Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:16][CH2:15][C:10]2([O:14][CH2:13][CH2:12][O:11]2)[CH2:9][C:8]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18])(=O)=O.[C:24]([O-:27])(=[S:26])[CH3:25].[K+]>CN(C)C=O>[C:24]([S:26][C:7]1[CH2:16][CH2:15][C:10]2([O:11][CH2:12][CH2:13][O:14]2)[CH2:9][C:8]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18])(=[O:27])[CH3:25]
Reactant: CC([O-])=S
Reactant: CCOC(=O)C1=C(OS(=O)(=O)C(F)(F)F)CCC2(C1)OCCO2
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1=C(SC(C)=O)CCC2(C1)OCCO2
Temperature: 0 °C
Yield: 45.1 %

Procedure:
19.97 g (55.4 mmol) of ethyl 8-trifluoromethanesulfonyloxy-1,4-dioxaspiro[4.5]dec-7-ene-7-carboxylate [compound described as compound 6 in Tetrahedron Letter, Vol. 39, pp. 6139-6142 (1998)] was dissolved in 200 ml of dimethylformamide, and 9.50 g (83.1 mmol) of potassium thioacetate was added thereto with stirring under ice-cooling, followed by stirring at room temperature for 91 hours. To the reaction solution was added ice water and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane:ethyl acetate=17:3) to give 7.15 g of the title compound as a pale brown oil (yield: 45%).
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]2[C:13]([OH:14])=[CH:12][CH:11]=[C:10]([C:15]#[N:16])[CH:9]=2)=[CH:6][C:5]([C:17]#[N:18])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:26][CH2:27]Br.O>CN(C)C=O>[CH:6]1[C:7]2[C:8]3[CH:9]=[C:10]([C:15]#[N:16])[CH:11]=[CH:12][C:13]=3[O:14][CH2:27][CH2:26][O:1][C:2]=2[CH:3]=[CH:4][C:5]=1[C:17]#[N:18]
Reactant: BrCCBr
Reactant: N#Cc1ccc(O)c(-c2cc(C#N)ccc2O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc2c(c1)-c1cc(C#N)ccc1OCCO2
Temperature: 150 °C
Yield: 29.8 %

Procedure:
A mixture of 6,6'-dihydroxy[1,1'-biphenyl]-3,3'-dicarbonitrile (11.8 g), sodium carbonate (10.6 g), and 1,2-dibromoethane (8.4 g) in 250 ml of anhydrous dimethylformamide is heated at 150° C for 18 hours under nitrogen. The reaction mixture is poured into water and extracted with three 200 ml portions of dichloromethane. The dichloromethane extracts are combined and washed with 10% sodium hydroxide, water, and brine. The solution is filtered through 100 ml of silica gel and concentrated. The resultant solid is recrystallized from benzene to yield 3.5 g of the title compound, melting point 195°-196° C.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([NH:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[O:13][CH2:14][CH3:15].N([O-])=O.[Na+].[N-:20]=[N+:21]=[N-].[Na+]>Cl>[N:1]([C:2]1[CH:12]=[CH:11][C:5]([C:6]([NH:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[O:13][CH2:14][CH3:15])=[N+:20]=[N-:21]
Reactant: [N-]=[N+]=[N-]
Reactant: CCNC(=O)c1ccc(N)c(OCC)c1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Product: CCNC(=O)c1ccc(N=[N+]=[N-])c(OCC)c1
Reaction time: 2 h
Yield: 83.9 %

Procedure:
To a solution of 4-amino-3-ethoxy-N-ethylbenzamide (0.53 g) obtained in Example 131c) in 0.2N hydrochloric acid (12.5 ml) was added 1M aqueous sodium nitrite solution (2.5 ml) under ice-cooling, and the mixture was stirred for 2 hr. To the obtained reaction mixture was added an aqueous solution (5 ml) of sodium azide (0.17 g) under ice-cooling, and the mixture was stirred for 30 min. The reaction mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a yellow oil (0.50 g, 85%).
Reaction SMILES: [NH2:1][C:2]([C:4]1[C:5]([F:18])=[C:6]([CH:14]=[CH:15][C:16]=1[F:17])[O:7][CH2:8][CH:9]=[CH:10][C:11]([OH:13])=[O:12])=[O:3]>C(O)CCC.[Rh]>[NH2:1][C:2]([C:4]1[C:5]([F:18])=[C:6]([CH:14]=[CH:15][C:16]=1[F:17])[O:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:2][CH2:4][CH2:16][CH3:15])=[O:12])=[O:3]
Reactant: NC(=O)c1c(F)ccc(OCC=CC(=O)O)c1F
Agent: [Rh]
Solvent: CCCCO
Product: CCCCOC(=O)CCCOc1ccc(F)c(C(N)=O)c1F
Yield: 174.4 %

Procedure:
4-[3-(Aminocarbonyl)-2,4-difluorophenoxy]-2-butenoic acid (100 mg, 0.32 mmol) was stirred with 5% Rh/C (5 mg) in butanol (5 ml) under H2, at r.t. for 21 h. The reaction mixture was filtered through a pad of celite and rinsed with CH2Cl2 (3×5 ml). The filtrate was evaporated to dryness, under reduced pressure, to give 88 mg of the desired product, yield 87%, mp 53-55° C. HPLC-MS (method 1): m/z 316 [M+H]+, Rt=3.49 min.
Reaction SMILES: Br[CH2:2][C@@H:3]([C:5]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[C:7]([F:14])[C:6]=1[F:15])[OH:4].BrC(C1C(F)=C(F)C(F)=C(F)C=1F)CO.C([SnH](CCCC)CCCC)CCC>CCCCCC>[F:11][C:10]1[C:5]([C@@H:3]([OH:4])[CH3:2])=[C:6]([F:15])[C:7]([F:14])=[C:8]([F:13])[C:9]=1[F:12]
Reactant: O[C@@H](CBr)c1c(F)c(F)c(F)c(F)c1F
Agent: CCCC[SnH](CCCC)CCCC
Agent: OCC(Br)c1c(F)c(F)c(F)c(F)c1F
Solvent: CCCCCC
Product: C[C@H](O)c1c(F)c(F)c(F)c(F)c1F
Temperature: 60 °C
Reaction time: 8 h
Yield: 48.7 %

Procedure:
To a solution of 11.26 g of (R)-(-)-2-bromo-1-(pentafluorophenyl)ethanol containing 20% of 2-bromo-2-(pentafluorophenyl)ethanol obtained in Example 7 in 50 ml of hexane, was added 11.4 ml of tributyltin hydride at room temperature. After stirring for eight hours at 60° C., the reaction mixture was concentrated under reduced pressure, purified by silica gel column chromatography and distilled under reduced pressure to give 4.0 g of (S)-(-)-1-(pentafluorophenyl)ethanol having the following physical properties.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:17]=[N:16][CH:15]=[CH:14][C:10]=2[C:11](O)=[O:12])=[C:4]([CH3:18])[CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:31][S:32]([NH2:35])(=[O:34])=[O:33].C1CCN2C(=NCCC2)CC1>C1COCC1>[I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:17]=[N:16][CH:15]=[CH:14][C:10]=2[C:11]([NH:35][S:32]([CH3:31])(=[O:34])=[O:33])=[O:12])=[C:4]([CH3:18])[CH:3]=1
Reactant: CS(N)(=O)=O
Reactant: Cc1cc(I)ccc1Nc1cnccc1C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1cc(I)ccc1Nc1cnccc1C(=O)NS(C)(=O)=O
Temperature: 40 °C
Reaction time: 16 h
Yield: 33 %

Procedure:
3-[(4-Iodo-2-methylphenyl)amino]isonicotinic acid (example 3) (50 mg, 0.141 mmol) was dissolved in 4 ml dry THF followed by the addition of 1,1′-carbonyldiimidazole (CDI) (0.311 mmol, 50 mg), methanesulfonamide (0.169 mmol, 16.1 mg) and DBU (0.169 mmol, 26 mg). The mixture was stirred for 16 h at 40° C. and the volatiles were removed in vacuo. The crude material was purified by preparative HPLC to give 20.3 mg (47 μmol; 33% yield) of pure desired product. LC-MS (method III): rt=2.74 min; m/z [M+H]+ 432.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]3[CH2:11][CH2:12][CH:13]([C:15]([OH:17])=O)[CH2:14][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH2:18]([NH:22][CH2:23][C:24]#[N:25])[CH2:19][CH2:20][CH3:21]>>[CH2:18]([N:22]([CH2:23][C:24]#[N:25])[C:15]([CH:13]1[CH2:12][CH2:11][C:10]2[C:3]3[C:2]([Cl:1])=[N:7][CH:6]=[N:5][C:4]=3[S:8][C:9]=2[CH2:14]1)=[O:17])[CH2:19][CH2:20][CH3:21]
Reactant: O=C(O)C1CCc2c(sc3ncnc(Cl)c23)C1
Reactant: CCCCNCC#N
Product: CCCCN(CC#N)C(=O)C1CCc2c(sc3ncnc(Cl)c23)C1

Procedure:
300 mg (1.12 mmol) (RS)-4-chloro-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxylic acid (prepared according to intermediate example 31b) were transformed in analogy to example 3 using (butylamino)acetonitrile to give after working up and purification 280 mg (69%) of the title compound.
Reaction SMILES: CN1C(C)=[C:9]2[C:4]([N:5]([CH3:15])[C:6](=[O:14])[N:7]([CH3:13])[C:8]2=[O:12])=N1.Br[CH2:17][C:18]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26]2[CH:31]=[C:30]([F:32])[C:29]([O:33][CH2:34][CH:35]3[CH2:38][CH2:37][CH2:36]3)=[C:28]([F:39])[CH:27]=2)[N:25]=1)=[O:19].[H-].[Na+]>CN(C=O)C>[CH:35]1([CH2:34][O:33][C:29]2[C:30]([F:32])=[CH:31][C:26]([C:24]3[N:25]=[C:21]([NH:20][C:18](=[O:19])[CH2:17][N:25]4[C:9]5[C:8](=[O:12])[N:7]([CH3:13])[C:6](=[O:14])[N:5]([CH3:15])[C:4]=5[CH:23]=[C:24]4[CH3:26])[S:22][CH:23]=3)=[CH:27][C:28]=2[F:39])[CH2:38][CH2:37][CH2:36]1
Reactant: Cc1c2c(=O)n(C)c(=O)n(C)c2nn1C
Reactant: O=C(CBr)Nc1nc(-c2cc(F)c(OCC3CCC3)c(F)c2)cs1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc2c(c(=O)n(C)c(=O)n2C)n1CC(=O)Nc1nc(-c2cc(F)c(OCC3CCC3)c(F)c2)cs1

Procedure:
The title compound was prepared according to the general procedure (Method A) by coupling Intermediate 2 (50 mg, 0.258 mmol) with 2-bromo-N-{4-[4-Cyclobutylmethoxy-3,5-difluorophenyl]-1,3-thiazol-2-yl}acetamide (129 mg, 0.308 mmol) in the presence of NaH (16 mg, 0.375 mmol) in dry DMF (5.0 mL) to give 65 mg of the product as an off-white solid; 1H NMR (δ ppm, 300 MHz, DMSO-d6) 1.82-1.88 (m, 4H), 2.00-2.06 (m, 2H), 2.26 (s, 3H), 2.65-2.70 (m, 1H), 3.17 (s, 3H), 3.33 (s, 3H), 4.10 (d, J=6.6 Hz, 2H), 5.33 (s, 2H), 6.06 (s, 1H), 7.63 (d, J=8.7 Hz, 2H), 7.77 (s, 1H), 12.71 (br s, 1H); APCI-MS (m/z) 530.16 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]2[C:17]3[CH:18]=[C:19]([F:23])[C:20]([F:22])=[CH:21][C:16]=3[N:15]=[C:14]2[C:24]2[C:25](Cl)=[N:26][CH:27]=[CH:28][CH:29]=2)=[CH:8][CH:7]=1.[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][OH:41])=[CH:36][CH:35]=1>>[CH3:1][O:2][C:3](=[O:31])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]2[C:17]3[CH:18]=[C:19]([F:23])[C:20]([F:22])=[CH:21][C:16]=3[N:15]=[C:14]2[C:24]2[C:25]([O:41][CH2:40][C:37]3[CH:38]=[CH:39][C:34]([O:33][CH3:32])=[CH:35][CH:36]=3)=[N:26][CH:27]=[CH:28][CH:29]=2)=[CH:8][CH:7]=1
Reactant: COc1ccc(CO)cc1
Reactant: COC(=O)CCc1ccc(Cn2c(-c3cccnc3Cl)nc3cc(F)c(F)cc32)cc1
Product: COC(=O)CCc1ccc(Cn2c(-c3cccnc3OCc3ccc(OC)cc3)nc3cc(F)c(F)cc32)cc1

Procedure:
The title compound was prepared in analogy to Example 4, intermediate, from 3-{4-[2-(2-chloro-pyridin-3-yl)-5,6-difluoro-benzoimidazol-1-ylmethyl]-phenyl}-propionic acid methyl ester and (4-methoxy-phenyl)-methanol (CAS Reg. No. 105-13-5). Colorless sticky solid (81%). MS (Turbo Spray): m/z=544.1 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([NH2:12])[C:9]([S:13]([CH2:16][CH3:17])(=[O:15])=[O:14])=[CH:8][C:4]=1[C:5]([OH:7])=O.O.Cl[C:20](OCC)=O.[CH:25]1([N:31]2[CH2:35][CH2:34][CH2:33][C:32]2(C)[CH2:36][NH2:37])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>C(N(CC)CC)C.CC(C)=O>[CH:30]1([CH2:25][N:31]2[CH2:35][CH2:34][CH2:33][CH:32]2[CH2:36][NH:37][C:5](=[O:7])[C:4]2[CH:8]=[C:9]([S:13]([CH2:16][CH3:17])(=[O:15])=[O:14])[C:10]([NH2:12])=[CH:11][C:3]=2[O:2][CH3:1])[CH2:20][CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: CC1(CN)CCCN1C1CCCCC1
Reactant: CCS(=O)(=O)c1cc(C(=O)O)c(OC)cc1N
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(C)=O
Product: CCS(=O)(=O)c1cc(C(=O)NCC2CCCN2CC2CCCCC2)c(OC)cc1N
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
25.9 g of 2-methoxy-4-amino-5-ethylsulphonyl benzoic acid, 40 ml of water, 200 ml of acetone and 13.9 ml of triethylamine (density 0.726) are placed in a 500 ml flask fitted with an agitator, a thermometer and a dropping funnel. The solution is cooled to about 0° to 5° C. and 10.9 g of ethyl chloroformate is dripped in. The mixture is agitated for 40 minutes at about 0° C., then 19.6 g of 1-cyclohexyl-methyl-2-aminomethyl pyrrolidine is added drop by drop. The mixture is agitated for 2 hours at room temperature then left to stand. The acetone is evaporated under vacuum and the residue is dissolved in 100 ml of water and 25 ml of acetic acid and filterd in the presence of vegetable black. The filtrate is made alkaline with 100 ml of 40% soda lye. A precipitate is formed; this is filtered, washed with plenty of water and dissolved moist in 230 ml of boiling acetone. The hot solution is filtered in the presence of vegetable black and the filtrate is crystallized. The product is drained, washed with a little acetone and dried in an oven at 50° C.
Reaction SMILES: [ClH:1].C(OC([CH2:9][NH:10][C@H:11]1[CH2:15][CH2:14][C@@H:13]([N:16]2[CH2:21][CH2:20][CH:19]([CH3:22])[CH2:18][CH2:17]2)[CH2:12]1)=O)(C)(C)C>Cl.CO>[ClH:1].[ClH:1].[CH3:9][NH:10][C@H:11]1[CH2:15][CH2:14][C@@H:13]([N:16]2[CH2:21][CH2:20][CH:19]([CH3:22])[CH2:18][CH2:17]2)[CH2:12]1
Reactant: CC1CCN([C@@H]2CC[C@H](NCC(=O)OC(C)(C)C)C2)CC1
Agent: Cl
Solvent: CO
Product: CN[C@H]1CC[C@@H](N2CCC(C)CC2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 184.3 %

Procedure:
cis-1-[(tert-Butyloxycarbonyl)methylamino]-3-(4-methylpiperidin-1-yl)cyclopentane hydrochloride (394.5 mg, 1.19 mmol) was dissolved in hydrogen chloride in methanol [prepared by cautious addition of acetyl chloride (2 ml) to methanol (20 ml)]. The resulting solution was stirred at room temperature for 3 hours, concentrated in vacuo to give an oil which was crystalized from methanol-ethyl acetate. The solid was collected under suction, washed with ethyl acetate and dried in vacuo to give the title compound (295.3 mg, 93%) as a white solid; δH (400 MHz, CD3OD) 1.02 (3H, d, J 6.4 Hz), 1.51-1.63 (2H, m), 1.73 (1H, m), 1.92-2.29 (7H, m), 2.67 (1H, m), 2.73 (3H, s), 2.98 (2H, m), 3.62 (4H, m); m/z (ES+) 197 ([M+H]+, 100%), 166.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([CH:10]([OH:16])[CH2:11][CH2:12][C:13]([O-:15])=[O:14])[C:4]=2[O:3][CH2:2]1.[Na+].[H-].[Na+].F[C:21]1[CH:28]=[C:27]([O:29][CH2:30][C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)[CH:26]=[CH:25][C:22]=1[C:23]#[N:24]>O1CCCC1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([CH:10]([O:16][C:25]3[CH:26]=[C:27]([O:29][CH2:30][C:31]4[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=4)[CH:28]=[CH:21][C:22]=3[C:23]#[N:24])[CH2:11][CH2:12][C:13]([OH:15])=[O:14])[C:4]=2[O:3][CH2:2]1
Reactant: O=C([O-])CCC(O)c1cccc2c1OCO2
Reactant: N#Cc1ccc(OCc2cccnc2)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1ccc(OCc2cccnc2)cc1OC(CCC(=O)O)c1cccc2c1OCO2
Temperature: 57.5 °C
Yield: 39.5 %

Procedure:
A solution of sodium (RS)-4-(benzo[1,3]dioxol-4-yl)-4-hydroxybutanoate (1.23 g) is added to a stirred suspension of sodium hydride (0.6 g, 60% dispersion in mineral oil) in tetrahydrofuran (50 mL). The mixture is stirred at room temperature for 1.5 hours when 2-fluoro-4-(3-pyridylmethoxy)benzonitrile (1.07 g) is added in one portion. The reaction mixture is heated at 55-60° C. for 18 hours and evaporated. The residue is dissolved in water (100 mL), the solution acidified to pH 2 with 1 N hydrochloric acid and the mixture extracted with ethyl acetate (100 mL). The organic phase is washed with water (100 mL), with brine (100 mL), dried over magnesium sulphate and evaporated. The yellow semi-solid residue is recrystallised from acetonitrile to give (RS)-4-(benzo[1,3]dioxol-4-yl)-4-[2-cyano-5-(3-pyridylmethoxy)phenoxy]butanoic acid (0.80 g) as a cream solid, m.p. 181-183° C. [Elemental analysis:- C,66.32; H,4.57; N,6.52%. Calculated :- C,66.66; H,4.66; N,6.48%]
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][C:8]1[CH2:9][CH2:10][NH:11][CH2:12][CH:13]=1.CN([CH2:17][C:18]1[C:26]2[C:21](=[N:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1)C>C1(C)C=CC=CC=1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][C:8]1[CH2:9][CH2:10][N:11]([CH2:17][C:18]2[C:26]3[C:21](=[N:22][CH:23]=[CH:24][CH:25]=3)[NH:20][CH:19]=2)[CH2:12][CH:13]=1
Reactant: CN(C)Cc1c[nH]c2ncccc12
Reactant: C1=C(CCc2ccco2)CCNC1
Solvent: Cc1ccccc1
Product: C1=C(CCc2ccco2)CCN(Cc2c[nH]c3ncccc23)C1
Yield: 22.7 %

Procedure:
A solution of 4-(2-[furan-2-yl]ethyl)-1,2,3,6-tetrahydropyridine (506 mg, 2.86 mmol) and 3-dimethylaminomethyl-1H-pyrrolo[2,3-b]pyridine (500 mg, 2.86 mmol) in toluene (10 ml) was stirred at reflux for 10 hours. The solvent was evaporated and the residue chromatographed with 3% methanol in dichloromethane as eluant to afford the title compound (200 mg, 23%) as a colourless solid, m.p. 105° C.; (Found: C, 73.84; H, 6.72; N, 13.31. C19H21N3O requires C, 74.24; H, 6.89; N, 13.67); δH (DMSO-d6) 2.00-2.06 (2H, m, tetrahydropyridinyl CH2), 2.22 (2H, t, J 7.7 Hz, CH2), 2.48-2.54 (2H, m, CH2), 2.68 (2H, t, J 7.3 Hz, tetrahydropyridinyl CH2), 2.84-2.89 (2H, m, tetrahydropyridinyl CH2), 3.66 (2H, s, NCH2Ar), 5.34-5.38 (1H, m, tetrahydropyridinyl 5-H), 6.06 (1H, d, J 2.9 Hz, furanyl 3-H), 6.31 (1H, dd, J 3.0, 1.9 Hz, furanyl 4-H), 7.02 (1H, dd, J 7.8, 4.6 Hz, 5-H), 7.32 (1H, d, J 2.3 Hz, furanyl 5-H), 7.46 (1H, d, J 3.0 Hz, 2-H), 7.99 (1H, m, dd, J 7.8, 4.1 Hz, 4-H), 8.18 (1H, dd, J 4.6, 1.4 Hz, 6-H), and 11.38 (1H, br s, NH); m/z (CI+, NH3) 308 (M+1)+.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH:11]1([CH2:14][CH2:15][NH2:16])[CH2:13][CH2:12]1.[Cl:17]CCl>>[Cl:17][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:16][CH2:15][CH2:14][CH:11]2[CH2:13][CH2:12]2)=[O:7])=[CH:4][CH:3]=1
Reactant: ClCCl
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: NCCC1CC1
Product: O=C(NCCC1CC1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 4-bromobenzoyl chloride (0.600 g, 2.700 mmol) in dichloromethane (20 mL) was added 2-cyclopropylethylamine (0.270 g, 3.28 mmol) at 0° C. The mixture was stirred at ambient temperature for 12 hours, then washed sequentially with diluted HCl solution and NaHCO3. The organic phase was separated, dried and concentrated. The residue was purified by column chromatography and recrystallization from ethyl acetate and hexane to afford 4-chloro-N-(2-cyclopropylethyl)benzamide.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](=O)[CH2:12]Br)(=O)C.[CH:15]([NH2:17])=[S:16].C(N)=O>CC(C)=O>[S:16]1[CH:12]=[C:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[OH:4])[N:17]=[CH:15]1
Reactant: CC(=O)Oc1ccccc1C(=O)CBr
Reactant: NC=S
Solvent: NC=O
Solvent: CC(C)=O
Product: Oc1ccccc1-c1cscn1
Temperature: 10 °C

Procedure:
o-(Bromoacetyl)phenyl acetate (5.0 g, 19.5 mmol) was treated with crude thioformamide (filtrate concentrated in vacuo from reaction of P2S5 (1.1 eq.) and (25 mmol) formamide in THF (30-40° C., 5 hours)) in refluxing acetone (60 mL). After 16 hours the reaction mixture was cooled to about 10° C. and the precipitated HBr salt of 2-(thiazol-4-yl)phenol was recovered. 31%, 1.50 g, LSIMS m/z=178 (MH+).
Reaction SMILES: [CH2:1]([C:3]1[C:7]([CH3:8])=[CH:6][NH:5][C:4]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:2].[I:14]I.[I-]>>[CH2:1]([C:3]1[C:7]([CH3:8])=[C:6]([I:14])[NH:5][C:4]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:2]
Reactant: II
Reactant: CCOC(=O)c1[nH]cc(C)c1CC
Agent: [I-]
Product: CCOC(=O)c1[nH]c(I)c(C)c1CC

Procedure:
reacting ethyl 3-ethyl-4-methylpyrrole-2-carboxylate with iodine and iodide to form ethyl 3-ethyl-5-iodo-4-methylpyrrole-2-carboxylate;
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][OH:6].[H-].[Na+].[CH2:9]([N:16]1[CH2:27][CH2:26][C:19]2[N:20]=[C:21]([Cl:25])[N:22]=[C:23](Cl)[C:18]=2[CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)(C)(C)C.C1COCC1>[CH2:9]([N:16]1[CH2:27][CH2:26][C:19]2[N:20]=[C:21]([Cl:25])[N:22]=[C:23]([O:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])[C:18]=2[CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COCCCO
Reactant: Clc1nc(Cl)c2c(n1)CCN(Cc1ccccc1)C2
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: COCCCOc1nc(Cl)nc2c1CN(Cc1ccccc1)CC2
Reaction time: 0.5 h

Procedure:
To a solution of 3-methoxypropan-1-ol (0.500 mL, 5.23 mmol) in t-butanol (5 mL) was added a 60% dispersion of NaH in oil (70 mg, 1.75 mmol). The resulting suspension was permitted to stir for 30 minutes at which time the reaction was placed at 0° C. and charged with 6-benzyl-2,4-dichloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (CAS#778574-06-4, 300 mg, 1.02 mmol) as a solution in THF (1.5 mL). After 20 minutes the mixture was quenched with saturated aqueous NH4Cl, and diluted with ethyl acetate and water. The layers were then separated and the organic layer was washed with brine and dried over Na2SO4, filtered and concentrated. The resulting residue was purified via silica gel flash chromatography to provide 6-benzyl-2-chloro-4-(3-methoxypropoxy)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine. MS (ESI+) m/z 348.1 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[F:12])[CH2:5][C:4]1=[O:13])[CH3:2].[N+:14]([O-])([O-:16])=[O:15].[Na+]>FC(F)(F)C(O)=O>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[CH:9][C:10]=2[F:12])[CH2:5][C:4]1=[O:13])[CH3:2]
Reactant: CCN1C(=O)Cc2cccc(F)c21
Reactant: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CCN1C(=O)Cc2cc([N+](=O)[O-])cc(F)c21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
1-Ethyl-7-fluoro-1,3-dihydro-indol-2-one (3.45 g, 19.3 mmol) is added portionwise to a mixture of sodium nitrate (1.64 g, 19.3 mmol) and trifluoroacetic acid (60 ml) and stirred at room temperature for 5 hours. The reaction is diluted with ice water and the resulting precipitate filtered, washed with water, and dried under vacuum to give the title compound as a brownish-yellow solid. HPLC r.t. 4.88 min; MS for C10H9FN2O3 m/z 223.0 (M-H)−.
Reaction SMILES: [CH2:1]1[CH2:6][C@H:5]([C:7]([OH:9])=[O:8])[CH2:4][CH2:3][C@H:2]1[CH2:10][NH2:11].[C:12]([O:17][CH:18]([O:21][C:22](ON1C(=O)CCC1=O)=[O:23])[CH2:19][CH3:20])(=[O:16])[CH2:13][CH2:14][CH3:15]>CC(OC)(C)C.CC(C)=O.O>[C:12]([O:17][CH:18]([O:21][C:22]([NH:11][CH2:10][C@H:2]1[CH2:3][CH2:4][C@H:5]([C:7]([OH:9])=[O:8])[CH2:6][CH2:1]1)=[O:23])[CH2:19][CH3:20])(=[O:16])[CH2:13][CH2:14][CH3:15]
Reactant: CCCC(=O)OC(CC)OC(=O)ON1C(=O)CCC1=O
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Solvent: COC(C)(C)C
Solvent: O
Solvent: CC(C)=O
Product: CCCC(=O)OC(CC)OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1

Procedure:
Following the general nucleophilic carbamoylation procedure, tranexamic acid (472 mg, 3.0 mmol) and 1-[(2,5-dioxopyrrolidinyl)oxycarbonyloxy]propyl butanoate (575 mg, 2.0 mmol) were reacted in the MTBE/acetone/water mixture (16 mL) to yield the title compound 29 (408 mg, 62% yield) as a white powder after work-up and mass-guided preparative HPLC purification. 1H NMR (400 MHz, DMSO-d6): δ=0.81-0.94 (br. m, 8H), 1.17-1.38 (br. m, 3H), 1.47-1.58 (m, 2H), 1.64-1.75 (m, 4H), 1.83-1.92 (br. m, 2H), 2.10 (tt, J=12.0, 3/6 Hz, 1H), 2.26 (t, J=7.2 Hz, 2H), 2.75-2.88 (m, 2H), 6.55 (t, J=5.2 Hz, 1H), 7.42 (t, J=5.6 Hz, 1H), 11.97 (br. s, 1H). MS (ESI) m/z 352.18 (M+Na)+; 328.14 (M−H)−.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[O:13]=[C:14]1[C:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:18][CH2:17][CH2:16][N:15]1[CH2:32][C:33](O)=[O:34].[F:36][C:37]1[CH:42]=[CH:41][C:40]([CH:43]2[CH2:48][CH2:47][CH2:46][CH2:45][NH:44]2)=[CH:39][CH:38]=1>ClCCl>[F:36][C:37]1[CH:38]=[CH:39][C:40]([CH:43]2[CH2:48][CH2:47][CH2:46][CH2:45][N:44]2[C:33](=[O:34])[CH2:32][N:15]2[CH2:16][CH2:17][CH2:18][C:19]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]2=[O:13])=[CH:41][CH:42]=1
Reactant: Fc1ccc(C2CCCCN2)cc1
Reactant: O=C(O)CN1CCCC(c2ccccc2)(c2ccccc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCCC(c2ccccc2)(c2ccccc2)C1=O)N1CCCCC1c1ccc(F)cc1
Reaction time: 8 h

Procedure:
A solution of N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.049 g, 0.254 mmol), 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (Example 68E, 0.050 g, 0.169 mmol) and 2-(4-fluorophenyl)piperidine (0.030 g, 0.169 mmol) in dichloromethane (0.5 mL) was stirred at room temperature. After stirring overnight, the reaction was loaded directly onto a SF10-4 column (Analogix®, Burlington, Wis.), and the title compound was eluted using a gradient of 5% to 70% ethyl acetate/hexanes over 20 minutes (flow=30 mL/minute). 1H NMR (300 MHz, CDCl3) δ ppm 7.46-7.09 (m, 12H), 7.03 (m, 2H), 4.58-4.23 (m, 2H), 3.57 (m, 2H), 2.72-2.55 (m, 2H), 2.45-2.23 (m, 2H), 2.02-1.75 (m, 3H), 1.75-1.47 (m, 6H); MS (DCI+) m/z 471 (M+H)+.