Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[CH2:3]([C:7]1[N:8]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]([OH:36])=[O:35])=[CH:24][CH:23]=2)[C:9]([C:16]([O:18]CC)=[O:17])=[C:10]([S:12][CH2:13][CH2:14][F:15])[N:11]=1)[CH2:4][CH2:5][CH3:6]>C(O)C>[CH2:3]([C:7]1[N:8]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]([OH:36])=[O:35])=[CH:26][CH:27]=2)[C:9]([C:16]([OH:18])=[O:17])=[C:10]([S:12][CH2:13][CH2:14][F:15])[N:11]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCc1nc(SCCF)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCc1nc(SCCF)c(C(=O)O)n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Reaction time: 72 h

Procedure:
2.25 cm3 of a 2N solution of sodium hydroxide is added at ambient temperature to 450 mg of the product obtained in Example 43 dissolved in 10 cm3 of ethanol, then the mixture is left for 3 days. The solvents are evaporated under reduced pressure, the residue is taken up in water, 2.25 cm3 of hydrochloric acid 2M/l is added. The precipitate formed is filtered, washed with water, dried under reduced pressure and 380 mg of expected product is obtained which is recrystallized from isopropanol. M.p.=185°-186° C.
Reaction SMILES: [CH2:1]([C:3]1([CH2:29][CH3:30])[N:12]2[CH2:13][CH2:14][C:15]3[C:20]([C:11]2=[C:10]([CH3:24])[C:9]2[CH:8]=[CH:7][C:6]([O:25][CH3:26])=[C:5]([O:27][CH3:28])[C:4]1=2)=[CH:19][C:18]1[O:21][CH2:22][O:23][C:17]=1[CH:16]=3)[CH3:2].[BH4-].[Na+]>CO>[CH2:29]([C:3]1([CH2:1][CH3:2])[N:12]2[CH2:13][CH2:14][C:15]3[C:20]([CH:11]2[CH:10]([CH3:24])[C:9]2[CH:8]=[CH:7][C:6]([O:25][CH3:26])=[C:5]([O:27][CH3:28])[C:4]1=2)=[CH:19][C:18]1[O:21][CH2:22][O:23][C:17]=1[CH:16]=3)[CH3:30]
Reactant: CCC1(CC)c2c(ccc(OC)c2OC)C(C)=C2c3cc4c(cc3CCN21)OCO4
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCC1(CC)c2c(ccc(OC)c2OC)C(C)C2c3cc4c(cc3CCN21)OCO4
Temperature: 0 °C
Reaction time: 2 h
Yield: 42 %

Procedure:
To a solution of 8,8-diethyl-9,10-dimethoxy-13-methyl-5,8-dihydro-6H-[1,3]dioxolo[4,5-g]isoquino[3,2-a]isoquinoline (100 mg, 0.25 mmol) in methanol (10 mL) was added sodium borohydride (23 mg, 0.61 mmol) in small portions at 0° C. After stirring at 0° C. for 2 h, the mixture was concentrated in vacuo. The resulting residue was extracted with diethyl ether (2×50 mL), washed with water (2×25 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was re-crystallized from methanol to afford 8,8-diethyl-9,10-dimethoxy-13-methyl-5,8,13,13a-tetrahydro-6H-[1,3]dioxolo[4,5-g]isoquino[3,2-a]isoquinoline (43 mg, 42%). LC/MS m/e calcd for C25H31NO4 (M+H)+: 410.53, observed: 410.2; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.48 (t, J=7.33 Hz, 3 H) 0.75 (d, J=6.82 Hz, 3 H) 0.85 (t, J=7.58 Hz, 3 H) 1.77-1.89 (m, 1 H) 1.94-2.06 (m, 1 H) 2.10-2.22 (m, 1 H) 2.23-2.36 (m, 1 H) 2.53-2.63 (m, 1 H) 2.64-2.74 (m, 1 H) 3.02 (dd, J=6.69, 2.91 Hz, 1 H) 3.16-3.26 (m, 1 H) 3.74 (s, 3 H) 3.80 (s, 3 H) 4.52 (s, 1 H) 5.94 (d, J=6.32 Hz, 2 H) 6.66 (s, 1 H) 6.79 (s, 1 H) 6.85 (d, J=8.59 Hz, 1 H) 6.96 (d, J=8.34 Hz, 1 H).
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[CH:15]=[CH:14][N:13]=[C:12]([N:16]([CH3:35])[CH2:17][C:18]4[CH:23]=[N:22][CH:21]=[C:20]5[N:24](COCC[Si](C)(C)C)[CH:25]=[CH:26][C:19]=45)[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O.[NH4+].[OH-]>O1CCCC1>[NH:24]1[C:20]2=[CH:21][N:22]=[CH:23][C:18]([CH2:17][N:16]([CH3:35])[C:12]3[N:11]=[C:10]([NH:9][C:6]4[CH:5]=[C:4]([CH:1]5[CH2:2][CH2:3]5)[NH:8][N:7]=4)[CH:15]=[CH:14][N:13]=3)=[C:19]2[CH:26]=[CH:25]1
Reactant: CN(Cc1cncc2c1ccn2COCC[Si](C)(C)C)c1nccc(Nc2cc(C3CC3)[nH]n2)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CN(Cc1cncc2[nH]ccc12)c1nccc(Nc2cc(C3CC3)[nH]n2)n1
Temperature: 80 °C
Yield: 22.7 %

Procedure:
A mixture of N4-(5-cyclopropyl-1H-pyrazol-3-yl)-N2-methyl-N2-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)methyl)pyrimidine-2,4-diamine (108 mg, 0.22 mmol) and tetrabutyl ammonium fluoride (580 mg, 2.2 mmol) in tetrahydrofuran (20 mL) was heated at 80° C. for 18 h. The reaction mixture was poured into water (100 mL) and the pH was adjusted to ca. 10 by adding an NH4OH solution. The mixture was extracted with EtOAc (50 mL×3) and the combined extracts dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC to afford 18 mg (22.7%) of N2-((1H-pyrrolo[2,3-c]pyridin-4-yl)methyl)-N4-(5-cyclopropyl-1H-pyrazol-3-yl)-N2-methylpyrimidine-2,4-diamine as a white solid. 1H NMR (500 MHZ, MeOD-d4) δ 8.62 (s, 1H), 7.82 (d, 2H), 7.59 (d, 1H), 6.59 (d, 1H), 6.12 (d, 1H), 5.84 (brs, 1H), 5.13 (s, 2H), 3.03 (s, 3H), 1.58 (brs, 1H), 0.68 (d, 2H), 0.27 (d, 2H); MS (ESI): m/z=361.2 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](F)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[Cl:12].[NH2:13][CH2:14][CH:15]1[CH2:30][CH2:29][CH2:28][C:17]2([O:21][C:20](=[O:22])[N:19]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:18]2)[CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>CC#N>[Br:1][C:2]1[C:3]([Cl:12])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH:13][CH2:14][CH:15]2[CH2:30][CH2:29][CH2:28][C:17]3([O:21][C:20](=[O:22])[N:19]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[CH2:18]3)[CH2:16]2)[CH:7]=1
Reactant: CC(C)(C)CN1CC2(CCCC(CN)C2)OC1=O
Reactant: O=[N+]([O-])c1cc(Cl)c(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)CN1CC2(CCCC(CNc3cc(Br)c(Cl)cc3[N+](=O)[O-])C2)OC1=O
Reaction time: 18 h
Yield: 44.3 %

Procedure:
A rt suspension of 1-bromo-2-chloro-5-fluoro-4-nitrobenzene (0.600 g, 2.36 mmol) in MeCN (8 mL) was treated with 7-(aminomethyl)-3-neopentyl-1-oxa-3-azaspiro[4.5]decan-2-one (0.400 g, 1.57 mmol) and potassium carbonate (0.543 g, 3.93 mmol). The reaction was stirred for 18 h, and the solids were filtered off and washed with EtOAc. The filtrate was concentrated and purified on a 40 g silica gel column (0-100% DCM/hexanes, 20 min gradient; 100% DCM, 15 min; 40 mL/min elution; 254 nm detection) to provide the title compound (0.340 g, 44% yield) as an orange solid. MS (m/z) 488.1, 490.1 (M+H+).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[Br:10][C:11]1[CH:36]=[CH:35][C:14]([CH2:15][C:16]23[CH2:23][CH2:22][CH2:21][N:20]2[C:19](=[O:24])[N:18]([C:25]2[CH:30]=[C:29]([Cl:31])[C:28]([OH:32])=[C:27]([Cl:33])[CH:26]=2)[C:17]3=[O:34])=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:15][C:16]23[CH2:23][CH2:22][CH2:21][N:20]2[C:19](=[O:24])[N:18]([C:25]2[CH:30]=[C:29]([Cl:31])[C:28]([O:32][CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[C:27]([Cl:33])[CH:26]=2)[C:17]3=[O:34])=[CH:35][CH:36]=1
Reactant: CCOC(=O)CCCBr
Reactant: O=C1N(c2cc(Cl)c(O)c(Cl)c2)C(=O)C2(Cc3ccc(Br)cc3)CCCN12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1c(Cl)cc(N2C(=O)N3CCCC3(Cc3ccc(Br)cc3)C2=O)cc1Cl
Temperature: 80 °C
Yield: 89.2 %

Procedure:
Ethyl 4-bromobutyrate (28 mg) was added to a mixture of the compound from Example 135 (55 mg) and K2CO3 (18 mg) in 2 mL anhydrous DMF and the resulting mixture was heated at 80° C. for 5 hours. The solution was partitioned between EtOAc/H2O. The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by preparative TLC to yield the titled compound (61 mg). MS (m/z) 583 (MH+).
Reaction SMILES: [C:1]1([C@H:7]2[C@H:16]3[CH2:17][CH2:18][N:19]([C:20]([C@H:22]4[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]4[NH:28][C:29]([C:31]4[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=4[C:33]([OH:35])=O)=[O:30])=[O:21])[C@H:15]3[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.CCOC(OC(OCC)=O)=O.O>CN(C=O)C>[C:1]1([C@H:7]2[C@H:16]3[CH2:17][CH2:18][N:19]([C:20]([C@H:22]4[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]4[N:28]4[C:33](=[O:35])[C:32]5[C:31](=[CH:39][CH:38]=[CH:37][CH:36]=5)[C:29]4=[O:30])=[O:21])[C@H:15]3[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[NH:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1ccccc1C(=O)N[C@@H]1CCCC[C@@H]1C(=O)N1CC[C@@H]2[C@H](c3ccccc3)Nc3ccccc3[C@@H]21
Agent: CCOC(=O)OC(=O)OCC
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C([C@H]1CCCC[C@H]1N1C(=O)c2ccccc2C1=O)N1CC[C@@H]2[C@H](c3ccccc3)Nc3ccccc3[C@@H]21
Temperature: 25 °C
Reaction time: 4 h
Yield: 82.2 %

Procedure:
To a solution of the compound (70 mg, 0.13 mmol) of Example 123 and triethylamine (20.9 μl, 0.15 mmol) in DMF (5 ml) was added DEPC (24.5 μl, 0.15 mmol) under ice-cooling, and the mixture was stirred at room temperature for 4 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate, the extract was washed with saturated brine and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography and eluted with hexane-ethyl acetate (3:1-1:1, v/v) to give the title compound (54 mg, 71%) as a white solid.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[CH:10]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:15]([CH3:18])([O-:17])=[O:16].C([O-])(=O)C.[NH4+].[BH4-].[Na+]>O.C(O)(=O)C>[N+:15]([CH2:18][CH2:10][C:9]1[CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:14]=[CH:13][CH:12]=1)([O-:17])=[O:16]
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1cccc(-c2ccccc2)c1
Agent: CC(=O)[O-]
Agent: [BH4-]
Agent: [NH4+]
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])CCc1cccc(-c2ccccc2)c1
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 69.7 %

Procedure:
To a mixture of 3-phenyl-benzaldehyde (430 mg, 2.4 mmol) described in Manufacturing Example 85-1-1 and acetic acid (7 mL) were added nitromethane (0.95 mL, 18 mmol) and ammonium acetate (540 mg, 7.1 mmol), which was stirred for 2.5 hours at 100° C. The reaction mixture was cooled to room temperature, and water was added at the same temperature, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. A mixture of dimethyl sulfoxide (9.3 mL) and acetic acid (0.62 mL) was added to the resulting residue, and sodium borohydride (140 mg, 3.8 mmol) was added to the reaction mixture at room temperature while cooling appropriately. The reaction mixture was stirred for 10 minutes at the same temperature. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and was concentrated under a reduced pressure. The resulting residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=5:1) to obtain the title compound (380 mg, 71%).
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH:6]=[N:5][C:4]([CH2:8][CH2:9][CH3:10])=[C:3]1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1.[CH3:26][C:27]1([CH3:39])[CH2:31][C:30]2[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][C:29]=2[O:28]1.C(N(CC)CC)C.N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(OCC)(=O)C.C(Cl)Cl>[CH3:26][C:27]1([CH3:39])[CH2:31][C:30]2[CH:32]=[C:33]([N:7]3[C:2](=[O:1])[C:3]([CH2:11][C:12]4[CH:17]=[CH:16][C:15]([C:18]5[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=5)=[CH:14][CH:13]=4)=[C:4]([CH2:8][CH2:9][CH3:10])[N:5]=[CH:6]3)[CH:34]=[CH:35][C:29]=2[O:28]1
Reactant: CCCc1nc[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CC1(C)Cc2cc(B(O)O)ccc2O1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCc1ncn(-c2ccc3c(c2)CC(C)(C)O3)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 51.6 %

Procedure:
A mixture of 4′-[(6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.02 g), (2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)boronic acid (0.78 g), molecular sieves 4 A (1.98 g), triethylamine (1.7 mL), pyridine (1.0 mL), copper(II) acetate (0.65 g) and methylene chloride (15 mL) was stirred at room temperature for 24 hr. Ethyl acetate was added to the reaction mixture, and the insoluble solid was filtered off. The solvent of the filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.76 g, 54%).
Reaction SMILES: [CH3:1][O-:2].[Na+].[NH2:4][C:5]1[N:6]=[C:7](Cl)[C:8]([C:11]#[N:12])=[N:9][CH:10]=1>O1CCOCC1>[NH2:4][C:5]1[N:6]=[C:7]([O:2][CH3:1])[C:8]([C:11]#[N:12])=[N:9][CH:10]=1
Reactant: N#Cc1ncc(N)nc1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1nc(N)cnc1C#N
Temperature: 90 °C
Yield: 32.9 %

Procedure:
Sodium methoxide (70 mg, 1.29 mmol) was added to a stirred solution of 5-amino-3-chloropyrazine-2-carbonitrile (100 mg, 0.647 mmol) in dioxane (1 mL). The reaction mixture was heated in a sealed tube at 90° C. overnight. The solvent was removed in vacuo, and the residue was partitioned between water and ethyl acetate. The aqueous layer was re-extracted with ethyl acetate. The combined organic layers were washed with brine, dried (Na2SO4) and concentrated to give the title compound (32 mg, 0.213 mmol, 33%). LC-MS (3) Rt=0.96 min; m/z (ESI+) 151 (M+H+).
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]1[CH2:18][CH:17]([N:19]2[CH2:24][C@H:23]([CH3:25])[O:22][C@H:21]([CH3:26])[CH2:20]2)[CH2:16]1)=O)(C)(C)C>>[NH:15]1[CH2:18][CH:17]([N:19]2[CH2:24][C@H:23]([CH3:25])[O:22][C@H:21]([CH3:26])[CH2:20]2)[CH2:16]1
Reactant: C[C@@H]1CN(C2CN(C(=O)OC(C)(C)C)C2)C[C@H](C)O1
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1CN(C2CNC2)C[C@H](C)O1

Procedure:
4-Azetidin-3-yl-2,6-(cis)-dimethyl-morpholine was prepared as a TFA salt from 3-(2,6-(cis)-Dimethyl-morpholin-4-yl)-azetidine-1-carboxylic acid tert-butyl ester following General Procedure H.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:21])=[CH:4][C:5]([O:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=2[F:20])=[C:6]([CH:10]=1)[C:7]([OH:9])=O>CCOC(C)=O>[Br:1][C:2]1[C:3]([F:21])=[CH:4][C:5]2[O:11][C:12]3[C:17](=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=3[F:20])[C:7](=[O:9])[C:6]=2[CH:10]=1
Reactant: COc1ccc(Oc2cc(F)c(Br)cc2C(=O)O)c(F)c1
Solvent: CCOC(C)=O
Product: COc1cc(F)c2oc3cc(F)c(Br)cc3c(=O)c2c1
Temperature: 140 °C
Reaction time: 0.25 h
Yield: 74.1 %

Procedure:
To a flaske charged with polyphosphoric acid (396 g, 4038 mmol) was added 5-bromo-4-fluoro-2-(2-fluoro-4-methoxyphenoxy)benzoic acid (58 g, 162 mmol) and the viscous mixture was heated at 140° C. for 2 hours. The viscous solution was cooled slightly and diluted with ice-water (1 L). After 15 min of stirring, EtOAc (1 L) was added and the aqueous fraction extracted with EtOAc (3×200 mL). The combined organic fractions were dried over sodium sulfate and concentrated. The solids were washed with 6 N NaOH, then water. The solids were then sequentially triturated with methanol and ethyl acetate. The resulting solid was dried under vacuum to afford 2-bromo-3,5-difluoro-7-methoxy-9H-xanthen-9-one (41 g, 120 mmol, 74.4% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:14]([O:15][CH3:16])=[CH:13][C:6]2[CH2:7][C:8](=[O:12])[NH:9][CH:10]=[CH:11][C:5]=2[CH:4]=1.CC(C)([O-])C.[K+].[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29]Cl)[CH:24]=1>CS(C)=O>[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][N:9]2[C:8](=[O:12])[CH2:7][C:6]3[CH:13]=[C:14]([O:15][CH3:16])[C:3]([O:2][CH3:1])=[CH:4][C:5]=3[CH:11]=[CH:10]2)[CH:24]=1
Reactant: COc1cc2c(cc1OC)CC(=O)NC=C2
Reactant: ClCc1cccnc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1cc2c(cc1OC)CC(=O)N(Cc1cccnc1)C=C2
Reaction time: 1 h

Procedure:
2.2 g (0.01 mol) of 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one are suspended in 10 ml of dimethyl-sulphoxide and 1.12 g (0.01 mol) of potassium tert.but-oxide are added with stirring. After 60 minutes, 1.3 g (0.01 mol) of 3picolylchloride dissolved in 10 ml of dimethylsulphoxide are added dropwize to the resulting solution with stirring. After 1 hour it is poured onto ice water. The aqueous phase is extracted twice with ethyl acetate. The combined organic phases are washed with water, dried over magnesium sulphate, concentrated by evaporation in vacuo and purified over 200 g of aluminium oxide (neutral, activity II-III) with methylene chloride and then with increasing quantities of methanol (up to 0.8%). Yield: 1.4 g (45.2% of theory), Melting point: 144°-146° C.
Reaction SMILES: Br[C:2]1[C:3]([NH2:22])=[N:4][CH:5]=[C:6]([CH:8]2[CH2:13][CH2:12][CH2:11][CH:10]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH2:9]2)[N:7]=1.[CH2:23]([NH:30][C:31]([C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][C:34]=1[F:42])=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.COCCOC.C([O-])([O-])=O.[Na+].[Na+]>CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[NH2:22][C:3]1[C:2]([C:36]2[CH:37]=[CH:38][C:33]([C:31]([NH:30][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[O:32])=[C:34]([F:42])[CH:35]=2)=[N:7][C:6]([CH:8]2[CH2:13][CH2:12][CH2:11][CH:10]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH2:9]2)=[CH:5][N:4]=1
Reactant: O=C(NCc1ccccc1)c1ccc(B(O)O)cc1F
Reactant: CC(C)(C)[Si](C)(C)OC1CCCC(c2cnc(N)c(Br)n2)C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC1CCCC(c2cnc(N)c(-c3ccc(C(=O)NCc4ccccc4)c(F)c3)n2)C1
Temperature: 120 °C

Procedure:
To 3-bromo-5-(3-((tert-butyldimethylsilyl)oxy)cyclohexyl)pyrazin-2-amine (68 mg, 0.176 mmol) in 2 mL MW vial was added (4-(benzylcarbamoyl)-3-fluorophenyl)boronic acid (72.1 mg, 0.264 mmol), PdCl2(dppf)-DCM (12.88 mg, 0.018 mmol), DME (1.32 mL) and 2M Na2CO3 solution (0.44 mL). The reaction mixture was heated at microwave synthesizer (12 min, 120° C.). The reaction mixture was diluted with EtOAc and washed with water three times, dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography eluting with 0-100% of EtOAc (containing 10% of MeOH)/heptane to provide 60 mg of crude cis racemate compound which was taken to the next reaction without further purification. LCMS (m/z): 535.4 (MH+), 1.31 min.
Reaction SMILES: [CH:1]1([C:6]2[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[N:8][CH:9]=[C:10]([CH:14]=2)[C:11]([OH:13])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:21][C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=1>>[C:26]([C:25]1[CH:28]=[CH:29][C:22]([NH:21][C:11](=[O:13])[C:10]2[CH:14]=[C:6]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[N:8][CH:9]=2)=[CH:23][CH:24]=1)#[N:27]
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(C2CCCC2)c1
Reactant: N#Cc1ccc(N)cc1
Product: N#Cc1ccc(NC(=O)c2cnc(OCC(F)(F)F)c(C3CCCC3)c2)cc1

Procedure:
This compound was prepared following the same procedure as described in Example 11 using 5-cyclopentyl-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid (Example 9c) (100 mg, 0.35 mmol) and 4-aminobenzonitrile (CAN 873-74-5, 49.0 mg, 0.41 mmol) as starting materials; off white solid (10 mg, 7.4%). MS (ESI): 388.2 (M+H)+.
Reaction SMILES: C([O-])([O-])=[O:2].C([O-])([O-])=O.OO.OO.OO.[Na+].[Na+].[Na+].[Na+].[CH3:19][O:20][C:21](=[O:30])[CH2:22][CH2:23][CH2:24][CH2:25][C:26](=[O:29])[CH:27]=[CH2:28].O>CO>[CH3:19][O:20][C:21](=[O:30])[CH2:22][CH2:23][CH2:24][CH2:25][C:26](=[O:29])[CH:27]1[O:2][CH2:28]1
Reactant: O=C([O-])[O-]
Reactant: C=CC(=O)CCCCC(=O)OC
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)CCCCC(=O)C1CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.4 %

Procedure:
39.1 g (250 mmol) of sodium percarbonate were added in four portions at room temperature, over a period of 2 hours, with stirring, to 13.9 g (82 mmol) of 6-oxo-7-octenoic acid methyl ester in 210 ml of methanol. After stirring for a further one hour at room temperature, the reaction mixture was added to 1000 ml of water and extracted several times with methylene chloride. The combined organic phases were washed with water. After drying over sodium sulfate, the solvent was distilled off using a rotary evaporator. 13.5 g (88%) of 7,8-epoxy-6-oxo-octanoic acid methyl ester were obtained.
Reaction SMILES: Cl.O1CCOCC1.C(OC([N:15]1[CH2:19][C@H:18]([CH2:20][N:21]([CH2:31][CH:32]([CH3:34])[CH3:33])[S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:24])=[O:23])[C@H:17]([CH2:35][N:36]([CH:53]([CH3:55])[CH3:54])[C:37](=[O:52])[C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[C:40]([O:46][CH2:47][CH2:48][CH2:49][O:50][CH3:51])[CH:39]=2)[CH2:16]1)=O)(C)(C)C>O1CCOCC1>[CH:53]([N:36]([CH2:35][C@H:17]1[C@H:18]([CH2:20][N:21]([CH2:31][CH:32]([CH3:34])[CH3:33])[S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH2:19][NH:15][CH2:16]1)[C:37](=[O:52])[C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[C:40]([O:46][CH2:47][CH2:48][CH2:49][O:50][CH3:51])[CH:39]=1)([CH3:55])[CH3:54]
Reactant: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@@H]2CN(CC(C)C)S(=O)(=O)c2ccccc2)C(C)C)ccc1OC
Agent: Cl
Solvent: C1COCCO1
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CNC[C@H]2CN(CC(C)C)S(=O)(=O)c2ccccc2)C(C)C)ccc1OC
Reaction time: 3 h

Procedure:
4N HCl/dioxane (4 mL) is added to a solution of (3R*,4R*)-3-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-4-[(isobutyl-phenylsulfonyl-amino)-methyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.804 g, 1.17 mmol) in dioxane (5 mL). After 3 h the solution is lyophilized to give the title compound a colorless powder. MS (LC-MS): 590.3 [M+H]+; tR (HPLC, Macherey-Nagel Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 mL/min): 4.91 min.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C@@H:7]([CH3:8])[CH2:6][C@@H:5]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH:27]([F:29])[F:28])[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:4]1.[C:36](Cl)(=[O:39])[CH2:37][CH3:38]>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[CH:24][C:25]([CH:27]([F:29])[F:28])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:35])=[C:12]([C:10]([NH:9][C@H:5]4[CH2:4][C@H:3]([NH:2][C:36](=[O:39])[CH2:37][CH3:38])[C@@H:7]([CH3:8])[CH2:6]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:34][CH2:33]1
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@@H]1C[C@H](C)[C@@H](N)C1
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N[C@H]1C[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(F)F)ccc4OCC4CC4)ncnc23)C[C@@H]1C

Procedure:
Starting from N-[(1R*,3S*,4S*)-3-amino-4-methylcyclopentyl]-4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f68) and commercially available propionyl chloride the title compound is obtained as colorless solid.