Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH2:2][SH:3].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[Cl-:19].[Cl-].[C:21]1([CH3:28])[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1>C1(C)C=CC=CC=1>[Cl:19][CH2:28][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][S:3][CH2:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])=[CH:23][CH:22]=1
Reactant: CCOC(=O)CS
Reactant: [Cl-]
Reactant: Cc1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCOC(=O)CSCc1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.3 %

Procedure:
To a mixture of 1.22 g of ethyl thioglycolate, 1.4 g of anhydrous potassium carbonate and 20 ml of N,N-dimethylformamide was added 5.3 g of p-xylene dichloride followed by stirring at room temperature overnight. To the reaction mixture was added 50 ml of toluene. The mixture was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was applied to silica gel column chromatography. Elution with a mixture of toluene-ethyl acetate (9:1) gave 1.61 g of oily ethyl [(p-chloromethylbenzyl)thio]acetate.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH:5]=[C:6]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.[C:21]1([CH2:27][N:28]2[CH2:33][CH2:32][NH:31][CH:30]([C:34]([NH2:36])=[O:35])[CH2:29]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C>CN(C)C=O>[F:13][C:10]1[CH:11]=[CH:12][C:7]([C:6]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:5][CH2:4][CH2:3][CH2:2][N:31]2[CH2:32][CH2:33][N:28]([CH2:27][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:29][CH:30]2[C:34]([NH2:36])=[O:35])=[CH:8][CH:9]=1
Reactant: Fc1ccc(C(=CCCCBr)c2ccc(F)cc2)cc1
Reactant: NC(=O)C1CN(Cc2ccccc2)CCN1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(=O)C1CN(Cc2ccccc2)CCN1CCCC=C(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 70 °C
Reaction time: 20 h
Yield: 61.9 %

Procedure:
A mixture of 74.2 parts of 1,1'-(5-bromo-1-penten-1-ylidene)bis[4-fluorobenzene], 43.8 parts of 4-(phenylmethyl)-2-piperazinecarboxamide, 38.9 parts of N,N-diethylethanamine and 1350 parts of N,N-dimethylformamide was stirred for 20 hours at 70° C. The reaction mixture was evaporated in vacuo and the residue was stirred in dichloromethane. The precipitate was filtered off. The filtrate was washed three times with 200 parts of water and once with 200 parts of a diluted ammonium hydroxide solution, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (97:3 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 58.9 parts (61.9%) of 1-[5,5-bis(4-fluorophenyl)-4-pentenyl]-4-(phenylmethyl)-2-piperazinecarboxamide as a residue (int. 33).
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[CH3:5][O:6][CH:7]([O:11][CH2:12][CH3:13])[C:8]([OH:10])=[O:9].C(OCC)C.[AlH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1>O.C(O)C>[CH3:5][O:6][CH:7]([O:11][CH2:12][CH3:13])[C:8]([O-:10])=[O:9].[C:1]([O-:4])(=[O:3])[CH3:2].[AlH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1
Reactant: CC(=O)O
Reactant: CCOC(OC)C(=O)O
Agent: C1CC[AlH]OC1
Solvent: CCO
Solvent: O
Solvent: CCOCC
Product: CC(=O)[O-]
Product: CCOC(OC)C(=O)[O-]
Reaction time: 2 h

Procedure:
Acetic acid (19.0 mL) and methoxy(ethoxy) acetic acid (152.0 mL) was dissolved in 500 mL of water and Vista Captal B boehmite (20 g) was slowly added and refluxed for 72 hours. The white solution was filtered and the filtrate was dissolved under reduced pressure to yield a brown gel. The gel was dissolved in ethanol (100 mL) and the white powder product was obtained by the addition of diethyl ether. Yield: 8.9 g. The TGA of the product showed 32.5% ceramic yield (weight loss of 67.5%). The alumoxane was heated from 25° C. to 200° C. at the rate of 1.5° C.min−1, soaked for 2 h. at 200° C., followed by a temperature ramp up to 1000° C. at the rate of 5° C.min−1, soaked for 2 h.
Reaction SMILES: [N:1]1([C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[C:17]=2[N:16]=[CH:15][CH:14]=[CH:13]3)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.O=[C:19]1[CH2:24][CH2:23][CH:22]([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[C:31]([C:34]#[N:35])[CH:32]=3)[NH:27][CH:26]=2)[CH2:21][CH2:20]1>>[C:34]([C:31]1[CH:32]=[C:33]2[C:28](=[CH:29][CH:30]=1)[NH:27][CH:26]=[C:25]2[CH:22]1[CH2:21][CH2:20][CH:19]([N:4]2[CH2:5][CH2:6][CH2:7][N:1]([C:8]3[CH:9]=[CH:10][CH:11]=[C:12]4[C:17]=3[N:16]=[CH:15][CH:14]=[CH:13]4)[CH2:2][CH2:3]2)[CH2:24][CH2:23]1)#[N:35]
Reactant: c1cnc2c(N3CCCNCC3)cccc2c1
Reactant: N#Cc1ccc2[nH]cc(C3CCC(=O)CC3)c2c1
Product: N#Cc1ccc2[nH]cc(C3CCC(N4CCCN(c5cccc6cccnc56)CC4)CC3)c2c1
Yield: 92 %

Procedure:
The title compound was prepared according to Example 3, Step 4 except that 8-[1,4]diazepan-1-yl-quinoline was used instead of 1-(2-methoxy-phenyl)-[1,4]diazepane and 3-(4-oxo-cyclohexyl)-1H-indole-5-carbonitrile was used in place of 4-(5-fluoro-1H-3-indolyl)-cyclohexanone. Yield: 92%; MS (ES) m/z (relative intensity): 450 (M++H, 100).
Reaction SMILES: [BrH:1].C(O)(=O)C.[Cl:6][C:7]1[CH:8]=[C:9]([C:13](=O)[CH2:14][S:15][C:16]#[N:17])[CH:10]=[CH:11][CH:12]=1.O>C(O)(=O)C>[Br:1][C:16]1[S:15][CH:14]=[C:13]([C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([Cl:6])[CH:8]=2)[N:17]=1
Reactant: Br
Reactant: N#CSCC(=O)c1cccc(Cl)c1
Solvent: O
Solvent: CC(=O)O
Product: Clc1cccc(-c2csc(Br)n2)c1
Temperature: 130 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A 25% hydrogen bromide/acetic acid (45 ml) solution was added to a solution of 2-(3-chlorophenyl)-2-oxoethyl thiocyanate (4.90 g, 23.2 mmol) in acetic acid (45 ml), and the mixture was stirred at 130° C. for 2 hours and at room temperature for 1 hour. Water (50 ml) was poured to the reaction mixture, and crystals were collected by filtration and washed with water to give 6.36 g (100%) of the desired product as a solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][CH:28]=1)[CH2:6][CH2:7][O:8][CH2:9][CH2:10][C:11]([N:13]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[CH2:14][CH:15]([O:18][CH3:19])[O:16][CH3:17])=[O:12])#N.N1C=CC=CC=1.O.O.[PH2]([O-])=[O:38].[Na+]>C(O)(=O)C.[Ni]>[CH:20]1([N:13]([CH2:14][CH:15]([O:18][CH3:19])[O:16][CH3:17])[C:11](=[O:12])[CH2:10][CH2:9][O:8][CH2:7][CH2:6][C:5]2[CH:26]=[CH:27][CH:28]=[C:3]([CH:1]=[O:38])[CH:4]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=[PH2][O-]
Reactant: COC(CN(C(=O)CCOCCc1cccc(C#N)c1)C1CCCCC1)OC
Agent: [Ni]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Solvent: CC(=O)O
Product: COC(CN(C(=O)CCOCCc1cccc(C=O)c1)C1CCCCC1)OC
Temperature: 45 °C

Procedure:
To 3-(3-cyanophenethoxy)-N-cyclohexyl-N-(2,2-dimethoxyethyl)propanamide [Example 10, Step i)] (600 mg) in acetic acid (6 mL), pyridine (9 mL) and water (6 mL) was added sodium hypophosphite monohydrate (1964 mg) and Raney (R) nickel (397 mg). The reaction was heated to 45° C. under nitrogen for 2 h, then cooled to room temperature, filtered and washed with water/ethyl acetate. The filtrate was diluted with ethyl acetate, which was washed with water then dried over brine, filtered and the solvent removed. The residue was azeotroped once with ethanol to afford a light yellow oil (600 mg). MS [M+H-MeOH]+=360 (MultiMode+)
Reaction SMILES: [CH2:1]([C:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][C:7]=1[C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([OH:25])[CH:19]=[CH:18]2)[CH2:2][CH2:3][CH2:4][CH3:5].[Br:26]Br.C([O-])(=O)C.[K+]>C(O)(=O)C>[Br:26][C:21]1[C:22]2[C:17](=[CH:16][C:15]([C:7]3[O:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[C:6]=3[CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:24][CH:23]=2)[CH:18]=[CH:19][C:20]=1[OH:25]
Reactant: BrBr
Reactant: CCCCCc1c(-c2ccc3cc(O)ccc3c2)oc2ccccc12
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: CCCCCc1c(-c2ccc3c(Br)c(O)ccc3c2)oc2ccccc12
Yield: 88 %

Procedure:
Following the procedure described in Step 4 of Example 1, 6-(3-pentyl-benzofuran-2-yl)-naphthalen-2-ol (3.3 g, 10.0 mmol) was brominated using bromine (0.6 mL, 11.8 mmol), and potassium acetate (1.0 g. 10.2 mmol) in glacial acetic acid (40 mL). Purification by chromatography on a Biotage apparatus using 5% % ethyl acetate in hexane as the mobile phase furnished the title compound as an off-white solid (3.6 g), mp 75-77° C. Mass spectrum (+APCl, [M+H]+) m/z 409. 1HNMR (300 MHz, DMSO-d6): δ10.76 (br s,1H), 8.25 (d, 1H, J=1.2 Hz), 8.14 (d, 1H, J=8.9 Hz), 7.98-7.92 (m, 2H), 7.68-7.58 (m, 2H), 7.35-7.27 (m, 3H), 2.98 (t, 2H, J=7.3 Hz), 1.71 (p, 2H, J=6.9 Hz), 1.42-1.27 (m, 4H), and 0.87-0.80 ppm (tm 3H). Elemental Analysis for C23H21BrO2.0.7H2O: Calculated: C, 65.47; H, 5.35; N, 0.00. Found: C, 65.17; H, 4.92; N, 0.08.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.C1COCC1.CCCCCC.Cl[Si:21]([CH3:24])([CH3:23])[CH3:22].[CH3:25][CH:26]([CH3:30])[C:27](=[O:29])[CH3:28]>CCCCC>[CH3:22][Si:21]([CH3:24])([CH3:23])[O:29][C:27](=[CH2:28])[CH:26]([CH3:30])[CH3:25]
Reactant: C[Si](C)(C)Cl
Reactant: CC(=O)C(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=C(O[Si](C)(C)C)C(C)C

Procedure:
To freshly prepared LDA-solution in THF/hexane (1.05 eq.) was added slowly at −78° C. chloro-trimethyl-silane 7.59 mL, 60 mmol, 1.2 eq.), followed by 3-methyl-butan-2-one 5.32 mL, 50 mmol). The reaction vessel was kept for 30 Min. at −78° C. and then allowed to reach RT. The reaction mixture was diluted with 200 mL of pentane and filtered. All volatile solvents were then evaporated from the filtrate and the residue distilled in vacuo (50 mbar, bp. 40-45° C.) to give 4.38 g of regioisomerically pure title compound as colorless liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([NH:23][N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:22])[C:9]=2SC)=[CH:4][CH:3]=1.Cl[C:33]1C=CC=C(C(OO)=O)C=1.O.ClC1C=CC(C2N(C3C=CC(Cl)=CC=3Cl)N=C(C(NN3CCCCC3)=O)C=2[S:73](C)=[O:74])=CC=1>ClCCl.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([NH:23][N:24]3[CH2:25][CH2:26][CH2:27][CH2:28][C:29]3=[S:73]=[O:74])=[O:22])[C:9]=2[CH3:33])=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CS(=O)c1c(C(=O)NN2CCCCC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reactant: CSc1c(C(=O)NN2CCCCC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: Cc1c(C(=O)NN2CCCCC2=S=O)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Yield: 21 %

Procedure:
To a magnetically stirred solution of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylsulfanyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide (0.70 gram, 1.41 mmol) was added m-chloro-perbenzoic acid (m-CPBA) (0.50 gram of a 70% aqueous solution, 2.0 mmol). The resulting mixture was reacted for 20 hours at room temperature and subsequently poured into water (25 ml). The resulting mixture was extracted with dichloromethane (25 ml). The organic layer was separated and dried over MgSO4, filtered and concentrated. Column chromatography (silica gel, dichloromethane/methanol=95/5 (v/v)) gave 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-sulfinyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide (150 mg, 21% yield) (compound 5).
Reaction SMILES: [C:1]([C:3]1[CH2:8][N:7]2[CH:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10](=[O:12])[CH:11]=[C:6]2[N:5]([CH3:18])[C:4]=1[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)#[N:2].[F:27][C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[CH2:30]Br.O>CN(C=O)C.[Ag-]=O>[C:1]([C:3]1[CH:4]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[N:5]([CH3:18])[C:6]2[N:7]([CH:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10](=[O:12])[CH:11]=2)[C:8]=1[CH2:30][C:29]1[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=1[F:27])#[N:2]
Reactant: CCOC(=O)C1C(=O)C=C2N(C)C(c3ccc(OC)cc3)=C(C#N)CN21
Reactant: Fc1ccccc1CBr
Agent: O=[Ag-]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1C(=O)C=C2N(C)C(c3ccc(OC)cc3)C(C#N)=C(Cc3ccccc3F)N21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To 3-cyano-6-ethoxycarbonyl-2-(4-methoxyphenyl)- 1-methyl-4H -pyrrolo[1,2-a]pyrimid-7-one (351 mg, 1.0 mmol.) in dry DMF (5 mL) under N2, 2-fluorobenzyl bromide (473 mg, 2.5 mmol) and silver(I) oxide (924 mg, 4 mmol) were added. The slurry was stirred for 2 days at room temperature and poured into water (10 mL). Crude product was extracted out from water by ethyl acetate (50 mL). The organic layer was then concentrated and purified by silica gel chromatography (ethyl acetate/hexane) to give a pure product. It was crystallized in ether/ethyl acetate to give the titled compound as off white crystals (310 mg, 52%); proton NMR (DMSO-d6): 8.67 (1H, s), 7.45-7.80 (6H, m), 7.00 (2H, d, J=7.8 Hz), 5.70 (2H, s), 4.18 (2H, q, J=6.6 Hz), 3.74 (3H, s), 2.56 (3H, s), 1.23 (3H, t, J=6.6 Hz); MS: 460 (MH+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:19])[C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[N:8][CH:7]=1.[N+:20]([O-])([OH:22])=[O:21].C(=O)([O-])O.[Na+]>C(Cl)Cl>[O:1]([CH2:2][CH2:3][NH:4][C:5](=[O:19])[C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17]2)=[N:8][CH:7]=1)[N+:20]([O-:22])=[O:21]
Reactant: CN1CCN(c2ccc(C(=O)NCCO)cn2)CC1
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CN1CCN(c2ccc(C(=O)NCCO[N+](=O)[O-])cn2)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To an ice-cooled solution of 11.00 g of the compound (obtained in Example 1) in 20 ml of methylene chloride was added dropwise 5 ml of fuming nitric acid while stirring below 0° C. The stirring was continued for 2 hours. The reaction mixture was poured into an aqueous sodium hydrogen carbonate solution and extracted with methylene chloride. The extract was washed twice with water and once with a saturated aqueous saline solution, dried over anhydrous magnesium sulfate and concentrated to afford N-(2-nitroxyethyl)-6-(4-methyl-1-piperazinyl)nicotinamide. The product was dissolved in ethanol and to the solution was added under ice-cooling hydrogen chloride-saturated ethanol. The hydrochloride thus formed was recrystallized from ethanol to give 0.54 g of N-(2-nitroxyethyl)-6-(4-methyl-1piperazinyl)nicotinamide dihydrochloride (yield 34%).
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH:8]1([N:13]2[C:17]3[N:18]=[C:19]([NH2:22])[N:20]=[CH:21][C:16]=3[C:15]3[CH:23]=[CH:24][N:25]=[CH:26][C:14]2=3)[CH2:12][CH2:11][CH2:10][CH2:9]1.Cl[C:28]1[N:33]=[CH:32][C:31]([CH2:34][N:35]2[CH2:40][CH2:39][N:38](C(OC(C)(C)C)=O)[CH2:37][C:36]2=[O:48])=[CH:30][CH:29]=1>>[CH:8]1([N:13]2[C:17]3[N:18]=[C:19]([NH:22][C:28]4[N:33]=[CH:32][C:31]([CH2:34][N:35]5[CH2:40][CH2:39][NH:38][CH2:37][C:36]5=[O:48])=[CH:30][CH:29]=4)[N:20]=[CH:21][C:16]=3[C:15]3[CH:23]=[CH:24][N:25]=[CH:26][C:14]2=3)[CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(Cl)nc2)C(=O)C1
Reactant: Nc1ncc2c3ccncc3n(C3CCCC3)c2n1
Solvent: O=C(O)C(F)(F)F
Product: O=C1CNCCN1Cc1ccc(Nc2ncc3c4ccncc4n(C4CCCC4)c3n2)nc1

Procedure:
Compound 357 was prepared as a off-white solid (TFA salt) from compound 4 and compound 358 using chemistry similar to that described in example 200. 1H NMR (500 MHz, CD3OD) δ ppm 9.67 (1 H, s), 9.35 (1 H, s), 8.70 (1 H, d), 8.66 (1 H, d), 8.48 (1 H, d, J=1.7 Hz), 8.20 (1 H, dd, J=8.8, 2.2 Hz), 7.91 (1 H, d, J=8.8 Hz), 5.48 (1 H, quin, J=8.7 Hz), 4.76 (2 H, s), 3.96 (2 H, s), 3.71 (2 H, t, J=5.7 Hz), 3.53-3.62 (2 H, m), 2.46-2.61 (2 H, m), 2.14-2.33 (4 H, m), 1.82-1.98 (2 H, m). LCMS-ESI (POS), M/Z, M+1: Found 442.9.
Reaction SMILES: C(N(CC)CC)C.CS(Cl)(=O)=O.[Cl:13][C:14]1[CH:15]=[C:16]([CH2:39]O)[CH:17]=[C:18]([CH2:20][N:21]2[C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:30]([CH3:33])=[N:31][N:32]=4)[C:24]=3[CH:23]=[C:22]2[C:34]2[O:35][CH:36]=[N:37][N:38]=2)[CH:19]=1.Cl.[NH:42]1[CH2:45][CH:44]([OH:46])[CH2:43]1.S([O-])(=O)(=O)C>C(Cl)Cl.C1COCC1>[Cl:13][C:14]1[CH:15]=[C:16]([CH:17]=[C:18]([CH2:20][N:21]2[C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:30]([CH3:33])=[N:31][N:32]=4)[C:24]=3[CH:23]=[C:22]2[C:34]2[O:35][CH:36]=[N:37][N:38]=2)[CH:19]=1)[CH2:39][N:42]1[CH2:45][CH:44]([OH:46])[CH2:43]1
Reactant: Cc1nnc2ccc3c(cc(-c4nnco4)n3Cc3cc(Cl)cc(CO)c3)n12
Reactant: OC1CNC1
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1nnc2ccc3c(cc(-c4nnco4)n3Cc3cc(Cl)cc(CN4CC(O)C4)c3)n12
Reaction time: 0.5 h

Procedure:
Triethylamine (49 μL, 0.35 mmol) and methanesulfonyl chloride (22 μL, 0.28 mmol, Aldrich) were added to a mixture of (3-chloro-5-{[1-methyl-7-(1,3,4-oxadiazol-2-yl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-c]pyridin-6-yl]methyl}phenyl)methanol (0.033 g, 0.084 mmol, from Step 4) in DCM (4.9 mL). After 30 minutes, additional triethylamine (49 μL, 0.35 mmol) and methanesulfonyl chloride (22 μL, 0.28 mmol) were added. After 30 additional minutes, the mixture was briefly heated to reflux and then cooled. The solvent was removed in vacuo. The crude mesylate was reconstituted in THF (1.9 mL) and Methanol (1.9 mL). Half of this solution was added to azetidin-3-ol hydrochloride (37 mg, 0.33 mmol, Aldrich) and triethylamine (46 μL, 0.33 mmol) in THF (0.2 mL). [The other half of the mesylate solution was used in Example 140]. After 20 minutes, additional azetidin-3-ol hydrochloride (125 mg, 1.12 mmol, Aldrich) and triethylamine (156 μL, 1.12 mmol) were added and the mixture was stirred overnight. Sequential preparative HPLC-MS runs were used to purify the product (Waters SunFire C18, eluting with a gradient of MeCN/H2O containing 0.1% TFA, followed by Waters XBridge C18, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH). Yield: (5 mg, 10%).
Reaction SMILES: [CH:1]([O:4][P:5]([C:11]1[CH:30]=[CH:29][C:14]([O:15][C:16]2[CH:17]=[C:18]([CH:22]=[C:23]([O:25][CH:26]([CH3:28])[CH3:27])[CH:24]=2)[C:19](O)=[O:20])=[CH:13][CH:12]=1)([O:7][CH:8]([CH3:10])[CH3:9])=[O:6])([CH3:3])[CH3:2].[NH2:31][C:32]1[S:33][CH:34]=[CH:35][N:36]=1.C(OC1C=C(C=C(C(=O)NC2SC=CN=2)C=1)OC1C=CC(P(=O)(O)O)=CC=1)(C)C>>[CH:8]([O:7][P:5]([C:11]1[CH:12]=[CH:13][C:14]([O:15][C:16]2[CH:17]=[C:18]([C:19](=[O:20])[NH:31][C:32]3[S:33][CH:34]=[CH:35][N:36]=3)[CH:22]=[C:23]([O:25][CH:26]([CH3:27])[CH3:28])[CH:24]=2)=[CH:29][CH:30]=1)(=[O:6])[O:4][CH:1]([CH3:2])[CH3:3])([CH3:10])[CH3:9]
Reactant: Nc1nccs1
Reactant: CC(C)Oc1cc(Oc2ccc(P(=O)(OC(C)C)OC(C)C)cc2)cc(C(=O)O)c1
Agent: CC(C)Oc1cc(Oc2ccc(P(=O)(O)O)cc2)cc(C(=O)Nc2nccs2)c1
Product: CC(C)Oc1cc(Oc2ccc(P(=O)(OC(C)C)OC(C)C)cc2)cc(C(=O)Nc2nccs2)c1

Procedure:
Starting from 3-[4-(diisopropoxy-phosphoryl)-phenoxy]-5-isopropoxy-benzoic acid (7.64 g, 17.6 mmol) and 2-aminothiazole (1.84 g, 18.4 mmol), {4-[3-isopropoxy-5-(thiazol-2-ylcarbamoyl)-phenoxy]-phenyl}-phosphonic acid was synthesized as yellow gum (8.80 g, 17.0 mmol) according to Step D in Example 1. 1H NMR (300 MHz, CDCl3): δ 7.78 (dd, J=9, 13 Hz, 2H), 7.29-7.30 (m, 1H), 7.18-7.20 (m, 2H), 7.04 (dd, J=4, 9 Hz, 2H), 6.94 (d J=4 Hz, 1H), 6.78 (dd, J=2, 2 Hz, 1H), 4.63-4.74 (m, 2H), 4.51-4.59 (m, 1H), 1.36 (d, J=6 Hz, 6H), 1.33 (d, J=6 Hz, 6H) 1.24 (d, J=6 Hz, 6H).
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[C:10](Cl)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl.[CH:15]1([N:19]2[CH2:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH2:18][CH2:17][CH2:16]1>>[CH:15]1([N:19]2[CH2:25][CH2:24][CH2:23][N:22]([C:10]([C@@H:8]3[CH2:9][C@H:7]3[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:11])[CH2:21][CH2:20]2)[CH2:18][CH2:17][CH2:16]1
Reactant: O=C(Cl)[C@@H]1C[C@H]1c1ccccc1
Reactant: C1CC(N2CCCNCC2)C1
Agent: Cl
Product: O=C([C@@H]1C[C@H]1c1ccccc1)N1CCCN(C2CCC2)CC1

Procedure:
This example was prepared according to Example 4 utilizing trans-2-phenyl-1-cyclopropanecarbonyl chloride and 1-N-cyclobutyl-1,4-diazepane dihydrochloride, which was prepared according to Zaragoza, et. al. J. Med. Chem. 2004, 47, 2833-2838. m/z (ES+) M+1=299.2; HPLC tR=1.62 min. 1H NMR (500 MHz, CDCl3) δ 7.26 (t, J=7.6 Hz, 2H), 7.20-7.15 (m, 1H), 7.13-7.08 (m, 2H), 3.73-3.59 (m, 4H), 2.92-2.83 (m, 1H), 2.54-2.36 (m, 5H), 2.08-1.98 (m, 2H), 1.97-1.90 (m, 1H), 1.89-1.74 (m, 4H), 1.66 (ddd, J=9.2, 5.3, 4.1 Hz, 2H), 1.63-1.55 (m, 1H), 1.25 (m, 1H).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([OH:12])=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][O-:14].[Na+].CO>C(OCC)(=O)C>[CH3:13][O:14][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([OH:12])=[CH:7][CH:8]=2)[N:3]=1
Reactant: C[O-]
Reactant: Oc1ccc2ccc(Cl)nc2c1
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc2ccc(O)cc2n1
Yield: 79 %

Procedure:
2-Chloro-quinolin-7-ol (4.2 g, 23.4 mmol, 1.0 eq) is added at room temperature to a stirred solution of sodium methoxide in methanol (15% weight, 200 mL, 561.6 mmol, 24.0 eq) and the resulting mixture is heated under reflux for 20 hours. Solvent is removed, the residue is dissolved in water (50 mL) and neutralized with acetic acid, followed by extraction with ethyl acetate (3×50 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a crude product that is purified by column chromatography (silica gel, eluent: petroleum ether:ethyl acetate, 6:1, v/v) to afford 2-methoxy-quinolin-7-ol as a yellow solid (3.3 g, 79% yield).
Reaction SMILES: Cl[C:2]1[S:3][C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.[C:16]([NH2:20])([CH3:19])([CH3:18])[CH3:17]>C(OCC)C>[CH3:17][C:16]([NH:20][C:2]1[S:3][C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1)([CH3:19])[CH3:18]
Reactant: CC(C)(C)N
Reactant: CCOC(=O)c1sc(Cl)nc1C(F)(F)F
Solvent: CCOCC
Product: CCOC(=O)c1sc(NC(C)(C)C)nc1C(F)(F)F

Procedure:
A stirred mixture of 2.6 g (10 mmol) of ethyl 2-chloro-4-trifluoromethyl-5-thiazolecarboxylate and ml of tert-butylamine was heated at reflux for 20 hours. The mixture was diluted with ethyl ether and washed twice with water. The ether phase was dried with magnesium sulfate and concentrated under reduced pressure to yield 2.85 g of a beige solid material which was recrystallized from methylcyclohexane to yield 2.4 g of a white plate crystal product (m.p.=104°-106° C.) identified in Table 1.
Reaction SMILES: Cl[C:2]1[N:3]([CH2:10][C@@:11]([CH3:32])([OH:31])[CH2:12][N:13]2[CH2:18][CH2:17][N:16]([N:19]=[CH:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)[CH2:15][CH2:14]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.CN(C=O)C.[H-].[Na+]>O>[CH3:32][C@@:11]1([CH2:12][N:13]2[CH2:18][CH2:17][N:16]([N:19]=[CH:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)[CH2:15][CH2:14]2)[O:31][C:2]2=[N:6][C:5]([N+:7]([O-:9])=[O:8])=[CH:4][N:3]2[CH2:10]1
Reactant: C[C@](O)(CN1CCN(N=Cc2ccc(C(F)(F)F)cc2)CC1)Cn1cc([N+](=O)[O-])nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@]1(CN2CCN(N=Cc3ccc(C(F)(F)F)cc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Reaction time: 2.5 h
Yield: 66.6 %

Procedure:
To a mixture of (S)-1-(2-chloro-4-nitroimidazol-1-yl)-2-methyl-3-{4-[(4-trifluoromethylbenzylidene)amino]piperazin-1-yl}propan-2-ol prepared in Example 496 (847 mg, 0.85 mmol) and DMF (4 ml), sodium hydride (69 mg, 1.73 mmol) was added followed by stirring for 2.5 hours with cooling on ice-bath. To the reaction mixture, water was added, and the precipitates were filtered off. The resulting solid was washed with methanol and recrystallized from acetone/water to afford (S)-N-[4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazin-1-yl]-N-(4-trifluoromethylbenzylidene)amine (248 mg, yield 69%) as a light yellow powder.