Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[OH:8][CH:9]([C:24]1[N:25]=[CH:26][N:27]([C:30]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:28]=1[CH3:29])[CH:10]1[C:22](=[O:23])[N:14]2[C:15]3[C:20]([CH:21]=[C:13]2[CH2:12][CH2:11]1)=[CH:19][CH:18]=[CH:17][CH:16]=3.C(=O)([O-])O.[Na+]>N1C=CC=CC=1.C(Cl)(Cl)Cl>[C:1]([O:8][CH:9]([C:24]1[N:25]=[CH:26][N:27]([C:30]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[C:28]=1[CH3:29])[CH:10]1[C:22](=[O:23])[N:14]2[C:15]3[C:20]([CH:21]=[C:13]2[CH2:12][CH2:11]1)=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(C(O)C2CCc3cc4ccccc4n3C2=O)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(=O)OC(c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1C)C1CCc2cc3ccccc3n2C1=O
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Acetic anhydride (1.26 g) was added to a solution of 8,9-dihydro-7-[(hydroxy)(5-methyl-1-trityl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one (1.34 g, a mixture of the isomers A and B) in pyridine (20 ml). After being stirred at 60° C. for 2 hours, the solution was evaporated in vacuo. The residue obtained was diluted with chloroform and neutralized with an aqueous sodium hydrogencarbonate solution. The separated organic layer was dried over anhydrous magnesium sulfate and evaporated in vacuo to give 7-[(acetoxy)(5-methyl-1-trityl-1H-imidazol-4-yl)methyl]-8,9-dihydropyrido[1,2-a]indol-6(7H)-one as an oil, which was used in the next reaction without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:24])([CH3:23])[C:9](=O)[CH2:10][NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[S:13])=[CH:4][C:3]=1[O:25][CH3:26].C(OCC)C>CC(O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:9]2[N:14]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[C:12]([SH:13])=[N:11][CH:10]=2)([CH3:24])[CH3:23])=[CH:4][C:3]=1[O:25][CH3:26]
Reactant: COc1cc(C(C)(C)C(=O)CNC(=S)Nc2ccc(F)cc2)ccc1Cl
Solvent: CC(=O)O
Solvent: CCOCC
Product: COc1cc(C(C)(C)c2cnc(S)n2-c2ccc(F)cc2)ccc1Cl
Yield: 94698.8 %

Procedure:
A solution of 1-(3-(4-chloro-3-methoxyphenyl)-3-methyl-2-oxobutyl)-3-(4-fluorophenyl)-thiourea (21) (230 g, 0.58 mmol) in HOAc (1 L) was heated to reflux for 4 h with mechanical stirring. The reaction mixture was cooled and evaporated to give a residue which was treated with diethyl ether to give 5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazole-2-thiol (22) (207 g, 95%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 6.91-7.19 (d, 1H), 6.86-6.88 (t, 2H), 6.81 (s, 1H), 6.86-6.91 (t, 2H), 6.81 (s, 1H), 6.59-6.63 (m, 2H), 6.50-6.53 (d, 2H), 6.45 (s, 1H), 3.74 (s, 3H), 1.46 (s, 6H).
Reaction SMILES: [I:1][C:2]1[C:7]([NH2:8])=[C:6]([I:9])[N:5]=[CH:4][N:3]=1.[H-].[Na+].[CH3:12]S(OC)(=O)=O.C(OCC)(=O)C>O1CCCC1>[I:1][C:2]1[C:7]([NH:8][CH3:12])=[C:6]([I:9])[N:5]=[CH:4][N:3]=1
Reactant: Nc1c(I)ncnc1I
Reactant: COS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNc1c(I)ncnc1I
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4,6-diiodopyrimidin-5-amine (1.0 g) in tetrahydrofuran (10 mL) was added sodium hydride (60%, 138 mg) under ice-cooling. The mixture was stirred at room temperature for 30 min. To the reaction system was added dropwise a solution of methyl methanesulfonate (0.256 mL) in tetrahydrofuran (4.0 mL). The mixture was stirred at room temperature for 3 hrs and ethyl acetate was added. The mixture washed with water and saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by silica gel column chromatography (hexane:ethyl acetate=9:1→3:1) to give the title compound (600 mg) as pale-yellow crystals.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[C:11]([C:12]#[N:13])=[C:10](/[N:14]=[CH:15]/[N:16](C)C)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].[F:19][C:20]1[CH:26]=[CH:25][C:23](N)=[CH:22][CH:21]=1.[K+].[Br-]>C(Cl)Cl.CCOC(C)=O>[F:19][C:20]1[CH:26]=[CH:25][C:23]([NH:13][C:12]2[C:11]3[C:10](=[CH:9][CH:8]=[C:6]4[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]4=3)[N:14]=[CH:15][N:16]=2)=[CH:22][CH:21]=1
Reactant: CN(C)/C=N/c1ccc2nc(C#N)sc2c1C#N
Reactant: Nc1ccc(F)cc1
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: N#Cc1nc2ccc3ncnc(Nc4ccc(F)cc4)c3c2s1
Yield: 92 %

Procedure:
Prepared from VII and 4-fluoroaniline. Flash chromatography eluent (DCM-EtOAc, 5:5). Yield: 92%; yellow solid; mp>260° C.; IR (KBr) νmax/cm−1 3049, 2840, 2226, 1722, 1643, 1610, 1581, 1557, 1502, 1377, 1355, 1305, 1269, 1227, 1208, 1166, 1130, 1090, 981, 846, 829, 818; 19F NMR (282 MHz, DMSO-d6) δ −120.31; 1H NMR (300 MHz, DMSO-d6) δ 8.51 (d, 1H, J=9.0 Hz), 8.16 (s, 1H), 7.76 (d, 1H, J=9.0 Hz), 7.26-7.08 (m, 4H); HRMS calcd for C16H9N5SF (M+H+): 322.0563, found 322.0551.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:17])[C:11]=2[CH:10]=[C:9]1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([N:8]1[C:16]2[C:11](=[C:12]([O:17][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCc1ccccc1
Reactant: Cc1cc2c(O)cccc2n1Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc2c(OCc3ccccc3)cccc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.5 %

Procedure:
4-hydroxy-2-methyl indole 1 (50 g, 0.339 mole) was dissolved in anhydrous DMF (1 L). To the mixture sodium hydride 60% in mineral oil (27.9 g, 0.697 mole) was added. The mixture was left to stir at rt. for 1 h. To the mixture benzyl bromide (82.7 mL, 0.697 mole) was added drop-wise. The mixture was left to stir at room temperature for 18 h. The reaction was diluted with ethyl acetate (4 L) and washed with water (5×500 mL) then brine (1 L). The organic layer was separated and dried with magnesium sulphate and concentrated. The orange oily residue was purified by column chromatography (6:1 Hexane:EtOAc) to afford 86 g (72%) of 2 as an yellow oil.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[CH:9]=[CH:8][C:7]([C:10]3[N:22]([CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=4)[C:13]4[CH:14]=[CH:15][C:16]5[N:17]([C:18]([CH3:21])=[N:19][N:20]=5)[C:12]=4[CH:11]=3)=[N:6]2)[CH2:2]1.[C:31](Cl)(=[O:33])[CH3:32].C(N(CC)CC)C>C(Cl)Cl>[C:31]([N:1]1[CH2:2][CH:3]([N:5]2[CH:9]=[CH:8][C:7]([C:10]3[N:22]([CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=4)[C:13]4[CH:14]=[CH:15][C:16]5[N:17]([C:18]([CH3:21])=[N:19][N:20]=5)[C:12]=4[CH:11]=3)=[N:6]2)[CH2:4]1)(=[O:33])[CH3:32]
Reactant: CC(=O)Cl
Reactant: Cc1nnc2ccc3c(cc(-c4ccn(C5CNC5)n4)n3Cc3cccc(Cl)c3)n12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CC(n2ccc(-c3cc4c(ccc5nnc(C)n54)n3Cc3cccc(Cl)c3)n2)C1
Reaction time: 0.03 h
Yield: 71.4 %

Procedure:
To 7-(1-azetidin-3-yl-1H-pyrazol-3-yl)-6-(3-chlorobenzyl)-1-methyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (6.0 mg, 0.014 mmol, from Step 1) was added acetyl chloride (1.2 μL, 0.017 mmol, Aldrich) in DCM (0.38 mL). Triethylamine (4.0 μL, 0.029 mmol) was then added and the reaction was complete in 2 minutes. Purification via preparative HPLC-MS (C18 eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) afforded clean product (4.6 mg, 70%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([C:11]#[N:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][C:22]=1[F:30])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:1][C:2]1[CH:10]=[C:9]([C:11]#[N:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C:24]1[CH:25]=[CH:26][C:21]([O:20][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[C:22]([F:30])[CH:23]=1
Reactant: OB(O)c1ccc(OCc2ccccc2)c(F)c1
Reactant: N#Cc1cc(Br)c2cc[nH]c2c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1cc(Br)c2ccn(-c3ccc(OCc4ccccc4)c(F)c3)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.1 %

Procedure:
To a solution of 4-bromo-6-cyanoindole (900 mg, 4.1 mmol) in dichloromethane (30 mL) was added 4-benzyloxy-3-fluorobenzeneboronic acid (2.0 g, 8.1 mmol), triethylamine (1.2 mL, 8.6 mmol), copper (II) acetate (1.5 g, 8.2 mmol) and powdered 4A molecular sieves (2.0 g). The reaction mixture was stirred at room temperature in the presence of air for 16 hours. Further quantities of 4-benzyloxy-3-fluorobenzeneboronic acid (500 mg), triethylamine (0.3 mL) and copper acetate (375 mg) were added and the mixture stirred at room temperature in the presence of air for a further 16 hours. The mixture was filtered and the solid washed with dichloromethane. The filtrate was concentrated at reduced pressure. The product was purified by silica gel chromatography eluting with 2-40% ethyl acetate in hexane to yield the title compound (D13), (1.09 g).
Reaction SMILES: [CH:1]([N:4]([C:6]1[CH:7]=[C:8]([OH:14])[C:9](=[CH:12][CH:13]=1)[CH:10]=O)[CH3:5])([CH3:3])[CH3:2].[NH2:15][CH2:16][C:17]([NH2:20])([CH3:19])[CH3:18]>>[CH:1]([N:4]([C:6]1[CH:7]=[C:8]([OH:14])[C:9](=[CH:12][CH:13]=1)[CH:10]=[N:15][CH2:16][C:17]([CH3:19])([N:20]=[CH:10][C:9]1[C:8](=[CH:7][C:6]([N:4]([CH3:5])[CH:1]([CH3:2])[CH3:3])=[CH:13][CH:12]=1)[OH:14])[CH3:18])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)N(C)c1ccc(C=O)c(O)c1
Reactant: CC(C)(N)CN
Product: CC(C)N(C)c1ccc(C=NCC(C)(C)N=Cc2ccc(N(C)C(C)C)cc2O)c(O)c1

Procedure:
Synthesis and working up are carried out as in Example 9, starting from 500 mg (2.59 mmol) of 4-(N-isopropyl-N-methylamino)salicylaldehyde and 109 mg (1.23 mmol) of 1,2-diamino-2-methylpropane.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:10]=2[F:12])[CH:5]=[C:4]([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)[N:3]=1.[H-].[Na+].[CH2:30](Br)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].O>CN(C=O)C>[F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:10]=2[F:12])[CH:5]=[C:4]([C:21]2[CH:22]=[CH:23][C:24]([O:27][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:25][CH:26]=2)[N:3]=1
Reactant: CCCCCCCCBr
Reactant: CCCCCCCCc1ccc2cc(-c3ccc(O)cc3)nc(F)c2c1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCOc1ccc(-c2cc3ccc(CCCCCCCC)c(F)c3c(F)n2)cc1
Reaction time: 0.5 h
Yield: 80 %

Procedure:
10 mmol of 1,8-difluoro-3-(4-hydroxyphenyl)-7-octylisoquinoline are dissolved in 50 ml of DMF, and 11 mmol of sodium hydride are added. After the mixture has been stirred for 30 minutes, 11 mmol of 1 -octyl bromide are added dropwise, and the mixture is stirred at 60° C. for a further 140 minutes and poured into water. The mixture is extracted with dichloromethane, the combined organic phases are dried, the solvent is removed in vacuo and the residue is chromatographed on silica gel, giving 8 mmol of 1,8-difluoro-3-[4-(octyloxy)phenyl]-7-octylisoquinoline.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[NH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>CN(C=O)C.O>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[N:4]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:3]=1
Reactant: CCOC(=O)CCl
Reactant: O=[N+]([O-])c1cccc2[nH]nc(Br)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cn1nc(Br)c2c([N+](=O)[O-])cccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89.3 %

Procedure:
A solution of 3-bromo-4-nitro-1H-indazole (Preparation B; 1.00 g, 4.13 mmol) in anhydrous DMF (20 mL) was treated at ambient temperature with potassium carbonate (2.28 g, 16.5 mmol). The reaction mixture was stirred at ambient temperature for 10 minutes and ethyl 2-chloroacetate (0.53 g, 4.34 mmol) was added dropwise. Stirring was continued under nitrogen for 16 hours. The reaction mixture was diluted with excess water and extracted multiple times with DCM and EtOAc. The combined extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the product (1.21 g) as a brown solid.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:15][CH2:16][CH3:17])[C:5]1[C:6]2[N:7]([CH:11]=[C:12]([CH3:14])[N:13]=2)[CH:8]=[CH:9][CH:10]=1)[CH3:2].[CH2:18]([CH:20]([C:23]1[C:24]2[N:25]([C:30](I)=[C:31]([CH3:33])[N:32]=2)[N:26]=[C:27]([CH3:29])[CH:28]=1)[CH2:21][CH3:22])[CH3:19]>>[CH2:1]([O:3][CH:4]([O:15][CH2:16][CH3:17])[C:5]1[C:6]2[N:7]([C:11]([C:30]3[N:25]4[N:26]=[C:27]([CH3:29])[CH:28]=[C:23]([CH:20]([CH2:18][CH3:19])[CH2:21][CH3:22])[C:24]4=[N:32][C:31]=3[CH3:33])=[C:12]([CH3:14])[N:13]=2)[CH:8]=[CH:9][CH:10]=1)[CH3:2]
Reactant: CCOC(OCC)c1cccn2cc(C)nc12
Reactant: CCC(CC)c1cc(C)nn2c(I)c(C)nc12
Product: CCOC(OCC)c1cccn2c(-c3c(C)nc4c(C(CC)CC)cc(C)nn34)c(C)nc12
Yield: 71.8 %

Procedure:
Using a procedure analogous to Example 16B, 8-diethoxymethyl-2-methyl-imidazo[1,2-a]pyridine (1.70 g, 7.26 mmol) and 8-(1-ethyl-propyl)-3-iodo-2,6-dimethyl-imidazo[1,2-b]pyridazine (2.49 g, 7.26 mmol) give the title compound (2.34 g, 5.21 mmol, 72%). 1H NMR (CDCl3): δ. 0.92 (t, J=7.5 Hz, 3H), 0.93 (t, J=7.5 Hz, 3H), 1.31 (t, J=7.1 Hz, 3H), 1.33 (t, J=7.1 Hz, 3H), 1.79-1.93 (m, 4H), 2.14 (s, 3H), 2.44 (s, 6H), 3.34-3.42 (m, 1H), 3.67-3.94 (m, 4H), 6.26 (s, 1H), 6.73 (s, 1H), 6.73-6.80 (m, 1H), 7.44-7.54 (m, 2H) ppm. ES-MS (m/z): calcd for C26H35N5O2 (M+H)+: 450.6. found: 450.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C@@H:19]3[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]3)[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)C(C)C)(C)C.[C:34]([O:41][CH3:42])(=[O:40])[CH2:35][CH2:36][C:37]([O-])=[O:38].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C@@H:19]3[CH2:24][CH2:23][CH2:22][N:21]([C:37](=[O:38])[CH2:36][CH2:35][C:34]([O:41][CH3:42])=[O:40])[CH2:20]3)[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)CCC(=O)[O-]
Reactant: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCN(C[C@@H]2CCCNC2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCC(=O)N1CCC[C@@H](CN2CCN(C(=O)Nc3ccc(Cl)c(Cl)c3)CC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.4 %

Procedure:
To a solution of N-(3,4-dichlorophenyl)-4-[(3R)-piperidin-3-ylmethyl]piperazine-1-carboxamide (200 mg), N,N-di-isopropylethylamine (0.19 mL) and monomethyl succinate (79 mg) in dimethylformamide (5 mL) was added O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-Tetramethyluronium Hexafluoro-Phosphate. The solution was stirred at room temperature overnight and then loaded directly onto an SCX-2 column and eluted with methanol then 7M NH3 in methanol. The basic fraction was concentrated at reduced pressure and the residue was purified by silica column chromatography, eluting with a gradient of 0 to 10% methanol in dichloromethane to give the title compound as a white foam (252 mg, 96%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[NH:12][C:11]([CH2:27][C:28]([O:30][CH3:31])=[O:29])=[C:10]1[C:32]([O:34][CH3:35])=[O:33].[CH3:36]N1CCNCC1.C=O>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[NH:12][C:11]([C:27](=[CH2:36])[C:28](=[O:29])[O:30][CH3:31])=[C:10]1[C:32]([O:34][CH3:35])=[O:33]
Reactant: COC(=O)CC1=C(C(=O)OC)C(c2c(Cl)cccc2Cl)C(C(=O)OC)=C(CCc2ccccc2)N1
Reactant: CN1CCNCC1
Agent: C=O
Solvent: CC(=O)O
Product: C=C(C(=O)OC)C1=C(C(=O)OC)C(c2c(Cl)cccc2Cl)C(C(=O)OC)=C(CCc2ccccc2)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.9 %

Procedure:
Dimethyl 4-(2,6-dichlorophenyl)-2-methoxycarbonylmethyl-6-[2-(phenyl)ethyl]-1,4-dihydropyridine-3,5-dicarboxylate (588 mg, 1.135 m mol) and N-methylpiperazine (0.132 ml, 1.19 m mol) were dissolved in acetic acid (3 ml) and to the solution was added paraformaldehyde. The mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo and partitioned between CH2Cl2 (50 ml) and aqueous NaHCO3 solution (20 ml). The aqueous layer was extracted with CH2Cl2 (30 ml). The combined organic layer and the extract were washed with brine (10 ml), dried (MgSO4), and concentrated in vacuo to give a yellow oil. This was crystallized from ethyl acetate and isopropyl ether gave a yellow solid (270 mg, 50.9%). Second crop was obtained from the mother liquid (78 mg, 14.7%). 1H NMR (D2O) δ7.35-7.16 (m, 7H), 7-05-6.97 (m, 1H), 6.21 (br.s, 1H), 6.06 (s, 1H), 5.52 (br.s, 1H), 5.43 (br.s, 1H), 3.73 (s, 3H), 3.57 (s, 3H), 3.46 (s, 3H), 3.10-2.80 (m, 4H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][S:9]([N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][NH2:19])[CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:21]1[N:26]=[C:25]([NH2:27])[CH:24]=[CH:23][N:22]=1>>[C:1]1([CH2:7][CH2:8][S:9]([N:12]2[CH2:13][CH2:14][CH:15]([CH2:18][NH:19][C:21]3[N:26]=[C:25]([NH2:27])[CH:24]=[CH:23][N:22]=3)[CH2:16][CH2:17]2)(=[O:10])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ccnc(Cl)n1
Reactant: NCC1CCN(S(=O)(=O)CCc2ccccc2)CC1
Product: Nc1ccnc(NCC2CCN(S(=O)(=O)CCc3ccccc3)CC2)n1

Procedure:
EXAMPLE 96 was prepared from C-[1-(2-phenyl-ethanesulfonyl)-piperidin-4-yl]-methylamine and 2-chloro-pyrimidin-4-ylamine (prepared from 2,4-chloro-pyrimidin-4-ylamine by hydrogenation in ethanol over 5% palladium on carbon, 1 atm of hydrogen): MS (m+1)=376.5.
Reaction SMILES: [C:1]1([O:11][CH2:12][CH2:13][CH2:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21](/[CH:24]=[CH:25]/[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:22]=3)[NH:17][C:16]=2[C:32]([OH:34])=[O:33])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C1CCCCC=1>C(O)C.[Pd]>[C:1]1([O:11][CH2:12][CH2:13][CH2:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([CH2:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:22]=3)[NH:17][C:16]=2[C:32]([OH:34])=[O:33])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1[nH]c2ccc(/C=C/c3ccccc3)cc2c1CCCOc1cccc2ccccc12
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CCO
Product: O=C(O)c1[nH]c2ccc(CCc3ccccc3)cc2c1CCCOc1cccc2ccccc12

Procedure:
A mixture of EXAMPLE 14 (0.005 g), cyclohexene (0.5 mL), Pd/C (catalytic) in ethanol (4 mL) was heated at 130° C. (270 W) in a microwave (CEM Discover) for 10 minutes. The reaction mixture was filtered and the filtrate was concentrated. The concentrate was purified by preparative reverse phase HPLC (Zorbax SB, C-18, 20% to 100% acetonitrile/water/0.1% trifluoroacetic acid) to afford the title compound. 1H NMR (500 MHz, DMSO-d6) δ 12.88 (brs, 1H), 11.32 (s, 1H), 8.34 (m, 1H), 7.84 (m, 1H), 7.53 (m, 2H), 7.42 (d, 1H), 7.34 (m, 2H), 7.23 (m, 3H), 7.13 (m, 1H), 7.01 (m, 3H), 6.84 (d, 1H), 4.08 (t, 2H), 2.56 (s, 4H), 2.19 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[C:30]1([CH3:40])[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1.Cl>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][S:36]([C:33]2[CH:34]=[CH:35][C:30]([CH3:40])=[CH:31][CH:32]=2)(=[O:38])=[O:37])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)O[C@H]2CCN(C(=O)OC(C)(C)C)C2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 84.5 %

Procedure:
To a 0° C. solution of (S)-3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (8.5 g, 45.4 mmol), triethylamine (9.47 ml, 68.1 mmol) and dimethylaminopyridine (0.55 g, 4.5 mmol) in CH2Cl2 (150 ml) was added portionwise p-toluenesulfonyl chloride (9.52 g, 49.9 mmol). After 48 hours stirring at room temperature, reaction mixture was acidified to pH 1 with 1N HCl and aqueous phase was extracted with CH2Cl2. Combined organic phases were washed with 1N HCl and H2O, dried over Na2SO4 and concentrated. The residue was chromatographed over silica gel (hexane-ethylacetate 9:1 then 8:2 then 1:1) to provide (S)-3-(toluene-4-sulfonyloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (13.1 g, 87%) as a slightly yellow oil, MS: m/e=268.1 (M-OtBu) and [α]D20=+17.55° (c=3.33, diethylether).
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]1[C:14]([OH:15])=[C:13]([F:16])[C:12]([F:17])=[CH:11][C:7]=1[C:8](O)=[O:9]>C1C=CC=CC=1>[F:5][C:6]1[C:14]([OH:15])=[C:13]([F:16])[C:12]([F:17])=[CH:11][C:7]=1[C:8]([Cl:3])=[O:9]
Reactant: O=C(O)c1cc(F)c(F)c(O)c1F
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: O=C(Cl)c1cc(F)c(F)c(O)c1F

Procedure:
300 ml of thionyl chloride were added to a solution of 100.0 g (0.52 moles) of 2,4,5-trifluoro-3-hydroxybenzoic acid [(XXIII), X=X'=F] (prepared as described in Preparation 13) in 400 ml of benzene, and the mixture was heated under reflux for 3 hours. At the end of this time, the solvent and excess thionyl chloride were removed by distillation under reduced pressure, to give 2,4,5-trifluoro-3-hydroxybenzoyl chloride. The whole of this chloride was added dropwise to 1500 ml of 28% w/v aqueous ammonia, whilst stirring and ice-cooling, and the mixture was then stirred for a further 2 hours. At the end of this time, the mixture was allowed to stand at room temperature overnight, after which it was acidified by the addition of dilute aqueous hydrochloric acid. The reaction mixture was then extracted with ethyl acetate, and the extract was washed with water and dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, to give 88.2 g of 2,4,5-trifluoro-3-hydroxybenzoyl amide as a colorless powder, melting at 153°-155° C.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:14]=[CH:15][C:16]=1[N+:17]([O-])=O)[O:8][CH2:9][CH2:10][N:11]([CH3:13])[CH3:12])([CH3:3])[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[CH3:12][N:11]([CH3:13])[CH2:10][CH2:9][O:8][C:7]1[CH:14]=[CH:15][C:16]([NH2:17])=[C:5]([O:4][CH:1]([CH3:2])[CH3:3])[CH:6]=1
Reactant: CC(C)Oc1cc(OCCN(C)C)ccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)Oc1cc(OCCN(C)C)ccc1N
Yield: 95.1 %

Procedure:
A mixture of [2-(3-isopropoxy-4-nitrophenoxy)ethyl]dimethylamine (2.0 g, 7.5 mmol) and 5% Pd—C (0.3 g) in ethyl acetate (70 mL) was shaken under 50 psi of hydrogen for 24 hours. The mixture was filtered through Celite and evaporated, providing 1.7 g of the product as a light gold oil, in 98% yield; 1H NMR (CDCl3) δ 1.34 (d, J=6.0 Hz, 6H), 2.32 (s, 6H), 2.68 (t, J=5.8 Hz, 2H), 3.48 (br, 2H), 3.98 (t, J=5.8 Hz, 2H), 4.48 (septet, J=6.0 Hz, 1H), 6.35 (dd, J=8.4 Hz, J=2.5 Hz, 1H), 6.50 (d, J=2.5 Hz, 1H), 6.63 (d, J=8.4 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([Br:8])[CH:7]=1.[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Br)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([O:9][CH2:16][C:15]2[CH:18]=[CH:19][C:12]([O:11][CH3:10])=[CH:13][CH:14]=2)[CH:5]=[C:6]([Br:8])[CH:7]=1
Reactant: Oc1cc(Br)cc(Br)c1
Reactant: COc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(COc2cc(Br)cc(Br)c2)cc1
Yield: 81.9 %

Procedure:
3,5-Dibromophenol (10.0 g), 4-methoxybenzyl bromide (8.8 g) and potassium carbonate (27.3 g) were combined in acetone (300 mL) and refluxed for 3 h. Then the insoluble material was removed by filtration, the filtrate was concentrated under reduced pressure and the resulting crude oil was purified on a silica gel column using ethyl acetate and hexanes to give light yellow oil which was then crystallized from hexanes to give the title compound (12.1 g, 82% yield). HRMS calcd for C14H12O2Br2 M+ 369.9203, observed 369.9198.