Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[CH2:21]Br)[CH:6]=1.Cl[C:25]1[CH:30]=[CH:29][C:28]([C@@H:31]2[O:35][C:34](=[O:36])[NH:33][C@@H:32]2[CH3:37])=[CH:27][CH:26]=1>>[CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[CH2:21][N:33]2[C@H:32]([CH3:37])[C@H:31]([C:28]3[CH:29]=[CH:30][CH:25]=[CH:26][CH:27]=3)[O:35][C:34]2=[O:36])[CH:6]=1
Reactant: COC(=O)Cc1ccc(OC)c(Oc2ccc(Br)cc2CBr)c1
Reactant: C[C@H]1NC(=O)O[C@H]1c1ccc(Cl)cc1
Product: COC(=O)Cc1ccc(OC)c(Oc2ccc(Br)cc2CN2C(=O)O[C@@H](c3ccccc3)[C@H]2C)c1

Procedure:
Prepared according to the procedure described in Example 6, Step 5, using the following starting materials: [3-(4-bromo-2-bromomethyl-phenoxy)-4-methoxy-phenyl]-acetic acid methyl ester and (4R,5S)-5-(4-chloro-phenyl)-4-methyl-oxazolidin-2-one.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][CH:18]([CH:20]4[CH2:25][CH2:24][N:23]([C:26]#[N:27])[CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[OH:28][NH:29][C:30](=N)[CH2:31][CH2:32][CH3:33]>>[CH3:1][S:2]([N:5]1[CH2:6][CH:7]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][CH:18]([CH:20]4[CH2:25][CH2:24][N:23]([C:26]5[O:28][N:29]=[C:30]([CH2:31][CH2:32][CH3:33])[N:27]=5)[CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:9][CH2:10]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)N1CC=C(c2cc3c(cn2)OC(C2CCN(C#N)CC2)C3)CC1
Reactant: CCCC(=N)NO
Product: CCCc1noc(N2CCC(C3Cc4cc(C5=CCN(S(C)(=O)=O)CC5)ncc4O3)CC2)n1

Procedure:
The title compound is prepared from 4-[5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2,3-dihydro-furo[2,3-c]pyridin-2-yl]-piperidine-1-carbonitrile and N-hydroxy-butyramidine following a procedure analogous to that described in Example 2. LC (method 5): tR=1.02 min; Mass spectrum (ESI+): m/z=474 [M+H]+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH2:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[N:14]1([CH2:13][CH2:12][NH:11][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: NCCN1CCCCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Product: O=[N+]([O-])c1ccc(NCCN2CCCCC2)cc1

Procedure:
Using an analogous procedure to that described in Method 23, but starting from 4-fluoronitrobenzene and 1-(2-aminoethyl)piperidine, the product was obtained. NMR: 1.3 (m, 2H), 1.5 (m, 4H), 2.3 (m, 4H), 2.4 (t, 2H), 3.2 (m, 2H), 6.6 (d, 2H), 7.1 (m, 1H), 8.0 (d, 2H); MS (MH+): 250.
Reaction SMILES: C([O:4][CH:5]([CH2:17][N:18]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]2[CH:29]=[CH:30][C:31]3[N:35]=[CH:34][N:33]([CH3:36])[C:32]=3[CH:37]=2)[CH:23]=1)[C:19](=[O:21])[CH3:20])[CH2:6][N:7]1[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8]1)(=O)C.[OH-].[Li+]>CCO.O>[CH2:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:15][CH2:16][N:7]1[CH2:6][CH:5]([OH:4])[CH2:17][N:18]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]2[CH:29]=[CH:30][C:31]3[N:35]=[CH:34][N:33]([CH3:36])[C:32]=3[CH:37]=2)[CH:23]=1)[C:19](=[O:21])[CH3:20]
Reactant: CC(=O)OC(CN1CCc2ccccc2C1)CN(C(C)=O)c1cccc(-c2ccc3ncn(C)c3c2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(=O)N(CC(O)CN1CCc2ccccc2C1)c1cccc(-c2ccc3ncn(C)c3c2)c1
Temperature: 25 °C
Yield: 6.7 %

Procedure:
To a solution of 1-(3,4-dihydroisoquinolin-2(1H)-yl)-3-(N-(3-(1-methyl-1H-benzo[d]imidazol-6-yl)phenyl)acetamido)propan-2-yl acetate (60 mg, 0.121 mmol) in EtOH (2 ml) and H2O (1 mL) was added lithium hydroxide (10 mg, 0.238 mmol). The mixture was stirred at 25° C. until LCMS indicated completion of the reaction. Solvents were evaporated and the residue dissolved in 30 mL DCM, washed with aq. NaHCO3 and water then dried over anhydrous Na2SO4, and filtrated. Solvent was removed from this filtrate leaving a residue which was then purified by prep-HPLC to afford the desired product as colorless oil (3.7 mg, 6.7%). 1H NMR (400 MHz, METHANOL-d4) δ 8.49 (br. s., 1H), 8.20 (s, 1H), 7.84 (s, 1H), 7.70-7.81 (m, 3H), 7.49-7.67 (m, 2H), 7.33-7.41 (m, 1H), 7.13-7.27 (m, 3H), 7.09 (d, J=6.90 Hz, 1H), 4.31 (br. s., 1H), 4.20 (s, 2H), 4.03 (dd, J=5.21, 13.99 Hz, 1H), 3.96 (s, 3H), 3.73-3.84 (m, 1H), 3.32-3.39 (m, 2H), 2.98-3.19 (m, 4H), 1.97 (s, 3H) LCMS (m/z): 455.2 [M+H]+
Reaction SMILES: C([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)C(O)(C)C)(=O)C.[CH3:14][CH:15]([OH:18])[C:16]#[CH:17].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.O>[CH3:14][CH:15]([O:18][C:4]1[CH:5]=[CH:6][CH:11]=[CH:12][CH:13]=1)[C:16]#[CH:17]
Reactant: C#CC(C)O
Reactant: CC(=O)c1cccc(C(C)(C)O)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: C#CC(C)Oc1ccccc1
Reaction time: 0.17 h

Procedure:
Phenol 27 (422.9 mg, 4.49 mmol), But-3-yn-2-ol (300 mg, 4.28 mmol) were dissolved in anhydrous THF (10 mL) under N2 atmosphere, at 0° C. was added Ph3P (1.12 g, 4.26 mmol) portion wise, stirred it for 10 min, and then DEAD (894.6 mg, 5.14 mmol) added slowly. The resultant solution was heated up to 70° C. stirred for 20 h. To the reaction mixture water added and extracted with DCM and dried organic layer on MgSO4, filtered, concentrated. Purified by flash chromatography using ethylacetate/n-hexane, 5:95) provided compound 28 (450 mg, 69%) as a solid. 1H NMR (CDCl3, 400 MHz) δ 1.67 (d, J=6.8 Hz, 3H), 2.47 (d, J=2 Hz, 1H), 4.88 (q, J=2 Hz, 1H), 6.97-7.03 (m, 3H), 7.28-7.32 (m, 2H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[F:11][C:12]([F:15])([F:14])[O-:13].CN([S+](N(C)C)N(C)C)C>C(#N)C>[F:11][C:12]([F:15])([F:14])[O:13][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: [O-]C(F)(F)F
Reactant: O=C(CBr)c1ccccc1
Agent: CN(C)[S+](N(C)C)N(C)C
Solvent: CC#N
Product: O=C(COC(F)(F)F)c1ccccc1
Temperature: 0 °C
Reaction time: 72 h

Procedure:
α-Bromoacetophenone, 13.61 g (0.068 mol), was added dropwise at 25° to a solution of 0.076 mol of tris(dimethylamino)sulfonium trifluoromethoxide (prepared as in Example 1) in 75 mL of acetonitrile. The reaction mixture was stirred for 3 days and then poured into ice-water. The aqueous mixture was extracted with ether, and the ether extracts were washed with water, dried (MgSO4), and distilled to give α-trifluoromethoxyacetophenone as a colorless liquid: bp 64°-65° (0.8 mm); 1H NMR (CDCl3) δ5.15 ppm (s, 2H), 7.50 ppm (m, 3H), 7.85 ppm (m, 2H); 19F NMR (CDCl3) δ-61.5 ppm(s).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[C:5](=[O:13])[CH2:4][CH2:3]1.[BH4-].[Na+]>CO.O>[CH3:1][C:2]1([CH3:14])[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[CH:5]([OH:13])[CH2:4][CH2:3]1
Reactant: CC1(C)CCC(=O)c2ccccc2C1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC1(C)CCC(O)c2ccccc2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 8,8-dimethyl-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-one (29.20 g, 155.1 mmol) in methanol (150 ml) was added sodium borohydride (5.87 g, 155 mmol) by small portions under ice-cooling, and the mixture was stirred at room temperature for 1 hr. The reaction solution was diluted with water and extracted twice with ethyl acetate. The recovered organic layer was-dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1-6/1) to give the objective substance.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].Br[C:15]1[S:16][C:17]([Cl:20])=[CH:18][CH:19]=1.N[C@@H]1CCCC[C@H]1N.C(=O)([O-])[O-].[K+].[K+]>[Cu](I)I.O1CCOCC1>[Cl:20][C:17]1[S:16][C:15]([N:10]2[CH2:11][CH2:12][N:8]([C:3]3[CH:4]=[N:5][CH:6]=[CH:7][C:2]=3[CH3:1])[C:9]2=[O:13])=[CH:19][CH:18]=1
Reactant: Clc1ccc(Br)s1
Reactant: Cc1ccncc1N1CCNC1=O
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCN(c2ccc(Cl)s2)C1=O
Yield: 48.2 %

Procedure:
Using the same reaction conditions as in Example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 300 mg, 1.6949 mmol) was reacted with 2-bromo-5-chloro-thiophene (0.185 mL, 1.6949 mmol), 1,4-dioxane (10 mL), copper iodide (32 mg, 0.169 mmol), trans-1,2-diamino cyclohexane (58 mg, 0.5084 mmol) and potassium carbonate (467 mg, 3.3898 mmol) to afford the crude product. Purification by column chromatography on silica gel (1% MeOH in DCM) afforded 240 mg of the product (48.4% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH2:14])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.C(O[C:23]1(O[Si](C)(C)C)[CH2:25][CH2:24]1)C.[BH4-].[Na+].C(=O)([O-])O.[Na+]>CO.O1CCCC1>[CH:23]1([NH:14][C:10]2[CH:9]=[C:8]([NH:7][C:6](=[O:15])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH:13]=[CH:12][CH:11]=2)[CH2:25][CH2:24]1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Reactant: CC(C)(C)OC(=O)Nc1cccc(N)c1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1cccc(NC2CC2)c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 59.1 %

Procedure:
To a solution of tert-butyl(3-aminophenyl)carbamate (6.91 g, 33.2 mmol) in methanol (30 mL) were added acetic acid (5.69 mL, 99.5 mmol) and [(1-ethoxycyclopropyl)oxy](trimethyl)silane (7.98 mL, 39.8 mmol), and the mixture was stirred at 60° C. for 4 hr. The reaction mixture was concentrated under reduced pressure. A solution of the obtained residue in tetrahydrofuran (20 mL) was added dropwise to a suspension of sodium tetrahydroborate (2.51 g, 66.4 mmol) and boron trifluoride diethyl ether complex (8.33 mL, 66.4 mmol) in tetrahydrofuran (30 mL) (the suspension was stirred in advance at room temperature for 1 hr) at 0° C. over 30 min, and the mixture was stirred at room temperature for 2.5 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (100 mL), and the mixture was extracted with ethyl acetate (2×50 mL). The combined organic layer was washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=95/5→90/10), and the fractions containing the object product were concentrated under reduced pressure to give the title compound (4.87 g, 59%) as a colorless solid.
Reaction SMILES: [CH3:1][CH2:2][CH2:3]Br.[Mg].Cl[SiH:7]1[CH2:12][CH2:11][CH:10]([CH2:13][CH2:14][C@H:15]2[CH2:20][CH2:19][C@H:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[CH:29][CH:28]=4)=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)[CH2:9][CH2:8]1>C1COCC1>[CH2:3]([Si@H:7]1[CH2:12][CH2:11][C@H:10]([CH2:13][CH2:14][C@H:15]2[CH2:16][CH2:17][C@H:18]([C:21]3[CH:22]=[CH:23][C:24]([C:27]4[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[CH:29][CH:28]=4)=[CH:25][CH:26]=3)[CH2:19][CH2:20]2)[CH2:9][CH2:8]1)[CH2:2][CH3:1]
Reactant: CCCBr
Reactant: N#Cc1ccc(-c2ccc([C@H]3CC[C@H](CCC4CC[SiH](Cl)CC4)CC3)cc2)cc1
Agent: [Mg]
Solvent: C1CCOC1
Product: CCC[Si@H]1CC[C@H](CC[C@H]2CC[C@H](c3ccc(-c4ccc(C#N)cc4)cc3)CC2)CC1

Procedure:
12.5 g (0.1 mol) of n-propyl bromide was dripped into a mixture of 2.5 g (0.1 mol) of magnesium and 500 ml of THF to obtain a Grignard's reagent. This solution was then dripped into a 300 ml THF solution of 42 g (0.1 mol) of 4-(trans-4-(2-(4-chloro-4-silacyclohexyl)ethyl)cyclohexyl)-4'-cyanobiphenyl to obtain 4-(trans-4-(2-(trans-4-n-propyl-4-silacyclohexyl)ethyl)cyclohexyl)-4'-cyanobiphenyl. The silacyclohexane rings of the product were a mixture of trans isomers and cis isomers. They were separated by means of chromatography to obtain 32.8 g (yield 76.4%) of the trans isomer.
Reaction SMILES: [F:1][C:2]1[C:12]([NH:13][NH:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][C:16]2=[N:21][OH:22])=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.N1C=CC=CC=1>O1CCCC1.O.S([O-])([O-])(=O)=O.[Cu+2]>[F:1][C:2]1[C:12]([N:13]2[N+:21]([O-:22])=[C:16]3[CH2:17][CH2:18][CH2:19][CH2:20][C:15]3=[N:14]2)=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: O=C1COc2cc(F)c(NNC3CCCCC3=NO)cc2N1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: c1ccncc1
Solvent: O
Solvent: C1CCOC1
Product: O=C1COc2cc(F)c(-n3nc4c([n+]3[O-])CCCC4)cc2N1
Temperature: 80 °C

Procedure:
To a solution of 2-[2-(7-fluoro-2H-1,4-benzoxazin-3(4H)-on-6-yl)hydrazino]cyclohexanone oxime (3.0 g) in tetrahydrofuran (100 ml), 15% aqueous pyridine (60 g) was added, and a solution of copper sulfate (6 g) in water (10 ml) was added thereto, followed by heating at 80° C. for 2 hours. After completion of the reaction, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with 10% aqueous copper sulfate solution, dried and concentrated. The residue was purified by silica gel column chromatography using ethyl acetate as an eluent to give 2-(7-fluoro-2H-1,4-benzoxazin-3(4H)-on-6-yl)-4,5,6,7-tetrahydro-1,2,3-benzotriazole-1-oxide. m.p., 219°-221° C.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:23])([F:22])[C:5]1[CH:6]=[C:7]([C@H:15]2[O:19][C:18](=[O:20])[NH:17][C@H:16]2[CH3:21])[CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1.[CH2:24](Br)[C:25]#[CH:26].[NH4+].[Cl-]>C1COCC1>[F:23][C:4]([F:3])([F:22])[C:5]1[CH:6]=[C:7]([C@H:15]2[O:19][C:18](=[O:20])[N:17]([CH2:26][C:25]#[CH:24])[C@H:16]2[CH3:21])[CH:8]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:10]=1
Reactant: C#CCBr
Reactant: C[C@@H]1NC(=O)O[C@@H]1c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C#CCN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (192 mg, 60% dispersion in mineral oil, 4.79 mmol) was added to a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (1.00 g, 3.19 mmol) in dry THF (30 mL) at room temperature under N2. After stirring for 30 min at room temperature, propargyl bromide (80 wt % solution in toluene, 712 μL, 570 mg, 4.17 mmol) was added. The reaction mixture was stirred overnight at room temperature. Saturated NH4Cl (20 mL) was added and the mixture was extracted with EtOAc (3×20 mL). The combined extracts were dried (MgSO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 40×160 mm, 0-40% EtOAc in hexanes gradient) to afford (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-3-prop-2-yn-1-yl-1,3-oxazolidin-2-one. Rf=0.31 (20% EtOAc/hexanes). LCMS calc.=352.1; found=352.1 (M+1)+. 1H NMR (600 MHz, CDCl3): δ 7.88 (s, 1H); 7.76 (s, 2H); 5-74 (d, J=8.2 Hz, 1H); 4.454-39 (m, 2H); 3.81 (dd, J=2.5, 17.8 Hz, 1H); 2.33 (t, J=2.5 Hz, 1H); 0.84 (d, J=6.6 Hz, 4H).
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]([CH2:19][CH3:20])[C:7](=[O:18])[CH:8]([NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH2:9][CH2:10][C:4]=2[C:3]=1[O:23][CH3:24].Cl[C:26]1[N:31]=[C:30]([NH:32][C@@H:33]2[CH2:38][CH2:37][CH2:36][CH2:35][C@H:34]2[NH:39][S:40]([CH3:43])(=[O:42])=[O:41])[C:29]([Cl:44])=[CH:28][N:27]=1>>[Cl:44][C:29]1[C:30]([NH:32][C@@H:33]2[CH2:38][CH2:37][CH2:36][CH2:35][C@H:34]2[NH:39][S:40]([CH3:43])(=[O:42])=[O:41])=[N:31][C:26]([NH:1][C:2]2[CH:22]=[CH:21][C:5]3[N:6]([CH2:19][CH3:20])[C:7](=[O:18])[CH:8]([NH:11][C:12](=[O:17])[C:13]([F:14])([F:15])[F:16])[CH2:9][CH2:10][C:4]=3[C:3]=2[O:23][CH3:24])=[N:27][CH:28]=1
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Reactant: CCN1C(=O)C(NC(=O)C(F)(F)F)CCc2c1ccc(N)c2OC
Product: CCN1C(=O)C(NC(=O)C(F)(F)F)CCc2c1ccc(Nc1ncc(Cl)c(N[C@@H]3CCCC[C@H]3NS(C)(=O)=O)n1)c2OC
Yield: 26.8 %

Procedure:
Following a procedure analogous to Example 113, N-(7-Amino-1-ethyl-6-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-2,2,2-trifluoro-acetamide (193 mgs) and N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (180 mgs) gave the title compounds as an off-white solid (92 mgs). 1:1 mix of diastereomers. 1H-NMR (CDCl3, 400 MHz): 8.29-8.24 (m, 1H), 8.05-8.02 (m, 1H), 7.59-7.52 (m, 1H), 7.02-7.00 (m, 1H), 4.55-4.53 (m, 2H), 3.94-3.90 (m, 1H), 3.85 (s, 1H), 3.59-3.53 (m, 1H), 3.38-3.32 (m, 1H), 3.16-3.10 (m, 1H), 2.90 (s, 3H), 2.76-2.68 (m, 1H), 2.57-2.52 (m, 1H), 2.20-1.20 (complex series of m, 12H); LC/MS: found (M+H)+=648; MP: 160-2° C.
Reaction SMILES: [CH3:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:14])=O>C(Cl)Cl.CN(C=O)C>[CH3:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:14])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1ncccc1C(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ncccc1C(=O)Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of methylnicotinic acid (500 mg, 3.6 mmol) in DCM (30 mL) is added oxalyl chloride (0.93 mL, 10.9 mmol) dropwise followed by DMF (1 drop). The reaction mixture is stirred at room temperature for 1 h and then concentrated in vacuo to give methylnicotinoyl chloride in a quantitative yield. A solution of I-83.1 (250 mg, 0.93 mmol) and methylnicotinoyl chloride (159.0 mg, 1.02 mmol) in DCM is stirred at room temperature for 1 h with the addition of more methylnicotinoyl chloride (28.9 mg, 0.19 mmol). The reaction mixture is then diluted with saturated aqueous NaHCO3 and the combined organics are dried over Na2SO4, The solvent is removed in vacuo to give I-110 (360 mg, quantitative).
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[N:5]=[C:4]([S:11]([CH3:14])(=[O:13])=[O:12])[N:3]=1.[CH3:15][O-:16].[Na+]>CO>[CH3:15][O:16][C:2]1[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[N:5]=[C:4]([S:11]([CH3:14])(=[O:13])=[O:12])[N:3]=1
Reactant: C[O-]
Reactant: CS(=O)(=O)c1nc(Cl)c2c(n1)CCC2
Agent: [Na+]
Solvent: CO
Product: COc1nc(S(C)(=O)=O)nc2c1CCC2
Reaction time: 2 h

Procedure:
18.05 g (90 mmol) of 4-chloro-2-methylsulfonyl-6,7-dihydro-5H-cyclopentapyrimidine were dissolved in 200 ml of methanol. At 45° C., 16.7 g of sodium methoxide (as 30% strength solutions in methanol) were added dropwise, and the mixture was stirred for 2 hours. The solution was evaporated, taken up in ethyl acetate and acidified with dilute hydrochloric acid, and the ethyl acetate extract was evaporated. 15.5 g of an oil remained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[NH2:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=3)=[CH:17][CH:18]=2)[N:13]=1.C(#N)C>O>[CH3:29][O:28][C:24]1[CH:23]=[C:22]([C:16]2[N:15]=[C:14]3[C:19]([CH:20]=[CH:21][C:12]([NH:11][C:5](=[O:7])[C:4]4[CH:8]=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=4)=[N:13]3)=[CH:18][CH:17]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: O=C(O)c1cccc(Br)c1
Reactant: COc1cccc(-c2ccc3ccc(N)nc3n2)c1
Solvent: CC#N
Solvent: O
Product: COc1cccc(-c2ccc3ccc(NC(=O)c4cccc(Br)c4)nc3n2)c1
Temperature: 4 °C
Yield: 13.2 %

Procedure:
The procedure is analogous to that described in Example 11, but starting with 3-bromobenzoic acid (4 g), N,N'-carbonyldiimidazole (3.2 g) and 2-amino-7-(3-methoxyphenyl)-1,8-naphthyridine (3.5 g). The product obtained by precipitation in water (4 g; m.p. approximately 90° C.) is dissolved in boiling acetonitrile (200 cc). After cooling for 3 hours at 4° C., the crystallized solid is separated by filtration, washed with acetonitrile (3×3 cc) and dried at 35° C. under reduced pressure (0.07 kPa). N-[7-(3-Methoxyphenyl)-1,8-naphthyridin-2-yl]-3-bromobenzamide (0.8 g), m.p. 104° C., is obtained.
Reaction SMILES: [CH2:1]([NH:7][S:8]([C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[C:13]([N+:18]([O-:20])=[O:19])[C:12]=1Cl)(=[O:10])=[O:9])[C@H:2]1[O:6][CH2:5][CH2:4][CH2:3]1.[H-].[Na+].[OH2:24]>>[CH2:1]([NH:7][S:8]([C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[C:13]([N+:18]([O-:20])=[O:19])[C:12]=1[OH:24])(=[O:10])=[O:9])[C@H:2]1[O:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)NC[C@@H]2CCCO2)c1Cl
Reactant: O
Agent: [H-]
Agent: [Na+]
Product: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)NC[C@@H]2CCCO2)c1O
Yield: 26.4 %

Procedure:
Following the general hydrolysis procedure outlined in example 15, N-((2S)-tetrahydrofurfuryl)-2,6-dichloro-3-nitrobenzenesulfonamide (1.12 g, 3.15 mmol), 80% NaH (284 mg, 9.47 mmol) and water (0.057 mL, 3.16 mmol) were reacted to form the desired product (280 mg, 26%). EI-MS m/z 335(M-H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21]Cl)=[CH:17][CH:16]=1.[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1B(O)O.ClCCl.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(COC)OC.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]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:25]2[S:24][CH:28]=[CH:27][CH:26]=2)=[CH:17][CH:16]=1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(CCl)cc1
Reactant: OB(O)c1cccs1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: COCCOC
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(Cc2cccs2)cc1
Yield: 61.7 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-4-(thiophen-2-ylmethyl)benzamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-(chloromethyl)benzamide (0.080 g; 0.230 mmol), thiophen-2-ylboronic acid (0.031 g; 0.242 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride, complex with dichloromethane (0.019 g; 0.023 mmol), sodium carbonate (0.050 g; 0.460 mmol), sodium iodide (0.069 g; 0.460 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 20 to 80% ethyl acetate in heptane) furnished 0.056 g (62%) of the title compound as a white solid.
Reaction SMILES: C([O:9][C@H:10]1[C@@H:14]2[CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18][N:13]2[CH2:12][CH2:11]1)(=O)C1C=CC=CC=1.CC(C)([O-])C.[K+]>CO>[OH:9][C@H:10]1[C@@H:14]2[CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18][N:13]2[CH2:12][CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCN2CC[C@@H](OC(=O)c3ccccc3)[C@@H]2C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN2CC[C@@H](O)[C@@H]2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of Example 35E (8 g, 0.023 mol) in methanol (25 mL) was added potassium t-butoxide (14.5 g, 0.129 mol), and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated, the residue was diluted with 5% citric acid in water (100 mL), and the mixture was extracted with ethyl acetate (50 mL×2). The combined organic layers were discarded. The aqueous layer was basified using K2CO3 to pH 8-9 and extracted with ethyl acetate (50 mL×2). The combined organic layers were dried over Na2SO4 and concentrated to give the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.48 (s, 9H), 1.56-1.69 (m, 1H), 1.86-1.97 (m, 1H), 2.10-2.35 (m, 3H), 2.35-2.48 (m, 1H), 2.52-2.72 (m, 1H), 2.78-2.97 (m, 2H), 3.03 (dt, 1H, J=17.1, 2.4 Hz), 3.92-4.15 (m, 2H), 4.32 (bs, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([O:10][CH:11]3[CH2:14][O:13][CH2:12]3)[N:7]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH2:21])[N:16]=3)[C:6]=2[CH:22]=1.[CH3:23][C:24]([OH:28])([C:26]#[CH:27])[CH3:25]>>[NH2:21][C:17]1[N:16]=[C:15]([N:7]2[C:6]3[CH:22]=[C:2]([C:27]#[C:26][C:24]([CH3:25])([OH:28])[CH3:23])[CH:3]=[CH:4][C:5]=3[N:9]=[C:8]2[O:10][CH:11]2[CH2:14][O:13][CH2:12]2)[CH:20]=[CH:19][N:18]=1
Reactant: Nc1nccc(-n2c(OC3COC3)nc3ccc(Br)cc32)n1
Reactant: C#CC(C)(C)O
Product: CC(C)(O)C#Cc1ccc2nc(OC3COC3)n(-c3ccnc(N)n3)c2c1

Procedure:
The title compound was prepared by the method described in Example 142-b, by reacting 4-[6-bromo-2-(oxetan-3-yloxy)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine with 2-methyl-3-butyn-2-ol: 1H NMR (DMSO, 500 MHz) delta 1.46 (6H, s), 4.73 (2H, dd, J=7.9, 4.9 Hz), 4.94 (2H, t, J=7.1 Hz), 5.40 (1H, s), 5.94-5.68 (1H, m), 7.17-6.99 (3H, m), 7.21 (1H, dd, J=8.2, 1.6 Hz), 7.41 (1H, d, J=8.2 Hz), 8.14 (1H, d, J=1.0 Hz), 8.39 (1H, d, J=5.5 Hz); LC-MS: m/z=+366.1 (M+H)+.