Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)O1.Br[C:20]1[CH:21]=[C:22]([CH2:26][C:27]([OH:29])=[O:28])[CH:23]=[CH:24][CH:25]=1.[OH-].[Na+]>C1COCC1.[Pd].C(OCC)(=O)C>[NH:13]1[C:14]2[C:10](=[C:9]([C:20]3[CH:21]=[C:22]([CH2:26][C:27]([OH:29])=[O:28])[CH:23]=[CH:24][CH:25]=3)[CH:17]=[CH:16][CH:15]=2)[CH:11]=[CH:12]1
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Reactant: O=C(O)Cc1cccc(Br)c1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(O)Cc1cccc(-c2cccc3[nH]ccc23)c1
Temperature: 70 °C
Yield: 84.3 %

Procedure:
To a mixture of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole (15.52 g, 63.72 mmol), and 3-bromo-phenylacetic acid (13.78 g, 63.72 mmol) in THF (192 mL) were added Palladium catalyst Pd(PPh3)4 (2.21 g, 1.9 mmol) and the freshly prepared sodium hydroxide solution (7.65 g in 90 mL of water). The system was degassed and then charged with nitrogen. The degas procedure was repeated for three times. The mixture was stirred under nitrogen in a 70° C. oil bath for over the weekend. TLC showed the completion of the coupling reaction. The mixture was cooled to room temperature, diluted with ethyl acetate, and separated from water layer. The water layer was acidified with dil. HCl solution to pH 4-5 and extracted with ethyl acetate. The ethyl acetate solution was washed with water, brine, and dried over Na2SO4. After filtration, the solvents were evaporated, and the crude product was purified on a silica gel column to give 13.5 g (84%) of [3-(1H-indol-4-yl)-phenyl]-acetic acid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C@H:15]([CH3:23])[CH2:16][CH2:17][CH2:18][CH:19]([CH3:22])[CH:20]=[CH2:21])[C:10]([O:12]CC)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.[Li+].[OH-]>C1COCC1.O>[C:1]([O:5][C:6]([NH:8][CH:9]([C@H:15]([CH3:23])[CH2:16][CH2:17][CH2:18][CH:19]([CH3:22])[CH:20]=[CH2:21])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CC(C)CCC[C@@H](C)C(NC(=O)OC(C)(C)C)C(=O)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: C=CC(C)CCC[C@@H](C)C(NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
To a solution of (3R)-ethyl 2-(tert-butoxycarbonylamino)-3,7-dimethylnon-8-enoate (2.7 g, 8.25 mmol) in THF/water (40 mL, 1:1) was added methanol (20 mL) followed by LiOH (0.987 g, 41.2 mmole) at room temperature. The reaction mass was stirred at room temperature overnight. Solvent was evaporated under reduced pressure and the residue was diluted with water (100 mL). The aqueous solution was acidified with aqueous 1.5 N HCl solutions to pH˜3 and extracted with ethyl acetate (100 mL×3). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduce pressure to get crude compound. The crude compound was purified by column chromotography (Silica gel, 3% methanol in DCM) to get 2.1 g (85%) of desired compound as gummy liquid. 1H NMR (400 MHz, DMSO-D6): δ ppm 12.2-12.02 (bs, 1H), 6.92-6.85 (m, 1H) 5.72-5.66 (m, 1H), 4.98-4.85 (dd, J=1.6, 2.8 Hz, 2H), 4.03-3.95 (m, 1H), 2.58-2.56 (m, 1H) 2.15-2.02 (m, 1H), 1.45-1.36 (m, 10H), 1.27-1.21 (m, 5H), 0.95-0.93 (m, 3H), 0.84-0.74 (m, 3H).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([F:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:25][C:24]([CH3:26])=[C:23]([C:27]([NH:29][CH:30]4[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]4)=[O:28])[C:18]=3[N:19]=[C:20]([CH3:22])[N:21]=2)[CH2:4][CH2:3]1.C([O:39][C@@H:40]([CH3:44])[C:41](Cl)=[O:42])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([F:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:25][C:24]([CH3:26])=[C:23]([C:27]([NH:29][CH:30]4[CH2:31][CH2:32][N:33]([C:41](=[O:42])[C@@H:40]([OH:39])[CH3:44])[CH2:34][CH2:35]4)=[O:28])[C:18]=3[N:19]=[C:20]([CH3:22])[N:21]=2)[CH2:4][CH2:3]1
Reactant: COc1cc(OCC2CC2)c(-c2nc(C)nc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)cc1F
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Agent: Cl
Product: COc1cc(OCC2CC2)c(-c2nc(C)nc3c(C(=O)NC4CCN(C(=O)[C@H](C)O)CC4)c(C)[nH]c23)cc1F

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-fluoro-4-methoxyphenyl]-2,6-dimethyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f58) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[C:18](=[O:22])[N:17]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:16]([CH2:27][NH:28]C(OC(C)(C)C)=O)=[C:15]2[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:42]>O1CCCC1.C(OCC)(=O)C>[ClH:42].[NH2:28][CH2:27][C:16]1[N:17]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:18](=[O:22])[C:19]2[C:14]([C:15]=1[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)=[CH:13][C:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])=[CH:21][CH:20]=2
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(NC(=O)OCc3ccccc3)ccc2c1=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)Cn1c(CN)c(-c2ccccc2)c2cc(NC(=O)OCc3ccccc3)ccc2c1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 81 %

Procedure:
To a solution of 6-benzyloxycarbonylamino-3-tert-butoxycarbonylaminomethyl-2-isobutyl-4-phenyl-1(2H)-isoquinolinone (0.07 g, 0.13 mmol) in tetrahydrofuran (2 mL) was added a solution, of 4N hydrogen chloride in ethyl acetate (10 mL). The obtained solution was stirred at room temperature for 5 h. The reaction mixture was concentrated under reduced pressure and the residue was crystallized from diethyl ether to give 3-aminomethyl-6-benzyloxycarbonylamino-2-isobutyl-4-phenyl-1(2H)-isoquinolinone hydrochloride (0.05 g, 81%) as crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:12][CH3:13])[C:5]2[N:6]([N:8]=[CH:9][C:10]=2I)[CH:7]=1.[CH:14]1([C:17]#[CH:18])[CH2:16][CH2:15]1.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C.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].[Cu]I>[Br:1][C:2]1[CH:3]=[C:4]([O:12][CH3:13])[C:5]2[N:6]([N:8]=[CH:9][C:10]=2[C:18]#[C:17][CH:14]2[CH2:16][CH2:15]2)[CH:7]=1
Reactant: COc1cc(Br)cn2ncc(I)c12
Reactant: C#CC1CC1
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(Br)cn2ncc(C#CC3CC3)c12
Temperature: 60 °C
Reaction time: 6 h

Procedure:
6-bromo-3-iodo-4-methoxypyrazolo[1,5-a]pyridine (50.0 mg, 0.142 mmol), cyclopropyl acetylene (0.018 ml, 0.212 mmol), tetrakis(triphenylphosphine)palladium (0) (16.4 mg, 0.014 mmol), and copper(I) iodide (4.1 mg, 0.02 mmol) were suspended in DMF (2 ml). Triethylamine (0.039 ml, 0.283 mmol) was added, the mixture was sparged with argon for 10 minutes, then heated to 60° C. overnight. LCMS analysis indicated incomplete reaction conversion. Cyclopropyl acetylene (0.018 ml, 0.212 mmol) was added and the mixture was stirred for 6 h, at which time, LCMS analysis indicated the reaction has proceeded further, but still conversion was still incomplete. Cyclopropyl acetylene (0.036 ml, 0.426 mmol) was added and the mixture was stirred overnight. The reaction mixture was diluted in ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and brine then dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate/isohexane gradient) to afford recovered 6-bromo-3-iodo-4-methoxypyrazolo[1,5-a]pyridine (faster eluting) along with 6-bromo-3-(cyclopropylethynyl)-4-methoxypyrazolo[1,5-a]pyridine (slower eluting).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14]2[N:22]=[C:21]3[C:17]([N:18]=[CH:19][NH:20]3)=[C:16]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Br:29]Br>O1CCOCC1.O>[Br:29][C:19]1[NH:20][C:21]2[C:17]([N:18]=1)=[C:16]([N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)[N:15]=[C:14]([NH:13][CH2:12][CH2:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[N:22]=2
Reactant: COc1ccc(CCNc2nc(N3CCOCC3)c3nc[nH]c3n2)cc1OC
Reactant: BrBr
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(CCNc2nc(N3CCOCC3)c3nc(Br)[nH]c3n2)cc1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 75.5 %

Procedure:
To a solution of [2-(3,4-dimethoxy-phenyl)-ethyl]-(6-morpholin-4-yl-9H-purin-2-yl) amine (1.16 g, 3 mmol) in dioxane (75 mL) was added bromine (0.180 mL, 3.3 mmol) in dioxane (5 mL) dropwise over a period of 1 hour. The mixture was stirred at room temperature for additional 4 hours and diluted with water (25 mL) and extracted with EtOAc. The organic phase was washed with brine, water, dried over Na2SO4. The solvent was evaporated in vacuo and solid was washed with methanol to give (8-bromo-6-morpholin-4-yl-9H-purin-2-yl)-[2-(3,4-dimethoxy-phenyl)-ethyl]-amine as a white solid (1.05 g, 75% yield).
Reaction SMILES: [C:1]([CH:4]1[N:12](C(OC(C)(C)C)=O)[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:6]2[CH2:5]1)(=[O:3])[NH2:2].[C:20]([OH:26])([C:22]([F:25])([F:24])[F:23])=[O:21]>C(Cl)Cl>[F:23][C:22]([F:25])([F:24])[C:20]([OH:26])=[O:21].[NH:12]1[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:6]2[CH2:5][CH:4]1[C:1]([NH2:2])=[O:3]
Reactant: CC(C)(C)OC(=O)N1c2ncccc2CC1C(N)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)C1Cc2cccnc2N1
Reaction time: 8 h
Yield: 90.2 %

Procedure:
To a solution of tert-butyl 2-carbamoyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (100 mg, 380 μmol, Eq: 1.00) in DCM (3 mL) was added TFA (2 mL, 26.0 mmol, Eq: 68.3) and the resulting mixture was stirred overnight. The reaction mixture was concentrated in vacuo and azeotroped with DCM (2×10 mL). The resulting residue was triturated with ether to give 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid amide, trifluoroacetate salt as an off-white solid (95 mg)
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:23]=[C:22](N)[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)=[N:6]1.N(OCCC(C)C)=O.CN(C)C=O>O1CCCC1>[F:1][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)=[N:6]1
Reactant: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc2ccccc12
Agent: CC(C)CCON=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Fc1ccccc1Cn1nc(-c2ncc3ccccc3n2)c2cccnc21
Temperature: 95 °C
Reaction time: 5 h

Procedure:
200 mg (0.540 mmol) of the compound from example 5 were suspended in tetrahydrofuran (2.0 ml), then 145 μl (1.08 mmol) of isopentyl nitrite were added and the reaction mixture was heated to reflux for 30 min. Subsequently, dimethylformamide (1.0 ml) and 145 μl of isopentyl nitrite were added and the mixture was stirred at 95° C. for a further 5 h. The reaction mixture was subsequently separated directly by means of preparative HPLC (eluent: acetonitrile-water with 0.1% formic acid gradient) and the product-containing mixed fractions were concentrated. The crude product was subsequently further purified by means of HPLC (eluent: water/methanol/1% trifluoroacetic acid 28:65:7). This gave 30 mg (15% of theory) of the title compound in solid form.
Reaction SMILES: C(N(CC1C=CC=CC=1)C1(C[NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([CH3:26])[CH:24]=3)[N:19]=[C:18]([N:27]3[CH2:33][C:32]4[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=4[S:30](=[O:39])(=[O:38])[CH2:29][CH2:28]3)[CH:17]=2)CCOC1)C1C=CC=CC=1.[NH:47]1[CH2:52][CH2:51][CH2:50][CH:49]([C:53](N)=[O:54])[CH2:48]1>>[O:39]=[S:30]1(=[O:38])[C:31]2[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=2[CH2:33][N:27]([C:18]2[CH:17]=[C:16]([NH:15][C:53]([CH:49]3[CH2:50][CH2:51][CH2:52][NH:47][CH2:48]3)=[O:54])[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([CH3:26])[CH:24]=3)[N:19]=2)[CH2:28][CH2:29]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC3(N(Cc4ccccc4)Cc4ccccc4)CCOC3)c2c1
Reactant: NC(=O)C1CCCNC1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NC(=O)C3CCCNC3)c2c1

Procedure:
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-bromo-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 2-1 by using 4,6-dibromoquinoline and 2,3,4,5-tetrahydro-1,4-benzothiazepine) and piperidine-3-carboxamide. MS obsd. (ESI+) [(M+H)+] 465, 1H NMR (400 MHz, CD3OD) δ ppm 8.47 (s, 1 H), 8.11 (s, 1 H), 8.07-8.05 (d, J=1.2 Hz, 1 H), 7.98-7.96 (d, J=7.2 Hz, 1 H), 7.83-7.80 (d, J=8.4 Hz, 1 H), 7.70-7.64 (m, 2 H), 7.58-7.54 (m, 1 H), 5.29 (s, 1 H), 4.61 (s, 2 H), 3.76 (s, 2 H), 3.55-3.52 (m, 2 H), 3.43-3.34 (m, 3 H), 3.22-3.15 (m, 1 H), 2.52 (s, 3 H), 2.29-2.27 (m, 1 H), 2.06-2.02 (m, 1 H), 1.97-1.89 (m, 2 H).
Reaction SMILES: [C:1]1([C:7]([CH3:14])([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][O:16]C(Cl)Cl.S(=O)(O)[O-].[Na+]>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH:15]([C:4]1[CH:5]=[CH:6][C:1]([C:7]([CH3:13])([CH3:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:2][CH:3]=1)=[O:16]
Reactant: COC(Cl)Cl
Reactant: CCOC(=O)C(C)(C)c1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C(C)(C)c1ccc(C=O)cc1
Temperature: 5 °C
Reaction time: 60 h

Procedure:
Ethyl 2-phenyl-2-methylpropionate (10 g) was dissolved in 50 mL of dichloromethane and cooled to 5° C. Titanium tetrachloride (10.5 mL) and 1,1-dichloromethyl methyl ether (7.5 mL) were added and the mixture was stirred at room temperature for 60 hours. The resulting dark solution was diluted with 50 mL of dichloromethane and washed twice with 50 mL of water. The organic solution was concentrated to give an oil which was treated with 30 mL of saturated aqueous sodium bisulfite solution for 12 hours. The precipitate was collected by filtration, washed with hexane, suspended in ethyl acetate and treated with excess potassium carbonate. The organic phase was separated, dried with sodium sulfate and stripped to provide 2 g of product.
Reaction SMILES: [C:1]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([O:15][CH3:16])[CH:9]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].C([Li])CCC.C(Br)C[Br:24]>O1CCCC1>[C:1]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([O:15][CH3:16])[C:9]=1[Br:24])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: COc1cc(NC(=O)C(C)(C)C)ccc1Cl
Reactant: BrCCBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1c(Cl)ccc(NC(=O)C(C)(C)C)c1Br
Temperature: 0 °C
Reaction time: 3 h
Yield: 5.7 %

Procedure:
To solution of N-pivaloyl-4-chloro-3-methoxyaniline (5.0 g, 21 mmol) in tetrahydrofuran (60 mL) at −60° C. was added n-butyl lithium (2.5M, 44 mmol). The solution was allowed to warm to 0° C. and stir for 3 hours. Ethylene dibromide (9.9 g, 53 mmol) was added and the solution stirred for 18 hours before being quenched with ammonium chloride (saturated solution, 20 mL) and extracted with ethyl ether (2×50 mL). The combined extracts were washed with brine, dried (sodium sulfate) and concentrated. The residue was purified by chromatography (10% ethyl acetate/hexanes) to give N-pivaloyl-2-bromo-4-chloro-3-methoxyaniline (3.7 g, 1.2 mmol): LC/MS (m/z=320).
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[N:17]([CH3:18])[C:9]2=[N:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:8]2[C:7](=[O:19])[N:6]([CH3:20])[CH2:5]1.C(O)(C)C.[C:25]([OH:32])(=[O:31])/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29].[CH3:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[C:25]([OH:32])(=[O:31])/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29].[CH3:18][N:17]1[C:9]2=[N:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:8]2[C:7](=[O:19])[N:6]([CH3:20])[CH2:5][CH:4]1[CH2:3][CH2:2][N:37]1[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]1
Reactant: CN1CC(CCCl)N(C)c2nc3ccccc3n2C1=O
Reactant: CN1CCNCC1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CC(C)O
Product: CN1CCN(CCC2CN(C)C(=O)n3c(nc4ccccc43)N2C)CC1
Temperature: 60 °C

Procedure:
To 20 mL of N-methylpiperazine was added 3.0 g (0.01 mol) of 2-(2-chloroethyl)-3,4-dihydro-1,4-dimethyl-1H-[1,3,5]triazepino[3,2-a]benzimidazol-5(2H)-one. The reaction mixture was heated to 60° C. for 24 hr. The excess amine was removed at 70° C., 0.5 mm Hg. The residual oil was taken up in 60 mL of CH2Cl2 and washed with 2×50 mL of 1N NaOH. The organic layer was dried over Na2SO4, filtered, concentrated by rotary evaporation, and further concentrated at 90° C., 0.5 mm Hg. The residual oil/glass was treated with 2 equivalent of fumaric acid isopropyl alcohol to give 3.4 g of solid. This was recrystallized from isopropyl alcohol to give 3.0 g (51%) off-white analytically pure material, mp 171°-79° C.
Reaction SMILES: Br[C:2]1[C:7]2[NH:8][C:9]3[CH:10]=[C:11]([Cl:15])[CH:12]=[CH:13][C:14]=3[C:6]=2[C:5](=[O:16])[NH:4][CH:3]=1.[CH3:17][N:18](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[Cl:15][C:11]1[CH:12]=[CH:13][C:14]2[C:6]3[C:5](=[O:16])[NH:4][CH:3]=[C:2]([C:17]#[N:18])[C:7]=3[NH:8][C:9]=2[CH:10]=1
Reactant: CN(C)C=O
Reactant: O=c1[nH]cc(Br)c2[nH]c3cc(Cl)ccc3c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1c[nH]c(=O)c2c1[nH]c1cc(Cl)ccc12
Temperature: 90 °C
Reaction time: 24 h

Procedure:
4-Bromo-7-chloro-2,5-dihydro-1H-pyrido[4,3-b]indol-1-one (35.55 g, 119 mmol), zinc cyanide (9.82 g, 84 mmol), and Pd(PPh3)4 (13.81 g, 11.95 mmol) were combined and stored under vacuum for 20 min before DMF (300 mL, presparged with nitrogen for 1 h) was transferred to the mixture via cannula. The reaction mixture was heated to 90° C. overnight. Additional Pd(PPh3)4 (13.0 g, 11.2 mmol) was added to the mixture, and the resultant mixture was heated to 90° C. for 20 h, cooled to room temperature, and left to stir for 1 d. The reaction mixture was filtered, and washed with DMF. The filtrate was treated with water (15 mL), aged at room temperature for 3 h, treated with additional water (70 mL), and the resultant slurry was left overnight. The mixture was treated with additional water (70 mL), filtered, washed with water, and dried under vacuum. The solid was suspended in EtOAc, aged, filtered, washed with EtOAc, and dried under vacuum to give the title compound. 1H NMR (600 MHz, CD3SOCD3) δ 12.66 (s, 1H); 12.19 (s, 1H); 8.31 (s, 1H); 8.06 (d, 1H); 7.55 (s, 1H); 7.30 (d, 1H). LRMS (APCI) calc'd for (C12H6ClN3O) [M+H]+, 244.0. found 244.0.
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([N:14]([NH2:20])C(OCC)=O)=[N:5][C:6]([OH:13])=[N:7]2.CN(C)[CH:23]=[O:24]>>[CH3:12][C:11]1[CH:10]=[CH:9][C:8]2[NH:7][C:6](=[O:13])[N:5]3[C:23](=[O:24])[NH:20][N:14]=[C:4]3[C:3]=2[C:2]=1[CH3:1]
Reactant: CN(C)C=O
Reactant: CCOC(=O)N(N)c1nc(O)nc2ccc(C)c(C)c12
Product: Cc1ccc2[nH]c(=O)n3c(=O)[nH]nc3c2c1C
Temperature: 25 °C

Procedure:
0.67 g (0.0020 mol) of ethyl 5,6-dimethyl-2-hydroxy-quinazolin-4-yl-carbazate in 38 ml of dimethylformamide was boiled under reflux for 2 hrs. The reaction mixture was cooled to room temperature and then poured on to ice-water. The precipitate was filtered off and dried in a vacuum. There were obtained white crystals which were recrystallized from methanol/dimethylformamide. Yield: 0.41 g (74%) of 9,10-dimethyl-2,3,5,6-tetrahydro-1,2,4-triazolo[4,3-c]quinazoline-3,5-dione as yellowish crystals; m.p. >350° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2[O:28][CH3:29])[N:3]=1.[NH2:30][C:31]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:32]=1[C:33]([NH:35][CH3:36])=[O:34]>>[F:41][C:39]1[CH:38]=[CH:37][C:32]([C:33](=[O:34])[NH:35][CH3:36])=[C:31]([NH:30][C:2]2[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]3[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=3[O:28][CH3:29])[N:3]=2)[CH:40]=1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Reactant: CNC(=O)c1ccc(F)cc1N
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3cc(F)ccc3C(=O)NC)n2)c(OC)c1)OCC

Procedure:
The title compound was prepared using the procedure from Example 102 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate and 2-Amino-4-fluoro-N-methylbenzamide. 1H NMR (DMSO-d6, 400 MHz): δ=1.19 (t, J=7.07 Hz, 6H), 2.77 (d, J=4.55 Hz, 3H), 3.16-3.24 (m, 2H), 3.78 (s, 3H), 3.92-4.01 (m, 4H), 6.83 (d, J=7.83 Hz, 1H), 6.93 (br. s., 1H), 6.99 (s, 1H), 7.53 (br. s., 1H), 7.78 (t, J=7.33 Hz, 1H), 8.25-8.48 (m, 2H), 8.62-9.04 (m, 2H), 11.86 (br. s., 1H). MS (ES+): m/z 586.18 [MH+] (TOF, polar).
Reaction SMILES: [CH3:1][N:2]([CH3:11])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.[CH3:12][Si:13]([CH3:28])([CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH2:14][CH2:15][CH2:16][O:17][CH2:18][CH:19]1[CH2:21][O:20]1>C(O)C>[CH3:1][N:2]([CH3:11])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:21][CH:19]([OH:20])[CH2:18][O:17][CH2:16][CH2:15][CH2:14][Si:13]([CH3:12])([CH3:28])[CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH2:7][CH2:6]1
Reactant: CN(C)CCN1CCNCC1
Reactant: C[Si](C)(C)CC[Si](C)(C)CCCOCC1CO1
Solvent: CCO
Product: CN(C)CCN1CCN(CC(O)COCCC[Si](C)(C)CC[Si](C)(C)C)CC1
Temperature: 70 °C

Procedure:
Dimethyl-(2-piperazin-1-yl-ethyl)-amine (1.14 g; 7.28 mMol) and 40 mL of ethanol were charged to a 100 mL RB flask equipped with a magnetic stirrer. The mixture was stirred and heated to 70° C. 2-{3-[Dimethyl-(2-trimethylsilanyl-ethyl)-silanyl]-propoxymethyl}-oxirane 8 (2 g; 7.28 mMol) mixed with 10 g ethanol was placed in an addition funnel and added dropwise to the flask. The mixture was stirred and maintained at 70° C. for an additional 4 hours. Ethanol was stripped off on the rotovap. The mixture was distilled under vacuum to remove impurities.
Reaction SMILES: CN(C1C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=CC=CC=1)C.Cl.[F:30][C:31]1([F:36])[CH2:35][CH2:34][NH:33][CH2:32]1.Cl[C:38]1[N:43]=[CH:42][C:41]2[O:44][C:45]3[C:50]([C@@:51]4([CH2:55][O:54][C:53]([NH2:56])=[N:52]4)[C:40]=2[CH:39]=1)=[CH:49][C:48]([C:57]#[C:58][C:59]1([CH3:63])[CH2:62][O:61][CH2:60]1)=[CH:47][CH:46]=3.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>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]>[F:30][C:31]1([F:36])[CH2:35][CH2:34][N:33]([C:38]2[N:43]=[CH:42][C:41]3[O:44][C:45]4[C:50]([C@@:51]5([CH2:55][O:54][C:53]([NH2:56])=[N:52]5)[C:40]=3[CH:39]=2)=[CH:49][C:48]([C:57]#[C:58][C:59]2([CH3:63])[CH2:60][O:61][CH2:62]2)=[CH:47][CH:46]=4)[CH2:32]1
Reactant: FC1(F)CCNC1
Reactant: CC1(C#Cc2ccc3c(c2)[C@@]2(COC(N)=N2)c2cc(Cl)ncc2O3)COC1
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Product: CC1(C#Cc2ccc3c(c2)[C@@]2(COC(N)=N2)c2cc(N4CCC(F)(F)C4)ncc2O3)COC1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
Tris(dibenzylideneacetone)dipalladium (0) (0.012 g, 0.013 mmol), 2-(dicyclohexylphosphino)-2′-(n,n-dimethylamino)biphenyl (0.015 g, 0.039 mmol), 3,3-difluoropyrolidine HCl, 98% (0.113 g, 0.786 mmol) and (S)-3-chloro-7-((3-methyloxetan-3-yl)ethynyl)-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-oxazol]-2′-amine (0.100 g, 0.262 mmol) were combined and degassed with nitrogen. LHMDS (1.06 m solution in THF) (1.571 mL, 1.571 mmol) was added and the mixture was stirred at 90° C. overnight. The solvent was removed and the crude material was purified by column chromatography with 0-5% 2M NH3 in MeOH/CH2Cl2 to provide the desired product as an off white solid. MS m/z=452.9 [M+H].