Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:7]([CH3:51])[C:8]([CH:10]1[CH:14]([C:15](=[O:32])[NH:16][C:17]2([C:22]([NH:24][S:25]([C:28]3([CH3:31])[CH2:30][CH2:29]3)(=[O:27])=[O:26])=[O:23])[CH2:19][CH:18]2C=C)[CH2:13][CH:12]([O:33][C:34](=[O:50])[NH:35][C:36]2[CH:41]=[C:40]([CH3:42])[CH:39]=[CH:38][C:37]=2[C:43]2[S:44][C:45](CC)=[CH:46][N:47]=2)[CH2:11]1)=[O:9])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].[CH:52]1(S(O)(=O)=O)C[CH2:53]1>>[CH3:51][N:7]1[C:8](=[O:9])[CH:10]2[CH:14]([CH2:13][CH:12]([O:33][C:34](=[O:50])[NH:35][C:36]3[CH:41]=[C:40]([CH3:42])[CH:39]=[CH:38][C:37]=3[C:43]3[S:44][CH:45]=[C:46]([CH2:52][CH3:53])[N:47]=3)[CH2:11]2)[C:15](=[O:32])[NH:16][C:17]2([C:22]([NH:24][S:25]([C:28]3([CH3:31])[CH2:30][CH2:29]3)(=[O:26])=[O:27])=[O:23])[CH:19]([CH2:18]2)[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2][CH2:1]1
Reactant: O=S(=O)(O)C1CC1
Reactant: C=CCCCCN(C)C(=O)C1CC(OC(=O)Nc2cc(C)ccc2-c2ncc(CC)s2)CC1C(=O)NC1(C(=O)NS(=O)(=O)C2(C)CC2)CC1C=C
Product: CCc1csc(-c2ccc(C)cc2NC(=O)OC2CC3C(=O)NC4(C(=O)NS(=O)(=O)C5(C)CC5)CC4C=CCCCCN(C)C(=O)C3C2)n1
Yield: 10 %

Procedure:
The procedure described in Example 18-10 was followed, but using the compound prepared in Example 22 (112) (22 mg, 30 μmol) instead of the corresponding cyclopropanesulphonic acid derivative, which gave the title compound (2.1 mg, 10%). LC/MS (Method I): tr=2.41 min, >95%, m/z (ESI+)=712 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8].[Cu](C#N)[C:12]#[N:13].N>CN(C=O)C>[C:12]([C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8])#[N:13]
Reactant: N#C[Cu]C#N
Reactant: NC(=O)c1cncc(Br)c1
Agent: N
Solvent: CN(C)C=O
Product: N#Cc1cncc(C(N)=O)c1
Temperature: 140 °C
Reaction time: 24 h
Yield: 16.6 %

Procedure:
5-Bromonicotinamide (905 mg) and copper cyanide (630 mg) were suspended in DMF (15 ml) and the mixture was stirred at 140° C. for 24 hrs. Aqueous ammonia was added to the reaction mixture at room temperature and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent, methanol:ethyl acetate=1:10) for purification to give the title compound (110 mg) as a colorless powder.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:20]([O:22]C)=[O:21])[C:12](=[C:17]([CH3:19])[CH:18]=1)[C:13]([O:15][CH3:16])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[OH-].[Na+].COCCOC>[C:13]([C:12]1[C:17]([CH3:19])=[CH:18][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:10][C:11]=1[C:20]([OH:22])=[O:21])([O:15][CH3:16])=[O:14]
Reactant: COC(=O)c1cc(OCc2ccccc2)cc(C)c1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Product: COC(=O)c1c(C)cc(OCc2ccccc2)cc1C(=O)O
Yield: 52.3 %

Procedure:
A solution of dimethyl 4-benzyloxy-6-methyl-phthalate (1.5 gm) in sodium hydroxide (2% solution, 12 ml) and 1,2-dimethoxyethane (12 ml) was stirred at room temperature for 4 hours. The solvent was removed under reduced pressure. The aqueous solution was washed with ethyl acetate (3×125 ml). The organic extract was dried over magnesium sulphate and evaporated to give a solid. This solid was recrystallized from ethyl acetate: pet. ether 30-60 to yield 2-carbomethoxy-3-methyl-5-benzyloxy-benzoic acid (750 mg), m.p. 132°-133° C., IR (KBr): 2500-3200, 1725, 1685, 1600 cm-1. Anal. calcd. for C17H16O5 : C, 67.99, H, 5.37. Found: C, 68.01, H, 5.42.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][CH2:12][C@H:11]([O:14][C:15]3[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=3)[C:18]([OH:20])=O)[CH2:10]2)=[CH:5][CH:4]=1)#[N:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH3:38][N:39]1[CH2:44][CH2:43][C:42]2[N:45]=[C:46]([NH2:48])[S:47][C:41]=2[CH2:40]1>CN(C=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][CH2:12][C@H:11]([O:14][C:15]3[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=3)[C:18]([NH:48][C:46]3[S:47][C:41]4[CH2:40][N:39]([CH3:38])[CH2:44][CH2:43][C:42]=4[N:45]=3)=[O:20])[CH2:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(N2CC[C@H](Oc3cccc(C(=O)O)c3)C2)cc1
Reactant: CN1CCc2nc(N)sc2C1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CN1CCc2nc(NC(=O)c3cccc(O[C@H]4CCN(c5ccc(C#N)cc5)C4)c3)sc2C1
Reaction time: 1 h

Procedure:
Dissolve 3-[(S)-1-(4-cyano-phenyl)-pyrrolidin-3-yloxy]-benzoic acid (80.2 mg, 0.26 mmol), EDC (99.2 mg, 0.52 mmol) and HOBT (79.6 mg, 0.52 mmol) into 2 mL of DMF. The mixture is stirred for 1 h. Add 5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-ylamine (46.5 mg, 0.28 mmol) to the mixture and place in a 60° C. bath with an Ar stream blowing over it. Stir mixture for 14 h resulting in a concentrated residue. LC-MS analysis indicates the desired product. Dissolve into 5 mL of DMF and purify via the Gilson Prep HPLC system (5%-80% CH3CN/H2O) to give 59.4 mg of the title compound, MS, electrospray 560.58 (M+H), rt 6.01 min.
Reaction SMILES: [C:1]1([CH3:29])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[O:9][C:10]1[C:11]2[N:27]([CH3:28])[CH:26]=[CH:25][C:12]=2[N:13]=[C:14]([NH:16][C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=2)[N:15]=1.C1C(=O)N([Cl:37])C(=O)C1>C(Cl)Cl>[Cl:37][C:25]1[C:12]2[N:13]=[C:14]([NH:16][C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=3)[N:15]=[C:10]([O:9][C:2]3[C:1]([CH3:29])=[CH:6][C:5]([CH3:7])=[CH:4][C:3]=3[CH3:8])[C:11]=2[N:27]([CH3:28])[CH:26]=1
Reactant: Cc1cc(C)c(Oc2nc(Nc3ccc(C#N)cc3)nc3ccn(C)c23)c(C)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: Cc1cc(C)c(Oc2nc(Nc3ccc(C#N)cc3)nc3c(Cl)cn(C)c23)c(C)c1
Yield: 16.3 %

Procedure:
To a solution of 4-(4-(mesityloxy)-5-methyl-5H-pyrrolo[3,2-d]pyrimidin-2-ylamino)benzonitrile (17.3 mg, 0.05 mmol) in CH2Cl2 (5 mL) was added NCS (6.03 mg, 0.05 mmol) and the resultant mixture was refluxed for 16 h. After completion of the reaction, the solvent was concentrated and purified by preparative TLC, eluting with hexanes:ethyl acetate (3:1), to give the product as an off-white solid (3.4 mg, 6%).
Reaction SMILES: [NH2:1][C:2](=[O:25])[C:3]([NH:5][C:6]1[CH:11]=[C:10]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[CH:9]=[CH:8][C:7]=1[NH:17]C(=O)OC(C)(C)C)=[O:4].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:17][C:7]1[CH:8]=[CH:9][C:10]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[CH:11][C:6]=1[NH:5][C:3](=[O:4])[C:2]([NH2:1])=[O:25]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)C(N)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)C(=O)Nc1cc(-c2cccs2)ccc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.7 %

Procedure:
To a solution of tert-butyl (2-(2-amino-2-oxoacetamido)-4-(thiophen-2-yl)phenyl)carbamate (0.1 g, 0.28 mmol) in DCM (3 mL) was added TFA (1 mL, 13 mmol) at 0° C. The reaction was warmed to room temperature and stirred for 2 h. The reaction was then concentrated under reduced pressure. The residue was basified with a saturated aqueous solution of Na2CO3. The obtained solid was filtered, washed with water and ether then dried to afford N1-(2-amino-5-(thiophen-2-yl)phenyl)oxalamide (40 mg, 55% yield). ESI+ MS: m/z 262 ([M+H]+), 1H NMR (500 MHz, d6-DMSO): δ 9.89 (s, 1H), 8.24 (s, 1H), 7.94 (s, 1H), 7.59 (d, J=2.0 Hz, 1H), 7.6 (d, J=5 Hz, 1H), 7.29-7.26 (m, 1H), 7.23 (d, J=4.0 Hz, 1H), 7.05 (t, J=4.0 Hz, 1H), 6.80 (d, J=9.0 Hz, 1H), 5.16 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([NH:15][C:16](=O)[CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:10][CH2:11][CH:12]([NH:15][CH2:16][CH2:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:13][CH2:14]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(N2CCC(NC(=O)CCc3ccccc3)CC2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: COc1ccc(N2CCC(NCCCc3ccccc3)CC2)cc1
Yield: 91.4 %

Procedure:
Following the general procedure of example 40b, N-[1-(4-methoxy-phenyl)-piperidin-4-yl]-3-phenyl-propionamide (1.87 g, 5.53 mmol) was reduced with LiAlH4 to give [1-(4-methoxy-phenyl)-piperidin-4-yl]-(3-phenyl-propyl)-amine (1.64 g, 91%, MS: m/e=325.4 (M+H+)) as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:10][CH3:11])=[N+:4]([O-])[C:5]([CH3:8])=[CH:6][CH:7]=1.[C:12]([O:15][C:16](=O)C)(=[O:14])C>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:12]([O:15][CH3:16])=[O:14])=[N:4][C:3]=1[O:10][CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: COc1c(Br)ccc(C)[n+]1[O-]
Product: COC(=O)Cc1ccc(Br)c(OC)n1

Procedure:
step c—A solution of 357b (0.47 g) and acetic anhydride (4.0 mL) was heated at 120° C. for 2 h, The reaction mixture was concentrated in vacuo and purified on a SiO2 column eluting with 5% EtOAc/hexane to afford methyl 5-bromo-6-methoxy-pyridin-2-yl-acetate (357c).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[O:4][C:3]=1[CH:13]([OH:15])[CH3:14].[CH3:16][N:17]([CH3:27])[C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1.C([O-])([O-])=O.[Cs+].[Cs+]>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>[CH3:16][N:17]([CH3:27])[C:18]1[CH:23]=[C:22]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:12])[O:4][C:3]=2[CH:13]([OH:15])[CH3:14])[CH:21]=[CH:20][CH:19]=1
Reactant: CN(C)c1cccc(B(O)O)c1
Reactant: CC(O)c1oc(=O)c2ccccc2c1Br
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: [Cs+]
Product: CC(O)c1oc(=O)c2ccccc2c1-c1cccc(N(C)C)c1
Yield: 34.8 %

Procedure:
The title compound was made in a similar way as that of the intermediate B1 using 4-bromo-3-(1-hydroxyethyl)-1H-isochromen-1-one (Intermediate A2, 0.5 g, 1.86 mmol), 3-(dimethylamino)phenylboronic acid (0.46 g, 2.79 mmol), Pd(PPh3)4 (0.11 g, 0.093 mmol) and Cs2CO3 (0.78 g, 2.41 mmol) to afford the title compound (0.2 g, 35%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)([C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[OH:19])[CH:16]=3)[N:11]=[C:10]([O:32]C)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([OH:19])([C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)[CH:16]=3)[NH:11][C:10](=[O:32])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(-c2cccc(Cl)c2)c2cc(C(O)(c3cccnc3)c3cccnc3)ccc2n1
Agent: Cl
Solvent: C1CCOC1
Product: O=c1cc(-c2cccc(Cl)c2)c2cc(C(O)(c3cccnc3)c3cccnc3)ccc2[nH]1
Yield: 99.9 %

Procedure:
Following the same procedure as described in example 1F, [4-(3-chloro-phenyl)-2-methoxy-quinolin-6-yl]-di-pyridin-3-yl-methanol (300 mg, 0.66 mmol) was treated with HCl in aqueous THF to yield the title compound (290 mg, 100% yield).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH3:7][O:8][C:9]1[CH:17]=[CH:16]C(C(O)=O)=[CH:11][C:10]=1[N+:18]([O-:20])=[O:19]>C1COCC1>[CH3:7][O:8][C:9]1[CH:17]=[CH:16][C:1]([C:2]([Cl:4])=[O:3])=[CH:11][C:10]=1[N+:18]([O-:20])=[O:19]
Reactant: COc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Cl)cc1[N+](=O)[O-]

Procedure:
Oxalyl chloride (15.8 ml, 180 mmol) was added dropwise with stirring to a solution of 4-methoxy-3-nitrobenzoic acid (7.00 g, 36.00 mmol) in THF containing 10 μL DMF. After 1 h the solvent was removed under reduced pressure. The product was used directly in the next step.
Reaction SMILES: [Si]([O:8][C@@H:9]([CH3:37])[C@H:10]([C:22]1[O:26][C:25]([C:27]2[CH:32]=[CH:31][C:30]([NH:33][C:34](=[O:36])[CH3:35])=[CH:29][CH:28]=2)=[N:24][N:23]=1)[NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[C:14]([Cl:20])[C:13]=1[CH3:21])(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Cl:20][C:14]1[C:13]([CH3:21])=[C:12]([NH:11][C@@H:10]([C:22]2[O:26][C:25]([C:27]3[CH:28]=[CH:29][C:30]([NH:33][C:34](=[O:36])[CH3:35])=[CH:31][CH:32]=3)=[N:24][N:23]=2)[C@@H:9]([OH:8])[CH3:37])[CH:17]=[CH:16][C:15]=1[C:18]#[N:19]
Reactant: CC(=O)Nc1ccc(-c2nnc([C@H](Nc3ccc(C#N)c(Cl)c3C)[C@H](C)O[Si](C)(C)C(C)(C)C)o2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(-c2nnc([C@H](Nc3ccc(C#N)c(Cl)c3C)[C@H](C)O)o2)cc1
Temperature: 11 °C
Yield: 88.1 %

Procedure:
To a pre-cooled (−55° C.) solution of N-(4-(5-((1R,2S)-2-(tert-butyldimethylsilyloxy)-1-(3-chloro-4-cyano-2-methylphenylamino)propyl)-1,3,4-oxadiazol-2-yl)phenyl)acetamide (216 mg, 0.40 mmol) in THF (20 mL) was added TBAF (0.48 mL, 0.48 mmol, 1 M solution in THF) over 5 minutes. Upon complete addition the reaction mixture was allowed to warm to 11° C. over 3 h and quenched with sat. aq. NH4Cl (15 mL). The resulting mixture was partitioned between H2O (25 mL) and EtOAc (40 mL). The aqueous layer was extracted with EtOAc (50 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure to provide a colourless oil, which was purified by flash chromatography over silica gel (50-100% EtOAc in hexanes) to provided the title compound as a colourless solid (150 mg, 88%): 1H NMR (400 MHz, d6-acetone, δ in ppm) 9.49 (s 1H), 7.90 (dm, J=9.0 Hz, 2H), 7.80 (dm, J=9.0 Hz, 2H), 7.47 (d, J=8.8 Hz, 1H), 6.85 (d, J=8.6 Hz, 1H), 5.66 (d, J=8.4 Hz, 1H), 5.07 (dd, J=3.7, 8.4 Hz, 1H), 4.84 (br s, 1H), 4.61 (dq, J=3.5, 5.9 Hz, 1H), 2.39 (s, 3H), 2.12 (s, 3H), 1.40 (d, J=6.3 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=1.C([Li])CCC.CCCCCC.[CH3:22][N:23]1[C:27](=[O:28])[CH2:26][CH2:25][C:24]1=[O:29]>O1CCCC1>[CH3:22][NH:23][C:24](=[O:29])[CH2:25][CH2:26][C:27](=[O:28])[C:4]1[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[CH:6][C:5]=1[O:9][CH3:10]
Reactant: CN1C(=O)CCC1=O
Reactant: COc1cccc(OC)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CNC(=O)CCC(=O)c1c(OC)cccc1OC
Reaction time: 8 h
Yield: 93.3 %

Procedure:
A solution of 1,3-dimethoxybenzene (89 ml, 0.064 mole) in dry tetrahydrofuran (480 ml) was added during 10 minutes to a stirred solution of n-butyl lithium in hexane (350 ml, 0.6 mole) under an atmosphere of nitrogen. The stirred mixture was heated under reflux for 90 minutes, then a solution of N-methyl succinimide (77 g, 0.68 mole) in dry tetrahydrofuran was added dropwise. The mixture was heated under reflux for an additional hour and then allowed to stand overnight. The supernatant was decanted and the residue was hydrolysed with 20% aqueous ammonium chloride solution (280 ml) and extracted with chloroform. The washed and dried extract was evaporated and the residue recrystallised from ethyl acetate to give N-methyl 3-(2,6-dimethoxybenzoyl)propionamide (15 g, 10%, m.p. 134°).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:22])OC2C=CC=CC=2)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[CH3:23][S:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:34]2[CH2:33][CH2:32][N:31]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[S:24][CH3:23])[CH2:36][CH2:35]2)=[O:22])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: COc1nc2ccccc2nc1NC(=O)Oc1ccccc1
Reactant: CSc1ccccc1N1CCNCC1
Product: COc1nc2ccccc2nc1NC(=O)N1CCN(c2ccccc2SC)CC1
Yield: 69.8 %

Procedure:
Phenyl N-(2-methoxyquinoxalin-3-yl)carbamate and 1-(2-methylthiophenyl)piperazine were reacted by the same way with the example 36 to obtain the titled compound.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH2:8][OH:9])[S:6][CH:7]=1)[CH3:2].[H-].[Na+].Cl[C:13]1[CH:21]2[CH:16]([CH:17]3[O:22][CH:20]2[CH2:19][CH2:18]3)[C:15](=[O:23])[CH:14]=1>C1COCC1>[CH2:1]([C:3]1[CH:4]=[C:5]([CH2:8][O:9][C:13]2[CH:21]3[CH:16]([CH:17]4[O:22][CH:20]3[CH2:19][CH2:18]4)[C:15](=[O:23])[CH:14]=2)[S:6][CH:7]=1)[CH3:2]
Reactant: CCc1csc(CO)c1
Reactant: O=C1C=C(Cl)C2C3CCC(O3)C12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1csc(COC2=CC(=O)C3C4CCC(O4)C23)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.7 %

Procedure:
To a solution of (4-ethyl-thiophen-2-yl)methanol (369 mg, 2 mmol) in THF (10 ml) is added sodium hydride, 60% dispersion in mineral oil, (88 mg, 2.2 mmol) in one portion and the reaction stirred at room temp for 3 hours. The resulting dark yellow solution is then cooled to 0° C., and 5-Chloro-10-oxa-tricyclo[5.2.1.0*2,6*]dec-4-en-3-one (341 mg, 2.4 mmol) is added and the resulting brown solution allowed to warm to ambient over 30 minutes, then stirred at room temp for 17 hours. Crude reaction is purified by flash chromatography to give 5-(4-ethyl-thiophen-2-ylmethoxy)-10-oxa-tricyclo[5.2.1.0*2,6*]dec-4-en-3-one as a white solid (515 mg).
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]([CH:9]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)[CH:10]([C:13]#[N:14])[C:11]#[N:12])[CH:6]=[CH:7][CH:8]=1.[C:25]1(C)C=CC=CC=1[Mg]Br>O1CCCC1>[CH3:25][C:6]1[CH:7]=[CH:8][CH:3]=[CH:4][C:5]=1[CH:9]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1)[CH:10]([C:13]#[N:14])[C:11]#[N:12]
Reactant: Cc1ccccc1[Mg]Br
Reactant: COc1cccc(C(c2cccc3ccccc23)C(C#N)C#N)c1
Solvent: C1CCOC1
Product: Cc1ccccc1C(c1cccc2ccccc12)C(C#N)C#N
Reaction time: 1.5 h

Procedure:
A flask was charged with (1-naphthalenylmethylene)-propanedinitrile of Example 3 (408 mg, 2 mmol) and 10 mL anhydrous tetrahydrofuran. To this stirred solution was added, at room temperature, ortho-tolyl magnesium bromide (1.2 mL, 2.4 mmol, 2 M in tetrahydrofuran). The reaction was stirred 1.5 hours, after which it was quenched with 1 N hydrochloric acid and taken up in ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, brine, dried over magnesium sulfate, filtered, and evaporated to dryness. Following purification on silica (20% ethyl acetate/hexanes) 455 mg product was isolated as an off white foam.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:10]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:17][C:18]([OH:20])=O)[CH:8]=[CH:9]2)[C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22].C([O:28][P:29]([CH2:34][O:35][NH2:36])([O:31]CC)=[O:30])C>>[NH2:1][C:2]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:10]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:17][C:18](=[O:20])[NH:36][O:35][CH2:34][P:29]([OH:31])([OH:30])=[O:28])[CH:8]=[CH:9]2)[C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)c1c2ccc(CC(=O)O)ccc-2c(C(=O)OCC)c1N
Reactant: CCOP(=O)(CON)OCC
Product: CCOC(=O)c1c2ccc(CC(=O)NOCP(=O)(O)O)ccc-2c(C(=O)OCC)c1N

Procedure:
In an analogous manner to that described in Example 26, from diethyl 2-amino-6-carboxymethyl-azulene-1,3-dicarboxylate and phosphonomethoxyamine (L. Maier, Phosphorus, Sulfur, and Silicon 1993, Vol. 76, 119-122) the title compound is obtained as an amorphous powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[OH:39])[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH2:12][NH:13][C:14](=[O:35])[CH2:15][NH:16][C:17](=[O:34])[C:18]2[CH:23]=[C:22]([F:24])[C:21]([F:25])=[CH:20][C:19]=2[NH:26]C(OC(C)(C)C)=O)[CH2:8][CH2:7]1.Cl>CO.O1CCOCC1>[NH2:26][C:19]1[CH:20]=[C:21]([F:25])[C:22]([F:24])=[CH:23][C:18]=1[C:17]([NH:16][CH2:15][C:14]([NH:13][CH2:12][CH:9]1[CH2:8][CH2:7][N:6]([CH2:5][C:4]2[CH:36]=[CH:37][C:38]([OH:39])=[C:2]([NH2:1])[CH:3]=2)[CH2:11][CH2:10]1)=[O:35])=[O:34]
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(F)cc1C(=O)NCC(=O)NCC1CCN(Cc2ccc(O)c(N)c2)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Nc1cc(CN2CCC(CNC(=O)CNC(=O)c3cc(F)c(F)cc3N)CC2)ccc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(3-amino-4-hydroxybenzyl)-4-[{N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl}aminomethyl]piperidine (20.0 mg, 0.035 mmol) in methanol (1 mL) was added 4 N HCl in dioxane (0.50 mL) and the solution was stirred at room temperature overnight. After the solution was concentrated, the residue was dissolved in methanol, loaded onto Varian™ SCX column, washed with CH3OH (5 mL×2), and eluted off using 2 N NH3 in CH3OH (5 mL). Concentration afforded 4-[{N-(2-amino-4,5-difluorobenzoyl)glycyl}aminomethyl]-1-(3-amino-4-hydroxybenzyl)piperidine (Compound No. 2141) (17.6 mg, quant.). The purity was determined by RPLC/MS (85%); ESI/MS m/e 448.3 (M++H, C22H27F2N5O3).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([C:11]2[S:15][C:14]([C:16]3[S:20][C:19]([CH:21]=O)=[C:18]([CH3:23])[CH:17]=3)=[N:13][N:12]=2)[CH:6]=[C:7]([CH3:10])[C:8]=1[OH:9])[CH3:2].[CH3:24][NH:25][CH3:26]>C(O)C>[CH3:24][N:25]([CH2:21][C:19]1[S:20][C:16]([C:14]2[S:15][C:11]([C:5]3[CH:6]=[C:7]([CH3:10])[C:8]([OH:9])=[C:3]([CH2:1][CH3:2])[CH:4]=3)=[N:12][N:13]=2)=[CH:17][C:18]=1[CH3:23])[CH3:26]
Reactant: CCc1cc(-c2nnc(-c3cc(C)c(C=O)s3)s2)cc(C)c1O
Reactant: CNC
Solvent: CCO
Product: CCc1cc(-c2nnc(-c3cc(C)c(CN(C)C)s3)s2)cc(C)c1O

Procedure:
The title compound (13 mg) is prepared staring from 5-[5-(3-ethyl-4-hydroxy-5-methyl-phenyl)-[1,3,4]thiadiazol-2-yl]-3-methyl-thiophene-2-carbaldehyde (21 mg, 61 μmol) and dimethylamine (33 mg, 244 μmol, as a 33% solution in ethanol) according to Method C; LC-MS: tR=0.56 min; [M+1]+=374.07; 1H NMR (D6-DMSO): δ1.18 (t, J=7.3 Hz, 3H), 2.20 (s, 3H), 2.24 (s, 6H), 2.26 (s, 3H), 2.67 (q, J=7.3 Hz, 2H), 3.57 (s, 2H), 7.47 (s, 1H), 7.56 (s, 2H).
Reaction SMILES: [CH2:1]1[C:6]2([CH2:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[CH2:7]2)[CH2:5][CH2:4][O:3][CH2:2]1.C1(C)C=CC=CC=1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[CH3:33][C:34]1[C:39]([Pb+3])=[C:38]([CH3:41])[CH:37]=[C:36]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:35]=1.Cl>CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[CH3:33][C:34]1[CH:35]=[C:36]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:37]=[C:38]([CH3:41])[C:39]=1[CH:9]1[C:10](=[O:12])[CH2:11][C:6]2([CH2:5][CH2:4][O:3][CH2:2][CH2:1]2)[CH2:7][C:8]1=[O:13]
Reactant: O=C1CC(=O)CC2(CCOCC2)C1
Reactant: Cc1cc(-c2ccccc2)cc(C)c1[Pb+3]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1cc(-c2ccccc2)cc(C)c1C1C(=O)CC2(CCOCC2)CC1=O
Temperature: 25 °C

Procedure:
To a mixture of 3-oxaspiro[5.5]undecane-8,10-dione (0.182 g, 1 mmol) and 4-dimethylamino-pyridine (0.61 g; 5 mmol) is added dry chloroform (4 ml), and the mixture is stirred under an atmosphere of nitrogen at room temperature until the solid dissolves. To this solution is then added dry toluene (2 ml), and then a solution of 3,5-dimethylbiphen-4-yllead triacetate (1.2 mmol) in chloroform is added. The reaction mixture is heated under reflux for 1 hour, then cooled to room temperature, acidified to pH=1 with 2N aqueous hydrochloric acid, filtered and the filtrate is extracted with dichloromethane (2×40 ml). The organic extracts are combined, dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated in vacuo. The residue is purified by column chromatography over silica gel to give 9-(3,5-dimethylbiphenyl-4-yl)-3-oxa-spiro[5.5]undecane-8,10-dione.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11](=[N:18][C:19]2[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=2)[NH:12][C:13](OCC)=[O:14])[CH:10]=1)=[O:5])[CH3:2].ClCCCl>[Ti](Cl)(Cl)(Cl)Cl.C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[NH:12][C:13](=[O:14])[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([Br:25])[CH:23]=3)[N:18]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)NC(=Nc1ccc(Br)cc1)n1cc(C(=O)OCC)cn1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: ClCCCl
Product: CCOC(=O)c1cnn(-c2nc3ccc(Br)cc3c(=O)[nH]2)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 64.2 %

Procedure:
Titanium (IV) chloride (2.47 mL, 22.5 mmol) was carefully added to a solution of 1-[(4-bromo-phenylimino)-ethoxycarbonylamino-methyl]-1H-pyrazole-4-carboxylic acid ethyl ester (1.84 g, 4.50 mmol) and DCE (45 mL), and the resulting solution was heated to 100° C. for 15 h. The reaction mixture was cooled to room temperature and poured into ice water (50 mL) and DCM (100 mL) was added. The biphasic mixture was stirred for 2 h, and the layers were separated. The aqueous layer was further extracted with DCM (2×50 mL). The combined organic layers were washed with brine (50 mL), dried (MgSO4), and concentrated. The residue was triturated from EtOH to yield the titled compound (1.05 g, 64% yield). MS (ESI/Cl): mass calcd. for C14H11BrN4O3, 362.0; m/z found, 363.0 [M+H]+. 1H NMR (600 MHz, DMSO-d6): 13.15 (s, 1H), 9.01 (d, J=0.5 Hz, 1H), 8.33 (s, 1H), 8.20 (d, J=2.3 Hz, 1H), 7.99 (dd, J=8.7, 2.4 Hz, 1H), 7.66 (d, J=8.8 Hz, 1H), 4.30 (q, J=7.1 Hz, 2H), 1.32 (t, J=7.1 Hz, 3H).