Azzindani/Open_Reaction_Data huggingface dataset:
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:11])=[CH:8][CH:7]=1.Br[CH:16]([CH3:20])[C:17](=O)[CH3:18]>C(#N)CC>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]2[O:11][C:16]([CH3:20])=[C:17]([CH3:18])[N:12]=2)=[CH:8][CH:7]=1
Reactant: NC(=O)c1ccc(OCCCCl)cc1
Reactant: CC(=O)C(C)Br
Solvent: CCC#N
Product: Cc1nc(-c2ccc(OCCCCl)cc2)oc1C
Yield: 10 %

Procedure:
A suspension of 4-(3-chloropropoxy)benzamide ax54 (1.2 g, 5.62 mmol) and 3-bromobutan-2-one (1.02 g, 6.74 mmol) is heated in propionitrile (50 ml) at reflux for 10 days. The mixture is then concentrated and the resulting black mixture is filtered through a pad of silicagel, eluting first with dichloromethane (100 ml) and then with a 96:4 mixture of dichloromethane and dimethoxymethane to afford two fractions. The second fraction is concentrated, and the resulting yellow solid (0.67 g) is further purified by chromatography over silicagel (eluent: dichloromethane) to afford 330 mg of 2-[4-(3-chloropropoxy)phenyl]-4,5-dimethyl-oxazole i30 as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH:6]([OH:8])[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1.[CH2:12]1[O:14][CH:13]1[CH2:15][OH:16]>C(O)(C)C>[OH:14][CH:13]([CH2:15][OH:16])[CH2:12][N:3]1[C:4]([CH3:10])([CH3:9])[CH2:5][CH:6]([OH:8])[CH2:7][C:2]1([CH3:11])[CH3:1]
Reactant: CC1(C)CC(O)CC(C)(C)N1
Reactant: OCC1CO1
Solvent: CC(C)O
Product: CC1(C)CC(O)CC(C)(C)N1CC(O)CO

Procedure:
2,2,6,6-Tetramethyl-4-piperidinol 15.7 g and glycidol 7.8 g were dissolved in 50 ml of isopropanol and refluxed for five hours. Isopropanol was distilled off and the residue was recrystallized from n-hexane. A white powder, 21.3 g m.p. 97° to 99° C., was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.[F:12][C:13]1[CH:14]=[C:15]([CH:25]([NH:27][C:28]([C:30]2[N:31]=[C:32](Cl)[O:33][CH:34]=2)=[O:29])[CH3:26])[CH:16]=[C:17]([F:24])[C:18]=1[NH:19][S:20]([CH3:23])(=[O:22])=[O:21].C([O-])([O-])=O.[Cs+].[Cs+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:24][C:17]1[CH:16]=[C:15]([CH:25]([NH:27][C:28]([C:30]2[N:31]=[C:32]([C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=3[Cl:1])[O:33][CH:34]=2)=[O:29])[CH3:26])[CH:14]=[C:13]([F:12])[C:18]=1[NH:19][S:20]([CH3:23])(=[O:22])=[O:21]
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Reactant: OB(O)c1cccc(Cl)c1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(NC(=O)c1coc(-c2cccc(Cl)c2Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 14.1 %

Procedure:
2,3-Dichlorobenzeneboronic acid (49.6 mg, 0.26 mmol) and 2-chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted using Pd(PPh3)2Cl2 (7 mg, 0.01 mmol), Cs2CO3 (127 mg, 0.39 mmol) as described above to give the title compound (9 mg, 14%) after purification by flash chromatography on silica gel (hexane: EtOAc=1:1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[CH3:10][N:11]1[CH2:16][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:14][CH2:13][CH2:12]1>C(OCC)C.C1(C)C=CC=CC=1>[CH3:10][N:11]1[CH2:12][CH2:13][CH:14]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:15]([C:17]([O:19][CH3:20])=[O:18])[CH2:16]1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: COC(=O)C1=CCCN(C)C1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COC(=O)C1CN(C)CCC1c1ccc(F)cc1
Temperature: -5 °C
Reaction time: 1 h

Procedure:
A 2 molar solution of 4-fluorophenylmagnesium bromide in diethyl ether (5 ml, 2 molar equivalents) was stirred at −5 to −10° C. under nitrogen, and a solution of arecoline (0.78 g) in toluene (5.0 ml) added over 15 minutes at −5° C. The clear solution was stirred at −5° C. for 1 hour, then quenched by the addition of a mixture of water (25 ml) and concentrated hydrochloric acid (3 ml). Analysis of the aqueous phase by HPLC showed that yield of cis/trans 1-methyl-3-carbomethoxy-4-(4-fluorophenyl)-piperidine was about 905 mg (72 %).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:28][CH3:29])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][CH2:26]Cl)[N:9]=2)[CH:7]=1.Cl.[NH2:31][CH:32]1[CH2:36][CH2:35][O:34][CH2:33]1.C(N(CC)C(C)C)(C)C>CN1CCCC1=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:28][CH3:29])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][CH2:26][NH:31][CH:32]3[CH2:36][CH2:35][O:34][CH2:33]3)[N:9]=2)[CH:7]=1
Reactant: NC1CCOC1
Reactant: COc1ccc(Cl)cc1-c1nn(CCCl)cc1NC(=O)c1cnn2cccnc12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: COc1ccc(Cl)cc1-c1nn(CCNC2CCOC2)cc1NC(=O)c1cnn2cccnc12
Reaction time: 18 h
Yield: 30.7 %

Procedure:
A solution of N-(3-(5-chloro-2-methoxyphenyl)-1-(2-chloroethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (0.040 g, 0.090 mmol, 1 equiv), 3-aminotetrahydrofuran hydrochloride (29 mg, 0.23 mmol, 2.50 equiv), and N,N-diisopropylethylamine (73 μL, 0.42 mmol, 4.5 equiv) in N-methylpyrrolidinone (1 mL) was heated at 100° C. After 18 h, the reaction mixture was partitioned between ethyl acetate (10 mL) and half-saturated aqueous sodium chloride solution (10 mL). The aqueous was extracted with ethyl acetate (2×10 mL). The combined organic was dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by preparative HPLC provided product (13.3 mg, 30% yield). 1H NMR (400 MHz, DMSO-d6), δ: 9.67 (s, 1H), 9.32 (dd, J=7.0, 1.5 Hz, 1H), 8.77 (dd, J=4.2, 1.6 Hz, 1H), 8.65 (s, 1H), 8.31 (s, 1H), 7.49 (dd, J=8.9, 2.7 Hz, 1H), 7.40 (d, J=2.7 Hz, 1H), 7.27-7.30 (m, 2H), 4.21 (t, J=6.4 Hz, 2H), 3.85 (s, 3H), 3.60-3.76 (m, 4H), 3.38 (m, 2H), 2.96 (m, 2H), 1.96 (m, 1H), 1.62 (m, 1H). LCMS (ESI): M+H=482.2.
Reaction SMILES: [CH:1]([C:3]1[CH:15]=[CH:14][C:6]([O:7][CH2:8][C:9]([O:11]CC)=[O:10])=[CH:5][CH:4]=1)=[O:2].C(C1C=C(C=CC=1)OCC(O)=O)=O>>[CH:1]([C:3]1[CH:15]=[CH:14][C:6]([O:7][CH2:8][C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1)=[O:2]
Reactant: CCOC(=O)COc1ccc(C=O)cc1
Agent: O=Cc1cccc(OCC(=O)O)c1
Product: O=Cc1ccc(OCC(=O)O)cc1
Yield: 57 %

Procedure:
Ethyl 2-(4-formylphenoxy)acetate (52) was treated in an analogous manner to compound 48 to yield the desired product (57%) as a white solid. NMR: δ 4.834 (s, 2H), 7.112 (d, J=7.2 Hz, 2H), 7.866 (d, J=7.6 Hz, 2H), 9.878 (s, 1H), 13.146 (s, 1H).
Reaction SMILES: [K].[C:2]([O-:13])(=[O:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([O-:9])=[O:8])=[CH:5][CH:4]=1.C(=O)=O>O>[C:2]([OH:13])(=[O:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1
Reactant: O=C([O-])c1ccc(C(=O)[O-])cc1
Agent: O=C=O
Agent: [K]
Solvent: O
Product: O=C(O)c1ccc(C(=O)O)cc1

Procedure:
0.22 grams of a potassium salt of terephthalate was dissolved in 10.5 grams of deionized water in a 20 ml vial, and 5 grams of dry ice was added directly, and the vial was loosely capped. After two to three minutes, the solution became cloudy, and soon a large quantity of flocculent terephthalic acid precipitate was formed. After filtration, about 40% of the theoretical yield of terephthalic acid was recovered. The filtrate was a clear solution of potassium salts. The pH increased from about 6 when chilled before filtration to about 7 after the dry ice had all sublimed, and the solution warmed to room temperature, showing the presence of excess base after the CO2 had outgassed.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][C:13]1[N:14]([CH3:24])[CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:17]=1)[CH:6]=[O:7].C(O)C.[BH4-].[Na+].O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][OH:7])[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][C:13]1[N:14]([CH3:24])[CH:15]=[C:16]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:17]=1
Reactant: COc1cc(C=O)ccc1OCc1nc(-c2ccccc2)cn1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(CO)ccc1OCc1nc(-c2ccccc2)cn1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.4 %

Procedure:
To a solution of 3-methoxy-4-[(1-methyl-4-phenyl-1H-imidazol-2-yl)methoxy]benzaldehyde (1.37 g) in tetrahydrofuran (50 mL)-ethanol (10 mL) was gradually added sodium borohydride (0.16 g) at room temperature, and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture and the precipitated crystals were collected by filtration to give {3-methoxy-4-[(1-methyl-4-phenyl-1H-imidazol-2-yl)methoxy]phenyl}methanol as colorless crystals (1.15 g, yield 85%). Recrystallization from ethyl acetate-hexane gave colorless needle crystals. melting point: 126-127° C.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH:28]1([CH2:34][C@H:35]([N:39]2[CH2:47][C:46]3[C:41](=[CH:42][C:43]([Cl:49])=[C:44]([Cl:48])[CH:45]=3)[C:40]2=[O:50])[C:36](O)=[O:37])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.Cl.[NH2:52][C:53]1[S:54][C:55]([Br:58])=[CH:56][N:57]=1.C1(C[C@H](N2CC3C(=CC=CC=3)C2=O)C(NC2SC=CN=2)=O)CCCCC1>>[Br:58][C:55]1[S:54][C:53]([NH:52][C:36](=[O:37])[CH:35]([N:39]2[CH2:47][C:46]3[C:41](=[CH:42][C:43]([Cl:49])=[C:44]([Cl:48])[CH:45]=3)[C:40]2=[O:50])[CH2:34][CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]2)=[N:57][CH:56]=1
Reactant: O=C(O)[C@H](CC1CCCCC1)N1Cc2cc(Cl)c(Cl)cc2C1=O
Reactant: Nc1ncc(Br)s1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(Nc1ncc(Br)s1)C(CC1CCCCC1)N1Cc2cc(Cl)c(Cl)cc2C1=O
Yield: 40 %

Procedure:
This compound was prepared via BOP coupling of (S)-3-cyclohexyl-2-(5,6-dichloro-1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid (prepared in Example 4, Step C; 248 mg; 0.70 mmol) and 2-amino-5-bromothiazole hydrochloride (154 mg; 0.89 mmol) in a manner similar to that used for the preparation of (S)-3-cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl-propionamide (outlined in Example 1, Step B) to provide N-(5-Bromo-thiazol-2-yl)-3-cyclohexyl-2-(5,6-dichloro-1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide as a beige solid in 40% yield: EI-HRMS m/e calcd for C20H20BrCl2N3O2S (M+) 514.9837, found 514.9836.
Reaction SMILES: C(O)C.[CH2:4](Cl)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O.O.O.[CH2:15]([N:17]([CH2:21][CH3:22])[C:18](=[S:20])[S-:19])[CH3:16].[Na+]>O>[CH2:15]([N:17]([CH2:21][CH3:22])[C:18](=[S:19])[S:20][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:16]
Reactant: ClCc1ccccc1
Reactant: CCN(CC)C(=S)[S-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCN(CC)C(=S)SCc1ccccc1
Temperature: 25 °C
Reaction time: 23 h
Yield: 93 %

Procedure:
More specifically, 10 ml of ethanol solution containing benzyl chloride (4.8 g, 38 mmol, Mw. 126.58) was added dropwise into 50 ml of ethanol solution containing sodium N,N-diethyldithiocarbamate trihydrate (10.3 g, 46 mmol, Mw. 225.31) in nitrogen atmosphere at 0° C. After agitating the reaction solution for 23 hours at room temperature, 150 ml of water was added and extracted by diethylether (200 ml×3 times). The organic layer was washed with water (100 ml×3 times) and was dried by sodium sulfate. Solvent was distilled away under reduced pressure using an evaporator so as to obtain benzyl N,N-diethyldithiocarbamate (colorless liquid). Yield point was 17.6 g (yield: 93%), 1H-NMR: δ7.407 ppm to 7.271 ppm (m, 5H, Ar—H), δ4.540 ppm (s, 2H, Ar—CH2S), δ4.082 ppm to 4.012 ppm (q, 2H, —N—CH2—), δ3.763 ppm to 3.692 ppm (q, 2H, —N—CH2—), δ1.311 to 1.252 ppm (m, 6H, —CH2—CH3).
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]2[NH:15][CH:16]=[N:17][C:12]2=[CH:11][CH:10]=1)C1C=CC=CC=1.[CH3:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:24]=1[CH3:25]>>[CH3:18][C:19]1[CH:20]=[C:21]([N:15]2[C:13]3=[N:14][C:9]([OH:8])=[CH:10][CH:11]=[C:12]3[N:17]=[CH:16]2)[CH:22]=[CH:23][C:24]=1[CH3:25]
Reactant: c1ccc(COc2ccc3nc[nH]c3n2)cc1
Reactant: Cc1ccc(B(O)O)cc1C
Product: Cc1ccc(-n2cnc3ccc(O)nc32)cc1C

Procedure:
From 5-(benzyloxy)-3H-imidazo[4,5-b]pyridine and 3,4-dimethylphenylboronic acid, prepared in a similar manner as the one described in Example 1.26, the title compound was obtained. LCMS m/z=239.9 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:45])[C@H:4]([N:11]([S:31]([C:34]1[C:39]([CH3:40])=[CH:38][C:37]([O:41][CH3:42])=[C:36]([CH3:43])[C:35]=1[CH3:44])(=[O:33])=[O:32])[CH2:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[N:18](S(CC[Si](C)(C)C)(=O)=O)[CH:17]=[CH:16]2)[CH2:5][O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH3:1][O:2][C:3](=[O:45])[C@H:4]([N:11]([S:31]([C:34]1[C:39]([CH3:40])=[CH:38][C:37]([O:41][CH3:42])=[C:36]([CH3:43])[C:35]=1[CH3:44])(=[O:33])=[O:32])[CH2:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[CH:16]2)[CH2:5][O:6][C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: COC(=O)[C@@H](COC(C)(C)C)N(Cc1ccc2c(ccn2S(=O)(=O)CC[Si](C)(C)C)c1)S(=O)(=O)c1c(C)cc(OC)c(C)c1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)[C@@H](COC(C)(C)C)N(Cc1ccc2[nH]ccc2c1)S(=O)(=O)c1c(C)cc(OC)c(C)c1C
Temperature: 40 °C
Reaction time: 1 h
Yield: 75.9 %

Procedure:
To a solution of 2(R)-{(4-methoxy-2,3,6-trimethylbenzenesulfonyl)-[1-(2-trimethylsilylethanesulfonyl)indol-5-ylmethyl]amino}-3-tert-butoxypropionic acid methyl ester (1.63 g, 2.55 mmol) in tetrahydrofuran (50 mL) was added 1M tetrabutylammonium fluoride (6.4 mL, 6.4 mmol) in tetrahydrofuran, and the mixture heated to 40° C. After 1 h, the reaction mixture was partitioned between ethyl acetate and 1M hydrochloric acid. The ethyl acetate layer was separated, dried over magnesium sulfate, and concentrated. The residue was purified by preparative chromatography (20% ethyl acetate-hexanes), to afford 2(R)-{(4-methoxy-2,3,6-trimethylbenzenesulfonyl)-[1H-indol-5-ylmethyl]amino}-3-tert-butoxypropionic acid methyl ester (1 g) which was taken directly into the next reaction.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[F:35][C:36]([F:53])([F:52])[C:37]1[CH:42]=[CH:41][C:40]([CH:43]2[C:48]3[CH:49]=[CH:50][S:51][C:47]=3[CH2:46][CH2:45][NH:44]2)=[CH:39][CH:38]=1.C(N(C(C)C)CC)(C)C>CN(C)C=O.O>[F:53][C:36]([F:35])([F:52])[C:37]1[CH:38]=[CH:39][C:40]([CH:43]2[C:48]3[CH:49]=[CH:50][S:51][C:47]=3[CH2:46][CH2:45][N:44]2[C:7]([C:6]2[CH:5]=[CH:4][C:3]([N:2]([CH3:1])[CH3:12])=[CH:11][CH:10]=2)=[O:9])=[CH:41][CH:42]=1
Reactant: FC(F)(F)c1ccc(C2NCCc3sccc32)cc1
Reactant: CN(C)c1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)c1ccc(C(=O)N2CCc3sccc3C2c2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4-Dimethylaminobenzoic acid (0.20 g, 1.2 mmol) was dissolved in N,N-dimethylformamide (3 ml) and 1-hydroxybenzotriazole (0.20 g, 1.5 mmol) was added. To the resulting mixture N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.28 g, 1.5 mmol) was added and the mixture was stirred at room temperature for 15 minutes. 4-(4-Trifluoromethylphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine (0.41 g, 1.5 mmol) followed by diisopropylethylamine (0.42 ml, 2.4 mmol) were added and the mixture was stirred at room temperature for 16 hours. water (2 ml) was added and the mixture was extracted with ethyl acetate (2×5 ml). The combined organic extracts were washed with saturated aqueous sodium chloride solution (4 ml), dried (MgSO4) and concentrated in vacuo to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>>[C:12]([NH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1)(=[O:14])[CH3:13]
Reactant: Cc1cc(N)ncc1[N+](=O)[O-]
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1cc(C)c([N+](=O)[O-])cn1
Yield: 93 %

Procedure:
2-Amino-4-methyl-5-nitropyridine (28.4 g, 0.185 mol) was heated at 90° C. in acetic anhydride (100 mL) for 3 hours. After cooling the solvent was evaporated in vacuo and the residue was azeotroped with toluene to give a yellow solid. This was triturated with ether and the solid was collected by filtration to give the title compound (33.8 g, 93%) as a pale yellow solid. mp 153°-154° C. 1H NMR (360 MHz, CDCl3) δ 2.27 (3H, s), 2.70 (3H, s), 8.17 (1H, br s), 8.24 (1H, s) and 8.96 (1H, s).
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)=[CH:6][CH:5]=1.[OH-].[Na+]>C(O)C>[N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:20]=[CH:21][C:12]=1[CH2:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:22])=[O:2])=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(OCc2ccc3ccccc3n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(OCc2ccc3ccccc3n2)cc1
Yield: 65.5 %

Procedure:
5.00 g of methyl-4-(quinolin-2-ylmethoxy)benzoate is dissolved in 120 ml of ethanol and 90 ml of 1 N sodium hydroxide and the mixture is stirred at room temperature for 4 days. The mixture is concentrated in vacuo to remove the ethanol. The residue is diluted with water, acidified to pH 6 and the resulting solid is filtered off and recrystallized from methanol to give 3.12 g 4-(quinolin-2-ylmethoxy)benzoic acid.
Reaction SMILES: [C:1]12([CH2:11][OH:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[Cl:13][C:14]1[C:15](Cl)=[N:16][CH:17]=[C:18]([CH:22]=1)[C:19]([OH:21])=[O:20].CC(C)([O-])C.[K+]>CS(C)=O.C(OCC)(=O)C.Cl>[C:1]12([CH2:11][O:12][C:15]3[C:14]([Cl:13])=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][N:16]=3)[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Reactant: OCC12CC3CC(CC(C3)C1)C2
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=C(O)c1cnc(OCC23CC4CC(CC(C4)C2)C3)c(Cl)c1
Temperature: 80 °C
Yield: 42 %

Procedure:
A mixture of 1-adamantylmethanol (5.32 g, 32.00 mmol), 5,6-dichloronicotinic acid (6.14 g, 32.00 mmol) and potassium tert-butoxide (8.3 g, 73.60 mmol) in anhydrous dimethyl sulfoxide (100 mL) was heated to 80° C. under nitrogen for 1 h. The reaction mixture was cooled to ambient temperature and diluted with ethyl acetate (500 mL) and 1.0 M aqueous hydrochloric acid (300 mL). The layers were separated and the organic layer was washed with 1.0 M aqueous hydrochloric acid (100 mL), brine (2×100 mL); dried over anhydrous sodium sulfate; filtered and concentrated in vacuo. The residue was triturated with diethyl ether to afford the title compound as a white solid (4.32 g, 42%); 1H NMR (300 MHz, DMSO-d6) 13.23 (br s, 1H), 8.56 (d, J=2.0 Hz, 1H), 8.14 (d, J=2.0 Hz, 1H), 3.95 (s, 1H), 2.00-1.88 (m, 3H), 1.71-1.50 (m, 12H); MS (ES−) m/z: 320.3, 322.3 (M−1).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:24][S:21]([C:18]1[CH:19]=[CH:20][C:15]([NH:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[N:16][CH:17]=1)(=[O:22])=[O:23]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(S(C)(=O)=O)cn2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc(NC2CCNCC2)nc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 74.1 %

Procedure:
To a stirred solution of 4-(5-methanesulfonyl-pyridin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (1.00 g, 2.8 mmol, 1.0 equiv) in ethanol (18 mL) was added 4 M HCl in dioxane (3.52 mL, 14.1 mmol, 5.0 equiv) drop by drop and the reaction mixture stirred at 50° C. for 2 h. It was then cooled down to rt, poured into ice water and the pH adjusted to 9-10 by addition of a sat. solution of potassium carbonate. The solution was extracted six times with a mixture of dichloromethane/isopropanol (4:1). The combined organic layers were concentrated by evaporation under reduced pressure and the crude product was purified by crystallization from heptane to give 0.53 g (74%) of the title compound as colorless solid. MS (ISP): 256.2 [M+H]+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[S:6][C:7]([C@@H:10]([NH:13]S(C(C)(C)C)=O)[CH2:11][CH3:12])=[CH:8][N:9]=1)(=[O:4])=[O:3].[ClH:20]>CO.O1CCOCC1>[ClH:20].[CH3:1][S:2]([C:5]1[S:6][C:7]([C@@H:10]([NH2:13])[CH2:11][CH3:12])=[CH:8][N:9]=1)(=[O:3])=[O:4]
Reactant: CC[C@H](NS(=O)C(C)(C)C)c1cnc(S(C)(=O)=O)s1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC[C@H](N)c1cnc(S(C)(=O)=O)s1
Reaction time: 1 h

Procedure:
To a solution of 2-methyl-propane-2-sulfinic acid [(S)-1-(2-methanesulfonyl-thiazol-5-yl)-propyl]-amide (80 mg, 0.3 mmol) in methanol (5 mL) was added a 4 N solution of hydrochloric acid (1 mL, 4 mmol) in dioxane. After 1 hour, the mixture was concentrated and diluted with dichloromethane (2 mL) followed by hexanes (10 mL), and concentrated to afford (S)-1-(2-methanesulfonyl-thiazol-5-yl)-propylamine hydrochloride.
Reaction SMILES: Cl.[CH2:2]([N:5]([CH2:38][CH2:39][CH3:40])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH2:32][C:33]2[NH:34][CH:35]=[CH:36][N:37]=2)[CH2:25][C:26]2[N:27]([CH3:31])[CH:28]=[CH:29][N:30]=2)=[CH:19][CH:18]=1)[CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH2:3][CH3:4].[CH3:41][CH:42](O)[CH3:43]>>[CH:42]([O:14][C:13](=[O:15])[CH2:12][CH2:11][N:10]([CH2:9][CH2:8][CH2:7][CH2:6][N:5]([CH2:2][CH2:3][CH3:4])[CH2:38][CH2:39][CH3:40])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH2:32][C:33]2[NH:34][CH:35]=[CH:36][N:37]=2)[CH2:25][C:26]2[N:27]([CH3:31])[CH:28]=[CH:29][N:30]=2)=[CH:19][CH:18]=1)([CH3:43])[CH3:41]
Reactant: CC(C)O
Reactant: CCCN(CCC)CCCCN(CCC(=O)O)Cc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1
Agent: Cl
Product: CCCN(CCC)CCCCN(CCC(=O)OC(C)C)Cc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1

Procedure:
The hydrochloride (88.0 mg) of the compound obtained in Example 51-1 was added with 2-propanol (10 ml) and the whole was refluxed under heating for 2 hours. After completion of the reaction, the solvent was distilled off. The resultant was dissolved in chloroform and added with a saturated aqueous sodium hydrogen carbonate solution and the whole was stirred for a while. The solution was subjected to extraction with chloroform and washed with a saturated saline solution. The organic layer was dried with anhydrous sodium sulfate. The solvent was distilled off. The residue was purified through silica gel column chromatography (chloroform/ethyl acetate), thereby obtaining the subject compound (32.8 mg) as a colorless oily substance.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[CH3:32][O:33][CH2:34][C:35](Cl)=[O:36]>>[CH3:32][O:33][CH2:34][C:35]([NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:30][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)=[O:36]
Reactant: Cc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c[nH]c23)c1
Reactant: COCC(=O)Cl
Product: COCC(=O)N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4cc(C)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from trans-4-(2-cyclopropylmethoxy-5-methyl-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A170) and methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:15])[CH2:13][CH3:14])=[C:5]2Cl.[CH3:17][N:18]([CH2:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1)[CH3:19]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:15])[CH2:13][CH3:14])=[C:5]2[NH:25][C:24]1[CH:23]=[CH:22][C:21]([CH2:20][N:18]([CH3:19])[CH3:17])=[CH:27][CH:26]=1
Reactant: CN(C)Cc1ccc(N)cc1
Reactant: CCC(=O)c1cnc2ccc(Br)cc2c1Cl
Product: CCC(=O)c1cnc2ccc(Br)cc2c1Nc1ccc(CN(C)C)cc1
Yield: 85.9 %

Procedure:
Following general procedure C, 1-(6-bromo-4-chloroquinolin-3-yl)propan-1-one (750 mg, 2.51 mmol) was reacted with 4-(dimethylaminomethyl)aniline (377 mg, 2.51 mmol) to afford the desired product (889 mg, 86%) as a yellow solid. APCI MS m/z 412 [C21H22BrN3O+H]+.