Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cu][C:2]#[N:3].[C:4]([O:12][C@@H:13]1[C@H:17]([O:18][C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@@H:16]([C:27]([NH:29][CH2:30][CH3:31])=[O:28])[O:15][C@H:14]1[N:32]1[CH:40]=[N:39][C:38]2[C:33]1=[N:34][C:35](I)=[N:36][C:37]=2[NH:41][CH2:42][CH:43]([C:51]1[CH:56]=[CH:55][C:54]([Cl:57])=[CH:53][CH:52]=1)[C:44]1[CH:49]=[CH:48][C:47]([Cl:50])=[CH:46][CH:45]=1)(=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>O>[C:4]([O:12][C@@H:13]1[C@H:17]([O:18][C:19](=[O:26])[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C@@H:16]([C:27]([NH:29][CH2:30][CH3:31])=[O:28])[O:15][C@H:14]1[N:32]1[CH:40]=[N:39][C:38]2[C:33]1=[N:34][C:35]([C:2]#[N:3])=[N:36][C:37]=2[NH:41][CH2:42][CH:43]([C:44]1[CH:45]=[CH:46][C:47]([Cl:50])=[CH:48][CH:49]=1)[C:51]1[CH:56]=[CH:55][C:54]([Cl:57])=[CH:53][CH:52]=1)(=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: N#C[Cu]
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccc(Cl)cc4)c4ccc(Cl)cc4)nc(I)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Solvent: O
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccc(Cl)cc4)c4ccc(Cl)cc4)nc(C#N)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
Copper (I) cyanide was added to a solution of (2R,3R,4S,5S)-4-(benzoyloxy)-2-(6-{[2,2-bis(4-chlorophenyl)ethyl]amino}-2-iodo-9H-purin-9-yl)-5-[(ethylamino)carbonyl]tetrahydro-3-furanyl benzoate (440 mg, 0.494 mmol) (Preparation 67) in N′N′-dimethylformamide (10 ml). The reaction mixture was stirred at 90° C. overnight. The reaction mixture was poured into water (15 ml). The precipitate was filtered off and stirred in dichloromethane (50 ml) for 10 minutes. The dichloromethane was filtered, dried over anhydrous magnesium sulphate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol (98:2 by volume). The solvent was removed under reduced pressure to give the title compound (227 mg) as a foam.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[O:16][CH:15]=[CH:14][C:13]=3[CH:12]=[C:11]([CH:18]=[O:19])[CH:10]=2)=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1>O>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[O:16][CH:15]=[CH:14][C:13]=3[CH:12]=[C:11]([CH:18]=[O:19])[CH:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cc(C=O)cc3ccoc23)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: O=Cc1cc(-c2ccc(O)cc2)c2occc2c1
Temperature: 190 °C
Yield: 161.1 %

Procedure:
To a 10 ml round bottom flask was added 7-(4-methoxyphenyl)-benzofuran-5-carbaldehyde (0.50 g, 1.98 mmol), and pyridine hydrochloride (1.2 g, 5.2 mmol). The mixture was heated to 190° C. for 2 h, cooled slightly, then water (10 ml) was added to dissolve the remaining pyridine hydrochloride. The aqueous was extracted with EtOAc (3×), passed through a silica plug, and concentrated to 450 mg (96%) of crude product as a light yellow foam. The crude from this reaction was combined with a second batch (1 g scale reaction) and purified by column chromatography (1:1 EtOAc/Hexanes) to afford 760 mg of product as a yellow solid: mp 154–155° C.; 1H NMR (300 MHz, DMSO-d6): δ 6.95 (2H, d, J=8.6 Hz), 7.21 (1H, d, J=2.2 Hz), 7.76 (2H, d, J=8.6 Hz), 7.98 (1H, d, J=1.5 Hz), 8.19 (1H, d, J=1.5 Hz), 8.22 (1H, d, J=2.2 Hz), 9.81 (1H, s), 10.12 (1H, s); MS (ESI) m/z 237 ([M−H]−).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:22][CH2:21][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([O:18]CC)=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:23][C@H:24]([C:29]2[CH:34]=[CH:33][C:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[C:37]([CH2:42][OH:43])[CH:36]=3)=[CH:31][C:30]=2[N:44]2[CH:48]=[CH:47][C:46]([CH3:49])=[N:45]2)[C:25]([F:28])([F:27])[F:26])[N:3]=1.O.[OH-].[Li+].Cl>C1COCC1.O>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:9][CH2:10][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:21][CH2:22]2)[CH:5]=[C:4]([O:23][C@H:24]([C:29]2[CH:34]=[CH:33][C:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[C:37]([CH2:42][OH:43])[CH:36]=3)=[CH:31][C:30]=2[N:44]2[CH:48]=[CH:47][C:46]([CH3:49])=[N:45]2)[C:25]([F:28])([F:27])[F:26])[N:3]=1
Reactant: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(-c5ccc(C)c(CO)c5)cc4-n4ccc(C)n4)C(F)(F)F)nc(N)n3)CC2)CN1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccn(-c2cc(-c3ccc(C)c(CO)c3)ccc2[C@@H](Oc2cc(N3CCC4(CC3)CN[C@H](C(=O)O)C4)nc(N)n2)C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-(hydroxymethyl)-4′-methyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate (50 mg, 0.08 mmol) from Step 2 in THF (2.0 mL) and water (0.2 mL), was added lithium hydroxide monohydrate (58 mg, 0.05 mmol). The reaction mixture was stirred at RT for 2 h, then the solution was neutralized with 1 N HCl, and concentrated in vacuo. Purification by normal phase silica gel column (EtOAc/heptane) provided the title compound as an off-white solid as the zwitterionic form.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[C:10]([C:14]([NH:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[O:15])[NH:11]2)=[C:7]([CH3:23])[CH:6]=1.C([O-])([O-])=O.[Cs+].[Cs+].[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>C(#N)C.O>[CH:17]1([NH:16][C:14]([C:10]2[NH:11][C:12]3[C:8]([CH:9]=2)=[C:7]([CH3:23])[CH:6]=[C:5]([O:4][CH2:3][CH2:2][N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[CH:13]=3)=[O:15])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: C1COCCN1
Reactant: Cc1cc(OCCBr)cc2[nH]c(C(=O)NC3CCCCC3)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: Cc1cc(OCCN2CCOCC2)cc2[nH]c(C(=O)NC3CCCCC3)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.8 %

Procedure:
To a stirred solution of 6-(2-bromoethoxy)-N-cyclohexyl-4-methyl-1H-indole-2-carboxamide (I-9A-c: 0.1 g, 0.26 mmol) in acetonitrile (5 mL) at 0° C. was added Cs2CO3 (172.7 mg, 0.53 mmol) followed by morpholine (46.12 mg, 0.53 mmol) dropwise. The resulting reaction mixture was stirred at room temperature for 16 h, diluted with water (10 mL) and extracted with ethyl acetate (2×20 mL). The combined ethyl acetate layers were washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude compound was purified by preparative HPLC to afford 70 mg (70%) of N-cyclohexyl-4-methyl-6-(2-morpholinoethoxy)-1H-indole-2-carboxamide (9A) as a white solid.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([CH:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:17][CH:16]=1>CN(C=O)C>[CH:29]1([CH:21]([C:18]2[CH:19]=[CH:20][C:15]([CH2:14][N:5]3[C:1](=[O:11])[C:2]4[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:4]3=[O:6])=[CH:16][CH:17]=2)[C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: CC(C)(C)OC(=O)C(c1ccc(CBr)cc1)C1CCCC1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C(c1ccc(CN2C(=O)c3ccccc3C2=O)cc1)C1CCCC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Under argon, 6.49 g (35 mmol) of potassium phthalimide were initially charged in 60 ml of DMF, 15 g (31.8 mmol) of tert-butyl(+/−)-2-(4-(bromomethyl)phenyl)-2-cyclopentylacetate were added and the mixture was stirred at 80° C. overnight. A further 0.5 equivalent of potassium phthalimide was then added, and the mixture was stirred at 80° C. for another 6 h. The reaction mixture was then filtered, and the filtrate was concentrated under reduced pressure. The residue was triturated with ethanol and the solid was filtered off with suction, washed with ethanol and dried under high vacuum. This gave 8.5 g (about 96% pure, 61% of theory) of the target compound.
Reaction SMILES: Cl[C:2]1[CH:30]=[CH:29][C:5]2[O:6][C:7]3[CH:28]=[CH:27][CH:26]=[CH:25][C:8]=3[CH:9]3[CH:13](C4C=CC(CC(O)=O)=CC=4)[O:12][C:11](=[O:24])[N:10]3[C:4]=2[CH:3]=1.[OH-].[Na+]>C1COCC1.CO>[CH:13]1[O:12][C:11](=[O:24])[N:10]2[C:9]=1[C:8]1[CH:25]=[CH:26][CH:27]=[CH:28][C:7]=1[O:6][C:5]1[CH:29]=[CH:30][CH:2]=[CH:3][C:4]2=1
Reactant: O=C(O)Cc1ccc(C2OC(=O)N3c4cc(Cl)ccc4Oc4ccccc4C23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=c1occ2n1-c1ccccc1Oc1ccccc1-2
Reaction time: 2.5 h
Yield: 126 %

Procedure:
To a stirring solution of 17 (77 mg, 0.18 mmol) in THF (3 mL) and MeOH (1.5 mL) was added NaOH (0.55 mL, 1M, 0.55 mmol). The resulting solution was stirred for 2.5 hours, followed by the removal of solvent under reduced pressure. To the residue was added 0.6 mL of 1M HCl. The resulting precipitate was collected by filtration and dried to yield 18 (57 mg): DSC: 217.88° C.; Analysis Calculated for C22H14NO5Cl×3.5 H2O: C, 56.24; H, 4.29; N, 2.98. Found: C, 55.84; H, 3.90; N, 2.91.
Reaction SMILES: [O:1]=[S:2]1(=[O:23])[C:8]2[CH:9]=[C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=3)[C:17]([OH:19])=O)[CH:11]=[CH:12][C:7]=2[O:6][CH2:5][CH2:4][NH:3]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[OH:55][NH:56][C:57](=[NH:59])[CH3:58]>C(Cl)Cl>[O:23]=[S:2]1(=[O:1])[C:8]2[CH:9]=[C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=3)[C:17]([NH:59]/[C:57](=[N:56]\[OH:55])/[CH3:58])=[O:19])[CH:11]=[CH:12][C:7]=2[O:6][CH2:5][CH2:4][NH:3]1
Reactant: CC(=N)NO
Reactant: O=C(O)c1cccc(Oc2ccc3c(c2)S(=O)(=O)NCCO3)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C/C(=N/O)NC(=O)c1cccc(Oc2ccc3c(c2)S(=O)(=O)NCCO3)c1
Reaction time: 0.33 h

Procedure:
To a suspension of the product obtained in Step A above (540 mg, 1.61 mmol) in 10 ml of CH2Cl2 there are added, in succession, 516 mg (1.61 mmol) of TBTU and then 364 μl (2.09 mmol) of DIEA. After stirring for 20 minutes, 120 mg (1.61 mmol) of N-hydroxyacetamidine are added and the reaction mixture is stirred for 1.5 hours at ambient temperature. The reaction mixture is washed with water and then with saturated NaCl solution, dried (MgSO4) and evaporated to dryness. The residue is taken up in CH2Cl2; a white precipitate forms which is filtered off to yield the expected product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:24]3[C:19](=[CH:20][N:21]=[C:22]([O:25][CH3:26])[CH:23]=3)[N:18]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:17]=2Cl)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:34][C:35]1[CH:36]=[CH:37][C:38]([CH3:42])=[C:39]([OH:41])[CH:40]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:24]3[C:19](=[CH:20][N:21]=[C:22]([O:25][CH3:26])[CH:23]=3)[N:18]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:17]=2[O:41][C:39]2[CH:40]=[C:35]([F:34])[CH:36]=[CH:37][C:38]=2[CH3:42])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc2c(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)c(Cl)n(-c3ccccc3)c2cn1
Reactant: Cc1ccc(F)cc1O
Product: COc1cc2c(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)c(Oc3cc(F)ccc3C)n(-c3ccccc3)c2cn1

Procedure:
The title compound was prepared from the compound of step 5 (100 mg, 212 μmol) and 5-fluoro-2-methylphenol analogously as described in example 1, step 6. Yield: 98.0 mg.
Reaction SMILES: Cl.[CH2:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2[CH:34]=[CH:33][C:17]([CH2:18][NH:19][C:20]3[CH:32]=[CH:31][C:23]4[O:24][C:25]([CH3:30])([CH3:29])[O:26][C:27](=[O:28])[C:22]=4[CH:21]=3)=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH3:5].[C:35](Cl)(=[O:41])[CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]>>[CH2:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]#[C:13][C:14]2[CH:34]=[CH:33][C:17]([CH2:18][N:19]([C:20]3[CH:32]=[CH:31][C:23]4[O:24][C:25]([CH3:30])([CH3:29])[O:26][C:27](=[O:28])[C:22]=4[CH:21]=3)[C:35](=[O:41])[CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[CH:16][CH:15]=2)=[CH:10][CH:11]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCCC(=O)Cl
Reactant: CCCCc1ccc(C#Cc2ccc(CNc3ccc4c(c3)C(=O)OC(C)(C)O4)cc2)cc1
Agent: Cl
Product: CCCCCC(=O)N(Cc1ccc(C#Cc2ccc(CCCC)cc2)cc1)c1ccc2c(c1)C(=O)OC(C)(C)O2

Procedure:
The titled compound was prepared following the procedure B using 6-({4-[(4-butylphenyl)ethynyl]benzyl}amino)-2,2-dimethyl-4H-1,3-benzodioxin-4-one hydrochloride and hexanoyl chloride as a colorless oil (88%). 1H NMR (CDCl3, 300 MHz) δ 7.70 (d, J=2.3 Hz, 1H), 7.44 (m, 4H), 7.16 (m, 4H), 7.05 (dd, J=8.6, 2.3 Hz, 1H), 6.91 (d, J=8.6 Hz, 1H) 4.88 (s, 2H), 2.63 (t, J=7.7 Hz, 2H), 2.06 (t, J=7.5 Hz. 2H), 1.75 (s, 6H), 1.61 (m, 4H), 1.36 (m, 2H), 1.23 (m, 4H), 0.94 (t, J=7.3 Hz, 3H), 0.85 (t, J=6.8 Hz, 3H). M+ (ESI): 538.4 HPLC, Rt: 5.95 min (Purity: 98.2%).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[CH:10]=[C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)[CH:8]=[C:7]([CH3:18])[C:6]=1[Cl:19].[NH4+:21].[OH-]>>[Cl:19][C:6]1[C:7]([CH3:18])=[CH:8][C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[CH:10][C:5]=1[CH2:4][C:3]([NH2:21])=[O:2]
Reactant: [NH4+]
Reactant: COC(=O)Cc1cc(N2CCN(C)CC2)cc(C)c1Cl
Agent: [OH-]
Product: Cc1cc(N2CCN(C)CC2)cc(CC(N)=O)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(5-Bromo-2-chloro-3-methyl-phenyl)-acetic acid methyl ester (2.0 g, 7.2 mmol), N-methylpiperazine (960 μL, 8.6 mmol) and Cs2CO3 (3.3 g, 10.1 mmol) are suspended in toluene (80 mL). Pd(OAc)2 (81 mg, 0.36 mmol) and BINAP (224 mg, 0.36 mmol) are added and the reaction is stirred at 100° C. overnight. The mixture is filtered through Celite and the solvent is evaporated. The residue is purified by FCC (AcOEt/AcOH/H2O 60:15:15) to afford 2-[2-chloro-3-methyl-5-(4-methyl-piperazin-1-yl)-phenyl]-acetic acid methyl ester. The ester is suspended in NH4OH 25% (60 mL). The mixture is stirred overnight at RT and the precipitate is filtered off to yield the amide. 1H NMR (DMSO, 400 MHz) δ 2.20 (s, 3H), 2.27 (s, 3H), 2.40-2.45 (m, 4H), 3.07-3.13 (m, 4H), 3.48 (s, 2H), 6.78 (s, 1H), 6.82 (s, 1H), 6.91 (br s, 1H), 7.34 (br s, 1H).
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:5]=[C:6]([C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:14])[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11].Cl>ClC(Cl)Cl>[C:13]([C:6]1[CH:7]=[CH:8][C:9]([N+:10]([O-:12])=[O:11])=[C:4]([CH:5]=1)[CH:3]=[O:2])(=[O:14])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COC(OC)c1cc(C(=O)c2ccccc2)ccc1[N+](=O)[O-]
Agent: Cl
Solvent: ClC(Cl)Cl
Product: O=Cc1cc(C(=O)c2ccccc2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 49 %

Procedure:
A mixture of 19 parts of intermediate 10, namely [3-(dimethoxymethyl)-4-nitrophenyl]phenylmethanone, 40 parts of an aqueous hydrochloric acid solution 5N and 120 parts of trichloromethane was stirred overnight at room temperature and for 4 hours at reflux temperature. After cooling, the organic layer was separated, basified with NH4OH (aq.), washed with water, dried, filtered and evaporated. The residue was crystallized from a mixture of 2,2'-oxybispropane and ethyl acetate. The product was filtered off, washed successively with a mixture of 2,2'-oxybispropane and ethyl acetate and with 2,2'-oxybispropane and dried in vacuo at 50° C., yielding 7.61 parts (49.0%) of 5-benzoyl-2-nitrobenzaldehyde; mp. 96.7° C. (interm. 11).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[F:27])=[C:6]([C:8]2[C:9]([O:16][CH2:17][CH3:18])=[CH:10][C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)[CH:7]=1.[N:28]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([O:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:32]=1)=[C:29]=[O:30]>>[F:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[O:19][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:29]([NH:28][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([O:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH:32]=2)=[O:30])=[CH:7][C:6]=1[C:8]1[C:9]([O:16][CH2:17][CH3:18])=[CH:10][C:11](=[O:15])[N:12]([CH3:14])[CH:13]=1
Reactant: CCOc1cc(=O)n(C)cc1-c1cc(N)ccc1Oc1ccc(F)cc1F
Reactant: O=C=Nc1cccc(Oc2ccccc2)c1
Product: CCOc1cc(=O)n(C)cc1-c1cc(NC(=O)Nc2cccc(Oc3ccccc3)c2)ccc1Oc1ccc(F)cc1F

Procedure:
A stock solution of Example 1G (0.73 M in pyridine, 458 μL, 0.033 mmol, 1.0 equivalent) and 1-isocyanato-3-phenoxybenzene (0.40 M in DMA, 108 μL, 0.043 mmol, 1.3 equivalents) were aspirated from their respective source vials, mixed through a perfluoroalkoxy mixing tube (0.2 mm inner diameter), and loaded into an injection loop. The reaction segment was injected into the flow reactor (Hastelloy coil, 0.75 mm inner diameter, 2.32 mL internal volume) set at 100° C., and passed through the reactor at 232 μL min−1 (10 minute residence time). Upon exiting the reactor, the reaction was loaded directly into an injection loop and purified by preparative HPLC on a Phenomenex Luna C8(2) 5 um 100 Å AXIA column (50 mm×21.2 mm). A gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used, at a flow rate of 30 mL/min (0-0.5 min 5% A, 0.5-6.5 min linear gradient 30-70% A, 6.5-7.0 min linear gradient 70-100% A, 7.0-8.5 min 100% A, 8.5-9.0 min linear gradient 100-5% A, 9.0-10 min 5% A) to yield the title compound. 1H NMR (400 MHz, DMSO-d6/D2O) δ 7.56 (s, 1H), 7.45-7.37 (m, 3H), 7.39-7.22 (m, 4H), 7.20-7.12 (m, 1H), 7.11 (ddd, J=8.0, 2.0, 1.0 Hz, 1H), 7.05-6.92 (m, 4H), 6.89 (d, J=8.7 Hz, 1H), 6.63 (ddd, J=8.1, 2.4, 0.9 Hz, 1H), 5.82 (s, 1H), 3.92 (q, J=6.9 Hz, 2H), 3.36 (s, 3H), 1.13 (t, J=6.9 Hz, 3H). MS (APCI+) m/z 583.7 (M+H)+.
Reaction SMILES: [N:1]1([C:6]2[O:10][C:9]([C:11](O)=O)=[C:8]([CH3:14])[CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:15][C:16]1[CH:17]=[C:18]([CH:27]=[CH:28][C:29]=1[NH2:30])[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:20].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>N1C=CC=CC=1>[N:1]1([C:6]2[O:10][C:9]([C:11]3[NH:15][C:16]4[CH:17]=[C:18]([C:19](=[O:20])[C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[CH:27]=[CH:28][C:29]=4[N:30]=3)=[C:8]([CH3:14])[CH:7]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1cc(N2CCCC2)oc1C(=O)O
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: c1ccncc1
Product: Cc1cc(N2CCCC2)oc1-c1nc2ccc(C(=O)c3ccccc3)cc2[nH]1
Temperature: 70 °C
Reaction time: 8 h
Yield: 54.2 %

Procedure:
5-Pyrrolidine-1-yl-methyl-furan-2-carboxylic acid (62% purity, 223 mg, 0.71 mmol) was added to a pyridine (3 ml) solution of 3,4-diaminobenzophenone (150 mg, 0.71 mmol). 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (149 mg, 0.78 mmol) and 1-hydroxybenzotriazole monohydrate (119 mg, 0.78 mmol) were further added, and the reaction mixture was heated to 70° C. and stirred overnight. The reaction mixture was allowed to cool to room temperature, and the solvent was evaporated. The residue was purified using medium pressure silica gel flash column chromatography (NH silica gel, chloroform:methanol=98:2), and the obtained residue was dissolved in acetic acid (3 ml) and stirred at 100° C. for 8 hours. The solution was allowed to cool to room temperature with stirring, and then the solvent was evaporated. The residue was purified using medium pressure silica gel flash column chromatography (NH silica gel, chloroform:methanol=98:2), to afford 2-(5-pyrrolidine-1-yl-methyl-furan-2-yl)-5-benzoylbenzimidazole (143 mg, 55% in two steps) as a yellow oil.
Reaction SMILES: C1C=CC=CC=1.[NH2:7][CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)[OH:10].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH2:28][C:29]([CH3:31])=O)[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]>O>[Cl:17][C:13]1[CH:12]=[C:11]([C@@H:9]([OH:10])[CH2:8][NH:7][C@H:29]([CH3:31])[CH2:28][C:22]2[CH:23]=[CH:24][C:25]([O:26][CH3:27])=[C:20]([O:19][CH3:18])[CH:21]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: NC[C@H](O)c1cccc(Cl)c1
Reactant: COc1ccc(CC(C)=O)cc1OC
Solvent: O
Solvent: c1ccccc1
Product: COc1ccc(C[C@@H](C)NC[C@H](O)c2cccc(Cl)c2)cc1OC
Reaction time: 24 h
Yield: 81 %

Procedure:
To 40 ml benzene solution of (R)-2-amino-1-(3-chlorophenyl)ethanol (0.304 g), was added 0.344 g of methyl 3,4-dimethoxyphenylmethyl ketone. The mixture was refluxed in an apparatus equipped with a water-trap for one hour and the water produced was removed from the reaction system. After cooling the reaction mixture, the solvent was distilled off under reduced pressure, and the residue was dissolved into 10 ml of methanol. To the mixture was added platinum oxide, and the reducing reaction was conducted at room temperature at 1 atm pressure under hydrogen atmosphere for 24 hours. After removing off platinum oxide by filtration, the solvent was distilled off under reduced pressure to give 0.501 g of white oil of (R,R)-1-(3-chlorophenyl)-2-[[2-(3,4-dimethoxyphenyl)-1-methylethyl]amino]ethanol (yield 81.0%). The optical purity of the (R,R)-isomer was 80%.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[CH:21]=[C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:19]=[C:18]([NH2:28])[N:17]=3)=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:29][O:30][CH2:31][C@@H:32]1[CH2:36][CH2:35][CH2:34][NH:33]1>>[CH3:29][O:30][CH2:31][C@@H:32]1[CH2:36][CH2:35][CH2:34][N:33]1[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]3[CH:21]=[C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:19]=[C:18]([NH2:28])[N:17]=3)=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: COC[C@@H]1CCCN1
Reactant: Nc1nc(Nc2ccc(Oc3ccnc(Cl)c3)cc2)cc(-c2ccccc2)n1
Product: COC[C@@H]1CCCN1c1cc(Oc2ccc(Nc3cc(-c4ccccc4)nc(N)n3)cc2)ccn1
Temperature: 80 °C

Procedure:
A mixture of N4-{4-[(2-chloropyridin-4-yl)oxy]phenyl}-6-phenylpyrimidine-2,4-diamine (0.15 g, 0.38 mmol, prepared in Example 48) and (S)-(+)-2-(methoxymethyl)pyrrolidine (2 mL) was heated at 80° C. for 3 days. The mixture was cooled to rt and separated by preparative HPLC directly. The desired fractions were combined, neutralized by 10% sodium carbonate, and extracted with EtOAc (3×). The extracts were combined, dried over magnesium sulfate, and evaporated to furnish pure product, 0.04 g (22%). 1H NMR (DMSO-d6) δ 9.24 (s, 1H), 7.89 (m, 3H), 7.78 (m, 2H), 7.42 (m, 3H), 7.00 (m, 2H), 6.44 (s, 1H), 6.34 (s, 2H), 6.10 (m, 1H), 5.85 (d, 1H), 4.06 (m, 2H), 3.40 (m, 1H), 3.21 (s, 3H), 3.08 (m, 4H), 1.82 (m, 4H); MS ES 469 (M+H)+ calc 469.
Reaction SMILES: [Na].[F:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:24])[NH:11][N:12]=[C:13]([OH:23])[C:14]2[CH:19]=[CH:18][CH:17]=[N:16][C:15]=2[C:20](=[O:22])[CH3:21])[CH:6]=[CH:7][CH:8]=1.[C:25]([O:28][CH2:29]Cl)(=[O:27])[CH3:26]>CN(C=O)C>[F:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:24])[NH:11][N:12]=[C:13]([O:23][CH2:29][O:28][C:25](=[O:27])[CH3:26])[C:14]2[CH:19]=[CH:18][CH:17]=[N:16][C:15]=2[C:20](=[O:22])[CH3:21])[CH:6]=[CH:7][CH:8]=1
Reactant: CC(=O)c1ncccc1C(O)=NNC(=O)Nc1cccc(F)c1
Reactant: CC(=O)OCCl
Agent: [Na]
Solvent: CN(C)C=O
Product: CC(=O)OCOC(=NNC(=O)Nc1cccc(F)c1)c1cccnc1C(C)=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of the sodium salt of compound 4 (1.0 g, 3.0 mmol) and chloromethyl acetate (0.4 g, 3.5 mmol) in 18 ml of DMF is stirred at RT for 3 days. The reaction mixture is poured onto ice. The solid which precipitates is collected by filtration, is washed with water and is air-dried. It is stirred in 50 ml of chloroform for 2 hours and is filtered. The filtrate is evaporated to give glass-like material, which is triturated with ether to give the crude product. Purification by prep. TLC gives acetyloxymethyl 2-acetylnicotinate 4-(3-fluorophenyl)semicarbazone, m.p. 159°-160° (compound 54, Table C).