Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:22][CH2:23][CH3:24])[N:10]=2)=[C:5]([CH3:25])[CH:4]=1.B(Br)(Br)Br.C1CCCCC=1>>[CH3:25][C:5]1[CH:4]=[C:3]([OH:2])[CH:8]=[CH:7][C:6]=1[C:9]1[C:17]2[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=2)[N:11]([CH2:22][CH2:23][CH3:24])[N:10]=1
Reactant: CCCn1nc(-c2ccc(OC)cc2C)c2cccc(C(F)(F)F)c21
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Product: CCCn1nc(-c2ccc(O)cc2C)c2cccc(C(F)(F)F)c21
Yield: 108.9 %

Procedure:
Prepared according to Method D step C from 3-(4-methoxy-2-methylphenyl)-1-propyl-7-(trifluoromethyl)-1H-indazole (0.087 g, 0.25 mmol), boron tribromide (0.136 mL, 1.4 mmol) and 1.0 mL of cyclohexene to give the product (0.091 g) as a white solid,
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[O:10][C:11]3[CH:17]=[C:16]([O:18][CH2:19][C@@H:20]([NH:22][C:23](=[O:25])[CH3:24])[CH3:21])[CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][C:7]=1[OH:8].[CH3:26]I>>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[O:10][C:11]3[CH:17]=[C:16]([O:18][CH2:19][C@@H:20]([NH:22][C:23](=[O:25])[CH3:24])[CH3:21])[CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:26]
Reactant: CI
Reactant: CC(=O)N[C@@H](C)COc1ccc2nc(-c3ccc(O)c(F)c3)oc2c1
Product: COc1ccc(-c2nc3ccc(OC[C@H](C)NC(C)=O)cc3o2)cc1F

Procedure:
Using N-((2S)-1-((2-(3-fluoro-4-hydroxyphenyl)-1,3-benzoxazol-6-yl)oxy)propan-2-yl)acetamide and methyl iodide, and in the same manner as in Example 5, the title compound was obtained.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([I:9])=[CH:5][C:4]=1[CH2:10]Br.[C:12]([NH2:31])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[I:9][C:6]1[CH:5]=[C:4]2[C:3](=[CH:8][CH:7]=1)[CH2:2][N:31]([C:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH2:10]2
Reactant: NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: BrCc1ccc(I)cc1CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Ic1ccc2c(c1)CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2
Temperature: 60 °C
Reaction time: 2 h
Yield: 47.2 %

Procedure:
A mixture of the product of Step B (0.34 g; 0.87 mmol) hydrochloride salt of tritylamine (0.22 g; 0.87 mmol) and N,N-diisopropylethylamine (DIPEA) (0.49 ml; 2.8 mmol) in anhydrous DMF (3 ml) was stirred for 2 h at 60° C. under N2. After removing the solvent in vacuo, the residue was diluted to 15 ml with ethyl acetate (EtOAc) and washed with, H2O, brine and dried over anhydrous MgSO4 and filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was purified by FCC (SiO2; hexane/EtOAc, 8:2) to give pure title compound (0.2 g; 48%) as colourless heavy syrup. 1H-NMR (CDCl3) 3.86 (s, 2H); 3.87 (s, 2H); 6.81-7.57 (m, 18H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[N:10]1.Cl.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH:29]1[CH2:34][C:35]([OH:37])=[O:36]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[NH:12][C:13]([CH2:20][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH:29]2[CH2:34][C:35]([OH:37])=[O:36])=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Reactant: O=C(O)CC1COCCN1
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCOCC2CC(=O)O)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Yield: 71.8 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.7 g, 1.4 mmol) was reacted with 2-(morpholin-3-yl)acetic acid hydrochloride (0.25 g, 1.4 mmol) according to the procedure as described in Example 1, Step C to give the title compound as a pale yellow solid (0.57 g, 72%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:22])[F:21])[CH:14]=3)=[CH:11][C:10]([NH2:24])=[N:9]2)=[CH:4][CH:3]=1.[CH3:25][C@H:26]1[C:30](=[O:31])[NH:29][CH2:28][C@@H:27]1[C:32](O)=[O:33].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C)C=O.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:22])([F:21])[F:23])[CH:14]=3)=[CH:11][C:10]([NH:24][C:32]([C@@H:27]3[C@@H:26]([CH3:25])[C:30](=[O:31])[NH:29][CH2:28]3)=[O:33])=[N:9]2)=[CH:4][CH:3]=1
Reactant: Nc1cc(-c2cccc(OC(F)(F)F)c2)n(-c2ccc(F)cc2)n1
Reactant: C[C@H]1C(=O)NC[C@@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H]1C(=O)NC[C@@H]1C(=O)Nc1cc(-c2cccc(OC(F)(F)F)c2)n(-c2ccc(F)cc2)n1
Yield: 64.8 %

Procedure:
To a solution of 1-(4-fluorophenyl)-5-(3-(trifluoromethoxy)phenyl)-1H-pyrazol-3-ylamine (90 mg) in N,N-dimethylformamide (0.9 ml) were added (3R,4R)-4-methyl-5-oxopyrrolidine-3-carboxylic acid (50 mg) prepared in Preparation 1, HOBt.H2O (61 mg) and WSC.HCl (77 mg), and the mixture was stirred at room temperature for 2 hours. To this mixture were added water and a saturated aqueous solution of sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The separated organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel thin-layer chromatography (eluent: chloroform/methanol=10/1) to give the titled compound (80 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[C:15]3[C:11]([C:12]([NH2:17])=[N:13][NH:14]3)=[CH:10][CH:9]=2)[CH:5]=[C:4](S(C)(=O)=O)[N:3]=1.[CH3:22][NH:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[NH2:17][C:12]1[C:11]2[C:15](=[CH:16][C:8]([C:6]3[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([N:23]([CH3:22])[CH2:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:5]=3)=[CH:9][CH:10]=2)[NH:14][N:13]=1
Reactant: CNCCc1ccccc1
Reactant: CS(=O)(=O)c1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CN(CCc1ccccc1)c1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Temperature: 160 °C
Yield: 14.1 %

Procedure:
A mixture of 6-[2-amino-6-(methylsulfonyl)-4-pyrimidinyl]-1H-indazol-3-amine (300 mg, 0.99 mmol), N-methyl-2-phenylethanamine (300 mg, 2.22 mmol), and Hunig's base (2 mL) in NMP (3 mL) was heated for 2 hours at 160° C. for in a BiotageInitiator® microwave synthesizer. Upon cooling, the mixture was decanted to remove the solids, and the resulting solution was concentrated to dryness. The crude material was purified by RPHPLC to afford the title compound (50 mg) as a yellow solid. LC-MS (ES) m/z=360 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 2.85 (t, J=7.6 Hz, 2H), 3.0 (s, 3H), 3.76 (t, J=7.6 Hz, 2H), 5.37 (s, 2H), 6.04 (s, 2H), 6.39 (s, 1H), 7.19-7.23 (m, 1H), 7.30-7.32 (m, 4H), 7.53 (d, J=8.4 Hz, 1H), 7.71 (d, J=8.8 Hz, 1H), 7.91 (s, 1H), 11.50 (s, 1H).
Reaction SMILES: [CH:1]([C@H:4]1[CH2:8][N:7]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:6](=[O:18])[NH:5]1)([CH3:3])[CH3:2].Cl[C:20]1[CH:25]=[CH:24][N:23]2[N:26]=[CH:27][CH:28]=[C:22]2[N:21]=1>>[CH:1]([C@H:4]1[CH2:8][N:7]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:6](=[O:18])[N:5]1[C:20]1[CH:25]=[CH:24][N:23]2[N:26]=[CH:27][CH:28]=[C:22]2[N:21]=1)([CH3:3])[CH3:2]
Reactant: Clc1ccn2nccc2n1
Reactant: COc1ccc(CN2C[C@H](C(C)C)NC2=O)cc1
Product: COc1ccc(CN2C[C@H](C(C)C)N(c3ccn4nccc4n3)C2=O)cc1
Yield: 54.2 %

Procedure:
(S)-4-Isopropyl-1-(4-methoxybenzyl)-3-(pyrazolo[1,5-a]pyrimidin-5-yl)imidazolidin-2-one (0.386 g, 52%) was prepared by the procedure described in Example 1, Step 4, from (S)-4-isopropyl-1-(4-methoxybenzyl)imidazolidin-2-one (0.500 g, 2.01 mmol) and 5-chloropyrazolo[1,5-a]pyrimidine (0.300 g, 1.95 mmol). LCMS (APCI+) m/z 366 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH:4]=[C:5]1[CH2:9][CH2:8][O:7][C:6]1=[O:10])C.C(N)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:1]([NH:2][CH:4]=[C:5]1[CH2:9][CH2:8][O:7][C:6]1=[O:10])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CN(C)C=C1CCOC1=O
Reactant: NCc1ccccc1
Product: O=C1OCCC1=CNCc1ccccc1
Yield: 88.6 %

Procedure:
Alternatively, using the abovementioned method B and using 3-dimethylaminomethylenedihydrofuran-2-one (10 mmol) and benzylamine (10 mmol), 3-benzylaminomethylenedihydrofuran-2-one (1.80 g, efficiency: 89%) is produced in the form of a pale yellow powder.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>CN(C)C=O.C(OCC)(=O)C>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:3][CH:4]=1)#[N:7]
Reactant: CCOC(=O)CBr
Reactant: N#Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 23 h

Procedure:
To a solution of 4-hydroxy-benzonitrile (1 g, 8.395 mmol) in dimethylformamide (10 mL) were added potassium carbonate (2.321 g, 16.79 mmol) and ethyl bromoacetate (1.117 mL, 10.07 mmol), respectively. The reaction mixture was stirred at room temperature for 23 h. It was taken in ethyl acetate and diethyl ether (1:1 ratio), and the solid was filtered off. The filtrate was washed with water, brine and dried over anhydrous sodium sulfate. The solid was then filtered off, and the filtrate was concentrated in vacuo to afford ethyl (4-cyano-phenoxy)-acetate. It was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:20][C:21]3[O:22][C:23]4[C:28]([C:29](=[O:38])[C:30]=3[C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=3)=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:9]=[C:10]([C:11]3[CH:16]=[C:15]([O:17]C)[CH:14]=[C:13]([F:19])[CH:12]=3)[C:3]=12>ClCCl.B(Br)(Br)Br>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:20][C:21]3[O:22][C:23]4[C:28]([C:29](=[O:38])[C:30]=3[C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=3)=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:9]=[C:10]([C:11]3[CH:16]=[C:15]([OH:17])[CH:14]=[C:13]([F:19])[CH:12]=3)[C:3]=12
Reactant: COc1cc(F)cc(-c2nn(Cc3oc4ccccc4c(=O)c3-c3cccc(F)c3)c3ncnc(N)c23)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Nc1ncnc2c1c(-c1cc(O)cc(F)c1)nn2Cc1oc2ccccc2c(=O)c1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 45.1 %

Procedure:
To a solution of example 67 (0.080 g, 0.156 mmoles) in dichloromethane (15 ml), BBr3 (1M in dichloromethane, 0.8 ml) was added at 0° C. and the reaction mixture was warmed to RT and then stirred for 12 h. The reaction mixture was quenched with 1.5N HCl solution and extracted with dichloromethane. The organic layer was dried over sodium sulphate and concentrated. The crude product was purified by column chromatography with methanol:dichloromethane to afford the title compound as off-white solid (0.035 g, 45% yield). MP: 235-237° C. 1H-NMR (δ ppm, DMSO-D6, 400 MHz): δ 10.17 (s, 1H), 8.20 (s, 1H), 8.06 (dd, J=8.2, 1.6 Hz, 1H), 7.80 (m, 1H), 7.51 (m, 2H), 7.38 (q, J=7.8 Hz, 1H), 7.17-7.07 (m, 3H), 6.84 (t, J=1.7 Hz, 1H), 6.81 (td, J=79.3, 2.1 Hz, 1H), 6.66 (td, J=10.2, 2.2 Hz, 1H), 5.53 (s, 2H). Mass: 497.87 (M+).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][S:13][C:14]1[S:15][C:16]([C:21](=[O:23])[CH3:22])=[CH:17][C:18]=1[C:19]#[N:20].C(=O)(O)[O-].[Na+]>C(Cl)Cl.O>[CH3:12][S:13]([C:14]1[S:15][C:16]([C:21](=[O:23])[CH3:22])=[CH:17][C:18]=1[C:19]#[N:20])=[O:9]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1sc(C(C)=O)cc1C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(=O)c1cc(C#N)c(S(C)=O)s1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
5.0 g of 83% m-chloroperbenzoic acid are gradually added while stirring at a temperature of 0°-5° C. in 45 minutes to a solution of 5.0 g of 2-methylthio-3-cyano-5-acetylthiophene in 500 ml of methylene chloride. After stirring for another 30 minutes at 5° C., a saturated solution of sodium bicarbonate in approximately 50 ml of water is added; the reaction mixture is then stirred for 60 minutes. The organic layer is separated, washed with water and dried. After distilling off the solvent, the desired product is obtained in a yield of 4.6 g; melting-point 150° C.
Reaction SMILES: [CH:1]12[CH2:8][CH:4]([CH2:5][CH:6]1[OH:7])[CH2:3][NH:2]2.F[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>CCOC(C)=O>[N+:16]([C:13]1[CH:14]=[CH:15][C:10]([N:2]2[CH2:3][CH:4]3[CH2:8][CH:1]2[CH:6]([OH:7])[CH2:5]3)=[CH:11][CH:12]=1)([O-:18])=[O:17]
Reactant: OC1CC2CNC1C2
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(N2CC3CC(O)C2C3)cc1
Temperature: 65 °C
Reaction time: 4 h
Yield: 48.3 %

Procedure:
To a round bottom flask was added 2-azabicyclo[2.2.1]heptan-6-ol (150 mg, 1.326 mmol), 1-fluoro-4-nitrobenzene (187 mg, 1.326 mmol), K2CO3 (366 mg, 2.65 mmol) and DMF (5 mL). The reaction was stirred at 65° C. for 4 hrs. The reaction was then diluted with EtOAc (35 ml). The organic solution was washed with water (3×20 ml) and saturated aqueous NaCl (20 ml). The organic layer was dried over MgSO4, filtered and concentrated. The resulting residue was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-100% EtOAc/Hex to give the product, 2-(4-nitrophenyl)-2-azabicyclo[2.2.1]heptan-6-ol (150 mg, 0.640 mmol, 49% yield), as a yellow solid. Anal. Calcd. for C12H14N2O3 m/z 234.2, found: 235.2 (M+H)+; 1H NMR (500 MHz, CDCl3) δ ppm 8.10 (d, J=9.90 Hz, 2H), 6.49 (d, J=8.25 Hz, 2H), 4.10 (s, 1H), 3.99 (br. s., 1H), 3.39 (dt, J=8.80, 2.75 Hz, 1H), 2.78 (d, J=8.80 Hz, 1H), 2.74 (br. s., 1H), 1.97 (d, J=9.90 Hz, 1H), 1.92 (ddd, J=13.61, 7.01, 2.47 Hz, 1H), 1.78-1.71 (m, 2H), 1.59-1.53 (m, 1H); 13C NMR (126 MHz, CDCl3) δ ppm 151.32, 136.88, 126.54, 110.27, 71.10, 61.88, 54.11, 40.73, 35.91, 34.23.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=O)[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)[CH3:2].F[P-](F)(F)(F)(F)F.[NH2:30][N+:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1.CN1CCCC1=O.CN(CCN(C)C)C>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]([C:12]3[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=3)[CH:36]3[N:31]([N:32]=[CH:33][CH:34]=[CH:35]3)[N:30]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(C(=O)Cc2ccc(S(C)(=O)=O)cc2)cc1
Reactant: N[n+]1ccccn1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: CN(C)CCN(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: CCOc1ccc(C2=NN3N=CC=CC3C2c2ccc(S(C)(=O)=O)cc2)cc1
Reaction time: 1 h

Procedure:
Titanium tetrachloride (3.45 mL) was added to a stirred mixture of 1-(4-ethoxyphenyl)-2-(4-methanesulfonyl-phenyl)-ethanone (10.0 g), N-amino-pyridazinium hexafluorophosphate (7.95 g) in dichloromethane (150 mL) at about 20° C. N-Methyl-pyrrolidinone (3.0 mL) was added at about 20° C. TMEDA (6.7 mL) was then added over a period of about 4 hours at about 20° C. After stirring the mixture for about 1 hour, a second portion of TMEDA (12.3 mL) was added over about 20 minutes, and the reaction mixture was stirred at about 20° C. for about 16 hours.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)[N:13]=[C:12]2[C:24]1[CH:29]=[C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[N:27]=[C:26](S(C)(=O)=O)[N:25]=1.[NH2:44][C@@H:45]1[CH2:50][CH2:49][CH2:48][N:47]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:46]1>CN1C(=O)CCC1.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)[N:13]=[C:12]2[C:24]1[CH:29]=[C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[N:27]=[C:26]([NH:44][C@@H:45]2[CH2:50][CH2:49][CH2:48][N:47]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:46]2)[N:25]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Reactant: COc1ccc(COc2cc(-c3nn(C4CCCCO4)c4ccc(-c5c(F)cccc5F)cc34)nc(S(C)(=O)=O)n2)cc1
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1ccc(COc2cc(-c3nn(C4CCCCO4)c4ccc(-c5c(F)cccc5F)cc34)nc(N[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)n2)cc1
Temperature: 125 °C
Yield: 47.9 %

Procedure:
A glass microwave reaction vessel was charged with 5-(2,6-difluorophenyl)-3-(6-(4-methoxybenzyloxy)-2-(methylsulfonyl)pyrimidin-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (200 mg, 0.330 mmol) and (R)-tert-butyl 3-aminopiperidine-1-carboxylate (198 mg, 0.989 mmol) in NMP (2.0 mL). The reaction was stirred and heated in a Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 125° C. for 2 h. The mixture was diluted with water and the resulting suspension was filtered. The solid was washed with water and dried to give 115 mg of the crude product, which was used in the next step without further purification. MS (ESI, pos. ion) m/z: 727.1 (M+1).
Reaction SMILES: C([NH:4][N:5]1[CH2:10][C:9]([CH3:11])=[N:8][NH:7][C:6]1=[O:12])(=O)C.C([O-])(=O)C.[Na+]>Cl>[NH2:4][N:5]1[CH2:10][C:9]([CH3:11])=[N:8][NH:7][C:6]1=[O:12]
Reactant: CC(=O)NN1CC(C)=NNC1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Product: CC1=NNC(=O)N(N)C1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
A mixture of 1.7 g of 4-acetylamino-6-methyl-3-oxo-2,3,4,5-tetrahydro-1,2,4-triazine and 10 ml of 2N hydrochloric acid is stirred for 5 hours at 80° C. After cooling, 1.7 g of sodium acetate are added, and the mixture is concentrated by evaporation in vacuo at a bath temperature of 60° C. The residue is taken up in ethanol, and salt precipitates are filtered off. The filtrate is concentrated to a small volume and caused to crystallise. The title compound is obtained in the form of colourless crystals having a melting point of 116°-119° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([Cl:29])[C:5]2[C:6]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17][C:7]=3[N:8]([CH2:11][C:12](OCC)=[O:13])[C:9]=2[CH:10]=1.[Li+].[BH4-].[OH-].[Na+].CCOC(C)=O>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([Cl:29])[C:5]2[C:6]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[CH2:18][CH2:17][C:7]=3[N:8]([CH2:11][CH2:12][OH:13])[C:9]=2[CH:10]=1
Reactant: CCOC(=O)Cn1c2c(c3c(Cl)cc(Cl)cc31)CCN(C(=O)OC(C)(C)C)CC2
Agent: [BH4-]
Agent: [Li+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2c(n(CCO)c3cc(Cl)cc(Cl)c23)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 58.9 %

Procedure:
A solution of tert-butyl 8,10-dichloro-6-(2-ethoxy-2-oxoethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (3.0 g, 6.8 mmol) in dry THF (30 mL) was cooled to 0° C. Then, LiBH4 (0.74 g, 34 mmol) was added and the reaction was allowed to warm slowly to rt. After 24 h, the reaction was diluted with H2O (75 mL) followed by addition of 10% aqueous NaOH (30 mL) and extraction with EtOAc (3×100 mL). The combined organic extracts were washed with brine, dried over Na2SO4, decanted, and concentrated. The crude product was purified by column chromatography (Biotage, 40M, SIM) with heptane/EtOAc (1:1) followed by crystallization from EtOAc/heptane gave 1.6 g (58%) of a white solid: mp 166.5-167.0° C.; IR (diffuse reflectance) 3462, 1665, 1458, 1426, 1367, 1362, 1342, 1264, 1249, 1165, 1115, 1081, 931, 828, 820cm−1; MS (El) m/z 398 (M+), 398, 342, 341, 298, 270, 268, 258, 256, 57, 56; Anal. Calcd for C19H24Cl2N2O3: C, 57.15; H, 6.06; N, 7.01; found: C, 57.08; H, 6.08; N, 6.97.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[N:5][C:6]2[C:7](=[C:9]([NH2:14])[N:10]=[C:11]([NH2:13])[N:12]=2)[N:8]=1.[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>>[N:15]1([CH2:2][C:3]2[N:4]=[N:5][C:6]3[C:7](=[C:9]([NH2:14])[N:10]=[C:11]([NH2:13])[N:12]=3)[N:8]=2)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: C1CCNC1
Reactant: Nc1nc(N)c2nc(CCl)nnc2n1
Product: Nc1nc(N)c2nc(CN3CCCC3)nnc2n1
Temperature: 80 °C

Procedure:
A mixture of 3-Chloromethyl-pyrimido[5,4-e][1,2,4]triazine-5,7-diamine 3 (70 mg; 0.33 mmol) and 1.0 mL of pyrrolidine were heated to 80° C. in a sealed tube for 7 h. The mixture was then allowed to cool to room temperature and concentrated in vacuo. The crude product was purified by reverse phase HPLC (Rainin C18, 0% CH3CN to 30% CH3CN gradient, CH3CN/H2O, 0.1% TFA) and the bright yellow fractions containing the product were lyophilized after removal of CH3CN in vacuo to give 50 mg of yellow colored 3-Pyrrolidin-1-ylmethyl-pyrimido[5,4-e][1,2,4]triazine-5,7-diamine as the trifluoroacetate salt.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:13][O:12][C:11](=[O:14])[C:10]2[CH:15]=[C:16]([O:27][CH3:28])[CH:17]=[C:18]([O:19][Si](C(C)(C)C)(C)C)[C:9]=2[CH2:8][S:7][CH2:6][C@@H:5]([C:29]([O:31][CH3:32])=[O:30])[NH:4][C:3]1=[O:33].[CH2:34]([CH2:37][C:38](O)=[O:39])[CH:35]=[CH2:36]>>[C:38]([NH:1][C@H:2]1[CH2:13][O:12][C:11](=[O:14])[C:10]2[CH:15]=[C:16]([O:27][CH3:28])[CH:17]=[C:18]([OH:19])[C:9]=2[CH2:8][S:7][CH2:6][C@@H:5]([C:29]([O:31][CH3:32])=[O:30])[NH:4][C:3]1=[O:33])(=[O:39])[CH2:37][CH2:34][CH:35]=[CH2:36]
Reactant: COC(=O)[C@@H]1CSCc2c(O[Si](C)(C)C(C)(C)C)cc(OC)cc2C(=O)OC[C@H](N)C(=O)N1
Reactant: C=CCCC(=O)O
Product: C=CCCC(=O)N[C@H]1COC(=O)c2cc(OC)cc(O)c2CSC[C@@H](C(=O)OC)NC1=O

Procedure:
Methyl (4R, 7S)-7-amino-14-(tert-butyldimethylsilyloxy)-1,3,4,5,6,7,8,10-octahydro-12-methoxy-6,10-dioxo-9,2,5-benzoxathiaazacyciododecine-4-carboxylate was acylated with allylacetic acid in an analogues manner as described in Example 122 and the protection groups were subsequently cleaved off using the procedure described in Example 13 to yield methyl (4R,7S)-7-(pent-4-enoylamino)-1,3,4,5,6,7,8,10-octahydro-14-hydroxy-12-methoxy-6,10-dioxo-9,2,5-benzooxathiaazacyclododecine-4-carboxylate as a white solid.
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[CH3:19])[N:12]=[C:11]([CH3:20])[C:10]=2[C:21]([O:23]CC)=[O:22])=CC=1.[OH-].[Na+].O>C(O)(C(F)(F)F)=O.CCO>[NH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[CH3:19])[N:12]=[C:11]([CH3:20])[C:10]=1[C:21]([OH:23])=[O:22]
Reactant: CCOC(=O)c1c(C)nc2cccc(C)c2c1NCc1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CCO
Product: Cc1nc2cccc(C)c2c(N)c1C(=O)O
Temperature: 100 °C
Reaction time: 1 h
Yield: 90.1 %

Procedure:
Ethyl 4-(4-methoxybenzylamino)-2,5-dimethylquinoline-3-carboxylate (Example 12a, 0.563 g, 1.54 mmol) was dissolved in TFA (8 mL) and the resultant solution was stirred at room temperature for 15 minutes, TFA was then removed under vacuum to give the crude ethyl 4 product, which was dissolved in EtOH (4 mL). To this solution was added NaOH (4.0 N, 3.86 mL) and the reaction mixture was stirred at 100° C. for 1 hr. Water (25 mL) was added, and the solvent was decanted away from insoluble material then acidified with AcOH to pH 5.5. The precipitate was collected by filtration to give the title compound (300 mg, 90%) as a white solid. 1H NR (400 MHz, DMSO-d6) δ 2.78 (s, 3H), 2.88 (s, 3H), 7.30 (d, J=7.2 Hz, 1H), 7.58 (d, J=8.0 Hz, 1H), 7.65 (m, 1H), 7.8-8.0 (br, 1H), 12.2-12.9 (br, 2H). MS 217 (MH+).