Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.C[O:8][C:9]1[CH:19]=[CH:18][C:12]([CH:13]=[CH:14][C:15]([OH:17])=[O:16])=[CH:11][CH:10]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.Cl>CCOCC>[O:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:13]=[CH:14][C:15]([OH:17])=[O:16])=[CH:18][CH:19]=1
Reactant: COc1ccc(C=CC(=O)O)cc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCOCC
Product: O=C(O)C=Cc1ccc(OC2CCCCO2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
14 ml of dihydropyran was added dropwise to a mixture of 17.8 g of 4-methoxycinnamic acid, 0.34 g of 4-toluene sulphonic acid and 100 ml of diethyl ether under a nitrogen atmosphere. After one hour stirring the solution became transparent. 150 ml of ether was added and it was extracted with 200 ml of 5% of sodium hydroxide solution and evaporated using a rotary evaporator. The residue was mixed with 50 ml of ethanol and a solution of 8 g of KOH in 50 ml of water and was refluxed for 1 hour upon which a transparent solution was obtained. It was cooled with 150 g of crushed ice. Then 50 ml of HCl (2.5 N) was added dropwise to the solution until pH=4 upon which a solid precipitated. It was filtered off and washed with water. The product was dried in a dessicator over silica. 19.59 g (yield 79%) of a white solid was obtained.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11](O)=[O:12])[CH:6]=[CH:7][CH:8]=1.CSC.B.Cl>O1CCCC1>[F:1][C:2]([F:14])([F:15])[C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11][OH:12])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)CCc1cccc(C(F)(F)F)c1
Agent: B
Agent: Cl
Solvent: CSC
Solvent: C1CCOC1
Product: OCCCc1cccc(C(F)(F)F)c1
Temperature: 2.5 °C
Yield: 89.9 %

Procedure:
Compound obtained from Example 1 (0.463 moles, 100 gms) was suspended in 500 ml of tetrahydrofuran under stirring. The reaction mass was cooled to 0-5° C. 94% solution of borane dimethyl sulfide solution (0.62 moles, 50 ml) was added drop wise maintaining the temperature of 0-5° C. The reaction mass was stirred at 25-30° C. for about 10 hours. 10% HCl (100 ml) was added drop wise to the reaction mass at 25-30° C. in about 2 hours and then extracted with toluene (2×250 ml). The organic layer was separated and washed with water (5×500 ml). Toluene was removed completely from the organic layer by distillation under vacuum to isolate the title compound as an oil (85 gms, Yield 90%).
Reaction SMILES: [CH2:1]([N:13]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:14]1=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:22]>C1C=CC=CC=1>[CH2:1]([N:13]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:14]1=[S:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCCCCCCCCCCCN1CCCCCC1=O
Solvent: c1ccccc1
Product: CCCCCCCCCCCCN1CCCCCC1=S
Temperature: 25 °C
Yield: 40 %

Procedure:
To a solution of 5g (17.7mmol) of 1-n-dodecylazacycloheptan-2-one in 150ml of benzene was added 4.18g (9.4mmol) of phosphorus pentasulfide and the mixture was refluxed for 1 hr. After cooling to room temperature, the mixture was filtered and the solid was washed with chloroform and ethanol. The filtrate was concentrated in vacuo and the residue was subjected to flash chromatography, (silica; (95:5)V/V hexane/ethyl acetate) to give 2.11g (40%) of 1-n-dodecylazacycloheptane-2-thione.
Reaction SMILES: Br[CH:2]([C:6]1[S:7][C:8]([C:17]2[N:21]=[CH:20][N:19](C3CCCCO3)[N:18]=2)=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:10]=1)[C:3]([CH3:5])=O.[NH2:28][C:29]1[S:30][CH:31]=[C:32]([CH3:34])[N:33]=1.Cl.[OH-].[Na+]>C1COCC1.CC(O)C>[CH3:34][C:32]1[N:33]2[C:2]([C:6]3[S:7][C:8]([C:17]4[N:21]=[CH:20][NH:19][N:18]=4)=[C:9]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[N:10]=3)=[C:3]([CH3:5])[N:28]=[C:29]2[S:30][CH:31]=1
Reactant: CC(=O)C(Br)c1nc(-c2ccccc2)c(-c2ncn(C3CCCCO3)n2)s1
Reactant: Cc1csc(N)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: C1CCOC1
Product: Cc1nc2scc(C)n2c1-c1nc(-c2ccccc2)c(-c2nc[nH]n2)s1
Temperature: 80 °C
Reaction time: 4 h
Yield: 9.3 %

Procedure:
To a mixture of 1-bromo-1-{4-phenyl-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-1,3-thiazol-2-yl}acetone (1.15 g, 2.5 mmol) obtained by similar manner with Example 116-B(vi) in THF (12.5 mL) and 2-propanol (12.5 mL), was added 2-amino-4-methylthiazole (1.43 g, 12.5 mmol), the mixture was stirred at 80° C. for 4 h. The reaction mixture was allowed to cool to 50° C., 2N hydrochloric acid (12.5 mL) was added, and the mixture was stirred for 12 h. The reaction mixture was allowed to cool to rt, and then neutralized by the addition of 2N aqueous sodium hydroxide solution (12.5 mL). The mixture was extracted with EtOAc (50 mL×2), and the combined organic layers were dried over anhydrous magnesium sulfate. Insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (EtOAc/hexane=50/50→100/0; then MeOH/EtOAc=30/70) followed by silica gel column chromatography (EtOAc/hexane=30/70→100/0) to give the title compound (88 mg, 9%) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[C:17]3[C:12](=[CH:13][N:14]=[C:15]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[CH:16]=3)[N:11](COCC[Si](C)(C)C)[N:10]=2)=[N:6][C:7]=1F.Cl.[NH:33]1[CH2:38][CH2:37][CH2:36][C@@H:35]([OH:39])[CH2:34]1>>[Br:1][C:2]1[C:7]([N:33]2[CH2:38][CH2:37][CH2:36][C@@H:35]([OH:39])[CH2:34]2)=[N:6][C:5]([C:9]2[C:17]3[C:12](=[CH:13][N:14]=[C:15]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[CH:16]=3)[NH:11][N:10]=2)=[CH:4][CH:3]=1
Reactant: O[C@@H]1CCCNC1
Reactant: C[Si](C)(C)CCOCn1nc(-c2ccc(Br)c(F)n2)c2cc(-c3cccnc3)ncc21
Agent: Cl
Product: O[C@@H]1CCCN(c2nc(-c3n[nH]c4cnc(-c5cccnc5)cc34)ccc2Br)C1
Yield: 29.9 %

Procedure:
Following the procedures as described in Example 241 and starting with 3-(5-bromo-6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine and (R)-piperidin-3-ol hydrochloride, 291 was obtained as an off-white solid (11.0 mg, 29.9%) over two steps. 1H NMR (400 MHz, DMSO) δ 9.31 (d, J=1.8 Hz, 1H), 9.24 (s, 1H), 9.01 (s, 1H), 8.60 (d, J=4.0 Hz, 1H), 8.44 (d, J=8.1 Hz, 1H), 8.06 (d, J=8.1 Hz, 1H), 7.70 (d, J=8.1 Hz, 1H), 7.51 (dd, J=8.0, 4.8 Hz, 1H), 4.93 (d, J=4.4 Hz, 1H), 3.97 (d, J=11.6 Hz, 1H), 3.83 (d, J=12.2 Hz, 1H), 3.74 (dd, J=9.2, 4.8 Hz, 1H), 2.99-2.81 (m, 2H), 2.02 (d, J=9.1 Hz, 1H), 1.88 (d, J=13.3 Hz, 1H), 1.72 (dd, J=22.7, 10.5 Hz, 1H), 1.39 (dd, J=22.0, 8.0 Hz, 1H); ESI MS m/z=451.1 (M+1)
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:30])[CH:25]=[CH:26][CH2:27][CH2:28][CH3:29])[CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:30])[CH2:25][CH:26]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[CH2:27][CH2:28][CH3:29])[CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:9]=2)(=[O:6])=[O:7])[CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: CCCC=CC(=O)N1CCC(N(C2CC2)S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1
Product: CCCC(CC(=O)N1CCC(N(C2CC2)S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1)N1CCOCC1
Yield: 40 %

Procedure:
N-Cyclopropyl-N-[1-(3-morpholin-4-yl-hexanoyl)piperidin-4-yl]-3-trifluoromethylbenzenesulfonamide (42) was prepared by reacting N-cyclopropyl-N-(1-hex-2-enoyl-piperidin-4-yl)-3-trifluoromethylbenzene-sulfonamide (30) (250 mg, 0.56 mmol) and morpholine (2 mL) as described in Example 26 above. The residue was chromatographed over flash silica eluting with ethyl acetate:methanol:ammonia (100:10:1) to give the title compound 42 (120 mg, 40%) as a white solid. LC: 100%. MS: m/z=532.3, 533.3 (M+H). 1H NMR (400 MHz, CDCl3): (1:1 mixture of rotamers) δ 8.15 (1H, s), 8.07 (1H, d, J=7.5 Hz), 7.88 (1H, d, J=7.5 Hz), 7.70 (1H, t, J=7.5 Hz), 4.75 (1H, d, J=15 Hz), 4.10 (1H, m), 3.96 (1H, d, J=15 Hz), 3.70 (4H, m), 3.09 (2H, m), 2.64-2.44 (6H, m), 2.20 (1H, dd, J=8.8 Hz), 1.99 (1H, m), 1.50-1.25 (4H, m), 1.02-0.70 (7H, m).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[C:6]([CH3:8])[CH:7]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:27]1([CH2:33][S:34][CH:35]([C:39](O)=[O:40])[C:36](O)=[O:37])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[O:11][C:36](=[O:37])[C:35]([S:34][CH2:33][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[C:39]([OH:40])[CH:10]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: O=C(O)C(SCc1ccccc1)C(=O)O
Reactant: CC(=O)c1cc(C)cc(C)c1
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(C)cc(-c2cc(O)c(SCc3ccccc3)c(=O)o2)c1

Procedure:
The title compound was prepared by Method A using 3',5'-dimethylacetophenone (0.785 g, 5.31 mmol), lithium bis(trimethylsilyl)amide (0.977 g, 5.84 mmol), chlorotrimethylsilane (0.741 mL, 5.84 mmol), THF (58 mL), and diethyl ester of [(phenylmethyl)thio]propanedioic acid (1.00 g, 3.54 mmol). m.p. dec. 170° C.; 1H NMR (400 MHz, DMSO-d6) δ2.33 (s, 6 H), 3.99 (s, 2 H), 6.67 (s, 1 H), 7.21 (m, 6 H), 7.39 (s, 2 H).
Reaction SMILES: C(OC([O:6][CH2:7][C:8]#[C:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)=[O:11])C)C.Cl>O1CCCC1>[OH:6][CH2:7][C:8]#[C:9][C:10]([C:12]1[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)=[O:11]
Reactant: CCOC(C)OCC#CC(=O)c1ccc(OC)cc1
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc(C(=O)C#CCO)cc1
Reaction time: 0.5 h

Procedure:
A solution of 7.3 g (27.8 mmol) of 4-(1-ethoxyethoxy)-1-(4-methoxyphenyl)-2-butyn-1-one in 95 ml of tetrahydrofuran was treated at room temperature with 28 ml of 2N hydrochloric acid, whereupon the mixture was stirred for 30 minutes. The reaction mixture was then extracted twice with ethyl acetate. The combined organic phases were washed in succession with saturated sodium carbonate solution and with water, dried over magnesium sulphate and concentrated. Crystallization of the residue from methylene chloride/hexane yielded 4-hydroxy-1-(4-methoxyphenyl)-2 -butyn-1-one of melting point 84°-85°.
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]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][C:23](O)=[O:24])[NH:8][CH2:7][CH2:6]2.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(#N)C>[CH3:14][O:13][C:12]1[C:3]([O:2][CH3:1])=[CH:4][C:5]2[CH2:6][CH2:7][N:8]3[C:23](=[O:24])[CH2:22][C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[CH2:15][CH:9]3[C:10]=2[CH:11]=1
Reactant: COc1cc2c(cc1OC)C(Cc1ccccc1CC(=O)O)NCC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: COc1cc2c(cc1OC)C1Cc3ccccc3CC(=O)N1CC2
Temperature: 25 °C
Reaction time: 6 h
Yield: 68.7 %

Procedure:
To an ice-chilled solution of 2-[(1,2,3,4-tetrahydro-6,7-dimethoxyisoquinolinyl)methyl]benzeneacetic acid (XIc, Ex. 16) (0.4 g, 1.17 mmole) and 4-dimethylaminopyridine (0.15 g, 1.23 mmol) in dry acetonitrile (45 ml) was added with stirring dicyclohexylcarbodiimide (0.24 g, 1.17 mmole). The resulting mixture was stirred at room temperature for 6 hours, then heated to boiling briefly. When the mixture was cooled to room temperature, there was separated a precipitate which was removed by filtration. The filtrate was concentrated to about 10 ml, and chilled in ice to cause a separation of a precipitate. The precipitate was collected on a filter and recrystallized from ethanol, giving the titled product (0.26 g, 69%) which is identical with that described in Example 15.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]([O:15]C)=[O:14])[C:7](=[O:17])[CH2:6]2>O1CCOCC1.Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]([OH:15])=[O:14])[C:7](=[O:17])[CH2:6]2
Reactant: COC(=O)CN1C(=O)Cc2cc(OC)ccc21
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc2c(c1)CC(=O)N2CC(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 61 %

Procedure:
To a solution of methyl 2-(5-methoxy-2-oxoindolin-1-yl)acetate (350 mg, 1.488 mmol) in dioxane (10 ml), 12N HCl (10 ml) was added, and the mixture was stirred at room temperature for 24 hours. Then the solvent was evaporated and the resulting crude was dissolved in MeOH (5 ml); by addition of iPrO2 (50 ml) the title compound precipitated, was filtered and used in the next step without further purification (200 mg, 0.904 mmol, 61% yield). MS/ESI+ 222.2 [MH]+.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:13]([CH2:14][C:15]3[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=3[C:17]#[N:18])[C:12](=[O:23])[N:11]([CH2:24]C3C=CC=C(C#N)C=3)[C:10](=[O:33])[CH:9]=2)[CH2:3]1.BrC[C:36]1[C:37]([C:42]#[N:43])=[CH:38][CH:39]=[CH:40][CH:41]=1>>[NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:13]([CH2:14][C:15]3[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=3[C:17]#[N:18])[C:12](=[O:23])[N:11]([CH2:24][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[C:42]#[N:43])[C:10](=[O:33])[CH:9]=2)[CH2:3]1
Reactant: N#Cc1ccccc1CBr
Reactant: N#Cc1cccc(Cn2c(=O)cc(N3CCC[C@@H](N)C3)n(Cc3ccccc3C#N)c2=O)c1
Product: N#Cc1ccccc1Cn1c(N2CCC[C@@H](N)C2)cc(=O)n(Cc2ccccc2C#N)c1=O

Procedure:
Title compound 18 was prepared by the methods used in the preparation of compound 17, except that α-bromo-o-tolunitrile was used in the place of m-cyano-benzyl bromide. 1H-NMR (400 MHz, CDCl3-CD3OD 10:1) δ 7.64 (d, J=6.8 Hz, 1H), 7.60 (d, J=7.8 Hz, 1H), 7.55 (t, J=7.8 Hz, 2 H), 7.44 (t, J=7.6 Hz, 1 H), 7.38 (t, J=7.5 Hz, 1 H), 7.31 (t, J=7.6 Hz, 1H), 7.27 (d, J=7.8 Hz, 1H), 7.12 (d, J=7.8 Hz, 1 H), 5.45 (s, 1 H), 5.15-5.32 (m, 4 H), 3.36-3.47 (m, 2 H), 2.98 (m, 2 H), 2.10 (m, 1 H), 1.91 (m, 1 H), 1.68 (m, 2 H). MS (ES) [m+H] calc'd for C25H25N6O2, 441.2. found 441.2.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([O:21][CH3:22])=[O:20])=[CH:13][C:12]=1[O:23][CH3:24].[I-:25].[Na+]>CC(C)=O>[I:25][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([O:21][CH3:22])=[O:20])=[CH:13][C:12]=1[O:23][CH3:24]
Reactant: COC(=O)/C=C/c1ccc(OCCCCCCCCCl)c(OC)c1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COC(=O)/C=C/c1ccc(OCCCCCCCCI)c(OC)c1
Yield: 89.3 %

Procedure:
26.8 g (75.52 mmol) methyl (2E)-3-{4-[(8-chloroctyl)oxy]-3-methoxyphenyl}-2-propenoate was dissolved in 1000 ml acetone. 65.16 g (435.15 mmol) sodium iodide were added. The reaction suspension was heated at reflux temperature for 24 hours. The reaction mixture was partitioned between diethylether and water. The organic phase was washed repeatedly with water, dried over sodium sulfate, filtered and concentrated by rotary evaporation. The crude product was recrystallised from 2-propanol yielded 30.1 g (90%) methyl (2E)-3-{4-[(8-iodoctyl)oxy]-3-methoxyphenyl}-2-propenoate as white crystals.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([B:10]2[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]2)=[CH:6][CH:5]=1)=[C:2]=[O:3].Cl.[NH2:20][CH2:21][C:22]([NH2:24])=[O:23].C(N(CC)CC)C>C1COCC1>[CH3:17][C:12]1([CH3:18])[C:13]([CH3:16])([CH3:15])[O:14][B:10]([C:7]2[CH:8]=[CH:9][C:4]([NH:1][C:2](=[O:3])[NH:20][CH2:21][C:22]([NH2:24])=[O:23])=[CH:5][CH:6]=2)[O:11]1
Reactant: NCC(N)=O
Reactant: CC1(C)OB(c2ccc(N=C=O)cc2)OC1(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1(C)OB(c2ccc(NC(=O)NCC(N)=O)cc2)OC1(C)C
Yield: 88.5 %

Procedure:
2-(4-isocyanatophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (300 mg, 1.22 mmol) was dissolved in dry THF and stirred with 2-aminoacetamide hydrochloride (108 mg, 1.46 mmol) and triethylamine (drops) at 60° C. overnight. The mixture was reduced in vacuo, yielding the title compound (345 mg, 1.08 mmol, 88%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][CH:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Br:27][C:28]1[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[C:30]([CH2:38]Br)[CH:29]=1>C(#N)C>[Br:27][C:28]1[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[C:30]([CH2:38][N:11]2[C:10](=[O:13])[N:9]([CH2:14][CH:15]([OH:20])[C:16]([F:18])([F:19])[F:17])[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[N:12]2)[CH:29]=1
Reactant: COC(=O)c1ccc(Br)cc1CBr
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1CC(O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)c1ccc(Br)cc1Cn1nc(-c2ccc(Cl)cc2)n(CC(O)C(F)(F)F)c1=O

Procedure:
450 mg (1.30 mmol) of the compound from Example 4A and 715 mg (2.19 mmol) of cesium carbonate were suspended in 6 ml of acetonitrile, and 708 mg (1.61 mmol) of methyl 4-bromo-2-(bromomethyl)benzoate were added. The mixture was stirred under reflux for 20 h. The precipitated solid was filtered off and the filtrate was concentrated under reduced pressure to a volume of about 1.5 ml. After addition of 1 ml of 1 N hydrochloric acid, the mixture was directly purified chromatographically [Method 19]. This gave 545 mg (64% of theory) of the target compound in a purity of 92%.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl:5][C:6]([Cl:22])([Cl:21])[CH:7]([OH:20])[CH:8]([N:15]1[CH:19]=[N:18][CH:17]=[N:16]1)[C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11]>CN(C)C=O>[Cl:22][C:6]([Cl:5])([Cl:21])[CH:7]([O:20][C:1](=[O:3])[CH3:2])[CH:8]([N:15]1[CH:19]=[N:18][CH:17]=[N:16]1)[C:9](=[O:14])[C:10]([CH3:12])([CH3:13])[CH3:11]
Reactant: CC(C)(C)C(=O)C(C(O)C(Cl)(Cl)Cl)n1cncn1
Reactant: CC(=O)Cl
Solvent: CN(C)C=O
Product: CC(=O)OC(C(C(=O)C(C)(C)C)n1cncn1)C(Cl)(Cl)Cl
Yield: 40.1 %

Procedure:
8.0 g (0.1 mol) of acetyl chloride were added to 31.5 g (0.1 mol) of 1,1,1-trichloro-2-hydroxy-3-(1,2,4-triazol-1-yl)-5,5-dimethyl-hexan-4-one in 100 ml of dimethylformamide at room temperature. Thereafter, the mixture was heated under reflux for 4 hours. It was left to cool and concentrated by distilling off the solvent in vacuo. The residue was taken up in methylene chloride and the methylene chloride solution was washed with aqueous sodium bicarbonate solution and dried over sodium sulphate. The solvent was distilled off and the residue was taken up in 100 ml of diisopropyl ether. After the diisopropyl ether mixture had stood for several hours, colorless crystals precipitated. 14.3 g (40% of theory) of 1,1,1-trichloro-2-acetoxy-3-(1,2,4-triazol-1-yl)-5,5-dimethylhexan-4-one were obtained as the pure diastereomer of the A* form of melting point 128°-130° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[C:15]([C:17]#[N:18])[C:14]3[N:19]=[CH:20][N:21]([CH3:22])[C:13]=3[CH:12]=2)=[CH:7][C:6]=1[C:23]([F:26])([F:25])[F:24].[O:27]=[C:28]1[CH2:33][NH:32][CH2:31][CH2:30][NH:29]1>CN(C=O)C>[CH3:22][N:21]1[C:13]2[CH:12]=[C:11]([C:8]3[CH:9]=[CH:10][C:5]([CH2:4][CH2:3][CH2:2][N:32]4[CH2:31][CH2:30][NH:29][C:28](=[O:27])[CH2:33]4)=[C:6]([C:23]([F:26])([F:25])[F:24])[CH:7]=3)[N:16]=[C:15]([C:17]#[N:18])[C:14]=2[N:19]=[CH:20]1
Reactant: O=C1CNCCN1
Reactant: Cn1cnc2c(C#N)nc(-c3ccc(CCCBr)c(C(F)(F)F)c3)cc21
Solvent: CN(C)C=O
Product: Cn1cnc2c(C#N)nc(-c3ccc(CCCN4CCNC(=O)C4)c(C(F)(F)F)c3)cc21
Yield: 28.7 %

Procedure:
6-(4-(3-Bromopropyl)-3-(trifluoromethyl)-phenyl)-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile (50 mg) and 2-oxopiperazine (103 mg) in DMF (750 μl) were heated at 100° C. in a microwave for 25 minutes. Purification by basic phase preparative LCMS afforded 1-methyl-6-{4-[3-(3-oxo-piperazin-1-yl)-propyl]-3-trifluoromethyl-phenyl}-1H-imidazo[4,5-c]pyridine-4-carbonitrile (15 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.Cl[C:12]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][CH:15]=[CH:14][N:13]=1.C(N(CC)CC)C>C(O)C>[N+:18]([C:17]1[C:12]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[CH:5]3)=[N:13][CH:14]=[CH:15][CH:16]=1)([O-:20])=[O:19]
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: O=[N+]([O-])c1cccnc1Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cccnc1Nc1ccc2[nH]ccc2c1
Temperature: 25 °C
Yield: 69 %

Procedure:
5-Aminoindole (0.264 g, 2.00 mmoles) and 2-chloro-3-nitropyridine (0.476 g, 3.00 mmoles) were combined with triethylamine (0.42 ml, 3.01 mmoles) in absolute ethanol. The reaction was heated at room temperature under nitrogen for 72 hours. The resulting reaction mixture was filtered to afford the title compound (69%) as a dark red solid. Mp, 162.0°-163.5° C.; Rf =0.6 in diethyl ether; 13C NMR (DMSO-d6) δ155.6, 150.5, 135.5, 133.5, 129.7, 127.9, 127.6, 125.9, 118.5, 115.0, 113.4, 111.2, 101.2. Analytical calculated for C13H10N4O2 : C, 61.41; H, 3.96; N, 22.04. Found: 61.22; H, 3.80; N, 22.08.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH2:12]([C:14]1[N:15]([CH2:27][C:28]#[CH:29])[C:16]2[C:25]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:19]=[CH:18][C:17]=2[N:26]=1)[CH3:13]>C(Cl)(Cl)Cl>[CH2:12]([C:14]1[N:15]([CH2:27][C:28]#[CH:29])[C:16]2[C:25]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N+:19]([O-:6])=[CH:18][C:17]=2[N:26]=1)[CH3:13]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C#CCn1c(CC)nc2cnc3ccccc3c21
Solvent: ClC(Cl)Cl
Product: C#CCn1c(CC)nc2c[n+]([O-])c3ccccc3c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 111.4 %

Procedure:
3-Chloroperoxybenzoic acid (1.21 g of 77%, 1.15 eq.) was added in a single portion to a solution of 2-ethyl-1-(2-propynyl)-1H-imidazo[4,5-c]quinoline (1.00 g, 4.25 mmol, 1.0 eq) in chloroform (42 mL). The reaction mixture was stirred at ambient temperature for 1 hour at which time analysis by thin layer chromatography (TLC) indicated that the reaction was complete. The reaction mixture was diluted with chloroform (150 mL) and washed with aqueous saturated sodium bicarbonate (2×50 mL). The combined aqueous layers were back extracted with chloroform (3×30 mL). The combined organics were dried over magnesium sulfate and concentrated under reduced pressure to provide 1.19 g of 2-ethyl-1-(2-propynyl)-1H-imidazo[4,5-c]quinoline 5-oxide as a white solid.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH:7]([C:9]1[CH:10]=[C:11]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[CH2:12][N:13]1[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]2[C:14]1=[O:23])=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH3:28][O:27][C:26]1[CH:25]=[CH:24][C:11]([CH2:12][N:13]2[C:17](=[O:18])[C:16]3=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]3[C:14]2=[O:23])=[CH:10][C:9]=1[CH:7]=[CH2:1]
Reactant: COc1ccc(CN2C(=O)c3ccccc3C2=O)cc1C=O
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=Cc1cc(CN2C(=O)c3ccccc3C2=O)ccc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.5 %

Procedure:
3.99 g of potassium-t-butoxide was added to 80 ml solution of 12.7 g methyltriphenyl phosphonium bromide in tetrahydrofuran at 0° C., 7 g of N-(3-formyl-4-methoxybenzyl)phthalimide was added thereto, and the mixture was stirred at room temperature for 1 hr. The reaction solution was filtered through Celite, and then evaporated. The resulting residue was purified by silica gel column chromatography to give 2.75 g of N-(4-methoxy-3-vinylbenzyl)phthalimide.