2:23]3)[CH:7]=[CH:6][C:5]2=1)(=[O:17])[NH2:16]
Reactant: Cn1ncc2cc(B(O)O)ccc21
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3c(c2)[nH]c2c(C(N)=O)cc(Br)cc23)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: COCCOC
Solvent: O
Product: Cn1ncc2cc(-c3cc(C(N)=O)c4[nH]c5cc(N6CCN(C(=O)OC(C)(C)C)CC6)ccc5c4c3)ccc21
Temperature: 100 °C
Reaction time: 4 h
Yield: 61.8 %

Procedure:
A 20 ml microwave vial was loaded with tert-butyl 4-(6-bromo-8-carbamoyl-9H-carbazol-2-yl)piperazine-1-carboxylate (0.49 g, 0.518 mmol), 1-methyl-1H-indazol-5-ylboronic acid (0.255 g, 1.377 mmol), DME (15 mL), PdCl2(dppf)-CH2Cl2 adduct (40 mg, 0.049 mmol) and Na2CO3 (2M) (1.55 mL, 3.10 mmol). The vial was sealed, flushed with nitrogen for 15 minutes, then heated to 100° C. for 2 hours. LCMS showed partial conversion of bromide starting material. 1-Methyl-1H-indazol-5-ylboronic acid (0.115 g, 0.621 mmol), PdCl2(dppf)-CH2Cl2 adduct (30 mg, 0.037 mmol) and Na2CO3 (2M) (1.0 mL, 2.0 mmol) were added and heating continued for 4 hours at 100° C. The reaction mixture was poured into a separating funnel that is loaded with 100 ml water+25 ml sat. aq. NH4Cl solution and extracted with EtOAc (2×). The organic layers were washed once with dilute NaHCO3 solution, then brine, then dried over MgSO4+3 g SILICYCLE® thiol resin [to capture Pd and ferrocene] overnight. Filtration and evaporation to dryness gave the crude product, which was purified by chromatography on silica. (Gradient from 100% dichloromethane to 50% DCM+50% EtOAc (85 fractions a 12 ml, fractions A), then gradient from 50% DCM+50% EtOAc to 40% DCM+40% EtOAc+20% MeOH (85 fractions a 12 ml, fractions B). Product containing fractions (B20-B27) were combined and evaporated to dryness to give 168 mg tert-butyl 4-(8-carbamoyl-6-(1-methyl-1H-indazol-5-yl)-9H-carbazol-2-yl)piperazine-1-carboxylate. Estimated purity ˜50% (contains significant amount of 1-methyl-1H-indazol-5-ylboronic acid). MS (ESI) m/e+=525.