Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[CH3:3][C@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C@H:9]1[CH2:13][CH2:12][NH:11][CH2:10]1.CC([O-])(C)C.[Na+].[C:20]([O:24][C:25](=[O:33])[C:26]1[CH:31]=[CH:30][C:29](Br)=[CH:28][CH:27]=1)([CH3:23])([CH3:22])[CH3:21].C1(C)C=CC=CC=1>CO.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[C:20]([O:24][C:25](=[O:33])[C:26]1[CH:31]=[CH:30][C:29]([N:11]2[CH2:12][CH2:13][C@H:9]([N:5]3[CH2:6][CH2:7][CH2:8][C@@H:4]3[CH3:3])[CH2:10]2)=[CH:28][CH:27]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: C[C@H]1CCCN1[C@H]1CCNC1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: C[C@H]1CCCN1[C@H]1CCN(c2ccc(C(=O)OC(C)(C)C)cc2)C1
Temperature: 80 °C
Yield: 79.3 %

Procedure:
(2S,3′S)-2-Methyl-[1,3′]bipyrrolidinyl dihydrochloride (1.1 g, 4 mmol) was treated with NaOt-Bu (1.1 g, 2equiv) in MeOH (30 mL), filtered, and concentrated. To this flask was charged with tert-Butyl-4-bromo-benzoate (1 g, 3.89 mmol), sodium tert-butoxide 538 mg, 5.6 mmol), tris(dibenzylideneacetone)dipalladium-(0) (35 mg, 0.039 mmol), BINAP (72 mg, 0.116 mmol), and toluene (40 mL) under argon. The reaction flask was heated to 80° C. (external) for 24 h with stirring until the starting material had been completely consumed as judged by TLC analysis. The mixture was allowed to cool to room temperature, taken up in DCM (50 mL), filtered, and concentrated. The crude product was then purified further by flash chromatography on a silica gel column eluted with 0-5% of 7N NH3/MeOH in DCM to get 1.02 g (80%) of the title compound as a yellow oil.
Reaction SMILES: Br[CH:2](Br)[CH2:3][C:4]12[CH2:17][CH:8]3[CH2:9][C:10]([CH2:13][CH:14](Br)Br)([CH2:12][C:6]([C:18]45[CH2:27][C:22]6([CH2:28][CH:29](Br)Br)[CH2:23][CH:24]([CH2:26][C:20]([CH2:32][CH:33](Br)Br)([CH2:21]6)[CH2:19]4)[CH2:25]5)([CH2:7]3)[CH2:5]1)[CH2:11]2.CC(C)([O-])C.[K+].O>CS(C)=O>[C:28]([C:22]12[CH2:23][CH:24]3[CH2:26][C:20]([C:32]#[CH:33])([CH2:19][C:18]([C:6]45[CH2:5][C:4]6([C:3]#[CH:2])[CH2:17][CH:8]([CH2:9][C:10]([C:13]#[CH:14])([CH2:11]6)[CH2:12]4)[CH2:7]5)([CH2:25]3)[CH2:27]1)[CH2:21]2)#[CH:29]
Reactant: BrC(Br)CC12CC3CC(CC(Br)Br)(C1)CC(C14CC5CC(CC(Br)Br)(CC(CC(Br)Br)(C5)C1)C4)(C3)C2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: C#CC12CC3CC(C#C)(C1)CC(C14CC5CC(C#C)(CC(C#C)(C5)C1)C4)(C3)C2
Reaction time: 48 h

Procedure:
The obtained 3,3′,5,5′-tetrakis(dibromoethyl)-1,1′-biadamantane was dissolved in 200 ml of dimethyl sulfoxide, and then 28 g (250 mmol) of potassium tert-butoxide was added at room temperature and the mixture was stirred for 48 hours. The reaction mixture was added to 400 ml of water, the mixture was extracted 3 times using 200 ml of dichloromethane each time and then washed with 200 ml of water and dried over magnesium sulfate, and the organic layer was concentrated to obtain 11.0 g of 3,3′,5,5′-tetraethynyl-1,1′-biadamantane.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[C:14]([C:18]1[N:22]([CH2:23][CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:21]2[CH:30]=[CH:31][C:32]([S:34]([N:37]3[CH:41]=[C:40]([C:42](O)=[O:43])[CH:39]=[N:38]3)(=[O:36])=[O:35])=[CH:33][C:20]=2[N:19]=1)([CH3:17])([CH3:16])[CH3:15].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:14]([C:18]1[N:22]([CH2:23][CH:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)[C:21]2[CH:30]=[CH:31][C:32]([S:34]([N:37]3[CH:41]=[C:40]([C:42]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:43])[CH:39]=[N:38]3)(=[O:36])=[O:35])=[CH:33][C:20]=2[N:19]=1)([CH3:15])([CH3:16])[CH3:17]
Reactant: CC(C)N
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)n3cc(C(=O)O)cn3)ccc2n1CC1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)NC(=O)c1cnn(S(=O)(=O)c2ccc3c(c2)nc(C(C)(C)C)n3CC2CCOCC2)c1
Yield: 70.2 %

Procedure:
Following the same procedure in Example 24, Step A, using iso-propylamine (9 mg, 0.15 mmol), DIPEA (28 uL, 21 mg, 0.16 mmol), 1-{[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]sulfonyl}-1H-pyrazole-4-carboxylic acid (0.073 mmol) and HATU (44 mg, 0.12 mmol) in DMF (2.5 mL). The crude product was purified by MPLC using Hex/EtOAc (1:2) on silica gel to give 25 mg (70%) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 1.17 (d, J=6.45 Hz, 6 H), 1.40-1.56 (m, 4 H), 1.59 (s, 9 H), 2.18-2.40 (m, 1 H), 3.23-3.39 (m, 2 H), 3.81-3.96 (m, 2 H), 4.02-4.18 (m, 1 H), 4.41 (d, J=7.42 Hz, 2 H), 7.91 (d, J=8.8 Hz, 1 H), 7.98 (dd, J=8.8, 1.8 Hz, 1 H), 8.04 (s, 1 H), 8.33 (d, J=1.76 Hz, 1 H), 8.77 (d, J=0.78 Hz, 1 H); MS (ESI) (M+H)+=488.0; Anal. Calcd for C24H33N5O4S+0.70 TFA+0.50 EtOAc+0.40H2O (624.71): C, 53.64; H, 6.21; N, 11.21. Found: C, 53.58; H, 6.23; N, 11.28.
Reaction SMILES: CC(O)CCCCCC.[CH2:10]([C:22]1C=CC=C[C:23]=1S(Cl)(=O)=O)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]CC.[C:32]1(C)[CH:37]=[CH:36][C:35]([S:38]([O:41][CH:42]([CH3:49])[CH2:43]CCCCC)(=[O:40])=[O:39])=[CH:34][CH:33]=1>>[CH2:19]([C:34]1[CH:33]=[CH:32][CH:37]=[CH:36][C:35]=1[S:38]([O:41][CH:42]([CH3:43])[CH3:49])(=[O:39])=[O:40])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:22][CH3:23]
Reactant: CCCCCCC(C)OS(=O)(=O)c1ccc(C)cc1
Reactant: CCCCCCCCCCCCc1ccccc1S(=O)(=O)Cl
Solvent: CCCCCCC(C)O
Product: CCCCCCCCCCCCc1ccccc1S(=O)(=O)OC(C)C
Yield: 83 %

Procedure:
In the Example of preparation of material 18, 2-octanol was used in place of 2-propanol in the Example of preparation of material 17. In the Example of preparation of material 19, dodecylbenzene sulfonyl chloride was used in place of p-toluene sulfonyl chloride in the Example of preparation of material 17. Other procedures were made in the same way as the Example of preparation of material 17. In the Example of preparation of material 18, 1-methylheptyl p-toluene sulfonate was obtained in the yield of 72% and, in the Example of preparation of material 19, 1-methylethyl dodecylbenzene sulfonate was obtained in the yield of 83%.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]([CH2:7][CH2:8][CH3:9])=[N:4][C:3]=1[CH2:10][OH:11].[N+]([O-])(O)=O>>[CH3:1][C:2]1[NH:6][C:5]([CH2:7][CH2:8][CH3:9])=[N:4][C:3]=1[CH:10]=[O:11]
Reactant: CCCc1nc(CO)c(C)[nH]1
Solvent: O=[N+]([O-])O
Product: CCCc1nc(C=O)c(C)[nH]1

Procedure:
An 80 gm. portion of 5-methyl-2-n-propyl-4-imidazolemethanol is oxidized with 67.3 ml. of concentrated HNO3. A second portion of 101.4 gm. of the above compound is oxidized with 77 ml. of the acid. The reaction mixtures are combined, neutralized and worked up as in Example 11, giving the desired product, m.p. 126°-129° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:8][C:9]1[CH:43]=[CH:42][C:12]([C:13]([NH:15][C:16]2[C:17]3[CH:30]=[C:29]([C:31]([NH:33][N:34]([CH3:41])[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[O:32])[S:28][C:18]=3[N:19](C(OC(C)(C)C)=O)[N:20]=2)=[O:14])=[CH:11][CH:10]=1.ClCC1C=CC(C(NC2C3C=C(C(NN(C4C=CC(Cl)=CC=4)C)=O)SC=3N(C(OC(C)(C)C)=O)N=2)=O)=CC=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[CH3:41][N:34]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[NH:33][C:31]([C:29]1[S:28][C:18]2[NH:19][N:20]=[C:16]([NH:15][C:13](=[O:14])[C:12]3[CH:42]=[CH:43][C:9]([CH2:8][N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:10][CH:11]=3)[C:17]=2[CH:30]=1)=[O:32]
Reactant: CN(NC(=O)c1cc2c(NC(=O)c3ccc(CCl)cc3)nn(C(=O)OC(C)(C)C)c2s1)c1ccccc1
Reactant: C1CCNCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CN(NC(=O)c1cc2c(NC(=O)c3ccc(CCl)cc3)nn(C(=O)OC(C)(C)C)c2s1)c1ccc(Cl)cc1
Agent: [I-]
Solvent: CN(C)C=O
Product: CN(NC(=O)c1cc2c(NC(=O)c3ccc(CN4CCCCC4)cc3)n[nH]c2s1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
27 mg (74 μmol) of tetrabutylammonium iodide and then 110 μL (1.11 mmol) of piperidine are added to a solution of 200 mg (0.37 mmol) of an approximately 70:30 mixture of tert-butyl 3-(4-chloromethylbenzoylamino)-5-(N′-methyl-N′-phenylhydrazinocarbonyl)thieno[2,3-c]pyrazole-1-carboxylate and tert-butyl 3-(4-chloromethylbenzoylamino)-5-(N′-(4-chlorophenyl)-N′-methylhydrazinocarbonyl)-thieno[2,3-c]pyrazole-1-carboxylate in 6 mL of dimethylformamide under argon. The reaction mixture is stirred at a temperature in the region of 25° C. for 16 hours, and then poured onto ice. It is then extracted twice with a 50/50 mixture of ethyl acetate and heptane. The organic extracts are combined, dried over magnesium sulfate and then concentrated to dryness under vacuum (2 kPa) at a temperature in the region of 40° C. The residue is dissolved in 4 mL of methanol and the solution is introduced into a microwave oven tube. The tube is stoppered and the reaction mixture is irradiated at a temperature in the region of 100° C. for 30 minutes. The reaction mixture is then concentrated to dryness under vacuum (2 kPa) at a temperature in the region of 40° C. The residue is purified by preparative LC/MS (conditions B). 75 mg of N-[5-(N′-methyl-N′-phenylhydrazinocarbonyl)-1H-thieno[2,3-c]pyrazol-3-yl]-4-piperidin-1-ylmethylbenzamide are thus obtained in the form of a yellow powder melting from 170 to 182° C. LC-MS-DAD-ELSD: 487(−)=(M−H)(−); 489(+)=(M+H)(+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:21]=[CH:22]/[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:24])[CH:6]=[C:7]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH3:20])[CH:15]=3)[CH:10]=2)[CH:8]=1>C(O)C.C1COCC1.[OH-].[OH-].[Pd+2]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:21][CH2:22][C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:24])[CH:6]=[C:7]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH3:20])[CH:15]=3)[CH:10]=2)[CH:8]=1
Reactant: COc1cc(/C=C/C(=O)Nc2ccccc2)cc(-c2ccc3cc(OC)ccc3c2)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc(CCC(=O)Nc2ccccc2)cc(-c2ccc3cc(OC)ccc3c2)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A suspension of (E)-3-[3-methoxy-5-(6-methoxynaphthalene-2-yl)phenyl]-N-phenylacrylic acid amide (70 mg, 0.17 mmol, 1 eq) and Pd(OH)2 (2.5 mg) in ethanol (1 ml) and THF (0.4 ml) is stirred for 20 h at RT under a hydrogen atmosphere. Filtration and concentration of the reaction mixture on a rotary evaporator yields the desired product in quantitative yield (70 mg).
Reaction SMILES: [CH:1]1[C:11]2[CH:10]([CH2:12][CH2:13][OH:14])[S:9][C:8]3[CH:15]=[CH:16][CH:17]=[CH:18][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.CS(Cl)(=O)=O.O[C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH:32]([O:38][CH2:39][CH3:40])[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC=CC=1.CN(C)C=O.O.C(N(CC)CC)C>[CH2:39]([O:38][CH:32]([CH2:31][C:28]1[CH:27]=[CH:26][C:25]([O:14][CH2:13][CH2:12][CH:10]2[S:9][C:8]3[CH:15]=[CH:16][CH:17]=[CH:18][C:7]=3[O:6][C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:11]2=3)=[CH:30][CH:29]=1)[C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH3:40]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Reactant: OCCC1Sc2ccccc2Oc2ccccc21
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1ccc(OCCC2Sc3ccccc3Oc3ccccc32)cc1)OCC
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A solution of 2-(11H-5-oxa-10-thia-dibenzo[a,d]cyclohepten-11-yl)-ethanol (4.1 g, 15.9 mmol) and triethylamine (5 ml) in benzene (80 ml) was treated with methanesulfonyl chloride (2.8 g, 24 mmol) and the mixture stirred for 2 h. The resulting reaction mixture was treated with water (50 ml) and the phases were separated. The organic phase was dried (MgSO4) and the solvent evaporated, affording a residue, which was dissolved in dimethylformamide (10 ml). To this solution were added ethyl 3-(4-hydroxyphenyl)-2-ethoxypropionate (3.8 g, 16 mmol) and potassium carbonate (2.8 g, 20 mmol), and the mixture was heated to 100° C. for 10 h. Water (100 ml) and benzene (150 ml) were added, and the organic phase was collected and washed with water (2×50 ml), dried (K2CO3) and evaporated. The resulting residue was purified by column chromatography on silica gel (benzene and chloroform as eluents) to give the title compound as an oil: 4.6 g (60%).
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC(=O)[NH:14][C@H:15]([C:18]1[N:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:21]2[CH:29]=[C:30]([F:33])[CH:31]=[CH:32][C:20]=2[N:19]=1)[CH2:16][CH3:17])(C)(C)C>C(Cl)Cl>[F:33][C:30]1[CH:31]=[CH:32][C:20]2[N:19]=[C:18]([C@@H:15]([NH2:14])[CH2:16][CH3:17])[N:22]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:21]=2[CH:29]=1
Reactant: CC[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)cc2n1-c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](N)c1nc2ccc(F)cc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84.7 %

Procedure:
TFA (0.50 mL, 6.73 mmol) was added to a solution of [(S)-1-(6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)propyl]carbamic acid tert-butyl ester (92 mg, 0.25 mmol) in DCM (2 mL) and the reaction stirred at RT for 1.5 h. The reaction mixture was concentrated in vacuo and passed through a 2 g Isolute® SCX-2 cartridge, eluting with 2M NH3/MeOH. The basic fraction was concentrated in vacuo to give the title compound (57 mg, 85%) as a red oil. LCMS (Method J): RT=2.08 min, [M+H]+=270.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][CH2:11][O:12][C:6]=2[CH:5]=[C:4]([CH2:13][NH:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH:3]=1.[CH3:19][C:20]([O:23][C:24]([NH:26][CH2:27][CH2:28][C:29](O)=[O:30])=[O:25])([CH3:22])[CH3:21].Cl.C(N=C=NCCCN(C)C)C.CC1C=CN=C(N)C=1C>ClCCl>[Cl:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][CH2:11][O:12][C:6]=2[CH:5]=[C:4]([CH2:13][N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:29](=[O:30])[CH2:28][CH2:27][NH:26][C:24]([O:23][C:20]([CH3:21])([CH3:19])[CH3:22])=[O:25])[CH:3]=1
Reactant: CC(C)CNCc1cc(Cl)c2c(c1)OCCCO2
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccnc(N)c1C
Agent: Cl
Solvent: ClCCl
Product: CC(C)CN(Cc1cc(Cl)c2c(c1)OCCCO2)C(=O)CCNC(=O)OC(C)(C)C

Procedure:
A mixture of N-(9-chloro-3,4-dihydro-2H-1,5-benzodioxepin-7-ylmethyl)-2-methylpropan-1-amine (140 mg), 3-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid (Boc-beta-alanine, 98 mg), of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (163 mg), and of dimethyl aminopyridine (113 mg) in dichloromethane (10 ml) was stirred overnight. The mixture was concentrated under reduced pressure. Desired compound [N-(9-chloro-3,4-dihydro-2H-1,5-benzodioxepin-7-ylmethyl)-N-isobutyl 3-[(2-methylpropan-2-yl)oxycarbonylamino]propanamide] was isolated by flash chromatography on silica (100% dichloromethane) as a resin: MS (m+1)=441.3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][C:3]=1[C:9]1[N:18]=[CH:17][C:16]2[CH2:15][CH2:14][C:13]3[N:19]=[C:20]([NH:22][C:23](=[O:25])[CH3:24])[S:21][C:12]=3[C:11]=2[N:10]=1.[CH3:26][NH:27][CH2:28][C:29]#[CH:30].C(N(C(C)C)CC)(C)C.O=O.N>O1CCCC1.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:30]#[C:29][CH2:28][NH:27][CH3:26])=[CH:4][C:3]=1[C:9]1[N:18]=[CH:17][C:16]2[CH2:15][CH2:14][C:13]3[N:19]=[C:20]([NH:22][C:23](=[O:25])[CH3:24])[S:21][C:12]=3[C:11]=2[N:10]=1
Reactant: CC(=O)Nc1nc2c(s1)-c1nc(-c3cc(I)ccc3Cl)ncc1CC2
Reactant: C#CCNC
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: N
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: CNCC#Cc1ccc(Cl)c(-c2ncc3c(n2)-c2sc(NC(C)=O)nc2CC3)c1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
1.0 g (2.1 mmol) N-[8-(2-chloro-5-iod-phenyl)-4,5-dihydro-thiazolo[4,5-h]quinazolin-2-yl]-acetamide are placed in 50 mL tetrahydrofuran under an argon atmosphere and combined with 0.6 ml (9 mmol) N-methylpropargylamine and 1 mL (6 mmol) diisopropylethylamine. The mixture is kept free from oxygen and 29 mg (0.04 mmol) triphenylphosphine palladium(II)-chloride and 8 mg (0.04 mmol) copper(I)-iodide are added. The mixture is stirred for 5 hours at 80° C. After cooling to ambient temperature the reaction mixture is combined with water and 10% ammonia solution and extracted with dichloromethane. The organic phase is dried and evaporated to dryness. The residue is purified by chromatography, the product obtained is triturated with diethyl ether and suction filtered.
Reaction SMILES: O1C2C=CC([C:10]3[C:19](N4CCC[C@@H]4C)=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:26]([O:28]C)=[O:27])[CH:16]=4)[N:11]=3)=CC=2OC1.[OH-].[Na+]>CO.O>[N:11]1[C:12]2[C:17](=[CH:16][C:15]([C:26]([OH:28])=[O:27])=[CH:14][CH:13]=2)[N:18]=[CH:19][CH:10]=1
Reactant: COC(=O)c1ccc2nc(-c3ccc4c(c3)OCO4)c(N3CCC[C@@H]3C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc2nccnc2c1
Reaction time: 0.14 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 2-(benzo[d][1,3]dioxol-5-yl)-3-((S)-2-methylpyrrolidin-1-yl)quinoxaline-6-carboxylate (94 mg, 0.24 mmol, 1.00 equiv) in methanol (15 mL). This was followed by the addition of a solution of sodium hydroxide (58.9 mg, 1.47 mmol, 5.00 equiv) in water (3 mL) dropwise with stirring. The resulting solution was stirred for 5 hr at 50° C. in an oil bath. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with H2O. The pH value of the aqueous solution was adjusted to 3-4 with 1N aqueous hydrogen chloride. The resulting solids were collected by filtration. The crude product (100 mg) was purified by Prep-HPLC with the following conditions (1#-Waters 2767-2): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (10% CH3CN up to 80% in 8.5 min, hold 80% in 1 min, up to 100% in 0.1 min, hold 100% in 0.8 min); Detector, UV 220&254 nm. This resulted in 40 mg (44%) of 2-(benzo[d][1,3]dioxol-5-yl)-3-(S)-2-methylpyrrolidin-1-yl)quinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:18][O:19][C:20]2[CH:29]=[C:28]3[C:23]([CH2:24][CH2:25][NH:26][CH2:27]3)=[CH:22][CH:21]=2)[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5])C.C(N(C(C)C)CC)(C)C.[ClH:39].[N:40]1([C:45](N)=[NH:46])C=CC=N1>CN(C)C=O>[ClH:39].[ClH:39].[C:45]([N:26]1[CH2:25][CH2:24][C:23]2[C:28](=[CH:29][C:20]([O:19][CH2:18][C:6]3([C:4]([OH:3])=[O:5])[CH2:7][CH2:8][N:9]([C:12]4[CH:17]=[CH:16][N:15]=[CH:14][N:13]=4)[CH2:10][CH2:11]3)=[CH:21][CH:22]=2)[CH2:27]1)(=[NH:40])[NH2:46]
Reactant: CCOC(=O)C1(COc2ccc3c(c2)CNCC3)CCN(c2ccncn2)CC1
Reactant: N=C(N)n1cccn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N=C(N)N1CCc2ccc(OCC3(C(=O)O)CCN(c4ccncn4)CC3)cc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 16.1 %

Procedure:
To a solution of 1-(pyrimidin-4-yl)-4-(1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidine-4-carboxylic acid ethyl ester (260 mg) in dimethylformamide (1 ml) were added diisopropylethylamine (0.24 ml) and 1H-pyrazole-1-carboxamidine hydrochloride (200 mg), and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was evaporated and the obtained residue was separated by HPLC (0.05% aqueous trifluoroacetic acid:methanol=6:4-2:8). The obtained residue was refluxed with conc. hydrochloric acid for 2 hours. After completion of the reaction, the solvent was evaporated and the obtained residue was washed with diethyl ether and dried under reduced pressure to give the title compound (51 mg).
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8](=[O:20])[C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:10][O:11]2)=[CH:6][CH:5]=1.Cl[CH:22]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:23][CH2:24][N:25]([CH3:27])[CH3:26]>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.C(Cl)Cl>[C:28]1([CH:22]([O:3][C:4]2[CH:13]=[C:12]3[C:7]([C:8](=[O:20])[C:9]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)=[CH:10][O:11]3)=[CH:6][CH:5]=2)[CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CN(C)CCC(Cl)c1ccccc1
Reactant: O=c1c(-c2ccccc2)coc2cc(O)ccc12
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: CN(C)CCC(Oc1ccc2c(=O)c(-c3ccccc3)coc2c1)c1ccccc1

Procedure:
200 ml of 50% aqueous sodium hydroxide solution and 1 g of triethylbenzylammonium chloride are added to a solution of 23.8 g of 7-hydroxyisoflavone in 100 ml of CH2Cl2, 20 g of 1-chloro-1-phenyl-3-dimethylaminopropane is added dropwise while stirring and stirring is continued for a further hour. Working up in the customary manner gives 7-(1-phenyl-3-dimethylaminopropoxy)-isoflavone. M.p. 128°-130°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[C:3]=1[O:13][CH3:14].S(Cl)([Cl:18])(=O)=O.C(=O)(O)[O-].[Na+].[Na+].[Cl-]>CC#N.CCOC(C)=O>[NH2:1][C:2]1[C:7]([Cl:18])=[C:6]([Cl:8])[N:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[C:3]=1[O:13][CH3:14]
Reactant: O=S(=O)(Cl)Cl
Reactant: COC(=O)c1nc(Cl)cc(N)c1OC
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)c1nc(Cl)c(Cl)c(N)c1OC
Reaction time: 0.5 h
Yield: 79.7 %

Procedure:
Methyl 4-amino-6-chloro-3-methoxypicolinate (260 mg, 1.2 mmol) was dissolved in dry CH3CN (7 mL), treated with sulfuryl chloride (120 μL, 1.5 mmol) and stirred for 30 min The solution was stirred with satd aq sodium bicarbonate (NaHCO3; 10 mL) for 20 min and then mixed with EtOAc (20 mL) and satd aq NaCl (10 mL). The aqueous phase was extracted with EtOAc (15 mL), and the combined organic phases were washed with satd aq NaCl (10 mL), dried (Na2SO4) and evaporated to give the title compound as a white solid (240 mg, 80%): mp 119-121° C.; 1H NMR (400 MHz, CDCl3) δ 5.04 (s, 2H), 3.97 (s, 3H), 3.93 (s, 3H); EIMS m/z 250.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[CH2:11][C:12]1[N:16]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=2)[CH:15]=[N:14][CH:13]=1.[CH3:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O>>[CH3:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[CH2:11][C:12]1[N:16]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]#[N:25])=[CH:22][CH:23]=2)[CH:15]=[N:14][CH:13]=1
Reactant: N#Cc1ccc(Cn2cncc2Cn2ccc3c(Br)cccc32)cc1
Reactant: Cc1ccccc1B(O)O
Product: Cc1ccccc1-c1cccc2c1ccn2Cc1cncn1Cc1ccc(C#N)cc1

Procedure:
Following the procedure described for Example 21, Step 3, 4-bromo-1-(1-(4-cyanobenzyl)-5-imidazolylmethyl)indole (Example 28) was coupled with 2-methylphenyl boronic acid to give the title compound.
Reaction SMILES: [CH:1]1([CH:7]=[O:8])[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.S(=O)(O)[O-].[Na+].[C-:14]#[N:15].[K+]>O>[CH:1]1([CH:7]([OH:8])[C:14]#[N:15])[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1
Reactant: [C-]#N
Reactant: O=CC1CC=CCC1
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: N#CC(O)C1CC=CCC1
Temperature: 5 °C
Reaction time: 0.17 h

Procedure:
3-Cyclohexene-1-carbaldehyde (11.7 ml. 0.1 mole) and sodium bisulfite (15.5 g., 0.15 mole) were combined with 150 ml. of H2O and heated at 50°-60° C. for 2 hours. The mixture was cooled to 5° C. and added dropwise over 10 minutes to a cold solution of KCN (19.5 g., 0.3 mole) in 50 ml. H2O. The mixture was warmed to 20° C., KCN (6.5 g., 0.1 mole) added as a solid, stirred for 10 minutes, and product extracted into 100 ml. ethyl acetate. The ethyl acetate extract was washed with brine and evaporated to yield title product as an oil, 8.5 g., Rf (5:1 hexane:ethyl acetate/5% CH3CO2H) 0.5.