Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Zn]CC)C.[Si:6]([O:23][CH2:24][C@@H:25]1[CH2:29][CH:28]=[CH:27][N:26]1[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])([C:19]([CH3:22])([CH3:21])[CH3:20])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.ClCI>C1(C)C=CC=CC=1>[Si:6]([O:23][CH2:24][C@@H:25]1[CH2:29][CH:28]2[CH:27]([CH2:1]2)[N:26]1[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])([C:19]([CH3:21])([CH3:22])[CH3:20])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1C=CC[C@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: CC[Zn]CC
Agent: ClCI
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1C2CC2C[C@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: -25 °C
Reaction time: 18.5 h
Yield: 90.8 %

Procedure:
Diethylzinc (19 mL of ˜1.1 M in toluene, 21 mmol) was added dropwise over 15 min to a cooled (−30° C.) toluene (27 mL) solution of (S)-tert-butyl 2-((tert-butyldiphenylsilyloxy)methyl)-2,3-dihydro-1H-pyrrole-1-carboxylate (3.94 g, 9.0 mmol). Chloroiodomethane (stabilized over copper; 3.0 mL, 41 mmol) was added dropwise over 10 min and stirred while maintaining the bath temperature at −25° C. for 1 h and between −25° C. and −21° C. for 18.5 h. The reaction mixture was opened to the air and quenched by the slow addition of 50% saturated NaHCO3 solution (40 mL) and then removed from the cooling bath and stirred at ambient temperature for 20 min. The reaction mixture was filtered through a filter paper and the white cake was washed with 50 mL of toluene. The organic phase of the filtrate was separated and washed with water (40 mL, 2×), dried (MgSO4) and concentrated in vacuo. The crude material was purified using by silica gel chromatography (350 g silica gel; sample was loaded with 7% EtOAc/hexanes; eluted with 7-20% EtOAc/hexanes) to afford (3S)-tert-butyl 3-((tert-butyldiphenylsilyloxy)methyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (3.69 g, 90.7%) as a mixture of cis/trans-isomers. [Note: the exact cis/trans-isomer ratio was not determined at this stage]. LC-MS: [M+Na]+=474.14. Rt=2.39 min under the following HPLC conditions: Solvent gradient from 100% A: 0% B to 0% A: 100% B (A=0.1% TFA in 1:9 MeOH/water; B=0.1% TFA in 9:1 MeOH/water) over 2 min and hold for 1 min; detection at 220 nm; PHENOMENEX® Luna 3.0×50 mm S10 column. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.62-7.60 (m, 4H), 7.49-7.40 (m, 6H), 3.77/3.67 (overlapping br s, 3H), 3.11-3.07 (m, 1H), 2.23 (app br s, 1H), 2.05-2.00 (m, 1H), 1.56-1.50 (m, 1H), 1.33 (very broad s, 9H), 1.00 (s, 9H), 0.80 (m, 1H), 0.30 (m, 1H).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([NH2:20])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:21]([O:23][C:24]1[CH:25]=[C:26]([CH2:35][C:36](O)=[O:37])[CH:27]=[CH:28][C:29]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH3:22]>>[CH2:21]([O:23][C:24]1[CH:25]=[C:26]([CH2:35][C:36]([NH:20][CH:7]([CH2:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:37])[CH:27]=[CH:28][C:29]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH3:22]
Reactant: NC(CC1CCCC1)c1ccccc1N1CCCCC1
Reactant: CCOC(=O)c1ccc(CC(=O)O)cc1OCC
Product: CCOC(=O)c1ccc(CC(=O)NC(CC2CCCC2)c2ccccc2N2CCCCC2)cc1OCC

Procedure:
Prepared analogously to Example 19 from α-cyclopentylmethyl-2-piperidino-benzylamine and 3-ethoxy-4-ethoxycarbonyl-phenyl-acetic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:13])([CH3:12])[C:7](=[O:14])[C:6]([C:15]([NH:17][CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])=[O:16])=[C:5]2[OH:26]>C(O)(C(F)(F)F)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:13])([CH3:12])[C:7](=[O:14])[C:6]([C:15]([NH:17][CH2:18][C:19]([OH:21])=[O:20])=[O:16])=[C:5]2[OH:26]
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2cc(F)ccc2C(C)(C)C1=O
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)C(=O)C(C(=O)NCC(=O)O)=C(O)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.9 %

Procedure:
A mixture of 1,1-dimethylethyl N-((6-fluoro-4-hydroxy-1,1-dimethyl-2-oxo-naphthalen-3-yl)carbonyl)glycinate (0.6 g, 2 mmol) in 3 mL TFA was stirred at room temperature for 30 minutes. The mixture was concentrated and triturated in ether 20 mL. The solid was filtered, washed with 10 mL ether, and dried under high vacuum to give 0.46 g of the product as an off-white solid. MS m/e=308 (M+H)+. Calculated for C15H14FNO5 307.09.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[Li]CCCC.[C:17]1(=[O:22])[O:21][CH2:20][CH2:19][CH2:18]1.[NH4+].[Cl-]>C1COCC1.CCCCCC>[OH:22][CH2:17][CH2:18][CH2:19][C:20]([C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1)=[O:21]
Reactant: O=C1CCCO1
Reactant: Brc1ccc2ccccc2c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(CCCO)c1ccc2ccccc2c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a cooled (−78° C.) solution of 2-bromonaphthalene (10.77 g) in THF (150 ml) was added n-BuLi in hexane (1.65M, 36 ml) and the mixture was stirred at −78° C. for 30 minutes. To the solution was added γ-butyrolactone (25 ml) and the mixture was stirred at −78° C. for 1 minute. Aqueous solution of NH4Cl was added and the mixture was extracted with ethyl acetate. The extract was washed with aqueous NH4Cl solution, water and brine, dried and concentrated. The residue was chromatographed on silica gel (hexane:ethyl acetate=3:1) followed by recrystallization from cyclohexane-ethyl acetate to give the titled compound (6.71 g) as a colorless solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:16](=[O:18])[CH3:17])[CH:10]=2)[N:3]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[NH2:24]>CCOC(C)=O>[CH3:31][O:30][C:26]1[CH:25]=[C:23]([NH:24][C:2]2[CH:7]=[N:6][CH:5]=[C:4]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:16](=[O:18])[CH3:17])[CH:10]=3)[N:3]=2)[CH:22]=[C:21]([O:20][CH3:19])[C:27]=1[O:28][CH3:29]
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: CC(=O)Nc1cccc(Oc2cncc(Cl)n2)c1
Solvent: CCOC(C)=O
Product: COc1cc(Nc2cncc(Oc3cccc(NC(C)=O)c3)n2)cc(OC)c1OC
Yield: 35 %

Procedure:
Using Method EE with 2-chloro-6-(3-acetamidophenyl-oxy)-pyrazine (150 mg, 0.57 mmol) and 3,4,5-trimethoxyaniline (125 mg, 0.68 mmol), and crystallisation (AcOEt), the title compound was obtained (81 mg). Yield: 35%. 1H NMR (250 MHz, DMSO-d6) δ 2.03 (s, 3H, CH3—NH), 3.44 (s, 6H, [CH3O]3+5), 3.56 (s, 3H, [CH3O]4), 6.80 (s, 2H, Harom2′+6′), 6.82-6.87 (m, 1H, Harom 5), 7.31-7.49 (m, 2H, Harom 4+6), 7.50 (s, 1H, Harom 2), 7.76 (s, 1H, HPz 5), 7.97 (s, 1H, HPz 3), 9.55 (s, 1H, NH), 10.04 (s, 1H, NH). m/z: 411.2 [(M+H)+, calcd for C21H22N4O5 410.2].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+]([O-])=O)[CH:5]=[C:4]([Cl:11])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:18]([OH:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN1C(=O)CCC1>[CH2:18]([O:25][C:6]1[CH:7]=[C:2]([Cl:1])[N:3]=[C:4]([Cl:11])[CH:5]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=[N+]([O-])c1cc(Cl)nc(Cl)c1
Reactant: OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Clc1cc(OCc2ccccc2)cc(Cl)n1
Temperature: 90 °C

Procedure:
A mixture of 2,6-dichloro-4-nitropyridine (1.0 equiv.), potassium carbonate (2 equiv.) and benzyl alcohol (2.4 equiv.) in NMP (4 M) were heated to 90° C. for 2 h in the microwave. The mixture was partitioned between water and EtOAc. The organic phase was washed with brine and dried over sodium sulfate. The solution was concentrated and dried under vacuo to give crude 4-(benzyloxy)-2,6-dichloropyridine and was used in the next step without further purification. LCMS (m/z) (M+H)=254.0/256.0, Rt=1.05 min.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=[O:11])=[CH:2]1.[C:13]([O-])(=[O:15])[CH3:14].[Na+]>C(OC(=O)C)(=O)C>[C:13]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=[O:11])=[CH:2]1)(=[O:15])[CH3:14]
Reactant: CC(=O)[O-]
Reactant: O=C(O)c1c[nH]c2ccccc12
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)n1cc(C(=O)O)c2ccccc21
Temperature: 110 °C
Reaction time: 16 h
Yield: 33.7 %

Procedure:
1H-Indole-3-carboxylic acid (400 mg) and sodium acetate (0.96 g) were suspended in acetic anhydride (4.8 ml). The mixture was stirred at 110° C. for 16 hours and extracted with chloroform. The organic phase was washed with 2 N hydrochloric acid, dried over sodium sulfate anhydrous, and concentrated under reduced pressure. The residue was purified by column chromatography (eluting solvent; dichloromethane:methanol 50:1) to give the title compound (170 mg, Y.:34%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]#[N:18])=[CH:10][C:9]=1[NH:19][C:20](=[O:36])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[O:34][N:33]=[C:32]([CH3:35])[CH:31]=2)[CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:15][N:14]([CH3:16])[C:12]1[C:11]([C:17]#[N:18])=[CH:10][C:9]2[NH:19][C:20](=[O:36])[CH2:21][C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]4[O:34][N:33]=[C:32]([CH3:35])[CH:31]=4)[CH:25]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C#N)c(N(C)C)cc3NC(=O)OC(C)(C)C)c2)on1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2cccc(C3=Nc4cc(N(C)C)c(C#N)cc4NC(=O)C3)c2)on1

Procedure:
The title compound was prepared from (4-cyano-5-dimethylamino-2-{3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionylamino}-phenyl)-carbamic acid tert-butyl ester (Example M85) (0.31 g, 0.62 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (171 mg, 72%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[CH:18]=[O:19]>>[F:1][C:2]1[C:3]([CH:18]([C:9]2[CH:10]=[CH:11][C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:8]=2)[OH:19])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc2ccccc2c1
Reactant: Fc1cccnc1
Product: OC(c1ccc2ccccc2c1)c1ncccc1F

Procedure:
In the manner as described in Production example 1 while using 5.2 mL of 3-fluoropyridine and 10.2 g of 2-naphthaldehyde as starting materials, 3.8 g of the title compound was obtained as pale yellow needle crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH2:11][CH:12](C)C)[N:10]=1)[C:5]([OH:7])=[O:6].[C:15](B1OB(C(C)=C)OB(C(C)=C)O1)(C)=C>>[CH:11]([C:9]1[CH:8]=[C:4]([CH:3]=[C:2]([CH3:1])[N:10]=1)[C:5]([OH:7])=[O:6])([CH3:12])[CH3:15]
Reactant: C=C(C)B1OB(C(=C)C)OB(C(=C)C)O1
Reactant: Cc1cc(C(=O)O)cc(CC(C)C)n1
Product: Cc1cc(C(=O)O)cc(C(C)C)n1

Procedure:
The title compound is prepared in analogy to 2-methyl-6-(2-methyl-propyl)-isonicotinic acid using 2,4,6-triisopropenyl-cyclotriboroxane; LC-MS: tR=0.23 min; [M+1]+=180.44.
Reaction SMILES: O[CH2:2][C:3]1[CH:19]=[CH:18][CH:17]=[CH:16][C:4]=1[CH2:5][O:6][C:7]1[C:8]([N+:13]([O-:15])=[O:14])=[N:9][CH:10]=[CH:11][CH:12]=1.S(Cl)([Cl:22])=O>ClCCl>[Cl:22][CH2:2][C:3]1[CH:19]=[CH:18][CH:17]=[CH:16][C:4]=1[CH2:5][O:6][C:7]1[C:8]([N+:13]([O-:15])=[O:14])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=[N+]([O-])c1ncccc1OCc1ccccc1CO
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: O=[N+]([O-])c1ncccc1OCc1ccccc1CCl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-(2-hydroxymethylbenzyloxy)-2-nitropyridine (4.09 g) in dichloromethane (40 ml) was added thionyl chloride (0.24 ml) and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure to give 3-(2-chloromethylbenzyloxy)-2-nitropyridine (4.10 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](OS(C(F)(F)F)(=O)=O)[C:5]([F:16])=[C:4]([C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1.[CH3:22][S-:23].[Na+]>COCCOC>[F:16][C:5]1[C:4]([C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)=[N:3][C:2]([NH2:1])=[N:7][C:6]=1[S:23][CH3:22]
Reactant: C[S-]
Reactant: Nc1nc(OS(=O)(=O)C(F)(F)F)c(F)c(-c2ccco2)n1
Agent: [Na+]
Solvent: COCCOC
Product: CSc1nc(N)nc(-c2ccco2)c1F
Yield: 36.1 %

Procedure:
A stirred solution of 260 mg (0.80 mmol) trifluoromethanesulfonic acid 2-amino-5-fluoro-6-furan-2-yl-pyrimidin-4-yl ester and 560 mg (7.99 mmol) sodium methanethiolate in 10 ml dry DME under argon was heated at 50° C. for 2 hours. The reaction mixture was then concentrated in vacuo. Flash chromatography (ethyl acetate/hexane 1/2) followed by trituration in ether/hexane afforded 65 mg (36%) 5-fluoro-4-furan-2-yl-6-methylsulfanyl-pyrimidin-2-ylamine as a white crystalline solid. EI-MS m/e (%): 225 (M+, 100), 180 (28).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][C:5]1[C:6]([CH3:21])=[N:7][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)[C:9]=1[CH3:10]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:22])[CH2:4][C:5]1[C:6]([CH3:21])=[N:7][N:8]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([NH2:18])=[CH:16][CH:17]=2)[C:9]=1[CH3:10]
Reactant: COC(=O)Cc1c(C)nn(Cc2ccc([N+](=O)[O-])cc2)c1C
Agent: [Pd]
Solvent: CO
Product: COC(=O)Cc1c(C)nn(Cc2ccc(N)cc2)c1C

Procedure:
To a solution of [3,5-dimethyl-1-(4-nitro-benzyl)-1H-pyrazol-4-yl]-acetic acid methyl ester (intermediate 1.1.2, 3.90 g, 10.3 mmol) in methanol (10 mL) was added 10% palladium on charcoal (500 mg) and the mixture was hydrogenated. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The mixture was purified via preparative reversed phase HPLC (gradient of methanol in water+0.1% NH3).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14](=[O:39])[CH:15]([C:30]2[CH:35]=[CH:34][C:33]3[O:36][CH2:37][O:38][C:32]=3[CH:31]=2)[O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25][CH3:26])=[O:24])=[CH:19][C:18]=2[CH2:27][CH2:28][CH3:29])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:40][Si]([NH-])(C)C.C[Si]([NH-])(C)C.[Li+].[Li+].IC>C1COCC1>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14](=[O:39])[C:15]([C:30]2[CH:35]=[CH:34][C:33]3[O:36][CH2:37][O:38][C:32]=3[CH:31]=2)([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25][CH3:26])=[O:24])=[CH:19][C:18]=2[CH2:27][CH2:28][CH3:29])[CH3:40])(=[O:12])=[O:11])=[CH:8][CH:9]=1)([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)[NH-]
Reactant: CCCc1cc(C(=O)OC)ccc1OC(C(=O)NS(=O)(=O)c1ccc(C(C)C)cc1)c1ccc2c(c1)OCO2
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CCCc1cc(C(=O)OC)ccc1OC(C)(C(=O)NS(=O)(=O)c1ccc(C(C)C)cc1)c1ccc2c(c1)OCO2
Temperature: -78 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
To a solution of 0.516 g (0.93 mmol) of the product of Example 57 dissolved in 1.0 mL of anhydrous THF was added 2.80 mL (2.80 mmol) of a 1.0M solution of lithim bis(trimethylsilylamide) in THF at -78° C. under a nitrogen atmosphere. The reaction mixture was magnetically stirred at -78° C. for 1 hour, then 174 μL (2.80 mmol) of iodomethane was added via syringe. The reaction was allowed to warm to room temperature and was stirred an additional 14 hours. The reaction was next quenched with excess 10% aqueous NaHSO4 and partitioned between EtOAc and water. The organic layer was washed with saturated aqueous NaCl, dried (MgSO4), filtered and evaporated. The residue was purified on a silica gel flash chromatography column eluted with CHCl3 --MeOH--NH4OH (90:10:1). Evaporation of the purified fractions and drying in vacuo afforded 0.293 g (55%) of the title compound as an amorphous solid.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C@@H:9]1[CH2:11][C@H:10]1[C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[O:19][CH2:20][CH:21]1[CH2:23][CH2:22]1)(C)(C)C.C(OCC)C.[ClH:30]>>[ClH:30].[CH:21]1([CH2:20][O:19][C:13]2[CH:14]=[CH:15][C:16]([F:18])=[CH:17][C:12]=2[C@@H:10]2[CH2:11][C@H:9]2[CH2:8][NH2:7])[CH2:23][CH2:22]1
Reactant: CC(C)(C)OC(=O)NC[C@@H]1C[C@H]1c1cc(F)ccc1OCC1CC1
Agent: Cl
Solvent: CCOCC
Product: NC[C@@H]1C[C@H]1c1cc(F)ccc1OCC1CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 91.5 %

Procedure:
The protected amine 11 (5.8 g, 17.3 mmol) was dissolved in a 2 N HCl solution in diethyl ether (43 mL, 86 mmol), and the reaction mixture was stirred at ambient temperature for 48 h. A white precipitate formed after several hours, and the mixture was stirred until the reaction was complete by TLC. The crude precipitate was filtered and purified by recrystallization from ethanol/Et2O to afford the title compound as a white powder (4.3 g, 91.5% yield). HPLC purity: 12.0 min, 99.8%. 1H NMR (400 MHz, MeOD) δ 6.86-6.70 (m, 3H), 3.91-3.78 (m, 2H), 3.04 (d, J=7.2 Hz, 2H), 2.18-2.12 (m, 1H), 1.32-1.28 (m, 1H), 1.16-1.02 (m, 2H), 0.64-0.62 (m, 2H), 0.39-0.37 (m, 2H). 13C NMR (100 MHz, MeOD) δ 158.6 (d, 1 J CF=236.9 Hz), 155.4, 132.7 (d, 3 J CF=7.6 Hz), 114.5, 114.2, 114.2, 114.0, 114.0, 75.1, 45.2, 19.8, 18.4, 13.4, 11.4, 4.0, 3.6. MS (ESI) m/z 236.2 [MH+].
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].[F:8][CH:9]([F:37])[CH2:10][NH:11][C:12]1[N:13]=[C:14]2[CH2:36][CH2:35][NH:34][CH2:33][C:15]2=[N:16][C:17]=1[N:18]1[CH2:23][CH2:22][CH:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[F:32])[CH2:20][CH2:19]1.CCN(C(C)C)C(C)C.[CH3:47][S:48](Cl)(=[O:50])=[O:49]>C(Cl)Cl.CN(C=O)C>[F:37][CH:9]([F:8])[CH2:10][NH:11][C:12]1[N:13]=[C:14]2[CH2:36][CH2:35][N:34]([S:48]([CH3:47])(=[O:50])=[O:49])[CH2:33][C:15]2=[N:16][C:17]=1[N:18]1[CH2:19][CH2:20][CH:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[F:32])[CH2:22][CH2:23]1.[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: Fc1ccc(OC2CCN(c3nc4c(nc3NCC(F)F)CCNC4)CC2)c(F)c1
Reactant: CS(=O)(=O)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CS(=O)(=O)N1CCc2nc(NCC(F)F)c(N3CCC(Oc4ccc(F)cc4F)CC3)nc2C1

Procedure:
A solution of N-(2,2-difluoroethyl)-3-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine TFA salt (17 mg, 0.032 mmol), DIPEA (12.2 mg, 0.095 mmol) and methanesulfonyl chloride (4.9 μL, 0.063 mmol) in DCM (315 μL) was stirred at room temperature overnight. The crude reaction mixture was diluted in DMF, filtered through a hydrophilic PTFE 0.45 μm filter (Millipore® Millex-LCR), and purified via HPLC Method A to give the title compound as a TFA salt (6 mg) as a clear oil. 1H NMR (400 MHz, methanol-d4) δ ppm 1.92-2.02 (m, 2H), 2.09-2.18 (m, 2H), 2.88 (t, J=5.9 Hz, 2H), 2.93 (s, 3H), 3.00 (ddd, J=12.4, 8.8, 3.3 Hz, 2H), 3.34-3.42 (m, 2H), 3.57 (t, J=5.9 Hz, 2H), 3.78 (td, J=14.5, 4.3 Hz, 2H), 4.28 (s, 2H), 4.46 (tt, J=7.5, 3.6 Hz, 1H), 5.89-6.22 (m, 1H), 6.84-6.91 (m, 1H), 6.98 (ddd, J=11.4, 8.6, 3.0 Hz, 1H), 7.17 (td, J=9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]+ 504.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]=[N:8][CH:7]=[C:6]2[CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH2:20][CH:19]([CH2:23][N:24]2[C:30](=[O:31])[CH2:29][C:28]3[CH:32]=[C:33]([O:38][CH3:39])[C:34]([O:36][CH3:37])=[CH:35][C:27]=3[CH:26]=[CH:25]2)[CH2:18]1.[H][H]>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]=[N:8][CH:7]=[C:6]2[CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH2:20][CH:19]([CH2:23][N:24]2[C:30](=[O:31])[CH2:29][C:28]3[CH:32]=[C:33]([O:38][CH3:39])[C:34]([O:36][CH3:37])=[CH:35][C:27]=3[CH2:26][CH2:25]2)[CH2:18]1
Reactant: [H][H]
Reactant: COc1cc2c(cc1OC)CC(=O)N(CC1CCCN(CCc3cncc4cc(OC)c(OC)cc34)C1)C=C2
Agent: [Pd]
Solvent: CCO
Product: COc1cc2c(cc1OC)CC(=O)N(CC1CCCN(CCc3cncc4cc(OC)c(OC)cc34)C1)CC2

Procedure:
Prepared from 3-[(N-(2-(6,7-dimethoxy-isoquinol-4-yl)-ethyl)-piperidin-3-yl)-methyl]-7,8-dimethoxy-2-oxo-1,3-dihydro-2H-3benzazepine by hydrogenation at 5 bar hydrogen pressure with 10% palladium/charcoal in ethanol at 70° C. analogously to Example 5.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][C:13]([CH3:31])([C:15]2[N:19]([CH3:20])[C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:30])([F:29])[F:28])=[N:17][N:16]=2)[CH3:14])=[C:6]([CH:11]=1)[C:7]([NH:9][NH2:10])=[O:8].C(N(CC)CC)C.Cl[C:40](=O)[C:41]([O:43][CH2:44][CH3:45])=[O:42].O>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][C:13]([CH3:31])([C:15]2[N:19]([CH3:20])[C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:29])([F:28])[F:30])=[N:17][N:16]=2)[CH3:14])=[C:6]([C:7]2[O:8][C:40]([C:41]([O:43][CH2:44][CH3:45])=[O:42])=[N:10][N:9]=2)[CH:11]=1
Reactant: CCOC(=O)C(=O)Cl
Reactant: Cn1c(-c2ccccc2C(F)(F)F)nnc1C(C)(C)Oc1ccc(Cl)cc1C(=O)NN
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1nnc(-c2cc(Cl)ccc2OC(C)(C)c2nnc(-c3ccccc3C(F)(F)F)n2C)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-chloro-2-(1-methyl-1-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}ethoxy)benzohydrazide (782 mg) was dissolved in THF (10 ml), and triethylamine (0.510 ml) was added thereto, followed by ice-cooling. Ethyl chloro(oxo)acetate (0.200 ml) was added thereto, followed by stirring at room temperature overnight. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was washed with diisopropylether. The resulting solid (650 mg) was dissolved in dichloromethane (10 ml), and pyridine (0.385 ml) was added thereto, followed by cooling to −78° C. Trifluoromethanesulfonic anhydride (0.385 ml) was added to the reaction solution and was elevated to room temperature, followed by stirring for 30 minutes. Saturated aqueous sodium bicarbonate was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was then evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=100:1). The resulting solid was washed with diisopropylether, to obtain, as a yellowish white solid, ethyl 5-[5-chloro-2-(1-methyl-1-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}ethoxy)phenyl]-1,3,4-oxadiazole-2-carboxylate (240 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH:4]([CH2:13][CH2:14][CH:15]=[CH2:16])[N:5]=CC1C=CC=CC=1.Cl.O>C(OCC)C>[CH3:1][O:2][C:3](=[O:17])[CH:4]([CH2:13][CH2:14][CH:15]=[CH2:16])[NH2:5]
Reactant: C=CCCC(N=Cc1ccccc1)C(=O)OC
Agent: Cl
Solvent: O
Solvent: CCOCC
Product: C=CCCC(N)C(=O)OC
Reaction time: 2 h

Procedure:
Dissolve N-(phenylmethylene)-2-(3-butenyl)glycine methy ester (25 g) in ethyl ether (400 mL) and stir with 1N hydrochloric acid (150 mL) and water (150 mL). Place under an argon atmosphere and stir for 2 hours. Separate the aqueous phase and adjust to pH 9, extract into chloroform, dry and evaporate the solvent in vacuo to give the title compound as a light oil (4.5 g).
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH:19]=[CH:20][C:21]4[N:30]=[C:29]5[C:24]([CH2:25][CH2:26][C:27](=[O:31])[NH:28]5)=[CH:23][CH:22]=4)[CH2:12][CH2:11]3)[CH:7]=[CH:6][CH:5]=2)[CH2:3][CH2:2]1>C1COCC1.[Pd]>[CH:1]1([C:4]2[N:9]=[C:8]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]4[N:30]=[C:29]5[C:24]([CH2:25][CH2:26][C:27](=[O:31])[NH:28]5)=[CH:23][CH:22]=4)[CH2:12][CH2:11]3)[CH:7]=[CH:6][CH:5]=2)[CH2:2][CH2:3]1
Reactant: O=C1CCc2ccc(C=CCCCN3CCN(c4cccc(C5CC5)n4)CC3)nc2N1
Agent: [Pd]
Solvent: C1CCOC1
Product: O=C1CCc2ccc(CCCCCN3CCN(c4cccc(C5CC5)n4)CC3)nc2N1
Yield: 82.6 %

Procedure:
7-{5-[4-(6-Cyclopropyl-pyridin-2-yl)-piperazin-1-yl]-pent-1-enyl}-3,4-dihydro-1H-[1,8]naphthyridin-2-one (0.347 g, 0.831 mmol) was hydrogenated using 20% Pd/C in THF for 15 h. The reaction was filtered and concentrated. Recrystallization from hot CH3CN gave the title compound as a white powder (288 mg, 0.686 mmol, 83%). MS: APCI: M+1: 420.3 (Exact Mass: 419.27).