Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: C1CCNC1
Solvent: ClCCl
Product: O=S(=O)(c1ccc(Br)cc1)N1CCCC1
Yield: 26.5 %

Procedure:
According to general procedure C, 4-Bromobenzene sulfonyl chloride (0.40 g, 1.56 mmol) and pyrrolidine (0.32 mL, 3.90 mmol) were stirred together in dry dichloromethane (5 mL) for 16 hours. 1-[(4-bromophenyl)sulfonyl]pyrrolidine (0.12 g) was provided after purification. HRMS: calcd for C10H12BrNO2S+H+, 289.98449; found (ESI, [M+H]+), 289.9847. HPLC purity 99.1% at 210-370 nm, 8.9 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C1(C)C=CC=CC=1>[C:9]1([C:2]2[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OB(O)c1ccccc1
Reactant: O=c1ccc(Br)c[nH]1
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: [Na+]
Solvent: Cc1ccccc1
Product: O=c1ccc(-c2ccccc2)c[nH]1
Temperature: 100 °C
Reaction time: 1 h
Yield: 20.3 %

Procedure:
A mixture of 5-bromopyridin-2(1H)-one (500 mg), phenylboronic acid (385 mg), tetrakis(triphenylphosphine)palladium(0) (498 mg), 2M aqueous sodium carbonate solution (2.87 mL) and toluene (7.0 mL) was stirred at 100° C. for 1 hr under microwave irradiation. The reaction mixture was cooled to room temperature, and filtered through celite. To the filtrate was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (100 mg).
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:51])[C@@H:15]([NH:21][C:22]([C:24]2[CH:28]=[C:27]([O:29][CH2:30][C:31]([N:33]3[CH2:37][CH2:36][CH2:35][C@H:34]3[C:38](=[O:44])[NH:39][CH:40]3[CH2:43][CH2:42][CH2:41]3)=[O:32])[N:26]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[N:25]=2)=[O:23])[CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].[CH2:52](Cl)CCl.CO>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:51])[C@@H:15]([NH:21][C:22]([C:24]2[CH:28]=[C:27]([O:29][CH2:30][C:31]([N:33]3[CH2:37][CH2:36][CH2:35][C@H:34]3[C:38](=[O:44])[NH:39][CH:40]3[CH2:43][CH2:42][CH2:41]3)=[O:32])[N:26]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[N:25]=2)=[O:23])[CH2:16][CH2:17][C:18]([O:20][CH3:52])=[O:19])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)O)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)CC1
Reactant: ClCCCl
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: CN(C)C=O
Product: CCCCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)CC1

Procedure:
To a solution of 120 mg 4-[(S)-4-Carboxy-2-({5-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid butyl ester in 3 ml DMF were added 39 mg EDC, 25 mg DMAP and 34 μl methanol. After 3 h the reaction mixture was concentrated and the residue purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were lyophilized to yield the pure product. Yield: 47 mg MS (ES+): m/e=724.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH2:7][C@H:8]([C:18]1[O:22][N:21]=[C:20]([C:23](OCC)=[O:24])[N:19]=1)[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:4])([CH3:3])[CH3:2].[CH2:29]([NH:36][CH3:37])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(O)C>[CH2:29]([N:36]([CH3:37])[C:23]([C:20]1[N:19]=[C:18]([C@H:8]([CH2:9][CH2:10][CH2:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:28])[O:22][N:21]=1)=[O:24])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CNCc1ccccc1
Reactant: CCOC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Solvent: CCO
Product: CN(Cc1ccccc1)C(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Temperature: 60 °C
Yield: 82.9 %

Procedure:
A solution of ethyl 5{(1R)-1-[2-(tert-butoxy)-2-oxoethyl]-4-cyclohexylbutyl}-1,2,4-oxadiazole-3-carboxylate (Preparation 3) (300 mg, 0.76 mmol) in ethanol (4 ml) was treated with N-benzyl-N-methylamine (0.98 ml, 7.60 mmol) and the resulting mixture was heated at 60° C. under a nitrogen atmosphere for 16 hours. The mixture was cooled and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:ethyl acetate (100:0) gradually changing to dichloromethane:ethyl acetate (95:5) to afford the title compound (296 mg).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]#[C:20][C:21]4[CH:31]=[CH:30][C:24]([C:25]([O:27]CC)=[O:26])=[CH:23][CH:22]=4)[CH:17]=3)[O:12][C:11]([CH3:33])([CH3:32])[CH:10]=2)=[CH:5][CH:4]=1)[CH3:2].[OH-].[Na+].Cl>C1COCC1.CCO>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]#[C:20][C:21]4[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:30][CH:31]=4)[CH:17]=3)[O:12][C:11]([CH3:32])([CH3:33])[CH:10]=2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(CC)cc2)=CC(C)(C)O3)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCc1ccc(C2=CC(C)(C)Oc3ccc(C#Cc4ccc(C(=O)O)cc4)cc32)cc1
Temperature: 35 °C
Reaction time: 8 h
Yield: 84.6 %

Procedure:
To a solution of ethyl 4-[[4-(4-ethylphenyl)-2,2-dimethyl-(2H)-chromen-6-yl]-ethynyl]-benzoate (Compound 267, 82.0 mg, 0.188 mmol) in 3.0 mL THF and 3.0 mL EtOH was added NaOH (120.0 mg, 3.0 mmol, 3.0 mL of a 1M aqueous solution). The resulting solution was heated to 35° C., cooled to room temperature and stirred overnight. The reaction mixture was acidified with 10% aqueous HCl and extracted with EtOAc. The combined organic layers were washed with H2O, saturated aqueous NaCl, and dried (Na2SO4) before the solvent was removed under reduced pressure. The residual solid was recrystallized from CH3CN to give 65.0 mg (85%) the title compound as a colorless solid. 1H NMR (300 MHz, d6 -acetone) δ: 8.01 (2H, d, J=8.4 Hz), 7.57 (2H, d, J=8.4 Hz), 7.40 (1H, dd, J=2.0, 8.3 Hz), 7.35-7.25 (4H, m), 7.17 (1H, d, J=2.0 Hz), 6.90 (1H, d, J=8.3 Hz), 5.77 (1H,s), 2.69 (2H, q, J=7.6 Hz), 1.49 (6H, s), 1.24 (2H, t, J=7.6 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:15][C:16](=[O:26])[CH:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:18][CH3:19])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][CH:7]=1.[N+:27]([C:30]1[CH:31]=[C:32]([S:36](Cl)(=[O:38])=[O:37])[CH:33]=[CH:34][CH:35]=1)([O-:29])=[O:28]>>[N+:27]([C:30]1[CH:31]=[C:32]([S:36]([NH:1][C:2]2[CH:3]=[C:4]([CH:8]([NH:15][C:16](=[O:26])[CH:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:18][CH3:19])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][CH:7]=2)(=[O:38])=[O:37])[CH:33]=[CH:34][CH:35]=1)([O-:29])=[O:28]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: CCOC(=O)CC(NC(=O)C(CC)c1ccccc1)c1cccc(N)c1
Product: CCOC(=O)CC(NC(=O)C(CC)c1ccccc1)c1cccc(NS(=O)(=O)c2cccc([N+](=O)[O-])c2)c1

Procedure:
Corresponding to Example 3c, 3.9 g of (7b) were reacted with 3-nitrophenylsulphonyl chloride. A solid was obtained (yield: 5.0 g).
Reaction SMILES: [CH3:1][C:2]1[C:9]([C:10]2[S:11][C:12]([C:21](O)=[O:22])=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)=[C:5]2[S:6][CH:7]=[CH:8][N:4]2[N:3]=1.C1C=C[C:27]2[N:32]([OH:33])N=NC=2C=1.[CH3:34]CN=C=NCCCN(C)C>CN(C=O)C>[CH3:34][O:33][N:32]([CH3:27])[C:21]([C:12]1[S:11][C:10]([C:9]2[C:2]([CH3:1])=[N:3][N:4]3[CH:8]=[CH:7][S:6][C:5]=23)=[N:14][C:13]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:22]
Reactant: CCN=C=NCCCN(C)C
Reactant: Cc1nn2ccsc2c1-c1nc(-c2ccccc2)c(C(=O)O)s1
Reactant: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1sc(-c2c(C)nn3ccsc23)nc1-c1ccccc1
Yield: 82.7 %

Procedure:
A mixture of 2-(6-methylpyrazolo[5,1-b][1,3]thiazol-7-yl)-4-phenyl-1,3-thiazole-5-carboxylic acid (1.53 g, 4.5 mmol) obtained in Example 35-B(viii), TEA (1.9 mL), N,O-dimethylamine hydrochloride (1.32 g, 13.5 mmol), HOBT (912 mg, 6.75 mmol), EDCI (1.30 g, 6.75 mmol) and DMF (45 mL) was stirred at rt for 16 h. The reaction mixture was concentrated under reduced pressure, and water (50 mL) was added to the reaction mixture. The aqueous layer was extracted with EtOAc (50 mL×2), and the combined organic layer was washed with saturated aqueous solution of sodium bicarbonate (50 mL) and dried over anhydrous magnesium sulfate. Insoluble materials were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/hexane=20/80→100/0) to give the title compound (1.43 g, 83%) as a yellow solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16][C:17]1[O:18][CH:19]=[CH:20][C:21]=1[C:22]([Cl:24])=[O:23]>C1C=CC=CC=1>[ClH:24].[C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:11][CH2:12][N:13]([C:22]([C:21]3[CH:20]=[CH:19][O:18][C:17]=3[CH3:16])=[O:23])[CH2:14][CH2:15]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(CCCN2CCNCC2)cc1
Reactant: Cc1occc1C(=O)Cl
Solvent: c1ccccc1
Product: Cc1occc1C(=O)N1CCN(CCCc2ccccc2)CC1
Product: Cl

Procedure:
The compound was obtained by following the same process as in Example 1 from a mixture of 1-(3-phenylpropyl)piperazine, 2-methyl-3-furoyl chloride and benzene.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[N:8]=[C:9]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)[S:10][CH:11]=2)[O:6]CCO1.[Cl:19][C:20]1[CH:21]=[C:22]([C:26]2[O:30][CH:29]=[N:28][C:27]=2[C:31](O)=[O:32])[CH:23]=[CH:24][CH:25]=1>>[C:2]([C:7]1[N:8]=[C:9]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:31]([C:27]3[N:28]=[CH:29][O:30][C:26]=3[C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([Cl:19])[CH:21]=3)=[O:32])[CH:15]=[N:14]2)[S:10][CH:11]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2csc(Cn3ncc(N)n3)n2)OCCO1
Reactant: O=C(O)c1ncoc1-c1cccc(Cl)c1
Product: CC(=O)c1csc(Cn2ncc(NC(=O)c3ncoc3-c3cccc(Cl)c3)n2)n1

Procedure:
Following general procedure A followed by B, starting from 2-[4-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-(3-chloro-phenyl)-oxazole-4-carboxylic acid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([NH2:12])=O)=[CH:8][CH:7]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:24]2)=CC=1.O>C(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](=[S:24])[NH2:12])=[CH:8][CH:7]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: NC(=O)c1ccc(OCCCCl)cc1
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: Cc1ccccc1
Product: NC(=S)c1ccc(OCCCCl)cc1
Temperature: 85 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
4-(3-Chloropropoxy)benzamide ax54 (1.0 g, 4.6 mmole, 1 eq) is dissolved in a 1:1 mixture of chloroform and toluene, 2,4-bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (1.5 g, 3.7 mmole, 0.8 eq) is added. The reaction is stirred overnight at 85° C. Water is then added and the phases are separated. The organic layer is dried over magnesium sulfate and concentrated under reduce pressure. The crude material is purified by chromatography on silicagel (eluent: dichloromethane/methanol/ammonia 98:1.8:0.2) to provide 0.91 g of 4-(3-chloropropoxy)benzenecarbothioamide ax71 as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:26]=1)[C:7]([C:9](=[CH:15][NH:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:8].C1CCN2C(=NCCC2)CC1>CC(C)=O>[Br:1][C:2]1[CH:26]=[C:6]2[C:5](=[CH:4][CH:3]=1)[N:16]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)[CH:15]=[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:7]2=[O:8]
Reactant: CCOC(=O)C(=CNCc1ccc(OC)cc1)C(=O)c1cc(Br)ccc1F
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(C)=O
Product: CCOC(=O)c1cn(Cc2ccc(OC)cc2)c2ccc(Br)cc2c1=O
Temperature: 20 °C
Reaction time: 16.5 h
Yield: 81.8 %

Procedure:
On a larger scale, ethyl 2-(5-bromo-2-fluorobenzoyl)-3-[(4-methoxyphenyl)methylamino]prop-2-enoate (8434 g, (7730 g assumed active), 17.71 mol) was charged to the vessel with acetone (23.2 L) at 15° C. DBU (2.8 L, 18.72 mol) was added over 25 minutes with an observed exotherm from 18-23° C. over the addition. A precipitate formed after ˜25 minutes and the batch continued to exotherm reaching a maximum of 37° C. after 1 h. The reaction was stirred at 20° C. for 16.5 h at which point HPLC indicated consumption of starting material and 96.5% product. The resulting precipitate was collected by filtration washing with TBME (4×3.4 L). The solid was then dried under vacuum at 40° C. to give 6033 g of the desired material as a white solid (81.6% yield over 3 steps, 99.8% purity by HPLC). Analytical data was consistent with that obtained on previous batches.
Reaction SMILES: [C:1](OC(OC(OC(C)(C)C)=O)=O)(OC(C)(C)C)=[O:2].[F:19][C:20]([F:34])([F:33])[C:21]1[CH:22]=[CH:23][C:24]([N:27]2[CH2:31][CH2:30][C@@H:29]([NH2:32])[CH2:28]2)=[N:25][CH:26]=1.[NH2:35][C:36]1[CH:45]=[CH:44][CH:43]=[C:42]2[C:37]=1[CH:38]=[CH:39][N:40]=[CH:41]2>C(Cl)Cl>[CH:41]1[C:42]2[C:37](=[C:36]([NH:35][C:1]([NH:32][C@@H:29]3[CH2:30][CH2:31][N:27]([C:24]4[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:33])[F:34])=[CH:26][N:25]=4)[CH2:28]3)=[O:2])[CH:45]=[CH:44][CH:43]=2)[CH:38]=[CH:39][N:40]=1
Reactant: Nc1cccc2cnccc12
Reactant: N[C@@H]1CCN(c2ccc(C(F)(F)F)cn2)C1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(=O)OC(C)(C)C
Solvent: ClCCl
Product: O=C(Nc1cccc2cnccc12)N[C@@H]1CCN(c2ccc(C(F)(F)F)cn2)C1
Temperature: 25 °C
Reaction time: 0.3 h

Procedure:
To a solution of di-tert-butyl tricarbonate, (0.681 g, 2.595 mmol), in dry DCM (1 ml) was added a solution of D2, (0.5 g, 2.162 mmol) in dry DCM (1 ml) in one portion. After the initial effervescence, the solution was stirred at room temperature for 0.3 h. A solution of 5-aminoisoquinoline, (0.312 g, 2.162 mmol) in dry DCM (1 ml) was added. The reaction mixture was stirred at room temperature overnight. The resultant precipitate was removed by centrifugation, and the solid washed with ether and dried to give the title compound as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[CH3:14].B([C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1)(O)O.C(=O)([O-])[O-].[Na+].[Na+].Cl>COCCOC.O>[CH3:14][C:3]1[CH:4]=[C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)[CH:6]=[CH:7][C:2]=1[C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1
Reactant: Cc1nnc(-c2ccc(Br)c(C)c2)o1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1nnc(-c2ccc(-c3ccc(C(=O)O)cc3)c(C)c2)o1
Yield: 80.7 %

Procedure:
A stirred solution of 2-(4-bromo-3-methylphenyl)-5-methyl-1,3,4-oxadiazole (EP 0533268 A1) (0.21 g, 0.0008 mole) in a mixture of DME (10 ml) and water (30 ml) under argon was treated with 4-boronobenzoic acid (0.14 g, 0.0008 mole), sodium carbonate (0.39 g, 0.0037 mole) and tetrakis (triphenylphosphine)palladium (0) (16 mg), then heated under reflux for 4 hours. The mixture was acidified with 1M hydrochloric acid and extracted with ethyl acetate. The extract was dried (Na2SO4) and concentrated in vacuo to leave the title compound as a white solid (0.19 g, 78%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:30])[C:11](Br)=[CH:12][N:13]2[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[C:15](=[O:28])[C:14]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.[S:47]1[CH:51]=[CH:50][N:49]=[C:48]1[Sn](CCCC)(CCCC)CCCC>O1CCOCC1.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.C(Cl)(Cl)Cl.[Pd].[Pd]>[CH2:1]([O:8][C:9]1[C:10](=[O:30])[C:11]([C:48]2[S:47][CH:51]=[CH:50][N:49]=2)=[CH:12][N:13]2[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[C:15](=[O:28])[C:14]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Reactant: O=C1c2c(OCc3ccccc3)c(=O)c(Br)cn2CCN1Cc1ccc(Cl)c(Cl)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: O=C1c2c(OCc3ccccc3)c(=O)c(-c3nccs3)cn2CCN1Cc1ccc(Cl)c(Cl)c1
Reaction time: 1 h

Procedure:
To a solution of 9-benzyloxy-7-bromo-2-(3,4-dichlorobenzyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione (150 mg) in dioxane (5 ml) were added tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (63 mg), tri-2-furylphosphine (57 mg) and (2-thiazolyl)tributyltin (0.285 ml) under an argon stream and a microwave at 80 W was irradiated under sealing for 1 hr. The obtained reaction mixture was concentrated, and then purified by silica gel column chromatography (chloroform:methanol=40:1) to give 9-benzyloxy-2-(3,4-dichlorobenzyl)-7-(thiazol-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione (95 mg).
Reaction SMILES: [NH2:1][C:2]1([C:22]#[N:23])[CH2:7][CH2:6][CH:5]([NH:8][S:9](C2C=CC(OCC)=C(C)C=2)(=[O:11])=[O:10])[CH2:4][CH2:3]1.[F:24][C:25]([F:44])([F:43])[C:26]1[CH:31]=[CH:30][C:29](S(NC2CCC(=O)CC2)(=O)=O)=[CH:28][CH:27]=1>>[NH2:1][C:2]1([C:22]#[N:23])[CH2:3][CH2:4][CH:5]([NH:8][S:9]([C:29]2[CH:30]=[CH:31][C:26]([C:25]([F:44])([F:43])[F:24])=[CH:27][CH:28]=2)(=[O:11])=[O:10])[CH2:6][CH2:7]1
Reactant: O=C1CCC(NS(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Reactant: CCOc1ccc(S(=O)(=O)NC2CCC(N)(C#N)CC2)cc1C
Product: N#CC1(N)CCC(NS(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1

Procedure:
Intermediate 125 was prepared by a method analogous to the method of preparing Intermediate 124 using 4-(trifluoromethyl)-N-(4-oxocyclohexyl)benzenesulfonamide (Intermediate 123) as the starting material.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[NH:12][C:13]([C:16](=[O:27])[NH:17][CH:18]2[CH2:23][CH2:22][N:21]([CH:24]([CH3:26])[CH3:25])[CH2:20][CH2:19]2)=[CH:14][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:35][C:36]1[CH:40]=[C:39]([C:41]2[S:42][C:43]([Cl:46])=[CH:44][CH:45]=2)[O:38][N:37]=1>CN(C=O)C>[CH2:1]([O:8][C:9]([C:11]1[N:12]([CH2:35][C:36]2[CH:40]=[C:39]([C:41]3[S:42][C:43]([Cl:46])=[CH:44][CH:45]=3)[O:38][N:37]=2)[C:13]([C:16](=[O:27])[NH:17][CH:18]2[CH2:23][CH2:22][N:21]([CH:24]([CH3:25])[CH3:26])[CH2:20][CH2:19]2)=[CH:14][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccc(-c2cc(CBr)no2)s1
Reactant: CC(C)N1CCC(NC(=O)c2ccc(C(=O)OCc3ccccc3)[nH]2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)N1CCC(NC(=O)c2ccc(C(=O)OCc3ccccc3)n2Cc2cc(-c3ccc(Cl)s3)on2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.1 %

Procedure:
To a solution of 5-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H-pyrrole-2-carboxylic acid benzyl ester (20 mg) in DMF (1 mL) was added Cs2CO3 μl mg). The mixture was stirred for 30 min at RT. 3-Bromomethyl-5-(5-chloro-thiophen-2-yl)-isoxazole (15 mg) was added and stirring was continued for 20 h at RT whereupon the mixture was filtered. The filtrate was directly subjected to preparative HPLC(CH3CN/H2O gradient+0.05% TFA). Pure 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-5-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H-pyrrol e-2-carboxylic acid benzyl ester (15 mg) was obtained as its trifluoroacetate salt. MS (ESI+): m/e=567 [M+H]+, chloro pattern.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[CH3:27][N:28]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[N:30]=[C:29]1[N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>>[F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:40]2[CH2:41][CH2:42][N:37]([C:29]3[N:28]([CH3:27])[C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[N:30]=3)[CH2:38][CH2:39]2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: Cn1c(N2CCNCC2)nc2ccccc21
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: Cn1c(N2CCN(CCCCC3(C(=O)NCC(F)(F)F)c4ccccc4-c4ccccc43)CC2)nc2ccccc21

Procedure:
Prepared analogously to Example 1e from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 1-methyl-2-(piperazin-1-yl)-benzimidazole.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[F:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=1>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:16]([CH2:31][C:30]3[CH:33]=[CH:34][C:27]([F:26])=[CH:28][CH:29]=3)[C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3[nH]2)CC1
Reactant: Fc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
Combine 1-t-butoxycarbonyl-4-(1H-benzimidazol-2-yl)[1,4]diazepane (0.82 g, 2.6 mmol) in dimethylformamide (20 mL). Add sodium hydride (0.15 g, 60% in oil, 3.75 mmol). After about 15 minutes, when the gas evolution ceases, add 4-fluorobenzyl bromide (0.35 mL, 2.81 mmol). Heat to 80° C. After 18 hours, cool the reaction mixture and dilute with ethyl acetate (100 mL) and extract five times with brine. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give 1-t-butoxycarbonyl-4-(1-(4-fluorobenzyl)-1H-benzimidazol-2-yl)[1,4]diazepane: Rf =0.42 (silica gel, 50% ethyl acetate/hexane).
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:30]([NH2:32])=[O:31])[CH:17]=[C:18]([C:21]4[CH:26]=[C:25]([CH:27]=O)[CH:24]=[CH:23][C:22]=4[F:29])[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[F:33][C:34]([F:38])([F:37])[CH2:35][NH2:36].[CH3:39][OH:40]>ClCCl.C(O)(=O)C>[F:33][C:34]([F:38])([F:37])[C:39]([OH:4])=[O:40].[CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:30]([NH2:32])=[O:31])[CH:17]=[C:18]([C:21]4[CH:26]=[C:25]([CH2:27][NH:36][CH2:35][C:34]([F:38])([F:37])[F:33])[CH:24]=[CH:23][C:22]=4[F:29])[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2]
Reactant: CO
Reactant: NCC(F)(F)F
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(C=O)ccc4F)cc23)CC1
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(CNCC(F)(F)F)ccc4F)cc23)CC1
Product: O=C(O)C(F)(F)F
Reaction time: 8 h
Yield: 24 %

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(2-fluoro-5-formylphenyl)-1H-indole-7-carboxamide (20 mg, 0.04 mmol) in dichloromethane (4 mL) and methanol (2 mL) was added 2 drops of acetic acid and 2,2,2-trifluoroethanamine (23 μL, 0.26 mmol). The resulting mixture was stirred overnight. All solvent was evaporated and dissolved in dimethyl sulfoxide (1 mL). Purified by Gilson Preparatory HPLC to give 5.2 mg of the title compound (24.0%).