Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][CH:12]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[O:11][C:10]2=[O:19])[CH:5]=[CH:6][C:7]=1I.C[Sn](C)(C)[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[O:11][C:10]2=[O:19])[CH:5]=[CH:6][C:7]=1[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1
Reactant: C[Sn](C)(C)c1ccncc1
Reactant: CC(=O)NCC1CN(c2ccc(I)c(F)c2)C(=O)O1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CC(=O)NC[C@H]1CN(c2ccc(-c3ccncc3)c(F)c2)C(=O)O1
Reaction time: 4 h

Procedure:
A slurry of (±)-N-[[3-(3-fluoro-4-iodophenyl)-2-oxo-5-oxazolidinyl]methyl]acetamide (PREPARATION 18, 0.063 g, 0.165 mmol) and trimethyl(4-pyridyl)tin (0.060 g, 0.248 mmol) in 1,4-dioxane (5 ml) is degassed by repeated evacuation and filling with nitrogen. Bis(triphenylphosphine)palladium (II) chloride (0.012 g, 0.0165 mmol) is added, the reaction again degassed, and then the mixture is brought to reflux under nitrogen. After 4 hr TLC (silica gel, 10% methanol/chloroform) reveals some of the iodide still remains. The mixture is refluxed a further 20 hr, cooled to 20°-25°, and concentrated under reduced pressure. The residue is chromatographed over silica gel, eluting with a little chloroform and then methanol/chloroform (1%, 2%, and then 5%). The appropriate fractions are pooled and concentrated to give the enantiomerically enriched title compound, mp 190.5°-191.0°; [α]25D -16.4° (c 0.5, CHCl3). The following characteristics are no for a racemic sample, mp 179°-180°; IR (internal reflectance) 3279, 3063, 1756, 1752, 1657, 1626, 1600, 1542, 1522, 1485, 1412, 1407, 1377, 1222, 1198 cm-1 ; NMR (CDCl3, 300 MHz) 8.67, 7.59, 7.50, 7.47, 7.33, 6.15, 4.84, 4.11, 3.85, 3.78-3.62, 2.04 δ; MS (m/z) 329 (39.8, M+), 285, 257, 201, 172, 73 and 42. ##STR3##
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][Br:7].[S:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[Li]>C1COCC1>[Br:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:9]1[S:8][CH:12]=[CH:11][CH:10]=1
Reactant: BrCCCCCBr
Reactant: [Li]c1cccs1
Solvent: C1CCOC1
Product: BrCCCCCc1cccs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
To a stirred solution of 1,5-dibromopentane (23.00 g, 0.1 mol) in THF (100 ml) at -60° C. under N2, was slowly added, during 30 min., 100 ml (0.10 mol) of a 1.0M solution of 2-thienyllithium in THF (Aldrich). Stirring was continued for 1 h at -60° C. After gradual warming to room temperature, the mixture was stirred for 2 h and slowly poured over a bed of ice (ca. 200 g). The organic layer was separated and the aqueous layer was extracted with Et2O (2×100 ml). The combined organic layer and the extracts were washed with saturated NaCl solution (2×75 ml), dried (MgSO4) and concentrated to a dark oil (23.13 g). Fractional distillation gave 12.34 g (53%) of 1-bromo-5-(2-thienyl) pentane as a colorless oil, b.p. 87°-88° C. (0.7 mm); nD23 1.5440.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].[CH2:12]([C:19]1[C:24]([Cl:25])=[CH:23][C:22]([N+:26]([O-:28])=[O:27])=[CH:21][C:20]=1[Cl:29])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[Cl:11][C:3]1[C:2]([Cl:1])=[CH:10][C:6]([C:7](=[O:8])[C:16]2[CH:17]=[CH:18][C:13]([CH2:12][C:19]3[C:20]([Cl:29])=[CH:21][C:22]([N+:26]([O-:28])=[O:27])=[CH:23][C:24]=3[Cl:25])=[CH:14][CH:15]=2)=[CH:5][N:4]=1
Reactant: O=C(Cl)c1cnc(Cl)c(Cl)c1
Reactant: O=[N+]([O-])c1cc(Cl)c(Cc2ccccc2)c(Cl)c1
Product: O=C(c1ccc(Cc2c(Cl)cc([N+](=O)[O-])cc2Cl)cc1)c1cnc(Cl)c(Cl)c1
Yield: 28.5 %

Procedure:
The title compound was prepared as pale yellow crystals at yield of 28.5%, in a similar manner as in Reference Example 1, by the reaction of 5,6-dichloronicotinoylchloride and 4-benzyl-3,5-dichloronitrobenzene.
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][C:5]([O:6][CH2:7][C@H:8]([OH:17])[CH2:9][CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:4][CH:3]=1.[C:20]([NH:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1)(=[O:22])[CH3:21]>C(O)C.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:20]([NH:23][C:24]1[CH:29]=[C:28]([C:2]2[CH:19]=[CH:18][C:5]([O:6][CH2:7][C@H:8]([OH:17])[CH2:9][CH2:10][C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)=[CH:4][CH:3]=2)[CH:27]=[CH:26][CH:25]=1)(=[O:22])[CH3:21]
Reactant: O[C@H](CCc1cccnc1)COc1ccc(Br)cc1
Reactant: CC(=O)Nc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(=O)Nc1cccc(-c2ccc(OC[C@H](O)CCc3cccnc3)cc2)c1
Yield: 89 %

Procedure:
Prepared according to the method described in Example 33a) from (2R)-1-(4-bromophenoxy)-4-(3-pyridyl)-2-butanol (0.50 g), 3-acetamidobenzeneboronic acid (0.38 g) and tetrakis(triphenylphosphine)palladium(0) (0.045 g) in ethanol (1.7 ml), aqueous sodium carbonate solution (2 M, 1.55 ml) and toluene (6.9 ml) with heating at reflux for 1 hour. The residue obtained after work-up was purified by column chromatography over silica eluting with dichloromethane:methanol (92:8) to give the title compound (0.52 g) as an oil which crystallised from ethyl acetate and was recrystallised from isohexane/ethyl acetate.
Reaction SMILES: [OH:1][C@@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[CH3:29][O:30][C:31]1[CH:32]=[C:33](O)[CH:34]=[CH:35][CH:36]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.N>C1COCC1.C(Cl)(Cl)Cl>[CH3:29][O:30][C:31]1[CH:36]=[C:35]([CH:34]=[CH:33][CH:32]=1)[O:1][C@H:2]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1
Reactant: COc1cccc(O)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@@H](O)c3ccccc3)CC2)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: COc1cccc(O[C@@H](CCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 46.5 %

Procedure:
A mixture of N-(3-{1-[(3R)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (5.20 mg, 0.0137 mmol), 3-methoxyphenol (100 mg), triphenylphosphine (30.0 mg, 0.115 mmol) and diethyl azodicarboxylate (7.42 mg, 0.0426 mmol) in THF (0.50 mL) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave the desired product (3.1 mg, 46.6% yield) as a thick oil: 1HNMR (400 MHz, CDCl3) δ 7.47 (d, 1H, J=6.7 Hz), 7.42 (s, 1H), 7.3–7.20 (m, 3H), 7.20 (m, 3H), 7.07 (t, 1H, J=8.4 Hz), 6.97 (apparent d, 1H, J=6.7 Hz), 6.40 (m, 3H), 5.27 (apparent dd, 1H, J=5.3, 8.0 Hz), 3.74 (s, 3H), 3.38 (m, 2H), 2.93 (m, 2H), 2.61 (s, 1H), 2.53 (apparent sept, partially hidden, 1H, J=6.5 Hz), 2.30–2.10 (m, 6H), 1.82 (m, 2H), 1.25 (d, 6H, J=6.9 Hz); ESMS m/e: 487.3 (M+H)+.
Reaction SMILES: [C:1]1([NH:7][CH2:8][C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].C(Cl)(Cl)Cl.[C:18]1([S:24](Cl)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O>[C:18]1([S:24]([N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][C:9]([OH:11])=[O:10])(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)CNc1ccccc1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(O)CN(c1ccccc1)S(=O)(=O)c1ccccc1
Reaction time: 0.5 h

Procedure:
7.7 Parts of N-phenylglycine and 5 parts of sodium hydroxide are dissolved in 30 parts of water. Into the resulting solution, 5 parts of chloroform containing 10 parts of benzenesulfonyl chloride is dropped with stirring. After the dropping, the resulting mixture is stirred at room temperature for 4 hours and then at 50° C for 30 minutes. Subsequently, the aqueous layer is separated from the reaction mixture and then acidified with hydrochloric acid to form an oily substance. By rubbing on the inner wall of a flask with spatula, crystallized products are formed. The crystals are recrystallized from a mixed solvent comprising methanol and water to obtain 4.2 parts of N-benzenesulfonyl-N-phenylglycine, m.p. 166°-167° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:21])=[C:16](F)[C:17]=2[F:19])[C:12](=[O:22])[C:11]([C:23]([OH:25])=[O:24])=[CH:10]1.Br.[N+:27]([C:30]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:31]=1[CH2:32][NH:33][CH2:34]2)([O-:29])=[O:28].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[N+:27]([C:30]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:31]=1[CH2:32][N:33]([C:16]1[C:17]([F:19])=[C:18]3[C:13]([C:12](=[O:22])[C:11]([C:23]([OH:25])=[O:24])=[CH:10][N:9]3[C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])=[CH:14][C:15]=1[F:21])[CH2:34]2)([O-:29])=[O:28]
Reactant: O=[N+]([O-])c1cccc2c1CNC2
Reactant: O=C(O)c1cn(-c2ccc(F)cc2F)c2c(F)c(F)c(F)cc2c1=O
Agent: Br
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: O=C(O)c1cn(-c2ccc(F)cc2F)c2c(F)c(N3Cc4cccc([N+](=O)[O-])c4C3)c(F)cc2c1=O
Yield: 15.7 %

Procedure:
213 mg of 1-(2,4-difluorophenyl)-6,7,8-trifluoro-1,4- dihydro-4-oxoquinoline-3-carboxylic acid, 176 mg of 4-nitroisoindoline hydrobromide, 164 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 47 mg of the target compound.
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[C:8]1[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1)[CH3:2].[CH3:15][N:16]=[C:17]=[O:18].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[CH3:15][NH:16][C:17](=[O:18])[O:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([CH:4]2[CH2:5][CH2:6][CH2:7][N:3]2[CH2:1][CH3:2])[CH:9]=1
Reactant: CCN1CCCC1c1cccc(O)c1
Reactant: CN=C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCN1CCCC1c1cccc(OC(=O)NC)c1
Yield: 96 %

Procedure:
To a solution of 3-[1-ethyl-2-pyrrolidinyl]phenol (0.8 g) in dry tetrahydrofuran (40 ml) was added methyl isocyanate (0.26 ml) at ambient temperature, under nitrogen, with stirring for ten mins. Milled potassium carbonate was added and the reaction mixture was stirred for 4 hrs, and filtered through a pad of celite. The solids were washed with ethyl acetate, and the combined filtrates were concentrated. The residue was purified by flash column chromatography (silica gel, dichloromethane/0-30% methanol), and the eluant flushed through alumina (ethyl acetate) to give 1.0 g (96%) of product. Recrystallization from ether/petroleum ether gave the analytical sample, mp 67°-69° C.
Reaction SMILES: [C:1]1([C:7]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=C(C=CC=1)C(OO)=[O:24]>C(Cl)(Cl)Cl>[C:1]1([C:7]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:11][CH:10]=[CH:9][N+:8]=2[O-:24])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: c1ccc(-c2cccnc2-c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: [O-][n+]1cccc(-c2ccccc2)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 86.2 %

Procedure:
1 g of 2,3-diphenylpyridine was dissolved in chloroform and 1.4 g of 70% m-chloroperoxybenzoic acid was added, followed by stirring at room temperature for 15 hours. After the reaction solution was washed with an aqueous 5% potassium carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure to obtain 1.3 g of a crude crystal. The crude crystal was washed with diisopropyl ether to obtain 922 mg of the desired compound as a colorless crystal having a melting point of 167 to 170° C.
Reaction SMILES: C([O:8][C@H:9](C)[C:10]([NH:12][C@H:13]1[CH2:17][C@@H:16]([N:18]2[CH:26]=[N:25][C:24]3[C:19]2=[N:20][C:21]([N:42]2[CH2:46]C[C@@H:44]([NH:47][C:48]([NH:50][C:51]4[CH:52]=[N:53][CH:54]=[CH:55][CH:56]=4)=[O:49])[CH2:43]2)=[N:22][C:23]=3[NH:27][CH2:28][CH:29]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@H:15]([OH:57])[C@@H:14]1[OH:58])=[O:11])C1C=CC=CC=1.[NH2:60][C@@H]1CCN(C2N=C3C(N=CN3[C@@H]3C[C@H](NC(=O)[C@H](OCC4C=CC=CC=4)C)[C@@H](O)[C@H]3O)=C(NCC(C3C=CC=CC=3)C3C=CC=CC=3)N=2)C1>>[C:30]1([CH:29]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:28][NH:27][C:23]2[N:22]=[C:21]([N:42]3[CH:43]=[C:44]([NH:47][C:48]([NH:50][C:51]4[CH:52]=[N:53][CH:54]=[CH:55][CH:56]=4)=[O:49])[N:60]=[CH:46]3)[N:20]=[C:19]3[C:24]=2[N:25]=[CH:26][N:18]3[C@@H:16]2[CH2:17][C@H:13]([NH:12][C:10](=[O:11])[CH2:9][OH:8])[C@@H:14]([OH:58])[C@H:15]2[OH:57])[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: C[C@@H](OCc1ccccc1)C(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)Nc5cccnc5)C4)nc32)[C@H](O)[C@@H]1O
Reactant: C[C@@H](OCc1ccccc1)C(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](N)C4)nc32)[C@H](O)[C@@H]1O
Product: O=C(CO)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(-n4cnc(NC(=O)Nc5cccnc5)c4)nc32)[C@H](O)[C@@H]1O

Procedure:
The title compound is prepared analogously to (R)-2-benzyloxy-N-((1S,2R,3S,4R)-4-{6-(2,2-diphenyl-ethylamino)-2-[(R)-3-(3-pyridin-3-yl-ureido)-pyrrolidin-1-yl]-purin-9-yl}-2,3-dihydroxy-cyclopentyl)-propionamide (Example 181, step 5), by substituting N-{(1S,2R,3S,4R)-4-[2-(4-amino-imidazol-1-yl)-6-(2,2-diphenyl-ethyl amino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-2-hydroxy-acetamide (Intermediate ZU) for (R)—N-{(1S,2R,3S,4R)-4-[2-((R)-3-amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-2-benzyloxy-propionamide (Example 181, step 4).
Reaction SMILES: [OH:1][CH:2]1[CH2:25][NH:24][CH2:23][CH2:22][C:3]21[C:7](=[O:8])[N:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH:16]([CH3:21])[C:17]([F:20])([F:19])[F:18])=[CH:11][CH:10]=1)[CH2:5][CH2:4]2.[CH3:26][N:27]1[C:31]([S:32](Cl)(=[O:34])=[O:33])=[CH:30][CH:29]=[N:28]1>>[OH:1][CH:2]1[CH2:25][N:24]([S:32]([C:31]2[N:27]([CH3:26])[N:28]=[CH:29][CH:30]=2)(=[O:34])=[O:33])[CH2:23][CH2:22][C:3]21[C:7](=[O:8])[N:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH:16]([CH3:21])[C:17]([F:20])([F:18])[F:19])=[CH:11][CH:10]=1)[CH2:5][CH2:4]2
Reactant: CC(Oc1ccc(N2CCC3(CCNCC3O)C2=O)cc1)C(F)(F)F
Reactant: Cn1nccc1S(=O)(=O)Cl
Product: CC(Oc1ccc(N2CCC3(CCN(S(=O)(=O)c4ccnn4C)CC3O)C2=O)cc1)C(F)(F)F

Procedure:
The title compound was prepared in analogy to example 2 step B from a mixture of (5SR,6RS)-6-hydroxy-2-[4-((rac)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-2,8-diaza-spiro[4.5]decan-1-one (described in example 10 step B) and 2-methyl-2H-pyrazole-3-sulfonyl chloride. Light yellow solid. MS (ESI): 503.1 (MH+)
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:10]3[CH2:9][N:8]([CH3:20])[C:7](=[O:21])[C:6]=2[CH:22]=1.[C-]#N.[K+].C(O)C[OH:28]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]([O:17][CH2:18][CH2:19][OH:28])=[O:16])=[C:10]3[CH2:9][N:8]([CH3:20])[C:7](=[O:21])[C:6]=2[CH:22]=1
Reactant: CCOC(=O)c1ncn2c1CN(C)C(=O)c1cc(F)ccc1-2
Reactant: OCCO
Agent: [C-]#N
Agent: [K+]
Product: CN1Cc2c(C(=O)OCCO)ncn2-c2ccc(F)cc2C1=O
Temperature: 130 °C
Reaction time: 6 h

Procedure:
A mixture of 6.08 g (20 mmol) of ethyl 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate, 100 mg of potassium cyanide and 60 ml of ethyleneglycol is stirred at 130° C. for 6 hours and subsequently evaporated. After taking up the residue in chloroform, the solution is washed with water, dried over magnesium sulphate and evaporated. After recrystallisation of the crude product from ethyl acetate, there is obtained 2-hydroxyethyl 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate of melting point 202°-204° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[N+:15]([O-])=O.CO.S(S([O-])=O)([O-])=O.[Na+].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>O>[NH2:15][C:3]1[CH:4]=[CH:5][C:6]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:7][C:2]=1[NH2:1]
Reactant: Nc1cc(Sc2ccccc2)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Nc1ccc(Sc2ccccc2)cc1N

Procedure:
4.5 Kg. of 1-amino-2-nitro-5-phenylthiobenzene in 60 l. of methanol and 30 l. of water is treated, under nitrogen, with 8.0 kg. of sodium dithionite and 2.0 kg. of sodium carbonate at reflux. The mixture is heated for 2 hours and the methanol is removed by distillation. The mixture is cooled and extracted with dichloromethane. The dichloromethane solution is filtered, dried over sodium sulfate, and 1,2-diamino-4-phenylthiobenzene is isolated by evaporation.
Reaction SMILES: [F:1][C:2]1[C:3]([F:25])=[CH:4][C:5]2[S:9][C:8]([NH:10][C:11]3[N:15]([CH3:16])[C:14]4[CH:17]=[CH:18][C:19]([C:21](O)=[O:22])=[CH:20][C:13]=4[N:12]=3)=[N:7][C:6]=2[CH:24]=1.CN(C(O[N:34]1N=N[C:36]2C=CC=C[C:35]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(N)C>[CH2:35]([NH:34][C:21]([C:19]1[CH:18]=[CH:17][C:14]2[N:15]([CH3:16])[C:11]([NH:10][C:8]3[S:9][C:5]4[CH:4]=[C:3]([F:25])[C:2]([F:1])=[CH:24][C:6]=4[N:7]=3)=[N:12][C:13]=2[CH:20]=1)=[O:22])[CH3:36]
Reactant: Cn1c(Nc2nc3cc(F)c(F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CCN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)c1ccc2c(c1)nc(Nc1nc3cc(F)c(F)cc3s1)n2C
Yield: 56.8 %

Procedure:
2-(5,6-Difluoro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid ethylamide (55 mg) was prepared by following General Procedure F starting from 2-(5,6-difluoro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (90 mg), ethylamine (2 M in THF, 250 uL), HBTU (114 mg), and DIEA (65 uL). LC/MS: m/z 388.9. 1H NMR (DMSO-d6, 400 MHz): δ 12.34 (bs, 1H), 8.42 (s, 1H), 8.04 (s, 1H), 7.95 (dd, 1H), 7.74 (d, 1H), 7.55 (s, 1H), 7.45 (d, 1H), 3.62 (s, 3H), 3.30 (q, 2H), 1.13 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7]([F:24])[C:8]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=3[F:23])=[C:9]([C:12]([OH:14])=O)[CH:10]=2)[N:5]=[N:4][CH:3]=1.C1C=CC2N(O)[N:32]=[N:31]C=2C=1.CCN=C=NCCCN(C)C.NN>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([F:24])[C:8]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=3[F:23])=[C:9]([C:12]([NH:31][NH2:32])=[O:14])[CH:10]=2)[N:5]=[N:4][CH:3]=1
Reactant: Nc1cnnc2c(F)c(Nc3ccc(Br)cc3F)c(C(=O)O)cc12
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: NN
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NNC(=O)c1cc2c(N)cnnc2c(F)c1Nc1ccc(Br)cc1F
Reaction time: 1 h

Procedure:
To a solution of 4-amino-7-(4-bromo-2-fluorophenylamino)-8-fluoro-cinnoline-6-carboxylic acid (1.00 equiv.) and HOBt (3.00 equiv.) in DMF is added EDCI (3.00 equiv.) at room temperature. After stirring for 1 hour, hydrazine (3.00 equiv.) and TEA (3.00 equiv.) are added. The reaction mixture is stirred for 1 hour and diluted with EtOAc. The resulting mixture is washed with saturated aqueous NH4Cl, brine, saturated aqueous NaHCO3, and brine. The organic layer is dried over MgSO4, filtered, and concentrated under reduced pressure to give the crude material that is used directly without further purification.
Reaction SMILES: C([NH:18][C@H:19]([C:30]([OH:32])=[O:31])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:29])[CH3:28])=[CH:23][CH:22]=1)(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O.N1CCCCC1>O>[C:27]([C:24]1[CH:25]=[CH:26][C:21]([CH2:20][C@@H:19]([C:30]([OH:32])=[O:31])[NH2:18])=[CH:22][CH:23]=1)(=[O:29])[CH3:28]
Reactant: CC(=O)c1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Solvent: O
Solvent: C1CCNCC1
Product: CC(=O)c1ccc(C[C@H](N)C(=O)O)cc1
Yield: 88 %

Procedure:
Fmoc-p-acetyl-L-phenylalanine was purchased from RSP Amino Acid Analogues, Inc. (Worcester, Mass.). This compound (1.0 g, 2.3 mmol) was stirred with 4 mL of piperidine (20% in dimethyl formamide (DMF)) for 2 hours at room temperature. The solvent was evaporated to obtain white powder. The solid was then resuspended in 10 mL of cold water (0.1% trifluoroacetic acid (TFA)), and the supernatant was collected by filtration. Preparative reverse-phase HPLC (Microsorb C18, Rainin Instrument Co., Inc., Woburn, Mass.) was used to separate the desired product from the reaction mixture (5–30% CH3CN in H2O with 0.1% TFA over 30 min). The eluant (tR=12 min) was lyophilized to obtain a white solid (0.45 g, 88%). 1H NMR (400 MHz D2O): δ 7.85–7.28 (m, 4H), 4.23 (dd, 1H, 5.4 Hz), 3.2 (m, 2H), 2.7 (s, 3H). MS electrospray ionization (ESI): [M+1]+ calcd for C11H13NO3 208.09, found 208.47.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>O=[Pt]=O.O>[C:1]1([CH:7]2[CH2:12][CH2:11][CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(-c2cccnc2)cc1
Agent: O=[Pt]=O
Agent: Cl
Solvent: O
Product: c1ccc(C2CCCNC2)cc1
Temperature: 0 °C
Reaction time: 24 h
Yield: 90.3 %

Procedure:
A mixture of 3-phenylpyridine (8.0 g, 51.5 mmol), PtO2 (0.8 g), 234 mL of H2O, and 16 mL of concentrated HCl was hydrogenated in a Parr shaker at room temperature for 24 hours. The mixture was filtered, and the filtrate was cooled to 0° C. and was basified with 10N NaOH solution. The mixture was extracted (4×) with CH2Cl2. The combined organic layers were washed with saturated NaCl solution, dried (MgSO4), filtered, and concentrated in vacuo to afford the title compound (7.5 g ) as a clear oil. 1H NMR (300 MHz, CDCl3) δ 1.62 (t, 2H), 1.80 (m, 1H), 2.01 (m, 1H), 2.67 (m, 3H), 3.05-3.23 (m, 2H), 7.20 (d, 2H), 7.29 (t, 3H). MS (DCl/NH3) m/e 162 (M+H)+.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[Cl:9][CH2:10][C:11]1[N:12]=[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]2[CH:19]=1>C(Cl)Cl>[Cl:1][C:19]1[N:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]2=[N:12][C:11]=1[CH2:10][Cl:9]
Reactant: ClCc1cn2ccccc2n1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: ClCc1nc2ccccn2c1Cl
Reaction time: 2 h
Yield: 90.4 %

Procedure:
N-Chloro succinimide (329 g, 2.46 mmol) was added to a solution of 2-(chloromethyl)imidazo[1,2-a]pyridine (450 mg, 2.2 mmol) in DCM (15 ml) at RT under an atmosphere of nitrogen. Stirring was continued for 2 h (reaction was monitored by TLC) upon which the reaction mixture was diluted with DCM and washed with water and brine solution. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 10% ethyl acetate in n-hexane and silica gel (230-400 mesh) to afford 3-chloro-2-(chloromethyl)imidazo[1,2-a]pyridine (400 mg, 76%) as Off-white solid. 1H NMR: 200 MHz, CDCl3: δ 8.4 (d, 1H), 7.7 (d, 1H), 7.5 (t, 1H), 7.1 (t, 1H), 4.85 (s, 2H). MS: [M+H]+: m/z=201.8. HPLC: (98.3%, Condition-A).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([OH:13])=O)=[CH:5][CH:4]=1.S(Cl)([Cl:16])=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([Cl:16])=[O:13])=[CH:5][CH:4]=1
Reactant: COc1ccc(CCC(=O)O)cc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1ccc(CCC(=O)Cl)cc1
Temperature: 65 °C

Procedure:
To a suspension of 3-(4-methoxyphenyl)propionic acid (10 g) in 150 ml of toluene are added 8 ml of thionyl chloride and the mixture is heated to 65° C. for 4 hours. The solvent is evaporated off under reduced pressure and the residue is redissolved in toluene and concentrated to dryness. Such steo is repeated twice. 11 g of the product are obtained as a yellow oil.