Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH:22]=O)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:24][O:25][CH2:26][C@H:27]1[CH2:31][CH2:30][CH2:29][NH:28]1>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].C(O)C>[CH3:24][O:25][CH2:26][C@H:27]1[CH2:31][CH2:30][CH2:29][N:28]1[CH2:22][C:16]1([C:13]2[CH:12]=[CH:11][C:10]([O:9][CH2:8][CH2:7][CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:15][CH:14]=2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: O=CC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reactant: COC[C@H]1CCCN1
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: CCO
Product: COC[C@H]1CCCN1CC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Yield: 59.4 %

Procedure:
4-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carbaldehyde (500 mg, 1.575 mmol), (R)-2-(methoxymethyl)pyrrolidine (347 mg, 4.21 mmol), absolute ethanol (20 ml), activated 3 Å molecular sieves (500 mg), titanium (IV) isopropoxide (2.33 ml, 7.88 mmol) and STAB (2.84 g, 13.4 mmol) were reacted in accordance with the general procedure D. The isolated waxy solid was purified by column chromatography on silica eluting with DCM:MeOH:NH3 95:14:1 to give the title compound as a viscous pale yellow oil (390 mg, 59%). 1H NMR (400 MHz, CDCl3) δ7.18 (d, 2H), 6.86 (d, 2H), 4.02 (t, 2H), 3.85-3.69 (m, 2H), 3.59 (td, 1H), 3.45 (td, 1H), 3.27 (s, 3H), 3.10 (dd, 1H), 3.02 (dd, 1H), 2.94 (d, 1H), 2.63 (t, 2H), 2.58-2.45 (m, 6H), 2.39 (m, 1H), 2.21 (m, 1H), 2.07-1.67 (m, 11H), 1.57-1.33 (m, 3H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([OH:11])(=[O:10])[CH:8]=[CH2:9].O1[CH2:16][CH2:15][CH2:14][CH2:13]1>C1(C)C=CC=CC=1>[CH:14]1[CH:15]=[CH:16][C:8]([C:7]([OH:11])=[O:10])=[CH:9][CH:13]=1
Reactant: C1CCOC1
Reactant: C=CC(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: O=C(O)c1ccccc1

Procedure:
Following the procedure of Example 1, "Westvaco 1550 Diacid" was reduced by lithium aluminum hydride in tetrahydrofuran to a diol having formula VIII in which m is 5, p is 7 and the broken line indicates a double bond. This diol (85 grams, 0.25 mole) was reacted with acrylic acid (90 ml., 1.28 mole) in toluene solution to yield the desired diacylate as a liquid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][C:12]([NH:14][C@H:15]2[CH2:20][C:19]3[CH:21]=[CH:22][CH:23]=[C:24]([C:25]([OH:27])=[O:26])[C:18]=3[O:17][B:16]2[OH:28])=[O:13])[CH2:7][CH2:6]1.C(O)(=O)C.[Si:33]([O:40][CH2:41][CH:42]=O)([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[Si:33]([O:40][CH2:41][CH2:42][NH:1][CH2:2][CH2:3][NH:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][C:12]([NH:14][C@H:15]2[CH2:20][C:19]3[CH:21]=[CH:22][CH:23]=[C:24]([C:25]([OH:27])=[O:26])[C:18]=3[O:17][B:16]2[OH:28])=[O:13])[CH2:7][CH2:6]1)([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34]
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Reactant: NCCN[C@H]1CC[C@H](CC(=O)N[C@H]2Cc3cccc(C(=O)O)c3OB2O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OCCNCCN[C@H]1CC[C@H](CC(=O)N[C@H]2Cc3cccc(C(=O)O)c3OB2O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid from Example 15 (92 mg) in MeOH (2 mL) was added TEA (70 μL), acetic acid (30 μL), 2-(tert-butyldimethylsilyloxy)acetaldehyde (35 mg) and sodium triacetoxyborohydride (212 mg). The reaction mixture was stirred overnight at RT. Solvent was removed under reduced pressure and the product was carried on to next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13](=[O:15])[CH3:14])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[Br:16]Br>>[Br:16][CH2:14][C:13]([C:5]1[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:15]
Reactant: COc1cc(C(C)=O)cc(OC)c1OC
Reactant: BrBr
Product: COc1cc(C(=O)CBr)cc(OC)c1OC

Procedure:
In a manner similar to Preparation 30 react 1-(3,4,5-trimethoxyphenyl)ethanone with bromine to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[CH:16][C:17]([CH:18]=O)=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[NH:20]1[CH2:26][C:24](=[O:25])[NH:23][C:21]1=[O:22].N1CCCCC1>CCO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[CH:16][C:17]([CH:18]=[C:26]4[NH:20][C:21](=[O:22])[NH:23][C:24]4=[O:25])=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CNC(=O)N1
Reactant: O=Cc1cnn2ccc(Nc3cccc(Cl)c3)nc12
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1NC(=O)C(=Cc2cnn3ccc(Nc4cccc(Cl)c4)nc23)N1
Temperature: 80 °C

Procedure:
To 5-(3-chlorophenylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (50 mg, 0.184 mmol) in 1 mL EtOH was added hydantoin (54 mg, 0.552 mmol) and piperidine (54 μL, 0.552 mmol). The mixture was heated in microwave for 60 minutes at 80° C. The solid formed was isolated by filtration and air dried to give 5-((5-(3-chlorophenylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione. LCMS (M+1=355)
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([NH2:12])[C:6]=2[CH:5]=[CH:4][N:3]=1.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]=[C:22]=[O:23])=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:20][NH:21][C:22]([NH:12][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:6]=2[CH:5]=[CH:4][N:3]=[C:2]3[Cl:1])=[O:23])=[CH:18][CH:19]=1
Reactant: O=C=NCc1ccc(Br)cc1
Reactant: Nc1cccc2c(Cl)nccc12
Solvent: Cc1ccccc1
Product: O=C(NCc1ccc(Br)cc1)Nc1cccc2c(Cl)nccc12
Temperature: 90 °C
Yield: 63.1 %

Procedure:
The product from Example 64A (520 mg, 2.91 mmol) in toluene (8 mL) was treated with 1-bromo-4-(isocyanatomethyl)benzene (0.41 mL, 2.93 mmol) with stirring and then the mixture was heated at 90° C. for 2 hours. The mixture was allowed to cool to room temperature, filtered, the filter cake washed with toluene, and air-dried to provide the title compound as an off-white solid (717 mg, 63%). 1H NMR (300 MHz, DMSO-d6) δ 8.89 (s, 1H), 8.34-8.37 (m, 2H), 8.00 (dd, J=6.1 Hz, 0.7 Hz, 1H), 7.92-7.95 (m, 1H), 7.73 (t, J=8.1, 1H), 7.53-7.56 (m, 2H), 7.30-7.33 (m, 2H), 7.12 (t, J=5.8Hz, 1H), 4.35 (d, J=5.8 Hz, 2H); MS (ESI+) m/z 390/392 (M+H+, 35Cl/37Cl).
Reaction SMILES: [CH2:1]([OH:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].[H-].[Na+].[CH2:11](Br)[C:12]#[CH:13]>O1CCCC1.CN(C)P(=O)(N(C)C)N(C)C>[CH2:13]([O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:8])[C:12]#[CH:11]
Reactant: OCCCCCCO
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: C#CCOCCCCCCO
Temperature: 0 °C

Procedure:
118 g. of 1,6-hexanediol are introduced into 800 ml. of absolute tetrahydrofuran and, while stirring well, treated portionwise over a period of 4 hours with 30 g. of sodium hydride. 60 ml. of hexamethylphosphoric acid triamide are then added, the mixture is heated to reflux and treated over a period of 12 hours with a solution of 149 g. of propargyl bromide and 200 ml. of tetrahydrofuran. The cooled mixture is poured on to ice-water and extracted three times with ether. The ether solutions are washed with water and sodium chloride solution, dried over sodium sulphate and evaporated. By distillation or chromatography there is obtained pure 6-(2-propynyloxy)-1-hexanol; boiling point (bulb-tube) = 75°C/0.015 mmHg; nD25 = 1.4560.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1.S(Cl)([Cl:15])=O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([Cl:15])=[O:12])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CCc1ccc(Br)cc1
Product: O=C(Cl)CCc1ccc(Br)cc1
Temperature: 25 °C
Yield: 99 %

Procedure:
A solution of 3-(4-bromophenyl)propanoic acid (14.5 g, 63.60 mmol, 1.00 equiv) in thionyl chloride (80 mL) was refluxed for 2 h. The reaction mixture was cooled to room temperature and then concentrated under vacuum to give 15.5 g (99%) of 3-(4-bromophenyl)propanoyl chloride as a light yellow oil.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH:17]3[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]3)[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[CH2:26]([O:28][C:29](=[O:50])[CH:30]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:27]>C1(C)C=CC=CC=1.C(OCC)C>[CH2:26]([O:28][C:29](=[O:50])[CH:30]=[C:20]1[CH2:19][CH2:18][CH:17]([CH2:16][CH2:15][N:12]2[CH2:11][CH2:10][N:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:25])([F:1])[F:24])[CH:4]=3)[CH2:14][CH2:13]2)[CH2:22][CH2:21]1)[CH3:27]
Reactant: O=C1CCC(CCN2CCN(c3cccc(C(F)(F)F)c3)CC2)CC1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCOC(=O)C=C1CCC(CCN2CCN(c3cccc(C(F)(F)F)c3)CC2)CC1
Yield: 44.7 %

Procedure:
A mixture of 2.77 g (7.8 mmol) of 4-{2-[4-(3-trifluoromethyl-phenyl)piperazin-1-yl]ethyl}cyclohexanone (example 1, path 11, step b) and 3.13 g (9.0 mmol) of (triphenyl-λ5-phosphanylidene)acetic acid ethyl ester in 40 mL of toluene is refluxed overnight. After concentration of toluene, the residue is taken off in diethyl ether and the solid is filtered. The filtrate is concentrated and purified over 150 g of silica gel (eluant dichloromethane/heptane 98/2) to give 1.48 g (45%) of (4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexylidene)acetic acid ethyl ester as an oil.
Reaction SMILES: [CH3:1][NH:2][S:3](Cl)(=[O:5])=[O:4].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][S:3](=[O:5])(=[O:4])[NH:2][CH3:1])=[CH:10][CH:9]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: CNS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNS(=O)(=O)Oc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.6 %

Procedure:
A solution of 18.1 g (0.14 mole) of N-methylsulfamoyl chloride (Example 2, pt. a) in 20 ml methylene chloride was added at 10°-20° C. to a solution of 12.8 g (0.10 mole) of 4-chlorophenol and 15 g (0.15 mole) of triethylamine in 50 ml of methylene chloride. The cooling was removed and the mixture stirred at ambient temperature for four hours. The mixture was filtered to remove the triethylamine hydrochloride. The filtrate was extracted with dilute HCl (6 ml of 37% hydrochloric acid in 60 ml water) followed by a water wash. The organic layer was then extracted with dilute potassium carbonate (8.0 g in 80 ml water) followed by a water wash. The methylene chloride layer was concentrated to 21.7 g of yellow oil which crystallized on cooling. The solid was stirred in a mixture of 10 ml toluene and 63 ml petroleum ether to obtain 20.3 g of yellow solid. The 20.3 g was recrystallized from 1:2 toluene: petroleum ether to give 8.73 g of white solid, mp 61°-62° C.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=4)[CH2:15][CH2:14]3)[CH:10]=[N:11][C:5]=2[N:4]2[CH2:28][CH2:29][CH2:30][C@@H:3]12.[NH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[N:31]1([C:23]([C:22]2[CH:21]=[CH:20][C:19]([N:16]3[CH2:15][CH2:14][N:13]([CH2:12][C:9]4[CH:10]=[N:11][C:5]5[N:4]6[CH2:28][CH2:29][CH2:30][C@H:3]6[C:2](=[O:1])[NH:7][C:6]=5[CH:8]=4)[CH2:18][CH2:17]3)=[CH:27][CH:26]=2)=[O:25])[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: O=C(O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)cc1
Reactant: C1CCNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C1Nc2cc(CN3CCN(c4ccc(C(=O)N5CCCC5)cc4)CC3)cnc2N2CCC[C@@H]12
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.7 %

Procedure:
In a 1 dram vial, (S)-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzoic acid (100 mg, 0.245 mmol) was suspended in DMF (Volume: 1.227 mL) then added pyrrolidine (0.024 mL, 0.295 mmol), HATU (140 mg, 0.368 mmol) and N-methylmorpholine (0.108 mL, 0.982 mmol). The r×n was stirred at RT overnight. The mixture was purified by prep HPLC-MS (acidic mode, 15-35%). The pH of the combined fractions was adjusted to pH=8-9 and extracted with EtOAc (3×30 ml), washed with brine, dried with MgSO4, filtered and concentrated to dryness. The residue was taken up with water/ACN (1:1), and concentrated in vacuo to provide the title compound as a fluffy white solid (29 mg, 26% yield). m.p.=121.3° C. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.73-1.87 (m, 4 H) 1.87-2.01 (m, 3 H) 2.14-2.21 (m, 1 H) 2.43-2.49 (m, 4 H) 3.15-3.23 (m, 4 H) 3.35 (br. s., 2 H) 3.37-3.49 (m, 5 H) 3.54-3.65 (m, 1 H) 3.95-4.04 (m, 1 H) 6.91 (d, J=9.09 Hz, 2 H) 6.99 (d, J=2.02 Hz, 1 H) 7.42 (d, J=8.84 Hz, 2 H) 7.62 (d, J=1.77 Hz, 1 H) 10.44 (s, 1 H). [M+H] calc'd for C26H32N6O2, 461; found, 461.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:15][CH2:14][N:13]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:12][CH2:11]2)=[N:7][CH:6]=1)=O.Cl.[NH2:29][OH:30].C[O-].[Na+].CO.Cl>O1CCOCC1>[OH:30][NH:29][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:15][CH2:14][N:13]([S:16]([C:19]3[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=3)(=[O:17])=[O:18])[CH2:12][CH2:11]2)=[N:7][CH:6]=1)=[O:2]
Reactant: COC(=O)c1cnc(N2CCN(S(=O)(=O)c3ccc([N+](=O)[O-])cc3)CC2)s1
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: O=C(NO)c1cnc(N2CCN(S(=O)(=O)c3ccc([N+](=O)[O-])cc3)CC2)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of compound 12g (125 mg, 0.303 mmol) in 1,4-dioxane (2 mL) were added hydroxylamine hydrochloride (210 mg, 3.03 mmol) and a freshly prepared solution of sodium methoxide in methanol (104 mg, 4.50 mmol of sodium dissolved in 1 mL of methanol) under N2 atmosphere. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was acidified to pH˜6 with 1M HCl and the formed precipitates were filtered off. The filtrate was diluted with ethyl acetate (5 mL) and water (2 mL) and the organic layer was separated. The aqueous layer was washed with ethyl acetate (5 mL) and the combined organic layers were dried on sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 13g
Reaction SMILES: Cl.[CH:2]([O:5][CH2:6][CH2:7][N:8]([C:13]1[CH:35]=[CH:34][C:16]([C:17]([N:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)[CH2:21][CH2:20]2)=[O:18])=[CH:15][CH:14]=1)[C:9](=[O:12])[CH2:10]Cl)([CH3:4])[CH3:3].[SH:36][CH:37]([CH2:41][C:42]([OH:44])=[O:43])[C:38]([OH:40])=[O:39]>>[CH:2]([O:5][CH2:6][CH2:7][N:8]([C:13]1[CH:35]=[CH:34][C:16]([C:17]([N:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)[CH2:21][CH2:20]2)=[O:18])=[CH:15][CH:14]=1)[C:9](=[O:12])[CH2:10][S:36][CH:37]([C:38]([OH:40])=[O:39])[CH2:41][C:42]([OH:44])=[O:43])([CH3:4])[CH3:3]
Reactant: CC(C)OCCN(C(=O)CCl)c1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1
Reactant: O=C(O)CC(S)C(=O)O
Agent: Cl
Product: CC(C)OCCN(C(=O)CSC(CC(=O)O)C(=O)O)c1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1

Procedure:
Analogously to Example 1, 1-{4-[N-(2-isopropoxyethyl)-N-chloroacetylamino]-benzoyl}-4-[2-(4-chlorophenyl)-ethyl]-piperazine hydrochloride is reacted with DL-2-mercapto-succinic acid (=DL-thiomalic acid), yielding (±)-1-{4-[N-(2-isopropoxyethyl)-N-(1,2-dicarboxyethylmercapto-acetyl)-amino]-benzoyl}-4-[2-(4-chlorophenyl)-ethyl]-piperazine.
Reaction SMILES: [ClH:1].[CH2:2]([CH:9]1[CH2:14][CH2:13][C:12](=[O:15])[CH:11]([CH2:16][N:17]([CH3:19])[CH3:18])[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=1>>[ClH:1].[CH2:2]([CH:9]1[CH2:14][CH2:13][C:12]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=2)([OH:15])[CH:11]([CH2:16][N:17]([CH3:18])[CH3:19])[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CN(C)CC1CC(Cc2ccccc2)CCC1=O
Reactant: COc1cccc(Br)c1
Agent: Cl
Product: COc1cccc(C2(O)CCC(Cc3ccccc3)CC2CN(C)C)c1
Yield: 55 %

Procedure:
The base of compound (36) was reacted with 1-bromo-3-methoxy-benzene corresponding to the conditions described in Example 1. The base obtained was purified with 7:1 ether/methanol via a silica gel column and was taken up in ether. After adding trimethylchlorosilane/water, compound (35) was obtained in a yield of 55% theoretical.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=3)[N:11]=[CH:10][N:9]=2)=[N:3]1.F[C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:21]=1[C:27](=[O:29])[CH3:28].C(O[K])(C)(C)C.O>CN(C)C(=O)C>[CH3:26][C:25]1[C:20]([O:18][C:15]2[CH:16]=[C:17]3[C:12](=[CH:13][CH:14]=2)[N:11]=[CH:10][N:9]=[C:8]3[NH:7][C:4]2[CH:5]=[CH:6][N:2]([CH3:1])[N:3]=2)=[C:21]([C:27](=[O:29])[CH3:28])[CH:22]=[CH:23][CH:24]=1
Reactant: CC(=O)c1cccc(C)c1F
Reactant: Cn1ccc(Nc2ncnc3ccc(O)cc23)n1
Agent: CC(C)(C)O[K]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(=O)c1cccc(C)c1Oc1ccc2ncnc(Nc3ccn(C)n3)c2c1
Temperature: 130 °C
Reaction time: 5 h
Yield: 5.4 %

Procedure:
4-[(1-Methyl-1H-pyrazol-3-yl)amino]quinazolin-6-ol (71 mg; 0.295 mmol) and 90 mg (0.592 mmol) of 1-(2-fluoro-3-methylphenyl)ethanone were added to a solution of 82 mg (0.732 mmol) of tert-butoxy potassium in 5 ml of N,N-dimethylacetamide and the mixture was stirred at 130° C. for 5 hours. Water was added to the reaction solution and the mixture was extracted with chloroform. The organic layer was dried and concentrated and the resulting residue was purified by a silica gel chromatography (chloroform:methanol=12:1) to give 6 mg (yield: 5%) of the title compound as a colorless solid.
Reaction SMILES: [OH-].[K+].[C:3]([O:7][OH:8])([CH3:6])([CH3:5])[CH3:4].[CH:9]([N:12]=[N:13][C:14]1(Cl)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)([CH3:11])[CH3:10].[OH-].[Na+]>>[CH:9]([N:12]=[N:13][C:14]1([O:8][O:7][C:3]([CH3:6])([CH3:5])[CH3:4])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)([CH3:11])[CH3:10]
Reactant: CC(C)N=NC1(Cl)CCCCC1
Reactant: CC(C)(C)OO
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Product: CC(C)N=NC1(OOC(C)(C)C)CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 24.7 grams (0.11 moles) of 25% potassium hydroxide in an erlenmeyer flask equipped with a magnetic stirrer, thermometer and addition funnel was added 14.0 grams (0.14 moles) of 90% tert.-butylhydroperoxide while holding the temperature below 30° C. with a cold water bath. After the addition was complete, the reaction was stirred for 30 minutes at room temperature, cooled to 18° C. and with rapid stirring 18.85 grams (0.1 mole) of 1-isopropylazo-1-chlorocyclohexane (from Example 3-2) was added dropwise from the addition funnel over 40 minutes while holding the reaction temperature at 20° C.± 2° C. After the addition was complete, the reaction was stirred for 10 minutes at 15° C., cooled to 0° C. and stirred an additional 30 minutes. At this point, 3.2 grams (0.04 mole) of 50% sodium hydroxide was added, the reaction stirred an additional 10 minutes, poured into 100 ml of ice water and the product extracted into 100 ml of pentane. The pentane solution was separated, washed with 50 ml portions of water and saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and the pentane evaporated at 0° C. under reduced pressure on a rotating evaporator. The product was a light yellow liquid weighing 18.7 grams (77% crude yield). It was stored in a dry ice chest to prevent decomposition and it was not shock sensitive. The infrared spectrum was in agreement with the structure of 1-isopropylazo-1-(tert.-butylperoxy)cyclohexane (absence of the carbon-chlorine band of the starting material at 800-825cm-1 and the presence of a tert.-butylperoxy band around 885 cm-1.) The presence of a weak OH band at 3350cm-1 indicates that a small amount of 1-isopropylazo-1-hydroxycyclohexane also formed.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20]([NH:22][C:23]4[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:24]=4[F:33])=[O:21])=[CH:15][CH:14]=3)[C:9]([CH2:11][OH:12])=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C1COCC1.CCOC(C)=O>[NH2:1][C:2]1[C:7]2=[C:8]([C:13]3[CH:14]=[CH:15][C:16]([NH:19][C:20]([NH:22][C:23]4[CH:28]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:26]=[CH:25][C:24]=4[F:33])=[O:21])=[CH:17][CH:18]=3)[C:9]([CH:11]=[O:12])=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1
Reactant: Nc1ncnn2cc(CO)c(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)cc3)c12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1ncnn2cc(C=O)c(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)cc3)c12
Temperature: 25 °C
Yield: 84.8 %

Procedure:
N-{4-[4-amino-6-(hydroxymethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea (40.0 mg, 0.09 mmol) was dissolved in THF (5.0 mL) and to it was added Dess-Martin Periodinane reagent (44.0 mg, 0.10 mmol). The reaction was stirred at rt until HPLC indicated completion of reaction. Reaction was diluted with EtOAc and washed with saturated aqueous NaHCO3/Na2S2O3 1:1 (3×). The aqueous layer was back extracted with EtOAc (2×). Organic was dried (Na2SO4) and evaporated to give a crude oil that was purified via HPLC (10-90% ACN/H2O) to give a yellow solid (35.0 mg, 88%). 1H-NMR (CD3OD) δ 9.76 (s, 1H), 8.61 (d, J=8.0 Hz, 1H), 8.11 (s, 1H), 7.87 (s, 1H), 7.65 (d, J=8.0 Hz, 1H), 7.46 (d, J=8.0 Hz, 1H), 7.30 (d, J=8.0 Hz, 1H); MS [M+H]+=459; LCMS RT=2.95 min.
Reaction SMILES: [CH3:1][C:2](=[CH2:27])[CH:3]([N:8]1[C:11](=[O:12])[CH:10]([N:13]2[C:17](=[O:18])[C:16]3=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]3[C:14]2=[O:23])[CH:9]1[S:24]([OH:26])=O)[C:4]([O:6][CH3:7])=[O:5].S(Cl)(Cl)=O>>[C:17]1(=[O:18])[N:13]([CH:10]2[C:11](=[O:12])[N:8]3[CH:3]([C:4]([O:6][CH3:7])=[O:5])[C:2](=[CH2:1])[CH2:27][S:24](=[O:26])[C@H:9]23)[C:14](=[O:23])[C:15]2=[CH:22][CH:21]=[CH:20][CH:19]=[C:16]12
Reactant: C=C(C)C(C(=O)OC)N1C(=O)C(N2C(=O)c3ccccc3C2=O)C1S(=O)O
Solvent: O=S(Cl)Cl
Product: C=C1CS(=O)[C@@H]2C(N3C(=O)c4ccccc4C3=O)C(=O)N2C1C(=O)OC

Procedure:
The same procedure was followed as in Example 1 (I) above except 0.20 g. of methyl 3-methyl-2-(2-sulfino-4-oxo-3-phthalimido-1-azetidinyl)-3-butenoate was employed as the starting material instead of the sulfinyl chloride. The reaction provided 0.10 g. of the title compound.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[C:11]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]([F:22])[CH:16]=2)[CH:12]=1.CN(C)[CH:25]=[O:26].[Cl-].[NH4+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:22][C:17]1[CH:16]=[C:15]([C:14]#[C:13][C:11]2[CH:12]=[C:7]([CH:25]=[O:26])[CH:8]=[N:9][CH:10]=2)[CH:20]=[CH:19][C:18]=1[F:21]
Reactant: CN(C)C=O
Reactant: Fc1ccc(C#Cc2cncc(Br)c2)cc1F
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=Cc1cncc(C#Cc2ccc(F)c(F)c2)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 60.5 %

Procedure:
Add a 2.5 M solution of butyllithium in hexanes (3.18 mL, 7.96 mmol) to anhydrous toluene (11 mL) at −78° C. Allow the internal temperature to return to −78° C., then add 3-bromo-5-(3,4-difluorophenylethynyl)-pyridine (1.56 g, 5.30 mmol), (prepared essentially as described in EXAMPLE 100), dissolved in anhydrous toluene (11 mL) at such a rate to maintain the reaction temperature below −60° C. Stir for 5 min, add N,N-dimethylformamide (0.47 g, 6.37 mmol) dropwise at a rate so as to maintain the reaction temperature below 60° C. Stir for 20 min, warm to 0° C. and add an aqueous saturated solution of ammonium chloride and ethyl acetate. Stir for 5 min and separate the layers. Dry (magnesium sulfate), filter and concentrate. Purify the residue by silica gel chromatography, eluting with 30:70 ethyl acetate:hexanes to give the title compound as a white solid (0.780 g, 61%).