Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:39][CH3:40])[C:4]([NH:6][C:7]1[C:8]([C:18]2[NH:22][C:21]3[CH:23]=[C:24]([F:38])[C:25]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)=[CH:26][C:20]=3[N:19]=2)=[N:9][N:10](C2CCCCO2)[CH:11]=1)=[O:5])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[CH2:39]([N:3]([CH2:1][CH3:2])[C:4]([NH:6][C:7]1[C:8]([C:18]2[NH:22][C:21]3[CH:23]=[C:24]([F:38])[C:25]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][N:32]4[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]4)=[CH:26][C:20]=3[N:19]=2)=[N:9][NH:10][CH:11]=1)=[O:5])[CH3:40]
Reactant: CCN(CC)C(=O)Nc1cn(C2CCCCO2)nc1-c1nc2cc(OCCCCN3CCCCC3)c(F)cc2[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN(CC)C(=O)Nc1c[nH]nc1-c1nc2cc(OCCCCN3CCCCC3)c(F)cc2[nH]1
Yield: 84.8 %

Procedure:
100 mg of 1,1-diethyl-3-[3-[6-fluoro-5-(4-piperidin-1-ylbutoxy)-1H-benzimidazol-2-yl]-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-yl}urea in solution in 2 mL of dichloromethane with 1 mL of trifluoroacetic acid are stirred at ambient temperature for 18 hours. The solvent is evaporated off under vacuum by flash chromatography on an Intelliflash apparatus on an Analogix RS-12 cartridge with an eluent of 100% dichloromethane to 85/15 dichloromethane/methanol. 72 mg of 1,1-diethyl-3-{3-[6-fluoro-5-(4-piperidin-1-ylbutoxy)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl}urea in the form of a trifluoroacetate salt are isolated in the form of a yellow solid. 1H NMR (400 MHz, DMSO-d6, δ in ppm). For this batch, we observe a 60%-40% resolution of tautomers with: 1.23 (m, 6H); from 1.30 to 1.91 (broad m, 10H); 2.70 to 3.53 (very broad m, 6H); 3.41 (m, 4H); 4.12 (m, 2H); 7.11 (d, J=8.0 Hz, 0.6H); from 7.24 to 7.30 (m, 0.8H); 7.44 (d, J=11.0 Hz, 0.6H); 8.00 (s, 1H); 8.94 (broad m, 1H); 9.77 (s, 0.4H); 9.79 (s, 0.6H); 12.9 (broad s, 0.4H); 12.95 (broad s, 0.6H); 13.0 (broad s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:6][C:5]=1[CH3:17])([O-:3])=[O:2].C[O:19]C(OC)N(C)C>CN(C=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:6][C:5]=1[CH:17]=[O:19])([O-:3])=[O:2]
Reactant: COC(OC)N(C)C
Reactant: Cc1cc(Oc2ccccc2)ccc1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: O=Cc1cc(Oc2ccccc2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-nitro-5-phenoxytoluene (57.3 g, 0.25 mol) prepared in Step A above and dimethylformamide dimethyl acetal (43.1 mL, 0.324 mol) in DMF (259 mL) was heated overnight at 140° C. The mixture was cooled to room temperature, and the solvent was evaporated in vacuo. The residue was dissolved in THF (500 mL) and transferred to a 3 L 3-neck flask equipped with an overhead stirrer. The mixture was diluted with 500 mL of water, and NalO4 (160 g, 0.75 mol) was added in portions (slight exotherm). The mixture was stirred overnight at room temperature. The solids were filtered and washed well with EtOAc. The filtrate was washed 3× with saturated aqueous NaHCO3 solution, and then dried (MgSO4). The solution was filtered and the solvent was evaporated in vacuo. The crude product was chromatographed (10-40% CH2Cl2:hexane) to yield 2-nitro-5-phenoxy-benzaldehyde as a yellow crystalline solid.
Reaction SMILES: [CH2:1]([O:6][C:7]1[N:12]=[C:11]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[N:10]=[C:9]([N:19]2[CH2:24][CH2:23][S:22][CH2:21][CH2:20]2)[C:8]=1[N+:25]([O-:27])=[O:26])[C:2]([CH3:5])([CH3:4])[CH3:3].Cl.[OH:29]O.[OH-].[Na+]>O>[CH2:1]([O:6][C:7]1[N:12]=[C:11]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[N:10]=[C:9]([N:19]2[CH2:20][CH2:21][S:22](=[O:29])[CH2:23][CH2:24]2)[C:8]=1[N+:25]([O-:27])=[O:26])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: OO
Reactant: CC(C)(C)COc1nc(N2CCNCC2)nc(N2CCSCC2)c1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)COc1nc(N2CCNCC2)nc(N2CCS(=O)CC2)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h

Procedure:
4.5 gm (0.011 mol) of 6-neopentyloxy-5-nitro-2-piperazino-4-thiomorpholino-pyrimidine were suspended in a mixture of 60 ml of water and 11.4 ml (0.022 mol) of 2 N hydrochloric acid. 1.66 gm (0.011 mol) of 30% hydrogen peroxide were added to the suspension, and the mixture was stirred for 24 hours at room temperature, whereby a clear solution was obtained. The solution was made alkaline by careful addition of 12 ml of 2 N sodium hydroxide, and the yellow precipitate formed thereby was suction-filtered off, washed with water and recrystallized from a mixture of 30 ml of methanol and 20 ml of water. Yield: 2.4 gm (51.2% of theory); m.p. 156°-158°C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[CH2:7][C:8]([CH3:10])=[O:9])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].C([Li])CCC.CCCCCC.[I:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=1>O1CCCC1>[C:1]([O:5][C:6](=[O:11])[CH2:7][C:8](=[O:9])[CH2:10][CH2:30][C:29]1[CH:32]=[CH:33][C:26]([I:25])=[CH:27][CH:28]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCc1ccc(I)cc1
Reactant: CC(=O)CC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)CC(=O)CCc1ccc(I)cc1
Temperature: 25 °C
Yield: 54.6 %

Procedure:
t-butylacetoacetate (1.5 mL, 9.2 mmol) was added dropwise over 2 minutes to a stirred suspension of sodium hydride (60% mineral oil suspension; 400 mg, 10.0 mmol) in tetrahydrofuran at 0° C. under nitrogen. After stirring for 10 minutes n-butyl lithium in hexane (1.6 M; 6.0 mL, 9.6 mmol) was added then stirring continued for a further ten minutes. The resulting solution was treated dropwise with a solution of 4-iodobenzyl bromide (2.97 g, 10.0 mmol) in tetrahydrofuran (4 mL) and then warmed to room temperature. The reaction was stirred for 40 minutes at room temperature and then quenched with 6 M HCl (5 mL). The resulting mixture was extracted with diethyl ether (3×50 mL). The organic phases were combined, washed with brine (50 mL) and dried (MgSO4) then the solvent evaporated under reduced pressure. The residue was purified via flash chromatography on silica gel (1:20 to 1:10 ethyl acetate/cyclohexane) to give the title compound (1.88 g, 54%) as a yellow oil. LC/MS: 3.66 min; z/e 375, calcd (M+1) 375. 1H NMR (400 MHz; CDCl3): 7.6 (2H), 6.93 (2H), 3.33 (2H), 2.85 (4H), 1.45 (9H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH2:8][OH:9])=[O:4].[CH:13]([N:16]=[C:17]=[N:18][CH:19]([CH3:21])[CH3:20])([CH3:15])[CH3:14]>CCCCCC>[CH:19]([NH:18][C:17](=[N:16][CH:13]([CH3:15])[CH3:14])[O:9][CH2:8][C:7]1[CH:10]=[CH:11][CH:12]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:6]=1)([CH3:21])[CH3:20]
Reactant: COC(=O)c1cccc(CO)c1
Reactant: CC(C)N=C=NC(C)C
Solvent: CCCCCC
Product: COC(=O)c1cccc(COC(=NC(C)C)NC(C)C)c1
Yield: 95.7 %

Procedure:
A mixture of 4.75 g (28.6 mmols) of m-methoxycarbonylbenzyl alcohol and 3.6 g (28.6 mmols) of N,N'-diisopropylcarbodiimide was stirred with 50 mg (0.51 mmols) of cuprous chloride at room temperature for 24 hours. The reaction was then diluted with 10 ml of hexane and eluted through a short column of neutral alumina with 20% ethyl acetate-hexane to give 8.0 g (96%) of N,N'-diisopropyl-O-(m-methoxycarbonylbenzyl)-isourea as a colorless oil.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][N:11]1[C:17]2[N:18]=[CH:19][CH:20]=[CH:21][C:16]=2[C:15]2[CH:22]=[CH:23][CH:24]=[CH:25][C:14]=2[C:13](=[N:26]O)[C:12]1=[O:28])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H][H]>[Ni].O1CCCC1>[NH2:26][CH:13]1[C:14]2[CH:25]=[CH:24][CH:23]=[CH:22][C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[N:18][C:17]=2[N:11]([CH2:10][CH2:9][O:8][Si:1]([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:2])[CH3:3])[C:12]1=[O:28]
Reactant: [H][H]
Reactant: CC(C)(C)[Si](C)(C)OCCn1c(=O)c(=NO)c2ccccc2c2cccnc21
Agent: [Ni]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCN1C(=O)C(N)c2ccccc2-c2cccnc21
Temperature: 62.5 °C
Reaction time: 24 h
Yield: 98.3 %

Procedure:
Combine 5-[2-(tert-butyl(dimethyl)silyl)oxyethyl]-7-hydroxyimino-pyrido[2,3-d][3]benzazepin-6-one (206.0 g, 0.52 mol) and tetrahydrofuran (2.3 L) into an autoclave under an atmosphere of nitrogen. Add Raney nickel (232.0 g, 1.13 wt/wt equivalents) to the reaction mixture and introduce hydrogen atmosphere (87 psi). Stir the reaction mixture at 60-65° C. for 24 hours. Filter the mixture over diatomaceous earth and wash the filter aid with tetrahydrofuran (500 mL). Concentrate the filtrate to obtain the title compound (196.0 g, 93.2%) as a brown oil. MS (m/z): 384 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:23][C:24]1[CH:25]=[C:26]([C:30]2[CH:35]=[C:34]([O:36][CH3:37])[C:33]([O:38][CH3:39])=[C:32]([O:40][CH3:41])[CH:31]=2)[CH:27]=[N:28][CH:29]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH2:23][C:24]2[CH:25]=[C:26]([C:30]3[CH:35]=[C:34]([O:36][CH3:37])[C:33]([O:38][CH3:39])=[C:32]([O:40][CH3:41])[CH:31]=3)[CH:27]=[N:28][CH:29]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc(-c2cncc(CCl)c2)cc(OC)c1OC
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(F)cc2)CC1
Product: COc1cc(-c2cncc(CN(c3ccc(F)cc3)C3CCN(C(=O)OC(C)(C)C)CC3)c2)cc(OC)c1OC

Procedure:
1-(tert-Butoxycarbonyl)-4-[(4-fluorophenyl)amino]piperidine (589 mg) and 5-chloromethyl-3-(3,4,5-trimethoxyphenyl)pyridine (588 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[C:35]([CH:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[C:35]([CH:37]3[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]3)=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCN(C(=O)C1CCCCC1)c1ccc2nc(CCCC)n(Cc3ccc(-c4ccccc4C(=O)OC(C)(C)C)cc3)c2c1
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCN(C(=O)C1CCCCC1)c1ccc2nc(CCCC)n(Cc3ccc(-c4ccccc4C(=O)O)cc3)c2c1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-buty1-6-(N-cyclohexylcarbonyl-n-hexylamino)-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:9]1([CH3:14])[O:13][CH2:12][CH2:11][O:10]1)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[Cl:15][C:16]1[CH:17]=[C:18]2[C:23](=O)[O:22][C:20](=[O:21])[C:19]2=[CH:25][C:26]=1[Cl:27]>>[Cl:15][C:16]1[CH:17]=[C:18]2[C:19](=[CH:25][C:26]=1[Cl:27])[C:20](=[O:21])[N:1]([CH2:2][CH:3]([C:9]1([CH3:14])[O:10][CH2:11][CH2:12][O:13]1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:23]2=[O:22]
Reactant: CCOC(=O)C(CN)C1(C)OCCO1
Reactant: O=C1OC(=O)c2cc(Cl)c(Cl)cc21
Product: CCOC(=O)C(CN1C(=O)c2cc(Cl)c(Cl)cc2C1=O)C1(C)OCCO1

Procedure:
Ethyl 3-(5,6-dichloro-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-(2-methyl-[1,3]dioxolan-2-yl)propionate was prepared (0.66 g, 50%) in the same manner as described in the above example 5 (20) from ethyl 3-amino-2-(2-methyl-[1,3]dioxolan-2-yl)propionate (0.60 g, 3.25 mmol) and 4,5-dichlorophthalic anhydride (0.85 g, 3.90 mmol), and the obtained product was identified with the following NMR data.
Reaction SMILES: [Na+].[N+:2]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([S:14]([OH:17])(=[O:16])=[O:15])[CH:13]=1)[C:8]([O-:10])=O)([O-:4])=[O:3].C(Cl)(=O)C(Cl)=O.[NH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]>N1C=CC=CC=1.C1COCC1>[N+:2]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([S:14]([OH:17])(=[O:16])=[O:15])[CH:13]=1)[C:8]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])=[O:10])([O-:4])=[O:3]
Reactant: O=C([O-])c1cc([N+](=O)[O-])cc(S(=O)(=O)O)c1
Reactant: NCCCCCC(=O)OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(CCCCCNC(=O)c1cc([N+](=O)[O-])cc(S(=O)(=O)O)c1)OCc1ccccc1
Reaction time: 2 h
Yield: 35.2 %

Procedure:
14.6 g of 3-nitro-5-sulfobenzoic acid monosodium salt were dissolved in 300 ml of pyridine and stirred for 2 hours, after which 2.2 ml of oxalyl chloride were added dropwise. After 1 hour, 16.6 g of benzyl ε-aminocaproate as a solution in 100 ml of THF were added dropwise and the mixture was stirred overnight. The mixture was concentrated on a rotary evaporator and then stirred with 100 g of strongly acid ion exchanger in 100 ml water for 50 hours. The mixture was filtered and washed with water, and the filtrate was concentrated. The residue was dissolved in 30% methanol/water, treated with 21 g of tetraethylammonium bromide and adjusted to pH 6.5 with sodium hydroxide solution. The resulting solution was chromatographed on 500 g of silanized silica gel (RP2) with 30% methanol. 8.6 g of benzyl ε-(3-nitro-5-sulfobenzoylamino)caproate were obtained in the form of the tetraethylammonium salt, which was stirred with 100 g of cation exchanger in water, filtered off and washed with water. The filtrate was concentrated and gave the corresponding free sulfonic acid. TLC (silica gel: HOAc/EtOAc=20%) Rf=0.7 (educt=0.4); TLC (silica gel: NH3/EtOH=1%) Rf=0.8 (educt=0.7); TLC (RP18: EtOH/Et4N+ (0.01M) phosphate buffer (0.1M; pH 6.5)=60% Rf=0.4 (educt=0.8). HPLC (RP18: MeCN/Et4N+ (0.01M) phosphate buffer (0.1M; pH 6.5)=30%) tR =5.9 min. (educt=1.3 min). 1.32 g of benzyl 6-(3-nitro-5-sulfobenzoylamino)hexanoate were dissolved in 30 ml ethanol/water=60%, 100 mg of Pd/C 10% were added and the mixture was hydrogenated while stirring (magnetic stirrer). The total absorption of hydrogen (1.5 hours) was 235 ml. TLC control showed that starting material was no longer present. In the TLC the amine is present practically at the start. The catalyst was filtered off and the solution was concentrated to dryness on a rotary evaporator. The IR control of the substance showed the complete absence of the original nitro group and of the benzyl group. The resulting 6-(3-amino-5-sulfobenzoylamino)hexanoic acid was used directly for the preparation of the azide.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C(Cl)Cl>[CH3:17][S:18]([NH:9][CH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: NCCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NCCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 106.4 %

Procedure:
To a 10° C. solution of phenethylamine (12.1 g, 0.100 mol) and triethylamine (11.1 g, 0.110 mol) in CH2Cl2 (50 mL) was added methanesulfonyl chloride (12.6 g, 0.110 mol) dropwise over 10 min. The solution was stirred at room temperature for 1.5 h and was then washed with 1N HCl (5×20 mL). The organic phase was directly concentrated to provide the intermediate title compound, (methylsulfonyl)(2-phenylethyl)amine, (21.2 g, 93.3%) as an oil.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[Cl:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:12]=1[CH3:18]>C(O)(=O)C>[Cl:10][C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([N+:6]([O-:9])=[O:7])=[CH:13][C:12]=1[CH3:18]
Reactant: Cc1ccc(C)c(Cl)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1cc([N+](=O)[O-])c(C)cc1Cl

Procedure:
A sulphonitric mixture at 0° C., composed of sulphuric acid (3.8 ml) and nitric acid (1 ml), is added dropwise to a mixture, cooled to 10° C., of 2-chloro-1,4-xylene (1.4 g), acetic acid (17 ml) and 98% sulphuric acid (1 ml). The reaction medium is poured into a water/ice mixture and then filtered. The yellow precipitate is recrystallized from petroleum ether to give the title compound.
Reaction SMILES: [Li]CCCC.[O:6]([C:13]1[CH:18]=[C:17]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:16]=[C:15]([S:26][CH3:27])[N:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:28](=[O:30])=[O:29].Cl>C1COCC1>[O:6]([C:13]1[C:18]([C:28]([OH:30])=[O:29])=[C:17]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:16]=[C:15]([S:26][CH3:27])[N:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CSc1nc(Oc2ccccc2)cc(Oc2ccccc2)n1
Reactant: O=C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CSc1nc(Oc2ccccc2)c(C(=O)O)c(Oc2ccccc2)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
n-BuLi (1.0M, 1.2 mmol) was added to a stirred solution of 4,6-diphenoxy-2-(methylthio)pyrimidine (298 mg, 1.0 mmol) in THF (2 ml) at −78° C. The reaction mixture was stirred for 2 hours and warmed up to 0° C. Dry ice (5 pieces) was added in small pieces over 10 minutes and the reaction was warmed to room temperature for 30 minutes. Dilute HCl was added and the mixture was extracted with EtOAc. The combined organic extract was dried over MgSO4, filtered and evaporated in vacuo to give a yellow solid that was recrystallized from ethyl acetate/hexanes to give a yellow solid (243 mg, 71% yield), m.p. 97-98° C.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:6][N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][S:10][C:9]2[CH:18]=[CH:19][CH:20]=[CH:21][C:8]1=2.[CH3:22][O:23][C:24]1[CH:32]=[CH:31][C:27]([CH2:28][CH2:29]Br)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.[I-].[Na+]>[CH3:22][O:23][C:24]1[CH:32]=[CH:31][C:27]([CH2:28][CH2:29][N:1]2[CH2:5][CH2:4][CH2:3][C@H:2]2[CH2:6][N:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH2:11][S:10][C:9]3[CH:18]=[CH:19][CH:20]=[CH:21][C:8]2=3)=[CH:26][CH:25]=1
Reactant: COc1ccc(CCBr)cc1
Reactant: c1ccc2c(c1)CSc1ccccc1N2C[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: COc1ccc(CCN2CCC[C@H]2CN2c3ccccc3CSc3ccccc32)cc1
Yield: 61.5 %

Procedure:
A mixture of (S)-5,11-dihydro-5-(2-pyrrolidinylmethyl)dibenzo[b,e][1,4]thiazepine (see Preparations 13 and 14) (2.8 g), 4-methoxyphenethyl bromide (2.6 g), sodium carbonate (1.30 g) and sodium iodide (50 mg) in acetonitrile (75 ml) was heated under reflux for 16 hours, evaporated under reduced pressure and the residue partitioned between ethyl acetate and water. The organic layer was washed with water, dried over sodium sulphate and evaporated under reduced pressure. The residue was purified by chromatography on silica gel, performing a gradient elution using initially dichloromethane as eluant and changing to dichloromethane/saturated methanolic ammonia (98:2). The appropriate fractions were combined and evaporated under reduced pressure to give the title compound as a colourless oil, (2.5 g, 62%).
Reaction SMILES: [F:1][C:2]1[CH:37]=[CH:36][C:5]([C:6]([N:8]2[CH2:12][C@H:11]([CH2:13][CH2:14][CH2:15][B:16]3[O:20]C(C)(C)C(C)(C)[O:17]3)[C@:10]([NH:29]C(=O)C(F)(F)F)([C:25]([O:27]C)=[O:26])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.O.[OH-].[Li+].[ClH:41]>C1COCC1.O>[ClH:41].[NH2:29][C:10]1([C:25]([OH:27])=[O:26])[CH:11]([CH2:13][CH2:14][CH2:15][B:16]([OH:20])[OH:17])[CH2:12][N:8]([C:6](=[O:7])[C:5]2[CH:36]=[CH:37][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:9]1
Reactant: COC(=O)[C@]1(NC(=O)C(F)(F)F)CN(C(=O)c2ccc(F)cc2)C[C@@H]1CCCB1OC(C)(C)C(C)(C)O1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: NC1(C(=O)O)CN(C(=O)c2ccc(F)cc2)CC1CCCB(O)O
Yield: 30 %

Procedure:
A stirred solution of racemic methyl (3R,4S)-1-(4-fluorobenzoyl)-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl]-3-[(trifluoroacetyl)amino]pyrrolidine-3-carboxylate (200 mg, 0.377 mmol) in THF (4.2 mL) and water (3.7 mL) was sparged with nitrogen for 5 min. Lithium hydroxide monohydrate (33.2 mg, 0.792 mmol) was added, and the mixture was sparged with nitrogen for 10 min and stirred under nitrogen at room temperature for 4 days, during which additional lithium hydroxide monohydrate (39.6 mg, 0.943 mmol) was added. The mixture was diluted with water (5 mL) and acidified to pH<1 with 3 M aqueous HCl. The resulting solution was washed with ethyl acetate (2×20 mL) and methylene chloride (2×20 mL). The aqueous phase was concentrated under reduced pressure and purified by reverse phase HPLC. Product fractions were pooled, concentrated, re-dissolved in 1M aqueous HCl, concentrated and lyophilized to give racemic (3R,4S)-3-amino-4-[3-(dihydroxyboryl)propyl]-1-(4-fluorobenzoyl)pyrrolidine-3-carboxylic acid hydrochloride (42 mg, 30%) as a white amorphous solid. MS (ESI+) m/z 321 (M−H2O+H+), 303 (M−2H2O+H+) and MS (ESI−) m/z 319 (M−H2O−H+).
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[C:11]([CH3:13])[C:10]2[C:9](=[O:14])[N:8]([CH2:15][CH2:16][OH:17])[C@@H:7]3[CH2:18][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][C@H:6]3[C:5]=2[CH:4]=1)[CH3:2].[C:28]1(O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1(C)C=CC=CC=1.Cl>[CH2:1]([C:3]1[CH:12]=[C:11]([CH3:13])[C:10]2[C:9](=[O:14])[N:8]([CH2:15][CH2:16][O:17][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@@H:7]3[CH2:18][N:19]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:20][C@H:6]3[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1cc(C)c2c(c1)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1N(CCO)C2=O
Reactant: Oc1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCc1cc(C)c2c(c1)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1N(CCOc1ccccc1)C2=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 59 %

Procedure:
To a solution of (±)-trans tert-butyl 8-ethyl-4-(2-hydroxyethyl)-6-methyl-5-oxo-3,3a,4,5-tetrahydro-1H-pyrrolo[3,4-c]isoquinoline-2(9bH)-carboxylate, from Example 86, Part B, (24 mg, 0.064 mmol) in 1 mL of toluene was added phenol (9 mg, 0.096 mmol), triphenylphosphine (20 mg, 0.077 mmol) and diethylazodicarboxylate (0.035 mL, 0.077 mmol). The resulting mixture was allowed to stir at ambient temperature for 18 h. The reaction was diluted with 10 mL of 1 N HCl and extracted with ethyl acetate. The organics were washed with sat'd aq NaHCO3 and brine, dried (MgSO4), filtered through a pad of silica gel and concentrated in vacuo. The residue was purified by flash chromatography (elution with 3:1 hexane/ethyl acetate) to afford 17 mg (59%) of the title compound as an oil. LRMS (ESI): 451.1 (M+H)+.