Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6]([CH3:18])([CH3:17])[CH2:7][CH2:8][O:9][Si](C(C)(C)C)(C)C)=[N+:2]=[N-:3].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O1CCCC1>[N:1]([CH2:4][CH2:5][C:6]([CH3:18])([CH3:17])[CH2:7][CH2:8][OH:9])=[N+:2]=[N-:3]
Reactant: CC(C)(CCN=[N+]=[N-])CCO[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(CCO)CCN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 0 %

Procedure:
Step C To a solution of (5-azido-3,3-dimethyl-pentyloxy)-tert-butyl-dimethyl-silane (0.8 g, 3 mmol) in tetrahydrofuran (5 mL) was added tetrahydrofuran solution (1 M, Aldrich) of TBAF (4.9 mL, 4.9 mmol). The reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated, the residue was partitioned between ethyl acetate and water. The organic layer was separated, dried over MgSO4, and concentrated. The residue was purified by chromatography (EtOAc:hexanes=1:3) to give 5-azido-3,3-dimethyl-pentan-1-ol as a colorless oil (0 g, 76%)
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:10]=1[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:20]([O:22][CH2:23][CH3:24])=[O:21].CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[CH2:1]([S:8][C:9]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:10]=1[NH:11][C:20](=[O:21])[O:22][CH2:23][CH3:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cc([N+](=O)[O-])ccc1SCc1ccccc1
Reactant: CCOC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)Nc1cc([N+](=O)[O-])ccc1SCc1ccccc1
Reaction time: 4 h

Procedure:
To the solution of 2-(benzylthio)-5-nitroaniline (2.61 g, 10 mmol) in DMF (10 ml), added ethyl chloroformate (1.05 ml, 1 lmmol), followed by DIPEA (2.1 ml, 12 mmol). Stirred for 4 hours. Diluted with EtOAc, washed with water and brine, dried over Na2SO4. Concentrated to give ethyl 2-(benzylthio)-5-nitrophenylcarbamate as product.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH2:9][C:10]#[N:11])=[C:4]([CH2:12][C:13]#[N:14])[CH:3]=1.O.[CH:16]([CH:18]=O)=O.C(C=O)=O.[OH-].[K+].Cl>CO>[CH3:8][C:7]1[CH:6]=[C:5]2[C:4](=[CH:3][C:2]=1[CH3:1])[C:12]([C:13]#[N:14])=[CH:18][CH:16]=[C:9]2[C:10]#[N:11]
Reactant: Cc1cc(CC#N)c(CC#N)cc1C
Reactant: O=CC=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc2c(C#N)ccc(C#N)c2cc1C
Reaction time: 5 h
Yield: 34 %

Procedure:
17 parts of 4,5-dimethyl-1,2-bis-cyanomethyl-benzene and 7.8 parts of glyoxal hydrate (trimer) (3C2H2O2.2H2O) containing 80% of glyoxal to be liberated, are stirred in 100 parts by volume of methanol. The reaction mixture is treated at 0° to 5° C., with stirring and under nitrogen, with 10.5 parts of powdered potassium hydroxide added by small amounts. After the addition of potassium hydroxide, stirring is continued for a further 5 hours at 0° to 5° C. under nitrogen. The slightly brown coloured reaction mixture is subsequently neutralised with dilute hydrochloric acid, freed from methanol in vacuo and extracted with methylene chloride. The methylene chloride extract is washed neutral with water, dried over sodium sulphate and concentrated to dryness in vacuo. Yield: 18 parts of a brown oil which is chromatographed over aluminium oxide. Elution with chlorobenzene yields 6.5 parts (34% of theory) of 6,7-dimethyl-1,4-di-cyanonaphthalene of formula ##STR45## in the form of white crystals with a melting point of 212°-220° C. Two recrystallisations from alcohol yield small white needles with a melting point of 225°-227° C.
Reaction SMILES: [C:1]([C:5]1[N:9]=[C:8]([N:10]2[CH2:15][CH2:14][CH:13]([NH:16][CH:17]3[CH2:19][CH2:18]3)[CH2:12][CH2:11]2)[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=1[C:30]1[O:34][CH:33]=[N:32][CH:31]=1)[C:24](O)=[O:25]>>[C:1]([C:5]1[N:9]=[C:8]([N:10]2[CH2:11][CH2:12][CH:13]([N:16]([CH:17]3[CH2:19][CH2:18]3)[C:24](=[O:25])[C:23]3[CH:27]=[CH:28][C:29]([C:30]4[O:34][CH:33]=[N:32][CH:31]=4)=[C:21]([F:20])[CH:22]=3)[CH2:14][CH2:15]2)[O:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1noc(N2CCC(NC3CC3)CC2)n1
Reactant: O=C(O)c1ccc(-c2cnco2)c(F)c1
Product: CC(C)(C)c1noc(N2CCC(N(C(=O)c3ccc(-c4cnco4)c(F)c3)C3CC3)CC2)n1

Procedure:
The title compound is prepared from [1-(3-tert-butyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-cyclopropyl-amine and 3-fluoro-4-oxazol-5-yl-benzoic acid following a procedure analogous to that described in Example 17. LC (method 1): tR=1.26 min; Mass spectrum (ESI+): m/z=454 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]([F:16])([F:15])[F:14])=[C:11]([C:17]([OH:19])=O)[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][CH:21]([CH3:39])[CH2:22][CH2:23][NH:24][C:25]([C:27]1[N:28]=[N:29][C:30]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[CH:31][CH:32]=1)=[O:26]>>[CH3:20][CH:21]([CH3:39])[CH2:22][CH2:23][NH:24][C:25]([C:27]1[N:28]=[N:29][C:30]([N:33]2[CH2:38][CH2:37][N:36]([C:17]([C:11]3[N:10]=[N:9][N:8]([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[C:12]=3[C:13]([F:14])([F:15])[F:16])=[O:19])[CH2:35][CH2:34]2)=[CH:31][CH:32]=1)=[O:26]
Reactant: CC(C)CCNC(=O)c1ccc(N2CCNCC2)nn1
Reactant: O=C(O)c1nnn(Cc2ccccc2)c1C(F)(F)F
Product: CC(C)CCNC(=O)c1ccc(N2CCN(C(=O)c3nnn(Cc4ccccc4)c3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 9, making variations only as required to use 1-benzyl-5-trifluoromethyl-1H-[1,2,3]triazole-4-carboxylic acid in place of 2,5-dichlorobenzoic acid to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-methylbutyl)amide, the title compound was obtained as a white powder (32% yield). 1H NMR (300 MHz, DMSO-d6) δ 8.03, 7.81, 7.33-7.27, 6.86, 5.92, 5.39, 3.71, 3.47, 3.05, 2.63, 2.43, 1.65, 1.48, 0.92. MS (ES+) m/z 531.2 (M+1).
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][CH2:5][N:6]1[CH:11]=[C:10]([C:12]2[O:16][C:15]([CH3:17])=[N:14][C:13]=2[CH3:18])[C:9](=[O:19])[NH:8][C:7]1=[O:20]>C1COCC1>[CH3:17][C:15]1[O:16][C:12]([C:10]2[C:9](=[O:19])[NH:8][C:7](=[O:20])[N:6]([CH2:5][CH2:4][CH:3]=[O:2])[CH:11]=2)=[C:13]([CH3:18])[N:14]=1
Reactant: COC(CCn1cc(-c2oc(C)nc2C)c(=O)[nH]c1=O)OC
Solvent: C1CCOC1
Product: Cc1nc(C)c(-c2cn(CCC=O)c(=O)[nH]c2=O)o1
Temperature: 45 °C
Reaction time: 1 h
Yield: 57.4 %

Procedure:
1-(3,3-Dimethoxy-propyl)-5-(2,4-dimethyl-oxazol-5-yl)-1H-pyrimidine-2,4-dione (Prep63, 150 mg, 0.49 mmol) was dissolved in THF (10 mL) and 1N HClaq (3 mL) was added. The mixture was stirred at 45° C. for 1 hour. After cooling and neutralization with a saturated solution of NaHCO3 the product was extracted with DCM. The organic phase was dried (Na2SO4) and evaporated to give 74 mg of the title compound (58% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][S:9]([C:12]1[S:16][C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[CH:13]=1)(=[O:11])=[O:10].CS([C:25]1[CH:26]=[CH:27][C:28]([O:35][CH3:36])=[C:29]([S:31](Cl)(=[O:33])=[O:32])[CH:30]=1)(=O)=O>C(Cl)Cl.N1C=CC=CC=1>[CH3:12][S:9]([C:26]1[CH:25]=[CH:30][C:29]([S:31]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[NH:8][S:9]([C:12]2[S:16][C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[CH:13]=2)(=[O:11])=[O:10])(=[O:32])=[O:33])=[C:28]([O:35][CH3:36])[CH:27]=1)(=[O:11])=[O:10]
Reactant: COc1ccc(S(C)(=O)=O)cc1S(=O)(=O)Cl
Reactant: Nc1ccccc1NS(=O)(=O)c1cc2ccccc2s1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(S(C)(=O)=O)ccc1S(=O)(=O)Nc1ccccc1NS(=O)(=O)c1cc2ccccc2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 119.4 %

Procedure:
To a solution of benzo[b]thiophene-2-sulfonic acid (2-amino-phenyl)-amide (1 mmol, prepared as in Example 1) in DCM (2 mL) and pyridine (2 mL), 5-methanesulfonyl-2-methoxybenzenesulfonyl chloride (1.1 mmol) was added at RT and the reaction mixture was then allowed to stir at RT overnight. The reaction mixture was then diluted with DCM (10 mL). The organic phase was washed with 10% aqueous HCl (10 mL), water (10 mL) and brine (10 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with DCM/EtOAc to obtain 330 mg of benzo[b]thiophene-2-sulfonic acid [2-(4-methanesulfonyl-2-methoxy-benzenesulfonylamino)phenyl]-amide. LC: Tr 1.06 min; MS: 553.8 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[C:5]([NH:7][CH2:8][C@H:9]([OH:21])[CH2:10][N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12]1)=[O:6].CC(O)=O.[O:29]1[CH2:34][CH2:33][C:32](=O)[CH2:31][CH2:30]1.[BH3-]C#N.[Na+]>CO>[CH2:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:19][CH2:20][N:11]1[CH2:10][C@@H:9]([OH:21])[CH2:8][NH:7][C:5](=[O:6])[C:4]1[CH:22]=[CH:23][CH:24]=[C:2]([NH:1][CH:32]2[CH2:33][CH2:34][O:29][CH2:30][CH2:31]2)[CH:3]=1
Reactant: O=C1CCOCC1
Reactant: Nc1cccc(C(=O)NC[C@H](O)CN2CCc3ccccc3C2)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=C(NC[C@H](O)CN1CCc2ccccc2C1)c1cccc(NC2CCOCC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.8 %

Procedure:
To a solution of (S)-3-amino-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxylpropyl)benzamide (400 mg, 1.23 mmol) in MeOH (8 mL) was added AcOH (0.05 mL) and dihydro-2H-pyran-4(3H)-one (123 mg, 1.23 mmol). The mixture was stirred at 25° C. for 2 h. NaBH3CN (387 mg, 6.15 mmol) was added and the resulting mixture was stirred at 25° C. for 2 h. The reaction solution was concentrated, and the residue was washed with water and extracted with EA. The organic layer was concentrated, and the residue was purified by prep-HPLC to give the title compound (160 mg, Yield 31.8%). 1H NMR (CD3OD, 400 MHz): δ 7.94-7.76 (m, 2H), 7.63-7.56 (m, 1H), 7.56-7.49 (m, 1H), 7.32-7.24 (m, 3H), 7.21-7.15 (m, 1H), 4.71-4.55 (m, 1H), 4.52-4.28 (m, 2H), 4.05-3.95 (m, 2H), 3.92-3.70 (m, 2H), 3.62-3.46 (m, 3H), 3.46-3.33 (m, 4H), 3.28-3.02 (m, 2H), 1.99-1.85 (m, 2H), 1.82-1.66 (m, 2H). LCMS (m/z): 410.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](Cl)=[N:7][N:6]=[CH:5]2.[CH3:13][CH:14]1[CH2:18][CH2:17][CH2:16][NH:15]1>CN(C=O)C.CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:15]1[CH2:16][CH2:17][CH2:18][CH:14]1[CH3:13])=[N:7][N:6]=[CH:5]2
Reactant: CC1CCCN1
Reactant: Clc1nncc2cc(Br)ccc12
Solvent: CO
Solvent: CN(C)C=O
Product: CC1CCCN1c1nncc2cc(Br)ccc12
Temperature: 120 °C

Procedure:
A mixture of 6-bromo-1-chlorophthalazine (500 mg, 2.0 mmol) and 2-methylpyrrolidine (524 μl, 5.1 mmol) in DMF (3 mL) was heated at 120° C. in an oil bath for 8 h. The mixture was diluted with MeOH and concentrated over silica gel. The residue was purified using column chromatography (0-40% EtOAc in hexanes) to give the title compound as a brown amorphous solid. MS (ESI, pos. ion) m/z: 292.0, 294.0 (M+1).
Reaction SMILES: [CH:1]([C@H:4]1[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[CH:12][CH:13]=[C:14]([CH:15]([CH3:17])[CH3:16])[C:6]=2[O:5]1)([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:21][C:22]([O:24][CH3:25])=[O:23]>CN(C)C=O.O>[CH:1]([C@H:4]1[C:9](=[O:10])[N:8]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[C:7]2[CH:11]=[CH:12][CH:13]=[C:14]([CH:15]([CH3:17])[CH3:16])[C:6]=2[O:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)c1cccc2c1O[C@@H](C(C)C)C(=O)N2
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CN1C(=O)[C@H](C(C)C)Oc2c(C(C)C)cccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 81.1 %

Procedure:
To a solution of (S)-2,8-diisopropyl-2H-1,4-benzoxazin-3(4H)-one (4.66 g) in dimethylformamide (60 ml), was added portionwise 60% sodium hydride in oil (0.84 g). The mixture was stirred at room temperature for 10 minutes, and a solution of methyl bromoacetate (2.0 ml) in dimethylformamide (6.0 ml) was added thereto. The whole was stirred at room temperature for 30 minutes, diluted with water, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated. The residue was crystallized from hexane to yield (S)-methyl 3,4-dihydro-2,8-diisopropyl-3-oxo-2H-1,4-benzoxazine-4-acetate as crystals (4.95 g, 81.1%). Recrystallization from hexane gave colorless needles, mp 67°-68° C. [α]D23 +3.7° (c=0.95, MeOH).
Reaction SMILES: [OH:1][C@@H:2]([C@@H:4]1[NH:36][C:35](=[O:37])[C@H:34]([C@H:38]([OH:45])[C@H:39]([CH3:44])[CH2:40]/[CH:41]=[CH:42]/[CH3:43])[N:33]([CH3:46])[C:32](=[O:47])[C@H:31]([CH:48]([CH3:50])[CH3:49])[N:30]([CH3:51])[C:29](=[O:52])[C@H:28]([CH2:53][CH:54]([CH3:56])[CH3:55])[NH:27][C:26](=[O:57])[C@H:25]([CH2:58][CH:59]([CH3:61])[CH3:60])[N:24]([CH3:62])[C:23](=[O:63])[C@@H:22]([CH3:64])[NH:21][C:20](=[O:65])[C@H:19]([CH3:66])[NH:18][C:17](=[O:67])[C@H:16]([CH2:68][CH:69]([CH3:71])[CH3:70])[N:15]([CH3:72])[C:14](=[O:73])[C@H:13]([CH2:74][CH:75]([CH3:77])[CH3:76])[NH:12][C:11](=[O:78])[C@H:10]([CH:79]([O:81][CH3:82])[CH3:80])[N:9]([CH3:83])[C:8](=[O:84])[C@@H:7]([CH3:85])[N:6]([CH3:86])[C:5]1=[O:87])[CH3:3]>CO.[Pd]>[OH:1][C@@H:2]([C@@H:4]1[NH:36][C:35](=[O:37])[C@H:34]([C@H:38]([OH:45])[C@H:39]([CH3:44])[CH2:40][CH2:41][CH2:42][CH3:43])[N:33]([CH3:46])[C:32](=[O:47])[C@H:31]([CH:48]([CH3:49])[CH3:50])[N:30]([CH3:51])[C:29](=[O:52])[C@H:28]([CH2:53][CH:54]([CH3:55])[CH3:56])[NH:27][C:26](=[O:57])[C@H:25]([CH2:58][CH:59]([CH3:61])[CH3:60])[N:24]([CH3:62])[C:23](=[O:63])[C@@H:22]([CH3:64])[NH:21][C:20](=[O:65])[C@H:19]([CH3:66])[NH:18][C:17](=[O:67])[C@H:16]([CH2:68][CH:69]([CH3:70])[CH3:71])[N:15]([CH3:72])[C:14](=[O:73])[C@H:13]([CH2:74][CH:75]([CH3:77])[CH3:76])[NH:12][C:11](=[O:78])[C@H:10]([CH:79]([O:81][CH3:82])[CH3:80])[N:9]([CH3:83])[C:8](=[O:84])[C@@H:7]([CH3:85])[N:6]([CH3:86])[C:5]1=[O:87])[CH3:3]
Reactant: C/C=C/C[C@@H](C)[C@@H](O)[C@H]1C(=O)N[C@@H]([C@@H](C)O)C(=O)N(C)[C@H](C)C(=O)N(C)[C@@H](C(C)OC)C(=O)N[C@@H](CC(C)C)C(=O)N(C)[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@H](C)C(=O)N(C)[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N(C)[C@@H](C(C)C)C(=O)N1C
Agent: [Pd]
Solvent: CO
Product: CCCC[C@@H](C)[C@@H](O)[C@H]1C(=O)N[C@@H]([C@@H](C)O)C(=O)N(C)[C@H](C)C(=O)N(C)[C@@H](C(C)OC)C(=O)N[C@@H](CC(C)C)C(=O)N(C)[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@H](C)C(=O)N(C)[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N(C)[C@@H](C(C)C)C(=O)N1C
Yield: 93.2 %

Procedure:
A solution of (3R,6S,9S,12S,15S,18S,21R,24S,27S,30S,33S)-6-[(1R)-1-hydroxyethyl]-9-[(1R,2R,4E)-1-hydroxy-2-methylhex-4-en-1-yl]-15,18,27,30-tetraisobutyl-12-isopropyl-33-(1-methoxyethyl)-1,3,4,10,13,19,21,24,28-nonamethyl-1,4,7,10,13,16,19,22,25,28,31-undecaazacyclotritriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone (60 mg) in MeOH (6.0 ml) was hydrogenated over 20% Pd/C (50% wet; 30 mg) at room temperature for 2 hrs. The mixture was filtered and the filtrate was concentrated. The residue was evaporated to give (3R,6S,9S,12S,15S,18S,21R,24S,27S,30S,33S)-6-[(1R)-1-hydroxyethyl]-9-[(1R,2R)-1-hydroxy-2-methylhexyl]-15,18,27,30-tetraisobutyl-12-isopropyl-33-(1-methoxyethyl)-1,3,4,10,13,19,21,24,28-nonamethyl-1,4,7,10,13,16,19,22,25,28,31-undecaazacyclotritriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone (56 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([NH:11][CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:5]2.[Cl:22][CH2:23][C:24](Cl)=[O:25]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([N:11]([C:24](=[O:25])[CH2:23][Cl:22])[CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19])[CH2:5]2
Reactant: CC(C)(C)OC(=O)NCCNC1Cc2ccc(Br)cc2C1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCN(C(=O)CCl)C1Cc2ccc(Br)cc2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-Butyl {2-[(5-bromo-2,3-dihydro-1H-inden-2-yl)amino]ethyl}carbamate (140 mg, 0.39 mmol) in 10 mL of DCM was added TEA (159 mg, 1.58 mmol) and chloroacetyl chloride (49 mg, 0.43 mmol) at 0° C. The mixture was stirred at RT for 2 hours. DCM was added to the mixture, and then washed 1N HCl and brine. The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was used directly in next step.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11](=[O:15])[CH:12]([CH3:14])[CH3:13])=[CH:8][C:9]=1[NH2:10])=[O:4].CO[CH:18]([N:21]([CH3:23])[CH3:22])OC>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11](=[O:15])[CH:12]([CH3:13])[CH3:14])=[CH:8][C:9]=1[N:10]=[CH:18][N:21]([CH3:23])[CH3:22])=[O:4]
Reactant: COC(=O)c1sc(C(=O)C(C)C)cc1N
Reactant: COC(OC)N(C)C
Product: COC(=O)c1sc(C(=O)C(C)C)cc1N=CN(C)C

Procedure:
3-Amino-5-isobutyrylthiophene-2-carboxylic acid methyl ester and dimethoxymethyldimethylamine were reacted by method B. The product with the molecular weight of 382.36 (C13H18N2O3S) was obtained in this way; MS (ESI): 383 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1I.[C:10]1(=[O:15])[CH2:14][CH2:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.CCOCC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:11]1[CH2:12][CH2:13][CH2:14][C:10]1=[O:15]
Reactant: Fc1ccc(I)c(Br)c1
Reactant: O=C1CCCC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOCC
Product: O=C1CCCC1c1ccc(F)cc1Br
Temperature: 25 °C
Yield: 14.3 %

Procedure:
Heat a mixture of 2-bromo-4-fluoro-1-iodobenzene (4.5 g, 15 mmol), cyclopentanone (2.65 mL, 29.9 mmol), cesium carbonate (10.72 g, 32.9 mmol), 4,5-bis(disphenylphosphino)-9,9-dimethylxanthene (0.54 g, 0.9 mmol), and Palladium2(dibenzalacetone)3 [Pd2(dba)3)](0.35 g, 0.37 mmol) in dioxane (10 mL) to 80° C. under N2 for 22 h. After cooling the mixture to RT, dilute with ether, filter through a celite pad, and remove the solvent. Purify the residue by column chromatography (hexane:ether/20:1) to give the title compound (0.55 g, 15%). MS (GC) m/z 258 [M]+.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:16]([O:17][C:18]3[CH:32]=[CH:31][C:21]([O:22][CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)=[CH:20][CH:19]=3)=[C:15]([C:33]3[CH:38]=[CH:37][C:36]([S:39]([CH2:42][CH3:43])(=[O:41])=[O:40])=[CH:35][CH:34]=3)[S:14][C:13]=2[CH:44]=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.C(OCC)(=O)C.[OH-].[Pd+2].[OH-]>[CH2:42]([S:39]([C:36]1[CH:37]=[CH:38][C:33]([C:15]2[S:14][C:13]3[CH:44]=[C:9]([OH:8])[CH:10]=[CH:11][C:12]=3[C:16]=2[O:17][C:18]2[CH:32]=[CH:31][C:21]([O:22][CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[CH:20][CH:19]=2)=[CH:34][CH:35]=1)(=[O:41])=[O:40])[CH3:43]
Reactant: CCS(=O)(=O)c1ccc(-c2sc3cc(OCc4ccccc4)ccc3c2Oc2ccc(OCCN3CCCCC3)cc2)cc1
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)c1ccc(-c2sc3cc(O)ccc3c2Oc2ccc(OCCN3CCCCC3)cc2)cc1
Yield: 87.2 %

Procedure:
Dissolve the compound of Example 87 (400 mg, 0.64 mmol) in methanol (7 mL) and ethyl acetate (7 mL). Add ammonium formate (521 mg, 8.3 mmol) and palladium hydroxide (240 mg) and heat to reflux for 5 hours. Filter the reaction mixture and concentrate in vacuo to give 300 mg of the title compound (86%): mass spectrum (ion spray): m/z=538 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[N:10][C:11]3[N:12]([C:14]([C:17]4([C:20]5[CH:21]=[C:22]6[C:27](=[CH:28][CH:29]=5)[N:26]=[CH:25][CH:24]=[CH:23]6)[CH2:19][CH2:18]4)=[N:15][N:16]=3)[N:13]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:30][N:31](C=O)C>[C-]#N.[Zn+2].[C-]#N.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.[Zn]>[N:26]1[C:27]2[C:22](=[CH:21][C:20]([C:17]3([C:14]4[N:12]5[N:13]=[C:8]([C:4]6[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=6)[C:30]#[N:31])[CH:9]=[N:10][C:11]5=[N:16][N:15]=4)[CH2:19][CH2:18]3)=[CH:29][CH:28]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: CN(C)C=O
Reactant: Brc1cccc(-c2cnc3nnc(C4(c5ccc6ncccc6c5)CC4)n3n2)c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1cccc(-c2cnc3nnc(C4(c5ccc6ncccc6c5)CC4)n3n2)c1
Temperature: 170 °C

Procedure:
A mixture of 6-{1-[6-(3-bromophenyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-3-yl]cyclopropyl}quinoline (Example 40, 10 mg, 0.02 mmol), zinc cyanide (3.24 mg, 0.0271 mmol), bis(tri-t-butylphosphine)palladium (7 mg, 0.01 mmol), and zinc powder (1.77 mg, 0.0271 mmol) in DMF (0.6 mL) was heated at 170° C. for 20 min under microwave. After cooling to ambient temperature, the mixture was filtered. The filtrate was diluted with methanol and subject to preparative RP-HPLC (pH=10) to afford the desired product. Analytical LCMS: (M+H)+=390.2.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:37]=[CH:36][C:9]2[N:10]([CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[N:19]=[C:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:17]=[C:16]4Cl)=[N:12][C:8]=2[CH:7]=1)=[O:5])C.C1(N2C3C=CC(C(O)=O)=CC=3N=C2C2C=C3C(=CC=2)N=C(C2C=CC=CC=2)C=C3N(C)C)CCCCC1.[C:75]1([OH:81])[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=1>>[CH:30]1([N:10]2[C:9]3[CH:36]=[CH:37][C:6]([C:4]([OH:5])=[O:3])=[CH:7][C:8]=3[N:12]=[C:11]2[C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]=[C:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:17]=[C:16]3[O:81][C:75]2[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=2)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1
Reactant: CCOC(=O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4)cc(Cl)c3c1)n2C1CCCCC1
Reactant: Oc1ccccc1
Agent: CN(C)c1cc(-c2ccccc2)nc2ccc(-c3nc4cc(C(=O)O)ccc4n3C3CCCCC3)cc12
Product: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4)cc(Oc4ccccc4)c3c1)n2C1CCCCC1

Procedure:
In this reaction 51 mg (0.1 mmol) of crude 2-(4-chloro-2-phenyl-quinolin-6-yl)-1-cyclohexyl-1H-benzoimidazole-5-carboxylic acid ethyl ester were used in the same reaction sequence as that used for Compound 481. The nucleophile used was phenol. Yield: 19 mg.
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[CH:16]=[C:17]3[C:22](=[C:23]([OH:25])[CH:24]=2)[O:21][C:20]([CH3:27])([CH3:26])[CH2:19][C:18]3([CH3:29])[CH3:28])=[CH:9][CH:8]=1)([CH3:6])[CH3:5].[OH-].[K+]>CO.O1CCCC1>[OH:25][C:23]1[CH:24]=[C:15]([C:14]#[C:13][C:10]2[CH:11]=[CH:12][C:7]([C:4]([CH3:6])([CH3:5])[C:3]([OH:30])=[O:2])=[CH:8][CH:9]=2)[CH:16]=[C:17]2[C:22]=1[O:21][C:20]([CH3:27])([CH3:26])[CH2:19][C:18]2([CH3:29])[CH3:28]
Reactant: COC(=O)C(C)(C)c1ccc(C#Cc2cc(O)c3c(c2)C(C)(C)CC(C)(C)O3)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC1(C)CC(C)(C)c2cc(C#Cc3ccc(C(C)(C)C(=O)O)cc3)cc(O)c2O1
Temperature: 80 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
A solution of 2-[4-(8-hydroxy-2,2,4,4-tetramethyl-chroman-6-ylethynyl)-phenyl]-2-methyl-propionic acid methyl ester (Intermediate 23, 0.035 g, 0.087 mmol) in methanol (2 mL) and tetrahydrofuran (1 mL) was treated with a 1M solution of potassium hydroxide (2 mL, 4 mmol) and the resulting reaction mixture was stirred at 80° C. for 2 h. The volatiles were evaporated in vacuo to a residue that was neutralized with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase was washed with water and brine, and dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title product as a yellow solid (0.034 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][CH3:11])=[O:9])[CH:3]=1.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)(O)[O-].[Na+].Cl.O1CCOCC1>C(O)CCC.C(O)C>[ClH:1].[CH3:11][NH:10][C:8]([C:4]1[CH:3]=[C:2]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:7]=[CH:6][N:5]=1)=[O:9]
Reactant: CNC(=O)c1cc(Cl)ccn1
Reactant: C1CNCCN1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCCCO
Solvent: C1COCCO1
Product: CNC(=O)c1cc(N2CCNCC2)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.2 %

Procedure:
A mixture of 4-Chloro-N-methyl-pyridine-2-carboxamide (400 mg, 2.345 mmol), piperazine (808 mg, 9.38 mmol) and sodium bicarbonate (591 mg, 7.03 mmol) in 1-butanol (4 ml) was heated under reflux for 18 hours. The mixture was filtered, the filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica, 1-5% MeOH—basified with ammonia—in DCM) to give a colourless oil. The oil was dissolved in 2 ml ethanol and 4N HCl in dioxane (1.11 ml, 4.4 mmol) was added. The mixture was stirred for 1 hour at room temperature and filtered. The filter residue was rinsed with DCM and ethanol, dried under reduced pressure to give 200 mg of a white solid (0.779 mmol, 33%). MS (ESI) m/z=221.2 [M+1]+.