Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][CH:5]1[C:14]2[C:9](=[C:10]([CH3:26])[CH:11]=[C:12]([C:16]([C:18]3[CH:19]=[N:20][N:21]([CH2:24][CH3:25])[C:22]=3[OH:23])=[O:17])[C:13]=2[CH3:15])[S:8](=[O:28])(=[O:27])[CH2:7][CH2:6]1.N1C=CC=N1.C(=O)([O-])[O-].[K+].[K+].[CH2:40]([S:43](Cl)(=[O:45])=[O:44])[CH2:41][CH3:42]>ClCCl.O.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[F:1][CH2:2][CH2:3][O:4][CH:5]1[C:14]2[C:9](=[C:10]([CH3:26])[CH:11]=[C:12]([C:16]([C:18]3[CH:19]=[N:20][N:21]([CH2:24][CH3:25])[C:22]=3[O:23][S:43]([CH2:40][CH2:41][CH3:42])(=[O:45])=[O:44])=[O:17])[C:13]=2[CH3:15])[S:8](=[O:28])(=[O:27])[CH2:7][CH2:6]1
Reactant: CCn1ncc(C(=O)c2cc(C)c3c(c2C)C(OCCF)CCS3(=O)=O)c1O
Reactant: CCCS(=O)(=O)Cl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CCCS(=O)(=O)Oc1c(C(=O)c2cc(C)c3c(c2C)C(OCCF)CCS3(=O)=O)cnn1CC
Yield: 63 %

Procedure:
1.00 Gram (2.44 mmol) of the 4-(2-fluoroethoxy)-5,8-dimethyl-6-(1-ethyl-5-hydroxypyrazol-4-yl)carbonylthiochroman-1,1-dioxide (corresponding to pyrazole derivative of the formula (Ia)) obtained in Preparation Example 1 was dissolved in 10 ml of dichloromethane. To this mixture solution was added a solution of 0.67 g (4.87 mmol) of potassium carbonate as a base in 10 ml of water. 0.42 Gram (2.93 mmol) of n-propanesulfonyl chloride (corresponding to compound of the formula (IV)) as a reaction reagent was added to the mixture, and 0.05 g (0.2 mmol) of benzyltriethylammonium chloride as a phase transfer catalyst was added. The mixture was allowed to react at room temperature for 2 hours, and then, further refluxed under heat for 2 hours. After the completion of the reaction, the reaction mixture was allowed to cool, and water and dichloromethane were added to separate the reaction mixture into two phases. The resultant organic layer was consecutively washed with distilled water, with a saturated sodium hydrogencarbonate and with a sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated and purified by flush column chromatography to give 0.79 g (yield 63%) of the subject end product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:9])[CH:5]=[CH:6][C:7]=1[F:8].[CH:10]1([NH:15][C:16]2[C:25]3[C:20](=[CH:21][N:22]=[C:23](F)[CH:24]=3)[N:19]=[CH:18][C:17]=2[C:27]#[N:28])[CH2:14][CH2:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:23]2[CH:24]=[C:25]3[C:20](=[CH:21][N:22]=2)[N:19]=[CH:18][C:17]([C:27]#[N:28])=[C:16]3[NH:15][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: N#Cc1cnc2cnc(F)cc2c1NC1CCCC1
Reactant: Nc1ccc(F)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#Cc1cnc2cnc(Nc3ccc(F)c(Cl)c3)cc2c1NC1CCCC1
Temperature: 200 °C
Yield: 39.3 %

Procedure:
A mixture of 3-chloro-4-fluorobenzenamine (550 mg, 3.78 mmol, 38 eq), 4-(cyclopentylamino)-6-fluoro-1,7-naphthyridine-3-carbonitrile (28 mg, 0.1 mmol, 1 eq), and cesium carbonate (506 mg, 1.55 mmol, 15.5 eq) in DMF (4 mL) was heated to 200° C. in a microwave tube for 1 hr using microwave reactor. Preparative HPLC purification yielded 15 mg product (36% yield): 1H NMR (400 MHz, DMSO-D6) δ ppm 1.52-1.68 (m, 2 H) 1.70-1.91 (m, 4 H) 1.99-2.16 (m, 2 H) 4.58-4.76 (m, 1 H) 7.33 (t, J=9.09 Hz, 1 H) 7.45-7.56 (m, 1 H) 7.76 (s, 1 H) 7.80 (d, J=7.07 Hz, 1 H) 7.87-7.97 (m, 1 H) 8.32 (s, 1 H) 8.90 (s, 1 H) 9.64 (s, 1 H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][CH2:21][O:22][CH3:23].[N:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][C:25]=1[C:34](Cl)=[O:35].C(N(CC)CC)C>ClCCl>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH2:20][CH2:21][O:22][CH3:23])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:34]([C:25]3[CH:26]=[CH:27][C:28]4[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:24]=3)=[O:35])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCCN
Reactant: O=C(Cl)c1ccc2ccccc2n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCCCNC(=O)c1ccc2ccccc2n1

Procedure:
According to the general method of Example 14, 1-(4-aminobutyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine and quinoline-2-carbonyl chloride were combined in dichloromethane and triethylamine (3 equivalents) to provide N2-{4-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butyl}-2-quinolinecarboxamide as a white solid, m.p. 78.1-79.9° C. 1H NMR (300 MHz, DMSO-d6) δ9.02 (t, J=6.1 Hz, 1H), 8.55 (d, J=8.5 Hz, 1H), 8.23 (d, J=8.5 Hz, 1H), 8.10 (t, J=7.6 Hz, 1H), 8.02 (d, J=7.6 Hz, 1H), 7.90-7.84 (m, 1H), 7.75-7.70 (m, 1H), 7.58 (dd, J=8.3, 1.0 Hz, 1H), 7.35-7.30 (m, 1H), 7.18-7.13 (m, 2H), 6.48 (broad s, 2H), 4.58 (m, 2H), 3.79 (t, J=6.7 Hz, 2H), 3.44 (m, 2H), 3.22 (m, 5H), 1.91-1.78 (m, 4H); MS (EI) m/e 468.2276 (468.2274 calcd for C27H28N6O2).
Reaction SMILES: [CH2:1]([N:3]([CH2:30][CH3:31])[CH2:4][CH2:5][O:6][C:7]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:8]=1[C:9]1[C:10]([O:28][CH3:29])=[CH:11][C:12]([O:24][CH2:25][CH2:26][CH3:27])=[C:13]([N+:21]([O-])=O)[C:14]=1[C:15]2=[O:20])[CH3:2].O.C(=O)(O)[O-].[Na+]>C(O)C.C(OCC)C>[NH2:21][C:13]1[C:14]2[C:15](=[O:20])[C:16]3[C:8](=[C:7]([O:6][CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:30][CH3:31])[CH:19]=[CH:18][CH:17]=3)[C:9]=2[C:10]([O:28][CH3:29])=[CH:11][C:12]=1[O:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCOc1cc(OC)c2c(c1[N+](=O)[O-])C(=O)c1cccc(OCCN(CC)CC)c1-2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Solvent: O
Product: CCCOc1cc(OC)c2c(c1N)C(=O)c1cccc(OCCN(CC)CC)c1-2

Procedure:
Prepare a solution, under argon, of 5-(2-diethylamino-ethoxy)-4-methoxy-1-nitro-2-propoxy-fluoren-9-one (0.52 g, 1.2 mmole) and stannous chloride (SnCl2, 1.3 g, 6 mmole) in 60 mL ethanol. Reflux overnight. Reduce volume on a rotovap. Add 200 mL deionized water and make basic with sodium bicarbonate. Extract with methylene chloride. Dry the organic layer with magnesium sulfate. Filter and evaporate on a rotary evaporator to give a red oil. Take up in anhydrous diethyl ether and filter through celite. Precipitate the hydrochloride salt by adding ethereal HCl. Filter the resulting red solid and wash with diethyl ether. Place under a high vacuum overnight at 100° C. to give the purified hydrochloride salt of the title compound. m.p. 163-165° C. Yield 0.338 g, 70%. Rf =0.33; 5% methanol/CH2Cl2.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[CH:3]1[O:5][CH2:4]1.C([Li])CCC.CON(C)[C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(OCC)C>C1COCC1.CCCCCC>[C:17]1([C:16]([C:3]2([C:2]([F:7])([F:6])[F:1])[CH2:4][O:5]2)=[O:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: FC(F)(F)C1CO1
Reactant: CON(C)C(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCCCCC
Product: O=C(c1ccccc1)C1(C(F)(F)F)CO1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
2.3 ml (26 mmol) 1,1,1-trifluoro-2,3-epoxypropane in 30 ml THF and 8 ml hexane are cooled to −100° C. and 6.3 ml of a 2.5 M n-butyl lithium solution (16 mmol) in hexane are added over 15 minutes while the temperature does not exceed −95° C. 10 Minutes after complete addition 2.0 (12 mmol) g N-methoxy-N-methylbenzamid in 38 ml THF are added over 15 minutes while the temperature does not exceed −95° C. After 5 hours at −100° C. 12 ml diethyl ether are added and the reaction mixture is warmed to room temperature over 14 hours. The reaction is quenched by addition of saturated ammonium chloride solution. The phases were separated and the aqueous layer is extracted twice with ethyl acetate, the combined organic phases washed with brine, dried over sodium sulphate and then evaporated to yield 2.59 g of Phenyl-[2-(trifluoromethyl)oxiranyl]methanone. 1H-NMR (CDCl3); δ=3.07 (dq, 1H), 3.38 (d, 1H), 7.50 (t, 2H), 7.65 (tt, 1H), 8.07 (d, 2H).
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.Cl.Cl[CH2:14][C:15]1[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=1[NH2:17]>C(O)(C)C>[CH3:11][C:9]1[CH:8]=[CH:7][C:5]2[NH:6][C:2]([S:1][CH2:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[NH2:17])=[N:3][C:4]=2[CH:10]=1
Reactant: Cc1ccc2nc(S)[nH]c2c1
Reactant: Nc1ccccc1CCl
Agent: Cl
Solvent: CC(C)O
Product: Cc1ccc2[nH]c(SCc3ccccc3N)nc2c1
Yield: 40.2 %

Procedure:
The title compound was prepared by the method of Example 1 using 2.50 g of 2-mercapto-5-methylbenzimidazole instead of 2-mercaptobenzimidazole and 2.71 g of 2-(chloromethyl)aniline hydrochloride instead of 2-(chloromethyl)-N,N-dimethylaniline in isopropyl alcohol. The basic extraction used 5% sodium hydroxide instead of sodium carbonate. Washing the solid residue from the dichloromethane extract with additional dichloromethane gave 1.65 g of the title compound. Analysis. Calc'd. for C15H15N3S: C, 66.89; H, 5.61; N, 15.60; S, 11.90. Found: C, 65.78; H, 5.48; N, 15.54; S, 11.94.
Reaction SMILES: [CH3:1][S:2][CH2:3][S:4](=[O:6])[CH3:5].[CH3:7][CH2:8][CH2:9][CH2:10]CC.C([Li])CCC>O1CCCC1>[CH3:1][S:2][C:3]1([S:4](=[O:6])[CH3:5])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CCCCCC
Reactant: CSCS(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CSC1(S(C)=O)CCCC1
Reaction time: 2.5 h
Yield: 71 %

Procedure:
Formaldehyde dimethyl mercaptal S-oxide (1.166g) was dissolved in 10 ml. of tetrahydrofuran, and at -16° C., 7.2 ml. of an n-hexane solution (1.4 millimols/milliliter) of n-butyl lithium was added, followed by stirring the mixture for 2.5 hours. 1,4-Bis(methanesulfonato)butane (904 mg) was added together with 35 ml. of tetrahydrofuran. The mixture was stirred for 21 hours at room temperature. Then, the same procedure as in Example A-14 was repeated to afford 465 mg of cyclopentanone dimethyl mercaptal S-oxide in a yield of 71%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][C@@H:13]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([O:28]C)=[O:27])=[C:20]([C:30]([O:32]C)=[O:31])[CH:19]=1)[C:14](O)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:41][CH:42]([NH2:57])[CH2:43][CH:44]([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:10]([NH:12][C@H:13]([C:14]([NH:57][CH:42]([CH3:41])[CH2:43][CH:44]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)=[O:15])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([OH:28])=[O:27])=[C:20]([CH:19]=1)[C:30]([OH:32])=[O:31])=[O:11])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: COC(=O)COc1ccc(C[C@H](NC(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)cc1C(=O)OC
Reactant: CC(N)CC(c1ccccc1)c1ccccc1
Product: CC(CC(c1ccccc1)c1ccccc1)NC(=O)[C@H](Cc1ccc(OCC(=O)O)c(C(=O)O)c1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Yield: 26.3 %

Procedure:
Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoyl}amino)-3-[3-(methoxycarbonyl)-4-(2-methoxy-2-oxoethoxy)phenyl]propanoic acid (88 mg, 0.16 mmol) and 1-methyl-3,3-diphenylpropylamine (45 mg, 0.19 mmol) according to Method C with HPLC purification to give the title compound (31 mg) as a diastereomeric mixture in a 2:1 ratio. HRMS m/z 737.3312 (calc. of monoisotopic mass for C42H47N3O9 gives 737.3329).
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:14])/[CH:9]=[CH:10]\[C:11]([OH:13])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][NH:16][C:17]([NH:19][CH3:20])=[O:18].C1(C)C(O)=CC=CC=1>>[CH3:15][N:16]1[C:10](=[CH:9][C:8]([NH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:14])[C:11](=[O:13])[N:19]([CH3:20])[C:17]1=[O:18]
Reactant: O=C(O)/C=C\C(=O)Nc1ccccc1
Reactant: CNC(=O)NC
Agent: Cc1ccccc1O
Product: CN1C(=O)C(=CC(=O)Nc2ccccc2)N(C)C1=O
Temperature: 165 °C
Reaction time: 2.5 h

Procedure:
A mixture of 19.1 parts of N-phenyl maleic acid monoamide 8.8 parts of N,N'-dimethyl urea and 100 parts of cresol is stirred for 2.5 hours at 165° C. The solvent is distilled off in vacuo and the residue fractionated. An oily liquid distills over at a boiling point of from 220° to 223° C./0.1 Torr and solidifies after a while. Recrystallisation from n-propanol gives the compound confirmed by IR- (bands characteristic of hydantoins at 1705 and 1765 cm-1 and of amide at 1690 cm-1) and NMR-spectra.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([N:22]4[CH2:27][CH2:26][CH2:25][CH:24]([C:28]([O:30]CC)=[O:29])[CH2:23]4)=[O:21])=[CH:14][C:13]=3[Cl:33])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[OH-].[Na+].CCO>>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([N:22]4[CH2:27][CH2:26][CH2:25][CH:24]([C:28]([OH:30])=[O:29])[CH2:23]4)=[O:21])=[CH:14][C:13]=3[Cl:33])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C1CCCN(C(=O)/C=C/c2ccc(Sc3ccc4c(c3)OCCO4)c(Cl)c2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C1CCCN(C(=O)/C=C/c2ccc(Sc3ccc4c(c3)OCCO4)c(Cl)c2)C1

Procedure:
The title compound was prepared by hydrolysis of the compound of Example 308 under basic condition (aq. NaOH/EtOH). 1H NMR (DMSO-d6, 300 MHz) δ 1.10-1.40 (m, 2H), 1.60 (m, 1H), 1.76-1.96 (m, 3H), 2.88 (m, 1H), 3.98 (m, 1H), 3.98 (m, 1H), 4.30 (m, 4H), 6.72 (d, J=8.0 Hz, 1H), 7.02 (m, 3H), 7.30 (m, 2H), 7.48 (m, 1H), 7.92 (m, 1H). MS (ESI) m/z 458 (M+H)+. Anal. calcd. for C23H21ClNO5SNa: C, 55.76; H, 4.58; N, 2.83. Found: C, 55.76; H, 4.78; N, 2.63.
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:12][N:11]=2)=[CH:6][CH:5]=1)[CH3:3].[C:27](O)(=[O:39])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38].C1(N=C=NC2CCCCC2)CCCCC1.N1(C2C=CN=CC=2)CCCC1>ClCCl>[C:27]([O:1][CH:2]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:12][N:11]=2)=[CH:8][CH:9]=1)[CH3:3])(=[O:39])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: CCCCCCCCCCOc1cnc(-c2ccc(C(C)O)cc2)nc1
Reactant: CCCCCCCCCCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: c1cc(N2CCCC2)ccn1
Solvent: ClCCl
Product: CCCCCCCCCCCC(=O)OC(C)c1ccc(-c2ncc(OCCCCCCCCCC)cn2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 93.9 %

Procedure:
Into 20 ml of dichloromethane were dissolved 1.78 g (5 millimoles) of the (+)-2-{4-(1-hydroxyethyl)phenyl}-5-decyloxypyrimidine obtained in Preparation Example [starting material compound (VI)]70 and 1.2 g (6 millimoles) of dodecanic acid, and then 1.4 g of N,N'-dicyclohexylcarbodiimide and 0.1 g of 4-pyrrolidinopyridine were added thereto, followed by stirring at room temperature for 24 hours. After completion of the reaction, the precipitates were filtered off and 200 ml of toluene were added thereto, followed by washing with water, 5% acetic acid, water, 5% aqueous sodium hydrogen carbonate solution and water in this order. After the organic phase was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent; toluene:ethyl acetate) to obtain 2.53 g (yield: 94%) of (+)-2-{4-(1-dodecanoyloxyethyl)phenyl}-5-decyloxypyrimidine. The physical values are shown in Table-1.
Reaction SMILES: [I-].[CH2:2]([N+:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[S:8][C:7]=1[CH3:13])[CH2:3][CH2:4][CH3:5].Cl.[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=1>CN(C1C=CN=CC=1)C>[CH2:2]([N:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[S:8]/[C:7]/1=[CH:13]\[C:15]([C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)=[O:22])[CH2:3][CH2:4][CH3:5]
Reactant: O=C(Cl)c1cccnc1
Reactant: CCCC[n+]1c(C)sc(C)c1C
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: [I-]
Product: CCCCN1C(C)=C(C)S/C1=C\C(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial 3-butyl-2,4,5-trimethylthiazol-3-ium iodide (48 mg in 0.5 mL DMA, 0.16 mmol, 1 equiv.) was added, followed by TEA (38 mg in 0.5 mL DMA, 0.37 mmol, 2.4 equiv.) and the solution went black. DMAP (2 mg in 0.5 mL DMA, 0.016 mmol, 0.1 equiv) was added next, followed by nicotinoyl chloride hydrochloride (0.9 mL of 0.2M in DMA, 1.2 equiv). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.94 (t, 3 H) 1.36-1.46 (m, 2 H) 1.61-1.68 (m, 2 H) 2.19 (s, 3 H) 2.22 (s, 3 H) 4.07-4.12 (m, 2 H) 6.69 (s, 1 H) 7.68-7.78 (m, 1 H) 8.54-8.61 (m, 1 H) 8.72-8.80 (m, 1 H) 9.18-9.29 (m, 1 H); MS (ESI) m/z 289 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]O)=[CH:5][CH:4]=1.[BrH:11]>CCOCC>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][Br:11])=[CH:5][CH:4]=1
Reactant: Br
Reactant: COc1ccc(CO)cc1
Solvent: CCOCC
Product: COc1ccc(CBr)cc1

Procedure:
A solution of 4-methoxybenzylalcohol (10 g) in ether (300 ml) was shaken with hydrobromic acid, 48%, (150 ml). The organic phase was washed with saturated sodium bromide, dried (K2CO3) and the solvents removed in vacuo to give 4-methoxybenzylbromide (13.17 g).
Reaction SMILES: [F:1][C:2]1[C:3]([OH:26])=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[CH2:8][CH:7]([C:13]1[CH:14]=[N:15][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:17][CH:18]=1)[CH2:6][CH2:5]2.[F:27][C@@H:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:29]O>>[F:1][C:2]1[C:3]([O:26][CH2:29][CH:28]([F:27])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[CH2:8][CH:7]([C:13]1[CH:14]=[N:15][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:17][CH:18]=1)[CH2:6][CH2:5]2
Reactant: CCCCCCCC[C@H](F)CO
Reactant: CCCCCCOc1ccc(C2CCc3c(cc(F)c(F)c3O)C2)cn1
Product: CCCCCCCCC(F)COc1c(F)c(F)cc2c1CCC(c1ccc(OCCCCCC)nc1)C2

Procedure:
From 6,7-difluoro-2-(6-hexyloxypyridin-3-yl)-5-hydroxy-1,2,3,4-tetrahydronaphthalene and 2-(S)-fluorodecan-1-ol by means of the Mitsunobu reaction.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9]([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[CH2:17][NH:16][CH2:15][CH2:14]2)=[O:10].[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][CH2:28][C:29](O)=[O:30])[CH:22]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.C(N(CC)CC)C>[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][CH2:28][C:29]([N:16]2[CH2:15][CH2:14][C:13]3[C:18](=[CH:19][CH:20]=[C:11]([C:9]([NH:8][O:7][CH:2]4[CH2:3][CH2:4][CH2:5][CH2:6][O:1]4)=[O:10])[CH:12]=3)[CH2:17]2)=[O:30])[CH:22]=1
Reactant: O=C(NOC1CCCCO1)c1ccc2c(c1)CCNC2
Reactant: O=C(O)CCc1cccnc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: O=C(NOC1CCCCO1)c1ccc2c(c1)CCN(C(=O)CCc1cccnc1)C2
Reaction time: 8 h
Yield: 52 %

Procedure:
A mixture of 200 mg N-(tetrahydro-2H-pyran-2-yloxy)-1,2,3,4-tetrahydroisoquinoline-6-carboxamide, 120 mg of 3-(3-pyridyl)propionic acid, 111 mg HOBt, 276 mg EDC, 0.603 ml triethylamine and 7 ml DMF is stirred overnight. The resulting reaction mixture is purified by silica gel chromatography. 154 mg of the title compound are obtained as colorless foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([S:15](=[O:18])(=[O:17])[NH2:16])=[CH:11][CH:10]=2)=[CH:7][C:6]([C:19]2[N:23]([CH3:24])[C:22]([C:25]([O:27]C)=[O:26])=[CH:21][C:20]=2[CH3:29])=[CH:5][CH:4]=1.[OH-].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([S:15](=[O:18])(=[O:17])[NH2:16])=[CH:11][CH:10]=2)=[CH:7][C:6]([C:19]2[N:23]([CH3:24])[C:22]([C:25]([OH:27])=[O:26])=[CH:21][C:20]=2[CH3:29])=[CH:5][CH:4]=1
Reactant: COC(=O)c1cc(C)c(-c2ccc(OC)c(-c3ccc(S(N)(=O)=O)cc3)c2)n1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(-c2c(C)cc(C(=O)O)n2C)cc1-c1ccc(S(N)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 95.8 %

Procedure:
Methyl 5-(6-methoxy-4′-sulfamoyl-[1,1′-biphenyl]-3-yl)-1,4-dimethyl-1H-pyrrole-2-carboxylate (step-2, 0.77 g, 1.85 mmol) was suspended in ethanol (15 ml), to this was then added aqueous solution of NaOH (0.37 g. 9.29 mmol in 5 ml water) at 0° C. The reaction mixture was stirred at 25° C. for 15 hours. The progress of the reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure. The residue obtained after concentration was then dissolved in water (10 ml) and dilute hydrochloric acid was added to the mixture so obtained to bring the pH of the mixture to between 6 and 7. The mixture was then extracted with ethyl acetate (2×50 ml). The separated combined organic layer was then dried over anhydrous sodium sulfate. The solvent was evaporated from the dried organic layer under reduced pressure to obtain the title compound 10c (0.71 g, 95.9%).
Reaction SMILES: [Cl:1][C:2]1[C:6]([CH3:7])=[CH:5][S:4][C:3]=1[C:8]([NH:10][NH:11][C:12]([NH:14][CH2:15][CH:16]([CH3:18])[CH3:17])=[O:13])=O>[OH-].[Na+]>[Cl:1][C:2]1[C:6]([CH3:7])=[CH:5][S:4][C:3]=1[C:8]1[N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12](=[O:13])[NH:11][N:10]=1
Reactant: Cc1csc(C(=O)NNC(=O)NCC(C)C)c1Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1csc(-c2n[nH]c(=O)n2CC(C)C)c1Cl
Reaction time: 8 h

Procedure:
A suspension of 1.28 g (4.42 mmol) of 2-[(3-chloro-4-methyl-2-thienyl)carbonyl]-N-isobutyl-hydrazinecarboxamide from Example 246A in 12 ml 3 N aqueous sodium hydroxide is first heated overnight under reflux. After cooling, it is filtered. The filtrate contains impure product, while the solid filtered off mainly corresponds to the educt. This solid is taken up again in ca. 15 ml of 3 N ethanolic aqueous sodium hydroxide and again heated overnight under reflux. After neutralization with 1 N hydrochloric acid and concentration, the residue together with the concentrated filtrate from the aqueous reaction is purified by preparative HPLC [Method 12]. After evaporation and drying of the product fractions, 562 mg (47% of theory) of the target compound are thus obtained.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].[H-].[Na+].CS(O[CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:28]=[C:27]([C:29]#[N:30])[C:26]3[N:31]=[CH:32][N:33]([CH3:34])[C:25]=3[CH:24]=2)=[CH:19][C:18]=1[C:35]([F:38])([F:37])[F:36])(=O)=O>CN1C(=O)CCC1>[CH3:34][N:33]1[C:25]2[CH:24]=[C:23]([C:20]3[CH:21]=[CH:22][C:17]([O:16][CH2:15][CH2:14][N:3]4[CH2:4][CH2:5][O:1][C:2]4=[O:6])=[C:18]([C:35]([F:37])([F:38])[F:36])[CH:19]=3)[N:28]=[C:27]([C:29]#[N:30])[C:26]=2[N:31]=[CH:32]1
Reactant: Cn1cnc2c(C#N)nc(-c3ccc(OCCOS(C)(=O)=O)c(C(F)(F)F)c3)cc21
Reactant: O=C1NCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Cn1cnc2c(C#N)nc(-c3ccc(OCCN4CCOC4=O)c(C(F)(F)F)c3)cc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 10.2 %

Procedure:
To oxazolidin-2-one (29.7 mg) in NMP (1 ml) was added sodium hydride is (60% in parafin oil, 13.6 mg). After stirring at room temperature for 10 minutes, 2-(4-(4-cyano-1-methyl-1H-imidazo[4,5-c]pyridin-6-yl)-2-(trifluoromethyl)phenoxy)ethyl methanesulfonate (100 mg) was then added and the mixture was stirred at room temperature for 14 hours. The mixture was purified directly using HPLC to give 1-methyl-6-{4-[2-(2-oxooxazolidin-3-yl)-ethoxy]-3-(trifluoromethyl)-phenyl}-1H-imidazo[4,5-c]pyridine-4-carbonitrile (10 mg).
Reaction SMILES: [CH3:1][C:2]([CH3:11])([CH3:10])[C:3](=[O:9])[CH:4]=[CH:5][C:6]([OH:8])=[O:7]>C(OCC)C>[C:2]([C:3]1([OH:9])[O:7][C:6](=[O:8])[CH:5]=[CH:4]1)([CH3:11])([CH3:10])[CH3:1]
Reactant: CC(C)(C)C(=O)C=CC(=O)O
Solvent: CCOCC
Product: CC(C)(C)C1(O)C=CC(=O)O1
Reaction time: 18 h

Procedure:
To 8.5 g. of pure 5,5-dimethyl-4-oxo-2-hexenoic acid in 150 ml. of diethyl ether was applied irradiation from a 300 watt sun-lamp. The solution was in a 500 ml. Pyrex flask, and the lamp was placed 5 cm. from the flask. The light emitted by the lamp was primarily of wave length 200 to 800 mμ. The irradiation was continued for about 18 hours. The mixture was then evaporated under vacuum to obtain 8.5 g. of the desired product as colorless crystals.