Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si](I)(C)C.[F:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:20](=[S:21])[N:19]([C:22]3[CH:23]=[C:24]([C:30]([F:33])([F:32])[F:31])[C:25]([C:28]#[N:29])=[N:26][CH:27]=3)[C:18](=[O:34])[C:14]32[CH2:17][CH2:16][CH2:15]3)=[CH:9][C:8]=1[O:35]C.O>C(#N)C>[F:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:20](=[S:21])[N:19]([C:22]3[CH:23]=[C:24]([C:30]([F:32])([F:33])[F:31])[C:25]([C:28]#[N:29])=[N:26][CH:27]=3)[C:18](=[O:34])[C:14]32[CH2:15][CH2:16][CH2:17]3)=[CH:9][C:8]=1[OH:35]
Reactant: COc1cc(N2C(=S)N(c3cnc(C#N)c(C(F)(F)F)c3)C(=O)C23CCC3)ccc1F
Agent: C[Si](C)(C)I
Solvent: O
Solvent: CC#N
Product: N#Cc1ncc(N2C(=O)C3(CCC3)N(c3ccc(F)c(O)c3)C2=S)cc1C(F)(F)F
Temperature: 25 °C
Yield: 49.4 %

Procedure:
Trimethylsilyl iodide (7.0 ml, 51.1 mmol) was added to a solution of 5-(5-(4-fluoro-3-methoxyphenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile (Compound 32, 3 g, 5.1 mmol) in acetonitrile (50 mL) and the mixture was refluxed for 24 h. The mixture was cooled to room temperature, poured into water, and extracted with EtOAc (3×). The organics were combined, washed with sat'd solution of NaHSO3, dried over MgSO4, and evaporated to dryness. The residue was purified by column chromatography on silica gel eluting with EtOAc/Hexane=1/5 to afford 1.1 g of 5-(5-(4-fluoro-3-hydroxyphenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile. 1H NMR (400 MHz, CDCl3) δ 9.10 (d, 1H), 8.38 (d, 1H), 7.27-7.22 (m, 1H), 6.93 (dd, 1H), 6.78 (m, 1H), 2.74-2.55 (m, 1H), 2.23 (m, 1H), 1.80-1.59 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[CH:8]2)=[O:4].C([Mg]Br)C.[CH3:18][C:19]1([CH3:27])[C:21]([CH3:23])([CH3:22])[CH:20]1[C:24](Cl)=[O:25]>ClCCl.[Cl-].[Zn+2].[Cl-]>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[C:24]([CH:20]1[C:21]([CH3:23])([CH3:22])[C:19]1([CH3:27])[CH3:18])=[O:25])=[O:4]
Reactant: COC(=O)c1ccc2[nH]ccc2c1
Reactant: CC1(C)C(C(=O)Cl)C1(C)C
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Product: COC(=O)c1ccc2[nH]cc(C(=O)C3C(C)(C)C3(C)C)c2c1
Yield: 64.7 %

Procedure:
Methyl-indole-5-carboxylate (Lancaster, 3.0 g, 17 mmol), ethylmagnesium bromide (1.0 M solution in THF, 21 mL, 21 mmol), zinc chloride (1.0 M solution in Et2O, 21 mL, 21 mmol) and the product of Example 1A (26 mmol) in 50 mL of dichloromethane were processed as described in Example 1B to provide the title compound (3.4 g, 11 mmol, 66% yield). MS (DCI/NH3) m/z 300 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[N:12]([CH2:13][CH2:14][O:15][CH:16]([CH3:18])[CH3:17])[C:11]([CH3:20])([CH3:19])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>>[CH:16]([O:15][CH2:14][CH2:13][N:12]1[C:4]2=[N:3][C:2]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[CH:7][C:6](=[O:8])[N:5]2[CH2:9][CH2:10][C:11]1([CH3:20])[CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)OCCN1c2nc(Cl)cc(=O)n2CCC1(C)C
Reactant: C1COCCN1
Product: CC(C)OCCN1c2nc(N3CCOCC3)cc(=O)n2CCC1(C)C
Yield: 29 %

Procedure:
0.19 g of 2-chloro-9-(2-isopropoxyethyl)-8,8-dimethyl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one in 2.5 mL of morpholine are heated in the microwave oven to 80° C. for 2 h. The crude is purified by flash chromatography on silica gel SiO2 (100% CH2Cl2 to 92/8 CH2Cl2/MeOH). 0.06 g (yield=29%) of 9-(2-isopropoxyethyl)-8,8-dimethyl-2-(morpholin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one are obtained as a white solid including the following characteristics:
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:11]([N:18]1[CH2:23][CH2:22][CH2:21][C@H:20]([OH:24])[CH2:19]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].F[C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[N+:33]([O-:35])=[O:34]>C1COCC1>[F:32][C:30]1[CH:29]=[CH:28][C:27]([N+:33]([O-:35])=[O:34])=[C:26]([CH:31]=1)[O:24][C@H:20]1[CH2:21][CH2:22][CH2:23][N:18]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](O)C1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H](Oc2cc(F)ccc2[N+](=O)[O-])C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
LiHMDS 1M solution in THF (6.4 ml) was added into a solution of (S)-1-Boc-3-hydroxypiperidine (1.3 g) in anhydrous THF (20.0 ml). The reaction was stirred at 0° C. for 0.5 h. Then 2,4-difluoro-1-nitro-benzene (703 μl) was added in a single portion. The reaction was allowed to warm to room temperature overnight when TLC indicated the consumption of the starting material. The reaction was quenched by addition of sat NH4Cl (5.0 ml) and diluted with EtOAc (100.0 ml). The organic layer was washed with sat. NH4Cl (50.0 ml) and the aqueous back extracted with EtOAc. The combined organic phases were washed with brine, dried, filtered and concentrated in vacuo. The residue was purified by chromatography to give the intended product.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20])(=[O:13])=[O:12].[CH3:21][N:22]1[CH2:27][C@@H:26]2[CH2:28][C@H:23]1[CH2:24][NH:25]2>>[CH3:21][N:22]1[CH2:27][C@@H:26]2[CH2:28][C@:23]1([C:2]1[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=1[CH:4]=[CH:5][N:6]3[S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20])(=[O:13])=[O:12])[CH2:24][NH:25]2
Reactant: Cc1ccccc1S(=O)(=O)n1ccc2c(Br)cccc21
Reactant: CN1C[C@@H]2C[C@H]1CN2
Product: Cc1ccccc1S(=O)(=O)n1ccc2c([C@@]34CN[C@H](CN3C)C4)cccc21
Yield: 19 %

Procedure:
The compound was prepared from 4-bromo-1-(2-methyl-benzenesulfonyl)-1H-indole and (1S,4S)-2-methyl-2,5-diazabicyclo[2.2.1]heptane according to Method 1 to give 25 mg (19%) of a white solid: 1H NMR (CD3OD) δ 7.91–6.44 (m, 9H), 4.67–4.63 (m, 1H), 4.35–4.33 (m, 1H), 4.09–4.07 (m, 1H), 3.99–3.95 (m, 1H), 3.72–3.70 (m, 1H), 3.21–3.17 (m, 1H), 2.95 (s, 3H), 2.33–2.31 (m, 2H); MS (ESI) 382.1 (M+H)+; Purity (HPLC) >95%.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:4]([NH2:13])=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2.C(N(CC)CC)C.Cl[C:22](=O)[CH:23]([CH3:29])[CH2:24][C:25]([O:27][CH3:28])=[O:26]>C(Cl)Cl>[CH3:1][N:2]1[C:3]2[C:4](=[C:5]3[C:10](=[CH:11][CH:12]=2)[N:9]=[CH:8][CH:7]=[CH:6]3)[N:13]=[C:22]1[CH:23]([CH3:29])[CH2:24][C:25]([O:27][CH3:28])=[O:26]
Reactant: COC(=O)CC(C)C(=O)Cl
Reactant: CNc1ccc2ncccc2c1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CC(C)c1nc2c3cccnc3ccc2n1C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 37.4 %

Procedure:
To a solution of N6-methylquinoline-5,6-diamine (914 mg, 5.28 mmol) in DCM (30 mL) was added triethylamine (1.07 g, 10.57 mmol). A solution of methyl 4-chloro-3-methyl-4-oxobutanoate (1.3 g, 7.90 mmol) in DCM (10 mL) was added dropwise to the above solution over 5 min. The resulting mixture was stirred at room temperature for 20 min. The mixture was concentrated to dryness. To the residue was added acetic acid (10 mL). The solution was stirred at 60° C. for 2 h. The solvent was removed under reduce pressure and to the residue was added saturated sodium bicarbonate aqueous solution (20 mL). The mixture was extracted with DCM (3×40 mL). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to dryness to give the crude product, which was purified by silica gel column chromatography (DCM/MeOH v/v 30:1) to give the title compound as a yellow solid (560 mg 33% yield). ESI MS: m/z 284.1 [M+H]+. 1H NMR (400 MHz, CDCl3): δ 8.94-8.88 (m, 2H), 7.95 (d, J=9.2 Hz, 1H), 7.71 (d, J=8.8 Hz, 1H), 7.50 (dd, J=4.4, 8.4 Hz, 1H), 3.94 (s, 3H), 3.70-3.63 (m, 4H), 3.28 (d, J=8.4 Hz, 0.5H), 3.23 (d, J=8.4 Hz, 0.5H), 2.86 (d, J=6.0 Hz, 0.5H), 2.82 (d, J=6.0 Hz, 0.5H), 1.47 (d, J=6.8 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:3]2[N:4]([C:8]([CH:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[N:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1.[Br:17]N1C(=O)CCC1=O.O>ClCCl>[Br:17][C:10]1[N:9]=[C:8]([CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[N:4]2[CH:5]=[CH:6][N:7]=[C:2]([CH3:1])[C:3]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nccn2c(C3CCOCC3)ncc12
Solvent: ClCCl
Solvent: O
Product: Cc1nccn2c(C3CCOCC3)nc(Br)c12
Temperature: 50 °C
Yield: 93.5 %

Procedure:
To a solution of 8-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazine (0.888 mmol, 193 mg) in dichloromethane (10 mL) was added N-bromosuccinimide (0.888 mmol, 158 mg) and the reaction mixture was heated at 50° C. (bath temperature) for 15 min. Dichloromethane and water were added, the organic layer separated, washed with an aqueous sodium hydrogencarbonate solution, dried (sodium sulfate) and concentrated in vacuo to afford 246 mg of 1-bromo-8-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]([CH2:17][C:18](=[O:20])[N:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C1CCNCC1
Reactant: O=C(O)Cn1c(-c2cccc(Cl)c2)nc2cccnc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(Cn1c(-c2cccc(Cl)c2)nc2cccnc21)N1CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2-(3-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.017 mole), 1,1'-carbonyldiimidazole (3.0 g, 0.018 mole), and anhydrous tetrahydrofuran (100 ml) was stirred at room temperature with a stream of nitrogen bubbling through it for 3 hours. The nitrogen flow was stopped and a solution of piperidine (1.6 g, 0.019 mole) in dry tetrahydrofuran (50 ml) was added. The solution was stirred at room temperature under nitrogen for 2 hours. The reaction was concentrated in vacuo and the residue triturated in water (100 ml) and the mix was filtered. The filter cake was recrystallized from isopropyl alcohol-isopropyl ether to give 3.4 g (56%) of off-white flakes, mp 149°-150° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])/[CH:5]=[C:6](/[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)\[CH3:7])[CH3:2].[Br:16]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:15])/[CH:5]=[C:6](/[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)\[CH2:7][Br:16])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)/C=C(\C)Oc1ccccc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)/C=C(\CBr)Oc1ccccc1
Yield: 74.5 %

Procedure:
To a stirred mixture of (E)-3-phenoxy-but-2-enoic acid ethyl ester (5.00 g, 0.024 mol) in carbon tetrachloride (20 mL) under a nitrogen atmosphere was added N-bromosuccinimide (6.50 g, 0.037 mol) and benzoyl peroxide (580 mg, 0.002 mol). Nitrogen gas was bubbled through the mixture for 5 min, and the resulting mixture was heated to reflux for 4 h. The reaction mixture was then placed in the refrigerator overnight. The solids formed were removed by filtration and the filtrate concentrated in vacuo. The crude product obtained was purified using flash column chromatography (silica gel (100-200 mesh), ethyl acetate/hexanes) to afford (E)-4-bromo-3-phenoxy-but-2-enoic acid ethyl ester (5.10 g, 74%) as a yellow oil.
Reaction SMILES: [CH:1]([C:4]1[NH:5][C:6]2[CH:12]=[C:11]([NH2:13])[CH:10]=[CH:9][C:7]=2[N:8]=1)([CH3:3])[CH3:2].[Br:14]Br>>[CH:1]([C:4]1[NH:5][C:6]2[C:12]([Br:14])=[C:11]([NH2:13])[CH:10]=[CH:9][C:7]=2[N:8]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1nc2ccc(N)cc2[nH]1
Reactant: BrBr
Product: CC(C)c1nc2ccc(N)c(Br)c2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
To a solution of 0.95 g (5.4 mmol) of 2-isopropyl-5-aminobenzimidazole in 50 ml of ACOH was added 0.19 ml (3.7 mmol) of Br2 dropwise and resulting reaction mixture was stirred for 1 h at 25° C. Reaction mixture was concentrated in vacuo and purified on silica gel column chromatography (5% MeOH/EtOAC) to yield 0.89 g (3.5 mmol, 95%) of the desired product.
Reaction SMILES: O[CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10](=[O:12])[CH3:11])[CH2:6][CH2:5]1.C(Br)(Br)(Br)[Br:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1>ClCCl>[Br:14][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10](=[O:12])[CH3:11])[CH2:6][CH2:5]1
Reactant: BrC(Br)(Br)Br
Reactant: CC(=O)N1CCC(CCO)CC1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(=O)N1CCC(CCBr)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1-[4-(2-hydroxy-ethyl)-piperidin-1-yl]-ethanone (0.500 g, 2.92 mmol) in dichloromethane (15 mL) was added carbon tetrabromide 1.45 g, 4.38 mmol), triphenyl phosphine (0.728 g, 2.77 mmol) and imidazole (0.398 g, 5.84 mmol) at 0° C. The temperature of the reaction mixture was slowly raised to room temperature and stirring continued at rt for 18 h. The reaction was diluted with dichloromethane and washed with water. The organic layer was dried (Na2SO4), filtered, and the solvent was evaporated. The product was chromatographed over silica gel using gradient of 0-10% methanol in dichloromethane. GC-MS m/z 235.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[N+:8]([C:11]1[CH:12]=[C:13]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:15][CH:16]=1)([O-:10])=[O:9]>O1CCCC1>[OH:4][CH2:3][CH2:2][N:1]([CH2:5][CH2:6][OH:7])[S:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([N+:8]([O-:10])=[O:9])[CH:12]=1)(=[O:18])=[O:19]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: OCCNCCO
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cccc(S(=O)(=O)N(CCO)CCO)c1
Reaction time: 72 h
Yield: 30.7 %

Procedure:
A solution of diethanolamine (2.1 g, 20 mmol) in tetrahydrofuran (20 ml) was added slowly to a stirred solution of 3-nitrobenzenesulfonyl chloride (2.2 g, 10 mmol) in tetrahydrofuran (80 ml) at 20°-25°. After stirring at this temperature for 3 days, solvent was removed under reduced pressure. The residue was partitioned between ethyl acetate and water. After drying the ethyl acetate extract (Na2SO4), filtering and concentrating, the residue was recrystallized from ethyl acetate-hexane to give 0.89 g of the sulfonamide, m.p. 100°-102° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.[CH:25]1([CH2:28][NH2:29])[CH2:27][CH2:26]1>>[CH:25]1([CH2:28][NH:29][C:19](=[O:21])[C:18]2[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:12]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[N:9][O:10][C:11]=3[CH3:24])=[N:16][CH:17]=2)[CH2:27][CH2:26]1
Reactant: Cc1onc(-c2ccc(F)cc2)c1COc1ccc(C(=O)O)cn1
Reactant: NCC1CC1
Product: Cc1onc(-c2ccc(F)cc2)c1COc1ccc(C(=O)NCC2CC2)cn1
Yield: 65 %

Procedure:
As described for example 105, 6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (99 mg, 0.33 mmol) was converted, using cyclopropanemethylamine instead of 2,2,2-trifluoroethylamine, to the title compound (74 mg, 65%) which was obtained as a white solid. MS: m/e=382.4 [M+H]+.
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].[Cl:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]=[C:11]([NH2:21])[N:12]=[C:13](N3C=NC=N3)[C:14]=2[N:15]=1>C1COCC1>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]=[C:11]([NH2:21])[N:12]=[C:13]([O:1][CH2:2][CH3:3])[C:14]=2[N:15]=1
Reactant: CC[O-]
Reactant: Nc1nc(-n2cncn2)c2nc(Cl)ccc2n1
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOc1nc(N)nc2ccc(Cl)nc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
Sodium ethoxide (2.2 mL; 21 wt % in ethanol) was added to a suspension of 6-chloro-4-[1,2,4]triazol-1-yl-pyrido[3,2-d]pyrimidin-2-ylamine (1 g) in THF (50 mL). After stirring at room temperature for 30 minutes, THF was removed in vacuo and the residue was diluted with ethyl acetate (100 mL) and washed with brine. The organic layer was dried over Na2SO4 and concentrated to afford 6-chloro-4-ethoxy-pyrido[3,2-d]pyrimidin-2-ylamine as a beige solid (0.71 g, yield: 79%) which was characterized by its mass spectrum as follows: MS (m/z) 225.0 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([CH2:19][CH:20]=[CH2:21])[CH2:4][C@H:5]1[CH2:9][O:8][C:7]([CH3:11])([CH3:10])[N:6]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].N1C=CN=C1.[CH3:27][C:28]([Si:31](Cl)([CH3:33])[CH3:32])([CH3:30])[CH3:29].O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Si:31]([O:1][CH2:2][C@H:3]([CH2:19][CH:20]=[CH2:21])[CH2:4][C@H:5]1[CH2:9][O:8][C:7]([CH3:11])([CH3:10])[N:6]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])([C:28]([CH3:30])([CH3:29])[CH3:27])([CH3:33])[CH3:32]
Reactant: C=CC[C@@H](CO)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: C=CC[C@@H](CO[Si](C)(C)C(C)(C)C)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.7 %

Procedure:
To a solution of (S)-tert-butyl 4-((R)-2-(hydroxymethyl)pent-4-enyl)-2,2-dimethyloxazolidine-3-carboxylate (11.5 g, 38.4 mmol), imidazole (7.84 g, 115.2 mmol) and DMAP (234 mg, 1.92 mmol) in CH2Cl2 (200 mL) was added a solution of TBSCl (8.68 g, 57.6 mmol) in CH2Cl2 (100 mL) dropwise. The reaction mixture was stirred at rt for overnight. Water (100 mL) was added and the aqueous layer was extracted with CH2Cl2 (3×100 mL). The combined organic layers was washed with brine (70 mL), then dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by column chromatography to afford (S)-tert-butyl 4-((R)-2-((tert-butyldimethylsilyloxy)methyl)pent-4-enyl)-2,2-dimethyloxazolidine-3-carboxylate (9 g, 57%).
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][CH:2]=1.Br[C:14]1[C:18]2=[N:19][CH:20]=[CH:21][CH:22]=[C:17]2[N:16]([CH2:23][CH3:24])[N:15]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]1([C:14]2[C:18]3=[N:19][CH:20]=[CH:21][CH:22]=[C:17]3[N:16]([CH2:23][CH3:24])[N:15]=2)[CH:6]=[CH:5][C:4]([C:14]2[C:18]3=[N:19][CH:20]=[CH:21][CH:22]=[C:17]3[N:16]([CH2:23][CH3:24])[N:15]=2)=[CH:3][CH:2]=1
Reactant: CCn1nc(Br)c2ncccc21
Reactant: OB(O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: CCn1nc(-c2ccc(-c3nn(CC)c4cccnc34)cc2)c2ncccc21
Yield: 7.3 %

Procedure:
A mixture of 1,4-phenylenediboronic acid (37.0 mg), 3-bromo-1-ethyl-1H-pyrazolo[4,3-b]pyridine (101 mg), Pd(PPh3)4 (25.8 mg) and Cs2CO3 (0.280 g) in DME/water (3/1, 4 mL) was exposed to microwave irradiation (120° C., 40 min), treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/hexane). Crystallization from AcOEt/hexane gave the title compound (6.00 mg).
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][CH:11]2[CH2:13][CH2:12]2)[C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2.[CH3:22][C:23]([CH3:38])([C:27]([NH:29][CH2:30][C:31]([F:37])([F:36])[C:32]([F:35])([F:34])[F:33])=[O:28])[C:24](O)=[O:25]>>[CH:11]1([CH2:10][N:7]2[C:8](=[O:9])[C@@H:2]([NH:1][C:24](=[O:25])[C:23]([CH3:22])([CH3:38])[C:27]([NH:29][CH2:30][C:31]([F:36])([F:37])[C:32]([F:33])([F:34])[F:35])=[O:28])[C:3]3[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=3[C:5]3[CH:17]=[CH:16][CH:15]=[CH:14][C:6]2=3)[CH2:13][CH2:12]1
Reactant: CC(C)(C(=O)O)C(=O)NCC(F)(F)C(F)(F)F
Reactant: N[C@@H]1C(=O)N(CC2CC2)c2ccccc2-c2ccccc21
Product: CC(C)(C(=O)NCC(F)(F)C(F)(F)F)C(=O)N[C@@H]1C(=O)N(CC2CC2)c2ccccc2-c2ccccc21

Procedure:
(S)-7-amino-5-cyclopropylmethyl-5H,7H-dibenzo[b,d]azepin-6-one was coupled with 2,2-dimethyl-N-(2,2,3,3,3-pentafluoro-propyl)-malonamic acid in analogy to the description in example 73 to yield N-((S)-5-cyclopropylmethyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-2,2-dimethyl-N′-(2,2,3,3,3-pentafluoro-propyl)-malonamide as white solid.
Reaction SMILES: [H-].[Na+].[C:3]1([CH:10]=[CH:9][C:7]([OH:8])=[CH:6][CH:5]=1)[OH:4].I[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][CH2:25][CH2:26][CH3:27].Cl>CN(C)C=O.O1CCCC1>[CH2:27]([O:4][C:3]1[CH:10]=[CH:9][C:7]([OH:8])=[CH:6][CH:5]=1)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12]
Reactant: CCCCCCCCCCCCCCCCI
Reactant: Oc1ccc(O)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCOc1ccc(O)cc1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
To a suspension of 28.99 g of 60% sodium hydride in 350 ml of N,N-dimethylformamide, cooled to 0° C. and under argon is added 60 g of hydroquinone in 450 ml of N,N-dimethylformamide with stirring over 40 minutes. After an additional 30 minutes, 450 ml of tetrahydrofuran is added followed by 192 g of 1-iodohexadecane over one hour. The mixture is stirred at room temperature for 3 hours. The reaction mixture is poured into dilute hydrochloric acid and extracted with chloroform. The organic layer is washed with water, dried and evaporated to give the desired product as an oil.
Reaction SMILES: [ClH:1].[Cl:2][C:3]1[CH:20]=[CH:19][C:6]2[C:7](Br)=[CH:8][CH2:9][N:10]=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:5]=2[CH:4]=1.[CH3:21][NH:22][CH2:23][C:24]#[CH:25].Cl>C(NCC)C.C(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[ClH:2].[ClH:1].[Cl:2][C:3]1[CH:20]=[CH:19][C:6]2[C:7]([C:25]#[C:24][CH2:23][NH:22][CH3:21])=[CH:8][CH2:9][N:10]=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:5]=2[CH:4]=1
Reactant: C#CCNC
Reactant: Clc1ccc2c(c1)C(c1ccccc1)=NCC=C2Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCNCC
Product: CNCC#CC1=CCN=C(c2ccccc2)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 3.7 g (10 mmole) of 8-chloro-5-bromo-1-phenyl-3H-2-benzazepine hydrochloride, 0.4 g (0.6 mmole) of dichlorobis(triphenylphosphine)palladium (II), 0.2 g (1 mmole) cuprous iodide and 2 ml (excess) of 97% N-methylpropargylamine in 50 ml of 98% diethylamine and 100 ml of methylene chloride was stirred at room temperature under nitrogen for 24 hr. The reaction was concentrated at reduced pressure to dryness. The residue was dissolved in methylene chloride and extracted with dilute ice cold hydrochloric acid. The acid extract was made alkaline with dilute ice cold sodium carbonate and extracted with ether. The ether solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure to dryness. Purification of the residue by column chromatography (silica gel, 20 g; eluent, 20% ether in methylene chloride followed by 10% methanol in methylene chloride) gave from the latter eluent an amber oil. The oil was dissolved in an excess of methanolic hydrogen chloride and concentrated at reduced pressure to dryness. The residue crystallized from isopropanol to give end product which when recrystallized from isopropanol gave tan crystals, mp 169°-175° C. dec.