Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7](Br)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([N+:32]([O-:34])=[O:33])[CH:27]=2)[CH2:18][CH2:17]1.OC1CCN(CCCOC2C=CC=CC=2[N+]([O-])=O)CC1>>[C:1]1([CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:15][CH:16]2[CH2:17][CH2:18][N:19]([CH2:22][CH2:23][CH2:24][O:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([N+:32]([O-:34])=[O:33])[CH:27]=3)[CH2:20][CH2:21]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: O=[N+]([O-])c1cccc(OCCCN2CCC(O)CC2)c1
Agent: O=[N+]([O-])c1ccccc1OCCCN1CCC(O)CC1
Product: O=[N+]([O-])c1cccc(OCCCN2CCC(OC(c3ccccc3)c3ccccc3)CC2)c1

Procedure:
The procedure of Example 1 (a) was repeated except for using diphenylmethyl bromide and 4-hydroxy-1-[3-(3-nitrophenoxy)propyl]piperidine instead of diphenylmethyl bromide and 4-hydroxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give oily 4-diphenylmethoxy-1-[3-(3-nitrophenoxy)propyl]piperidine.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].[CH2:13](I)[CH2:14][CH3:15]>>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH2:14][CH3:15])[CH:8]=[CH:7]2)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Reactant: CCCI
Product: CCCn1ccc2cc([N+](=O)[O-])ccc21
Yield: 96 %

Procedure:
The title compound was prepared in 96% yield from 5-nitroindole and propyl iodide using a procedure similar to that in Description 2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:5]=[C:6]([F:9])[C:7]=1F.C(=O)([O-])[O-].[K+].[K+].[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][C:22]=1[N+:28]([O-:30])=[O:29]>CN(C=O)C.CC(CC(C)=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:5]=[C:6]([F:9])[C:7]=1[O:27][C:24]1[CH:25]=[CH:26][C:21]([CH3:20])=[C:22]([N+:28]([O-:30])=[O:29])[CH:23]=1
Reactant: Fc1cc(C(F)(F)F)cc(Cl)c1F
Reactant: Cc1ccc(O)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(=O)CC(C)C
Product: Cc1ccc(Oc2c(F)cc(C(F)(F)F)cc2Cl)cc1[N+](=O)[O-]
Reaction time: 2 h
Yield: 92 %

Procedure:
3-Chloro-4,5-difluorobenzotrifluoride (99 g) was dissolved in dry MBIK (100 cm3) and 25 drops of dry DMF and dry potassium carbonate (48 g) added. The mixture was stirred and brought to reflux when a solution of 4-methyl-3-nitrophenol (35 g) in dry MIBK (70 cm3) was added over 1 hour. When the addition was complete stirring and reflux were continued for 2 hours. The solvent was removed from the reaction mixture under vacuum and the residue triturated with water (500 cm3). The solid obtained was filtered off, washed with water and air dried. The crude solid was recrystallised from ethanol to give 4-(2-chloro-6-fluoro-4-trifluoromethylphenoxy)-2-nitrotoluene (73.5 g) as an off white solid, m.p. 112.8°-115.4° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:13][O:14][C:15]3[CH:16]=[C:17]([CH2:21][N:22]4C(=O)C5=CC=CC=C5C4=O)[CH:18]=[CH:19][CH:20]=3)[S:11][CH:12]=2)=[CH:4][CH:3]=1.O.NN>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([CH2:13][O:14][C:15]3[CH:16]=[C:17]([CH2:21][NH2:22])[CH:18]=[CH:19][CH:20]=3)[S:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1cccc(OCc2nc(-c3ccc(Cl)cc3)cs2)c1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCc1cccc(OCc2nc(-c3ccc(Cl)cc3)cs2)c1
Temperature: 25 °C

Procedure:
The phthalimide compound (1.65 grams) (Scheme C, Compound C2) was suspended in ethanol (100 mL). Hydrazine hydrate (1 mL) was added and the reaction was stirred at reflux for 2 hours before being cooled to ambient temperature. The mix was then filtered and the filtrate was evaporated. The crude solid was dissolved in dichloromethane, then sequentially washed with 1 N potassium hydroxide and water. The organic layer was then evaporated to give 3-[[4-(4-chlorophenyl)-2-thiazolyl]methoxy]benzenemethanamine Compound 11. Mp 117–118.5° C.; MS 331 (MH+); 1HNMR (CDCl3) δ 7.85 (d, 2H), 7.50 (s, 1H), 7.40 (d, 2H), 5.43 (s, 2H), 3.86 (s, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][C:14]1[CH:15]=[C:16]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)[CH:17]=[C:18]([CH2:20][P:21]([O:26][CH2:27][CH3:28])([O:23][CH2:24][CH3:25])=[O:22])[CH:19]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.O.O.O.O.[OH-].C[N+](C)(C)C.[CH2:47](Br)[CH:48]=[CH:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>CN(C)C=O>[CH2:47]([O:11][C:10](=[O:12])[CH:9]([NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:13][C:14]1[CH:15]=[C:16]([C:29]2[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=2)[CH:17]=[C:18]([CH2:20][P:21]([O:26][CH2:27][CH3:28])([O:23][CH2:24][CH3:25])=[O:22])[CH:19]=1)[CH:48]=[CH:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1
Reactant: CCOP(=O)(Cc1cc(CC(NC(=O)OC(C)(C)C)C(=O)O)cc(-c2ccc(Cl)cc2)c1)OCC
Reactant: BrCC=Cc1ccccc1
Agent: C[N+](C)(C)C
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(=O)(Cc1cc(CC(NC(=O)OC(C)(C)C)C(=O)OCC=Cc2ccccc2)cc(-c2ccc(Cl)cc2)c1)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1.05 g of the product of step b) in 5 ml dimethylformamide are added 362 mg tetramethyl ammonium hydroxide pentahydrate. The mixture is stirred at room temperature 11/2 hours and then treated with 394 mg cinnamyl bromide. The mixture is stirred at room temperature 17 hours. The mixture is diluted with ice/water (about 50 ml) and extracted with diethyl ether. The extracts are washed with 10 ml aqueous 1N KHCO3 solution, dried (Na2SO4) and evaporated to give the heading compound as an oil.
Reaction SMILES: Br[C:2]1[N:3]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[C:4]2[C:9]([N:10]=1)=[C:8]([NH2:11])[N:7]=[C:6]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[N:5]=2.[CH3:24][O-:25].[Na+]>CO>[CH3:24][O:25][C:2]1[N:3]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[C:4]2[C:9]([N:10]=1)=[C:8]([NH2:11])[N:7]=[C:6]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[N:5]=2
Reactant: CCCCCNc1nc(N)c2nc(Br)n(C3CCCCO3)c2n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCCCNc1nc(N)c2nc(OC)n(C3CCCCO3)c2n1
Temperature: 60 °C
Reaction time: 48 h

Procedure:
To a solution of 8-bromo-N2-pentyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-2,6-diamine (607 mg) in dry MeOH (4.75 mL) was added sodium methoxide solution (0.906 mL, 30% wt. MeOH) and the mixture was stirred at 60° C. for 48 h. The reaction was concentrated in vacuo. The residue was taken up in EtOAc (25 mL) and washed with saturated ammonium chloride (25 mL). The organics were separated, dried over MgSO4, filtered and concentrated in vacuo to give the title compound as a red/brown viscous oil (520 mg) which was used crude in the next step.
Reaction SMILES: [CH2:1]([C:8]1[C:13](I)=[CH:12][CH:11]=[C:10]([N:15]2[CH2:19][C@H:18]([F:20])[C@H:17]([OH:21])[CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([C@:24]1([OH:32])[CH:29]2[CH2:30][CH2:31][N:26]([CH2:27][CH2:28]2)[CH2:25]1)#[CH:23].C(N(CC)CC)C.N>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.CN(C)C=O>[CH2:1]([C:8]1[C:13]([C:23]#[C:22][C@:24]2([OH:32])[CH:29]3[CH2:30][CH2:31][N:26]([CH2:27][CH2:28]3)[CH2:25]2)=[CH:12][CH:11]=[C:10]([N:15]2[CH2:19][C@H:18]([F:20])[C@H:17]([OH:21])[CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#C[C@@]1(O)CN2CCC1CC2
Reactant: O[C@@H]1CN(c2ccc(I)c(Cc3ccccc3)n2)C[C@@H]1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O[C@@H]1CN(c2ccc(C#C[C@@]3(O)CN4CCC3CC4)c(Cc3ccccc3)n2)C[C@@H]1F
Temperature: 75 °C
Reaction time: 3 h
Yield: 69.9 %

Procedure:
A mixture of 50 mg of 2-benzyl-6-[(3R,4S)-3-hydroxy-4-fluoropyrrolidine-1-yl]-3-iodopyridine, 21 mg of (3R)-3-ethynyl-3-quinuclidinol, 15 mg of tetrakis(triphenylphosphine)palladium(0), 1 mg of cuprous iodide, 53 μl of triethylamine and 3.0 ml of N,N-dimethylformamide was heated under stirring for 3 hours at 75° C. in a nitrogen atmosphere. The reaction solution was poured into an aqueous dilute ammonia, was then extracted with ethyl acetate. Then, the organic phase was washed with brine and the solvent was removed. The residue was subjected to NH-silica gel (Fuji Silicia) column chromatography and eluted with hexane/ethyl acetate (1:1) and then with ethyl acetate/methanol (15:1), to give 37 mg of the target compound.
Reaction SMILES: Cl.Cl.Cl.[NH2:4][C:5]1[C:10]2=[C:11]([C:29]3[S:30][C:31]4[C:37]([O:38][CH3:39])=[CH:36][C:35]([CH3:40])=[CH:34][C:32]=4[CH:33]=3)[C:12]([CH2:21][N:22]3[CH2:27][CH2:26][NH:25][C:24](=[O:28])[CH2:23]3)=[C:13]([CH2:14][N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[N:9]2[N:8]=[CH:7][N:6]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:47](Cl)(=[O:49])[CH3:48]>ClCCl.C1COCC1>[C:47]([N:18]1[CH2:17][CH2:16][N:15]([CH2:14][C:13]2[N:9]3[C:10]([C:5]([NH2:4])=[N:6][CH:7]=[N:8]3)=[C:11]([C:29]3[S:30][C:31]4[C:37]([O:38][CH3:39])=[CH:36][C:35]([CH3:40])=[CH:34][C:32]=4[CH:33]=3)[C:12]=2[CH2:21][N:22]2[CH2:27][CH2:26][NH:25][C:24](=[O:28])[CH2:23]2)[CH2:20][CH2:19]1)(=[O:49])[CH3:48]
Reactant: CC(=O)Cl
Reactant: COc1cc(C)cc2cc(-c3c(CN4CCNC(=O)C4)c(CN4CCNCC4)n4ncnc(N)c34)sc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1cc(C)cc2cc(-c3c(CN4CCNC(=O)C4)c(CN4CCN(C(C)=O)CC4)n4ncnc(N)c34)sc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of Example 49 (310 mg, 522 μmol) in dichloromethane/THF (2.5:1, 9.64 ml) was treated with sodium carbonate (442 mg, 4.17 mmol) and stirred at rt for 30 min. Acetyl chloride (74 μl, 1.04 mmol) was added, and the resulting mixture was stirred at rt for 2 h. After quenching with methanol, the mixture was evaporated, and the residue was purified by preparative RP-HPLC (Reprosil C18, gradient 10-95% acetonitrile/0.1% aq. formic acid) affording 133 mg (45% of th.) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:17]=[CH:16][C:15](Br)=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[CH3:13])=[O:5].[N:19]1([CH2:25][C:26]2[S:30][C:29](B3OC(C)(C)C(C)(C)O3)=[CH:28][CH:27]=2)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[NH2:1][C:2]1[N:17]=[CH:16][C:15]([C:29]2[S:30][C:26]([CH2:25][N:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)=[CH:27][CH:28]=2)=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[CH3:13])=[O:5]
Reactant: Cc1cnccc1NC(=O)c1cc(Br)cnc1N
Reactant: CC1(C)OB(c2ccc(CN3CCOCC3)s2)OC1(C)C
Product: Cc1cnccc1NC(=O)c1cc(-c2ccc(CN3CCOCC3)s2)cnc1N

Procedure:
Reaction of 2-amino-5-bromo-N-(3-methyl-pyridin-4-yl)-nicotinamide with 5-(4-morpholinylmethyl)thiophene-2-boronic acid pinacol ester gives the compound “A21”; HPLC/MS: 0.97 min, [M+H]=410;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([OH:14])=O)=[CH:6]2.[CH2:15]([NH:18][CH2:19][CH2:20][CH3:21])[CH2:16][CH3:17].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O.C(OCC)C>[CH2:15]([N:18]([CH2:19][CH2:20][CH3:21])[C:12]([C:7]1[NH:8][C:9]2[C:5]([CH:6]=1)=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)=[O:14])[CH2:16][CH3:17]
Reactant: CCCNCCC
Reactant: COc1ccc2[nH]c(C(=O)O)cc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCCN(CCC)C(=O)c1cc2cc(OC)ccc2[nH]1
Temperature: 25 °C
Reaction time: 12 h
Yield: 73.7 %

Procedure:
To a solution of 5-methoxyindole-2-carboxylic acid (500 mg, 2.62 mmol) in 13 mL of N,N-dimethylformamide was added di-n-propylamine (1.07 mL, 7.8 mmol) and HATU (1.09 g, 2.88 mmol) at 0° C. After the reaction mixture was stirred at room temperature for 12 h, the reaction mixture was diluted with diethyl ether, and washed with water and brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography to obtain the title compound (0.53 g, 74%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](Br)[C:20]([C:24]#[N:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[Br-].[F:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33][Zn+]>C(C1C=CC=C(C(C)C)C=1N1C=CN(C2C(C(C)C)=CC=CC=2C(C)C)C1=[Pd-3](Cl)(Cl)C1C(Cl)=CC=CN=1)(C)C>[CH3:1][O:2][C:3](=[O:27])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:33][C:32]5[CH:35]=[CH:36][CH:37]=[C:30]([F:29])[CH:31]=5)[C:20]([C:24]#[N:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C#N)c4Br)ccc21
Reactant: Fc1cccc(C[Zn+])c1
Agent: CC(C)c1cccc(C(C)C)c1-n1ccn(-c2c(C(C)C)cccc2C(C)C)c1=[Pd-3](Cl)(Cl)c1ncccc1Cl
Agent: [Br-]
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C#N)c4Cc3cccc(F)c3)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-4-bromo-5-cyano-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 3-fluoro-benzylzinc bromide following a procedure analogous to that described in Step 6 of Intermediate 1; [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]-(3-chloropyridyl)-palladium(II) dichloride (Pd-PEPPSI-IPr) is used as catalyst. LC (method 4): tR=1.22 min; Mass spectrum (ESI+): m/z=458 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:7][CH2:6]1.[O:21]1[CH:26]2[CH:22]1[CH2:23][O:24][CH2:25]2.C(N(CC)CC)C>ClCCl>[OH:21][C@@H:22]1[CH2:23][O:24][CH2:25][C@H:26]1[O:1][CH2:2][CH2:3][O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:12])[CH2:7][CH2:6]1
Reactant: O=C(OCc1ccccc1)N1CCC(OCCO)CC1
Reactant: C1OCC2OC12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCC(OCCO[C@@H]2COC[C@H]2O)CC1
Reaction time: 16 h
Yield: 48.8 %

Procedure:
Benzyl 4-(2-hydroxyethoxy)piperidine-1-carboxylate (6.70 g, 24.0 mmol) produced in Reference Example 1 (1b) and 3,4-epoxytetrahydrofuran (1.03 g, 12.0 mmol) were dissolved in dichloromethane (5.0 mL). To the resulting mixture, a boron trifluoride diethyl ether complex (0.34 g, 2.4 mmol) was added at room temperature, followed by stirring for 16 hours. More boron trifluoride diethyl ether complex (0.34 g, 2.4 mmol) was added, followed by further stirring for two hours. Triethylamine (1.82 g, 18.0 mmol) was then added, and the resulting reaction liquid was directly purified by basic silica gel column chromatography (hexane:ethyl acetate, 100:0-0:100, ethyl acetate:methanol, 100:0-95:5, V/V) to give the desired title compound (2.14 g, yield 49%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]([CH3:21])([C:17]([F:20])([F:19])[F:18])[C:14](O)=[O:15].S(Cl)([Cl:24])=O.CN(C)C=O>C1C=CC=CC=1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]([CH3:21])([C:17]([F:20])([F:19])[F:18])[C:14]([Cl:24])=[O:15]
Reactant: CC(OCc1ccc2ccccc2c1)(C(=O)O)C(F)(F)F
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CC(OCc1ccc2ccccc2c1)(C(=O)Cl)C(F)(F)F

Procedure:
A solution of (±)-2-(2-naphthylmethoxy)-3,3,3-trifluoro-2-methylpropionic acid (6.0 g.), thionyl chloride (7.5 ml.) and dimethylformamide (0.2 g.) in benzene (50 ml.) is heated under reflux for 10 minutes. The mixture is evaporated, benzene (20 ml.) is added and the evaporation repeated twice. Light petroleum (b.p. 40°-60° C., 150 ml.) and carbon are added to the residue, and the solution is filtered and evaporated to give (±)-2-(2-naphthylmethoxy)- 3,3,3-trifluoro-2-methylpropionyl chloride (5.35 g.) m.p, 39°-43° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH:5]([NH2:9])[C:6](=[NH:8])[NH2:7])[CH3:2].[CH:11]([C:13]([C:15]([F:18])([F:17])[F:16])=O)=O.C([O-])(=O)C.[Na+]>O>[CH2:1]([O:3][C:4]([C:5]1[C:6]([NH2:7])=[N:8][C:13]([C:15]([F:18])([F:17])[F:16])=[CH:11][N:9]=1)=[O:10])[CH3:2]
Reactant: CCOC(=O)C(N)C(=N)N
Reactant: O=CC(=O)C(F)(F)F
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1ncc(C(F)(F)F)nc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of amino-carbamimidoyl-acetic acid ethyl ester (2 g, 9.22 mmol) and water (50 ml), a 20% aqueous solution of trifluoropyruvic aldehyde (2.32 g, 18.43 mmol) was added. To this mixture, sodium acetate (5.29 g, 64.52 mmol) was added (pH of the reaction mixture was pH5). The reaction mixture was left to stir at RT overnight. The resultant precipitate was filtered under vacuum purification by chromatography on silica eluting with iso-hexane: EtOAc (gradient of 0 to 10% EtOAc) afforded the title compound
Reaction SMILES: [N:1]1([CH2:5][CH2:6][C:7]2[NH:8][C:9]([C:13]3[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=3[CH3:22])[C:16]([OH:18])=O)=[C:10]([Cl:12])[N:11]=2)[CH2:4][CH2:3][CH2:2]1.ClC1N=C(COC)NC=1C1C=C(C=CC=1C)C(O)=O.Cl.[NH:43]1[CH2:46][CH:45]([C:47]2[CH:54]=[CH:53][C:50]([C:51]#[N:52])=[CH:49][CH:48]=2)[CH2:44]1.Cl.N1CCC(C2C=CC(C#N)=CC=2)CC1>>[N:1]1([CH2:5][CH2:6][C:7]2[NH:8][C:9]([C:13]3[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=3[CH3:22])[C:16]([N:43]3[CH2:46][CH:45]([C:47]4[CH:54]=[CH:53][C:50]([C:51]#[N:52])=[CH:49][CH:48]=4)[CH2:44]3)=[O:18])=[C:10]([Cl:12])[N:11]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: N#Cc1ccc(C2CNC2)cc1
Reactant: Cc1ccc(C(=O)O)cc1-c1[nH]c(CCN2CCC2)nc1Cl
Agent: COCc1nc(Cl)c(-c2cc(C(=O)O)ccc2C)[nH]1
Agent: Cl
Agent: N#Cc1ccc(C2CCNCC2)cc1
Product: Cc1ccc(C(=O)N2CC(c3ccc(C#N)cc3)C2)cc1-c1[nH]c(CCN2CCC2)nc1Cl

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 27, except 3-(2-(2-(azetidin-1-yl)ethyl)-4-chloro-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 157.3) was used in place of 3-(4-chloro-2-(methoxymethyl)-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 27.5) and 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2) was used in place of 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.2). m/z (ES+) 460 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([O:9]C)=[O:8])=[CH:5][C:4]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=2)=[C:3]1[C:20]([O:22]C)=[O:21].[OH-].[Na+]>CO.O>[CH3:1][N:2]1[C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=2)=[C:3]1[C:20]([OH:22])=[O:21]
Reactant: COC(=O)c1cc(COc2cccc(C)c2)c(C(=O)OC)n1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cccc(OCc2cc(C(=O)O)n(C)c2C(=O)O)c1
Temperature: 75 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
To a stirred suspension of dimethyl 1-methyl-3-[(m-methylphenoxy)methyl]pyrrole-2,5-dicarboxylate (0.32 g, 0.001 m) in a mixture of methanol (10 ml) and water (6 ml), ice cooling, was added under a nitrogen atmosphere 2.5 N sodium hydroxide solution (1.2 ml). The mixture was allowed to come to room temperature, and then set in an oil-bath at 50° C., the temperature of the bath raised to 75° C., and kept at this temperature for ca. one hour. After stirring overnight at ambient temperature, water (55 ml) was added over 5 minutes, the mixture filtered, the volume of the filtrate adjusted to 100 ml with water, and the stirred filtrate acidified dropwise with 2 ml of 2 N hydrochloride acid. After aging for 20 minutes, the mixture was filtered, the precipitate washed with water and dried to give 0.27 g (90%) of 1-methyl-3-[(m-methylphenoxy)methyl]-pyrrole-2,5-dicarboxylic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][C:10]#[N:11])[CH:5]=[CH:6][CH:7]=1.O.[NH2:14][NH2:15]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([NH2:11])[NH:15][N:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: N#CCC(=O)c1cccc(Br)c1
Reactant: NN
Solvent: CCO
Solvent: O
Product: Nc1cc(-c2cccc(Br)c2)n[nH]1
Reaction time: 0.08 h
Yield: 80.8 %

Procedure:
A mixture of 3-(3-bromophenyl)-3-oxopropanenitrile (35 g, 156 mmol) and hydrazine hydrate (11.34 mL, 234 mmol) in ethanol (600 mL) was refluxed for 16 h. Mixture was then cooled and concentrated in vacuuo. Crude product was diluted with dichloromethane and stirred for 5 min. Solids were filtered and dried to afford 3-(3-bromophenyl)-1H-pyrazol-5-amine (30 g, 126 mmol, 81% yield) as off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 12.02 (br. s., 0.4H), 11.66 (br. s., 0.6H), 7.86 (t, J=1.6 Hz, 1H), 7.67 (d, J=7.5 Hz, 1H), 7.45 (d, J=6.8 Hz, 1H), 7.37-7.18 (m, 1H), 5.78 (br. s., 1H), 5.08 (br. s., 1.2H), 4.68 (br. s., 0.8H). LCMS (M+H)=240.1.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:24])[C:15]2[C:20]([C:21](=O)[CH3:22])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN.[OH-].[K+]>C(O)COCCOCCO>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]([CH3:24])[C:15]2[C:20]([CH2:21][CH3:22])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1cccnc1N(C)C1CCN(Cc2ccccc2)CC1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCOCCO
Product: CCc1cccnc1N(C)C1CCN(Cc2ccccc2)CC1
Reaction time: 2 h

Procedure:
A mixture of 1-benzyl-4-(N-methyl-N-(3-acetyl-2-pyridyl)amino)piperidine (XXXIV, EXAMPLE 43, 260 mg), hydrazine monohydrate (0.78 ml) and powdered potassium hydroxide (0.90 g) in triethylene glycol (16 ml) is stirred at 120° for 2 hrs. The condenser is removed, the mixture is heated up to approximately 185°-190°, the condenser is replaced, and the mixture is stirred at 190° for 3 hrs. After cooling to 20°-25°, the mixture is added to water (50 ml) and extracted with methylene chloride (2×50 ml), and the organic phase is washed with water (20 ml) and saline (20 ml), dried over sodium sulfate, concentrated under reduced pressure and chromatographed (silica gel, 70-230 mesh, 25 g; eluting with a gradient of ethyl acetate/hexane (25/75→50/50)) to give the title compound, NMR (CDCl3, 400 MHz) 8.16, 7.46, 7.31, 7.26, 6.88, 3.50, 3.15, 2.92, 2.73, 2.63, 2.00, 1.82, 1.73 and 1.23δ.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH:5]=[CH:6][CH:7]=1.[CH3:22][O:23][CH2:24][CH2:25]O>>[CH3:22][O:23][CH2:24][CH2:25][O:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH:5]=[CH:6][CH:7]=1
Reactant: COCCO
Reactant: O=C1c2ccccc2C(=O)N1CCCc1cccc(O)c1
Product: COCCOc1cccc(CCCN2C(=O)c3ccccc3C2=O)c1

Procedure:
Mitsunobu reaction of phenol 58 with 2-methoxyethanol gave 2-(3-(3-(2-methoxyethoxy)phenyl)propyl)isoindoline-1,3-dione as a clear oil. Yield (0.225 g, 19%): 1H NMR (400 MHz, DMSO-d6) δ 7.81-7.84 (m, 2H), 7.67-7.72 (m, 2H), 7.10-7.16 (m, 1H), 6.76-6.80 (m, 2H), 6.67-6.72 (m, 1H), 4.07-4.11 (m, 2H), 3.70-3.76 (m, 4H), 3.45 (s, 3H), 2.55 (t, J=7.6 Hz, 2H), 1.98-2.05 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[F:31])[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([OH:27])=[CH:13][C:14]=2[O:16][CH2:17][C@H:18]2[CH2:22][CH2:21][CH2:20][N:19]2[C:23](=[O:26])[CH2:24][OH:25])[N:9]=[CH:8][N:7]=1.[CH2:32]([O:34][CH2:35][CH2:36]Br)[CH3:33]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[F:31])[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:27][CH2:33][CH2:32][O:34][CH2:35][CH3:36])=[CH:13][C:14]=2[O:16][CH2:17][C@H:18]2[CH2:22][CH2:21][CH2:20][N:19]2[C:23](=[O:26])[CH2:24][OH:25])[N:9]=[CH:8][N:7]=1
Reactant: O=C(CO)N1CCC[C@@H]1COc1cc(O)cc2ncnc(Nc3ccc(F)c(Cl)c3)c12
Reactant: CCOCCBr
Product: CCOCCOc1cc(OC[C@H]2CCCN2C(=O)CO)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Yield: 48 %

Procedure:
The procedure described in Example 17 was repeated using 4-[3-chloro-4-fluoro-anilino]-5-{[(2R)-1-glycoloylpyrrolidin-2-yl]-methoxy}-quinazolin-7-ol (70 mg) and 2-bromoethyl ethyl ether (26 μl) to give the title compound as a white solid in 48% yield; NMR Spectrum (DMSO-d6 at 373 K) 9.80 (br s, 1H), 8.40 (s, 1H), 8.15 (m, 1H), 7.65 (m, 1H), 7.33 (m, 1H), 6.80 (m, 2H), 4.60 (m, 1H), 4.50 (m, 1H), 4.30-4.10 (m, 4H), 4.0 (m, 2H), 3.75 (t, 2H), 3.55 (q, 2H), 3.48-3.37 (m, 2H), 2.10-1.85 (m, 4H), 1.15 (t, 3H); Mass spectrum MH+ 519.