Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[N:8]=1)=O.[F:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32]N)=[CH:28][CH:27]=1>>[F:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)=[CH:28][CH:27]=1
Reactant: NNc1ccc(F)cc1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(S(C)(=O)=O)cc2)ccc1=O
Product: CS(=O)(=O)c1ccc(-n2ccc(=O)c(-c3ccnn3-c3ccc(F)cc3)n2)cc1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-methansulfonyl-phenyl)-1H-pyridazin-4-one (A-16) and 4-fluoro-phenylhydrazine according to the method described for example 43. MS: M=411.1 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[C:17](OC(=O)C)(=[O:19])[CH3:18]>C1C=CC=CC=1>[C:17]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:6][CH:7]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(-c2nc3ccccc3o2)cc1
Solvent: c1ccccc1
Product: CC(=O)Nc1ccc(-c2nc3ccccc3o2)cc1

Procedure:
2-(4'-Aminophenyl)benzoxazole (1.0 g, 4.76 mmol) was treated with acetic anhydride (5 g) in benzene according to the above-described general procedure for acetylation. A red powder was afforded (0.9 g, 75%), m.p. 213.5-214.8° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[F:18].[CH3:19][C:20]1[CH:21]=[CH:22][C:23]([O:29][CH3:30])=[C:24](B(O)O)[CH:25]=1>>[F:17][C:14]1[CH:15]=[CH:16][C:11]([S:8]([C:5]2[CH:6]=[CH:7][C:2]([C:22]3[CH:21]=[C:20]([CH3:19])[CH:25]=[CH:24][C:23]=3[O:29][CH3:30])=[C:3]([F:18])[CH:4]=2)(=[O:10])=[O:9])=[CH:12][CH:13]=1
Reactant: O=S(=O)(c1ccc(F)cc1)c1ccc(Br)c(F)c1
Reactant: COc1ccc(C)cc1B(O)O
Product: COc1ccc(C)cc1-c1ccc(S(=O)(=O)c2ccc(F)cc2)cc1F

Procedure:
The subtitle compound was prepared by the method of example 2 step (ii) using the product of example 9 step (i) and 5-methyl-2-methoxybenzene boronic acid.
Reaction SMILES: [OH:1][CH:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-:18])=[O:17])[C:3]#[C:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:19][O:20][C:21]1[CH:30]=[CH:29][C:24]([CH2:25][N:26]=[N+:27]=[N-:28])=[CH:23][CH:22]=1>C1(C)C=CC=CC=1>[OH:1][CH:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-:18])=[O:17])[C:3]1[N:26]([CH2:25][C:24]2[CH:29]=[CH:30][C:21]([O:20][CH3:19])=[CH:22][CH:23]=2)[N:27]=[N:28][C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: COc1ccc(CN=[N+]=[N-])cc1
Reactant: CCOC(=O)C#CC(O)c1ccccc1[N+](=O)[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1nnn(Cc2ccc(OC)cc2)c1C(O)c1ccccc1[N+](=O)[O-]
Temperature: 100 °C

Procedure:
To a solution of diisopropylamine (6.6 ml, 47.1 mmole) in tetrahydrofuran (80 ml) at -78° C. under an argon atmosphere was added 2.5 N butyllithium (17.4 ml, 43.5 mmole), and the mixture was stirred for 30 minutes. To this reaction mixture were next added a solution of ethyl propionate (4.0 ml, 39.5 mmole) in tetrahydrofuran (20 ml) and a solution of 2-nitrobenzaldehyde (4.0 g, 26.5 mmole) in tetrahydrofuran (20 ml) in this sequence, and the resulting mixture was further stirred at -78° C. for 30 minutes. To the reaction mixture were added tetrahydrofuran (10 ml) followed by water, and the mixture was extracted with ethyl acetate. The organic layer was washed with dilute hydrochloric acid, a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous saline in this sequence. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure to give ethyl 4-hydroxy-4-(2-nitrophenyl)-2-butynoate as an oily product. After the ethyl 4-hydroxy-4-(2-nitrophenyl)-2-butynoate thus obtained was dissolved in toluene (80 ml), 4-methoxybenzylazide (13.0 g, 79.7 mmole) was added to the solution and stirred under heating at 100° C. for 3 hours. The reaction mixture was then cooled to room temperature. Precipitates were collected by filtration, washed with toluene and desiccated to give ethyl 5-[hydroxy-(2-nitrophenyl)methyl]-1-(4-methoxybenzyl)-1,2, 3-triazole-4-carboxylate (a-2: highly polar product (MP)) (2.55 g, 15.7%). Furthermore, the filtrate was concentrated and purified by silica gel column chromatography (toluene : ethyl acetate =1:1) to give a 3:1 mixture (6.09 g, 37.4%) of ethyl 4-(hydroxy-(2-nitrophenyl)methyl)-1-(4-methoxybenzyl)-1, 2,3-triazole-5-carboxylate (a-1: low polar product (LP)) and a compound a-2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:10])=[C:6]([CH:9]=1)[CH2:7]O.P(Br)(Br)[Br:12].O>COCCOC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:10])=[C:6]([CH:9]=1)[CH2:7][Br:12]
Reactant: OCc1cc(Br)ccc1Cl
Reactant: BrP(Br)Br
Solvent: O
Solvent: COCCOC
Product: Clc1ccc(Br)cc1CBr
Temperature: 25 °C
Reaction time: 1 h
Yield: 252.1 %

Procedure:
20.0 g of 5-bromo-2-chlorobenzyl alcohol was dissolved in 100 ml of ethylene glycol dimethyl ether. To this solution, 9.4 g of phosphorus tribromide was added at −20° C., followed by stirring at room temperature for 1 hour. To the reaction solution, water was added, followed by extraction with toluene, and washing with an aqueous sodium hydrogencarbonate solution. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 24.9 g of a crude product of 5-bromo-2-chlorobenzyl bromide as white crystals.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[Br:34][C:35]1[CH:36]=[CH:37][C:38]2[N:42]=[C:41]([CH:43]3[CH2:46][C:45](=O)[CH2:44]3)[N:40](C)[C:39]=2[CH:49]=1>C1COCC1>[Br:34][C:35]1[CH:36]=[CH:37][C:38]2[N:42]=[C:41]([CH:43]3[CH2:44][C:45](=[CH:2][O:3][CH3:4])[CH2:46]3)[NH:40][C:39]=2[CH:49]=1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cn1c(C2CC(=O)C2)nc2ccc(Br)cc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC=C1CC(c2nc3ccc(Br)cc3[nH]2)C1
Reaction time: 0.5 h
Yield: 30 %

Procedure:
To a stirred solution of (methoxymethyl)triphenylphosphonium chloride (4.98 g) in THF (20 ml) was added lithium hexamethyldisilazide (1.0 M solution in hexane, 29 ml) at −15° C., and the resulting mixture was stirred at the same temperature for 30 min. A solution of 3-(6-bromo-1-methyl-1H-benzimidazol-2-yl)cyclobutanone (2.7 g) in THF (5 ml) was added to the reaction mixture, and the resulting mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with saturated NH4Cl solution, concentrated in vacuo and diluted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, concentrated in vacuo and purified by column chromatography (hexane/EtOAc) to afford the title compound (850 mg) as a yellow solid.
Reaction SMILES: [CH2:1]1[O:10][C:9]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=2[O:2]1.O=[C:12]1[CH2:17][CH2:16][N:15]([C@H:18]([CH3:22])[CH2:19][C:20]#[N:21])[CH2:14][CH2:13]1.[C-]#N.[Na+]>O.CO>[NH2:21][CH2:20][CH2:19][C@H:18]([N:15]1[CH2:16][CH2:17][CH:12]([NH:6][C:5]2[CH:7]=[CH:8][C:9]3[O:10][CH2:1][O:2][C:3]=3[CH:4]=2)[CH2:13][CH2:14]1)[CH3:22]
Reactant: C[C@H](CC#N)N1CCC(=O)CC1
Reactant: Nc1ccc2c(c1)OCO2
Agent: [C-]#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C[C@H](CCN)N1CCC(Nc2ccc3c(c2)OCO3)CC1

Procedure:
Using general procedure A with 3,4-(methylenedioxy)aniline (250 mg, 1.8 mmol) and (R)-3-(4-oxo-piperidin-1-yl)-butyronitrile (329 mg, 2.0 mmol) followed by general procedure J gave a green oil, which was subsequently treated with a solution of NaCN (175 mg) in H2O (5 mL) and MeOH (5 mL) to afford [1-((R)-3-amino-1-methyl-propyl)-piperidin-4-yl]-benzo[1,3]dioxol-5-yl-amine as a white solid (281 mg, 68% over 2 steps) after work-up and purification.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[C:19](=O)[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1.O.[NH2:30][NH2:31].O>CN(C=O)C>[F:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][C:19]2[C:3]3[C:4](=[O:18])[N:5]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:6]4[N:7]=[CH:8][CH:9]=[CH:10][C:11]=4[C:2]=3[NH:31][N:30]=2)=[CH:22][CH:23]=1
Reactant: NN
Reactant: O=C(Cc1ccc(F)cc1)c1c(O)c2cccnc2n(-c2ccccc2)c1=O
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2c(Cc3ccc(F)cc3)n[nH]c2c2cccnc2n1-c1ccccc1
Temperature: 130 °C
Reaction time: 2 h
Yield: 98.5 %

Procedure:
To a suspension of 4-hydroxy-3-[1-oxo-2-(4-fluorophenyl)ethyl]-1-phenyl-1,8-naphthyridin-2 (1H)-one (3.2 g, 8.5 mmol, prepared in Synthetic Example 27) in DMF (50 ml) was added hydrazine monohydrate (80%, 1.2 ml, 30 mmol, 3.5 eq.), and the mixture was then stirred at 130° C. for 2 hours. The reaction mixture was admixed with water to precipitate crystals, allowed to stand until it was cooled, filtered off, washed with water, and dried to give 3-(4-fluorobenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (3.1 g, 98%).
Reaction SMILES: O.O.O.[Na+:4].[Na+].[O:6]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][CH:19]([P:24](=[O:27])([O-:26])[O-:25])[P:20](=[O:23])([OH:22])[OH:21])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>O>[OH2:6].[Na+:4].[O:6]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][CH:19]([P:24](=[O:25])([OH:26])[O-:27])[P:20](=[O:21])([OH:22])[OH:23])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1.[O:6]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][CH:19]([P:24](=[O:25])([OH:26])[O-:27])[P:20](=[O:21])([OH:22])[OH:23])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1.[Na+:4]
Reactant: O=P([O-])([O-])C(NCCCCCOc1ccccc1)P(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=P([O-])(O)C(NCCCCCOc1ccccc1)P(=O)(O)O
Yield: 102.2 %

Procedure:
5-Phenoxypentylaminomethylenebisphosphonic acid disodium salt trihydrate (1.0 g) was dissolved in water (5 ml). The solution was processed with a column of CG-50 (H type, 32 ml). The solid matter obtained from the acidic portion eluted with water was recrystallized from water-methanol to afford 5-phenoxypentylaminomethylenebisphosphonic acid monosodium salt hemihydrate (0.58 g, 68%) as colourless prisms, m.p.>300° C.
Reaction SMILES: [O:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][CH2:4][CH2:3][CH2:2]1.[N:12]([O-])=[O:13].[Na+]>Cl.O>[N:12]([N:5]1[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[O:1][CH2:2][CH2:3][CH2:4]1)=[O:13]
Reactant: O=N[O-]
Reactant: c1ccc2c(c1)NCCCO2
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=NN1CCCOc2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.1 %

Procedure:
To a stirred, cold slurry of 2,3,4,5-tetrahydro-1,5-benzoxazepine (13.72 g, 91.96 mmol) in 2N aqueous HCl (105 mL) was added dropwise a solution of NaNO2 (7.30 g, 105.75 mmol) in H2O (16 mL) and stirred at room temperature for 2 hrs. The mixture was taken up in H2O (800 mL), extracted with ether (3×200 mL), dried over MgSO4, and stripped of the solvent under reduced pressure to yield 15.59 g (95%) of 5-nitroso-2,3,4,5-tetrahydro-1,5-benzoxazepine as a tan powder. (M+H)+ 178.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].CC1(C)C(C)(C)OB([C:27]2[CH:28]=[N:29][NH:30][CH:31]=2)O1>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:27]3[CH:28]=[N:29][NH:30][CH:31]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Product: CCCNC(=O)c1nnc2c(-c3cn[nH]c3)cccc2c1N
Yield: 24.4 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (150 mg, 0.485 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (194 mg, 1.000 mmol) were reacted to afford the title compound (35 mg, 25% yield) as an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ 12.97 (br, 1H), 9.20 (broad triplet, 1H), 8.48 (br, 2H), 8.23 (d, J=8.3 Hz, 1H), 8.14 (d, J=6.6 Hz, 1H), 7.70 (m, 1H), 3.32 (m, 2H), 1.62 (apparent sextet, J=7.0 Hz, 2H), 0.93 (t, J=7.0 Hz, 3H). MS APCI, m/z=297 (M+H). HPLC 1.43 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2.[C:17](O)(=[O:25])[C:18]1[C:19](=[CH:21][CH:22]=[CH:23][CH:24]=1)[OH:20]>>[OH:20][C:19]1[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=1[C:17]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:25]
Reactant: O=C(O)c1ccccc1O
Reactant: Nc1ccccc1-c1cc2ccccc2[nH]1
Product: O=C(Nc1ccccc1-c1cc2ccccc2[nH]1)c1ccccc1O
Yield: 46 %

Procedure:
Prepared from 2-(2-aminophenyl) indole and salicylic acid in 46% yield following procedure 1. The compound was chromatographed on silica using an ethylacetate/hexane gradient. % Purity by LC/MS (230 DAD), Mass-spec (M+H+)=329, 1H NMR (MeOH-d4): 6.66 s (1H), 6.86 dd,
Reaction SMILES: O[C:2]1[CH:10]=[C:9]([CH3:11])[C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.P(Cl)(Cl)([Cl:14])=O>O>[CH3:11][C:9]1[C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=[C:2]([Cl:14])[CH:10]=1
Reactant: Cc1cc(O)ncc1C(=O)O
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Product: Cc1cc(Cl)ncc1C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
6-Hydroxy-4-methylnicotinic acid (10 g, 65.3 mmol) and phosphorus oxychloride (33 mL) were combined and refluxed for 3 hours. The reaction solution was poured into 300 mL of ice and then 600 mL of water was added. The solution was boiled for 30 minutes before cooling and extracting the product into ether. The solvent was removed and the residue was recrystallized from 900 mL of hot water. Yellow solid, 9.06 g (81% yield). Mp 170–172° C. 1H NMR (CD3OD): δ 2.61 (s, 3H), 7.41 (s, 1H), 8.80 (s, 1H). LC-MS, M+1=172.
Reaction SMILES: [Br:1][C:2]1[C:15]2[CH:14]=[CH:13][C:12]3[N:11]=[C:10](NC(=O)C(C)(C)C)[NH:9][C:8](=[O:23])[C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CCOCC>[CH2:24]([NH:31][C:10]1[NH:9][C:8](=[O:23])[C:7]2[C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([Br:1])[C:15]=3[CH:14]=[CH:13][C:12]=2[N:11]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NCc1ccccc1
Reactant: CC(C)(C)C(=O)Nc1nc2ccc3c(Br)cccc3c2c(=O)[nH]1
Solvent: CCOCC
Product: O=c1[nH]c(NCc2ccccc2)nc2ccc3c(Br)cccc3c12

Procedure:
A mixture of N-(7-bromo-1,2-dihydro-1-oxobenzo[f]quinazolin-3-yl)pivalamide (0.3 g, 0.8 mmole) and benzylamine (10 ml) was stirred and heated at reflux under a nitrogen atmosphere for 18 hours. The cooled reaction mixture was then mixed with 4 volumes of ether to cause precipitation of the product. The precipitate was filtered and recrystallized from methanol to give 3-(benzylamino)-7-bromobenzo-[f]quinazolin-1(2H)-one as an off-white solid. (0.11 g, 37%) 1H NMR(DMSO-d6, 200 MHz) δ: 4.62(d, J=5.7 Hz, 2H, CH2); 7.02(m, 1H, benzyl-NH); 7.20-7.55(m, 7H, Ar); 7.79(dd, J=7.5, 1.1 Hz, 1H, Ar); 8.30(d, J=9.2 Hz, 1H, Ar); 9.74(d, J=8.6 Hz, 1H, Ar); 11.2(br s, 1H, pyr-NH).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[C:6]([CH2:8][OH:9])[CH:7]=1>[Pd].CO.C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)=[C:6]([CH2:8][OH:9])[CH:7]=1
Reactant: COc1ccc(/C=C/c2ccc(F)cc2CO)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CO
Product: COc1ccc(CCc2ccc(F)cc2CO)cc1
Reaction time: 1 h
Yield: 86.8 %

Procedure:
A mixture of 6.8 g (26.33 mmol) of E-{5-fluoro-2-[2-(4-methoxyphenyl)vinyl]phenyl}methanol from Example 30A and 0.5 g of palladium on carbon (10%) in 50 ml of methanol and 250 ml of ethanol is hydrogenated under atmospheric pressure at room temperature for 1 hour. After reaction has stopped, the mixture is filtered through kieselguhr and the filtrate is then concentrated to dryness. The residue is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 10:1→4:1→1:1). 5.95 g (87% yield) of a colorless solid are obtained.
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][NH:7][CH:8]=1)([O-:3])=[O:2].Br[CH:10]([CH2:13][CH3:14])[CH2:11][CH3:12]>>[CH2:11]([CH:10]([N:7]1[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[N:5]=[CH:6]1)[CH2:13][CH3:14])[CH3:12]
Reactant: O=[N+]([O-])c1c[nH]cn1
Reactant: CCC(Br)CC
Product: CCC(CC)n1cnc([N+](=O)[O-])c1

Procedure:
4-nitroimidazole was alkylated with 3-bromopentane to provide the title compound: 1H NMR (400 MHz, CDCl3) 0.84-0.90 (m, 6H), 1.71-1.82 (m, 2H), 1.86-1.96 (m, 2H), 3.79 (p, 1H, J=4.8 Hz), 7.41 (d, 1H, J=1.6 Hz), 7.73 (d, 1H, J=1.3 Hz); MS 184.2 m/z (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH2:5]Cl.[C-:12]#[N:13].[Na+].O>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:5][C:12]#[N:13])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(CCl)cc1Cl
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(CC#N)cc1Cl
Reaction time: 6 h
Yield: 99 %

Procedure:
145 grams of 3-chloro-4-methoxybenzyl chloride was added to a solution comprising 40.6 grams of sodium cyanide in 230 ml of dimethylsulfoxide over a 40 minute time period at a temperature within the range of 40°-45° C. The reaction mixture was then stirred at this temperature for 6 hours and poured into 800 ml of water, the separated oil being extracted with 3 200 ml portions of ether. The ethereal solution was next washed with a dilute (1:1) hydrochloric acid solution in two 100 ml portions, with two 100 ml portions of water and dried over magnesium sulfate. The ether was then driven off, yielding 136.5 grams of crystalline 3-chloro-4-methoxy-phenylacetonitrile, m.p. 54°-56° C., which was refluxed for 16 hours with 420 ml of 48% hydrobromic acid. Following, the reaction mixture was cooled to -5° C. and, after two hours at this temperature, the precipitate filtered, triturated with ether in three 400 ml portions, dried over magnesium sulfate and boiled down to yield 137 grams (97.7%) of 3-chloro-4-hydroxyphenyl acetic acid, m.p. 101°-104° C.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][O:6][C:7]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:8]=1[CH2:9]O.N1C(C)=CC(C)=CC=1C>C(Cl)Cl>[CH3:5][O:6][C:7]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:8]=1[CH2:9][Cl:3]
Reactant: COc1ccc(OC)c(CO)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: Cc1cc(C)nc(C)c1
Product: COc1ccc(OC)c(CCl)c1
Reaction time: 0.5 h

Procedure:
Thionyl chloride (108 g) is slowly added during 1 hour to a stirred mixture of 2,5-dimethoxybenzyl alcohol (150 g), 2,4,6-collidine (108 g), and methylene chloride (750 ml) at room temperature. The reaction is slightly exothermic. After stirring for another 30 minutes, the mixture is washed with hydrochloric acid (2 N) and water and then dried (MgSO4). Evaporation gives a residue of 2,5-dimethoxybenzyl chloride which crystallizes (127 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:18][C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=1)[C:22]([O:24][CH3:25])=[O:23]>CN(C)C=O.O>[Cl:1][C:2]1[C:3]2[N:10]([CH2:18][C:19]3[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=3)[C:22]([O:24][CH3:25])=[O:23])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2cc[nH]c12
Reactant: COC(=O)c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(Cn2ccc3ncnc(Cl)c32)c1
Temperature: 25 °C
Yield: 54.1 %

Procedure:
To a suspension of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (300 mg) in N,N-dimethylformamide (2.0 mL) was added cesium carbonate (955 mg) under ice-cooling, and the mixture was stirred while warming to room temperature for 15 min. To the reaction mixture was added methyl 3-(bromomethyl)benzoate (671 mg), and the mixture was stirred at room temperature for 4 hrs. The reaction mixture was diluted with water (40 mL), and extracted with a mixed solvent (40 mL×3) of ethyl acetate/tetrahydrofuran (1/1). The organic layer washed with saturated brine (120 mL×3) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (silica gel, eluent:hexane/ethyl acetate=80/20→10/90). The object fraction was concentrated under reduced pressure. Chloroform/diisopropyl ether (4/1) was added to the residue, and the resultant precipitate was collected by filtration, washed and dried under reduced pressure to give the title compound (319 mg) as a pale-brown powder.
Reaction SMILES: [C:1]1([CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:16][C:17]1([CH3:20])[CH2:19][O:18]1>CO>[CH:7]([N:8]1[CH2:19][C:17]([CH3:20])([OH:18])[CH2:16]1)([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC1(CCl)CO1
Reactant: NC(c1ccccc1)c1ccccc1
Solvent: CO
Product: CC1(O)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 63.2 %

Procedure:
Diphenylmethanamine (68.8 mL, 375 mmol) was added dropwise into a solution of 2-(chloromethyl)-2-methyloxirane (40 g, 375 mmol) in methanol (160 mL) and the reaction was stirred at rt for 72 h and then at reflux for 20 h. The reaction was cooled to ambient temperature, evaporated in vacuo and suspended in acetone (200 mL). The solid was collected by filtration to give 1-benzhydryl-3-methyl-azetidin-3-ol (60 g, 63%) as a white solid. 1H NMR (DMSO-d6, 400 MHz): δ7.61 (m, 4H), 7.31 (m, 6H), 6.43 (m, 1H), 6.00 (m, 1H), 3.80-4.00 (m, 4H), 1.45 (m, 3H).
Reaction SMILES: [CH3:1][Mg]Br.[F:4][C:5]1[CH:10]=[CH:9][C:8]([C@H:11]2[CH2:13][C@@H:12]2[C:14](N(OC)C)=[O:15])=[CH:7][CH:6]=1>C1COCC1>[F:4][C:5]1[CH:10]=[CH:9][C:8]([C@H:11]2[CH2:13][C@@H:12]2[C:14](=[O:15])[CH3:1])=[CH:7][CH:6]=1
Reactant: CON(C)C(=O)[C@H]1C[C@@H]1c1ccc(F)cc1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(=O)[C@H]1C[C@@H]1c1ccc(F)cc1
Reaction time: 2 h

Procedure:
Methylmagnesium bromide (0.717 mL, 3M in ether, 2.150 mmol) was added dropwise to a 0° C. solution of (1S,2S)-2-(4-fluorophenyl)-N-methoxy-N-methyl cyclopropanecarboxamide (400 mg, 1.792 mmol) in THF (15 mL). After 2 h, an additional equivalent of methylmagnesium bromide (0.717 mL, 2.150 mmol) was added. The reaction was slowly quenched with sat'd ammonium chloride (2 mL). The mixture was diluted with EtOAc, washed with H2O, washed with brine, dried over magnesium sulfate, and concentrated to give (1S,2S)-1-(2-(4-fluorophenyl)cyclopropyl)ethanone as a slightly colored oil (304 mg, 95%). 1H NMR (500 MHz, CHLOROFORM-d) δ 7.12-7.04 (m, 2H), 7.03-6.95 (m, 2H), 2.53 (ddd, J=9.1, 6.5, 4.0 Hz, 1H), 2.37-2.30 (m, 3H), 2.18 (ddd, J=8.2, 5.1, 4.0 Hz, 1H), 1.67 (ddd, J=9.2, 5.1, 4.3 Hz, 1H), 1.35 (ddd, J=8.1, 6.6, 4.3 Hz, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:7]2[C:8](C)=[CH:9][NH:10][C:6]=2[C:5](=[O:12])[N:4]([CH3:13])[C:3]1=[O:14].Br[CH2:16][C:17]([NH:19][C:20]1[S:21][CH:22]=[C:23]([C:25]2[CH:30]=[C:29]([Cl:31])[C:28]([O:32][CH2:33][CH2:34][C:35]([F:38])([F:37])[F:36])=[C:27]([Cl:39])[CH:26]=2)[N:24]=1)=[O:18].[H-].[Na+]>CN(C=O)C>[Cl:39][C:27]1[CH:26]=[C:25]([C:23]2[N:24]=[C:20]([NH:19][C:17](=[O:18])[CH2:16][N:10]3[C:6]4[C:5](=[O:12])[N:4]([CH3:13])[C:3](=[O:14])[N:2]([CH3:1])[C:7]=4[CH:8]=[CH:9]3)[S:21][CH:22]=2)[CH:30]=[C:29]([Cl:31])[C:28]=1[O:32][CH2:33][CH2:34][C:35]([F:36])([F:37])[F:38]
Reactant: O=C(CBr)Nc1nc(-c2cc(Cl)c(OCCC(F)(F)F)c(Cl)c2)cs1
Reactant: Cc1c[nH]c2c(=O)n(C)c(=O)n(C)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(ccn2CC(=O)Nc2nc(-c3cc(Cl)c(OCCC(F)(F)F)c(Cl)c3)cs2)n(C)c1=O

Procedure:
The title compound was prepared according to the general procedure (Method A) by coupling Intermediate 1 (50 mg, 0.279 mmol) with 2-bromo-N-{4-[3,5-dichloro-4-(3,3,3-trifluoropropoxy)phenyl]-1,3-thiazol-2-yl}acetamide (160 mg, 0.334 mmol) in the presence of NaH (16 mg, 0.666 mmol) in dry DMF (5.0 mL) to give 30 mg of the product as a white solid; 1H NMR (δ ppm, DMSO-d6, 300 MHz) 2.85-2.92 (m, 2H), 3.17 (s, 3H), 3.39 (s, 3H), 4.18-4.23 (m, 2H), 5.32 (s, 2H), 6.23 (s, 1H), 7.35 (s, 1H), 7.88 (s, 1H), 8.00-8.08 (m, 2H), 12.71 (br s, 1H); APCI-MS (m/z) 576.23 (M+H)+.