Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:44]=[CH:43][CH:42]=[CH:41][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]2[O:30][CH2:31][C:32](=[O:40])[NH:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:13][CH:12]=1.Cl[CH2:46][CH2:47][CH2:48][CH2:49][O:50][CH3:51]>>[CH3:1][O:2][C:3]1[CH:44]=[CH:43][CH:42]=[CH:41][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]2[O:30][CH2:31][C:32](=[O:40])[N:33]([CH2:46][CH2:47][CH2:48][CH2:49][O:50][CH3:51])[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[CH:15][CH:16]=1
Reactant: COCCCCCl
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCC(=O)Nc2ccccc2)cc1
Product: COCCCCN(C(=O)COC1CN(C(=O)OC(C)(C)C)CCC1c1ccc(OCCCOCc2ccccc2OC)cc1)c1ccccc1

Procedure:
Analogously to Example 2c, 0.49 g of tert-butyl 4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}-3-phenylcarbamoylmethoxypiperidine-1-carboxylate (Example 62b) and 0.37 g of 1-chloro-4-methoxybutane are reacted. The title compound is obtained as a yellow oil. Rf=0.20 (1:1 EtOAc-heptane); Rt=5.89.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH2:10]([N:2]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)CCN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CCN(Cc1ccccc1)Cc1ccccc1
Yield: 97 %

Procedure:
Heat a solution of ethyl 3-aminopropanoate hydrochloride (80.0 g, 0.52 mol), benzylbromide (186.7 g, 1.1 mol) and K2CO3 (179.4 g, 1.3 mol) in acetonitrile (1 L) at 40° C. overnight. Concentrate the mixture to dryness, treat with water, extract with EtOAc (3×), wash the combined organics with brine, dry over Na2SO4, concentrate to dryness and purify via silica gel chromatography chromatography (Pet Ether/EtOAc, 50:1) to afford the title compound (150 g, 97% yield). 1H NMR (400 MHz, CDCl3): δ 7.35-7.21 (m, 10H), 4.09 (q, J=7.2 Hz, 2H), 3.58 (s, 4H), 2.82 (t, J=7.2 Hz, 2H), 2.50 (t, J=7.2 Hz, 2H), 1.21 (t, J=7.2 Hz, 3H).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[C:27]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2>CN(C=O)C.C1COCC1>[Br:1][C:24]1[CH:25]=[CH:26][C:27]2[N:15]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]=3)[C:16]3[C:21]([C:22]=2[CH:23]=1)=[CH:20][CH:19]=[CH:18][CH:17]=3
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc(-n2c3ccccc3c3ccccc32)nc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Brc1ccc2c(c1)c1ccccc1n2-c1ccccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-bromosuccinimide (17.8 g, 100 mmol) in DMF (50 mL) was added slowly to 9-(pyridin-2-yl)-9H-carbazole (24 g, 100 mmol) in THF (250 mL) at 0° C. over 30 min. The reaction was allowed to warm to room temperature and stir overnight. The reaction mixture was then evaporated and extracted with dichloromethane, and the organic layer was dried over magnesium sulfate and the solvent was then evaporated. The residue was then purified by column using toluene:hexane (1:1, v/v) as eluent and the product was further purified by recrystallization from toluene:ethanol (1:1, v/v), and after cooling, 24.3 g (75%) of the product was collected as a white solid after filtration.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]([OH:15])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14].[C:16]1([C:22]2[N:31]=[C:30](Cl)[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CO.[OH-].[Na+]>O>[OH2:6].[CH3:14][O:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[O:6][CH2:5][CH:4]([OH:15])[CH2:3][NH:2][C:30]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=[C:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:31]=1
Reactant: COc1ccccc1OCC(O)CN
Reactant: Clc1nc(-c2ccccc2)nc2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccccc1OCC(O)CNc1nc(-c2ccccc2)nc2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.6 %

Procedure:
A mixture containing 5.8 g (0.025 mole) of 1-amino-3-ortho-methoxyphenoxy 2-propanol hydrochloride, 6 g (0.025 mole) of 2-phenyl-4-chloroquinazoline, 150 ml of methanol, 1.0 g of sodium hydroxide (in one ml of water) was refluxed for 6 hrs. Another one gram of sodium hydroxide (in one ml of water) was added and refluxing was continued for 2 hrs. The resulting reaction mixture was cooled to room temperature and filtered. The gummy substance which as obtained when the filtrate was mixed with 300 ml of water was separated, washed with water, then dissolved in acetone. The acetone solution was treated with one ml of 12 N hydrochloric acid and the white crystalline precipitate was separated, dissolved in water, adjusted to pH=7.5. A white crystalline solid was obtained. This crystalline solid was recrystallized with methanol and water to give 1.5 g of the title compound, m.p. 138°-140° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:20]([Cl:21])=[CH:19][C:18]([Cl:22])=[CH:17][C:16]=4[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24](Cl)[C:25]([F:28])([F:27])[F:26])=[CH:4][CH:3]=1.[N-:30]=[N+:31]=[N-:32].[Na+]>CS(C)=O.C(OCC)(=O)C>[N:30]([CH:24]([C:5]1[C:6]2[N:7]3[CH2:14][CH2:13][CH2:12][N:11]([C:15]4[C:16]([Cl:23])=[CH:17][C:18]([Cl:22])=[CH:19][C:20]=4[Cl:21])[C:8]3=[N:9][C:10]=2[C:2]([Cl:1])=[CH:3][CH:4]=1)[C:25]([F:27])([F:28])[F:26])=[N+:31]=[N-:32]
Reactant: FC(F)(F)C(Cl)c1ccc(Cl)c2nc3n(c12)CCCN3c1c(Cl)cc(Cl)cc1Cl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: [N-]=[N+]=NC(c1ccc(Cl)c2nc3n(c12)CCCN3c1c(Cl)cc(Cl)cc1Cl)C(F)(F)F
Temperature: 100 °C
Reaction time: 2 h
Yield: 97.2 %

Procedure:
A mixture of 9-chloro-6-(1-chloro-2,2,2-trifluoroethyl)-1-(2,4,6-trichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole (290 mg, 0.576 mmol) and sodium azide (74.9 mg, 1.15 mmol) in dimethylsulfoxide (2.8 mL) was stirred at 100° C. for 2 h. After the mixture was diluted with ethyl acetate, the resultant mixture was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 0-30% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless amorphous solid (286 mg, 0.560 mmol, 97%).
Reaction SMILES: [N+:1]([C:4]1[N:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O>C1COCC1.[Ni]>[N:10]1([C:7]2[CH:8]=[N:9][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: O=[N+]([O-])c1ccc(N2CCCCC2)cn1
Agent: [Ni]
Solvent: C1CCOC1
Product: Nc1ccc(N2CCCCC2)cn1
Reaction time: 4 h
Yield: 121.3 %

Procedure:
6′-Nitro-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl (4.69 g, 22.6 mmol) was dissolved in THF (100 mL) to which Raney Nickel (1.08 g) was added. The reaction was shaken under a hydrogen atmosphere (50 psi) for 4 hours. The catalyst was removed by filtration and the solvent evaporated to give 3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-ylamine as a purple solid (4.86 g, 85.7%). 1H NMR δ(400 MHz, CDCl3) 7.76 (d, J=2.4 Hz, 1H), 7.19 (dd, J=2.9, 8.8 Hz, 1H), 6.47 (dd, J=0.7, 8.8 Hz, 1H), 4.18 (s, 2H), 2.97 (m, 4H), 1.71 (m, 4H), 1.53 (m, 2H).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)C(C)C)C.[F:22][C:23]1[CH:31]=[C:30]([F:32])[C:29]([F:33])=[CH:28][C:24]=1[C:25]([OH:27])=O.[CH3:34][CH:35]([S:38]([NH2:41])(=[O:40])=[O:39])[CH2:36][CH3:37]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH:35]([S:38]([NH:41][C:25](=[O:27])[C:24]1[CH:28]=[C:29]([F:33])[C:30]([F:32])=[CH:31][C:23]=1[F:22])(=[O:40])=[O:39])([CH2:36][CH3:37])[CH3:34]
Reactant: O=C(O)c1cc(F)c(F)cc1F
Reactant: CCC(C)S(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC(C)S(=O)(=O)NC(=O)c1cc(F)c(F)cc1F
Reaction time: 18 h
Yield: 46 %

Procedure:
N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.41 g, 2.1 mmol), 4-dimethylaminopyridine (0.26 g, 2.1 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.9 mL, 4.2 mmol) were added to a solution of 2,4,5-trifluorobenzoic acid (0.25 g, 1.4 mmol) in DCM. After 10 minutes butane-2-sulfonamide (Preparation 29, 0.29 g, 2.1 mmol) was added and the reaction was left at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and the residue purified by preparative HPLC to yield the title compound as a white solid (0.19 g, 31% yield):
Reaction SMILES: C([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][S:28][CH2:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Li+]>CO.O>[CH3:26][C:23]1[C:22]([CH2:27][S:28][CH2:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[C:21]([C:18]2[CH:19]=[CH:20][C:15]([C:12]3[CH:11]=[CH:10][C:9]([C:6]4([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]4)=[CH:14][CH:13]=3)=[CH:16][CH:17]=2)[O:25][N:24]=1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CSCCc4ccccc4)cc3)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1CSCCc1ccccc1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
To 1-[4′-(3-methyl-4-phenethylsulfanylmethyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester (1.13 mmol) in MeOH and H2O was added lithium hydroxide (excess) and the reaction was stirred at 70° C. for 3 hours. After acidic workup, the crude material was purified by silica gel chromatography to give the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[C:6]([O:10][C:11](SC1N=C(C)C=C(C)N=1)=[O:12])([CH3:9])([CH3:8])[CH3:7]>CO>[C:6]([O:10][C:11]([NH:1][CH2:2][CH2:3][CH2:4][OH:5])=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: NCCCO
Reactant: Cc1cc(C)nc(SC(=O)OC(C)(C)C)n1
Solvent: CO
Product: CC(C)(C)OC(=O)NCCCO
Reaction time: 6 h
Yield: 84.2 %

Procedure:
Into 30 ml of methanol, was dissolved 1.5 g (20 mmoles) of 3-amino-1-propanol followed by the addition of 4.8 g (20 mmoles) of S-tert-butoxycarbonyl-4,6-dimethyl-2-mercaptopyrimdine (a product of Kokusan Kagaku Co.). After stirring for 6 hours, the reaction mixture was evaporated to drynes, dissolved in 200 ml of chloroform, and washed with 200 ml of water. The chloroform layer was concentrated and subjected to column chromatography using 300 g of silica gel (Wako Gel® C-200) and a toluene-ethyl acetate (1:1 by volume) mixture as a developing solvent. The Fraction Nos. 82 to 151 (each 15 ml in volume) were combined and evaporated to obtain 2.95 g (84% yield) of 3-tert-butoxycarbonylamino-1-propanol in the form of colorless oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:78])[CH2:7][CH2:8][C@H:9]([C:40](=[O:77])[NH:41][C@@H:42]([C:64](=[O:76])[NH:65][C:66]1([CH:69]([OH:75])[CH2:70][C:71]([O:73]C)=[O:72])[CH2:68][CH2:67]1)[CH2:43][S:44][C:45]([C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[NH:10][C:11](=[O:39])[CH2:12][C@H:13]([OH:38])/[CH:14]=[CH:15]/[CH2:16][CH2:17][S:18][C:19]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>C1COCC1.O>[C:1]([O:5][C:6](=[O:78])[CH2:7][CH2:8][C@H:9]([C:40](=[O:77])[NH:41][C@@H:42]([C:64](=[O:76])[NH:65][C:66]1([CH:69]([OH:75])[CH2:70][C:71]([OH:73])=[O:72])[CH2:67][CH2:68]1)[CH2:43][S:44][C:45]([C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)([C:58]1[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=1)[C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1)[NH:10][C:11](=[O:39])[CH2:12][C@H:13]([OH:38])/[CH:14]=[CH:15]/[CH2:16][CH2:17][S:18][C:19]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CC(O)C1(NC(=O)[C@@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)NC(=O)[C@@H](CCC(=O)OC(C)(C)C)NC(=O)C[C@H](O)/C=C/CCSC(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)CC[C@@H](NC(=O)C[C@H](O)/C=C/CCSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)N[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)NC1(C(O)CC(=O)O)CC1
Reaction time: 3.25 h
Yield: 86.2 %

Procedure:
To 7 (927.1 mg, 0.850 mmol) in THF (12 mL) at 0° C. was added LiOH (30.6 mg, 1.28 mmol) in water (3 mL) and the reaction mixture was stirred for 3.25 h. The mixture was then quenched with 1M HCl (aq) (20 mL), diluted with water (20 mL), and treated with EtOAc (60 mL). The layers were separated, and the product was extracted with EtOAc (3×60 mL). The organic layers were combined, washed with saturated brine (50 mL), dried (MgSO4), and concentrated in vacuo to give the product 8 (789.1 mg, 86%) as a white solid (diastereoisomers 1:1 ratio). Compound 8 was used in the next step further purification [MS (ES+) 1097.4 (100%, [M+Na]+)].
Reaction SMILES: Cl[C:2]1[N:6]=[CH:5][N:4]([C:7]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[N:8]=2)[N:3]=1.[NH2:27][C:28]1[CH:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][N:29]=1>>[F:14][C:13]([F:16])([F:15])[C:11]1[CH:10]=[C:9]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[N:8]=[C:7]([N:4]2[CH:5]=[N:6][C:2]([C:31]3[CH:32]=[CH:33][C:28]([NH2:27])=[N:29][CH:30]=3)=[N:3]2)[CH:12]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)cc(-n3cnc(Cl)n3)n2)cc1
Product: Nc1ccc(-c2ncn(-c3cc(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)n3)n2)cn1

Procedure:
The title compound was prepared from 2-(3-chloro-[1,2,4]triazol-1-yl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyridine (example E.92) (0.314 g, 0.8 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.176 g, 0.8 mmol) according to the general procedure VI. Obtained as a white solid (0.027 g, 8%). MS (ISP) 451.2 [(M+H)+].
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C:7](=[O:12])[CH2:6][CH2:5]2.Cl[C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][N:15]=1.C([O-])([O-])=O.[K+].[K+]>>[O:1]=[C:2]1[CH2:11][CH2:10][C:9]2[CH:8]=[C:7]([O:12][C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][N:15]=3)[CH:6]=[CH:5][C:4]=2[CH2:3]1
Reactant: O=C1CCc2cc(O)ccc2C1
Reactant: NC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: NC(=O)c1ccc(Oc2ccc3c(c2)CCC(=O)C3)nc1
Yield: 49 %

Procedure:
Using a method similar to Intermediate 1, using 6-hydroxy-2-tetralone (Journal of Organic Chemistry (1999), 64(26), 9719-9721.) (1.55 g, 9.55 mmol), 6-chloronicotinamide (1.49 g, 9.55 mmol) and K2CO3 (1.98 g, 14.3 mmol) gives the title compound (1.32 g), after purification on silica gel (50% THF/DCM), as an amber foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[C:5]([OH:7])=O.[C:15](N)(=O)C1C=CC=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5](=[O:7])[CH3:15])[CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12]
Reactant: COc1cc(C(=O)O)cc(Cl)c1OC
Reactant: NC(=O)c1ccccc1
Product: COc1cc(C(C)=O)cc(Cl)c1OC

Procedure:
3-Chloro-4,5-dimethoxybenzoic acid (1 g) was converted to the benzamide derivative analogously to O3.043, and the latter to the title compound analogously to O2.059. 495 mg of the title compound were obtained. LC-MS rt: 1.55 min [M+H]+: 215.1 (met. a)
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C@:3]([C:7]1[N:8]=[N:9][N:10]([CH2:12][C:13]2[CH:22]=[C:21]3[C:16]([C:17]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)=[CH:18][C:19]([CH:23]([OH:25])[CH3:24])=[N:20]3)=[CH:15][CH:14]=2)[CH:11]=1)([OH:6])[CH2:4][CH3:5].I[CH3:36].[H-].[Na+]>C1COCC1>[F:34][C:2]([F:1])([F:33])[C@:3]([C:7]1[N:8]=[N:9][N:10]([CH2:12][C:13]2[CH:22]=[C:21]3[C:16]([C:17]([C:26]4[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=4)=[CH:18][C:19]([CH:23]([O:25][CH3:36])[CH3:24])=[N:20]3)=[CH:15][CH:14]=2)[CH:11]=1)([OH:6])[CH2:4][CH3:5]
Reactant: CC[C@](O)(c1cn(Cc2ccc3c(-c4ccc(F)cc4)cc(C(C)O)nc3c2)nn1)C(F)(F)F
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC[C@](O)(c1cn(Cc2ccc3c(-c4ccc(F)cc4)cc(C(C)OC)nc3c2)nn1)C(F)(F)F
Reaction time: 2 h

Procedure:
To a solution of (S)-1,1,1-trifluoro-2-(1-{[4-(4-fluorophenyl)-2-(1-hydroxyethyl)quinolin-7-yl]methyl}-1H-1,2,3-triazol-4-yl)butan-2-ol (33 mg, 0.070 mmol) in THF (1 mL) was added iodomethane (5 μL, 0.077 mmol) and sodium hydride 60% in oil (6 mg, 0.15 mmol). After 2 h at rt, the reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduce pressure. Purification on silica gel (eluting with acetone/dichloromethane, 2:8) gave the title compound. MS (+ESI): 490 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[N:15]=[CH:14][CH:13]=[C:12]2Cl)C1C=CC=CC=1>C(N(CC)CC)C.CN(C)C=O.[OH-].[Pd+2].[OH-]>[OH:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[N:15]=[CH:14][CH:13]=[CH:12]2
Reactant: COc1cc2nccc(Cl)c2cc1OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc2ncccc2cc1O
Temperature: 25 °C
Reaction time: 6 h
Yield: 84.1 %

Procedure:
6-Benzyloxy-4-chloro-7-methoxy-quinoline (525 mg) was dissolved in triethylamine/N,N-dimethylformamide (5 ml/20 ml) to prepare a solution. 20% palladium hydroxide (1.52 g) was added to the solution, and the mixture was stirred at room temperature under a hydrogen gas atmosphere for 6 hr. The reaction solution was filtered, and the solvent was then removed by distillation under the reduced pressure. Water was added to the residue, the mixture was extracted with chloroform, and the chloroform layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-chloroform to give 6-hydroxy-7-methoxyquinoline (258 mg, yield 84%).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])[N:3]=1.[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C.ClCCl>[C:11]1([CH:9]([O:8][C:4]2[CH:5]=[N:6][CH:7]=[C:2]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:3]=2)[CH3:10])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C1CNCCN1
Reactant: CC(Oc1cncc(Cl)n1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: CC(Oc1cncc(N2CCNCC2)n1)c1ccccc1
Temperature: 90 °C

Procedure:
A mixture of the product from step 1 above (1.53 g, 6.5 mmol), piperazine (1.62 g, 18.9 mmol) and K2CO3 (0.90 g, 6.5 mmol) in acetonitrile (6 mL) was heated in a sealed pyrex flask at 90° C. for 3.5 h. The reaction mixture was diluted with dichloromethane, filtered and concentrated in vacuo. The semi-solid residue was purified by silica gel chromatography (13×4 cm) using CHCl3/MeOH (9:1) as eluent. Solvents were evaporated off and the remaining oil was redissolved in CHCl3, filtered through a short plug of alumina and concentrated in vacuo. This gave 1.34 g (72%) of the title compound as an oil that solidified when refrigerated. HRMS m/z calcd for C16H20N4O (M)+ 284.1637, found 284.1650. Anal. (C16H20N4O.C4H4O4) C, H, N.
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]=[C:5]([C:10]([NH:12][C@H:13]2[CH2:18][CH2:17][NH:16][CH2:15][C@H:14]2[O:19][CH2:20][CH3:21])=[O:11])[NH:6][C:7]=1[CH2:8][CH3:9].Cl[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.C(OCC)(=O)C>[Cl:2][C:3]1[N:4]=[C:5]([C:10]([NH:12][C@H:13]2[CH2:18][CH2:17][N:16]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[CH2:15][C@H:14]2[O:19][CH2:20][CH3:21])=[O:11])[NH:6][C:7]=1[CH2:8][CH3:9]
Reactant: CCO[C@@H]1CNCC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Reactant: Clc1ccccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCO[C@@H]1CN(c2ccccn2)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Yield: 3.5 %

Procedure:
cis(±)-4-Chloro-N-(3-ethoxypiperidin-4-yl)-5-ethyl-1H-imidazole-2-carboxamide hydrochloride obtained in Example (131a) (100 mg, 0.297 mmol), 2-chloropyridine (0.035 mL, 0.37 mmol) and sodium carbonate (157 mg, 1.48 mmol) were suspended in DMF (1 mL), and the suspension was heated using a microwave reactor at 180° C. for 30 minutes. The reaction solution was diluted with ethyl acetate, washed with water and brine, and dried over anhydrous sodium sulfate. Following concentration under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=7/3→1/0) to obtain 3.9 mg of the title compound as a white amorphous solid (3%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:18]=[CH:17][O:16][C:15]=2[CH2:19][O:20]S(C2C=CC(C)=CC=2)(=O)=O)[CH2:10][CH2:9]1)=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+].[C:37]1(O)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.[C:44]([OH:50])([C:46]([F:49])([F:48])[F:47])=[O:45]>CC#N>[O:20]([CH2:19][C:15]1[O:16][CH:17]=[CH:18][C:14]=1[CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.[C:44]([OH:50])([C:46]([F:49])([F:48])[F:47])=[O:45]
Reactant: Oc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OCc2occc2C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(OCc2occc2C2CCNCC2)cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
4-[2-(Toluene-4-sulfonyloxymethyl)furan-3-yl]piperidine-1-carboxylic acid t-butyl ester (65 mg, 0.15 mmol, 1.0 eq.) was dissolved in MeCN (770 μL) and added to a mixture of potassium carbonate (32 mg, 230 mmol, 1.6 eq.) and phenol (21.1 mg, 224 μmol, 1.5 eq.). The resulting mixture was shaken at 50° C. overnight. The mixture was then cooled and the solids removed. The supernatant was combined with TFA (12 μL, 160 mmol, 1.0 eq.) and the resulting mixture was shaken overnight at room temperature. The solution was concentrated using an evaporator, then dissolved in 1:1 AcOH:H2O (5.0 mL) then an additional 2.0 ml AcOH, filtered, and purified by preparative HPLC to yield the title compound as a TFA salt (1.4 mg, 88% purity). MS m/z: [M+H]+ calcd for C16H19NO2, 258.14. found 258.2.
Reaction SMILES: C(O[C:6](=[O:18])[CH2:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([S:16][CH3:17])[N:11]=1)=O)(C)(C)C.Cl.Cl.[NH:21]1[CH2:25][CH2:24][CH2:23][NH:22]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:17][S:16][C:12]1[N:11]=[C:10]([C:8]2[N:22]3[CH2:23][CH2:24][CH2:25][N:21]3[C:6](=[O:18])[CH:7]=2)[CH:15]=[CH:14][N:13]=1
Reactant: CSc1nccc(C(=O)CC(=O)OC(C)(C)C)n1
Reactant: C1CNNC1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CSc1nccc(-c2cc(=O)n3n2CCC3)n1
Reaction time: 4 h

Procedure:
To a solution of 3-(2-methylsulfanyl-pyrimidin-4-yl)-3-oxo-propionic acid tert-butyl ester, 19, (6.8 g, 25.4 mmol), pyrazolidine-bishydrochloride (5.5 g, 38.1 mmol) and 4-angstrom molecular sieves (8.5 g) in toluene is added triethylamine (10.6 mL, 76.1 mmol). The reaction mixture is stirred for 4 hours at reflux. The solution is filtered through celite and washed with ether. The resulting yellow solid is purified over silica (10% MeOH/chloroform) to afford 5 g of the desired product as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 8.72 (d, J=5.1 Hz, 1H), 7.62 (d, J=5.1 Hz, 1H), 6.08 (s, 1H), 4.26 (t, J=7.5 Hz, 2H), 3.80 (t, J=7.8 Hz, 2H), 2.62 (dddd, J=7.5, 7.5, 7.5, 7.5 Hz, 2H), 2.60 (s, 3H); ESI+ MS: m/z (rel intensity) 249.1 (70, M++H).