Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH3:4].[CH:5]([OH:9])([CH2:7][CH3:8])[CH3:6]>>[CH:2]([O:9][CH:5]([CH2:7][CH3:8])[CH3:6])([CH2:3][CH3:4])[CH3:1]
Reactant: CCC(C)O
Reactant: C=CCC
Product: CCC(C)OC(C)CC

Procedure:
From the recycle, a 76% residual gas containing 95.2 grams of n-butenes (1.7 moles) and 30.4 grams of n-butene (0.52 mole) was removed per hours, was depressured to normal atmospheric pressure in the second separator and was discharged. In the second separator 140 grams (1.9 moles) of secondary butyl alcohol and 0.7-1.4 grams of di-sec. butyl ether were obtained per hour after removing the C4 -components in the form of a 77 to 89% crude alcohol still containing 10-22% water. The space-time yield of secondary butyl alcohol was 1.6 moles per liter of catalyst an hour, the selectivity being more than 99%.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][N:7]1[CH3:12].[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23](OCC)=[O:24].[H-].[Na+].O>CS(C)=O>[CH3:12][N:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH:6]1[CH2:5][CH2:4][C:3]1[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=1[NH:1][C:23](=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][N:17]=1
Reactant: CN1CCCCC1CCc1ccccc1N
Reactant: CCOC(=O)c1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CN1CCCCC1CCc1ccccc1NC(=O)c1ccccn1
Reaction time: 2 h

Procedure:
A solution of 2-(o-aminophenethyl)-1-methylpiperidine (8.0 g., 0.037 mole) and ethyl picolinate (5.5 g., 0.037 mole) in DMSO (20 ml.) is treated with NaH (57%) in oil (1.6 g., 0.037 mole) with intermittent cooling to moderate the resulting vigorous reaction. After 2 hr., the mixture is poured into 150 ml. of H2O and the product isolated according to the procedure of Example 25. Crystallization from isopropyl ether affords 5.9 (50%) of analytically pure 2'-[2-(1-methyl-2-piperidyl)ethyl]picolinanilide, m.p. 65.5°-67° C. (corr.).
Reaction SMILES: ClC1C(C(O)=O)=CN=C(Cl)C=1C.BrC1C=CC(NC2C(C(O)=O)=CN3C=CN=C3C=2C)=C(Cl)C=1.[N-:35]=[N+:36]=[N-:37].[Na+].[CH3:39][O:40][C:41](=[O:59])[C:42]1[C:47]([NH:48][C:49]2[CH:54]=[CH:53][C:52]([Br:55])=[CH:51][C:50]=2[Cl:56])=[C:46]([CH3:57])[C:45](Cl)=[N:44][CH:43]=1>>[CH3:39][O:40][C:41](=[O:59])[C:42]1[C:47]([NH:48][C:49]2[CH:54]=[CH:53][C:52]([Br:55])=[CH:51][C:50]=2[Cl:56])=[C:46]([CH3:57])[C:45]([N:35]=[N+:36]=[N-:37])=[N:44][CH:43]=1
Reactant: COC(=O)c1cnc(Cl)c(C)c1Nc1ccc(Br)cc1Cl
Reactant: [N-]=[N+]=[N-]
Agent: Cc1c(Cl)ncc(C(=O)O)c1Cl
Agent: Cc1c(Nc2ccc(Br)cc2Cl)c(C(=O)O)cn2ccnc12
Agent: [Na+]
Product: COC(=O)c1cnc(N=[N+]=[N-])c(C)c1Nc1ccc(Br)cc1Cl
Temperature: 50 °C

Procedure:
4,6-Dichloro-5-methylnicotinic acid (J. Heterocyclic Chemistry 1999, 36, 953-957) was converted to 7-(4-bromo-2-chloro-phenylamino)-8-methylimidazo[1,2-a]pyridine-6-carboxylic acid according to the steps described in the alternate synthesis of Step D, Example 9. It was determined that addition of sodium azide to the 4-(4-bromo-2-chloro-phenylamino)-6-chloro-5-methylnicotinic acid methyl ester intermediate required heating to 50° C., which results in a separable mixture of the desired methyl ester, 6-azido-4-(4-bromo-2-chlorophenylamino)-5-methylnicotinic acid methyl ester, and the corresponding carboxylic acid. MS ESI (+) m/z 380, 382 (M+, Cl, Br pattern) detected. 1H NMR (400 MHz, DMSO-d6) δ 9.46 (s, 1H), 9.40 (br s, 1H), 8.25 (d, 1H), 8.12 (d, 1H), 7.79 (m, 1H), 7.42 (dd, 1H), 6.80 (d, 1H), 2.07 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[C:13]([C:15]2[O:16][CH:17]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:19]=2)[CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].FC(F)(F)S(O[CH2:33][CH:34]([F:36])[F:35])(=O)=O>CN(C=O)C.C(OCC)(=O)C.O>[C:1]([O:5][C:6]([N:8]([CH2:33][CH:34]([F:36])[F:35])[C:9]1[CH:14]=[C:13]([C:15]2[O:16][CH:17]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:19]=2)[CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1coc(-c2ccnc(NC(=O)OC(C)(C)C)c2)n1
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1coc(-c2ccnc(N(CC(F)F)C(=O)OC(C)(C)C)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.4 %

Procedure:
To a solution of ethyl 2-(2-((tert-butoxycarbonyl)amino)pyridin-4-yl)-1,3-oxazole-4-carboxylate (58 mg) in DMF (2 mL) was added a sodium hydride 60% dispersion in mineral oil (9.05 mg), and then 2,2-difluoroethyl trifluoromethanesulfonate (74.5 mg) was added thereto. The reaction mixture was stirred at room temperature for 30 min, and diluted with ethyl acetate, and water was added thereto. The organic layer was separated, washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (69.4 mg).
Reaction SMILES: [CH3:1][C:2]1([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C@H:18]4[CH2:19][CH2:20][CH2:21][CH2:22][C@@H:17]4[NH:16][C:15]3=[O:23])[CH2:10][CH2:9]2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(C(C)C)CC)(C)C.Cl[C:34]([O:36][CH:37]([CH3:39])[CH3:38])=[O:35].C1(C)C=CC=CC=1.C([O-])(O)=O.[Na+]>ClCCl>[O:23]=[C:15]1[N:14]([CH:11]2[CH2:12][CH2:13][N:8]([C:2]3([CH3:1])[CH2:7][CH2:6][N:5]([C:34]([O:36][CH:37]([CH3:39])[CH3:38])=[O:35])[CH2:4][CH2:3]3)[CH2:9][CH2:10]2)[C@H:18]2[CH2:19][CH2:20][CH2:21][CH2:22][C@@H:17]2[NH:16]1
Reactant: CC(C)OC(=O)Cl
Reactant: CC1(N2CCC(N3C(=O)N[C@H]4CCCC[C@@H]43)CC2)CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)OC(=O)N1CCC(C)(N2CCC(N3C(=O)N[C@H]4CCCC[C@@H]43)CC2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 48 %

Procedure:
A solution of (3aS,7aS)-1-[1-(4-methyl-4-piperidyl)-4-piperidyl]-3a,4,5,6,7,7a-hexahydro-3H-benzoimidazol-2-one (HCl salt, 99 mg, 0.25 mmol) and diisopropylethylamine (129.3 mg, 1.0 mmol) in dry dichloromethane (5 mL) at 0° C. was added with a solution of 1.0 N isopropyl chloroformate in toluene (0.3 mL, 0.3 mmol) dropwise and stirred at room temperature for 3 h. Saturated NaHCO3 (5 mL) was added followed by dichloromethane (20 mL). The phases were separated and the aqueous phase was extracted with dichloromethane (2×10 mL). The combined organic phases were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified with preparative LC/MS (high pH) to give the title compound (49 mg, 48%). 1H NMR (400 MHz, METHANOL-D4) δ ppm 0.95 (s, 3H), 1.21 (d, J=6.25 Hz, 6H), 1.31-1.49 (m, 6H), 1.52-1.64 (m, 1H), 1.65-1.88 (m, 7H), 1.95 (d, J=7.42 Hz, 1H), 2.10-2.20 (m, 2H), 2.26 (d, J=7.81 Hz, 1H), 2.89-3.15 (m, 4H), 3.31-3.44 (m, 2H), 3.42-3.51 (m, 2H), 3.53-3.64 (m, 1H), 4.78-4.90 (m, 1H). MS (M+1): 407.2.
Reaction SMILES: CS(O[CH2:6][CH:7]([NH:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[CH3:8])(=O)=O.C(O)(=O)C[SH:22].[O-:25][CH2:26][CH3:27].[Na+]>C(O)C>[CH2:13]([O:12][C:10]([NH:9][CH:7]([CH3:8])[CH2:6][CH2:27][C:26]([OH:25])=[S:22])=[O:11])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(COS(C)(=O)=O)NC(=O)OCc1ccccc1
Reactant: CC[O-]
Reactant: O=C(O)CS
Agent: [Na+]
Solvent: CCO
Product: CC(CCC(O)=S)NC(=O)OCc1ccccc1
Reaction time: 0.5 h
Yield: 107.5 %

Procedure:
In ethanol (120 ml) was dissolved 34.9 g (120 mmol) of 2-(benzyloxycarbonylamino)propyl methanesulfonate, followed by adding dropwise thereto a thiolate separately prepared from 14.42 g (120 mmol) of thioglycolic acid and a solution of sodium ethoxide (120 mmol) in ethanol. The reaction was carried out at room temperature for 30 minutes and then at 50° C. for 2 hours, after which the solvent was distilled off and water was added to the residue, followed by three runs of extraction with ethyl acetate. The extract solution was washed with saturated aqueous sodium hydrogencarbonate solution and then saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain 34.5 g (yield 92%) of 2-(benzyloxycarbonylamino)propylthioacetic acid.
Reaction SMILES: Br[CH2:2][CH:3]=[CH:4][C:5]([OH:7])=[O:6].C([CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[NH:16]C2C(C=1)=CC=CC=2)(O)=O.CC(CCCC(Cl)=O)C(Cl)=O>>[C:5]([C:4]1[NH:16][C:15]2[C:2]([CH:3]=1)=[CH:11][CH:12]=[CH:13][CH:14]=2)([OH:7])=[O:6]
Reactant: O=C(O)CCCCc1cc2ccccc2[nH]1
Reactant: O=C(O)C=CCBr
Agent: CC(CCCC(=O)Cl)C(=O)Cl
Product: O=C(O)c1cc2ccccc2[nH]1

Procedure:
Refer to 32(a) using 4-bromo-2-butenoic acid as the alkylating agent. Preparation of 2-(4-carboxy-n-butyl)indole: Refer to Example 3 using methyl adipyl chloride as the acid chloride. The methyl ester was hydrolyzed in the cyclization workup to provide the product carboxyindole. In the alternative, refer to Example 32b) using 2-(4-carboxy-3-buten-1-yl)indole as the starting material.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[C:11]([CH3:12])=[CH:10][C:9]([NH:13][C:14]([CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][CH:21]([O:24][C:25](=[O:39])[NH:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:20][CH2:19]2)=[O:15])=[C:8]([CH3:40])[CH:7]=1.C(#N)C.Cl.[OH-].[Na+]>C(OCC)(=O)C>[CH:2]([C:6]1[C:11]([CH3:12])=[CH:10][C:9]([NH:13][C:14]([CH2:16][CH2:17][N:18]2[CH2:19][CH2:20][CH:21]([O:24][C:25](=[O:39])[NH:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:22][CH2:23]2)=[O:15])=[C:8]([CH3:40])[CH:7]=1)=[O:1]
Reactant: Cc1cc(C2OCCO2)c(C)cc1NC(=O)CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1cc(NC(=O)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)c(C)cc1C=O
Temperature: 30 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
To a 500 mL round-bottom flask was added biphenyl-2-ylcarbamic acid 1-[2-(4-[1,3]dioxolan-2-yl-2,5-dimethylphenylcarbamoyl)ethyl]piperidin-4-yl ester (15 g, 27.6 mmol) and acetonitrile (150 mL) to form a slurry. Aqueous 2 M hydrochloric acid (75 mL) was added and the resulting mixture was stirred at 30° C. for 1 hour. The mixture was then cooled to room temperature and ethyl acetate (150 mL) was added. Aqueous 2 M sodium hydroxide (75 mL) was added, the pH was checked and then additional 2 M sodium hydroxide was added until the pH of the solution was in the range of 9 to 10. The layers were separated and the organic layer was washed with diluted brine (75 mL; 1:1 brine/water), dried over anhydrous sodium sulfate and the solvent removed on a rotary evaporator to give biphenyl-2-ylcarbamic acid 1-[2-(4-formyl-2,5-dimethylphenyl-carbamoyl)ethyl]piperidin-4-yl ester (12.5 g, about 98% purity). If desired, the purity of this intermediate can be increased by forming a slurry with ethanol (3 volumes of ethanol), heating the slurry to 80° C., and then cooling slowly to room temperature and isolating by filtration.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[N:5]([N:19]=[C:20]([C:22]3([C:25]([OH:27])=[O:26])[CH2:24][CH2:23]3)[N:21]=2)[C:6]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[C:14](=[O:18])[O:13][CH2:12]3)=[CH:7][CH:8]=1.[CH3:28][C@@H:29](O)[CH2:30][CH3:31].CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]2[N:5]([N:19]=[C:20]([C:22]3([C:25]([O:27][C@H:29]([CH3:28])[CH2:30][CH3:31])=[O:26])[CH2:23][CH2:24]3)[N:21]=2)[C:6]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[C:14](=[O:18])[O:13][CH2:12]3)=[CH:7][CH:8]=1
Reactant: CC[C@@H](C)O
Reactant: COc1ccc(-c2ccc3c(c2)COC3=O)n2nc(C3(C(=O)O)CC3)nc12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC[C@@H](C)OC(=O)C1(c2nc3c(OC)ccc(-c4ccc5c(c4)COC5=O)n3n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.9 %

Procedure:
A mixture of 1-[8-methoxy-5-(1-oxo-3H-isobenzofuran-5-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxylic acid (400 mg, 1.095 mmol), (2R)-butan-2-ol (122 mg, 1.64 mmol), DMAP (147 mg, 1.20 mmol) and EDCI.HCl (231 mg, 1.20 mmol) in DCM (10 mL) was stirred at RT overnight before it was evaporated to dryness. Column chromatography (gradient MeOH 0 to 5% in DCM) followed by recrystallization in EtOH and freezedrying afforded the title compound as colorless powder (138 mg, 30%). HPLC-Retention time (XE Metode 7 CM): 2.33 minutes. Detected “M+1”-mass: 422.15.
Reaction SMILES: ClC1C=C(C=CC=1Cl)CN(C)C(=O)C=C1C(=O)OC(C)(C)O1.C=O.[CH2:25]([C:28]([NH:30][CH2:31][C:32]([OH:34])=[O:33])=[O:29])[CH2:26][NH2:27].[Cl:35][C:36]1[CH:37]=[C:38]([CH:61]=[CH:62][C:63]=1[Cl:64])[CH2:39][N:40]([CH3:60])[C:41]([C:43]1[CH2:47]N(CCC(NCCC(O)=O)=O)[C:45](=[O:58])[C:44]=1[OH:59])=[O:42]>>[Cl:35][C:36]1[CH:37]=[C:38]([CH:61]=[CH:62][C:63]=1[Cl:64])[CH2:39][N:40]([CH3:60])[C:41]([C:43]1[CH2:47][N:27]([CH2:26][CH2:25][C:28]([NH:30][CH2:31][C:32]([OH:34])=[O:33])=[O:29])[C:45](=[O:58])[C:44]=1[OH:59])=[O:42]
Reactant: NCCC(=O)NCC(=O)O
Reactant: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CCC(=O)NCCC(=O)O)C1
Agent: C=O
Agent: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C=C1OC(C)(C)OC1=O
Product: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CCC(=O)NCC(=O)O)C1
Yield: 7 %

Procedure:
N-(3,4-Dichloro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methyl-acetamide (Compound 37-A) was treated with paraformaldehyde and H-β-ala-gly-OH as described in the preparation of Compound 37. The title compound was purified by chromatography (YMC Combiprep ODS-A, 30 mm×50 mm, MeOH/H2O/0.1% TFA) to yield the title compound as an amber powder (0.0158 g, 7% yield). 1H NMR (300 MHz, DMSO) δ: 2.45 (t, J=6.9 Hz, 2H), 2.98 (m, 3H), 3.60 (m, 2H), 3.73 (d, J=5.7 Hz, 2H), 4.06 (s, 2H), 4.57 (s, 2H), 7.23 (d, J=7.2, 1H), 7.65 (d, J=8.4 Hz, 1H), 8.32 (m, 1H), 10.98 (bs, 1H), 12.50 (bs, 1H). HRMS (M−H) calcd for C18H19N3Cl2O6: 442.05727. found: 442.0584.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15]I)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[N-:17]=[N+:18]=[N-:19].[Na+]>CS(C)=O.CCOC(C)=O>[C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][N:17]=[N+:18]=[N-:19])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCC(CCI)CC1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(CCN=[N+]=[N-])CC1

Procedure:
To 1-4 (27.9 g, 0.082 moles) dissolved in DMSO (400 ml) was added sodium azide (5.61 g, 0.086 moles) at room temperature and the resulting solution was heated at 65° for 2 hrs. The cooled reaction mixture was diluted with 250 ml EtOAc, extracted with 2×100 ml portions of water, 2×50 ml portions of brine and then dried (MgSO4). Solvent removal provided 1-5 as a pale yellow oil, Rf 0.5 (silica gel, 20% acetone/hexane). ##STR13##
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH:10]1[N:14]2[CH:15]=[N:16][CH:17]=[C:13]2[CH2:12][CH2:11]1)[C:5]#[N:6].CCN(CC)CC.[C:25](Cl)(=[O:29])[CH2:26][CH2:27][CH3:28]>CN(C=O)C>[C:5]([C:4]1[CH:7]=[CH:8][C:9]([CH:10]2[N:14]3[CH:15]=[N:16][CH:17]=[C:13]3[CH2:12][CH2:11]2)=[C:2]([NH:1][C:25](=[O:29])[CH2:26][CH2:27][CH3:28])[CH:3]=1)#[N:6]
Reactant: N#Cc1ccc(C2CCc3cncn32)c(N)c1
Reactant: CCCC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCC(=O)Nc1cc(C#N)ccc1C1CCc2cncn21

Procedure:
A DMF (3 mL) solution of 3-Amino-4-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)benzonitrile (0.095 g, 0.42 mmol), given as example 6B, is treated with Et3N (0.09 mL, 0.64 mmol) and butyryl chloride (0.05 mL, 0.51 mmol) at room temperature. After 1 h the solution is concentrated. Purification via prep HPLC gives N-[5-Cyano-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-phenyl]-butyramide. MS (ESI) m/z 295.1 (M+H); 1H NMR (400 MHz, CDCl3) δ ppm 1.01 (t, J=7.3 Hz, 3H), 1.67-1.80 (m, 2H), 2.35 (t, J=7.5 Hz, 2H), 2.49-2.61 (m, 1H), 2.88-3.01 (m, 2H), 3.05-3.18 (m, 1H), 5.56 (dd, J=8.0, 5.9 Hz, 1H), 6.84 (s, 1H), 6.97 (d, J=8.1 Hz, 1H), 7.40 (s, 1H), 7.45 (dd, J=8.1, 1.5 Hz, 1H), 7.70 (br s, 1H), 7.91 (s, 1H).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11])[CH3:2].[CH3:13][Si:14](Cl)([CH3:16])[CH3:15]>>[Cl:11][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([Si:14]([CH3:16])([CH3:15])[CH3:13])[C:5]=1[C:4]([NH:3][CH2:1][CH3:2])=[O:12]
Reactant: C[Si](C)(C)Cl
Reactant: CCNC(=O)c1ccccc1Cl
Product: CCNC(=O)c1c(Cl)cccc1[Si](C)(C)C

Procedure:
The compound of Example f (2.2 g, 0.012 mol) was reacted with TMSCl (3.91 g, 0.036 mol) using General Method A. The title compound was recrystallized from ether/hexanes as a solid. m.p. 105°-107° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[S:9][C:10]([CH3:13])=[N:11][N:12]=2)[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][CH:15]=1.[CH3:23][N:24]1[CH2:29][CH2:28][C:27]2([C:40]3[C:32](=[CH:33][C:34]4[CH2:35][CH2:36][NH:37][C:38]=4[CH:39]=3)[O:31][CH2:30]2)[CH2:26][CH2:25]1>>[CH3:23][N:24]1[CH2:25][CH2:26][C:27]2([C:40]3[C:32](=[CH:33][C:34]4[CH2:35][CH2:36][N:37]([C:20]([C:17]5[CH:18]=[CH:19][C:14]([C:3]6[CH:4]=[CH:5][C:6]([C:8]7[S:9][C:10]([CH3:13])=[N:11][N:12]=7)=[CH:7][C:2]=6[CH3:1])=[CH:15][CH:16]=5)=[O:22])[C:38]=4[CH:39]=3)[O:31][CH2:30]2)[CH2:28][CH2:29]1
Reactant: Cc1nnc(-c2ccc(-c3ccc(C(=O)O)cc3)c(C)c2)s1
Reactant: CN1CCC2(CC1)COc1cc3c(cc12)NCC3
Product: Cc1nnc(-c2ccc(-c3ccc(C(=O)N4CCc5cc6c(cc54)C4(CCN(C)CC4)CO6)cc3)c(C)c2)s1

Procedure:
Crude 2'-methyl-4'-(5-methyl-1,3,4-thiadiazol-2-yl)biphenyl-4-carboxylic acid (D73, 500 mg) and 1'-methyl-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (D8) afforded the title compound according to the general method of Example 1. Preparative HPLC afforded 10 mg of pure compound.
Reaction SMILES: CO[C:3](=[O:13])[C:4]1[CH:12]=[CH:11][CH:10]=[C:6]([C:7]([OH:9])=[O:8])[CH:5]=1.CCN(CC)CC.ClC(OCC(C)C)=O.[CH3:29][NH:30][CH2:31][CH:32]=[CH2:33]>C1COCC1.O>[CH2:31]([N:30]([CH3:29])[C:3](=[O:13])[C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8])[CH:32]=[CH2:33]
Reactant: COC(=O)c1cccc(C(=O)O)c1
Reactant: C=CCNC
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: C=CCN(C)C(=O)c1cccc(C(=O)O)c1

Procedure:
A solution of 2.5 g (13.9 mmol) isophthalic acid mono methyl ester in 25 ml THF, cooled at −30° C. is treated with 2.32 ml (16.9 mmol) Et3N followed by 2.0 ml (15.3 mmol) isobutyl chloroformate. After 30 min at −20° C. are added 1.4 ml (13.9 mmol) methyl allyl amine to the white suspension. After 4 h at −20° C. the mixture is poured into 50 ml water and extracted with EtOAc. The organic phase is washed with water, dried with Na2SO4 and evaporated. The residue is purified via chromatography on silica gel (EtOAc/hexane 1:2), yielding the methyl ester of the title compound. This ester is taken up in 5 ml MeOH and 5 ml 1N NaOH. After stirring for 2 h the mixture is acidified with 6 ml 1N HCl and extracted with EtOAc. The organic layer is dried with Na2SO4 and evaporated to yield the title compound as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([NH:8][CH3:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].Cl.[CH3:15][N:16]([CH3:20])[CH2:17][CH2:18]Cl>C1COCC1>[CH3:15][N:16]([CH3:20])[CH2:17][CH2:18][N:8]([CH3:9])[C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:11][CH:10]=1
Reactant: CNc1ccc([N+](=O)[O-])cc1
Reactant: CN(C)CCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)CCN(C)c1ccc([N+](=O)[O-])cc1
Temperature: 60 °C
Reaction time: 0.08 h
Yield: 55.1 %

Procedure:
To a solution containing 1.52 g of 4-nitro-N-methylaniline (10 mmol) in 30 mL THF, was added 0.8 g of sodium hydride (60% dispension in oil, 20 mmol). After 5 minutes at room temperature, 2.59 g of 2-(dimethylamino)ethyl chloride hydrochloride (18 mmol) and 0.4 g of sodium hydride (60% dispension in oil, 10 mmol) were added. The reaction was heated at 60° C. for 5 hours. The solvent was concentrated in vacuo to yield a residue which was partitioned between ethyl acetate and 2 M sodium hydroxide solution. The organic phase was washed with water (3×), dried over anhydrous sodium sulphate, filtered, and concentrated in vacuo to yield the title compound as a brown oil (1.23 g, 55%). MS (ES+) m/e 224 [M+H]+.
Reaction SMILES: CN(C)P([N:8]([CH3:10])[CH3:9])(N(C)C)=O.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]1[CH2:25][CH2:26][O:27][C:28]1[C:37]2C(=[CH:33][C:34]([Cl:48])=[C:35]([NH:38][C:39]([NH:41][C:42]3[CH:47]=[CH:46][N:45]=[CH:44][N:43]=3)=[O:40])[CH:36]=2)N[C:30](=[O:49])[C:29]=1[C:50]1[CH:55]=[C:54]([CH3:56])[CH:53]=[C:52]([CH3:57])[CH:51]=1)=[O:18])([CH3:15])([CH3:14])[CH3:13].I[CH3:59]>O1CCCC1>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]1[CH2:25][CH2:26][O:27][C:28]1[C:37]2[C:10](=[CH:33][C:34]([Cl:48])=[C:35]([N:38]([CH3:59])[C:39]([NH:41][C:42]3[CH:47]=[CH:46][N:45]=[CH:44][N:43]=3)=[O:40])[CH:36]=2)[N:8]([CH3:9])[C:30](=[O:49])[C:29]=1[C:50]1[CH:51]=[C:52]([CH3:57])[CH:53]=[C:54]([CH3:56])[CH:55]=1)=[O:18])([CH3:14])([CH3:15])[CH3:13]
Reactant: CI
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Reactant: Cc1cc(C)cc(-c2c(OCC[C@@H]3CCCCN3C(=O)OC(C)(C)C)c3cc(NC(=O)Nc4ccncn4)c(Cl)cc3[nH]c2=O)c1
Solvent: C1CCOC1
Product: Cc1cc(C)cc(-c2c(OCC[C@@H]3CCCCN3C(=O)OC(C)(C)C)c3cc(N(C)C(=O)Nc4ccncn4)c(Cl)cc3n(C)c2=O)c1
Temperature: 0 °C
Reaction time: 1.25 h

Procedure:
To a solution of lithium bis(trimethylamide) (0.43 mL of a 1M solution in 1.0 mL dry tetrahydrofuran) at -78° C. was added 0.198 mL hexamethylphosphoramide (HMPA) followed by a solution of (S)-2-{2-[7-chloro-3-(3,5-dimethylphenyl)-2-oxo-6-(3-pyrimidin-4-yl-ureido)-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester (prepared essentially as described in EXAMPLE 1, 69 mg in 1.5 mL dry tetrahydrofuran) and the mixture stirred at low temperature for 75 minutes. At this time, 0.036 mL of iodomethane was added and the mixture warmed to 0° C. After 4 hours, the reaction was quenched by the addition of IN hydrochloric acid, extracted with methylene chloride washed with brine and dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (ethyl acetate:hexane 3:7; then 5:5; then 7:3) gave the title compound (30 mg).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:28][C:29]1[CH:30]=[C:31]([CH2:35][O:36][CH2:37][CH2:38]O)[CH:32]=[CH:33][CH:34]=1>C(Cl)Cl.[Al]>[Br:1][CH2:38][CH2:37][O:36][CH2:35][C:31]1[CH:32]=[CH:33][CH:34]=[C:29]([F:28])[CH:30]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: OCCOCc1cccc(F)c1
Agent: [Al]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Fc1cccc(COCCBr)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 78.3 %

Procedure:
N-bromosuccinimide (146 mg, 0.820 mmol) was added to resin-bound triphenylphosphine (274 mg, 0.822 mequiv, Fluka) and 2-{[(3-fluorophenyl)methyl]oxy}ethanol (70 mg, 0.411 mmol) in DCM (4 mL). The reaction vial was sealed with a Teflon-lined cap, wrapped in aluminum foil, and shaken at rt for 17 h. The reaction was filtered through a SPE cartridge (5 g silica) eluting with the following 10 mL fractions: DCM (fraction 1), 30% EtOAc/hexanes (fraction 2), and 50% EtOAc/hexanes (fraction 3) to give the title compound (75 mg, 78%). The product was characterized by 1H NMR (400 MHz) in CDCl3.
Reaction SMILES: C(OC([NH:8][C:9]([NH:26]C(OC(C)(C)C)=O)=[N:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:12]=1)=O)(C)(C)C.[ClH:34]>ClCCl.O1CCOCC1>[ClH:34].[ClH:34].[N+:23]([C:22]1[C:17]([C:13]2[CH:12]=[C:11]([NH:10][C:9]([NH2:26])=[NH:8])[CH:16]=[CH:15][CH:14]=2)=[N:18][CH:19]=[CH:20][CH:21]=1)([O-:25])=[O:24]
Reactant: CC(C)(C)OC(=O)NC(=Nc1cccc(-c2ncccc2[N+](=O)[O-])c1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: N=C(N)Nc1cccc(-c2ncccc2[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of N,N′-bis(tert-butoxycarbonyl)-N″-(3-(3-nitropyridin-2-yl)phenyl)guanidine (200 mg) in dichloromethane (2 ml) was added 4N hydrogen chloride in 1,4-dioxane (2 ml), and the mixture was stirred at room temperature for 16 hours. The solvent was evaporated under reduced pressure. To the residue was added 5% ethanol in ethyl acetate (100 ml), and the.precipitate was collected by filtration and dried under reduced pressure to give 3-(3-nitropyridin-2-yl)phenylguanidine dihydrochloride (127 mg).