Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[CH:15][N:16]([CH3:28])[C:17]=2[C:18]2[S:27][C:21]3[N:22]=[CH:23][N:24]=[C:25]([NH2:26])[C:20]=3[CH:19]=2)=[CH:9][CH:8]=1>C(Cl)Cl>[NH2:26][C:25]1[C:20]2[CH:19]=[C:18]([C:17]3[N:16]([CH3:28])[CH:15]=[N:14][C:13]=3[C:10]3[CH:11]=[CH:12][C:7]([OH:6])=[CH:8][CH:9]=3)[S:27][C:21]=2[N:22]=[CH:23][N:24]=1
Reactant: COc1ccc(-c2ncn(C)c2-c2cc3c(N)ncnc3s2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cn1cnc(-c2ccc(O)cc2)c1-c1cc2c(N)ncnc2s1
Temperature: 25 °C
Reaction time: 120 h
Yield: 71.4 %

Procedure:
Boron tribromide (1.0M in DCM) (10.1 mL) was added dropwise to 6-[4-(4-methoxyphenyl)-1-methyl-1H-imidazol-5-yl]thieno[2,3-d]pyrimidin-4-amine (Intermediate 107) (0.91 g) in DCM (20 mL) then stirred for 5 days at ambient temperature. The reaction mixture was concentrated in vacuo and the residue partitioned between DCM and water. The aqueous layer was separated and extracted with DCM (3×20 mL), the aqueous layer was then adjusted to pH 9 with concentrated aqueous NH3, the resultant solid filtered and dried in vacuo to give the title compound as a brown solid (623 mg, 71%);
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].[C:10](OC(=O)C)(=[O:12])[CH3:11]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:10](=[O:12])[CH3:11])[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(F)c(Cl)c1
Product: CC(=O)Nc1ccc(F)c(Cl)c1
Reaction time: 3 h
Yield: 98 %

Procedure:
Acetic anhydride (30 mL) was added at room temperature dropwise to 3-chloro-4-fluoroaniline (13.0 g, 0.1 mol) and stirred for 3 h. The reaction mixture was poured on ice (300 g) and the solid was filtered and dried to afford N-(3-chloro-4-fluorophenyl)acetamide (18.4 g, 98%) as a white solid. mp 96-97° C.; IR (KBr) 3303, 1671 cm-1 ; 1H NMR (CDCl3) δ 2.20 (s, 3H, CH3), 7.05 (t, J=8.9 Hz, 1H), 7.28 (m,1H), 7.66 (d, J=4.6 Hz, 1H), 8.05 (s, 1H, NH); Mass (m/z) 187 (M+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].[H-].[Na+].[CH2:13]([N:20]1[C:24]2[N:25]=[C:26]([NH2:30])[N:27]=[C:28](Cl)[C:23]=2[CH:22]=[CH:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN1C=CC=CC1=O>[CH2:13]([N:20]1[C:24]2[N:25]=[C:26]([NH2:30])[N:27]=[C:28]([O:10][C:3]3[C:4]([CH3:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=3[CH3:1])[C:23]=2[CH:22]=[CH:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Nc1nc(Cl)c2ccn(Cc3ccccc3)c2n1
Reactant: Cc1cc(C)c(O)c(C)c1
Agent: Cn1ccccc1=O
Agent: [H-]
Agent: [Na+]
Product: Cc1cc(C)c(Oc2nc(N)nc3c2ccn3Cc2ccccc2)c(C)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 76.5 %

Procedure:
To a solution of 2,4,6-trimethylphenol (161 mg, 1.16 mmol) in 1-methyl-2-pyridone (2 mL) in a sealed tube was added NaH (46 mg, 1.16 mmol). The reaction mixture was stirred at room temperature for 15 min and a solution of 7-benzyl-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine (100 mg, 0.39 mmol) in 1-methyl-2-pyridone (1 mL) was added to the mixture. The mixture was heated at 150° C. for 16 h and cooled to room temperature. The reaction mixture was poured into ice water and extracted with EtOAc (2×20 mL). The combined organic solution was washed with H2O (20 mL) and brine (20 mL), dried with Na2SO4, and concentrated to dryness. Silica gel chromatography (Hexanes:EtOAc=75:25) yielded 107 mg (77%) of 7-benzyl-4-(2,4,6-trimethyl-phenoxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7][C@@H:8]([CH2:12][CH:13]=[CH2:14])[C:9]([OH:11])=O)([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:17][C@@H:18]([CH:32]([CH3:34])[CH3:33])[C:19]([NH:21][C@@H:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:23][O:24][CH3:25])=[O:20]>>[CH3:25][O:24][CH2:23][C@@H:22]([NH:21][C:19]([C@@H:18]([NH:17][C:9]([C@H:8]([CH2:12][CH:13]=[CH2:14])[CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:15])=[O:11])[CH:32]([CH3:33])[CH3:34])=[O:20])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: C=CC[C@H](CC(=O)OC(C)(C)C)C(=O)O
Reactant: COC[C@@H](NC(=O)[C@@H](N)C(C)C)c1ccccc1
Agent: Cl
Product: C=CC[C@H](CC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)N[C@H](COC)c1ccccc1)C(C)C
Yield: 80 %

Procedure:
According to the method of Preparation 2, (2R)-2-[2-(tert-butoxy)-2-oxoethyl]pent-4-enoic acid (646 mg, 3.02 mmol) was reacted with (2S)-amino-N-[(1S)-2-methoxy-1-phenylethyl]-3-methylbutanamide hydrochloride (from b) above)(908 mg, 3.17 mmol) for 1 h at 4° C. and then 18 h at 20° C. The mixture was concentrated under reduced pressure, and partitioned between ethyl acetate (100 mL) and saturated aqueous sodium bicarbonate (100 mL). The layers were separated and aqueous layer extracted again with ethyl acetate (100 mL). The combined organic layers were dried (MgSO4), and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with dichloromethane:methanol 98:2) to give tert-butyl (3R)-3-({[({[(1S)-2-methoxy-1-phenylethyl]amino}carbonyl)-(1S)-2-methyl-1-propyl]amino}carbonyl)hex-5-enoate (1.08 g, 80%), as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[CH:13][N:14]3[CH2:17][C:18]([OH:20])=O)=[C:10]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH:27]1[CH2:32][CH2:31][NH:30][CH2:29][C:28]1=[O:33]>>[OH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[CH:13][N:14]3[CH2:17][C:18]([N:30]3[CH2:31][CH2:32][NH:27][C:28](=[O:33])[CH2:29]3)=[O:20])=[C:10]([N:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CNCCN1
Reactant: O=C(O)Cn1cnc2c(N3CCOCC3)nc(-c3cccc(O)c3)nc21
Product: O=C1CN(C(=O)Cn2cnc3c(N4CCOCC4)nc(-c4cccc(O)c4)nc32)CCN1

Procedure:
Crude 2-(2-(3-hydroxyphenyl)-6-morpholino-9H-purin-9-yl)acetic acid (50 mg) was reacted with piperazin-2-one via General Procedure F and purified via reverse phase HPLC to give 1.9 mg of 139 as a white solid. MS (Q1) 438.2 (M)+
Reaction SMILES: [C:1]([C:3](=[C:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[CH2:22]1C2C[CH:28](O)[CH:24]([CH2:25]2)[CH2:23]1.C([O-])([O-])=O.[Na+].[Na+]>>[C:1]([C:3](=[C:9]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]([O:6][C:7]12[CH2:28][CH:24]([CH2:23][CH2:22]1)[CH2:25][CH2:8]2)=[O:5])#[N:2]
Reactant: CCOC(=O)C(C#N)=C(c1ccccc1)c1ccccc1
Reactant: OC1CC2CCC1C2
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: N#CC(C(=O)OC12CCC(CC1)C2)=C(c1ccccc1)c1ccccc1
Reaction time: 4 h
Yield: 53.9 %

Procedure:
55.4 g (0.2 mol) of ethyl 2-cyano-3,3-diphenylacrylate (Uvinul 3035), 100 g of norborneol and 4 g of Na2CO3 were reacted with one another at about 185° C. with distillative removal of the ethanol formed, assisted by a stream of nitrogen. After about 4 h, the reaction mixture was filtered hot in order to remove the Na2CO3. After the filtrate had been cooled, the precipitate which had formed was filtered off, washed with cyclohexane and dried, giving 37 g (53%) of norbornyl 2-cyano-3,3-diphenylacrylate [λmax=304 nm, E11 =386] as a colorless solid.
Reaction SMILES: Cl.[O:2]1[C:11]2[CH:10]=[C:9]([CH2:12][NH:13][CH2:14][CH:15]3[CH2:19][CH2:18][NH:17][CH2:16]3)[N:8]=[CH:7][C:6]=2[O:5][CH2:4][CH2:3]1.C[O-].[Na+].CO.[F:25][C:26]1[CH:35]=[C:34]2[C:29]([CH:30]=[CH:31][C:32](=[O:39])[N:33]2[CH2:36][CH:37]=O)=[N:28][CH:27]=1.C([BH3-])#N.[Na+].C(=O)([O-])O.[Na+]>CO.C(OCC)(=O)C.C(O)(=O)C>[O:2]1[C:11]2[CH:10]=[C:9]([CH2:12][NH:13][CH2:14][CH:15]3[CH2:19][CH2:18][N:17]([CH2:37][CH2:36][N:33]4[C:34]5[C:29](=[N:28][CH:27]=[C:26]([F:25])[CH:35]=5)[CH:30]=[CH:31][C:32]4=[O:39])[CH2:16]3)[N:8]=[CH:7][C:6]=2[O:5][CH2:4][CH2:3]1
Reactant: c1nc(CNCC2CCNC2)cc2c1OCCO2
Reactant: O=CCn1c(=O)ccc2ncc(F)cc21
Agent: C[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=c1ccc2ncc(F)cc2n1CCN1CCC(CNCc2cc3c(cn2)OCCO3)C1
Reaction time: 0.5 h
Yield: 14.2 %

Procedure:
To a suspension of 0.10 g of 1-(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-yl)-N-(pyrrolidin-3-ylmethyl)methanamine hydrochloride in 5 mL of methanol, 0.17 g of a 28% sodium methoxide/methanol solution, 66 mg of (7-fluoro-2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehyde, 0.10 g of molecular sieves 3A, 33 μL of acetic acid and 18 mg of sodium cyanoborohydride were added at room temperature, and the mixture was stirred at the same temperature for 2 hours 30 minutes. To the reaction mixture, a saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, the resultant solution was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by basic silica gel column chromatography using an eluent of chloroform:methanol=30:1 to obtain 20 mg of 1-(2-(3-(((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)methyl)pyrrolidin-1-yl)ethyl)-7-fluoro-1,5-naphthyridin-2(1H)-one as a yellow oily substance.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:9][CH:8]=2)[CH:5]=[CH:4][N:3]1[C:20]1[CH:25]=[CH:24][C:23]([NH:26]C(=O)C)=[CH:22][CH:21]=1.Cl.N>C(O)C>[NH2:26][C:23]1[CH:22]=[CH:21][C:20]([N:3]2[CH:4]=[CH:5][N:6]([C:7]3[CH:12]=[CH:11][C:10]([O:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)=[CH:9][CH:8]=3)[C:2]2=[O:1])=[CH:25][CH:24]=1
Reactant: CC(=O)Nc1ccc(-n2ccn(-c3ccc(Oc4ccccc4)cc3)c2=O)cc1
Agent: Cl
Agent: N
Solvent: CCO
Product: Nc1ccc(-n2ccn(-c3ccc(Oc4ccccc4)cc3)c2=O)cc1

Procedure:
A solution of N-{4-[2-oxo-3-(4-phenoxyphenyl)-2,3-dihydroimidazol-1-yl]phenyl}acetamide (4.0 g) in ethanol (100 ml) was heated to reflux with hydrochloric acid (20% strength, 30 ml) for 16 hours. After cooling, ammonia solution (10% strength) was added until the reaction was basic. The precipitated solid was filtered off and dried in a vacuum oven at 40° C. The product with the molecular weight of 343.39 (C21H17N3O2); MS (ESI): 344 ([M+H]+) was obtained in this way.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[CH:4]=[CH:3]1.CC([O-])(C)C.[K+].[SiH:17]([CH2:22][CH3:23])([CH2:20][CH3:21])[CH2:18][CH3:19]>O1CCCC1>[CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[CH:4]=[C:3]1[Si:17]([CH2:22][CH3:23])([CH2:20][CH3:21])[CH2:18][CH3:19]
Reactant: CC[SiH](CC)CC
Reactant: Cn1ccc2cccnc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)c1cc2cccnc2n1C
Yield: 72.2 %

Procedure:
The reaction was conducted according to the General Procedure by heating N-methyl-1H-pyrrolo[2,3-b]pyridine (66 mg, 0.5 mmol, 1 equiv.), KOt-Bu (11 mg, 0.1 mmol, 0.2 equiv.) and Et3SiH (239 microliters, 1.5 mmol, 3 equiv.) in 1 mL of tetrahydrofuran for 45 hours at 35° C. After aqueous work up, the crude reaction mixture was purified by chromatography on silica using step gradient elution (starting with 100% hexanes and increasing the polarity of the eluent stepwise to 30% EtOAc in Hexanes) to obtain 89 mg (73%) of the title compound as a pale yellow oil. 1H NMR (500 MHz, THF-d8) δ 8.45-7.95 (m, 1H), 7.97-7.66 (m, 1H), 6.95 (dd, J=7.7, 4.6 Hz, 1H), 6.68 (s, 1H), 3.94 (s, 2H), 1.05-1.00 (m, 9H), 0.97 (td, J=7.1, 1.7 Hz, 6H). 13C NMR (126 MHz, THF-d8) δ 150.95, 142.87, 137.82, 127.38, 120.13, 114.79, 110.76, 30.27, 6.74, 3.31. HRMS: [C14H23N2Si] calculated 247.1642, measured 247.1631. The HSQC spectrum of this reaction product as provided in FIG. 10.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:8]([NH:15][C@H:16]([C:19](O)=[O:20])[CH2:17][OH:18])([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]>>[C:11]([O:10][C:8](=[O:9])[NH:15][C@@H:16]([CH2:19][OH:20])[C:17]([N:5]1[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]1)=[O:18])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Reactant: OC1CCNCC1
Product: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)N1CCC(O)CC1

Procedure:
4-Hydroxypiperidine (6.7 mmol) and Boc-L-serine (6.4 mmol) were coupled according to Procedure A (60 hour reaction time) with the following workup: the reaction mixture was concentrated, the residue dissolved in chloroform and 1N NaOH (6 mL), and the resulting solution extracted repeatedly (ten or mor times) with chloroform. The chloroform extracts were concentrated and the residue purified by chromatography on silica gel eluted with 1-16% ethanol in dichloromethane. Yield 751 mg, 41%; HPLC (40/60) 2.72 minutes (96%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCO[CH2:17][CH2:16]1>O.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH:16]([C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH2:1])[CH:7]=1)=[CH2:17]
Reactant: C1COCCO1
Reactant: Nc1cc(Cl)ncn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Product: C=Cc1cc(N)ncn1
Temperature: 100 °C
Yield: 80 %

Procedure:
A mixture of 4-amino-6-chloropyrimidine (2.5 g, 19.2 mmol), 1,1′-bis(diphenylphosphino)ferrocene palladium dichloride (810 mg, 1.2 mmol), sodium carbonate (8.14 g, 76.8 mmol) and vinyl borane pinacol ester (3.9 mL, 23 mmol) in dioxane (11.5 mL) and water (11.5 mL) under nitrogen, was heated at 100° C. for 20 hours then cooled to ambient temperature. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (0-10% methanol in DCM) to afford the title compound as a yellow solid (1.87 g, 80% yield). 1H NMR (300 MHz, DMSO-d6): δ 8.30 (s, 1H), 6.83 (s, 2H), 6.57 (dd, J=17.2, 10.5 Hz, 1H), 6.36 (s, 1H), 6.26 (dd, J=17.2, 2.1 Hz, 1H), 5.48 (dd, J=10.5, 2.1 Hz, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N+:12]([O-])=O)[C:3]1=[O:15].O.O.[Sn](Cl)Cl.O1CCCC1>>[NH2:12][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[CH:10]=[CH:11][N:2]([CH3:1])[C:3]2=[O:15]
Reactant: Cn1ccc2c([N+](=O)[O-])cccc2c1=O
Agent: Cl[Sn]Cl
Solvent: C1CCOC1
Solvent: O
Product: Cn1ccc2c(N)cccc2c1=O

Procedure:
2-Methyl-5-nitro-2H-isoquinolin-1-one (0.69 g, 0.0032 mol) and tin dichloride dihydrate (2 g, 0.01 mol) were stirred in tetrahydrofuran (10 mL, 0.1 mol) at room temperature overnight. The mixture was purified via flash chromatography (40 g of silica gel, 50% EtOAc/Hexanes) to give a brown solid. MS m/z (M+H) 174.9.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)[CH:3]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[O:25])=[CH:19][C:18]=1[C:26]([F:29])([F:28])[F:27]>C1COCC1.CCOC(C)=O.C([O-])(O)=O.[Na+].O>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:15]=[CH:14][C:12]([NH:13][C:24]([NH:23][C:20]3[CH:21]=[CH:22][C:17]([Cl:16])=[C:18]([C:26]([F:28])([F:27])[F:29])[CH:19]=3)=[O:25])=[CH:11][CH:10]=2)[CH:3]=1
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: Nc1ccc(Oc2cc(Cl)ncn2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(Oc2cc(Cl)ncn2)cc1)Nc1ccc(Cl)c(C(F)(F)F)c1

Procedure:
To a solution of 4-(6-chloro-pyrimidin-4-yl-oxy)-aniline (Stage 21.1; 3.77 g, 15 mmol) in THF (40 ml) under N2-atmosphere, 4-chloro-3-trifluoromethylphenyl isocyanate (4.98 g, 22.5 mmol) dissolved in THF (20 ml) is added. After 1 h at rt the solution is diluted with AcOEt and NaHCO3 in water, the aqueous layer separated off and extracted twice with AcOEt. The organic phases are washed with water and brine, dried (Na2SO4) and concentrated in vacuo. Stirring of the resulting solid in Et2O finally yields the title compound: m.p.: 180-181° C.; 1H-NMR (DMSO-d6): 9.22 (s, HN), 8.97 (s, HN), 8.65 (s, 1H), 8.11 (s, 1H), 7.65 (m, 1H), 7.63 (m, 1H), 7.53 (d, 2H), 7.34 (s, 1H), 7.19 (d, 2H); Anal.: CHNClFO.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:12][C:13]([CH:15]3[CH2:17][CH2:16]3)=[O:14])[N:8]=[CH:9]2)=[CH:4][CH:3]=1.O1CCCC1.C[CH2:24][O:25][C:26]([C@@H:28](O)[CH3:29])=[O:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C(OCC)(=O)C>[CH:15]1([C:13]([NH:12][C:7]2[N:8]=[CH:9][C:10]3[C:5]([CH:6]=2)=[CH:4][CH:3]=[C:2]([O:1][C@H:28]([CH3:29])[C:26]([O:25][CH3:24])=[O:27])[CH:11]=3)=[O:14])[CH2:16][CH2:17]1
Reactant: O=C(Nc1cc2ccc(O)cc2cn1)C1CC1
Reactant: CCOC(=O)[C@H](C)O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H](C)Oc1ccc2cc(NC(=O)C3CC3)ncc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-(7-hydroxyisoquinolin-3-yl)cyclopropanecarboxamide (68.7 mg, 0.301 mmol) in tetrahydrofuran (3.0 mL, 37 mmol) was added ethyl L-(−)-lactate (44 uL, 0.39 mmol) and triphenylphosphine (108.4 mg, 0.4133 mmol), followed by dropwise addition of diethyl azodicarboxylate (62 uL, 0.39 mmol). The resulting mixture was stirred at room temperature for 1 hour, and then ethyl L-(−)-lactate (13 uL, 0.11 mmol) and diethyl azodicarboxylate (19 uL, 0.12 mmol) were added. After an additional 2.5 hours, the reaction mixture was poured into ethyl acetate, washed with water and brine, dried over MgSO4, filtered, and evaporated in vacuo. The crude material was purified via flash chromatography on silica gel (12 g silica, solvent gradient: 0-80% ethyl acetate in heptanes) to provide a quantitative yield of (R)-methyl 2-(3-(cyclopropanecarboxamido)isoquinolin-7-yloxy)propanoate. LCMS (ESI): M+H=329.2.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:23]=[C:24](OCC)[C:25]=1F)[CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[CH:18]=[N:19][CH:20]=[N:21][CH:22]=2)=[O:16])[CH2:10][CH2:9]1)[CH3:2].[CH2:30]([O:32]C1C=C(C=CC=1OC)C=O)C.C([BH3-])#N.[Na+].C(N(C(C)C)C(C)C)C>C(O)C.C(O)(=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][C:25]=1[O:32][CH3:30])[CH2:7][N:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]([C:17]2[CH:18]=[N:19][CH:20]=[N:21][CH:22]=2)=[O:16])[CH2:12][CH2:13]1)[CH3:2]
Reactant: CCOc1cc(CN2CCC(NC(=O)c3cncnc3)CC2)cc(OCC)c1F
Reactant: CCOc1cc(C=O)ccc1OC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Solvent: CC(=O)O
Product: CCOc1cc(CN2CCC(NC(=O)c3cncnc3)CC2)ccc1OC

Procedure:
In analogy to the procedure described in example 50k), pyrimidine-5-carboxylic acid piperidin-4-ylamide (example 56) was reacted with 3-ethoxy-4-methoxy-benzaldehyde, sodium cyanoborohydride, N-ethyl-diisopropylamine and acetic acid in ethanol at 50° C. to yield the title compound as colorless solid. MS: 371.1 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([N:28]5[CH2:33][C@H:32]([CH3:34])[NH:31][C@H:30]([CH3:35])[CH2:29]5)[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1.Br[CH2:37][CH2:38]F.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([N:28]5[CH2:33][C@H:32]([CH3:34])[N:31]([CH2:37][CH3:38])[C@H:30]([CH3:35])[CH2:29]5)[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1
Reactant: FCCBr
Reactant: C[C@@H]1CN(c2ccc3c(n2)-c2sc(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)C[C@H](C)N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCN1[C@H](C)CN(c2ccc3c(n2)-c2sc(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)C[C@@H]1C
Temperature: 120 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
A mixture of 2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene (150 mg, 0.3 mmol), 1-Bromo-2-fluoro-ethane (65 mg, 0.45 mmol) and Cesium carbonate (200 mg, 0.6 mmol) in N,N-Dimethyl-formamide (2 mL) was stirred at 120° C. for 1 h under the irradiation of microwave. The reaction mixture was filtered over celite and purified by pre-TLC (Hexanes/EtOAc=1:1) to afford 314 Yield=56%. 1H NMR (CDCl3, 400 MHz): δ8.02 (s, 1 H), 7.49-7.46 (m, 1 H), 7.11-6.97 (m, 4 H), 6.45 (d, J=8.8 Hz, 1 H), 4.18 (t, J=4.8 Hz, 2 H), 3.86 (d, J=11.6 Hz, 2 H), 3.07 (t, J=4.8 Hz, 2H), 2.96 (q, J1=7.2 Hz, J2=5.2 Hz, 2 H), 2.64-2.51 (m, 4 H), 1.13 (d, J=6.0 Hz, 6 H), 0.88-0.81 (m, 3H). ESI− MS: m/z=523 [M+H+]
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([S:8](Cl)(=[O:10])=[O:9])[CH2:4][CH2:3]1.[C@H:12]1([NH:21][C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[C:27]([NH2:32])[CH:28]=3)[N:23]=2)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13]1>>[C@H:12]1([NH:21][C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[C:27]([NH:32][S:8]([N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)(=[O:10])=[O:9])[CH:28]=3)[N:23]=2)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13]1
Reactant: CN1CCN(S(=O)(=O)Cl)CC1
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Product: CN1CCN(S(=O)(=O)Nc2ccc3nc(N[C@@H]4CCc5ccccc54)ccc3c2)CC1

Procedure:
The title compound was prepared in accordance with the general method described in example 66 from 4-methyl-piperazine-1-sulfonyl chloride and (R)—N2-indan-1-yl-quinoline-2,6-diamine; MS: m/e=438.8 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][S:7][C:8]=1[N:9]1[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:10]1)([O-])=O.[In].[NH4+].[Cl-].N#N>CCO>[NH2:1][C:4]1[CH:5]=[N:6][S:7][C:8]=1[N:9]1[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:19])[CH3:21])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2sncc2[N+](=O)[O-])C1
Agent: N#N
Agent: [Cl-]
Agent: [In]
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2sncc2N)C1
Yield: 87.8 %

Procedure:
tert-butyl ((3S)-1-(4-amino-5-isothiazolyl)-3-piperidinyl) carbamate. A 30 mL Bohdan microwave vessel was charged with tert-butyl ((3S)-1-(4-nitro-5-isothiazolyl) -3-piperidinyl)carbamate (672 mg, 2.05 mmol), EtOH (11 mL), indium powder (963 mg, 8.39 mmol, Aldrich), 4.1 M aqueous NH4Cl (4.99 mL, 20.46 mmol) and a stirbar. The vessel was swept with N2, and crimped with a PTFE-lined seal. The vessel was placed into a 120° C. heat transfer block for 1.5 h. The vessel was briefly cooled, and de-pressurized by inserting a 25 gauge needle through the PTFE septa. The crimp-seal was removed, and the slurry was N2-pressure filtered warm through a 10 mL Bohdan glass frit fitted with a 0.22 μm PTFE, 25 mm syringe filter unit (Millipore, SLFG025NK). The solids were washed with hot EtOH (3×5 mL), and discarded. The filtrate and washes were combined and concentrated under a stream of N2. The residue was suspended in H2O (50 mL), and extracted with CHCl3 (5×20 mL). The combined extracts were washed with H2O (2×20 mL), and treated with MgSO4. The resulting slurry was vacuum filtered through a fine glass frit. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (9/1 CHCl3/THF) to afford tert-butyl ((3S)-1-(4-amino-5-isothiazolyl)-3-piperidinyl)-carbamate (536 mg, 1.80 mmol, 88% yield). MS (ESI, pos. ion) m/z: 299.0 (M+1). 1H NMR (400 MHz, CDCl3) δ ppm 1.45 (s, 9 H) 1.48-1.56 (m, 1 H) 1.67-1.79 (m, 1 H) 1.79-1.92 (m, 2 H) 2.76 (dd, J=11.05, 7.14 Hz, 1 H) 2.85-2.95 (m, 1 H) 2.95-3.05 (m, 1 H) 3.18-3.47 (m, 3 H) 3.84 (br. s., 1 H) 4.82 (br. s., 1 H) 8.02 (s, 1 H).
Reaction SMILES: [CH3:1][N:2]([CH3:9])[CH2:3][CH2:4][CH2:5][NH:6][CH2:7][CH3:8].[C:10](Cl)(=[O:26])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>C(Cl)Cl>[CH3:1][N:2]([CH3:9])[CH2:3][CH2:4][CH2:5][N:6]([CH2:7][CH3:8])[C:10](=[O:26])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: CCNCCCN(C)C
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCC(=O)N(CC)CCCN(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N,N-dimethyl-N'-ethyl-1,3-propanediamine (1.18 g, 9.06 mmole) in methylene chloride (20 mL) was added palmitoyl chloride (2.20 g, 8.00 mmole) dropwise. The reaction mixture was stirred at room temperature overnight.