Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].C([O:6][CH:7](OCCCC)[C@H:8]([CH2:39][CH2:40][CH2:41][NH:42][C:43](=[NH:45])[NH2:44])[NH:9][C:10](=[O:38])[C@H:11]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[NH:12][C:13](=[O:30])[C@@H:14]1[CH2:18][CH2:17][C:16](=[O:19])[N:15]1[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])CCC.Cl.[OH-].[Na+]>C(#N)C>[ClH:1].[CH2:23]([O:22][C:20]([N:15]1[C:16](=[O:19])[CH2:17][CH2:18][C@H:14]1[C:13]([NH:12][C@H:11]([C:10]([NH:9][C@H:8]([CH:7]=[O:6])[CH2:39][CH2:40][CH2:41][NH:42][C:43](=[NH:44])[NH2:45])=[O:38])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:30])=[O:21])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCCCOC(OCCCC)[C@H](CCCNC(=N)N)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCC(=O)N1C(=O)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: N=C(N)NCCC[C@@H](C=O)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCC(=O)N1C(=O)OCc1ccccc1
Yield: 61.3 %

Procedure:
To a solution of N-benzyloxycarbonyl-L-pyroglutamyl-L-phenylalanyl-L-argininal dibutylacetal hydrochloride (72 mg, 0.10 mmol) in acetonitrile (10 ml) was added 1N hydrochloric acid aqueous solution (5 ml). The mixture was reacted at 36° C. for 1.5 hour with stirring. After completion of the reaction, pH of the reaction mixture was adjusted to 4.8 with 1N sodium hydroxide aqueous solution. The solvent was distilled off under reduced pressure and chloroform was added to the residue. Insoluble matters were removed by filtration. After the filtrate was concentrated, the residue was recrystallized from chloroform-hexane to give 36 mg (61%) of N-benzyloxycarbonyl-L-pyroglutamyl-L-phenylalanyl-L-argininal hydrochloride.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:39]=[CH:38][C:18]([C:19]([O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([O:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([OH:37])[CH:32]=3)=[O:29])=[CH:24][CH:23]=2)=[O:20])=[CH:17][CH:16]=1.[CH2:40]([O:42][C:43]([S:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][O:58][C:59]1[CH:76]=[CH:75][C:62]([C:63]([O:65][C:66]2[CH:74]=[CH:73][C:69]([C:70](O)=[O:71])=[CH:68][CH:67]=2)=[O:64])=[CH:61][CH:60]=1)=[S:44])[CH3:41].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.CC(=O)OCC>[CH2:40]([O:42][C:43]([S:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][O:58][C:59]1[CH:76]=[CH:75][C:62]([C:63]([O:65][C:66]2[CH:74]=[CH:73][C:69]([C:70]([O:37][C:33]3[CH:34]=[CH:35][CH:36]=[C:31]([O:30][C:28](=[O:29])[C:25]4[CH:24]=[CH:23][C:22]([O:21][C:19](=[O:20])[C:18]5[CH:38]=[CH:39][C:15]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Br:1])=[CH:16][CH:17]=5)=[CH:27][CH:26]=4)[CH:32]=3)=[O:71])=[CH:68][CH:67]=2)=[O:64])=[CH:61][CH:60]=1)=[S:44])[CH3:41]
Reactant: CCOC(=S)SCCCCCCCCCCCCOc1ccc(C(=O)Oc2ccc(C(=O)O)cc2)cc1
Reactant: O=C(Oc1ccc(C(=O)Oc2cccc(O)c2)cc1)c1ccc(OCCCCCCCCCCCCBr)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Product: CCOC(=S)SCCCCCCCCCCCCOc1ccc(C(=O)Oc2ccc(C(=O)Oc3cccc(OC(=O)c4ccc(OC(=O)c5ccc(OCCCCCCCCCCCCBr)cc5)cc4)c3)cc2)cc1

Procedure:
Synthesized as described for the preparation of compound BC1. Quantities: 25 (0.22 g, 0.37 mmol), 22 (0.20 g, 0.37 mmol), DMAP (0.045 g, 0.37 mmol), DCC (0.15 g, 0.73 mmol). Yield 0.25 g (61%). EA: Found: C, 64.49; H, 6.81. C61H73BrO11S2 requires C, 65.05; H, 6.53%. 1H NMR: δH (CDCl3; 300 MHz): 1.22-1.62 (35 H, m, CH2/O—CH2—CH3), 1.71 (2 H, m, S—CH2—CH2), 1.87 (6 H, m, O—CH2—CH2/Br—CH2—CH2), 3.13 (2 H, t, 3J=7.4 Hz, SCH2), 3.42 (2 H, t, 3J=6.8 Hz, CH2Br), 4.07 (4 H, t, 3J=6.5 Hz, OCH2), 4.66 (2 H, q, 3J=7.1 Hz, O—CH2—CH3), 7.01 (2 H, d, 3J=8.7 Hz, Ar—H), 7.21 (3 H, m, Ar—H), 7.40 (4 H, d, 3J=8.5 Hz, Ar—H), 7.51 (1 H, t, 3J=8.1 Hz, Ar—H), 8.17 (4 H, d, 3J=8.7 Hz, Ar—H), 8.30 (4 H, d, 3J=8.5 Hz, Ar—H). 13C NMR: δC (CDCl3; 75 MHz): 13.8, 26.0, 28.2, 28.3, 28.8, 28.9, 29.0, 29.3, 29.35, 29.4, 29.5, 31.7, 32.8, 34.0, 35.9, 53.8, 68.4, 69.5, 69.7, 114.4, 115.8, 119.3, 120.9, 122.1, 126.6, 129.9, 131.9, 132.4, 151.4, 155.5, 163.8, 164.1, 164.3, 210.8. m/z (MALDI) 1147.56 (100%) and 1149.59 (97%) [M+Na]+, C61H73BrNaO11S2 requires 1147.37 (100.0%) and 1149.37 (97%).
Reaction SMILES: [C:1]([OH:13])(=[O:12])[CH2:2][C:3]([CH2:8][C:9]([OH:11])=[O:10])([C:5]([OH:7])=[O:6])[OH:4].I[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>CN(C)C=O>[CH2:15]([O:10][C:9](=[O:11])[CH2:8][C:3]([C:5]([O:7][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH3:15])=[O:6])([OH:4])[CH2:2][C:1]([O:13][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH3:15])=[O:12])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCCCCCCCCCCI
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCOC(=O)CC(O)(CC(=O)OCCCCCCCCCCCCCCCC)C(=O)OCCCCCCCCCCCCCCCC
Temperature: 50 °C
Reaction time: 21 h
Yield: 83 %

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene(1,5-5)(4.567 g, 30 mmol) was added at room temperature to a solution of citric acid (1.924 g, 10 mmol) in N,N-dimethylformamide (50 ml). 1-Iodohexadecane (10.570 g, 30 mmol) was added and the resulting mixture was stirred at 50° C. for 21 hours. The precipitated product was filtered off and washed with N,N-dimethylformamide and the crude product was purified by flash chromatography on silica gel using chlorform/hexane for elution. Yield: 83%. 1H-NMR (300 MHz, CDCl3): δ 088(t,9H), 1.26(m,78H), 1.60(m,6H), 2.84(q,4H), 4.07(t,4H), 4.13(s,1H), 4.20(t,2H). FAB-MS: 887.6(M+Na).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)=[O:9].[NH2:16][C:17]1[C:18](Cl)=[N:19][CH:20]=[CH:21][CH:22]=1>>[NH2:16][C:17]1[C:18]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[O:9])=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: Nc1cccnc1Cl
Reactant: Nc1ccccc1C(=O)c1ccccn1
Product: Nc1cccnc1Nc1ccccc1C(=O)c1ccccn1

Procedure:
The title compound is prepared by reacting (2-aminophenyl)(2-pyridinyl)methanone, as prepared by Schofield, K., J. Chem. Soc. 1949, 2408-12, with 3-amino-2-chloropyridine.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:13][CH:12]2[N:14]([S:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH:8]([CH2:9][C:10](=[O:25])[CH2:11]2)[CH2:7]1)=[O:5])[CH3:2].[CH:26](OCC)=[O:27].[O-]CC.[Na+]>C1COCC1.C(O)C>[CH2:1]([O:3][C:4]([CH:6]1[CH2:7][CH:8]2[N:14]([S:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH:12]([CH2:11][C:10](=[O:25])[C:9]2=[CH:26][OH:27])[CH2:13]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CC2CC(=O)CC(C1)N2S(=O)(=O)c1ccc(Cl)cc1
Reactant: CCOC=O
Agent: CC[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)C1CC2CC(=O)C(=CO)C(C1)N2S(=O)(=O)c1ccc(Cl)cc1
Temperature: 60 °C
Yield: 94 %

Procedure:
9-(4-Chloro-benzenesulfonyl)-7-oxo-9-aza-bicyclo[3.3.1]nonane-3-carboxylic acid ethyl ester (2.49 g, 6.45 mmol) was dissolved in THF/ethanol (14 mL, 1/1, v/v). Ethyl formate (5.19 mL, 64.53 mmol) was added followed by sodium ethoxide (6.2 mL of 21% solution in ethanol). The resulting mixture was heated to 60° C. for 30 minutes after which the solution was cooled to room temperature and quenched by the addition of saturated aqueous NH4Cl (10 mL). The resulting mixture was extracted with EtOAc (2×20 mL) and the combined organic phases were dried (Na2SO4), filtered and concentrated under vacuum to yield 2.51 g (94%) of 9-(4-chloro-benzenesulfonyl)-6-hydroxymethylene-7-oxo-9-aza-bicyclo[3.3.1]nonane-3-carboxylic acid ethyl ester as a yellow oil. Retention time (min)=2.017, method [1], MS (ESI) 414.0 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:11][C@@H:10]([O:12][S:13]([CH3:16])(=[O:15])=[O:14])[C@@H:9](OS(C)(=O)=O)[C@H:8]([N:22]=[N+]=[N-])[CH:7]=1)=[O:5])[CH3:2].[P:25]([O:32]CC)([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28]>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[CH2:11][C@@H:10]([O:12][S:13]([CH3:16])(=[O:15])=[O:14])[C@@H:9]2[C@@H:8]([N:22]2[P:25]([O:29][CH2:30][CH3:31])([O:26][CH2:27][CH3:28])=[O:32])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOP(OCC)OCC
Reactant: CCOC(=O)C1=C[C@@H](N=[N+]=[N-])[C@H](OS(C)(=O)=O)[C@H](OS(C)(=O)=O)C1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1=C[C@H]2[C@@H]([C@H](OS(C)(=O)=O)C1)N2P(=O)(OCC)OCC
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
(3R,4S,5R)-3-azido-4,5-bis-methanesulfonyloxy-cyclohex-1-enecarboxylic acid ethyl ester (44) was dissolved under argon with stirring in toluene. The clear solution was treated at room temperature with triethyl phosphite and stirred at room temperature for 30 minutes whereby after about 5 minutes gas evolution started. The light yellow reaction mixture was heated to reflux for 6 hours, evaporated at 40° C./60-10 mbar to yield of the crude product (1S,5R,6S)-7-(diethoxy-phosphoryl)-5-methanesulfonyloxy-7-aza-bicyclo[4.1.0]hept-2-ene-3-carboxylic acid ethyl ester (45) as a yellow oil, which was used in the next step without further purification. An analytical sample of (1S,5R,6S)-7-(diethoxy-phosphoryl)-5-methanesulfonyloxy-7-aza-bicyclo[4.1.0]hept-2-ene-3-carboxylic acid ethyl ester was obtained via a silica column chromatography using a 2:1 mixture of toluene and acetone. The combined fractions were evaporated and dried on a rotary evaporator at 40° C./250-10 mbar to obtain 45 as a yellow oil (45).
Reaction SMILES: [C-:1]#[N:2].[Na+].S(=O)(=O)(O)O.Br[CH2:10][C:11]1[CH:27]=[C:26]([Cl:28])[C:14]([CH2:15][C:16]2[CH:17]=[C:18]([CH:23]([CH3:25])[CH3:24])[C:19](=[O:22])[NH:20][N:21]=2)=[C:13]([Cl:29])[CH:12]=1.C(=O)(O)[O-].[Na+]>CS(C)=O.O>[Cl:29][C:13]1[CH:12]=[C:11]([CH2:10][C:1]#[N:2])[CH:27]=[C:26]([Cl:28])[C:14]=1[CH2:15][C:16]1[CH:17]=[C:18]([CH:23]([CH3:25])[CH3:24])[C:19](=[O:22])[NH:20][N:21]=1
Reactant: CC(C)c1cc(Cc2c(Cl)cc(CBr)cc2Cl)n[nH]c1=O
Reactant: [C-]#N
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)c1cc(Cc2c(Cl)cc(CC#N)cc2Cl)n[nH]c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of sodium cyanide (270 mg, 5.51 mmol) in dimethyl sulfoxide (2 mL) at room temperature was treated with concentrated sulfuric acid (0.1 mL, 1.88 mmol) and a solution of 6-(4-bromomethyl-2,6-dichloro-benzyl)-4-isopropyl-pyridazin-3-one (54) (70 mg, 0.180 mmol) in dimethyl sulfoxide (2 mL). The reaction mixture was stirred at room temperature for 30 min and then at 50° C. for 1 h. The reaction was cooled to room temperature, poured into a saturated aqueous sodium bicarbonate solution (50 mL), was diluted with water (20 mL) and then extracted with ethyl acetate (3×75 mL). The organic layers were combined and washed with a saturated aqueous sodium chloride solution (50 mL), dried over magnesium sulfate, filtered, and concentrated under vacuum. The resulting oil was dried under high vacuum to afford [3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-ylmethyl)-phenyl]-acetonitrile (55) as an orange oil (assume 0.180 mmol) which was used without further purification.
Reaction SMILES: Cl.Cl.[CH:3]12[NH:10][CH:7]([CH2:8][CH2:9]1)[CH2:6][CH:5]([NH:11][C:12]([N:14]1[CH2:18][CH2:17][C@@H:16]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][N:21]=3)[CH2:15]1)=[O:13])[CH2:4]2.CCN(C(C)C)C(C)C.[Si]([N:41]=[C:42]=[O:43])(C)(C)C>C(Cl)Cl>[C:26]([C:23]1[CH:24]=[CH:25][C:20]([NH:19][C@@H:16]2[CH2:17][CH2:18][N:14]([C:12]([NH:11][CH:5]3[CH2:6][CH:7]4[N:10]([C:42]([NH2:41])=[O:43])[CH:3]([CH2:9][CH2:8]4)[CH2:4]3)=[O:13])[CH2:15]2)=[N:21][CH:22]=1)#[N:27]
Reactant: C[Si](C)(C)N=C=O
Reactant: N#Cc1ccc(N[C@@H]2CCN(C(=O)NC3CC4CCC(C3)N4)C2)nc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(N[C@@H]2CCN(C(=O)NC3CC4CCC(C3)N4C(N)=O)C2)nc1
Reaction time: 8 h

Procedure:
To a stirred solution of (3R)—N-(8-azabicyclo[3.2.1]octan-3-yl)-3-(5-cyanopyridin-2-ylamino)pyrrolidine-1-carboxamide dihydrochloride salt (17.5 mg, 0.042 mmol) and i-Pr2NEt (0.032 mL, 0.18 mmol) in CH2Cl2 (1 mL) was added Me3SiNCO (0.008 mL, 0.06 mmol). The mixture was stirred at overnight and concentrated. The residue was purified by prep HPLC to give two isomeric products.
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][C:6]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])=[N:5][C:4]=2[CH:3]=1.[CH3:19][C:20]1[C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][N:22](C(OC(C)(C)C)=O)[N:21]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>O>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:6]1[NH:7][C:8](=[O:11])[C:9]2[S:10][C:2]([C:24]3[CH:23]=[N:22][NH:21][C:20]=3[CH3:19])=[CH:3][C:4]=2[N:5]=1
Reactant: O=c1[nH]c(-c2ccccc2Cl)nc2cc(Br)sc12
Reactant: Cc1nn(C(=O)OC(C)(C)C)cc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1[nH]ncc1-c1cc2nc(-c3ccccc3Cl)[nH]c(=O)c2s1
Temperature: 100 °C
Reaction time: 1 h
Yield: 27.3 %

Procedure:
6-Bromo-2-(2-chlorophenyl)thieno[3.2-d]pyrimidin-4 (3H)-one (157 mg), tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (425 mg), sodium carbonate (138 mg), 1,2-dimethoxyethane (4.0 mL) and water (2.0 mL) were placed in a flask, and the atmosphere in the flask was purged with argon. [1,1′-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride-dichloromethane complex (1:1) (38 mg) was added, and the atmosphere in the flask was purged again with argon. The reaction system was stirred at 100° C. for 1 hr, 8M aqueous sodium hydroxide solution (1 mL) was added, and the mixture was stirred at 100° C. for 30 min. After stirring, the mixture was extracted with ethyl acetate/tetrahydrofuran mixture, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and the obtained pale-yellow solid was crystallized from methanol/ethyl acetate to give the title compound (43 mg) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].[H-].[Na+].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O1CCCC1>[CH2:12]([O:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[Cl:1])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc(F)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Fc1ccc(OCc2ccccc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.2 %

Procedure:
To a solution of 2-chloro-4-fluorophenol (617, 7 g, 0.05 mol) in tetrahydrofuran (100 mL) was added sodium hydride (1.8 g, 95% dry powder, 0.071 mol) at room temperature over 15 minutes under an atmosphere of nitrogen. The reaction mixture was stirred at room temperature for 30 minutes. Benzyl bromide (10 g, 0.060 mol) was added slowly to the reaction mixture, then stirred at room temperature overnight. The reaction mixture was poured into ice water, extracted with ethyl acetate, washed with hydrochloric acid (10%), water, brine, and dried over magnesium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with ethyl acetate in hexane to provide compound as a white solid (618, 7.6 g, 60%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:14]=[N:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][C:3]=1[O:23][CH3:24].[Li]CCCC.S([N:40]=[N+:41]=[N-:42])(C1C=CC(C)=CC=1)(=O)=O>C1COCC1>[N:40]([C:14]1[N:15]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)[C:11]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([O:23][CH3:24])[CH:4]=2)([CH3:9])[CH3:10])=[CH:12][N:13]=1)=[N+:41]=[N-:42]
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: COc1cc(C(C)(C)c2cncn2-c2ccc(F)cc2)ccc1Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(C(C)(C)c2cnc(N=[N+]=[N-])n2-c2ccc(F)cc2)ccc1Cl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 54.8 %

Procedure:
To a −78° C. solution of 5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazole (0.215 g, 0.62 mmol) in 3 mL of THF (3 mL) was added 1.67 M BuLi (0.45 mL, 0.75 mmol). The reaction was stirred at −78° C. for 30 min and then tosyl azide (0.160 g, 0.81 mmol) in THF (0.5 mL) was added dropwise. The reaction was stirred at −78° C. for 1 h when it was determined to be complete by LCMS. The reaction was quenched at −78° C. with pH 7 buffer and allowed to warm to room temperature. The mixture was extracted with DCM (3×10 mL) and dried with MgSO4. The residue was purified by column chromatography using Hex:EtOAc as eluents to afford 2-azido-5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazole (131 mg) as a yellow oil. MS (EI) m/z 386 [M+H]+.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:28][CH:29]([CH2:39]O)[CH2:30][NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35].N1C=CC=CC=1>ClCCl>[Br:8][CH2:39][CH:29]([F:28])[CH2:30][NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)(C)OC(=O)NCC(F)CO
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NCC(F)CBr
Reaction time: 0.17 h

Procedure:
To a suspension of NBS (20 g, 110 mmol, 3.0 equiv) in dichloromethane (250 mL) was added dropwise triphenylphosphine (28 g, 110 nmol, 3.0 equiv) in dichloromethane (100 mL). After addition was complete, the reaction mixture was stirred for 10 min and a solution of tert-butyl 2-fluoro-3-hydroxypropylcarbamate (1-8) (7.0 g, 36 mmol, 1 equiv) in dichloromethane (100 mL) followed by pyridine (3.5 g, 44 mmol, 1.2 equiv) were added. The resulting mixture was stirred at 23° C. under nitrogen for 16 h. The reaction solution was concentrated and purified by silica gel chromatography (100% hexanes to 100% ethyl acetate over 1 h, analysis by Ninhydrin stain) to yield tert-butyl 3-bromo-2-fluoropropylcarbamate (1-9) as a clear oil. 1H NMR (500 MHz, CDCl3) δ 4.89-4.68 (m, 2H), 3.55-3.40 (m, 2H), 1.45 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:39])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[NH:11][C:10]([C:21]3[C:22]([O:36][CH2:37][CH3:38])=[CH:23][C:24]([Cl:35])=[C:25]([S:27]([NH:30][C:31]([CH3:34])([CH3:33])[CH3:32])(=[O:29])=[O:28])[CH:26]=3)=[N:9]2)=[CH:4][CH:3]=1.[C:40](Cl)([Cl:42])=[O:41]>C(N(CC)CC)C>[C:31]([NH:30][S:27]([C:25]1[C:24]([Cl:35])=[CH:23][C:22]([O:36][CH2:37][CH3:38])=[C:21]([C:10]2[N:9]([C:40]([Cl:42])=[O:41])[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)([CH3:39])[C:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)([CH3:13])[N:11]=2)[CH:26]=1)(=[O:29])=[O:28])([CH3:32])([CH3:33])[CH3:34]
Reactant: CCOc1cc(Cl)c(S(=O)(=O)NC(C)(C)C)cc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1
Reactant: O=C(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOc1cc(Cl)c(S(=O)(=O)NC(C)(C)C)cc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl

Procedure:
In a manner analogous to the method described in example 3, rac-(4S*,5R*)-5-[4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl]-N-tert-butyl-2-chloro-4-ethoxybenzene-sulfonamide (example 44) was reacted with phosgene in the presence of triethylamine to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][CH2:17][OH:18])=[N:12][C:11]=2[CH:19]([CH3:21])[CH3:20])[CH:5]=[C:6]([Cl:8])[CH:7]=1.CO[C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][CH2:26][CH:25]=1>>[Cl:8][C:6]1[CH:5]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][CH2:17][O:18][C:27]3[C:28]4[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:24][CH2:25][CH:26]=3)=[N:12][C:11]=2[CH:19]([CH3:21])[CH3:20])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: COC1=CCCc2ccccc21
Reactant: CC(C)c1nc(CCO)n(C)c1Sc1cc(Cl)cc(Cl)c1
Product: CC(C)c1nc(CCOC2=CCCc3ccccc32)n(C)c1Sc1cc(Cl)cc(Cl)c1
Yield: 47.7 %

Procedure:
The compound 22 (345 mg, 1 mmol) was converted to the enol ether with 1-methoxy-3,4-dihydronaphthalene (801 mg, 10 mmol) in the same manner as the example 41 to give the compound 51 (226 mg, 47.8%). Mp 99-102° C. PMR (CDCl3 -0.1% d5 -Py): δH1.26 (6 H, d, J 7 Hz, (CH3)2C), 2.73 (2 H, t, J 7.8 Hz, =-CH2), 3.27 (2 H, t, J 6.2 Hz, CH2 -Im), 3.11 (1 H, m, (CH3)2CH), 3.54 (3 H, s, NCH3), 4.22 (2 H, t, J 6.2 Hz, OCH2), 5.04 (1 H, t, J 6.4 Hz, =CH), 6.79 (2 H, d, J 1.6 Hz, arom-H), 7.4-7.0 (5 H, m, arom-H) IR(KBr)cm-1 : 3434, 3060, 1636, 1566, 1252, 1099. Elementary analysis (for C25H26N2Ocl2S) Calcd. : C, 63.42% H, 5.53% N, 5.92% S, 6.77% Cl, 14.98% Found: C, 64.13% H, 5.74% N, 5.74% S, 6.62% Cl, 14.11%
Reaction SMILES: [C:1](=[O:23])([O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)[O:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][CH3:11])=[CH:6][CH:5]=1.C(Cl)[Cl:25]>>[C:1](=[O:23])([O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)[O:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([S:10][CH2:11][Cl:25])=[CH:8][CH:9]=1
Reactant: ClCCl
Reactant: CSc1ccc(COC(=O)OCc2ccc([N+](=O)[O-])cc2)cc1
Product: O=C(OCc1ccc(SCCl)cc1)OCc1ccc([N+](=O)[O-])cc1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
A cold (5° C.) solution of p-(methylthio)benzyl p-nitrobenzyl carbonate (1.0 g, 3 mmol) in CH2Cl2 (50 mL) was treated dropwise (2 min) with S02Cl2 (0.425 g, 3.15 mmol). After stirring the resulting solution for 30 min at 5° C., the solvent was evaporated to leave the title compound as an oil which solidified (1.10 g yield, 99.7%). The solid was used without purification in the next step.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15](Cl)=[C:6]2[CH:5]=[N:4]1)=[CH:13][CH:12]=[CH:11][C:10]=3[Br:17])[CH3:2].CS(C)=O.[CH:22]1([CH2:28][NH2:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([NH:29][CH2:28][CH:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)=[C:6]2[CH:5]=[N:4]1)=[CH:13][CH:12]=[CH:11][C:10]=3[Br:17])[CH3:2]
Reactant: NCC1CCCCC1
Reactant: CCn1ncc2c(Cl)c3cccc(Br)c3nc21
Solvent: CS(C)=O
Solvent: O
Product: CCn1ncc2c(NCC3CCCCC3)c3cccc(Br)c3nc21
Temperature: 25 °C
Yield: 80.2 %

Procedure:
A mixture of 1-ethyl-4-chloro-8-bromo-1H-pyrazolo[3,4-b]quinoline (2.0 g, 6.44 mmol), DMSO (5 mL) and cyclohexylmethylamine (1.46 g, 12.9 mmol) was heated at 80°-90° C. for 3 hours. The reaction mixture was cooled to room temperature and then was poured into water. The resulting solid was collected by filtration, washed with water and evaporated. The residue was purified by column chromatography on silica gel eluting with CH2Cl2 /ether (9/1) to afford 2.0 g (80%) of 1-ethyl-8-bromo-N-(cyclohexylmethyl)-1H-pyrazolo[3,4-b]quinolin-4-amine, as a yellow solid, m.p. 160°-162° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[N:14][CH:15]=[CH:16][C:11]=3[NH:10][CH:9]=2)=[CH:4][CH:3]=1.C([Li])CCC.[C:22]1([S:28](Cl)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1.CCCCCC>[C:22]1([S:28]([N:10]2[C:11]3[CH:16]=[CH:15][N:14]=[CH:13][C:12]=3[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:9]2)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Fc1ccc(-c2c[nH]c3ccncc23)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=S(=O)(c1ccccc1)n1cc(-c2ccc(F)cc2)c2cnccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
106 mg (0.5mM) of the product of Step 3, above, in 5 ml of absolute THF is cooled to -78°. 0.328 ml (0.525mM) of 1.6M n-butyllithium in hexane is added and the mixture stirred for 1 hour whilst allowing the temperature to rise to 0°. The mixture is then re-cooled to -60° and 97mg (0.55mM) of benzenesulfonyl chloride is added. After allowing to warm to RT overnight, the mixture is quenched with aqueous NaHCO3 and extracted with ethyl acetate. After washing with NaHCO3 the mixture is dried over Na2SO4 and evaporated to dryness. The residue is triturated with ether and the solids produced precipitated and dried to produce the title product of this step.