Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:21](=[O:22])[N:13]2[CH2:14][CH:15]3[CH2:20][CH2:19][N:18]([C:12]2=[N:11][C:10]=1[C:23]([OH:25])=O)[CH2:17][CH2:16]3)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[F:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][NH2:35])=[C:30]([N:36]2[CH2:40][C:39]([CH3:42])([CH3:41])[N:38]([CH3:43])[S:37]2(=[O:45])=[O:44])[CH:29]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C1C=CN=CC=1.CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[C:21](=[O:22])[N:13]2[CH2:14][CH:15]3[CH2:20][CH2:19][N:18]([C:12]2=[N:11][C:10]=1[C:23]([NH:35][CH2:34][C:31]1[CH:32]=[CH:33][C:28]([F:27])=[CH:29][C:30]=1[N:36]1[CH2:40][C:39]([CH3:41])([CH3:42])[N:38]([CH3:43])[S:37]1(=[O:45])=[O:44])=[O:25])[CH2:17][CH2:16]3)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1nc2n(c(=O)c1OCc1ccccc1)CC1CCN2CC1
Reactant: CN1C(C)(C)CN(c2cc(F)ccc2CN)S1(=O)=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CN1C(C)(C)CN(c2cc(F)ccc2CNC(=O)c2nc3n(c(=O)c2OCc2ccccc2)CC2CCN3CC2)S1(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 3-(benzyloxy)-4-oxo-6,7,8,9-tetrahydro-4H-7,10-ethanopyrimido[1,2-a][1,3]diazepine-2-carboxylic acid (0.03 g, 0.088 mmol), 1-(4-fluoro-2-(4,4,5-trimethyl-1,1-dioxido-1,2,5-thiadiazolidin-2-yl)phenyl)methanamine hydrochloride salt (0.043 g, 0.132 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (0.100 g, 0.264 mmol), 4-(dimethylamino)pyridine (DMAP) (1.074 mg, 8.79 μmol) and diisopropyl ethylamine (0.077 mL, 0.439 mmol) in DMF (2 mL) was stirred at room temperature for 1 h. The mixture was diluted with ethyl acetate and washed with 0.5 N HCl, water followed by brine. The organic phase was dried (Na2SO4), filtered and concentrated to give the title compound as a crude yellow oil. LCMS (M+H) calcd for C30H36FN6O5S: 611.24; found: 611.33.
Reaction SMILES: [N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([OH:20])[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[CH2:21]([C@H:23]([CH:33](O)[CH2:34][CH3:35])[CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH3:22].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.O.C(OCC)(=O)C>[N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:20][CH:33]([CH2:34][CH3:35])[C@@H:23]([CH2:21][CH3:22])[CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:29])([CH3:30])[CH3:31])[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CCC(O)[C@@H](CC)CNC(=O)OC(C)(C)C
Reactant: Oc1cccc2ccc(-c3nnc4ccccn34)nc12
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC(Oc1cccc2ccc(-c3nnc4ccccn34)nc12)[C@@H](CC)CNC(=O)OC(C)(C)C

Procedure:
2-([1,2,4]Triazolo[4,3-a]pyridin-3-yl)quinolin-8-ol (101 mg, 0.385 mmol), tert-butyl (2S )-2-ethyl-3-hydroxypentylcarbamate (89 mg, 0.385 mmol), PPh3 (151 mg, 0.577 mmol) and DEAD (90.9 μL, 0.577 mmol) were combined at ambient temperature in 5 mL anhydrous THF. The reaction mixture was heated at reflux for 6 hours. The crude mixture was cooled to ambient temperature and diluted with water and ethyl acetate. The crude mixture was extracted with ethyl acetate, and the combined organic layers were dried over Na2SO4 and concentrated in vacuo to provide the desired product.
Reaction SMILES: [I-].[Na+].[C:3]1([CH:9]2[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:23][Si:24]([CH3:27])([CH3:26])Cl>C(#N)C.CCCCCC.CCCCC>[CH3:23][Si:24]([CH3:27])([CH3:26])[O:15][C:12]1[CH2:13][CH2:14][CH:9]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:10][CH:11]=1
Reactant: C[Si](C)(C)Cl
Reactant: O=C1CCC(c2ccccc2)CC1
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: C[Si](C)(C)OC1=CCC(c2ccccc2)CC1
Temperature: 0 °C
Yield: 73 %

Procedure:
sodium iodide (12.4 mmol) dissolved in acetonitrile (12.4 ml), is added dropwise at room temperature to a solution of 4-phenylcyclohexanone (10 mmol) in hexane (10 ml), followed by triethylamine (12.4 mmol) and trimethylchlorosilane (12.4 mmol). After stirring for two hours cold pentane and ice water are added. The aqueous phase is extracted with hexane. The combined organic phases are washed with ice water, dried over sodium sulphate and the solvent is removed in a vacuum. Trimethyl-(4-phenyl-cyclohex-1-enyloxy)-silane (1.8 g) is obtained in pure form in a yield of 73% (Tetrahedron 1987, 43, 9, 2075-2088): tR 2.29 min (LC-2); ESI-MS (+): m/z 247.27 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:12][C:13](=[O:15])[CH3:14])[CH:6]=[C:7]([C:9]([CH3:11])=[CH2:10])[CH:8]=1)#[N:2].[BH4-].[Na+].Cl>CCO>[NH2:2][CH2:1][C:3]1[CH:4]=[C:5]([NH:12][C:13](=[O:15])[CH3:14])[CH:6]=[C:7]([CH:9]([CH3:11])[CH3:10])[CH:8]=1
Reactant: C=C(C)c1cc(C#N)cc(NC(C)=O)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(=O)Nc1cc(CN)cc(C(C)C)c1

Procedure:
To a stirring solution of 91.9 mg (0.459 mmol) of N-(3-cyano-5-(prop-1-en-2-yl)phenyl)acetamide and 110 mg (0.466 mmol) of CoCl2.6H2O in 3 mL of EtOH at 50° C. was added 118 mg of NaBH4 in 2 portions. After 3 h 45 min., 5 N HCl was added to a pH=1, and the mixture was concentrated. Ammonium hydroxide was added to a pH=9, and H2O was also added. The aqueous layer was extracted with the extract of (40 mL CHCl3: 5 mL of MeOH: 5 mL of H2O) (2×). The combined extracts were dried over Na2SO4, filtered, and concentrated to provide the crude N-(3-(aminomethyl)-5-isopropylphenyl)acetamide which was used without further purification.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[C:4]([OH:11])(=[O:10])/[CH:5]=[CH:6]\[C:7]([OH:9])=[O:8].NC[C:14]([NH:16][C:17]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:25]([F:28])([F:27])[F:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15].[C:35](O)(=O)/C=C\C(O)=O>CO>[C:4]([OH:11])(=[O:10])/[CH:5]=[CH:6]\[C:7]([OH:9])=[O:8].[CH3:1][N:2]([CH3:35])[CH2:3][C:14]([NH:16][C:17]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:25]([F:28])([F:27])[F:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15]
Reactant: CNC
Reactant: NCC(=O)NC(Cc1ccccc1)(c1ccccc1)C(F)(F)F
Agent: O=C(O)/C=C\C(=O)O
Solvent: CO
Product: CN(C)CC(=O)NC(Cc1ccccc1)(c1ccccc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 48 h
Yield: 64.5 %

Procedure:
To a stirred solution of dimethylamine (25 ml, 0.38 mol) in 150 ml of methanol at 0° C. under nitrogen, was added 2-chloro-N-[1,2-diphenyl-1-(trifluoromethyl)ethyl]acetamide (from Example 1) (7.0 g, 0.020 mol). The mixture was allowed to slowly warm to ambient temperature and stirred for 48 hours. The solvent was evaporated and the residue was dissolved in 150 ml of chloroform and 150 ml of water. The aqueous solution was basified to a pH of 10 with 50% NaOH. The phases were separated, the aqueous phase extracted with chloroform (2×75 ml) and the combined organic phases were washed with brine (75 ml), dried and evaporated to a dark oil, 7.2 g. This oil was purified by chromatograhy on a Prep 500 HPLC on silica gel, eluting with 10% ethylacetate/hexane. Pure fractions were combined and evaporated to 4.0 g of an oil. This oil was dissolved in 125 ml of methanol and treated with maleic acid (1.3 g, 0.012 mol) at reflux. The solution was concentrated to a volume of 75 ml. The crystalline salt which formed, was vacuum dried to give 3.61 g of 2-(dimethylamino)-N-[1,2-diphenyl-1-(trifluoromethyl)ethyl]acetamide maleate as a white solid, mp 213°-215° C.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:16]2[C:11](=[CH:12][C:13]([Br:17])=[CH:14][CH:15]=2)[NH:10][C:9]1=[O:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([S:36]([N:39]([CH3:41])[CH3:40])(=[O:38])=[O:37])=[CH:32][CH:31]=1>CN(C)C=O>[C:1]([O:5][C:6]([C:8]1([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:16]2[C:11](=[CH:12][C:13]([Br:17])=[CH:14][CH:15]=2)[N:10]([CH2:29][C:30]2[CH:31]=[CH:32][C:33]([S:36](=[O:38])(=[O:37])[N:39]([CH3:40])[CH3:41])=[CH:34][CH:35]=2)[C:9]1=[O:18])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)C1(C(=O)OC(C)(C)C)C(=O)Nc2cc(Br)ccc21
Reactant: CN(C)S(=O)(=O)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)S(=O)(=O)c1ccc(CN2C(=O)C(C(=O)OC(C)(C)C)(C(=O)OC(C)(C)C)c3ccc(Br)cc32)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 114.2 %

Procedure:
6-Bromo-2-oxo-1,2-dihydro-indole-3,3-dicarboxylic acid di-tert-butyl ester (5.10 g, 12.4 mmol) was dissolved in 40 ml of anhydrous N,N-dimethylformamide (DMF) under an atmosphere of dry N2. The solution was cooled to 0° C. after which time 60% sodium hydride in oil (500 mg, 12.4 mmol) was added and the solution was then stirred for 15 minutes at this temperature. The reaction mixture was the warmed to ambient temperature and stirred for 15 minutes after which time 4-bromomethyl-N,N-dimethyl-benzenesulfonamide (3.44 g, 12.4 mmol) was added. The mixture was stirred overnight after which time it was concentrated under vacuum and partitioned between DCM and water. The DCM layer was washed 3 more times with water, once with brine, dried over MgSO4, filtered and concentrated under vacuum to give 8.63 g of the titled compound as a yellow solid
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.O1[CH2:14][CH2:13][NH:12]C1=O>COCCOCCO>[CH3:2][C:3]1[CH:9]=[CH:8][C:6]([NH:7][CH2:14][CH2:13][NH2:12])=[CH:5][CH:4]=1
Reactant: Cc1ccc(N)cc1
Reactant: O=C1NCCO1
Agent: Cl
Solvent: COCCOCCO
Product: Cc1ccc(NCCN)cc1
Temperature: 170 °C
Yield: 76 %

Procedure:
A mixture of 4-methylaniline hydrochloride (15.0 g, 0.10 mole), 2-oxazolidinone (8.7 g, 0.10 mole) and 40 ml of 2-(2-methoxyethoxy)ethanol was heated in an oil bath to 170° C. for four hours. On cooling to room temperature, a solid formed. Workup as described in Examples 1 and 8, followed by distillation at 110° C. to 120° C. (1.5 mm Hg) gave a 76 percent yield of the material as a clear liquid which slowly solidified on standing at ambient temperatures to a low-melting solid.
Reaction SMILES: C(N)(=O)C.[CH3:5][N:6]1[C:11]2=[CH:12][N:13]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[NH:27]C(=O)C)[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:10]2[C:9](=[O:31])[N:8]([CH3:32])[C:7]1=[O:33]>Cl>[NH2:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[N:13]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:10]2[C:11]([N:6]([CH3:5])[C:7](=[O:33])[N:8]([CH3:32])[C:9]2=[O:31])=[CH:12]1
Reactant: CC(=O)Nc1ccccc1-n1cc2c(c1-c1ccccc1)c(=O)n(C)c(=O)n2C
Agent: CC(N)=O
Agent: Cl
Product: Cn1c(=O)c2c(-c3ccccc3)n(-c3ccccc3N)cc2n(C)c1=O
Yield: 69.3 %

Procedure:
Acetamide compound 5 (200 mg, 0.5 mmol) was refluxed in hydrochloric acid (4 N, 10 mL) for 6 h. The reaction mixture was evaporated under vacuum, and the residue was dissolved in water and neutralized to give 6 (120 mg, 67%) as a white precipitate: mp>300° C.; 1H NMR (DMSO-d6): δ 7.32-7.26 (m, 2H), 7.23-7.15 (m, 3H), 7.00 (t, 1H, J=7.32 Hz), 6.87 (s, 1H), 6.80 (d, 1H, J=7.69), 6.70 (d, 1H, J=8.06 Hz), 6.41 (t, 1H, J=7.32 Hz), 5.00 (s, 2H), 3.29 (s, 3H), 3.16 (s, 3H); MS (ES+) (m/z): [M+1]+ calculated for C20H19N4O2, 347.39. found 347.10.
Reaction SMILES: [Cl:1][C:2]1[C:19]([F:20])=[CH:18][CH:17]=[C:16]([F:21])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13](I)=[CH:14][C:6]1=2.[Cl:22][C:23]1[CH:28]=[CH:27][C:26](B2OC(C)(C)C(C)(C)O2)=[CH:25][N:24]=1>>[Cl:1][C:2]1[C:19]([F:20])=[CH:18][CH:17]=[C:16]([F:21])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13]([C:27]3[CH:26]=[CH:25][N:24]=[C:23]([Cl:22])[CH:28]=3)=[CH:14][C:6]1=2
Reactant: Fc1ccc(F)c(CN2CCNc3ncc(I)cc32)c1Cl
Reactant: CC1(C)OB(c2ccc(Cl)nc2)OC1(C)C
Product: Fc1ccc(F)c(CN2CCNc3ncc(-c4ccnc(Cl)c4)cc32)c1Cl
Yield: 50 %

Procedure:
1-(2-Chloro-3,6-difluorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (308 mg) was coupled to 2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine as in General Procedure 4B to give the title compound (50% yield). LCMS: m/z=407.32 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 3.30 (2H, t, J=4.8 Hz), 3.56 (2H, m), 4.34 (2H, s), 5.35 (1H, bs), 7.06 (2H, m), 7.15 (1H, m), 7.33 (1H, dd, J=5.3, 1.5 Hz), 5.46 (1H, m), 7.80 (1H, d, J=1.5 Hz), 8.34 (1H, d, J=5.3 Hz).
Reaction SMILES: C[O-].[Na+].[OH:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][OH:10])=[CH:7][CH:6]=1.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20](Br)[SiH:21]([CH3:23])[CH3:22])=[CH:16][CH:15]=1>CN(C=O)C>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([CH:20]([SiH:21]([CH3:23])[CH3:22])[O:4][C:5]2[CH:12]=[CH:11][C:8]([CH2:9][OH:10])=[CH:7][CH:6]=2)=[CH:18][CH:19]=1
Reactant: C[SiH](C)C(Br)c1ccc(Br)cc1
Reactant: OCc1ccc(O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[SiH](C)C(Oc1ccc(CO)cc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.6 %

Procedure:
Sodium methoxide (4.17 g, 73.4 mmole) was added under argon to a solution of 4-hydroxybenzyl alcohol (8.67 g, 69.9 mmol) in dry DMF (70 mL) and the reaction mixture was stirred for 30 minutes at room temperature. 4-Bromophenyldimethylsilylmethyl-bromide (22.6 g, 73.4 mmol) was added through a canula and the reaction was stirred at RT for 30 minutes and at 65° C. for 45 minutes. The reaction was poured into ice water (250 mL) and extracted with ethyl acetate. The combined extracts were washed with water, 5% sodium bicarbonate and brine and the dried (Na2 SO4). The solution was concentrated to an oil at reduced pressure and purified by flash chromatography (silica gel, 20% ethyl acetate/hexane) to yield the product as a clear, colorless oil (9.23 g, 38%). 1H NMR (400 MHz, CDCl3) 7.48 (dd, 4H), 7.10 (dd, 4H), 4.61 (s, 2H), 3.77 (s, 2H), 0.42 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:22])=[C:5]([C:13]([C:15]2[CH:16]=[N:17][N:18]([CH3:21])[C:19]=2[OH:20])=[O:14])[CH:6]=[CH:7][C:8]=1[S:9]([CH3:12])(=[O:11])=[O:10].C(N(CC)CC)C.[CH3:30][CH2:31][S:32][C:33](Cl)=[O:34].C(OCC)(=O)C>O1CCCC1>[CH3:1][O:2][C:3]1[C:4]([CH3:22])=[C:5]([C:13]([C:15]2[CH:16]=[N:17][N:18]([CH3:21])[C:19]=2[O:20][C:33]([S:32][CH2:31][CH3:30])=[O:34])=[O:14])[CH:6]=[CH:7][C:8]=1[S:9]([CH3:12])(=[O:10])=[O:11]
Reactant: COc1c(S(C)(=O)=O)ccc(C(=O)c2cnn(C)c2O)c1C
Reactant: CCSC(=O)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCSC(=O)Oc1c(C(=O)c2ccc(S(C)(=O)=O)c(OC)c2C)cnn1C
Reaction time: 1 h

Procedure:
To a solution of 5-hydroxy-1-methylpyrazol-4-yl 3-methoxy-2-methyl-4-(methylsulfonyl)phenyl ketone (100 mg, 0.3 mmol) in dry tetrahydrofuran (5 mL) were added triethylamine (61 mg) and 96% S-ethyl chlorothiolformate (50 mg) at room temperature. After the reaction solution was stirred for 1 hour, 150 mL of ethyl acetate was added. The mixture was washed twice with a saturated brine, the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1) to obtain the desired product as an oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[C:14]([NH2:17])[CH:15]=[CH:16][C:11]=3[N:10]=[CH:9]2)[CH:5]=[N:4][CH:3]=1.[CH2:18]([NH:20][CH2:21][CH3:22])[CH3:19].CCN(C(C)C)C(C)C>C(OC(O)C)C>[CH2:18]([N:20]([CH2:21][CH3:22])[C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[C:14]([NH2:17])[CH:15]=[CH:16][C:11]=3[N:10]=[CH:9]2)[CH:5]=[N:4][CH:3]=1)[CH3:19]
Reactant: Nc1ccc2ncn(-c3cncc(Cl)n3)c2c1
Reactant: CCNCC
Agent: CCOC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)c1cncc(-n2cnc3ccc(N)cc32)n1

Procedure:
A solution of 1-(6-chloropyrazin-2-yl)-1H-benzimidazol-6-amine (100 mg, 0.41 mmol) and diethylamine (430 μL, 4.1 mmol) in ethoxyethanol (2 mL) containing DIPEA (140 μL) was heated in a sealed tube overnight under N2. The solution was concentrated under reduced pressure and the residue dissolved in EtOAc (20 mL) and washed successively with H2O (20 mL) and brine (20 mL). After drying (Na2SO4) the solvent was removed under reduced pressure and the residue chromatographed eluting with dichloromethane-methanol (9:1-94:6) to separate pure product from the lower fractions (110 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:16]([O-])=O)=[C:6]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:7]=1>CO.[Pd]>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:16])=[C:6]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:7]=1
Reactant: Cc1ccc([N+](=O)[O-])c(CCN2CCOCC2)c1
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(N)c(CCN2CCOCC2)c1
Temperature: 40 °C
Reaction time: 1 h
Yield: 83.3 %

Procedure:
4-[2-(5-Methyl-2-nitro-phenyl)ethyl]morpholine (150 mg, 0.599 mmol) and Pd (10%, wet) (128 mg, 0.0599 mmol) were brought up in methanol (5 mL) under H2 atmosphere and stirred vigorously for 1 h at 40° C. The reaction was filtered and concentrated in vacuo to provide 4-methyl-2-(2-morpholinoethyl)aniline (110 mg, 0.499 mmol, 83%) as an amber oil. LC/MS m/z 221.2 [M+H]+. 1H NMR (400.0 MHz, DMSO-d6) δ 6.72-6.68 (m, 2H), 6.51 (d, J=7.9 Hz, 1H), 4.64 (s, 2H), 3.58 (t, J=4.6 Hz, 4H), 2.57-2.53 (m, 2H), 2.44-2.40 (m, 6H), 2.11 (s, 3H).
Reaction SMILES: [O:1]([CH2:8][C:9]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[C:12]2[CH:26]=[CH:27][C:28]([C:30]([OH:32])=O)=[CH:29][C:11]=2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)N=C=NC(C)C.[CH2:42]([NH2:49])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48]>C1COCC1>[CH2:42]([NH:49][C:30]([C:28]1[CH:27]=[CH:26][C:12]2[N:13]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]([F:23])([F:24])[F:25])=[CH:19][CH:20]=3)[C:9]([CH2:8][O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[N:10][C:11]=2[CH:29]=1)=[O:32])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48]
Reactant: CCCCCCCN
Reactant: O=C(O)c1ccc2c(c1)nc(COc1ccccc1)n2Cc1ccc(OC(F)(F)F)cc1
Agent: CC(C)N=C=NC(C)C
Solvent: C1CCOC1
Product: CCCCCCCNC(=O)c1ccc2c(c1)nc(COc1ccccc1)n2Cc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.16 mmol of 2-phenoxymethyl-1-(4-trifluoromethoxy-benzyl)-1H-benzoimidazole-5-carboxylic acid were dissolved in 1 ml THF with 1 eq. DIC. After 15 min 1.5 eq of heptylamine were added and the reaction stirred at room temperature for 16 h. The crude material was purified via reversed phase preparative HPLC. MS(ISP): 540.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[C:9]1([S:15]([N:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20](B(O)O)=[CH:19]2)(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.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:9]1([S:15]([N:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)=[CH:19]2)(=[O:17])=[O:16])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: O=S(=O)(c1ccccc1)n1cc(B(O)O)c2ccccc21
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: [Na+]
Solvent: CC#N
Solvent: O
Product: O=S(=O)(c1ccccc1)n1cc(-c2ccnc(Cl)n2)c2ccccc21

Procedure:
A solution of 2,4-dichloropyrimidine (2.42 g, 16 mmol), 1-(phenylsulfonyl)-1H-indol-3-ylboronic acid (3.89 g, 13 mmol) and sodium carbonate (5.03 g, 47 mmol) in acetonitrile/water (2:1, 60 mL) was degassed with argon, then tetrakis(triphenylphosphine)palladium (300 mg, 1.6 mol) was added. The resulting mixture was heated to reflux for 2 h while a white suspension formed. The precipitate was cooled and filtered through a CELITE™/Silica gel plug. The filter cake was washed with EtOAc, the organic layer separated, washed with brine, dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was recrystallized from EtOAc/hexanes to give 1-benzenesulfonyl-3-(2-chloro-pyrimidin-4-yl)-1H-indole as a light-pink solid. The solid filtrate from the reaction mixture was dissolved in DCM, dried over Na2SO4, filtered, and combined with the previous batch of product. The collected solids were dissolved in DCM, the solvent was evaporated under reduced pressure and EtOAc was added to form a suspension, the product was filtered and washed with hexanes, to give 1-benzenesulfonyl-3-(2-chloro-pyrimidin-4-yl)-1H-indole (2.0 g, 33% yield) as a light-pink solid. An additional 0.45 g of product was obtained from the mother liquors.
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH:12]=[C:13]([O:16][CH2:17][CH2:18][O:19][CH2:20][C:21]([OH:23])=[O:22])[CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:30](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C)C=O>[CH3:30][O:22][C:21](=[O:23])[CH2:20][O:19][CH2:18][CH2:17][O:16][C:13]1[CH:14]=[CH:15][C:10]2[N:9]=[C:8]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:11]=2[CH:12]=1
Reactant: O=C(O)COCCOc1ccc2nc(-c3ccccc3)n(-c3ccccc3)c2c1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)COCCOc1ccc2nc(-c3ccccc3)n(-c3ccccc3)c2c1
Reaction time: 20 h

Procedure:
35 mg of 2-[2-[(1,2-diphenyl-1H-benzimidazol-6-yl)oxy]ethoxy]acetic acid was dissolved in 0.4 ml of N,N-dimethylformamide and mixed with 29 mg of cesium carbonate and 50 μl of methyl iodide. It was stirred for 20 hours, then concentrated by evaporation in a vacuum and chromatographed on silica gel.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:13][CH2:12][C@@H:11]3[CH2:14][CH2:15][CH2:16][N:10]3[C:9](=[O:17])[C:8]=2[CH:18]=1)([O-])=O.CO.[H][H]>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[O:13][CH2:12][C@@H:11]3[CH2:14][CH2:15][CH2:16][N:10]3[C:9](=[O:17])[C:8]=2[CH:18]=1
Reactant: [H][H]
Reactant: O=C1c2cc([N+](=O)[O-])ccc2OC[C@@H]2CCCN12
Agent: [Pd]
Solvent: CCO
Solvent: CO
Product: Nc1ccc2c(c1)C(=O)N1CCC[C@H]1CO2
Yield: 93.8 %

Procedure:
A solution of (S)-7-nitro-2,3,11,11a-tetrahydro-1H,5H-pyrrolo[2,1-c][1,4]benzoxazepine-5-one (7.4 g), prepared as described in Example 3L, in ethanol (100 ml) and methanol (50 ml) was hydrogenated over 10% palladium on activated carbon under 2 bar hydrogen, until the uptake of hydrogen ceased. The mixture was filtered to remove the catalyst and evaporated to dryness in vacuo. The crude product was passed through a short silica column (eluting with 10% methanol in dichloromethane) to give the title product (6.1 g). EIMS: m/z=219 [M+H]+