Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH:14]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=2)[NH:13][C:12](=[O:24])[C@@H:11]1[CH2:25][CH:26]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Br[CH2:34][C:35]([O:37][CH3:38])=[O:36]>CN(C=O)C>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH:14]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=2)[N:13]([CH2:34][C:35]([O:37][CH3:38])=[O:36])[C:12](=[O:24])[C@@H:11]1[CH2:25][CH:26]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CC(c2cc(F)cc(F)c2)NC(=O)[C@@H]1CC1CCCCCC1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CN1C(=O)[C@H](CC2CCCCCC2)N(C(=O)OC(C)(C)C)CC1c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under a nitrogen atmosphere 10 mg (0.23 mmol) sodium hydride were added at 0° C. to 90 mg (0.21 mmol) (2S)-tert-butyl-2-(cycloheptylmethyl)-5-(3,5-difluorophenyl)-3-oxopiperazine-1-carboxylate in 3 ml DMF. After 30 min at 0° C. 0.02 ml (0.26 mmol) methyl bromoacetate were added and then the reaction mixture was heated to RT overnight.
Reaction SMILES: [C:1](=[O:10])([O:6][CH:7]([CH3:9])[CH3:8])[O:2][CH:3](Cl)[CH3:4].[I-:11].[Na+].C1OCCOCCOCCOCCOCCOC1.C(OCC)(=O)C>C1(C)C=CC=CC=1>[C:1](=[O:10])([O:6][CH:7]([CH3:9])[CH3:8])[O:2][CH:3]([I:11])[CH3:4]
Reactant: CC(C)OC(=O)OC(C)Cl
Reactant: [I-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)OC(=O)OC(C)I
Temperature: 100 °C
Reaction time: 5 h
Yield: 97.5 %

Procedure:
To a solution of 1-chloroethyl isopropyl carbonate (1.00 g) in toluene (30 mL), sodium iodide (2.10 g) and 18-crown-6 (185 mg) were added at room temperature, and the mixture was stirred at 100° C. for 5 hours. To the reaction solution, ethyl acetate was added, and the mixture was washed with water and 5% aqueous sodium thiosulfate in this order and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain a crude product of the title compound (1.51 g).
Reaction SMILES: [C:1]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:6]=[CH:5][C:4]([N:7]2[C:19]3[CH:18]=[C:17]4[C:20]([CH3:28])([CH3:27])[C:21]5[C:26]([C:16]4=[CH:15][C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)=[CH:25][CH:24]=[CH:23][CH:22]=5)=[CH:3][CH:2]=1.[Br:35]N1C(=O)CCC1=O>C(#N)C>[C:1]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:2]=[CH:3][C:4]([N:7]2[C:19]3[CH:18]=[C:17]4[C:20]([CH3:27])([CH3:28])[C:21]5[C:26]([C:16]4=[CH:15][C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[C:11]([Br:35])[CH:12]=3)=[CH:25][CH:24]=[CH:23][CH:22]=5)=[CH:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1(C)c2ccccc2-c2cc3c4ccccc4n(-c4ccc(-c5ccccc5)cc4)c3cc21
Solvent: CC#N
Product: CC1(C)c2ccccc2-c2cc3c4cc(Br)ccc4n(-c4ccc(-c5ccccc5)cc4)c3cc21
Reaction time: 18 h
Yield: 52.7 %

Procedure:
17.5 g (40.18 mmol) of 10-biphenyl-4-yl-12,12-dimethyl-10,12-dihydro-10-azaindeno[2,1-b]fluorene are suspended in 450 ml of acetonitrile, and 7.15 g (40.18 mmol) of N-bromosuccinimide are added in portions at −20° C. at such a rate that the reaction temperature does not rise above −20° C. The mixture is stirred for a further 18 h, during which the temperature is allowed to come to RT. The reaction mixture is subsequently evaporated in a rotary evaporator, dissolved in dichloromethane and washed with water. The residue is dried, evaporated and subsequently recrystallised from toluene to a purity of 99.3%, giving 10.9 g (53%) of the product as a white solid.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:14]1(=O)[CH2:18][CH2:17][CH2:16][CH2:15]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>ClCCCl.C1COCC1>[CH:14]1([N:11]2[CH2:12][CH2:13][N:8]([C:5]3[CH:4]=[CH:3][C:2]([I:1])=[CH:7][CH:6]=3)[CH2:9][CH2:10]2)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=C1CCCC1
Reactant: Ic1ccc(N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Ic1ccc(N2CCN(C3CCCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 82 %

Procedure:
To a mixture of 1-(4-iodophenyl)piperazine (1.44 g, 5 mmol) and cyclopentanone (840 mg, 10 mmol) in DCE/THF (40 mL/20 mL) was added NaBH(OAc)3 (1.484 g, 7 mmol), followed by AcOH (0.5 mL). After addition, the resulting mixture was stirred 22 h at rt. After quenching with sat. NaHCO3 (20 mL), H2O (20 mL) and brine (20 mL), the solution was extracted with EtOAc (60 mL+30 mL). Removal of solvents, followed by trituration with MeOH afforded the crude title compound as a pale yellow solid (1.46 g, 82%). 1H NMR (400 MHz, DMSO-d6) δ 7.52 (d, J=8.4 Hz, 2H), 6.70 (d, J=8.4 Hz, 2H), 3.20 (t, J=4.8 Hz, 4H), 2.66 (t, J=4.6 Hz, 4H), 2.54 (p, J=7.6 Hz, 1H), 1.96-1.87 (m, 2H), 1.78-1.52 (m, 4H), 1.50-1.38 (m, 2H); MS ESI 357.0 [M+H]+, calcd. for [C15H21IN2+H]+ 357.1.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:20]2[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=2)[C:14]([N:22]2[C:26]([C:27]3[C:35]4[C:30](=[CH:31][C:32]([O:36]CC5C=CC=CC=5)=[CH:33][CH:34]=4)[N:29]([CH3:44])[CH:28]=3)=[N:25][NH:24][C:23]2=[O:45])=[CH:13]1>CO.[Pd]>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:20]2[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=2)[C:14]([N:22]2[C:26]([C:27]3[C:35]4[C:30](=[CH:31][C:32]([OH:36])=[CH:33][CH:34]=4)[N:29]([CH3:44])[CH:28]=3)=[N:25][NH:24][C:23]2=[O:45])=[CH:13]1
Reactant: Cn1cc(-c2n[nH]c(=O)n2-c2cn(CCCN)c3ccc(F)cc23)c2ccc(OCc3ccccc3)cc21
Agent: [Pd]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: Cn1cc(-c2n[nH]c(=O)n2-c2cn(CCCN)c3ccc(F)cc23)c2ccc(O)cc21
Yield: 69.5 %

Procedure:
The compound obtained in Example 63 (176 mg, 0.28 mmol) was dissolved in methanol (100 mL) and palladium (10 wt. % on activated charcoal, 200 mg) was added. The mixture was hydrogenated at ambient temperature at 60 psi over night, filtered through Celite® and concentrated in vacuo. The residue was purified by HPLC and lyophilized to give the title compound (104 mg, 69%).
Reaction SMILES: [CH:1]1([O:4][C@H:5]2[CH2:10][CH2:9][C@H:8]3[C@H:11]4[C@H:21]([CH2:22][CH2:23][C@:6]23[CH3:7])[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:24])[CH2:17][CH2:18]2)[CH2:13][CH2:12]4)[CH2:3][CH2:2]1.CC(C)([O-])C.[K+].[N+:31]([O-])([O:33]C(C)C)=[O:32].CO>C(Cl)(Cl)Cl>[CH:1]1([O:4][C@H:5]2[CH2:10][CH2:9][C@H:8]3[C@H:11]4[C@H:21]([CH2:22][CH2:23][C@:6]23[CH3:7])[C@:19]2([CH3:20])[C:14](=[C:15]([N+:31]([O-:33])=[O:32])[C:16](=[O:24])[CH2:17][CH2:18]2)[CH2:13][CH2:12]4)[CH2:2][CH2:3]1
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2OC1CC1
Reactant: CC(C)O[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: C[C@]12CC[C@H]3[C@@H](CCC4=C([N+](=O)[O-])C(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2OC1CC1

Procedure:
17β-cyclopropyloxy-androst-4-en-3-one (9.70 g, 29.5 mM), potassium tert-butoxide (7.0 g, 62.4 mM), and isopropyl nitrate (2.99 ml) are reacted by the method of Example 1 to yield 17β-cyclopropyloxy-4-nitroandrost-4-en-3-one, m.p. 137°-38° C. (methanol) IR (CHCl3) , 1695, 1622(m) , 1535, 1373 cm-1MS(CI) 374(100%, M+10, 316(20%, M+1-c-C3H5 -O) 1H-NMR (CDCl3) 0.38-0.61(4H, m), 0.80(3H, s, C18 -Me), 1.29(s, C19 -Me), 3.25-3.33(1H, m, cyclopropyl-CHO), 3.44(1H, t, C17 -H) .
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9](=[O:14])N(OC)C)([CH3:4])([CH3:3])[CH3:2].Br[C:25]1[CH:26]=[CH:27][C:28]([O:31][CH:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[N:29][CH:30]=1>>[C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9](=[O:14])[C:25]1[CH:30]=[N:29][C:28]([O:31][CH:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[CH:27][CH:26]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CON(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1
Reactant: Brc1ccc(OC2CCOCC2)nc1
Product: CC(C)(C)OC(=O)NC(C(=O)c1ccc(OC2CCOCC2)nc1)c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared from rac-[(3,4-dichloro-phenyl)-(methoxy-methyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester (Intermediate 9) and 5-bromo-2-(tetrahydro-pyran-4-yloxy)-pyridine (Intermediate 20) in analogy to Example 1a): MS (ISN): 479.1 and 481.2 (M−H)−.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([N:6]1[CH:14]2[CH:9]([CH2:10][CH2:11][CH2:12][CH2:13]2)[CH2:8][C@H:7]1[C:15]([OH:17])=[O:16])=[O:5])[CH3:3].[O:18]([CH2:25][C:26](=O)[C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O(CC(=O)C(O)=O)C1C=CC=CC=1.C([BH3-])#N.[Na+]>>[C:27]([CH:26]([NH:1][C@H:2]([C:4]([N:6]1[CH:14]2[CH:9]([CH2:10][CH2:11][CH2:12][CH2:13]2)[CH2:8][C@H:7]1[C:15]([OH:17])=[O:16])=[O:5])[CH3:3])[CH2:25][O:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)([O:29][CH2:30][CH3:31])=[O:28]
Reactant: CCOC(=O)C(=O)COc1ccccc1
Reactant: C[C@H](N)C(=O)N1C2CCCCC2C[C@H]1C(=O)O
Agent: O=C(O)C(=O)COc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCOC(=O)C(COc1ccccc1)N[C@@H](C)C(=O)N1C2CCCCC2C[C@H]1C(=O)O

Procedure:
React 1-[(S)-alanyl]octahydroindole-2(S)-carboxylic acid (preparable as described in Example 1) and ethyl phenoxypyruvate, (prepared from esterification of phenoxypyruvic acid as described in Example 9) with sodium cyanoborohydride as described in Example 1 to give the title compound.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][Si:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][CH:3]=1.[CH2:14]([C:18]1[CH:23]=[CH:22][C:21]([C:24]#[CH:25])=[CH:20][CH:19]=1)[CH2:15][CH2:16][CH3:17].C(N(CC)CC)C>[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.C1COCC1>[CH3:11][Si:10]([C:9]#[C:8][C:5]1[CH:6]=[CH:7][C:2]([C:25]#[C:24][C:21]2[CH:22]=[CH:23][C:18]([CH2:14][CH2:15][CH2:16][CH3:17])=[CH:19][CH:20]=2)=[CH:3][CH:4]=1)([CH3:13])[CH3:12]
Reactant: C#Cc1ccc(CCCC)cc1
Reactant: C[Si](C)(C)C#Cc1ccc(I)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCc1ccc(C#Cc2ccc(C#C[Si](C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 39.7 %

Procedure:
4-iodophenytrimethyl silylacetylene (5.0 g, 16.6 mmol), 4-n-butylphenylacetylene (2.67 g, 16.0 mmol), CuI (32 mg, 0.16 mmol), bis(triphenylphosphine)palladium(II)dichloride (0.35 g, 0.48 mmol), triethylamine (50 mL) and THF (50 mL) were added together and stirred at ambient temperature under N2 for 18 h. The reaction mixture was filtered to remove solids and concentrated to dryness, redissolved in CHCl3, washed with water (2×), brine, dried with MgSO4, filtered, concentrated and the solid recrystallized from hexanes to give 2.10 g (40%) product. The crude product could also be purified by washing with MeOH. This gave 1.94 g additional product for a total yield of 79%. 1H NMR (CDCl3) δ: 7.46 (m, 6H), 7.20 (d, J=8.11 Hz, 2H); 2.63 (t, J=7.6 Hz, 2H); 1.62 (m, 2H); 1.38 (m, 2H); 0.95 (t, J=7.2 Hz, 3H); 0.28 (s, 9H). 13C {1H} NMR (CDCl3): 143.7, 131.9, 131.6, 131.3, 128.5, 123.6, 122.7, 120.1, 104.7, 96.1, 91.6, 88.4, 35.6, 33.4, 22.3, 14.0, −0.1 ppm.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[C:5]([OH:12])[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O.[CH:13](O)=O>CO.[Fe]>[CH3:1][N:2]1[C:3]2[CH:4]=[C:5]([OH:12])[CH:6]=[CH:7][C:8]=2[N:9]=[CH:13]1
Reactant: O=CO
Reactant: CNc1cc(O)ccc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CO
Product: Cn1cnc2ccc(O)cc21
Temperature: 100 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
To a suspension of 3-methylamino-4-nitro-phenol (300 mg, 1.786 mmol) in formic acid (4 mL) was added iron powder (1.0 g, 17.86 mmol). The reaction mixture was stirred at 100° C. overnight, then it was cooled to room temperature and diluted with methanol. The insolubles were filtered and washed with methanol. The filtrate was concentrated in vacuo and adsorbed on silica gel. Purification by flash chromatography on silica gel using a gradient of 0-15% methanol/dichloromethane afforded 249 mg of 3-methyl-3H-benzoimidazol-5-ol as a light brown solid (94% yield): 1H NMR (DMSO-d6) δ 3.71 (s, 3H), 6.69 (dd, 1H), 6.81 (d, 1H), 7.40 (d, 1H), 7.94 (s, 1H), 9.3 (broad s, 1H); MS (m/z) 149 [M+H]+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][C:13](=[O:17])[NH:14]2)=[CH:9][CH:8]=1.[F:18][C:19]1[CH:33]=[CH:32][C:22]2[C:23]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[N:24][O:25][C:21]=2[CH:20]=1.C(=O)([O-])[O-].[K+].[K+].Cl.CCO>C(O)C.CC(C)=O>[ClH:1].[F:18][C:19]1[CH:33]=[CH:32][C:22]2[C:23]([CH:26]3[CH2:27][CH2:28][N:29]([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]4[CH:16]=[C:15]5[C:10]([CH2:11][CH2:12][C:13](=[O:17])[NH:14]5)=[CH:9][CH:8]=4)[CH2:30][CH2:31]3)=[N:24][O:25][C:21]=2[CH:20]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: O=C1CCc2ccc(OCCCCCl)cc2N1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCO
Product: O=C1CCc2ccc(OCCCCN3CCC(c4noc5cc(F)ccc45)CC3)cc2N1
Yield: 42.2 %

Procedure:
7-(4-chlorobutoxy)-3,4-dihydro-2(1H)-quinolinone (297 mg, 1 mmol), 4-(6-fluoro-1,2-benzisoxazolyl)-piperidine (242 mg, 1.1 mmol), and anhydrous potassium carbonate powder (414 mg, 3.3 mmol) are added to 10 ml and react at reflux for 24 hours. The reaction solution is evaporated to dryness and dispersed with 20 ml of dichloromethane and 20 ml of water respectively. The organic layer is extracted with water (20 ml×2) and saturated saline (20 ml) successively, dried over anhydrous magnesium sulfate, and evaporated to dryness to obtain a light yellow powder. The powder is dissolved with 5 ml of acetone and stirred in an ice bath. A white solid precipitates and is filtered, washed with small amount of acetone, and dried to obtain 260 mg of a whiter powder. The powder is dissolved in anhydrous ethanol and then thereto is drop-added HCl/EtOH to adjust to pH=2. A white deposit precipitates and is filtered out and recrystallized in anhydrous ethanol to obtain 200 mg of a product, with a yield of 42%.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][C@@H:9]([CH3:12])[CH2:10][CH3:11])=[C:6](Cl)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:16][CH:15]=2)[N:3]=1.C[C@@H](CC)CBr.C(OCC)(=O)CC(OCC)=O.C[O-].[Na+].Cl.C(OC1C=CC(C(N)=N)=CC=1)CCCCCC.OC1C(C[C@@H](C)CC)=C(O)N=C(C2C=CC(OCCCCCCC)=CC=2)N=1.CN(C)C1C=CC=CC=1.[H][H]>[Pd].C(N(CC)CC)C.CO>[CH2:21]([O:20][C:17]1[CH:18]=[CH:19][C:14]([C:4]2[N:3]=[CH:2][C:7]([CH2:8][C@@H:9]([CH3:12])[CH2:10][CH3:11])=[CH:6][N:5]=2)=[CH:15][CH:16]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: [H][H]
Reactant: CCCCCCCOc1ccc(-c2nc(Cl)c(C[C@@H](C)CC)c(Cl)n2)cc1
Agent: [Pd]
Agent: CCCCCCCOc1ccc(-c2nc(O)c(C[C@@H](C)CC)c(O)n2)cc1
Agent: CCCCCCCOc1ccc(C(=N)N)cc1
Solvent: CN(C)c1ccccc1
Solvent: CO
Solvent: CCOC(=O)CC(=O)OCC
Product: CCCCCCCOc1ccc(-c2ncc(C[C@@H](C)CC)cn2)cc1

Procedure:
A mixture of 40 g of (S)-4,6-dichloro-2-(p-heptyloxyphenyl)-5-(2-methylbutyl)-pyrimidine [obtainable by reacting (S)-2-methylbutyl bromide with diethyl malonate in the presence of sodium methanolate, followed by condensation of the resultant diethyl (S)-2-methylbutyl malonate with p-heptyloxybenzamidine hydrochloride, and reacting the resultant (S)-4,6-dihydroxy-2-(p-heptyloxyphenyl)-5-(2-methylbutyl)-pyrimidine with phosphoroxy trichloride and dimethylaniline],400 ml of methanol, 40 ml of triethylamine and 20 g of Pd-C (5%) is hydrogenated at room temperature under normal pressure until the theoretical amount of hydrogen has been taken up. After filtering off the catalyst and distilling off the solvent, the residue is recrystallized from ethanol. (S)-2-(p-Heptyloxyphenyl)-5-(2-methylbutyl)-pyrimidine is obtained.
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[CH:15]=[CH:14][N:13]=[C:12]([O:17]C)[C:11]=2[CH:10]=[C:9]1[CH3:19]>C(O)(=O)C>[C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[CH:15]=[CH:14][N:13]=[C:12]([OH:17])[C:11]=2[CH:10]=[C:9]1[CH3:19]
Reactant: COc1nccc2c1cc(C)n2Cc1ccccc1-c1ccccc1
Solvent: CC(=O)O
Product: Cc1cc2c(O)nccc2n1Cc1ccccc1-c1ccccc1
Temperature: 105 °C

Procedure:
To a solution of intermediate (4) in acetic acid (45 mL) hydrogen bromide (48% solution, 15 mL) was added. The mixture was heated at 105° C. for 18 h. The reaction mixture was concentrated, then dissolved in dichloromethane (100 mL) and washed with ammonium chloride solution (100 mL). The organic layer was separated, dried over magnesium sulphate and concentrated to afford intermediate (5) as a solid. Yield: 0.65 g, 62%.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]=[C:3]2[C:7](=[O:10])[S:8][CH2:9][CH:2]12.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.C1(C=CC(O)=CC=1)O.O=O>C1C=CC=CC=1.O>[O:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[C:7](=[O:10])[S:8][CH2:9][CH:2]12
Reactant: O=C1SCC2OCCC=C12
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=O
Agent: Oc1ccc(O)cc1
Solvent: c1ccccc1
Solvent: O
Product: O=C1SCC2OC=CC=C12

Procedure:
A magnetically-stirred solution of 3,5,6,7-tetrahydro-1H-thieno[3,4-b]pyran-5-one (14.32 g, 0.09168 mol) in benzene (150 mL) was treated, in portions, with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (21.29 g, 0.09378 mol). The DDQ dissolved exothermically, giving a dark brown solution which gradually faded to orange, as the crystalline hydroquinone separated. The solids were removed by filtration and rinsed with CH2Cl2. The filtrates were concentrated in vacuo, and the residue was twice distilled (Kugelrohr) to give a mobile light orange oil. (bp>141° C./1.8 Torr or 126°-145° C./0.55 Torr, external temperature). Yield: 11.98 g (84.7%). The product solidified upon storage under N2 at -20° C. NMR and GC/MS data were in agreement with the proposed structure. The compound is sensitive to water, oxygen and light.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([OH:13])=O)[N:2]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:47][O:48][C:49]([C:51]1[C:59]2[N:58]=[C:57]([NH2:60])[NH:56][C:55]=2[C:54]([F:61])=[C:53]([O:62][CH2:63][CH3:64])[CH:52]=1)=[O:50]>CN(C=O)C>[CH3:47][O:48][C:49]([C:51]1[C:59]2[NH:58][C:57]([NH:60][C:11]([C:3]3[N:2]=[CH:1][C:10]4[C:5]([CH:4]=3)=[CH:6][CH:7]=[CH:8][CH:9]=4)=[O:13])=[N:56][C:55]=2[C:54]([F:61])=[C:53]([O:62][CH2:63][CH3:64])[CH:52]=1)=[O:50]
Reactant: O=C(O)c1cc2ccccc2cn1
Reactant: CCOc1cc(C(=O)OC)c2nc(N)[nH]c2c1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc(C(=O)OC)c2[nH]c(NC(=O)c3cc4ccccc4cn3)nc2c1F
Yield: 44 %

Procedure:
0.3 g (1.5 mmol) of isoquinoline-3-carboxylic acid and 0.6 g (1.6 mmol) of HBTU were dissolved in 3.0 mL of DMF and 0.6 mL of DIEA and treated with 0.25 g (1.0 mmol) of 2-amino-6-ethoxy-7-fluoro-1H benzoimidazole-4-carboxylic acid methyl ester as described in general procedure A to produce 0.18 g (0.44 mmol, 44%) of 6-ethoxy-7-fluoro-2-[(isoquinoline-3-carbonyl)-amino]-3H-benzoimidazole-4-carboxylic acid methyl ester. LCMS: 409 (M+1)+.
Reaction SMILES: [OH:1][CH:2]1[N:14]([CH3:15])[C:13](=[O:16])[C:12]2[C:11]3[CH:10]=[C:9]([CH3:17])[CH:8]=[CH:7][C:6]=3[NH:5][C:4]=2[CH2:3]1.[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]=[CH2:26])=[CH:21][N:20]=1.[OH-].[K+]>CN1C(=O)CCC1>[OH:1][CH:2]1[N:14]([CH3:15])[C:13](=[O:16])[C:12]2[C:11]3[CH:10]=[C:9]([CH3:17])[CH:8]=[CH:7][C:6]=3[N:5]([CH2:26][CH2:25][C:22]3[CH:21]=[N:20][C:19]([CH3:18])=[CH:24][CH:23]=3)[C:4]=2[CH2:3]1
Reactant: Cc1ccc2[nH]c3c(c2c1)C(=O)N(C)C(O)C3
Reactant: C=Cc1ccc(C)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(C)nc2)CC(O)N(C)C1=O

Procedure:
The title compound is prepared from a mixture of 3,4-dihydro-3-hydroxy-2,8-dimethyl-2H-pyrido[4,3-b]indol-1(5H)-one, 2-methyl-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: Cl[C:2]1[C:7]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([O:19][CH3:20])[N:13]=2)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.FC1C=C(OC)C=C(F)C=1CN.C(N1C=CN=C1)(N1C=CN=C1)=O.C(N(CC)CC)C.[F:52][C:53]1[CH:82]=[C:81]([O:83][CH3:84])[CH:80]=[C:79]([F:85])[C:54]=1[CH2:55][N:56]1C2N=CC=CC=2S(=O)(=O)N(C2C=CC(OC)=C(OC)C=2)[C:57]1=[O:78]>>[F:52][C:53]1[CH:82]=[C:81]([O:83][CH3:84])[CH:80]=[C:79]([F:85])[C:54]=1[CH2:55][N:56]1[C:2]2[N:3]=[CH:4][CH:5]=[CH:6][C:7]=2[S:8](=[O:10])(=[O:9])[N:11]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([O:19][CH3:20])[N:13]=2)[C:57]1=[O:78]
Reactant: COc1nc(NS(=O)(=O)c2cccnc2Cl)ccc1C
Reactant: COc1cc(F)c(CN2C(=O)N(c3ccc(OC)c(OC)c3)S(=O)(=O)c3cccnc32)c(F)c1
Agent: COc1cc(F)c(CN)c(F)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Product: COc1cc(F)c(CN2C(=O)N(c3ccc(C)c(OC)n3)S(=O)(=O)c3cccnc32)c(F)c1

Procedure:
The title compound (110 mg, 0.23 mmol) was prepared in two steps from 2-chloro-N-(6-methoxy-5-methylpyridin-2-yl)pyridine-3-sulfonamide (IntC11) (320 mg, 1.02 mmol) and 2,6-difluoro-4-methoxybenzylamine (212 mg, 1.22 mmol); followed by 1,1′-carbonyldiimidazole (403 mg, 2.49 mmol) and triethylamine (173 uL, 1.24 mmol) using the methods of (95).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4]1.[CH2:12]([C:20]1[CH:30]=[CH:29][C:23]([O:24][CH2:25][CH:26]2[CH2:28][O:27]2)=[CH:22][CH:21]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[Na+].[Cl-]>CN(C=O)C>[N:3]1([CH2:28][CH:26]([OH:27])[CH2:25][O:24][C:23]2[CH:29]=[CH:30][C:20]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:21][CH:22]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4]1
Reactant: CCCCCCCCc1ccc(OCC2CO2)cc1
Reactant: c1ccc2[nH]ncc2c1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCc1ccc(OCC(O)Cn2ncc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
0.048 g (1.20 mmol) sodium hydride as a 60% dispersion in mineral oil is suspended in 10 ml absolute DMF, stirred at room temperature for 10 min and mixed with a solution of 0.135 g (1.14 mmol) indazole. Having stirred for 1 hour, a solution of 0.300 g (1.14 mmol) 2-(4-octylphenoxymethyl)oxirane in 10 ml absolute DMF is added drop-wise. The mixture is stirred for 40 hours, hydrolyzed with a semi-saturated NaCl solution and extracted four times using diethyl ether. The combined organic phases are concentrated to half the volume on the rotary evaporator and washed three times with saturated NaCl solution. Drying on sodium sulfate, filtration and reconcentration on the rotary evaporator leave a white solid which is recrystallized from petroleum ether/ethyl acetate (80:20).