Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:9]2[C:4]([CH2:5][NH:6][CH2:7][CH2:8]2)=[CH:3][C:2]1=[O:10].[CH3:11][C:12]1[CH:13]=[CH:14][C:15]([S:18]([OH:21])(=[O:20])=[O:19])=[CH:16][CH:17]=1.[C:22]([Si:26]([CH3:29])([CH3:28])Cl)([CH3:25])([CH3:24])[CH3:23].C(N(CC)CC)C>C(Cl)Cl>[Si:26]([O:10][C:2]1[S:1][C:9]2[CH2:8][CH2:7][NH:6][CH2:5][C:4]=2[CH:3]=1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:29])[CH3:28].[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([OH:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1C=C2CNCCC2S1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)Oc1cc2c(s1)CCNC2

Procedure:
A mixture of 5.00 g of 5,6,7,7a-tetrahydro-4H-thieno[3,2-c]pyridin-2-one.p-toluenesulfonate, 2.47 g of tert-butyldimethylchlorosilane, 1.66 g of triethylamine and 15 ml of methylene chloride was stirred at room temperature (20° C.) for 3 hours. The produced 2-(tert-butyldimethylsilyloxy)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-p-toluenesulfonate was not isolated, 5.90 g of 2-chloro-α-methoxycarbonylbenzyl bromide and 3.02 g of triethylamine were added thereto, and the mixture was allowed to react.
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].C([O-])([O-])=O.[K+].[K+].[Cl:16][C:17]1[CH:39]=[C:38]([Cl:40])[CH:37]=[CH:36][C:18]=1[CH2:19][O:20][C:21]1[CH:35]=[CH:34][C:24]2[C:25]([OH:33])=[C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[S:27][C:23]=2[CH:22]=1.CN(C=O)C>O>[C:6]([O:5][C:3](=[O:4])[CH2:2][O:33][C:25]1[C:24]2[CH:34]=[CH:35][C:21]([O:20][CH2:19][C:18]3[CH:36]=[CH:37][C:38]([Cl:40])=[CH:39][C:17]=3[Cl:16])=[CH:22][C:23]=2[S:27][C:26]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29])([CH3:9])([CH3:8])[CH3:7]
Reactant: CCOC(=O)c1sc2cc(OCc3ccc(Cl)cc3Cl)ccc2c1O
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1sc2cc(OCc3ccc(Cl)cc3Cl)ccc2c1OCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of t-butyl bromoacetate (0.736 mL), K2CO3 (0.626 g), ethyl 6-((2,4-dichlorobenzyl)oxy)-3-hydroxy-1-benzothiophene-2-carboxylate (1.8 g) and DMF (20 mL) was stirred at room temperature for 20 h. Water was added to the mixture and the mixture was extracted with EtOAc. The EtOAc extract was washed successively with water and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (1.330 g). The obtained crystals were recrystallized from acetone-hexane.
Reaction SMILES: [F:1][C:2]([F:20])([S:16]([OH:19])(=[O:18])=[O:17])[C:3]([F:15])([F:14])[C:4]([F:13])([F:12])[C:5]([F:11])([F:10])[S:6](O)(=[O:8])=[O:7].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>>[F:11][C:5]1([F:10])[S:6](=[O:7])(=[O:8])[O:17][S:16](=[O:19])(=[O:18])[C:2]([F:20])([F:1])[C:3]([F:15])([F:14])[C:4]1([F:12])[F:13]
Reactant: O=S(=O)(O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)S(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: O=S1(=O)OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C1(F)F
Temperature: 160 °C

Procedure:
Perfluorobutane-1,4-bis-sulphonic acid (11.0 g, ˜30 mmol) was mixed with P2O5 (40 g, ˜10 eq) and sand. The mixture was heated to 140-180° C. and distilled under reduced pressure with dry-ice cooling collector to afford crude product (5.12 g). Redistilation gives pure perfluorobutane-1,4-bis-sulphonic acid anhydride.
Reaction SMILES: [OH:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([NH:8][CH2:9][C@H:10]([N:15]2[CH2:20][CH2:19][N:18]([S:21]([CH3:24])(=[O:23])=[O:22])[CH2:17][CH2:16]2)[C:11]([O:13][CH3:14])=[O:12])=[O:7])=[CH:4][CH:3]=1.[C:27]([Si:31]([O:34][CH2:35][C:36]#[C:37][CH2:38]Cl)([CH3:33])[CH3:32])([CH3:30])([CH3:29])[CH3:28]>>[Si:31]([O:34][CH2:35][C:36]#[C:37][CH2:38][O:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([NH:8][CH2:9][C@H:10]([N:15]2[CH2:16][CH2:17][N:18]([S:21]([CH3:24])(=[O:23])=[O:22])[CH2:19][CH2:20]2)[C:11]([O:13][CH3:14])=[O:12])=[O:7])=[CH:4][CH:3]=1)([C:27]([CH3:28])([CH3:29])[CH3:30])([CH3:32])[CH3:33]
Reactant: CC(C)(C)[Si](C)(C)OCC#CCCl
Reactant: COC(=O)[C@H](CNC(=O)c1ccc(O)cc1)N1CCN(S(C)(=O)=O)CC1
Product: COC(=O)[C@H](CNC(=O)c1ccc(OCC#CCO[Si](C)(C)C(C)(C)C)cc1)N1CCN(S(C)(=O)=O)CC1
Yield: 89.8 %

Procedure:
In a manner similar to example 4-5, starting from 400 mg (1 mmol) of methyl (S)-3-(4-hydroxybenzoylamino)-2-(4-methanesulphonylpiperazin-1-yl)propanoate (prepared as described in example 4-4) and from 270 mg (1.2 mmol) of tert-butyl(4-chloro-but-2-ynyloxy)-dimethylsilane; 510 mg (88%) of methyl (S)-3-{4-[4-(tert-butyldimethylsilanyloxy)but-2-ynyloxy]benzoyl-amino}-2-(4-methanesulphonylpiperazin-1-yl)propanoate are obtained in the form of a colourless oil.
Reaction SMILES: [OH:1][C:2]1[C:3]2[CH:11]=[N:10][CH:9]=[C:8]([C:12]([O:14]C)=O)[C:4]=2[N:5]=[CH:6][N:7]=1.[NH4+:16].[OH-]>CO>[OH:1][C:2]1[C:3]2[CH:11]=[N:10][CH:9]=[C:8]([C:12]([NH2:16])=[O:14])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: COC(=O)c1cncc2c(O)ncnc12
Reactant: [NH4+]
Agent: [OH-]
Solvent: CO
Product: NC(=O)c1cncc2c(O)ncnc12
Yield: 41.1 %

Procedure:
The mixture of methyl 4-hydroxypyrido[4,3-d]pyrimidine-8-carboxylate (47 mg, 0.1 mmol), NH4OH (3 mL) and MeOH (10 mL) was heated to reflux for 20 hours in a sealed tube. The mixture was then concentrated and purified by prep-HPLC to afford the title compound as a white solid (yield 41.1%).
Reaction SMILES: [F:1][C:2]1([CH2:15]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[C:27]1(=[O:37])[NH:31][C:30](=[O:32])[C:29]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:28]12.[K].O>CN(C=O)C>[O:32]=[C:30]1[C:29]2[C:28](=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:27](=[O:37])[N:31]1[CH2:15][C:2]1([F:1])[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:6][CH2:7]1
Reactant: Cc1ccc(S(=O)(=O)OCC2(F)CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(F)(CN2C(=O)c3ccccc3C2=O)CC1
Temperature: 150 °C

Procedure:
To a solution of 3-2 (6.78 g, 17.5 mmol) in 70 mL DMF was added potassium phthalimide (4.21 g, 22.7 mmol) and the mixture was heated at 150° C. for 2.5 h. The mixture was allowed to cool to ambient temperature, poured into H2O (150 mL), and extracted with EtOAc (3×150 mL). The combined organic layers were washed with brine (200 mL), dried over MgSO4, filtered, and concentrated in vacuo, giving 11.0 g of crude 3-3 as a tan solid. 1H NMR (CDCl3, 300 MHz): 7.85 (dd, J=5.4, 3.0 Hz, 2H), 7.76 (dd, J=5.4, 3.0 Hz, 2H), 3.96 (br, 2H), 3.04 (m, 2H), 1.70 (m, 6H), 1.43 (s, 9H); MS (Electrospray): m/z 385.2 (M+Na), 347.3 (M−Me+H).
Reaction SMILES: [NH2:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:43])[N:15]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[C:16](=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:4].[C:44]([NH:54][CH2:55][C:56]([NH:58][CH2:59][C:60](O)=[O:61])=[O:57])([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45]>O1CCCC1>[C:44]([NH:54][CH2:55][C:56]([NH:58][CH2:59][C:60]([NH:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:43])[N:15]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[C:16](=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:4])=[O:61])=[O:57])([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45]
Reactant: CCCCCCCCCCCCCCN(C(=O)CCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CN
Reactant: O=C(O)CNC(=O)CNC(=O)OCc1ccccc1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCN(C(=O)CCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CNC(=O)CNC(=O)CNC(=O)OCc1ccccc1
Yield: 52 %

Procedure:
from N-(2-glycyl-amino-2-deoxy-β-D-glucopyranosyl)-N-tetradecyl-dodecanamide and N-carbobenzoxy-glycyl-glycine. Yield 52%. [α]D =+14.7° (c=1.01, tetrahydrofuran). m.p., 99-100°.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[S:11][S:12][C:13]([CH2:16][OH:17])=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.O>C1COCC1>[Si:1]([O:8][CH2:9][C:10]1[S:11][S:12][C:13]([CH:16]=[O:17])=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCC1=CC=C(CO)SS1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCC1=CC=C(C=O)SS1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
To a solution of 3-[(tert-butyldimethylsilyloxy)methyl]-6-(hydroxymethyl)-1,2-dithiin (U.S. Ser. No. 08/212,096) (600 mg, 2.07 mmol) in THF (25 mL) at 0° C. was added quickly the Dess-Martin periodinane reagent (1.20 g, 2.83 mmol) and the mixture was stirred at 0° C. for 30 min, then at room temperature for another 30 min. Upon completion of the reaction (monitored by TLC), 12 mL of H2O was added and the mixture was extracted with ether (3×). The combined organics washings were washed with H2O, sodium hydrogen carbonate (3%-soln.), brine, dried (Na2SO4) and evaporated. Flash chromatography (eluting with hexane/EtOAc 3/1) yielded 560 mg (94%) of the title aldehyde as a dark red, almost purple, crystalline compound.
Reaction SMILES: C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[CH3:34][O:35][CH2:36][CH2:37][N:38]1[CH:42]=[CH:41][C:40]([C:43]2[CH:47]=[CH:46][S:45][CH:44]=2)=[C:39]1[C:48](=[O:52])[C:49]([OH:51])=O.[CH3:53][C:54]1[CH:59]=[C:58]([CH3:60])[N:57]=[C:56]([N:61]2[CH2:66][CH2:65][N:64]([C:67]3[CH:72]=[CH:71][C:70]([NH2:73])=[CH:69][CH:68]=3)[CH2:63][CH2:62]2)[CH:55]=1>ClCCl>[CH3:53][C:54]1[CH:59]=[C:58]([CH3:60])[N:57]=[C:56]([N:61]2[CH2:66][CH2:65][N:64]([C:67]3[CH:72]=[CH:71][C:70]([NH:73][C:49](=[O:51])[C:48]([C:39]4[N:38]([CH2:37][CH2:36][O:35][CH3:34])[CH:42]=[CH:41][C:40]=4[C:43]4[CH:47]=[CH:46][S:45][CH:44]=4)=[O:52])=[CH:69][CH:68]=3)[CH2:63][CH2:62]2)[CH:55]=1
Reactant: Cc1cc(C)nc(N2CCN(c3ccc(N)cc3)CC2)c1
Reactant: COCCn1ccc(-c2ccsc2)c1C(=O)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCn1ccc(-c2ccsc2)c1C(=O)C(=O)Nc1ccc(N2CCN(c3cc(C)cc(C)n3)CC2)cc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 26.3 %

Procedure:
Diisopropylethylamine (0.40 mL, 2.17 mmol), (2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (0.28 mg, 0.72 mmol) was added to a solution of [1-(2-methoxy-ethyl)-3-thiophen-3-yl-1H-pyrrol-2-yl]-oxo-acetic acid (200 mg, 0.72 mmol) in dry dichloromethane at room temperature and the reaction mixture stirred for 1 h. 4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenylamine (160 mg, 0.56 mmol) was added and the mixture was then heated in a sealed tube at 90° C. for 18 h. The reaction mixture was cooled to room temperature, washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to give crude compound which was purified by preparative HPLC to afford N-{4-[4-(4,6-dimethyl-pyridin-2-yl)piperazin-1-yl]-phenyl}-2-[1-(2-methoxy-ethyl)-3-thiophen-3-yl-1H-pyrrol-2-yl]-2-oxo-acetamide (80 mg, 20%) as a solid.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[O:13]1[C:17]2[CH:18]=[CH:19][C:20]([CH:22]([C:26]3[C:34]4[C:29](=[CH:30][C:31]([C:35](=[O:37])[NH2:36])=[CH:32][CH:33]=4)[N:28]([CH3:38])[CH:27]=3)[C:23](O)=[O:24])=[CH:21][C:16]=2[O:15][CH2:14]1.CN(C1C=CC=CN=1)C.[C:48]1([CH3:58])[CH:53]=[CH:52][C:51]([S:54]([NH2:57])(=[O:56])=[O:55])=[CH:50][CH:49]=1>ClCCl.CN(C)C=O>[O:13]1[C:17]2[CH:18]=[CH:19][C:20]([CH:22]([C:26]3[C:34]4[C:29](=[CH:30][C:31]([C:35]([NH2:36])=[O:37])=[CH:32][CH:33]=4)[N:28]([CH3:38])[CH:27]=3)[C:23]([NH:57][S:54]([C:51]3[CH:52]=[CH:53][C:48]([CH3:58])=[CH:49][CH:50]=3)(=[O:55])=[O:56])=[O:24])=[CH:21][C:16]=2[O:15][CH2:14]1
Reactant: Cn1cc(C(C(=O)O)c2ccc3c(c2)OCO3)c2ccc(C(N)=O)cc21
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)NC(=O)C(c2ccc3c(c2)OCO3)c2cn(C)c3cc(C(N)=O)ccc23)cc1
Yield: 67.1 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (65 mg, 0.34 mmol) was added to a stirred solution. 2-(1,3-benzodioxol-5-yl)-2-(6-carbamoyl-1-methyl-1H-3-indolyl)acetic acid (from step (f). 100 mg, 0.28 mmol), dimethylaminopyridine (45 mg, 0.37 mmol) and p-toluenesulphonamide (53 mg, 0.31 mmol) in dichloromethane (5 ml) and dimethylformamide (1 ml) at room temperature under a nitrogen atmosphere. After 14 h the solvent was removed in vacuo and the product was extracted from 1N hydrochloric acid (50 ml) with ethyl acetate (2×50 ml). The organic layers were dried and concentrated to give a fawn foam. Flash column chromatography (elution with 95% dichloromethane/5% methanol) gave the product (95 mg) as a white solid.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:17][CH2:16][C:15]2[C:14]3[CH:13]=[C:12]([CH3:18])[CH:11]=[CH:10][C:9]=3[NH:8][C:7]=2[CH2:6][CH2:5]1.Cl[CH2:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([CH3:29])[CH2:25][CH2:24]1)=[O:22].Cl>C1COCC1>[CH3:3][N:4]1[CH2:17][CH2:16][C:15]2[C:14]3[CH:13]=[C:12]([CH3:18])[CH:11]=[CH:10][C:9]=3[N:8]([CH2:20][C:21]([N:23]3[CH2:28][CH2:27][CH:26]([CH3:29])[CH2:25][CH2:24]3)=[O:22])[C:7]=2[CH2:6][CH2:5]1
Reactant: CC1CCN(C(=O)CCl)CC1
Reactant: Cc1ccc2[nH]c3c(c2c1)CCN(C)CC3
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)c1c(n2CC(=O)N2CCC(C)CC2)CCN(C)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of sodium hydride (46 mg, 1.16 mmol) in THF (5 ml), 3,9-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.1 g, 0.46 mmol) was added at 0° C. and stirred at RT for 30 min. 2-Chloro-1-(4-methylpiperidin-1-yl)ethanone (98 mg, 0.55 mmol) was added slowly dropwise at RT and stirred for 2 h at RT. After completion of the reaction (monitored by TLC & LCMS), the reaction was quenched with ice water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography to afford free base, which was converted to HCl salt using ethanolic HCl. 1H NMR (DMSO-d6, HCl salt) δ (ppm): 11.22 (bs, 1H), 7.20 (m, 2H), 5.0-5.20 (m, 2H), 4.23 (d, 1H), 4.0 (d, 1H), 3.5-3.6 (m, 2H), 3.0-3.23 (m, 4H), 2.8-2.95 (m, 2H), 2.26-2.42 (m, 2H), 1.5-1.8 (m, 3H), 1.09-1.2 (m, 1H), 0.96 (d, 3H).
Reaction SMILES: [CH:1]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:2]=1[C:3](=[O:18])[N:4]1[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][C:5]1=[N:6]2.[C:19]12([C:26](Br)=[O:27])[CH2:25][CH:22]([CH2:23][CH2:24]1)[CH2:21][CH2:20]2>>[C:19]12([C:26]([N:11]3[C:5]4=[N:6][C:7]5[C:2]([C:3](=[O:18])[N:4]4[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:12]3=4)=[CH:1][CH:10]=[CH:9][CH:8]=5)=[O:27])[CH2:25][CH:22]([CH2:23][CH2:24]1)[CH2:21][CH2:20]2
Reactant: O=c1c2ccccc2nc2[nH]c3ccccc3n12
Reactant: O=C(Br)C12CCC(CC1)C2
Product: O=C(n1c2ccccc2n2c(=O)c3ccccc3nc12)C12CCC(CC1)C2

Procedure:
6-(Bicyclo[2.2.1]heptanoyl)benzimidazo[2,1-b]quinazolin-12(6H)one is prepared with benzimidazo[2,1-b]quinazolin-12(6H)one and bicyclo[2.2.1]heptanoyl bromide.
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[CH2:19]([NH:21][CH3:22])[CH3:20]>O>[CH2:19]([N:21]([CH3:22])[C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:6][N:7]=1)[CH3:20]
Reactant: COc1ccc2nc(-c3ccc(F)nc3)sc2c1
Reactant: CCNC
Solvent: O
Product: CCN(C)c1ccc(-c2nc3ccc(OC)cc3s2)cn1
Temperature: 100 °C

Procedure:
In a microwave vial were added 2-(6-fluoropyridin-3-yl)-6-methoxy-1,3-benzothiazole (75 mg, 0.289 mmol), water (2.0 mL) and ethylmethylamine (0.50 mL) and the reaction was heated in a microwave oven at 100° C. for 5 min. The precipitated product was filtered off, washed with water and dried in a desicator over P2O5 to yield the product (70 mg) as a beige solid. 1H NMR δ ppm 8.71 (d, 1 H) 8.06 (dd, 2.53 Hz, 1 H) 7.85 (d, 1 H) 7.66 (d, 1H) 7.08 (dd, 1 H) 6.76 (d, 1 H) 3.84 (s, 3 H) 3.64 (q, 2 H) 3.08 (s, 3 H) 1.12 (t, 3 H); MS m/z (M+H) 300.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[C:4]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)[N:3]=1.[NH:16]1[C:24]2[C:19](=[CH:20][C:21]([CH2:25][NH2:26])=[CH:22][CH:23]=2)[CH:18]=[CH:17]1.N=C=N.O.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:26][CH2:25][C:21]2[CH:20]=[C:19]3[C:24](=[CH:23][CH:22]=2)[NH:16][CH:17]=[CH:18]3)=[O:10])[CH:5]=[C:4]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)[N:3]=1
Reactant: NCc1ccc2[nH]ccc2c1
Reactant: Nc1nc(C(=O)O)cc(-c2ccco2)n1
Agent: N=C=N
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nc(C(=O)NCc2ccc3[nH]ccc3c2)cc(-c2ccco2)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 59.4 %

Procedure:
A mixture consisting of 2-amino-6-(2-furyl)pyrimidine-4-carboxylic acid (206 mg, 1.0 mmol), indole-5-methanamine (146 mg, 1.0 mmol), polymer supported carbodiimide (Argonaut Technologies, loading 1.38 mmol/g, 1.10 g, 1.5 mmol) and 1-hydroxybenzotriazole hydrate (203 mg, 1.5 mmol) in DMF (5 mL) was stirred at room temperature for 24 hr. The mixture was filtered through a pad of Celite, washing through with EtOAc. The filtrate was washed successively with H2O (10 mL), 2-M Na2CO3 (2×10 mL) and H2O (10 mL), dried (MgSO4) and concentrated in vacuo. The resulting oil was dissolved in MeOH (1.0 mL), added dropwise with stirring to H2O (2 mL) and the resulting precipitate filtered to give the title compound (198 mg, 59%) as a cream solid.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([C:21]2([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=3)[C:29]3[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=3)[NH:23][C:22]2=[O:31])[CH2:17][CH2:16]1)=O)(C)(C)C>ClCCl>[Cl:30][C:26]1[CH:25]=[C:24]2[C:29]([C:21]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=3)([CH:18]3[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]3)[C:22](=[O:31])[NH:23]2)=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Trifloroacetic Acid (5 mL) was added to a solution of rac-4-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carboxylic acid tert-butyl ester (0.24 g, 0.5 mmol) (from Example 12c supra) in dichloromethane (5 mL). The mixture was stirred at room temperature for 30 minutes. The solvent was evaporated in vacuo. To the residue was added saturated aqueous sodium bicarbonate solution, and extracted three times with ethyl acetate. The organic layers were combined, washed with water and brine, dried over Na2SO4 and concentrated to give rac-6-chloro-3-(3-chlorobenzyl)-3-piperidin-4-yl-1,3-dihydro-indol-2-one as a white solid. (Yield 0.18 g, 95%).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[CH2:14][CH2:13][C:12](=[O:15])[N:11]1[CH2:16][C:17]([NH2:19])=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:29])=CC=1.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>C(Cl)Cl>[Si:1]([O:8][CH2:9][C@H:10]1[CH2:14][CH2:13][C:12](=[O:15])[N:11]1[CH2:16][C:17](=[S:29])[NH2:19])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CCC(=O)N1CC(N)=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OC[C@H]1CCC(=O)N1CC(N)=S
Yield: 105.6 %

Procedure:
To a solution of the compound 67 (9.50 g) in methylene chloride (133 mL) was added Lawesson's reagent (6.71 g) at 0° C. and the solution was stirred for 3 Hours. To the reaction solution was added an aqueous saturated sodium bicarbonate solution and ethyl acetate and then the solution was separated. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with an aqueous saturated sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate:methanol=60:40:033:67:00:90:10) to give the title compound (5.30 g) having the following physical data.
Reaction SMILES: CO[C:3]1[CH:11]=[C:10]2[C:6]([C:7]3[CH:16]([CH3:17])[CH2:15][CH2:14][CH2:13][CH2:12][C:8]=3[NH:9]2)=[CH:5][CH:4]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH2:22]([SH:24])[CH3:23].Cl>C(Cl)Cl>[CH2:22]([S:24][C:3]1[CH:11]=[C:10]2[C:6]([C:7]3[CH:16]([CH3:17])[CH2:15][CH2:14][CH2:13][CH2:12][C:8]=3[NH:9]2)=[CH:5][CH:4]=1)[CH3:23]
Reactant: COc1ccc2c3c([nH]c2c1)CCCCC3C
Reactant: CCS
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCSc1ccc2c3c([nH]c2c1)CCCCC3C
Temperature: 0 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
500 mg (1.9 mmol) of the compound obtained in Stage B of Example 1, predissolved in 5 cm3 of methylene chloride distilled over phosphoruspentoxide are added dropwise to a mixture, cooled to 0° C., of 380 mg (2.84 mmol) of aluminum chloride and 2.3 g (37.9 mmol) of ethanethiol. After stirring for 1 h at 0° C., 1.5 eq. of aluminum chloride and 20 eq. of ethanethiol are added again. The mixture is stirred again for 1 h at 0° C. and then poured onto ice, treated with 1N hydrochloric acid and then extracted with dichloromethane. After treatment of the organic phase and purification of the crude product by chromatography on asilica column, the expected compound is obtained.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2].[CH:16]1([NH2:19])[CH2:18][CH2:17]1>>[CH:16]1([NH:19][CH:12]2[CH2:13][CH2:14][N:9]([C:6]3[CH:5]=[N:4][C:3]([CH2:1][CH3:2])=[CH:8][N:7]=3)[CH2:10][CH2:11]2)[CH2:18][CH2:17]1
Reactant: NC1CC1
Reactant: CCc1cnc(N2CCC(=O)CC2)cn1
Product: CCc1cnc(N2CCC(NC3CC3)CC2)cn1

Procedure:
The title compound is prepared from 1-(5-ethyl-pyrazin-2-yl)-piperidin-4-one and cyclopropylamine following a procedure analogous to that described in Intermediate 7. LC (method 1): tR=0.65 min; Mass spectrum (ESI+): m/z=247 [M+H]+.
Reaction SMILES: [ClH:1].O1CCOCC1.[N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][CH:16]2[CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18][N:17]2[C:29]([O:31][CH:32]2[CH2:37][CH2:36][N:35]([C:38](=[O:40])[CH3:39])[CH2:34][CH2:33]2)=[O:30])[CH:9]=1>CO>[ClH:1].[ClH:1].[N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][CH:16]2[CH2:21][NH:20][CH2:19][CH2:18][N:17]2[C:29]([O:31][CH:32]2[CH2:37][CH2:36][N:35]([C:38](=[O:40])[CH3:39])[CH2:34][CH2:33]2)=[O:30])[CH:9]=1
Reactant: CC(=O)N1CCC(OC(=O)N2CCN(C(=O)OC(C)(C)C)CC2COc2cccnc2)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CC(=O)N1CCC(OC(=O)N2CCNCC2COc2cccnc2)CC1
Reaction time: 1 h
Yield: 97 %

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution of 1-(1-acetylpiperidin-4-yl) 4-tert-butyl 2-((pyridin-3-yloxy)methyl)piperazine-1,4-dicarboxylate (112.5 mg, 0.195 mmol) in MeOH (1 mL). After 1 h, the reaction mixture was concentrated under reduced pressure, yielding 82.4 mg (97%) of the desired product as a white solid. LC-MS: RT=1.66 min, [M+H]+=363.2.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:26])=[C:8]2[CH:16]=[CH:15][N:14](CC3C=CC(OC)=CC=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2].[C:27]([O:30][C:31](=O)[CH3:32])(=O)C>C(N(CC)CC)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:26][C:1](=[O:3])[CH3:2])=[C:8]2[CH:16]=[CH:15][N:14]([C:6]3[CH:4]=[CH:32][C:31]([O:30][CH3:27])=[CH:8][CH:7]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)c1nc(C#N)c2c(ccn2Cc2ccc(OC)cc2)c1O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1nc(C#N)c2c(ccn2-c2ccc(OC)cc2)c1OC(C)=O

Procedure:
Prepared in analogy to that of Example 120(a) from 7-cyano-4-hydroxy-1-(4-methoxy-benzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, acetic anhydride, and triethyl amine. The title compound, ESI MS (m/z): 380 (M+H)+.