Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[OH:2][C:3]1[C:4]([O:25][CH3:26])=[CH:5][C:6]2[CH2:15][CH:14]3[N:9]([CH2:10][CH2:11][C:12]4[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[CH:16][C:13]=43)[CH2:8][C:7]=2[CH:24]=1.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:35]=[C:36]([O:40][CH3:41])[C:37]=1[O:38][CH3:39])[C:32](Cl)=O>N1C=CC=CC=1>[CH3:23][O:22][C:17]1[C:18]([O:20][CH3:21])=[CH:19][C:12]2[CH2:11][CH2:10][N:9]3[CH:14]([CH2:15][C:6]4[CH:5]=[C:4]([O:25][CH3:26])[C:3]([O:2][CH2:32][C:31]5[CH:35]=[C:36]([O:40][CH3:41])[C:37]([O:38][CH3:39])=[C:29]([O:28][CH3:27])[CH:30]=5)=[CH:24][C:7]=4[CH2:8]3)[C:13]=2[CH:16]=1
Reactant: COc1cc2c(cc1O)CN1CCc3cc(OC)c(OC)cc3C1C2
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Agent: Cl
Solvent: c1ccncc1
Product: COc1cc2c(cc1OC)C1Cc3cc(OC)c(OCc4cc(OC)c(OC)c(OC)c4)cc3CN1CC2
Yield: 45.8 %

Procedure:
1.9 g of 10-hydroxy-2,3,11-trimethoxy-5,6,13,13a-tetrahydro-8H-dibenzo[a, g]quinolizine hydrochloride was treated in the same manner as described in Example 6, using 2.0 g of 3,4,5-trimethoxybenzoyl chloride and 200 ml of anhydrous pyridine and there was obtained 1.2 g (44.4% yield) of 5,6,13,13a-tetrahydro-2,3,11-trimethoxy-10-(3', 4', 5'-trimethoxybenzoxy)-8H-dibenzo-[a, g]quinolizine as a pale yellow powder. The methiodide derived from this compound was found to be in agreement with the methiodide of the compound obtained in Example 3 as determined from the melting point and IR spectrum.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[C:9]1[O:13][N:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH:21]([CH3:23])[CH3:22])=[C:16]([Cl:24])[CH:15]=2)[N:10]=1)[NH2:5].O=[C:26]1[CH2:29][CH:28]([C:30]([OH:32])=[O:31])[CH2:27]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][CH:26]2[CH2:29][CH:28]([C:30]([OH:32])=[O:31])[CH2:27]2)[CH:6]=[CH:7][C:8]=1[C:9]1[O:13][N:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH:21]([CH3:22])[CH3:23])=[C:16]([Cl:24])[CH:15]=2)[N:10]=1
Reactant: CC(C)Oc1ccc(-c2noc(-c3ccc(N)cc3Cl)n2)cc1Cl
Reactant: O=C1CC(C(=O)O)C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)Oc1ccc(-c2noc(-c3ccc(NC4CC(C(=O)O)C4)cc3Cl)n2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.2 %

Procedure:
3-chloro-4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)aniline (200 mg, 0.549 mmol) and 3-oxocyclobutanecarboxylic acid (62.7 mg, 0.549 mmol) in methanol (1280 μl) at room temperature was added acetic acid (842 μl, 14.72 mmol). The reaction mixture was stirred at room temperature for 10 minutes before addition of sodium cyanoborohydride (17.25 mg, 0.275 mmol) as a single portion. The reaction mixture was stirred at room temperature overnight. LCMS (2007—9476) indicated a 43% by ELSD (2.90 min)s conversion to (M+H) 462.16. The solvent was removed and the crude material purified by FCC (50% EA/Hept) to afford 3-(3-chloro-4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)phenylamino)cyclobutanecarboxylic acid (135 mg, 0.292 mmol, 53.2% yield) as a white solid. LCMS (Table A, Method b) indicated 100% by UV (3.06 mins) to (M+H)+ 364.12.
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([Br:16])[C:7]=2[C:8]=1[NH2:9])(=[O:3])[CH3:2].[CH:17]([C:20]1[S:21][C:22]([CH:25]=O)=[CH:23][N:24]=1)([CH3:19])[CH3:18].[OH-].[Na+].O>C1COCC1>[NH2:9][C:8]1[C:7]2[C:10]([Br:16])=[C:11]([O:14][CH3:15])[CH:12]=[CH:13][C:6]=2[O:5][C:4]=1[C:1](=[O:3])/[CH:2]=[CH:25]/[C:22]1[S:21][C:20]([CH:17]([CH3:19])[CH3:18])=[N:24][CH:23]=1
Reactant: COc1ccc2oc(C(C)=O)c(N)c2c1Br
Reactant: CC(C)c1ncc(C=O)s1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2oc(C(=O)/C=C/c3cnc(C(C)C)s3)c(N)c2c1Br
Temperature: 0 °C
Reaction time: 8 h
Yield: 63.9 %

Procedure:
A mixture of 12G (1.5 g, 5.2 mmol), 2-isopropyl-thiazole-5-carbaldehyde (1.2 g, 7.7 mmol) in THF (20 mL) was cooled to 0° C. To the mixture was added NaOH (1.5 g), then stirred at room temperature overnight. TLC monitored the reaction. After the reaction completed, the reaction mixture was added dropwise into water. The precipitated solids were collected by filtration to give 14A (1.4 g, 62.9% yield).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][C:9]=2[CH2:15][N:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)[CH2:4][CH2:3]1.Cl[C:24]1[C:33]2[C:28](=[CH:29][C:30]([Cl:34])=[CH:31][CH:32]=2)[N:27]=[CH:26][CH:25]=1.Cl>C(#N)C>[Cl:34][C:30]1[CH:29]=[C:28]2[C:33]([C:24]([NH:12][C:11]3[CH:13]=[CH:14][C:8]([N:5]4[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]4)=[C:9]([CH2:15][N:16]4[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]4)[CH:10]=3)=[CH:25][CH:26]=[N:27]2)=[CH:32][CH:31]=1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Reactant: CN1CCN(Cc2cc(N)ccc2N2CCN(C)CC2)CC1
Agent: Cl
Solvent: CC#N
Product: CN1CCN(Cc2cc(Nc3ccnc4cc(Cl)ccc34)ccc2N2CCN(C)CC2)CC1
Yield: 47.9 %

Procedure:
4-(4-methylpiperazin-1-yl)-3-[(4-methylpiperazin-1-yl)methyl]aniline (68 mg, 0.22 mmol) and 4,7-dichloroquinoline (44 mg, 1 eq) were refluxed overnight in 10 mL of acetonitrile with 0.66 mL of HCl 1M. The reaction mixture was then evaporated and purified by preparative thin-layer chromatography (DCM/MeOH/NH4O/18/210.1) to yield expected compound as a pale yellow solid (49 mg, 48% yield). m/z (ESI) 465.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([C:8]([CH3:19])([CH3:18])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)[CH:7]=1.[NH2:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH:25]=[CH:26][C:27]([O:33][CH3:34])=[N:28]2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C1(C)C=CC=CC=1>C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([C:8]([CH3:18])([CH3:19])[CH2:9][C:10]([C:13]([F:15])([F:16])[F:14])([OH:17])[CH2:11][NH:22][C:23]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:24]=2[CH:25]=[CH:26][C:27]([O:33][CH3:34])=[N:28]3)[CH:7]=1
Reactant: COc1ccc2c(N)cccc2n1
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(C=O)C(F)(F)F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COc1ccc2c(NCC(O)(CC(C)(C)c3cc(F)ccc3OC)C(F)(F)F)cccc2n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 32.3 %

Procedure:
300 mg (0.97 mmol) of 4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 202 mg (1.16 mmol) of 5-amino-2-methoxyquinoline in 10 ml of acetic acid are refluxed for 5 hours. It is allowed to cool to room temperature, 640 mg (3 mmol) of sodium triacetoxy borohydride is added thereto, and it is stirred for 15 hours at room temperature. After toluene is added, the batch is concentrated by evaporation, the residue is taken up in ethyl acetate, washed with saturated NaHCO3 solution, dried and concentrated by evaporation. Column chromatography on silica gel with hexane-ethyl acetate yields 146 mg of the product as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[C:20]([O:21][CH3:22])=[C:19]([O:23][CH3:24])[CH:18]=[C:17]([CH3:25])[C:3]=1[C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=O.C1(C)C=CC=CC=1.Cl>O>[OH:1][C:2]1[C:20]([O:21][CH3:22])=[C:19]([O:23][CH3:24])[CH:18]=[C:17]([CH3:25])[C:3]=1[CH2:4][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15]
Reactant: COc1cc(C)c(C(=O)CCCCCCCCC(=O)O)c(O)c1OC
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc(C)c(CCCCCCCCCC(=O)O)c(O)c1OC

Procedure:
9-(2'-Hydroxy-3',4'-dimethoxy-6'-methylbenzoyl)nonanoic acid (formula II-1, wherein R=H3CO, X=H, Y=OH, n=8, in the free form) (0.254 part), zinc amalgam (0.56 part), toluene (1 volume part), 35% hydrochloric acid (0.5 volume part) and a small proportion of water were refluxed for 5 hours. The toluene layer was separated and the water layer was extracted with diethyl ether. The toluene layer was combined with the ethereal layer, washed with water and dried. The solvents were then distilled off under reduced pressure and the residue was recrystallized from ligroine. The foregoing procedure provided 10-(2'-hydroxy-3',4'-dimethoxy-6'-methylphenyl)decanoic acid (formula II-2 wherein R=H3CO, X=H, Y=OH, n=8, in the free form) (0.14 part) as colorless powdery crystals melting at 62.5°-66° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[CH:9]([CH3:11])[CH3:10].FC(F)(F)C(O)=O.[CH2:19]([O:26][C:27](=[O:55])[N:28]([CH2:53][CH3:54])[CH2:29][CH2:30][N:31]1[CH:35]=[C:34]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[C:38]([C:43]([F:46])([F:45])[F:44])[CH:37]=2)[N:33]=[C:32]1[CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O>[CH2:19]([O:26][C:27](=[O:55])[N:28]([CH2:29][CH2:30][N:31]1[CH:35]=[C:34]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[C:38]([C:43]([F:45])([F:46])[F:44])[CH:37]=2)[N:33]=[C:32]1[CH:47]1[CH2:48][CH2:49][N:50]([C:2]2[C:3]([CH:9]([CH3:11])[CH3:10])=[C:4]([NH2:8])[N:5]=[CH:6][N:7]=2)[CH2:51][CH2:52]1)[CH2:53][CH3:54])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)c1c(N)ncnc1Cl
Reactant: CCN(CCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCNCC1)C(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Product: CCN(CCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C(C)C)CC1)C(=O)OCc1ccccc1
Temperature: 120 °C
Reaction time: 48 h

Procedure:
A reaction mixture of 6-chloro-5-isopropyl-pyrimidin-4-ylamine (40.0 mg; 0.23 mmol; 1.0 eq.), ethyl-{2-[4-(4-fluoro-3-trifluoromethyl-phenyl)-2-piperidin-4-yl-imidazol-1-yl]-ethyl}-carbamic acid benzyl ester trifluoroacetate (2) (174.0 mg; 0.23 mmol; 1.0 eq.), and Cs2CO3 (303.7 mg; 0.93 mmol; 4.0 eq.) in DMSO (1.5 ml) was stirred at 120° C. for 48 hr. The crude was purified by prep HPLC to yield the title compound.
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])C.NC1C=CC([F:18])=CC=1S.CI>>[CH3:1][S:3][C:4]1[CH:10]=[C:9]([F:18])[CH:8]=[CH:7][C:5]=1[NH2:6]
Reactant: CCSc1ccccc1N
Reactant: Nc1ccc(F)cc1S
Solvent: CI
Product: CSc1cc(F)ccc1N

Procedure:
Under conditions similar to those used for the preparation of 2-(ethylthio)aniline in Example 2, 2-amino-5-fluorothiophenol was alkylated with methyl iodide to give 2-methylthio-4-fluoroaniline.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)=[N:10][C:11]([CH3:17])=[C:12]([CH:16]=2)[C:13](O)=[O:14])=[CH:4][CH:3]=1.B.CO>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[C:12]([CH2:13][OH:14])[C:11]([CH3:17])=[N:10][C:9]=2[C:18]2[CH:19]=[CH:20][C:21]([C:24]([F:25])([F:26])[F:27])=[CH:22][CH:23]=2)=[CH:6][CH:7]=1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)c(-c2ccc(Cl)cc2)cc1C(=O)O
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)c(-c2ccc(Cl)cc2)cc1CO
Temperature: 25 °C

Procedure:
To a solution of 1.6 g of 5-(4-Chloro-phenyl)-2-methyl-6-(4-trifluoromethyl-phenyl)-nicotinic acid in 38 ml of THF, were added dropwise 12 ml of a 1M solution of borane in THF at room temperature. Then, the reaction mixture was heated to reflux for 5 h. The reaction mixture was cooled to room temperature and 20 ml of methanol were carefully added. The solvents were removed under reduced pressure and the residue was dissolved in ethyl acetate. The organic layer was washed with 1 M hydrochloric acid, saturated sodium chloride solution and saturated sodium hydrogen carbonate solution. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. the residue was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 1.2 g.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2)[CH:4]=[CH2:5].[CH2:16](I)[C:17]([CH3:20])([CH3:19])[CH3:18]>O1CCCC1>[CH2:3]([O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH:11]=[CH:10]2)[CH:4]=[CH2:5]
Reactant: CC(C)(C)CI
Reactant: C=CCOc1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCOc1ccc2c(ccn2CC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of sodium hydride (60%, 254 mg, 6.35 mmol) in 15 mL tetrahydrofuran (THF) was added 5-allyloxyindole (Step A; 1.0 g, 5.77 mmol) in 5 mL THF and the mixture was stirred for 1 hour at ambient temperature. Neopentyl iodide (0.69 mL, 6.35 mmol) was added and the reaction heated to reflux for 21 hours. After cooling, the reaction was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over magnesium sulfate, filtered, concentrated in vacuo, and the crude residue purified by flash chromatography on silica gel (15% ethyl acetate/hexane) to provide the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:30])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH:18][C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[N:14]=[CH:15]3)=[C:10]([CH:24]3[CH2:28][CH:27]([OH:29])[O:26][CH2:25]3)[N:9]=2)[CH:7]=1.[BH4-].[Na+]>O1CCCC1.C(OCC)(=O)C>[OH:26][CH2:25][CH:24]([C:10]1[N:9]=[C:8]([C:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[CH3:30])[CH:17]=[C:16]2[C:11]=1[CH:12]=[C:13]([NH:18][C:19]([CH:21]1[CH2:23][CH2:22]1)=[O:20])[N:14]=[CH:15]2)[CH2:28][CH2:27][OH:29]
Reactant: Cc1ccc(F)cc1-c1cc2cnc(NC(=O)C3CC3)cc2c(C2COC(O)C2)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(F)cc1-c1cc2cnc(NC(=O)C3CC3)cc2c(C(CO)CCO)n1
Reaction time: 1 h

Procedure:
To a solution of N-(7-(5-fluoro-2-methylphenyl)-5-(5-hydroxytetrahydrofuran-3-yl)-2,6-naphthyridin-3-yl)cyclopropanecarboxamide (45 mg, 0.11 mmol) in tetrahydrofuran (1 mL) cooled at 0° C. was added sodium tetrahydroborate (8.4 mg, 0.22 mmol), and the reaction mixture was stirred at this temperature for 1 hour. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (100 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford a residue that was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[C:16]([O:24][CH2:25][C:26]([F:29])([F:28])[F:27])[CH:15]=3)[CH:11]=[C:10]([C:30]([F:33])([F:32])[F:31])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:34][C:35]1[CH:40]=[CH:39][C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][N:36]=1>>[F:27][C:26]([F:29])([F:28])[CH2:25][O:24][C:16]1[CH:15]=[C:14]([C:12]2[CH:11]=[C:10]([C:30]([F:33])([F:32])[F:31])[N:9]=[C:8]([C:4]3[CH:3]=[C:2]([C:38]4[CH:39]=[CH:40][C:35]([NH2:34])=[N:36][CH:37]=4)[CH:7]=[CH:6][CH:5]=3)[N:13]=2)[CH:19]=[CH:18][C:17]=1[C:20]([F:23])([F:22])[F:21]
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: FC(F)(F)COc1cc(-c2cc(C(F)(F)F)nc(-c3cccc(Br)c3)n2)ccc1C(F)(F)F
Product: Nc1ccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)c(OCC(F)(F)F)c4)cc(C(F)(F)F)n3)c2)cn1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-4-[3-(2,2,2-trifluoroethoxy)-4-trifluoromethyl-phenyl]-6-trifluoromethyl-pyrimidine (example E.55) (0.273 g, 0.5 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.13 g, 0.6 mmol) according to the general procedure VI. Obtained as an off-white solid (0.20 g, 73%). MS (ISP) 559.2 [(M+H)+]; mp 220° C.
Reaction SMILES: [C:1]([C:3]1[CH:7]=[CH:6][S:5][CH:4]=1)#[N:2].C[O-].[Na+].[C:11](O)(=[O:13])C>CO>[S:5]1[CH:6]=[CH:7][C:3]([C:1](=[NH:2])[O:13][CH3:11])=[CH:4]1
Reactant: CC(=O)O
Reactant: N#Cc1ccsc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=N)c1ccsc1
Temperature: 25 °C
Reaction time: 28 h

Procedure:
3-cyanothiophene (0.66 g, 6.0 mmol) was dissolved in methanol (6 ml), and sodium methoxide (0.03 g, 0.6 mmol) was added. The mixture was stirred at room temperature for 28 hours. After the reaction was completed, acetic acid (0.03 g, 0.6 mmol) was added to neutralize the reaction solution, and the solution was concentrated under reduced pressure. Diethyl ether (50 ml) was added to the concentrated residue, and insolubles were removed by filtration. The filtrate was concentrated under reduced pressure to give the crude product of methyl 3-thiophenecarboximidate.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[F:12].[C:13]1(=[O:23])[NH:17][C:16](=[O:18])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12.[K]>CN(C)C=O.C(OCC)(=O)C>[F:12][C:4]1[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:3]=1[CH2:2][N:17]1[C:13](=[O:23])[C:14]2[C:15](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:16]1=[O:18]
Reactant: O=[N+]([O-])c1ccc(CBr)c(F)c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2C(=O)N1Cc1ccc([N+](=O)[O-])cc1F
Reaction time: 18 h
Yield: 71.8 %

Procedure:
To a stirred solution of crude 1-(bromomethyl)-2-fluoro-4-nitrobenzene (1.335 g, 5.705 mmol) in dimethylformamide was added potassium phthalimide (2.324 g, 12.55 mmol). The reaction mixture was stirred for 18 h The mixture was dissolved in ethyl acetate, washed with water and brine. The organic layer was dried over magnesium sulfate and filtered. The filtrate was removed in vacuo. The crude was purified by column chromatography to give 2-(2-fluoro-4-nitrobenzyl)isoindoline-1,3-dione (1.229 g, 88%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:3]=1[C:4](O)=[O:5].C(N1C=CN=C1)([N:17]1C=CN=C1)=O.O1CCCC1.N>O>[NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:3]=1[C:4]([NH2:17])=[O:5]
Reactant: COc1cc(N)c(C(=O)O)cc1OC
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(N)c(C(N)=O)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 23.3 %

Procedure:
A mixture of 23.7 g of 2-amino-4,5-dimethoxybenzoic acid, 19.5 g of 1,1'-carbonyldiimidazole and 600 ml of tetrahydrofuran Was stirred for 2 hours at room temperature and then saturated with anhydrous ammonia with ice bath cooling. After 24 hours, the reaction mixture was diluted with 50 ml of water, heated at reflux for 2 hours and then concentrated under reduced pressure to about 50 ml. This liquid was mixed with 100 ml of 0.1N sodium hydroxide and then extracted with three 200 ml portions of dichloromethane. The extracts were combined, dried and evaporated. The residue was crystallized from acetonitrile, giving 5.5 g of 2-amino-4,5-dimethoxybenzamide as light grey crystals, mp 135°-138° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH:13]2[CH2:18][N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[O-:24][C:25]#[N:26].[Na+]>C(O)(=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:25]([NH2:26])=[O:24])[CH2:14][CH:13]2[CH2:18][N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(Cc1ccc(Cl)c(Cl)c1)N1CCNCC1CN1CCCC1
Reactant: N#C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: NC(=O)N1CCN(C(=O)Cc2ccc(Cl)c(Cl)c2)C(CN2CCCC2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.9 %

Procedure:
A solution of 1-[(3,4-dichlorophenyl)acetyl]-2-(1-pyrrolidinylmethyl) piperazine (200 mg) in acetic acid (0.5 ml) and water (1 ml) was treated with a solution of sodium cyanate (73 mg) in water (0.5 ml). The resulting solution was stirred at room temperature for 2 h. The solvent was removed in vacuo, the residue was basified with aqueous 2N sodium carbonate solution and extracted with dichloromethane (2×25 ml). The combined organic extracts were dried and evaporated to give a foam (206 mg) which was purified by flash column chromatography eluting with dichloromethane:methanol:0.880 NH3 (200:8:1) to give a solid (120 mg). Crystallisation from ethyl acetate/methanol gave the title compound as a solid (58 mg) m.p. 206°-209° C.
Reaction SMILES: [C:1]([N:8]1[C@H:12]([CH3:13])[CH2:11][CH2:10][C@H:9]1[CH2:14][OH:15])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C:36]1[CH:45]=[CH:44][C:39]([C:40]([O:42][CH3:43])=[O:41])=[CH:38][CH:37]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[C:1]([N:8]1[C@H:12]([CH3:13])[CH2:11][CH2:10][C@H:9]1[CH2:14][O:15][C:36]1[CH:45]=[CH:44][C:39]([C:40]([O:42][CH3:43])=[O:41])=[CH:38][CH:37]=1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: COC(=O)c1ccc(O)cc1
Reactant: C[C@@H]1CC[C@@H](CO)N1C(=O)OC(C)(C)C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COC(=O)c1ccc(OC[C@@H]2CC[C@@H](C)N2C(=O)OC(C)(C)C)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
To a stirred solution of N-Boc-2-(S)-hydroxymethyl-5-(R)-methylpyrrolidine (820 mg, 3.81 mmol), triphenylphosphine (1.10 g, 4.19 mmol) and methyl 4-hydroxybenzoate (580 mg, 3.81 mmol) was added diisopropyl azodicarboxylate (841 ml, 4.19 mmol) at rt, and the resulting mixture was stirred at 60° C. for 1 h. The mixture was concentrated in vacuo, and the residue was chromatographed on silica gel with hexane-EtOAc (5:1) as eluent to give methyl 4-[N-Boc-5-(R)-methyl-2-(S)-pyrrolidinylmethoxy]benzoate (1.32 g, 80%) as a colorless oil. 1H-NMR (CDCl3) δ1.24 (brs, 3 H), 1.49 (s, 9 H), 1.55-1.70 (m, 2 H), 1.94-2.11 (m, 2 H), 3.88 (s, 3 H), 3.88 (overlap, 1H), 4.06-4.20 (m, 2H), 6.93-6.96 (m, 2H), 7.97 (d, J=8.8 Hz, 2 H); MS (ESI) m/z, 350 (M++H).
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH:13]([CH3:15])[CH3:14])[CH:8]=1.C([O:19][B:20](OC(C)C)[O:21]C(C)C)(C)C.Cl>C1COCC1>[CH:13]([C:9]1[CH:8]=[C:7]([B:20]([OH:21])[OH:19])[CH:12]=[CH:11][CH:10]=1)([CH3:15])[CH3:14]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC(C)c1cccc(Br)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)c1cccc(B(O)O)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93.2 %

Procedure:
n-BuLi (7.7 mL, 14.0 mmol) was added dropwise to a stirred solution of 1-bromo-3-isopropyl-benzene (2.4 g, 12.1 mmol) in dry THF (40 mL) over 30 min at −70° C. under nitrogen. The reaction mixture was degassed for 15 min, and triisopropylborate (2.63 g, 14.0 mmol) was added at the same temperature. The reaction mixture was gradually warmed to 0° C. during 90 min and stirred for an additional 30 min at 0° C. The reaction mixture was then cooled to −20° C., and an aqueous solution of 2N HCl (20 mL) was added slowly. THF was distilled off and the reaction mixture was extracted with ethyl acetate (2×20 mL). The combined organic layers were dried over Na2SO4, and concentrated in vacuo to obtain the crude product (1.85 g, 93.5%), which was used for the next step without further purification.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]=[C:10]([NH:12][C:13](=[O:30])[CH:14]([NH:18][C:19](=[O:29])[CH2:20][C:21]3[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=3)[CH2:15][CH2:16][CH3:17])[N:9]=[CH:8]2)[CH2:3][CH2:2]1.O.C=O.[CH:34](O)=O>C1COCC1>[CH3:34][N:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]=[C:10]([NH:12][C:13](=[O:30])[CH:14]([NH:18][C:19](=[O:29])[CH2:20][C:21]3[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=3)[CH2:15][CH2:16][CH3:17])[N:9]=[CH:8]2)[CH2:3][CH2:2]1
Reactant: O=CO
Reactant: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(C2CCNCC2)cn1
Agent: C=O
Solvent: C1CCOC1
Solvent: O
Product: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(C2CCN(C)CC2)cn1
Temperature: 80 °C

Procedure:
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid (1-piperidin-4-yl-1H-imidazol-4-yl)-amide (200 mg, 4.8 mmol) was dissolved in 5 mL of THF and 0.5 mL of water and 0.04 mL of 38% formaldehyde and 0.06 mL of formic acid was added. The reaction was heated for 12 h at 80° C. The solution was extracted with methylene chloride and sodium bicarbonate. The resultant organics were concentrated and purified by silica gel chromatography to afford the title compound: C13 NMR (100 MHz, CDCl3) 13.9, 18.9, 33.3, 36.0, 43.1, 46.1, 53.0, 54.7, 55.3, 102.6, 102.9, 103.1, 105.9, 112.3, 112.6, 131.5, 137.7, 138.7, 162.0, 164.5, 169.2; MS432.2 m/z (M+1).