Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C@H:9]([CH2:20][CH2:21]/[CH:22]=[CH:23]/[N+:24]([O-:26])=[O:25])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:34][C:35]1[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=1B(O)O.O.C(=O)(O)[O-].[Na+].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1>[C:1]([O:5][C:6]([N:8]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C@@H:9]([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[CH2:20][CH2:21][C@@H:22]([C:39]1[CH:38]=[CH:37][CH:36]=[C:35]([F:34])[C:40]=1[F:41])[CH2:23][N+:24]([O-:26])=[O:25])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1cccc(F)c1F
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@H](CC/C=C/[N+](=O)[O-])C(=O)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@H](CC[C@H](C[N+](=O)[O-])c1cccc(F)c1F)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
A solution of benzyl (2R,5E)-2-[bis(tert-butoxycarbonyl)amino]-6-nitrohex-5-enoate from Step B (34.0 g, 73.2 mmol), 2,3-difluorophenylboronic acid (28.9 g, 183 mmol) and water (4.62 mL, 256 mmol) in dioxane (240 mL) was degassed with argon for 15 min. To this solution was added sodium bicarbonate (3.08 g, 36.6 mmol), (S)-BINAP (1.28 g, 2.05 mmol) and acetylacetanotobis(ethylene)rhodium(I) (0.472 g, 1.83 mmol). The mixture was stirred at ambient temperature for 2 min then heated to 35° C. After 4 h, (S)-BINAP (255 mg, 0.41 mmol) and acetylacetanotobis(ethylene)rhodium(I) (94 mg, 0.36 mmol) were added. After an additional 2 h, the reaction was partitioned between CH2Cl2 and aqueous NaHCO3. The aqueous layer was extracted with another portion of CH2Cl2. The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—95:5 to 40:60, to give the title compound. MS: m/z=379 (M-C10H15O4).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23](O)=[O:24])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.Cl.[NH2:27][CH2:28][CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl>CN(C=O)C.O>[CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][C:23]([NH:27][CH2:28][CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:24])=[CH:19][CH:20]=2)=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)CCN
Reactant: C[C@@H]1CCCN1CCc1ccc(-c2ccc(CCC(=O)O)cc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H]1CCCN1CCc1ccc(-c2ccc(CCC(=O)NCCC(=O)OC(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-3-(4′-(2-(2-methylpyrrolidin-1-yl)ethyl)biphenyl-4-yl)propanoic acid (30 mg, 0.089 mmol), tert-butyl 3-aminopropanoate hydrochloride (19.38 mg, 0.107 mmol), and TEA (0.037 mL, 0.267 mmol) in DMF (1 mL) was added HATU (40.6 mg, 0.107 mmol). The reaction was stirred at room temperature overnight. The mixture was added H2O (1 mL) and 1M HCl (1 mL) and purified by HPLC to give the title compound. LCMS m/z=465.5 [M+H]+; 1H NMR (400 MHz, CD3CN) δ ppm 1.27 (d, J=6.8 Hz, 0.4H), 1.44 (s, 9H), 1.46 (d, J=6.5 Hz, 2.6H), 1.69-1.82 (m, 1H), 2.02-2.12 (m, 2H), 2.23-2.32 (m, 1H), 2.35 (t, J=6.6 Hz, 2H), 2.46 (t, J=7.6 Hz, 2H), 2.93 (t, J=7.6 Hz, 2H), 3.05-3.22 (m, 4H), 3.31-3.38 (m, 2H), 3.38-3.49 (m, 1H), 3.52-3.63 (m, 1H), 3.72-3.82 (m, 1H), 6.50 (s, 1H), 7.32 (d, J=8.1 Hz, 2H), 7.39 (d, J=8.2 Hz, 2H), 7.57 (d, J=8.2 Hz, 2H), 7.63 (d, J=8.2 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3=[N:13][CH:14]=[N:15][C:16]([NH2:17])=[C:11]3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:18][CH:19]([CH2:24][CH3:25])[CH2:20][C:21](O)=[O:22].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C=O)C.CO>[NH2:17][C:16]1[N:15]=[CH:14][N:13]=[C:12]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:21](=[O:22])[CH2:20][CH:19]([CH3:18])[CH2:24][CH3:25])=[CH:3][CH:4]=3)[N:9]=[CH:10][C:11]=12
Reactant: Nc1ccc(-n2ncc3c(N)ncnc32)cc1
Reactant: CCC(C)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CO
Product: CCC(C)CC(=O)Nc1ccc(-n2ncc3c(N)ncnc32)cc1
Reaction time: 0.17 h
Yield: 62.5 %

Procedure:
Title compound 11A, 1-(4-amino-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (40 mg, 1.1 eq, 0.18 mmol) was added to a solution 3-methylpentanoic acid (20 μl, 1.0 eq, 0.16 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (27 mg, 1.1 eq, 0.18 mmol), 1-hydroxybenzotriazole (22 mg, 1.0 eq, 0.17 mmol) in DMF (1 ml) which had been stirred for 10 minutes under an inert atmosphere. The reaction was stirred at room temperature for 48 hours, after which methanol (1 ml) was added, and the solvents were removed in vacuo. The residue was purified by mass directed preparative HPLC to yield the title compound as a white solid (31 mg, 0.10 mmol, 61%). LCMS: [M+H]+=325, Rt=1.64 min, 100% purity.
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:13])[CH:10]=2)[C:5]1=O.O.[NH2:16][CH2:17][CH:18]([OH:20])[CH3:19]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[F:13][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[C:5]1[N:16]([CH2:17][CH:18]([OH:20])[CH3:19])[CH:2]=[CH:3][C:4]=1[CH2:12]2
Reactant: O=CCC1Cc2cc(F)ccc2C1=O
Reactant: CC(O)CN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(O)Cn1ccc2c1-c1ccc(F)cc1C2
Reaction time: 0.75 h
Yield: 69 %

Procedure:
A solution of 2.0 g of (RS)-2-(2-oxoethyl)-5-fluoro-1-indanone and 85 mg of p-toluenesulfonic acid in 70 ml of anhydrous toluene was heated on a water separator. A solution of 3.12 g of (RS)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 45 minutes, during which the solvent was reduced to a volume of 20 ml. The cooled reaction mixture was purified by column chromatography on silica gel (ethyl acetate/toluene 2:3). 1.66 g (69%) of (RS)-1-(6-fluoro-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol were obtained as a brown oil.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[H-].[Na+].[CH3:11][O:12][CH2:13][CH2:14][CH2:15]Br>CN(C)C=O>[CH3:11][O:12][CH2:13][CH2:14][CH2:15][O:2][C:1]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4]
Reactant: Oc1ccccc1O
Reactant: COCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCCOc1ccccc1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 22 g of pyrocatechol in 80 ml of dimethylformamide is added at room temperature, within a period of 30 minutes, to a suspension of 8.4 g of NaH (60% dispersion in mineral oil) in 300 ml of dimethylformamide, and the mixture is stirred for one hour at room temperature. A solution of 49.3 g of 3-bromopropyl methyl ether in 80 ml of dimethylformamide is then added dropwise. The reaction mixture is stirred for a further 80 hours at room temperature and is then concentrated by evaporation under reduced pressure at a bath temperature of 30° C. The residue is partitioned between diethyl ether and water. The combined organic phases are dried over magnesium sulfate and concentrated by evaporation, and the residue is purified by FC (100 g of silica gel, hexane/dichloromethane=5:95), yielding the title compound: Rf (dichloromethane/diethyl ether=96:4)=0.35; HPLC Rt =11.2 minutes.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([N:11]2[C:19]3[C:14](=[C:15]([O:32][CH3:33])[CH:16]=[C:17]([C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=4)=[O:21])[CH:18]=3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.F[C:35]1C=C(S(Cl)(=O)=O)C=C[CH:40]=1>>[CH2:35]([O:28][C:27](=[O:29])[C:26]1[CH:30]=[CH:31][C:23]([NH:22][C:20]([C:17]2[CH:18]=[C:19]3[C:14]([CH2:13][CH2:12][N:11]3[S:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)(=[O:10])=[O:9])=[C:15]([O:32][CH3:33])[CH:16]=2)=[O:21])=[CH:24][CH:25]=1)[CH3:40]
Reactant: COc1cc(C(=O)Nc2ccc(C(=O)O)cc2)cc2c1CCN2S(=O)(=O)c1cccc(F)c1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Product: CCOC(=O)c1ccc(NC(=O)c2cc(OC)c3c(c2)N(S(=O)(=O)c2cccc(F)c2)CC3)cc1

Procedure:
4-{[1-(3-Fluoro-benzenesulfonyl)-4-methoxy-2,3-dihydro-1H-indole-6-carbonyl]-amino}-benzoic acid, m/z (ES+): 471.15 (M+H+.), was prepared in analogy to example 26, steps 1 to 6. Step 5 was performed using 3-fluoro-benzenesulfonyl chloride, yielding 4-{[1-(3-fluoro-benzenesulfonyl)-4-methoxy-2,3-dihydro-1H-indole-6-carbonyl]-amino}-benzoic acid ethyl ester, which was hydrolyzed in step 6.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17]([C:19]1[CH:41]=[CH:40][C:22]([O:23][C:24]2[CH:25]=[C:26]([NH2:39])[CH:27]=[C:28]([O:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]#[N:38])=[CH:33][CH:32]=3)[CH:29]=2)=[CH:21][CH:20]=1)#[N:18]>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14](=[O:16])[NH:39][C:26]2[CH:27]=[C:28]([O:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]#[N:38])=[CH:33][CH:32]=3)[CH:29]=[C:24]([O:23][C:22]3[CH:40]=[CH:41][C:19]([C:17]#[N:18])=[CH:20][CH:21]=3)[CH:25]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: N#Cc1ccc(Oc2cc(N)cc(Oc3ccc(C#N)cc3)c2)cc1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2cc(Oc3ccc(C#N)cc3)cc(Oc3ccc(C#N)cc3)c2)CC1
Yield: 51.7 %

Procedure:
Following the procedure of Example 9(e) piperidine-1,4-dicarboxylic acid mono-tert-butyl ester 0.7 g (3.05 mmol) and [3,5-bis-(4-cyano-phenoxy)-phenyl]-amine (1.0 g, 3.05 mmol) were used to afford 0.85 g of the required product. 1H NMR (DMSO-d6): δ 1.2 (4H, m), 1.31 (9H, s), 1.8 (4H, d), 2.21 (1H, t), 3.1 (1H, m), 6.81 (1H, d), 7.04 (1H, s), 7.2 (6H, m), 7.91 (4H, dd), 10.0 (1H, brs).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([CH:13]2[CH2:18][N:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:16][CH2:15][N:14]2[CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:12])=[CH:6][CH:5]=1)([O-])=O.O.O.[Sn](Cl)Cl>>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]([CH:13]2[CH2:18][N:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:16][CH2:15][N:14]2[CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:12])=[CH:8][CH:9]=1
Reactant: O=C(Nc1ccc([N+](=O)[O-])cc1)C1CN(c2ccccc2)CCN1Cc1ccccc1
Agent: Cl[Sn]Cl
Solvent: O
Product: Nc1ccc(NC(=O)C2CN(c3ccccc3)CCN2Cc2ccccc2)cc1

Procedure:
In a manner similar to Preparation 20, react N-(4-nitrophenyl)-4-phenyl-1-(phenylmethyl)-2-piperazinecarboxamide (6.85 g, 16.8 mmol) with tin (II) chloride dihydrate (18.5 g, 82 mmol) to obtainthe title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2Cl.[S-:13][CH2:14][CH3:15].[Na+]>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[S:13][CH2:14][CH3:15]
Reactant: Clc1ccnc2ccc(Br)cc12
Reactant: CC[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCSc1ccnc2ccc(Br)cc12
Reaction time: 15 h
Yield: 89.3 %

Procedure:
To a solution of 6-bromo-4-chloro-quinoline (1.5 g, 6.18 mmol) in DMF (60 mL) was added sodium thioethoxide (624 mg, 7.42 mmol) at 0° C. After addition, it was turned to a dark green solution which then turned to a yellow cloudy solution after 15 h at room temperature. Then, the mixture was diluted with water and extracted with ethyl acetate (3×50 mL). The combined extracts were washed with brine solution and dried over anhydrous magnesium sulfate. After filtration of the drying agent, the filtrate was removed under the vacuum and the residue was purified by using a Biotage silica gel column chromatography to afford 1.48 g (89.6% yield) of 6-bromo-4-ethylsulfanyl-quinoline as an yellow solid: EI-HRMS m/e calcd for C11H10BrNS (M+) 266.9717, found 266.9715.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12](=[O:20])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=1.[C:21](Cl)(=[O:26])[CH2:22][CH2:23][CH2:24][CH3:25]>>[Cl:11][C:7]1[CH:6]=[C:5]2[C:10]([C:2]([NH:1][C:21](=[O:26])[CH2:22][CH2:23][CH2:24][CH3:25])=[C:3]([C:12](=[O:20])[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=3)[NH:4]2)=[CH:9][CH:8]=1
Reactant: Cc1cccc(C(=O)c2[nH]c3cc(Cl)ccc3c2N)c1
Reactant: CCCCC(=O)Cl
Product: CCCCC(=O)Nc1c(C(=O)c2cccc(C)c2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 19 employing 3-amino-6-chloro-2-(3-methylbenzoyl)indole (Example 21) and valeryl chloride. m.p.: 124-126° C. 1H-NMR (CDCl3) δ: 10.02 (1H, br s), 8.40-8.18 (2H, m), 7.62-7.54 (2H, m), 7.47-7.42 (2H, m), 7.28 (1H, s), 7.09 (1H, d, J=8.8 Hz), 2.55-2.45 (5H, m), 1.82-1.68 (2H, m), 1.52-1.38 (2H, m), 0.98 (3H, t, J=7.0 Hz)
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[C:5]([N:14]2[N:18]=[CH:17][CH:16]=[N:15]2)=[N:6][CH:7]=[C:8]([CH:13]=1)[C:9]([O:11]C)=[O:10].Cl>C1COCC1.CO>[F:3][C:4]1[C:5]([N:14]2[N:18]=[CH:17][CH:16]=[N:15]2)=[N:6][CH:7]=[C:8]([CH:13]=1)[C:9]([OH:11])=[O:10]
Reactant: COC(=O)c1cnc(-n2nccn2)c(F)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cnc(-n2nccn2)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.5 %

Procedure:
A 5M potassium hydroxide aqueous solution (2 ml) was added to a THF/MeOH (2 ml/2 ml) solution containing methyl 5-fluoro-6-(2H-1,2,3-triazol-2-yl)nicotinate (250 mg), followed by stirring at room temperature for 1 hour. 6M hydrochloric acid was added to the reaction solution so as to acidify the reaction solution, followed by extraction with ethyl acetate. The organic layers were washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure and a white solid of 5-fluoro-6-(2H-1,2,3-triazol-2-yl)nicotinic acid (198 mg) was thus obtained.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[CH2:12][CH2:11]2.[C:19]1([SH:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:19]1([S:25][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[CH2:12][CH2:11]3)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Sc1ccccc1
Reactant: O=C1CCc2cc(OCCCCCBr)ccc2N1
Product: O=C1CCc2cc(OCCCCCSc3ccccc3)ccc2N1

Procedure:
Prepared analogous to Example 1 from 6-(5-bromo-pentoxy)-3,4-dihydro-carbostyril and thiophenol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([Cl:17])[CH:16]=1)[O:5][CH:6]1[CH2:10][CH2:9][N:8]([C:11](Cl)=[O:12])[CH2:7]1.[CH2:18]([N:20]([CH2:26][CH3:27])[CH2:21][CH2:22][NH:23][CH2:24][CH3:25])[CH3:19].C(O)(=O)C(O)=O>O1CCCC1.CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([Cl:17])[CH:16]=1)[O:5][CH:6]1[CH2:10][CH2:9][N:8]([C:11]([N:23]([CH2:22][CH2:21][N:20]([CH2:26][CH3:27])[CH2:18][CH3:19])[CH2:24][CH3:25])=[O:12])[CH2:7]1
Reactant: O=C(Cl)N1CCC(Oc2cc(Cl)cc(Cl)c2)C1
Reactant: CCNCCN(CC)CC
Agent: O=C(O)C(=O)O
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CCN(CC)CCN(CC)C(=O)N1CCC(Oc2cc(Cl)cc(Cl)c2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.7 %

Procedure:
A stirred solution of 7 g (0.024 mole) of 3-(3,5-dichlorophenoxy)-1-pyrrolidinecarbonyl chloride in 70 ml of tetrahydrofuran was treated with 7 g (0.05 mole) of N,N,N'-triethylethylenediamine (slight exothermic) and stirred at ambient temperature overnight. The mixture filtered to remove a small amount of precipitate. The filtrate was diluted with 200 ml of ice water, extracted with 3×100 ml of benzene and the combined extracts washed with water, dried over magnesium sulfate and concentrated in vacuo to give a pale brown oil, 8.24 g. The oil was dissolved in acetone, treated with 1.9 g of oxalic acid and heated until dissolved. A fine amorphous gel was removed by filtration and the filtrate diluted with isopropyl ether until cloudy. The salt was allowed to precipitate overnight. After 2 weeks the oil which separated from the acetone/isopropyl ether failed to crystallize. The solvents were removed by decantation and the residual oil converted back to the free base. The free base in methylene chloride was treated with 200 g of florisil and diluted with enough methylene chloride to give a stirrable slurry. After 30 minutes the slurry was filtered and the florisil washed with 2 volumes of methylene chloride. The florisil was suspended in 500 ml of methanol and transferred to a column. The column was washed with an additional 500 ml of methanol. Concentration in vacuo of the combined methanol effluents gave 7.6 g of dark oil which was chromatographed on a 100 g alumina column by eluting with a 0-5% methanol/acetonitrile gradient. The first 2 fractions were discarded and the remainder combined and concentrated to an oil (5.2 g). The oil was dissolved in ethyl ether, filtered to remove traces of alumina, concentrated in vacuo and excess solvent removed by pumping under high vacuum at 55° C. for 18 hours.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([O:10][C:11]3[CH:12]=[C:13]([CH:28]=[CH:29][CH:30]=3)[CH:14]=[C:15]3[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34]>C(Cl)Cl>[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34].[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([O:10][C:11]3[CH:30]=[CH:29][CH:28]=[C:13]([CH:14]=[C:15]4[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]4)[CH:12]=3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(Oc3ccc(C4CC4)cn3)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C(=C1CCNCC1)c1cccc(Oc2ccc(C3CC3)cn2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.9 %

Procedure:
To a solution of tert-butyl 4-(3-(5-cyclopropylpyridin-2-yloxy)benzylidene)piperidine-1-carboxylate (350 mg, 0.861 mmol) in CH2Cl2 (10 mL) was added trifluoroacetic acid (2 mL, 25.8 mmol). The reaction was stirred at RT overnight. The reaction was concentrated to give an oil. CH2Cl2 was added and the mixture was concentrated again to give the title compound as an oil (253 mg, 70% yield).
Reaction SMILES: [CH3:1][O:2][P:3]([Cl:5])Cl.C[Si](C)(C)[N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1>C(Cl)Cl>[Cl:5][P:3]([O:2][CH3:1])[N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: C[Si](C)(C)N1CCCC1
Reactant: COP(Cl)Cl
Solvent: ClCCl
Product: COP(Cl)N1CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a solution of methyldichlorophosphite (10.0 g, 75.24 mmol, 7.1 mL) in CH2Cl2 (50 mL) was added dropwise 1-(trimethylsilyl)pyrrolidine (13.1 mL, 10.8 g, 75.2 mmol) at 0° C. The resulting mixture was stirred for 2 h at room temperature. The solvent was removed under reduced pressure to give a colorless oil (11.97 g, 95%) as a product. 31P NMR (CDCl3) δ 182.3.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH:11]([CH2:15][CH2:16][OH:17])[CH2:12][CH2:13][OH:14]>CO.ClCCl>[OH:14][CH2:13][CH2:12][N:11]([C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1)[CH2:15][CH2:16][OH:17]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: OCCNCCO
Solvent: CO
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(N(CCO)CCO)cc1
Temperature: 130 °C
Yield: 84.6 %

Procedure:
A mixture of 4-fluoronitrobenzene (5 g, 35 mmol) and diethanolamine (7.5 g, 71 mmol) was heated to 130° C. without solvent for 4 hours. The crude reaction mixture after chromatography on silica gel (gravity, methanol: dichloromethane 1:19 then 1:9) gave the title compound (6.7 g, 85% yield). 1H NMR (300 MHz, DMSO-d6) δ 7.98 (d, 2H), 6.78 (d, 2H), 4.83 (t, 2H), 3.50-3.65 (m, 8H). 13C NMR (75 MHz, DMSO-d6) 6 154.36, 136.16, 126.77, 111.66, 58.89, 54.17. Mass spectrum m/z 227 (MH+). Anal. calcd. for C10H14N2O4 C, 53.09; H, 6.24; N, 12.38. Found C, 53.09, H, 6.32, N, 12.34.
Reaction SMILES: CN1CCOCC1.Cl.[CH3:9][O:10][C:11](=[O:15])[C@H:12]([CH3:14])[NH2:13].C1C=CC2N(O)N=NC=2C=1.[C:26]([NH:33][C@@H:34]([C:39](O)=[O:40])[CH2:35][CH2:36][S:37][CH3:38])([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27]>CN(C=O)C>[NH:33]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C@@H:34]([C:39]([NH:13][C@H:12]([C:11]([O:10][CH3:9])=[O:15])[CH3:14])=[O:40])[CH2:35][CH2:36][S:37][CH3:38]
Reactant: CSCC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)[C@H](C)N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)[C@H](C)NC(=O)[C@@H](CCSC)NC(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 77.1 %

Procedure:
N-methylmorpholine (5.6 g), L-alanine methyl ester hydrochloride (3.9 g), HOBt (4.6 g) and 1-(3-dimethlylaminopropyl)-3-ethylcarbodiimide (5.3 g) was added to a solution of Boc-(D)-Methionine (7 g, 0.028 mol) in dry DMF (50 ml). The mixture was stirred overnight. Solvent was removed by evaporation and the residue was partitioned between dichloromethane (100 ml) and 5% aqueous acetic acid (5 ml). On standing HOBt crystallised and was removed by filtration, and the organic layer was separated and washed with aqueous sodium bicarbonate, dried (MgSO4) and evaporated. The residue (8.5 g) was purified by flash chromatography in a sinter funnel eluting with a mixture of dichloromethane and ether (0% to 100% ether). The fractions containing product were combined and evaporated to give Boc-(D)-Met-(L)-Ala-OMe (7.2 g) as a gum which crystallised on standing; NMR (CDCl3): 1.4 (d, 3H), 1.45 (s, 9H), 1.95 (m, 1H), 2.1 (s, 3H), 2.1 (m, 1H), 2.6 (m, 2H), 3.75 (s, 3H), 4.3 (bs, 1H), 4.6 (m, 1H), 5.3 (m, 1H), 6.9 (bs, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][C:5]([Cl:23])=[CH:4][N:3]=1.[Cl:24][C:25]1[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][C:26]=1[OH:32]>>[Cl:23][C:5]1[CH:6]=[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[C:2]([O:32][C:26]2[CH:27]=[CH:28][CH:29]=[C:30]([Cl:31])[C:25]=2[Cl:24])=[N:3][CH:4]=1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Cl)cc1
Reactant: Oc1cccc(Cl)c1Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Oc2cccc(Cl)c2Cl)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 45 from methyl 4-((1S)-1-{[(2,5-dichloropyridin-3-yl)carbonyl]amino}ethyl)benzoate (step 1 of Example 48) and 2,3-dichlorophenol: 1H-NMR (CDCl3) δ 8.55 (1H, d, J=2.6 Hz), 8.10–7.99 (4H, m), 7.48–7.21 (5H, m), 5.45–5.34 (1H, m), 3.90 (3H, s), 1.61 (3H, d, J=7.1 Hz).
Reaction SMILES: [C:1](=[S:3])=S.C(O)C.[NH2:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[NH2:14]>O>[NH:7]1[CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]2[NH:14][C:1]1=[S:3]
Reactant: S=C=S
Reactant: NC1CCCCC1N
Solvent: O
Solvent: CCO
Product: S=C1NC2CCCCC2N1

Procedure:
To a mixture of 67 g. of carbon disulfide in 300 ml. of ethanol is added dropwise with stirring a solution of 100 g. of 1,2-diaminocyclohexane in 100 ml. of ethanol. The resulting solution is stirred one-half hour after addition; liquid eliminated and the residue dissolved in 300 ml. of water and heated at reflux for 18 hours. The precipitate which forms on cooling is filtered off, washed with water and then with ether and dried under reduced pressure to obtain 3a,4,5,6,7,7a-hexahydro-2-benzimidazolin-thione, m.p. 170°C.