Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:12])(=O)[C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=O)[CH:3]=1.[NH2:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][NH:25][S:26]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]2[C:44]3[C:39](=[C:40]([Cl:46])[CH:41]=[C:42]([Cl:45])[CH:43]=3)[CH2:38][N:37]([CH3:47])[CH2:36]2)[CH:30]=1)(=[O:28])=[O:27]>>[Cl:45][C:42]1[CH:43]=[C:44]2[C:39](=[C:40]([Cl:46])[CH:41]=1)[CH2:38][N:37]([CH3:47])[CH2:36][CH:35]2[C:31]1[CH:30]=[C:29]([S:26]([NH:25][CH2:24][CH2:23][O:22][CH2:21][CH2:20][O:19][CH2:18][CH2:17][O:16][CH2:15][CH2:14][NH:13][C:5](=[O:7])[C:4]2[CH:8]=[CH:9][CH:10]=[C:2]([C:1]([NH:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][NH:25][S:26]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]4[C:44]5[C:39](=[C:40]([Cl:46])[CH:41]=[C:42]([Cl:45])[CH:43]=5)[CH2:38][N:37]([CH3:47])[CH2:36]4)[CH:30]=3)(=[O:28])=[O:27])=[O:12])[CH:3]=2)(=[O:28])=[O:27])[CH:34]=[CH:33][CH:32]=1
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCOCCOCCOCCN)c2)C1
Reactant: O=C(O)c1cccc(C(=O)O)c1
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCOCCOCCOCCNC(=O)c3cccc(C(=O)NCCOCCOCCOCCNS(=O)(=O)c4cccc(C5CN(C)Cc6c(Cl)cc(Cl)cc65)c4)c3)c2)C1
Yield: 77 %

Procedure:
Compound 228 was prepared following the procedure outlined in Example 215 using isophthalic acid (8.0 mg, 0.0484 mmol) and N-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)-3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide (Compound 28, 75 mg, 0.0968 mmol). Purification by preparative HPLC gave the title compound (45.6 mg) as a TFA salt. 1H-NMR (400 MHz, CD3OD): δ 8.25 (s, 1H), 7.92 (d, 2H), 7.85 (d, 2H), 7.73 (s, 2H), 7.58 (t, 2H), 7.49 (m, 5H), 6.81 (s, 2H), 4.83-4.71 (m, 4H), 4.49 (d, 2H), 3.87 (m, 2H), 3.67-3.54 (m, 28H), 3.45 (t, 5H), 3.44 (q, 5H), 3.14 (s, 7H), 2.99 (t, 4H). MS (m/z): 1223.19 [M+H]+.
Reaction SMILES: [CH2:1]([CH:3]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:4][C:5]1[C:13]2[S:14][CH:15]=[CH:16][C:12]=2[C:11]([CH2:17][CH:18]([CH2:23][CH3:24])[CH2:19][CH2:20][CH2:21][CH3:22])=[C:7]2[S:8][CH:9]=[CH:10][C:6]=12)[CH3:2].C([Li])CCC.[CH3:34][Sn:35](Cl)([CH3:37])[CH3:36].O>O1CCCC1>[CH2:23]([CH:18]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:17][C:11]1[C:7]2[S:8][C:9]([Sn:35]([CH3:37])([CH3:36])[CH3:34])=[CH:10][C:6]=2[C:5]([CH2:4][CH:3]([CH2:1][CH3:2])[CH2:25][CH2:26][CH2:27][CH3:28])=[C:13]2[S:14][C:15]([Sn:35]([CH3:37])([CH3:36])[CH3:34])=[CH:16][C:12]=12)[CH3:24]
Reactant: C[Sn](C)(C)Cl
Reactant: CCCCC(CC)Cc1c2ccsc2c(CC(CC)CCCC)c2ccsc12
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCCCC(CC)Cc1c2cc([Sn](C)(C)C)sc2c(CC(CC)CCCC)c2cc([Sn](C)(C)C)sc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of 4,8-bis(2-ethylhexyl)benzo[1,2-b:4,5-b′]dithiophene (237 mg, 0.57 mmol) in dry tetrahydrofuran (11 mL) was added n-butyllithium (2.5 M in hexane, 0.5 mL, 1.25 mmol) at −78° C. After 1 hour, trimethyltin chloride (264 mg, 1.32 mmol) was added in one portion. The mixture was stirred at room temperature for 2 hours, poured into water (20 mL) and extracted with ether three times. The organic layer was washed with brine and dried over anhydrous MgSO4. Upon evaporating the solvent, a pale yellow oil was obtained (437 mg, yield 100%). Upon standing in a freezer for 2 days, pale yellow crystals emerged and were collected (326 mg, yield 77%). 1H NMR (CDCl3, 500 MHz) δ=7.51 (s, 2H), 3.07-3.23 (m, 4H), 1.96-2.07 (m, 2H), 1.21-1.50 (m, 16H), 0.94 (t, J=7.0 Hz, 6H), 0.89 (t, J=7.0 Hz, 6H), 0.46 (s, 18H).
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15]1(=[O:21])[O:20][C:18](=[O:19])[CH2:17][CH2:16]1>>[NH:7]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:21])[CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:10][CH:9]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ccc(Nc2ccccc2)cc1
Reactant: O=C1CCC(=O)O1
Product: O=C(O)CCC(=O)Nc1ccc(Nc2ccccc2)cc1

Procedure:
The experimental protocol used is the same as that described in J. Amer. Chem. Soc. (1951) 73, 4007, starting from N1-phenyl-1,4-benzenediamine and succinic anhydride in order to produce a pale grey-blue powder. Melting point: 175-176° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[CH3:22]O>>[C:1]1([CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:22])=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CCC/C=C\CCc1ccccc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CCC/C=C\CCc1ccccc1

Procedure:
A solution of (Z)-8-phenyl-5-octenoic acid (12.6 g), see Example 1(a), and concentrated sulphuric acid (0.1 ml) in methanol (300 ml) was heated under reflux for 2 hours. The solution was evaporated and the residue distilled under vacuum to give the ester b.p. 110° to 113° C./0.1 mm.
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4](CC2C=CC=CC=2)[C:3]1=[S:20].[Cl-].[Al+3].[Cl-].[Cl-]>C1(C)C=CC=C(C)C=1>[CH3:1][N:2]1[C:7]([C:8]([F:10])([F:11])[F:9])=[CH:6][C:5](=[O:12])[NH:4][C:3]1=[S:20]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(Cc2ccccc2)c1=S
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1cccc(C)c1
Product: Cn1c(C(F)(F)F)cc(=O)[nH]c1=S
Yield: 48.6 %

Procedure:
2,3-Dihydro-1-methyl-3-(phenylmethyl)-2-thioxo-6-(trifluoromethyl)-4(1H)-pyrimidinone (1.0 g) was dissolved in m-xylene (15 ml) and anhydrous aluminum chloride (0.58 g) was added. The solution was refluxed for 4 hr and poured onto ice water. Extraction with ethyl acetate and evaporation of the solvent in vacuo afforded a residue which was triturated with diethyl ether to afford the title compound (0.34 g). 1H NMR, CDCl3, 3.86 (3H, m), 6.49 (1H, s), 10.62 (1H, br s).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[C:17]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=4)=[N:18][C:19]([CH3:23])=[C:20]([CH3:22])[CH:21]=3)=[CH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:31][CH3:32].C(=O)([O-])[O-].[K+].[K+].[NH2:39][CH2:40][CH2:41][OH:42]>CN(C)C=O>[CH3:32][O:31][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:5]=1[O:4][CH2:3][CH2:2][NH:39][CH2:40][CH2:41][OH:42])[N:12]=[CH:11][CH:10]=[C:9]2[O:15][C:16]1[C:17]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=2)=[N:18][C:19]([CH3:23])=[C:20]([CH3:22])[CH:21]=1
Reactant: NCCO
Reactant: COc1cc2c(Oc3cc(C)c(C)nc3-c3cccc(C)n3)ccnc2cc1OCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc(C)c(C)nc3-c3cccc(C)n3)ccnc2cc1OCCNCCO
Temperature: 70 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
3-[7-(2-Chloro-ethoxy)-6-methoxy-quinolin-4-yloxy]-5,6,6′-trimethyl-[2,2′]bipyridine (compound 465) (35 mg) was dissolved in N,N-dimethylformamide (2 ml) to prepare a solution. Potassium carbonate (108 mg) and 2-aminoethanol (0.14 ml) were added to the solution, and the mixture was stirred at 70° C. overnight. The solvent was removed by distillation under the reduced pressure, water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (24 mg, yield 64%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][NH:10][C:9]=2[CH:13]=O)=[CH:4][CH:3]=1.[NH2:15]OS(O)(=O)=O>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][NH:10][C:9]=2[C:13]#[N:15])=[CH:4][CH:3]=1
Reactant: O=Cc1[nH]ccc1-c1ccc(Cl)cc1
Reactant: NOS(=O)(=O)O
Solvent: O
Product: N#Cc1[nH]ccc1-c1ccc(Cl)cc1
Yield: 63.7 %

Procedure:
A mixture of 0.63 g (3.1 mmol) of 3-(p-chlorophenyl)-pyrrole-2-carboxaldehyde in 10 mL of water is stirred and ice-cooled while 0.52 g (4.6 mmol) of hydroxylamine-o-sulfonic acid in 10 mL of water is slowly added. After the addition, the cooling bath is removed and the mixture is heated for 25 minutes. On cooling, the resulting solid is collected and shown, by NMR, to be a mixture of product and starting aldehyde. This mixture is reacted in the same manner with an additional 0.49 g (4.2 mmol) of hydroxylamine-O-sulfonic acid in a total of 30 mL of water. The mixture is heated at 60°-70° C. for 2 hours. The mixture is cooled and the resulting solids are collected and purified by chromatography or silica gel using 1:1 ethyl acetate hexane to give 0.40 g of pink solid, m.p. 114°-115° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1.CC1C=CC(S(O[CH2:31][CH2:32][Cl:33])(=O)=O)=CC=1>O>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:31][CH2:32][Cl:33])=[CH:15][CH:14]=1
Reactant: Oc1ccc(Br)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: ClCCOc1ccc(Br)cc1
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 85.5 %

Procedure:
With reference to the document (J. Org. Chem., (2002), 67, 1093-1101), potassium carbonate (83.0 g, 600 mmol) was added to a solution of DMF (500 mL) containing 4-bromophenol (50.4 g, 291 mmol) at room temperature. The mixture was stirred at the same temperature for 30 minutes, and then 2-chloroethyl 4-methylbenzenesulfonate (70.2 g, 299 mmol) was added thereto. The mixture was stirred at 50° C. for 24 hours. The reaction solution was cooled to 10° C., and water (500 mL) was added thereto to precipitate a white solid. This white solid was collected by filtration, washed with water (500 mL), and dried at 50° C. under reduced pressure to give 58.6 g of the title compound (yield: 86%).
Reaction SMILES: [CH2:1]([C@H:8]([NH:37][C:38](=[O:48])[O:39][C@@H:40]1[C@H:47]2[C@H:43]([O:44][CH2:45][CH2:46]2)[O:42][CH2:41]1)[C@H:9]([OH:36])[CH2:10][N:11]([S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28]CC2C=CC=CC=2)[CH:23]=1)(=[O:21])=[O:20])[O:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OCC)(=O)C.[Pd]>[CH2:1]([C@H:8]([NH:37][C:38](=[O:48])[O:39][C@@H:40]1[C@H:47]2[C@H:43]([O:44][CH2:45][CH2:46]2)[O:42][CH2:41]1)[C@H:9]([OH:36])[CH2:10][N:11]([O:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=1)(=[O:21])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)[C@H](O)CN(OC1CCCCC1)S(=O)(=O)c1cccc(OCc2ccccc2)c1)O[C@H]1CO[C@H]2OCC[C@H]21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(N[C@@H](Cc1ccccc1)[C@H](O)CN(OC1CCCCC1)S(=O)(=O)c1cccc(O)c1)O[C@H]1CO[C@H]2OCC[C@H]21
Reaction time: 16 h
Yield: 81.6 %

Procedure:
A solution of (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-1-benzyl-3-[{[3-(benzyloxy)phenyl]sulfonyl}(cyclohexyloxy)amino]-2-hydroxypropylcarbamate (131 mg, 0.193 mmol) in ethyl acetate (˜5 mL) was combined with Palladium on carbon (10 wt %, 25 mg) and reduced under an atmosphere of Hydrogen gas. After stirring for 16 hours, the reaction mixture was filtered and evaporated in vacuo to a residue. The residue was purified on a preparative TLC plate (20×20 cm, 500 μM) eluting with 3:2 ethyl acetate:hexane. The product band was removed, eluted with 3:1 methylene chloride:methanol, filtered, and evaporated in vacuo. The residue was triturated with water, filtered and dried under high vacuum to provide (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-1-benzyl-3-{(cyclohexyloxy)[(3-hydroxyphenyl)sulfonyl]amino}-2-hydroxypropylcarbamate (93 mg, 82%) as a white solid. H1-NMR (chloroform-D3): 1.28 (m, 6H), 1.67 (m, 5H), 2.06 (m, 2H), 2.96 (m, 4H), 3.09 (b, 1H), 3.87 (m, 6H), 4.19 (m, 1H), 5.01 (m, 2H), 5.69 (d, 1H), 6.60 (b, 1H), 7.23 (m, 9H). MS(ESI): 613(M+Na).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([N:17]([C:19]2[CH:24]=[CH:23][C:22]([NH:25]/[C:26](=[C:33]3\[C:34](=[O:45])[NH:35][C:36]4[C:41]\3=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=4)/[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:21][CH:20]=2)[CH3:18])=[O:16])[CH2:10][CH2:9]1)C1C=CC=CC=1.[Cl:46]C(OC(Cl)C)=O>ClCCl>[ClH:46].[ClH:46].[N:11]1([CH2:14][C:15]([N:17]([C:19]2[CH:20]=[CH:21][C:22]([NH:25]/[C:26](=[C:33]3\[C:34](=[O:45])[NH:35][C:36]4[C:41]\3=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=4)/[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[CH:23][CH:24]=2)[CH3:18])=[O:16])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CN(C(=O)CN1CCN(Cc2ccccc2)CC1)c1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1
Reactant: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Product: CN(C(=O)CN1CCNCC1)c1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1
Product: Cl

Procedure:
Prepared analogously to Example 54 from (Z)-3-{1-[4-(N-(4-benzylpiperazinomethylcarbonyl)-N-methyl-amino)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone and 1-chloroethyl chloroformate in dichloromethane.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1.C([O-])([O-])=O.[K+].[K+].[C:20]([O:24][C:25](=[O:50])[CH2:26][N:27]1[C:31]2[CH:32]=[CH:33][C:34]([NH:36][S:37]([C:40]3[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=3)(=[O:39])=[O:38])=[CH:35][C:30]=2[N:29]=[C:28]1[CH2:47][CH2:48][CH3:49])([CH3:23])([CH3:22])[CH3:21]>CC#N.CCOC(C)=O.O>[C:20]([O:24][C:25](=[O:50])[CH2:26][N:27]1[C:31]2[CH:32]=[CH:33][C:34]([N:36]([CH2:8][C:7]3[CH:10]=[CH:11][C:4]([O:3][C:2]([F:13])([F:12])[F:1])=[CH:5][CH:6]=3)[S:37]([C:40]3[CH:41]=[CH:42][C:43]([F:46])=[CH:44][CH:45]=3)(=[O:38])=[O:39])=[CH:35][C:30]=2[N:29]=[C:28]1[CH2:47][CH2:48][CH3:49])([CH3:23])([CH3:22])[CH3:21]
Reactant: CCCc1nc2cc(NS(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)OC(C)(C)C
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: CCCc1nc2cc(N(Cc3ccc(OC(F)(F)F)cc3)S(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 8 h

Procedure:
4-Trifluoromethoxybenzyl bromide (0.27 mmol) and K2CO3 (63 mg, 0.45 mmol) were added to a solution of [5-(4-fluoro-benzenesulfonylamino)-2-propyl-benzoimidazol-1-yl]-acetic acid tert-butyl ester (40 mg, 0.09 mmol) in CH3CN (1 mL), and stirred overnight at 80° C. The reaction mixture was diluted with EtOAc and H2O, and then filtered through an Extrelut column. The column was washed with EtOAc, and the filtrate was concentrated. The crude product was carried onto the next reaction without any further purification or characterization.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[Cl:13][C:14]1[C:23]([NH2:24])=[C:22]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1.N1C=CC=CC=1.C(#N)C>C1COCC1>[Cl:13][C:14]1[C:23]2[N:24]=[C:1]([OH:2])[N:25]([CH2:26][C:27]3[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=3)[C:22]=2[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:15]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc(CNc2c(N)c(Cl)nc3ccccc23)cc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: CC#N
Product: COc1ccc(Cn2c(O)nc3c(Cl)nc4ccccc4c32)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 41.8 %

Procedure:
1,1′-Carbonyldiimidazole (6.53 g, 40.3 mmol) was added to a solution of 2-chloro-N4-(4-methoxybenzyl)quinoline-3,4-diamine (11.49 g, 36.62 mmol) and pyridine (75 mL) in THF (75 mL), and the reaction was heated at 80° C. overnight. An analysis by LC/MS indicated the presence of starting material, and additional 1,1′-carbonyldiimidazole (1 equivalent) was added. The reaction was stirred overnight at 80° C., and additional 1,1′-carbonyldiimidazole (1 equivalent) was added. The reaction was stirred overnight at 80° C. and allowed to cool, and the solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (500 mL), and the resulting solution was washed sequentially with brine and water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide a solid. The solid was mixed with acetonitrile and isolated by filtration to provide 5.2 g of 4-chloro-1-(4-methoxybenzyl)-1H-imidazo[4,5-c]quinolin-2-ol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:32][C@@H:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[CH:36]=1)[OH:34])[CH2:9][CH2:10][NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([OH:26])=O)=[C:20]([O:27][CH2:28][CH:29]([CH3:31])[CH3:30])[CH:19]=2)=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.N1CCCN2CCCCCC=12.[C:65]([O:68][CH2:69][CH2:70][CH2:71][S:72]([NH2:75])(=[O:74])=[O:73])(=[O:67])[CH3:66]>CN(C)C=O>[C:65]([O:68][CH2:69][CH2:70][CH2:71][S:72]([NH:75][C:24]([C:21]1[CH:22]=[CH:23][C:18]([C:15]2[CH:14]=[CH:13][C:12]([NH:11][CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:32][C@@H:33]([C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[CH:36]=3)[OH:34])=[CH:17][CH:16]=2)=[CH:19][C:20]=1[O:27][CH2:28][CH:29]([CH3:30])[CH3:31])=[O:26])(=[O:73])=[O:74])(=[O:67])[CH3:66]
Reactant: CC(C)COc1cc(-c2ccc(NCCN(C[C@H](O)c3cccc(Cl)c3)C(=O)OC(C)(C)C)cc2)ccc1C(=O)O
Reactant: CC(=O)OCCCS(N)(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(=O)OCCCS(=O)(=O)NC(=O)c1ccc(-c2ccc(NCCN(C[C@H](O)c3cccc(Cl)c3)C(=O)OC(C)(C)C)cc2)cc1OCC(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 44.4 %

Procedure:
To a solution of 4′-[[2-[(tert-butoxycarbonyl)[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]amino]-3-isobutoxy-4-biphenylcarboxylic acid (60.0 mg) in N,N-dimethylformamide (0.450 ml) was added 1,1′-carbonylbis-1H-imidazole (18.3 mg) and the mixture was stirred at room temperature for 1.5 hours under nitrogen atmosphere. To the mixture were added 2,3,4,6,7,8,9,10-octahydropyrimido-[1,2-a]azepine (0.0185 ml) and a solution of 3-(aminosulfonyl)propyl acetate (22.4 mg) in N,N-dimethylformamide (0.300 ml) and the mixture was stirred at room temperature for 2 days. The reaction mixture was warmed to 120° C. and stirred at the same temperature for 2 hours. After cooling to room temperature, the reaction mixture was extracted with ethyl acetate, washed with water and brine and dried over magnesium sulfate. Filtration followed by evaporation gave the crude product which was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=1/3 to 1/1) to give 3-[[[[4′-[[2-[(tert-butoxycarbonyl)[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]amino]-3-isobutoxy-4-biphenylyl]carbonyl]amino]sulfonyl]propyl acetate (34.1 mg) as a yellow paste.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]2[C:9]([C:12]3[CH:13]=[C:14]([NH:18][C:19]([NH:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[O:20])[CH:15]=[CH:16][CH:17]=3)=[CH:10][N:11]=[C:5]2[CH:4]=1)#[N:2].[N-:27]=[N+:28]=[N-:29].[Na+].[Cl-].[NH4+]>CN(C=O)C>[N:2]1[NH:27][N:28]=[N:29][C:1]=1[C:3]1[CH:8]=[CH:7][N:6]2[C:9]([C:12]3[CH:13]=[C:14]([NH:18][C:19]([NH:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[O:20])[CH:15]=[CH:16][CH:17]=3)=[CH:10][N:11]=[C:5]2[CH:4]=1
Reactant: N#Cc1ccn2c(-c3cccc(NC(=O)NCC(F)(F)F)c3)cnc2c1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(-c4nn[nH]n4)ccn23)c1
Temperature: 90 °C
Yield: 19.3 %

Procedure:
1-[3-(7-Cyano-imidazo[1,2-a]pyridin-3-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea (65 mg, 0.18 mmol), sodium azide (14 mg, 0.19 mmol) and ammonium chloride (11 mg, 0.20 mmol) were dissolved in DMF (2 ml) and heated at 90° C. for 18 h. The reaction mixture was cooled, the solvent removed in vacuo and the crude reaction mixture purified using reverse phase HPLC. This afforded the title compound as a white solid (14 mg). MS: [M+H]+ 403.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:29][C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=1)[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][C@H:10]([N:13]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[C:23]([NH2:28])[CH:22]=1)(=[O:20])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:11][OH:12])=[O:4].[C:40](O)(=[O:47])[C:41]1[CH:46]=[CH:45][N:44]=[CH:43][CH:42]=1>>[NH2:28][C:23]1[CH:22]=[C:21]([S:18]([N:13]([CH2:14][CH:15]([CH3:16])[CH3:17])[C@H:10]([CH2:11][OH:12])[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:3]([C@@H:2]([NH:1][C:40](=[O:47])[C:41]2[CH:46]=[CH:45][N:44]=[CH:43][CH:42]=2)[CH2:29][C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=2)=[O:4])(=[O:19])=[O:20])[CH:26]=[CH:25][C:24]=1[F:27]
Reactant: O=C(O)c1ccncc1
Reactant: CC(C)CN([C@H](CO)CCCCNC(=O)[C@@H](N)Cc1ccc2ccccc2c1)S(=O)(=O)c1ccc(F)c(N)c1
Product: CC(C)CN([C@H](CO)CCCCNC(=O)[C@H](Cc1ccc2ccccc2c1)NC(=O)c1ccncc1)S(=O)(=O)c1ccc(F)c(N)c1

Procedure:
The title compound was prepared from (2S,5S)-2-amino-N-{5-[(3-amino-4-fluoro-benzenesulfonyl)-isobutyl-amino]-6-hydroxy-hexyl}-3-naphthalen-2-yl-propionamide (example 81) as described in general procedure E using isonicotinic acid. The final product was obtained in 66% yield.
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][CH2:14][P:15]([CH2:18][CH2:19][CH2:20][CH3:21])(=[O:17])[OH:16])=O)C1C=CC=CC=1.C1OC1C>Cl.CO>[NH2:11][CH2:12][CH2:13][CH2:14][P:15]([CH2:18][CH2:19][CH2:20][CH3:21])(=[O:16])[OH:17]
Reactant: CCCCP(=O)(O)CCCNC(=O)OCc1ccccc1
Agent: CC1CO1
Agent: Cl
Solvent: CO
Product: CCCCP(=O)(O)CCCN
Temperature: 25 °C

Procedure:
A solution of 6.7 g of 3-(benzyloxycarbonylamino)propyl(n-butyl) phosphinicacid in 125 ml of 36% hydrochloric acid is heated at reflux for 1.5 hour. The mixture is evaporated to an oil and the oil is co-evaporated with water (2×50 ml) to give a white solid. This solid is then dissolved in 50 ml of dry methanol, 1-3 ml of propylene oxide is added and the solution is stirred at room temperature. The precipitated product is collected by filtration and dried to give 3-aminopropyl(n-butyl) phosphinic acid, m.p. 231°-234° (dec.), 31P-NMR : δ=+44.6 ppm (D2O).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:12])[CH:9]([F:11])[F:10])=[CH:4][CH:3]=1.[CH3:13][Mg]Cl>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:12])([CH3:13])[CH:9]([F:11])[F:10])=[CH:6][CH:7]=1
Reactant: O=C(c1ccc(Br)cc1)C(F)F
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: CC(O)(c1ccc(Br)cc1)C(F)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(4-bromophenyl)-2,2-difluoroethanone (2.5 g, 10.6 mmol) in THF (60 mL) was added methylmagnesium chloride (10 mL, 30 mmol; 3 M in THF) at 0° C. over ˜10 min and the mixture was stirred at 0° C. for 1 h. A mini-worked up showed starting material remained and more methylmagnesium chloride (5 mL, 15 mmol, 3 M in THF) was added. After further stirred for 15 min., the mixture was quenched with H2O, carefully acidified with 1 M HCl (100 mL) and extracted with Ethyl acetate. Purification by combi-flash chromatography (120 g column; eluted with hexanes—Ethyl acetate (5% -25%) in 20 min.; flow rate: 70 mL/min and collected 25 mL/fraction) yielded the title compound as a colorless liquid.