Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]2[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=2)=[C:6]([CH2:20][CH2:21][CH3:22])[C:5]=1[O:23][CH3:24])(=[O:3])[CH3:2].C([O-])(=O)C.[Na+].[S:30]1[CH2:36][C:34](=[O:35])[NH:33][C:31]1=[S:32]>C(O)(=O)C>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]2[CH:19]=[CH:18][C:15]([CH:16]=[C:36]3[S:30][C:31](=[S:32])[NH:33][C:34]3=[O:35])=[CH:14][CH:13]=2)=[C:6]([CH2:20][CH2:21][CH3:22])[C:5]=1[O:23][CH3:24])(=[O:3])[CH3:2]
Reactant: CCCc1c(COc2ccc(C=O)cc2)ccc(C(C)=O)c1OC
Reactant: O=C1CSC(=S)N1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCCc1c(COc2ccc(C=C3SC(=S)NC3=O)cc2)ccc(C(C)=O)c1OC

Procedure:
Under nitrogen atmosphere in a round bottom flask 4-[(4-acetyl-3-methoxy-2-propylphenyl)methoxy]benzaldehyde (0.33 g, 1.01 mmol) was dissolved in 5 ml of acetic acid with stirring. To this solution was added sodium acetate (0.29 g, 3.53 mmol) followed by the addition of rhodanine (0.13 g, 0.98 mmol). The reaction mixture was heated to reflux. The progress of the reaction was monitored by thin layer chromatography. The reaction was allowed to reflux overnight.
Reaction SMILES: C1COCC1.Br[C:7]1[N:11]([CH3:12])[N:10]=[CH:9][N:8]=1.[CH2:13]([CH:15]([C:18]1[C:19]2[N:20]([C:25]([C:29]3[S:30][C:31](I)=[CH:32][C:33]=3[O:34][CH3:35])=[C:26]([CH3:28])[N:27]=2)[N:21]=[C:22]([CH3:24])[CH:23]=1)[CH2:16][CH3:17])[CH3:14]>CCOC(C)=O.[Zn].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>[CH2:13]([CH:15]([C:18]1[C:19]2[N:20]([C:25]([C:29]3[S:30][C:31]([C:7]4[N:11]([CH3:12])[N:10]=[CH:9][N:8]=4)=[CH:32][C:33]=3[O:34][CH3:35])=[C:26]([CH3:28])[N:27]=2)[N:21]=[C:22]([CH3:24])[CH:23]=1)[CH2:16][CH3:17])[CH3:14]
Reactant: Cn1ncnc1Br
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(I)cc3OC)c(C)nc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC(CC)c1cc(C)nn2c(-c3sc(-c4ncnn4C)cc3OC)c(C)nc12
Temperature: 65 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
To a slurry of 0.05 g/mL of Reike® Zn in THF (2.8 mL, 2.11 mmol) is added 5-bromo-1-methyl-1H-[1,2,4]triazole and THF (2 mL). The solution is heated at 65° C. for 1 hour, cooled to ambient temperature and the excess Zn allowed to settle for 1 hour. The solution is transferred to a flask containing 8-(1-ethyl-propyl)-3-(5-iodo-3-methoxy-thiophen-2-yl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.32 g, 0.70 mmol) and Pd(PPh3)4 (0.041 g, 0.035 mmol). The solution is heated at 65° C. overnight, diluted with EtOAc (30 mL) washed with sat. NH4Cl (30 mL). The aqueous phase is extracted with EtOAc (20 mL). The combined organic layers are dried over MgSO4, filtered and concentrated. The reside is purified by ISCO column chromatography (20%-65% EtOAc/hexane gradient) followed by ISCO column chromatography (100% Et2O) furnish the title compound (0.19 g, 0.46 mmol, 62%). 1H NMR (CDCl3) δ 0.86 (t, J=7.5 Hz, 6H), 1.73-1.91 (m, 4H), 2.51 (s, 3H), 2.52 (s, 3H), 3.26-3.37 (m, 1H), 3.92 (s, 3H), 4.15 (s, 3H), 6.67 (s, 1H), 7.48 (s, 1H), 7.89 (s, 1H). LC/MS (m/z): calcd. for C21H26N6OS (M+H)+: 411.5. found: 411.3.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][C:13](=[O:15])[NH:12][C:11]([CH3:16])=[C:10]2[C:17](O)=[O:18])=[CH:5][CH:4]=1.[NH2:22][C:23]1[CH:24]=[C:25]2[C:29](=[C:30]([Cl:32])[CH:31]=1)[NH:28][N:27]=[CH:26]2.C(Cl)CCl.CCN(CC)CC>CN(C=O)C.CCOC(C)=O.Cl>[Cl:32][C:30]1[CH:31]=[C:23]([NH:22][C:17]([C:10]2[CH:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:20])([F:21])[F:1])=[CH:8][CH:7]=3)[CH2:14][C:13](=[O:15])[NH:12][C:11]=2[CH3:16])=[O:18])[CH:24]=[C:25]2[C:29]=1[NH:28][N:27]=[CH:26]2
Reactant: Nc1cc(Cl)c2[nH]ncc2c1
Reactant: CC1=C(C(=O)O)C(c2ccc(C(F)(F)F)cc2)CC(=O)N1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC1=C(C(=O)Nc2cc(Cl)c3[nH]ncc3c2)C(c2ccc(C(F)(F)F)cc2)CC(=O)N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 12 %

Procedure:
The product of Example 5, Step 2 (250 mg, 0.835 mmol, 1.00 equiv), 5-amino-7-chloroindazole (140 mg, 0.835 mmol, 1.0 equiv), and EDC (191 mg, 1.00 mmol, 1.20 equiv) were suspended in 2.0 mL DMF. Et3N (0.140 mL, 1.00 mmol, 1.2 equiv) was added and the solution was stirred at room temperature for 18 hrs. The reaction mixture was diluted with EtOAc and 1N HCl. The phases were separated, and the organic phase was washed twice with 1N HCl, once with satd. NaHCO3, and once with satd. NaCl. The organic phase was dried over Na2SO4, filtered, and concentrated en vacuo. The residue was purified by flash chromatography (20-100% EtOAc in Hexanes) and further purified by reverse-phase HPLC (10-80% CH3CN/H2O—NH4OH to pH 10 over 17 minutes, retention time 11.67 min) to provide 45 mg (12%) of the title compound as a white solid. MS (ES+) m/e 449 [M+H]+
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].Cl.O(N)C.[NH2:10][C:11]1[C:20]2[N:21]=[C:22]([CH2:30]Cl)[N:23]([CH2:24][C:25]3([OH:29])[CH2:28][CH2:27][CH2:26]3)[C:19]=2[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1.Cl.ClCC1N(CC(C)C)C2C(C)=C(C)N=C(N)C=2N=1>>[NH2:10][C:11]1[C:20]2[N:21]=[C:22]([CH2:30][N:3]([O:4][CH3:5])[CH3:2])[N:23]([CH2:24][C:25]3([OH:29])[CH2:28][CH2:27][CH2:26]3)[C:19]=2[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: Nc1nc2ccccc2c2c1nc(CCl)n2CC1(O)CCC1
Reactant: CNOC
Agent: CON
Agent: Cc1nc(N)c2nc(CCl)n(CC(C)C)c2c1C
Agent: Cl
Product: CON(C)Cc1nc2c(N)nc3ccccc3c2n1CC1(O)CCC1

Procedure:
1-[(4-Amino-2-{[methoxy(methyl)amino]methyl}-1H-imidazo[4,5-c]quinolin-1-yl)methyl]cyclobutanol was prepared according to the general methods of Part I of Example 9 using N,O-dimethyl hydroxylamine hydrochloride in lieu of methoxylamine hydrochloride and using 1-{[4-amino-2-(chloromethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclobutanol in lieu of 2-(chloromethyl)-1-isobutyl-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-4-amine hydrochloride. The crude product was purified by HPFC eluting with a gradient of 0-35% CMA in chloroform and then recrystallized from acetonitrile to provide pure product as a white powder, mp 219.0-221.0° C. Anal. Calcd for C18H23N5O2 C, 63.32; H, 6.79; N, 20.51. Found: C, 63.12; H, 6.56; N, 20.16.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:5][N:4]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH2:3]1.ClC1C=C(C=CC=1)C(OO)=[O:21]>C(Cl)(Cl)Cl>[O:21]1[C:2]2([CH2:5][N:4]([C:6]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:7])[CH2:3]2)[CH2:1]1
Reactant: C=C1CN(C(=O)OCc2ccccc2)C1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: O=C(OCc1ccccc1)N1CC2(CO2)C1
Temperature: 25 °C
Yield: 82.9 %

Procedure:
To a solution of phenylmethyl 3-methylideneazetidine-1-carboxylate (2.46 g, 0.0121 mol) in chloroform (100 mL) was added 3-chloroperoxybenzoic acid (12.5 g, 0.0726 mol) at 0° C. The reaction mixture was allowed to warm up to room temperature over a period of 12 hours then quenched with 1 M sodium thiosulfate/saturated aqueous sodium bicarbonate (1:1). The layers were separated and the organic layer was dried over anhydrous magnesium sulfate then concentrated. The residue was purified by flash chromatography (5-15% ethyl acetate in hexanes) to afford phenylmethyl 1-oxa-5-azaspiro[2.3]hexane-5-carboxylate (2.2 g, 83% yield) as clear and colorless oil. 1H NMR (400 MHz, CDCl3): 7.37-7.29 (m, 5H), 5.12 (s, 2H), 4.35-4.26 (m, 4H), 2.85 (s, 2H). MS (EI) for C12H13NO3: 220 (MH+).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH:14][CH:15]1[CH2:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]([CH2:25][C@@H:26]3[CH2:30][O:29]C(C)(C)[O:27]3)[C:16]1=[O:33])=[O:13])=[CH:6]2.C([O-])(O)=O.[Na+]>>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH:14][CH:15]1[CH2:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]([CH2:25][C@@H:26]([OH:27])[CH2:30][OH:29])[C:16]1=[O:33])=[O:13])=[CH:6]2
Reactant: CC1(C)OC[C@@H](CN2C(=O)C(NC(=O)c3cc4cc(Cl)ccc4[nH]3)Cc3ccccc32)O1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(NC1Cc2ccccc2N(C[C@@H](O)CO)C1=O)c1cc2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.8 %

Procedure:
6N HCl was added dropwise to a solution of 5-chloro-N-(1-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)-1H-indole-2-carboxamide (Method 7, 500 mg, 1.1 mmol) and the reaction was stirred at ambient temperature for 2 hours. Saturated NaHCO3 solution was added cautiously until the reaction mixture was at pH 8, the mixture was extracted with EtOAc (2×20 mL), the combined organic phases dried (MgSO4) and the volatiles removed under reduced pressure to give the title compound (450 mg, 99%) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1[OH:10])[CH:5]=[O:6].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CC#N>[CH2:18]([O:10][C:9]1[C:2]([F:1])=[CH:3][C:4]([CH:5]=[O:6])=[CH:7][C:8]=1[F:11])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=Cc1cc(F)c(O)c(F)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: O=Cc1cc(F)c(OCc2ccccc2)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
3,5-Difluoro-4-hydroxy-benzaldehyde obtained in Step A was dissolved in CH3CN (15 mL), and Cs2CO3(6.3 g, 19.23 mmol) was added to the solution. The mixture was cooled to 0˜5° C. Benzylbromide (1.1 mL, 9.23 mmol) was added slowly thereto, and the mixture was stirred at room temperature for 2 hours. After the termination of the reaction, the reactant was filtered and then concentrated under reduced pressure. The residue was purified by column chromatography (eluent, EtOAc/Hex=1/7) to obtain the title compound (1.76 g, 92%).
Reaction SMILES: [NH2:1][CH:2]1[C:6](=[O:7])[N:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:4][CH:3]1[C:13]([O:15][CH2:16][CH3:17])=[O:14].C(N(CC)CC)C.[CH:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][C:26]=1[C:35](Cl)=[O:36]>C(Cl)Cl>[CH:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][C:26]=1[C:35]([NH:1][C@H:2]1[C:6](=[O:7])[N:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:4][C@H:3]1[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:36]
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: CCCCCN1CC(C(=O)OCC)C(N)C1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCN1C[C@@H](C(=O)OCC)[C@@H](NC(=O)c2ccc3ccccc3c2)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 87.6 %

Procedure:
To a solution of the aminopyrrolidinone of Example R (120 mg, 0.495 mmol) and triethylamine (0.35 ml, 2.48 mmol) in CH2Cl2 was added a solution of 2-naphthoyl chloride (94 mg, 0.495 mmol) in CH2Cl2 dropwise via syringe. After stirring for 12 h at room temperature the reaction mixture was evaporated in vacuo to give a residue which was chromatographed on silica gel eluting with EtOH/CH2Cl2 (2%-5%) to give the title compound (172 mg, 69%) as a colorless solid. MS M+1 calcd for C23H28N2O4 397; found 397.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9]([C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10].[F-].[K+].O>C1(C)C=CC=CC=1>[C:9]([C:13]1[CH:18]=[CH:17][C:16]([C:2]2[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=2)=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: Oc1ccc(Cl)nc1
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)c1ccc(-c2ccc(O)cn2)cc1
Temperature: 25 °C
Yield: 37.9 %

Procedure:
To a solution of 6-Chloro-pyridin-3-ol (3.10 g, 23.9 mmol) in toluene (30 ml) is added 4-tert-butyl-phenylboronic acid (5.46 g, 30.6 mmol), potassium fluoride (2.82 g, 47.9 mmol), and palladium tetrakis triphenylphosphine (1.20 g, 1.20 mmol). Water (15 mL) is added and the reaction mixture is heated to reflux overnight. After cooling to rt, the reaction mixture is partitioned between ethyl acetate and water. The aqueous layer is back-extracted with ethyl acetate, the combined organic layers are dried and concentrated. The resulting residue is applied to silica gel and eluted using hexanes with an ethyl acetate gradient to give the title compound (2.06 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH:19][C:4]2[CH:5]=[N:6][C:7]([O:8][C:9]3[CH:10]=[N:11][C:12]4[C:17]([CH:18]=3)=[CH:16][CH:15]=[CH:14][CH:13]=4)=[C:2]([Cl:1])[CH:3]=2)(=[O:29])=[O:28])=[CH:23][CH:22]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: Nc1cnc(Oc2cnc3ccccc3c2)c(Cl)c1
Product: O=S(=O)(Nc1cnc(Oc2cnc3ccccc3c2)c(Cl)c1)c1ccc(Cl)cc1

Procedure:
The title compound was prepared by reacting 5-chloro-6-(quinolin-3-yloxy)pyridin-3-amine (obtained as per procedure described in preparation 1) and 4-chlorobenzene-1-sulfonyl chloride.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[NH:19]1[CH2:22][CH:21]([N:23]2[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25][CH2:24]2)[CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][N:19]3[CH2:22][CH:21]([N:23]4[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25][CH2:24]4)[CH2:20]3)=[CH:8][C:6]=2[N:7]=1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: OC1CCN(C2CNC2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: OC1CCN(C2CN(Cc3cc4nc(Cl)nc(N5CCOCC5)c4s3)C2)CC1
Reaction time: 18 h
Yield: 75.2 %

Procedure:
A mixture of 2-chloro-4-morpholin-4-ylthieno[3,2-d]pyrimidine-6-carbaldehyde (136 mg, 0.48 mmol), 1-azetidin-3-ylpiperidin-4-ol (90 mg, 0.58 mmol) and 4 Å powdered molecular sieves (260 mg) in DCE (15 mL) was stirred for 5 h before the addition of sodium triacetoxyborohydride (202 mg, 0.96 mmol). The resulting mixture was stirred for 18 h then filtered through Celite® and the filtrate loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH/DCM. The resulting residue was purified by column chromatography (Si—PCC, MeOH:DCM, 0-10%) affording the title compound as a pale yellow oil (153 mg, 75%). LCMS (method H): RT 1.88 min [M+H]+ 424.3
Reaction SMILES: [CH2:1]([NH:4][CH2:5][C:6]([OH:8])=O)[CH:2]=[CH2:3].[CH3:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:11]=1[N:17]=[C:18]=[S:19].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([N:4]1[CH2:5][C:6](=[O:8])[N:17]([C:11]2[C:12]([CH3:16])=[CH:13][CH:14]=[CH:15][C:10]=2[CH3:9])[C:18]1=[S:19])[CH:2]=[CH2:3]
Reactant: Cc1cccc(C)c1N=C=S
Reactant: C=CCNCC(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCN1CC(=O)N(c2c(C)cccc2C)C1=S
Yield: 16.3 %

Procedure:
A mixture of N-allyl glycine (17.4 g), 2,6-dimethylphenyl-isothiocyanate (20 g), triethylamine (20.2 g), and methylene chloride (150 mL) was heated at reflux for 3 hours. The reaction mixture was evaporated to dryness. The residual gum was dissolved in diethyl ether, then treated with etheral hydrogen chloride. A white solid formed. The solid was filtered and discarded. The filtrate was concentrated to a residue. The residue was chromatographed on silica gel (CH2Cl2) to give title compound (5.2 g) as an orange solid, m.p. 43°-46° C. Anal. Calcd. for. C14H16N2O S: C, 64.59; H, 6.19; N, 10.76. Found: (2, 64.52; H, 6.08; N, 10.66. Mass spectrum (EI, M.+) m/z 260.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([CH2:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[CH:8]=2)[CH2:3][CH2:2]1.C[O:24][C:25](=[O:35])[C:26]1[CH:31]=[CH:30][C:29]([Br:32])=[C:28]([CH2:33]Br)[CH:27]=1>>[Br:32][C:29]1[CH:30]=[CH:31][C:26]([C:25]([OH:35])=[O:24])=[CH:27][C:28]=1[CH2:33][N:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([CH2:16][C:17]3[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=3)[CH:8]=2)[CH2:3][CH2:2]1
Reactant: c1ccc2c(c1)c(C1CCNCC1)cn2Cc1ccncc1
Reactant: COC(=O)c1ccc(Br)c(CBr)c1
Product: O=C(O)c1ccc(Br)c(CN2CCC(c3cn(Cc4ccncc4)c4ccccc34)CC2)c1

Procedure:
This compound was prepared following the procedure described in example 13 (part D) starting with 1.5 g (50 mmol) of 3-piperidin-4-yl-1-pyridin-4-ylmethyl-1H-indole and 1.7 g (55 mmol) of 4-bromo-3-bromomethyl-benzoic acid methyl ester. After standard work-up and recrystallisation with ethyl ether, 1.7 g (68% of yield) of the expected acid were obtained.
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[C:8]#[N:9])[CH2:3][CH3:4].CCN(CC)CC.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl>[CH3:20][S:21]([O:1][CH:2]([C:5]1[CH:12]=[CH:11][CH:10]=[C:7]([C:8]#[N:9])[CH:6]=1)[CH2:3][CH3:4])(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: CCC(O)c1cccc(C#N)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(OS(C)(=O)=O)c1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 71.3 %

Procedure:
A mixture of 3-(1-hydroxypropyl)benzonitrile (0.273 g, 1.694 mmol; ref. Synlett (2002), (11), 1922-1924), Et3N (0.354 mL, 2.54 mmol) and MsCl (0.198 mL, 2.54 mmol) in CH2Cl2 (5 mL) was stirred at rt. After 90 min, an additional 0.75 eq each of Et3N and MsCl were added. After 1 h, the reaction mixture was concentrated to dryness, and the residue was partitioned between EtOAc (20 mL) and 0.1N HCl (20 mL). The organic phase was washed with water and brine, dried over Na2SO4, filtered and concentrated. The residue was chromatographed over silica gel using a 5-30% EtOAc-hexane gradient to give 1-(3-cyanophenyl)propyl methanesulfonate (0.289 g, 68% yield) (the product is somewhat unstable, and it needs to be used shortly thereafter or stored at low temperatures).
Reaction SMILES: [ClH:1].[CH3:2][CH:3]([CH3:45])[CH2:4][CH2:5][N:6]([CH2:40][CH2:41][CH:42]([CH3:44])[CH3:43])[C:7]([C:9]1[CH:10]=[CH:11][C:12]2[N:16]=[C:15]([NH:17][C:18]3[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=3)[N:14]([CH2:28][CH2:29][CH2:30][NH:31]C(OC(C)(C)C)=O)[C:13]=2[CH:39]=1)=[O:8]>O1CCOCC1.C(OCC)(=O)C>[ClH:1].[ClH:1].[NH2:31][CH2:30][CH2:29][CH2:28][N:14]1[C:13]2[CH:39]=[C:9]([C:7]([N:6]([CH2:5][CH2:4][CH:3]([CH3:2])[CH3:45])[CH2:40][CH2:41][CH:42]([CH3:44])[CH3:43])=[O:8])[CH:10]=[CH:11][C:12]=2[N:16]=[C:15]1[NH:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=1
Reactant: COC(=O)c1ccc(Nc2nc3ccc(C(=O)N(CCC(C)C)CCC(C)C)cc3n2CCCNC(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Nc2nc3ccc(C(=O)N(CCC(C)C)CCC(C)C)cc3n2CCCN)cc1
Temperature: 20 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
A solution of hydrochloric acid in dioxane (4N, 2 ml) is added to a solution of methyl 4-[(6-{[bis(3-methylbutyl)amino]carbonyl}-1-{3-[(tert-butoxycarbonyl)amino]propyl}-1H-benzimidazol-2-yl)amino]benzoate (180 mg) in ethyl acetate (2 ml). After stirring for 1 hour at a temperature of approximately 20° C., the mixture is concentrated under reduced pressure at 40° C. The solid obtained is washed with ethyl ether and dried (165 mg; 96% yield).
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8]([NH:11][C:12](=[O:18])NCCCC)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C(Cl)(Cl)=O>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[C:7]([S:8]([N:11]=[C:12]=[O:18])(=[O:9])=[O:10])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CCCCNC(=O)NS(=O)(=O)c1cccnc1Cl
Agent: O=C(Cl)Cl
Solvent: Cc1ccccc1C
Product: O=C=NS(=O)(=O)c1cccnc1Cl

Procedure:
To 125 ml of dry xylene was added with stirring 20.7 g of 2-chloro-N-(butylcarbamoyl)-3-pyridinesulfonamide. This solution was heated to reflux, and phosgene added until no further uptake of this gas was observed. It was then cooled, filtered and the solvent was removed in vacuo to yield 2-chloro-3-pyridinesulfonylisocyanate as an oil Bp 108°-110° (0.7 mm Hg). This product showed a sharp absorption peak in the infrared region at 2220 cm-1.
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N:17]3[CH2:21][CH:20]([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=5[C:37]#[N:38])[CH:23]=4)[CH2:19][C:18]3=[O:39])[N:12]=2)=[O:10])=CC=1.C(O)(C(F)(F)F)=O>>[C:37]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[O:30][C:24]1[CH:23]=[C:22]([CH:20]2[CH2:21][N:17]([C:13]3[N:12]=[C:11]([C:9]([NH2:8])=[O:10])[CH:16]=[CH:15][CH:14]=3)[C:18](=[O:39])[CH2:19]2)[CH:27]=[CH:26][C:25]=1[O:28][CH3:29])#[N:38]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)C(=O)c2cccc(N3CC(c4ccc(OC)c(Oc5ccccc5C#N)c4)CC3=O)n2)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C2CC(=O)N(c3cccc(C(N)=O)n3)C2)cc1Oc1ccccc1C#N
Temperature: 100 °C

Procedure:
Crude product of 6-{4-[3-(2-cyanophenoxy)-4-methoxyphenyl]-2-oxo-pyrrolidin-1-yl}pyridine-2-carboxylic acid bis-(4-methoxy-benzyl)-amide was added to a TFA (0.5 mL) solution and heated to 100° C. for 8 h. After cooling down to r.t., the mixture was concentrated and purified by preparative LC-MS to provide the desired product.
Reaction SMILES: C([N:8]1[CH2:17][CH2:16][C:15]2[N:14]=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:12]=[CH:11][C:10]=2[CH2:9]1)C1C=CC=CC=1.ClCCC(Cl)=O>ClCCl>[F:21][C:18]([F:19])([F:20])[C:13]1[CH:12]=[CH:11][C:10]2[CH2:9][NH:8][CH2:17][CH2:16][C:15]=2[N:14]=1
Reactant: FC(F)(F)c1ccc2c(n1)CCN(Cc1ccccc1)C2
Agent: O=C(Cl)CCCl
Solvent: ClCCl
Product: FC(F)(F)c1ccc2c(n1)CCNC2
Temperature: 40 °C
Reaction time: 18 h

Procedure:
To a solution of 5 (500 mg, 1.7 mmol) in dichoromethane (8 mL) was added compound 6, 3-chloro propionyl chloride (0.22 mL, 2.1 mmol) and the reaction mixture was stirred at 40° C. for 18 h. The reaction was then cooled to room temperature and concentrated. The resulting residue was dissolved in methanol (16 mL) and stirred at 40° C. for 3 h. The mixture was then cooled to room temperature and concentrated.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([NH2:9])=[NH:8])[CH2:2][CH3:3].Cl[C:15]1[C:20]([C:21](OCC)=[O:22])=[CH:19][N:18]=[C:17]([S:26][CH3:27])[N:16]=1>CC(O)C>[CH3:27][S:26][C:17]1[N:18]=[C:19]2[N:8]=[C:7]([C:6]3[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=3[O:4][CH2:1][CH2:2][CH3:3])[NH:9][C:21](=[O:22])[C:20]2=[CH:15][N:16]=1
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Reactant: CCCOc1ccccc1C(=N)N
Solvent: CC(C)O
Product: CCCOc1ccccc1-c1nc2nc(SC)ncc2c(=O)[nH]1
Temperature: 2 °C
Reaction time: 2 h

Procedure:
2-Propoxybenzamidine (from sodium, 0.3 g, in ethanol, 50 ml, and 2-propoxybenzamidine hydrochloride, 2.77 g) was dissolved in 2-propanol (20 ml) and the resulting cooled (2° C.) solution was added to a cooled (2° C.) solution of ethyl 4-chloro-2-methylthio-5-pyrimidine carboxylate (2 g) in 2-propanol (30 ml). The reaction mixture was stirred at 2° C. for 2 hours and was then left overnight at ambient temperature to yield a white crude product, 1.18 g, m.p. 179°-181° C. Recrystallisation from ethanol yielded the title compound, 0.92 g, m.p. 186°-187° C.