Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([CH2:18][CH2:19][CH3:20])[N:12]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]3[N:38]([CH2:39][O:40][CH3:41])[N:37]=[N:36][N:35]=3)=[CH:24][CH:23]=1)[C:11]2=[O:42])(=O)C.C1COCC1.[OH-].[Na+].Cl>CO>[OH:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([CH2:18][CH2:19][CH3:20])[N:12]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]3[N:38]([CH2:39][O:40][CH3:41])[N:37]=[N:36][N:35]=3)=[CH:26][CH:27]=1)[C:11]2=[O:42]
Reactant: CCCc1nc2ccc(OCCOC(C)=O)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2COC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCc1nc2ccc(OCCO)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2COC)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 6-(2-acetoxyethyloxy)-3-[[2'-(N-methoxymethyltetrazol-5-yl)biphenyl-4-yl]methyl]-2-propyl-4(3H)-quinazolinone (0.42 g) in a mixture of methanol (3 ml), THF (2 ml) and 1N aqueous sodium hydroxide (1.5 ml) was stirred at room temperature for 1 hour. After addition of 1N hydrochloric acid (1.5 ml), the reaction mixture was extracted with ethyl acetate and the extract was washed with water, dried and evaporated to dryness. The residue was purified by column chromatography on silica gel to give a white powder.
Reaction SMILES: [CH2:1]([C:3]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH2:12][CH3:13])[C:4]=1[CH2:5]O)[CH3:2].S(Cl)([Cl:16])=O>C1(C)C=CC=CC=1>[CH2:1]([C:3]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH2:12][CH3:13])[C:4]=1[CH2:5][Cl:16])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCc1cc(C)cc(CC)c1CO
Solvent: Cc1ccccc1
Product: CCc1cc(C)cc(CC)c1CCl
Yield: 158.3 %

Procedure:
To a mixture of 138.41 g of 2,6-diethyl-4-methylbenzyl alcohol and 820 g of toluene was added dropwise 60.96 g of thionyl chloride at 25° C. over 4.5 hours. The resultant mixture was stirred for 15 hours. The reaction mixture was concentrated to obtain 159.58 g of 2,6-diethyl-4-methylbenzyl chloride (GC-area: 71%) as a brown oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([OH:18])[CH2:9][CH2:10][NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH:5]=[CH:6][CH:7]=1.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=1[C:27]#[CH:28]>>[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=1[C:27]#[C:28][C:2]1[CH:3]=[C:4]([CH:8]([OH:18])[CH2:9][CH2:10][NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NCCC(O)c1cccc(Br)c1)C(F)(F)F
Reactant: C#Cc1c(Cl)cccc1Cl
Product: O=C(NCCC(O)c1cccc(C#Cc2c(Cl)cccc2Cl)c1)C(F)(F)F

Procedure:
Sonogashira reaction of 25 with 1,3-dichloro-2-ethynyl-benzene gave N-(3-(3-(2-(2,6-dichlorophenyl)ethynyl)phenyl)-3-hydroxypropyl)-2,2,2-trifluoroacetamide as dark brown oil. Yield (0.32 g, 37%). This compound could not be separated completely from the starting bromide and was used directly in the step.
Reaction SMILES: [ClH:1].Cl.[O:3]([CH2:5][CH:6](O)[CH2:7][NH:8][CH3:9])[NH2:4].S(F)(F)(F)[F:12]>F>[ClH:1].[ClH:1].[O:3]([CH2:5][CH:6]([F:12])[CH2:7][NH:8][CH3:9])[NH2:4]
Reactant: CNCC(O)CON
Reactant: FS(F)(F)F
Agent: Cl
Agent: F
Product: CNCC(F)CON
Reaction time: 24 h

Procedure:
4.8 g (25 mmol) of N-(3-aminoxy-2-hydroxypropyl)-methylamine dihydrochloride are dissolved at -78° in 80 g of liquid hydrogen fluoride in a Teflon autoclave. 5.6 g of sulfur tetrafluoride are introduced and the vessel is closed and left to stand for 24 hours at room temperature. After degassing, the residue is dissolved in 2N hydrochloric acid. This solution is filtered and the filtrate is neutralised, in portions, with solid sodium hydrogen carbonate; a solution of 13 g of di-tert-butyl dicarbonate in 50 ml of tetrahydrofuran is added and the mixture is left to stand for 1 hour. The reaction mixture is diluted with 200 ml of ether and the organic phase is separated off, washed with water, dried over magnesium sulfate, filtered and concentrated by evaporation. The oil that remains behind is chromatographed with a mixture of hexane:ethyl acetate 3:1 over 500 g of silica gel, yielding the starting compound in the form of a yellow oil, Rf value 0.18.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[CH:14][CH:13]=1.C[Si](OS(C(F)(F)F)(=O)=O)(C)C.C(N(CC)CC)C.[C:41]1([CH2:47][CH2:48][S:49][CH:50]([C:54](O)=[O:55])[C:51](O)=[O:52])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.[K+].[Br-]>>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[O:20][C:51](=[O:52])[C:50]([S:49][CH2:48][CH2:47][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[C:54]([OH:55])[CH:19]=2)=[CH:16][CH:17]=1
Reactant: O=C(O)C(SCCc1ccccc1)C(=O)O
Reactant: COC(=O)c1ccccc1COc1ccc(C(C)=O)cc1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: [Br-]
Agent: [K+]
Solvent: CCN(CC)CC
Product: COC(=O)c1ccccc1COc1ccc(-c2cc(O)c(SCCc3ccccc3)c(=O)o2)cc1

Procedure:
The title compound was prepared by Method A using 2-[[(4-acetyl)phenoxy]methyl]benzoic acid methyl ester (2.0 g, 7.04 mmol), trimethylsilyltrifluoromethylsulfonate (1.57 g, 7.04 mmol), triethylamine (1.42 g, 14.08 mmol) and diethyl ester of [(2-phenylethyl)thio]propanedioic acid (1.04 g, 3.52 mmol). m.p. 161°-162° C.; 1H NMR (400 MHz, DMSO-d6) δ 2.78 (t, 2 H), 2.97 (t, 2 H), 3.81 (s, 3 H), 5.5 (s, 2 H), 6.69 (s, 1 H), 7.14 (m, 3 H), 7.25 (m, 4 H), 7.5 (m, 2 H), 7.78 (m, 2 H), 7.78 (d, 2 H), 7.94 (d, 1 H); IR (KBr) 3028, 2949, 2909, 2675, 1715, 1638, 1510, 1402, 1291, 1267, 1181, 1030, 828, 747 cm-1 ; MS (CI) m/e 489 (M+H, 51), 384 (3), 353 (1), 149 (100), 135 (47), 105 (33).
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:6](=[C:7]([F:20])[C:8]3[C:13]([C:14]=2[O:16][CH3:17])=[CH:12][C:11]([O:18][CH3:19])=[CH:10][CH:9]=3)[CH:5]=[C:4]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:3]=1.[C:26](=O)([O-])[O-].[K+].[K+].IC>C(#N)C>[F:20][C:7]1[C:8]2[C:13]([C:14]([O:16][CH3:17])=[C:15]3[C:6]=1[CH:5]=[C:4]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:3]=[C:2]3[O:1][CH3:26])=[CH:12][C:11]([O:18][CH3:19])=[CH:10][CH:9]=2
Reactant: CCOC(=O)c1cc(O)c2c(OC)c3cc(OC)ccc3c(F)c2c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: CCOC(=O)c1cc(OC)c2c(OC)c3cc(OC)ccc3c(F)c2c1
Reaction time: 2 h

Procedure:
Ethyl 4-hydroxy-6,10-dimethoxy-9-fluoroanthracene-2-carboxylate (4 g) was dissolved in acetonitrile. Potassium carbonate (2.5 g) and iodomethane (3 g) were added. The mixture was heated under reflux with vigorous stirring under nitrogen for 2 hours. The solution was filtered to remove solids and washed with water. The organic phase was washed, dried (MgSO4), filtered and concentrated to give the above compound as a yellow solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:32][C@:31]2([C:33](O)=[O:34])[C@@H:10]([CH2:11][C@H:12]3[CH:25]4[C@@:16]([F:29])([C@:17]5([CH3:28])[C:22]([C@@H:23]([F:26])[CH2:24]4)=[CH:21][C:20](=[O:27])[CH:19]=[CH:18]5)[C@@H:15]([OH:30])[CH2:14][C@@:13]32[CH3:36])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SH:37][CH:38]1[CH2:42][CH2:41][O:40][C:39]1=[O:43]>CN(C=O)C.CN(C)C1C=CN=CC=1.CCOC(C)=O>[O:43]=[C:39]1[CH:38]([S:37][C:33]([C@:31]23[C@@:13]4([CH3:36])[CH2:14][C@H:15]([OH:30])[C@@:16]5([F:29])[C@H:25]([C@@H:12]4[CH2:11][C@H:10]2[CH2:9][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:32]3)[CH2:24][C@H:23]([F:26])[C:22]2[C@:17]5([CH3:28])[CH:18]=[CH:19][C:20](=[O:27])[CH:21]=2)=[O:34])[CH2:42][CH2:41][O:40]1
Reactant: C[C@]12C=CC(=O)C=C1[C@@H](F)CC1[C@@H]3C[C@H]4CN(Cc5ccccc5)C[C@@]4(C(=O)O)[C@@]3(C)C[C@H](O)[C@@]12F
Reactant: O=C1OCCC1S
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@]12C=CC(=O)C=C1[C@@H](F)C[C@H]1[C@@H]3C[C@H]4CN(Cc5ccccc5)C[C@@]4(C(=O)SC4CCOC4=O)[C@@]3(C)C[C@H](O)[C@@]12F
Temperature: 25 °C
Reaction time: 1 h
Yield: 13.14 %

Procedure:
A solution of compound 93 and 1,1-carbonyldiimidazole (74.3 mg, 0.458 mmol) in dry DMF (3 ml) is stirred under nitrogen at RT for 1 hour and at 65° C. for 1 hour 30 minutes. The mixture is cooled to RT and 4-dimethylaminopyridine (46.7 mg, 0.382 mmol) and a solution of 3-mercaptodihydrofuran-2(3H)-one (54.1 mg, 0.458 mmol) in dry DMF (1.2 ml) are added. The mixture is stirred at RT for 1 hour then at 70° C. for 48 hours. The mixture is diluted with AcOEt and washed with brine. The organic phase is dried over Na2SO4 and filtered. The solvent is evaporated to give a brown oil which is purified by silica gel chromatography (AcOEt/petroleum ether 45/55) to afford the title compound (30 mg, 0.050 mmol, 13.14% yield).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]2[O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:4]=2[N:3]=1.[Cl:21]C1C=C2C(C3OC4C=CC=CC=4C=3N=C2O)=CC=1>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6]([C:5]3[O:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[C:4]=3[N:3]=[C:2]2[Cl:21])=[CH:7][CH:8]=1
Reactant: Oc1nc2c3ccccc3oc2c2ccc(Cl)cc12
Reactant: COc1ccc2c(c1)c(O)nc1c3ccccc3oc21
Product: COc1ccc2c(c1)c(Cl)nc1c3ccccc3oc21

Procedure:
The procedure was similar to step S19C, while the starting material was 25B in stead of 19B.
Reaction SMILES: [NH2:1][C@H:2]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)[C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:17][N:18]([CH3:20])[CH3:19])[CH2:7][CH2:6]1)=[O:4].[N:29]1([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:31][C@H:30]1[C:39](O)=[O:40].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[CH3:19][N:18]([CH2:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[N:8]1[CH2:7][CH2:6][N:5]([C:3](=[O:4])[C@H:2]([NH:1][C:39]([C@@H:30]2[CH2:31][C:32]3[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:38][N:29]2[C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=[O:40])[CH2:21][C:22]2[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=2)[CH2:10][CH2:9]1)[CH3:20]
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)O
Reactant: CN(C)Cc1ccccc1N1CCN(C(=O)[C@H](N)Cc2ccc(Cl)cc2)CC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: CN(C)Cc1ccccc1N1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)[C@@H]2Cc3ccccc3CN2C(=O)OC(C)(C)C)CC1
Yield: 57 %

Procedure:
tert-Butyl 3-{N-[(1R)-2-(4-{2-[(dimethylamino)methyl]phenyl}piperazinyl)-1-[(4-chlorophenyl)methyl]-2-oxoethyl]carbamoyl}(3S)-1,2,3,4-tetrahydroisoquinoline-2-carboxylate was prepared according to the procedure described in Preparation V, (2R)-2-amino-1-(4-{2-[(dimethylamino)methyl]phenyl}piperazinyl)-3-(4-chlorophenyl)propan-1-one (0.34 g, 0.85 mmol), Boc-L-Tic-OH (Peptech Corp.) (0.26 g, 0.93 mmol), EDC (0.2 g, 1.0 mmol), HOBT (used in place of HOAT) (Bachem) (0.14 g, 0.93 mmol) and CH2Cl2 (4 mL). The crude compound was purified on a Biotage 40S column (CH2Cl2/MeOH 95:5) to give tert-butyl 3-{N-[(1R)-2-(4-{2-[(dimethylamino)methyl]phenyl}piperazinyl)-1-[(4-chlorophenyl)methyl]-2-oxoethyl]carbamoyl}(3S)-1,2,3,4-tetrahydro-isoquinoline-2-carboxylate as a white foam (0.32 g). MS m/z: 660 (M+H). Calc'd for C37H46ClN5O4: 660.25.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH2:9][CH3:10])[CH:7]=1.[CH2:11]([O:13][C:14]([O:20][CH2:21][CH3:22])([O:17][CH2:18][CH3:19])[C:15]#[CH:16])[CH3:12]>>[CH2:9]([O:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:16]#[C:15][C:14]([O:17][CH2:18][CH3:19])([O:13][CH2:11][CH3:12])[O:20][CH2:21][CH3:22])[CH:7]=1)[CH3:10]
Reactant: C#CC(OCC)(OCC)OCC
Reactant: CCOc1cncc(Br)c1
Product: CCOc1cncc(C#CC(OCC)(OCC)OCC)c1
Yield: 37 %

Procedure:
The title compound was synthesized from 3-bromo-5-ethoxy-pyridine and 3,3,3-triethoxypropyne using the procedure described in Example 43, step (e), in 37% yield. 1H NMR (CDCl3) δ 8.27 (bs, 1H), 8.24 (bs, 1H), 7.21 (m, 1H), 4.02 (q, 2H, J=7.0 Hz), 3.72 (q, 6H, J=7.0 Hz), 1.39 (t, 3H, J=7.0 Hz), 1.23 (t, 9H, J=7.0 Hz).
Reaction SMILES: [H-].[Na+].[N:3]1[O:7][N:6]=[C:5]2[C:8]([OH:12])=[CH:9][CH:10]=[CH:11][C:4]=12.[CH2:13]([CH:15]1[O:17][CH2:16]1)Br.O>CN(C)C=O>[N:3]1[O:7][N:6]=[C:5]2[C:8]([O:12][CH2:13][CH:15]3[O:17][CH2:16]3)=[CH:9][CH:10]=[CH:11][C:4]=12
Reactant: Oc1cccc2nonc12
Reactant: BrCC1CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1cc(OCC2CO2)c2nonc2c1
Temperature: 50 °C

Procedure:
Sodium hydride (620 mg; 60% oil dispersion) was added in portions to benzofurazan-4-ol (1.74 g) in dimethyl formamide (30ml). The mixture was heated at 50° C. for 30 min. Epibromohydrin (1.6 ml) was added and the mixture was heated at 60° C. for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was washed with water, dried over Na2SO4, and evaporated. The residue was chromatographed on silica gel (50% ethyl acetate/hexane) to give 1-(4-benzofurazanyloxy)-2,3-epoxypropane (1.6 g), mp 75° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:21][CH3:22])=[CH:4][C:5]2[NH:11][C:10](=O)[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[C:6]=2[CH:20]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1>COCCOC>[Br:1][C:2]1[C:3]([O:21][CH3:22])=[CH:4][C:5]2[NH:11][C:10](=[S:32])[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[C:6]=2[CH:20]=1
Reactant: COc1cc2c(cc1Br)C(c1ccccc1Cl)=NCC(=O)N2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: COCCOC
Product: COc1cc2c(cc1Br)C(c1ccccc1Cl)=NCC(=S)N2
Temperature: 85 °C
Yield: 81.1 %

Procedure:
A mixture of 2.0 g (0.0053 mole) of 7-bromo-5-(2-chlorophenyl)-1,3-dihydro-8-methoxy-2H-1,4-benzodiazepin-2-one (Id), 200 mL of 1,2-dimethoxyethane and 2.13 g (0.0053 mole) of Lawesson's reagent (2,4-bis(4-methoxyphenyl)-2,4-disulfide-1,3,2,4-dithiadiphosphetane) was heated at 85° C. for 1 hour, then cooled and poured onto ice cold sodium bicarbonate solution. The mixture was extracted twice with ethyl acetate-methanol (9:1), and the organic layers washed successively with water and brine. The combined extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Trituration of the residue with ethyl acetate provided 1.7 g of 7-bromo-5-(2-chlorophenyl)-1,3-dihydro-8-methoxy-2H-1,4-benzodiazepin-2-thione (IId). MH+/Z=395.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][CH2:12][N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[N:6]=[C:5]3[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[S:20][C:3]=1[C:4]=23.Cl[CH2:26][CH2:27][N:28]1[CH2:32][CH2:31][O:30][C:29]1=[O:33]>C(Cl)(Cl)Cl>[CH2:14]([N:13]([CH2:16][CH3:17])[CH2:12][CH2:11][N:7]1[C:8]2[CH:9]=[CH:10][C:2]([NH:1][CH2:26][CH2:27][N:28]3[CH2:32][CH2:31][O:30][C:29]3=[O:33])=[C:3]3[S:20][C:19]4[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=4[C:5]([C:4]=23)=[N:6]1)[CH3:15]
Reactant: CCN(CC)CCn1nc2c3c(c(N)ccc31)Sc1ccccc1-2
Reactant: O=C1OCCN1CCCl
Solvent: ClC(Cl)Cl
Product: CCN(CC)CCn1nc2c3c(c(NCCN4CCOC4=O)ccc31)Sc1ccccc1-2
Temperature: 150 °C
Reaction time: 2 h

Procedure:
A mixture of 5.8 g 0.017 mol) of 5-amino-N,N-diethyl-2H[1]benzothiopyrano[4,3,2-cd]indazole-2-ethanamine and 5.1 g (0.034 mol) of 3-(2-chloroethyl)-2-oxazolidinone was stirred at 150° C. for two hours, dissolved in 100 ml of CHCl3 and washed twice with 2N NaOH. The solution was dried (MgSO4) and concentrated in vacuo to dryness. The residue was flash chromatographed over silica gel, eluting with a CHCl3 /MeOH (4/1) mixture. The appropriate fractions were combined and concentrated to dryness in vacuo. The residue was treated with 20 ml of acetone and the resulting suspension was treated with 150 ml of Et2O. The resulting precipitate was collected and dried to give 4.9 g of product, mp 90°-94° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:32])[CH2:16][N:17]2[CH:20]([S:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH:29]=[CH2:30])=[O:26])[CH2:19][C:18]2=[O:31])=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:41])C=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:32])[CH2:16][N:17]2[CH:20]([S:21]([CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH:29]=[CH2:30])=[O:26])=[O:41])[CH2:19][C:18]2=[O:31])=[CH:6][CH:7]=1
Reactant: C=CCOC(=O)CCCSC1CC(=O)N1CC(=O)NCCCCCCc1ccc(F)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Product: C=CCOC(=O)CCCS(=O)C1CC(=O)N1CC(=O)NCCCCCCc1ccc(F)cc1
Yield: 21 %

Procedure:
Treatment of N-[6-(4-Fluorophenyl)hexyl]-[4-(3-allyloxycarbonylpropyl)thio-2-oxo-azetidin-1-yl]-acetamide with mCPBA as described for Example 17 gave thetitle compound as a white crystalline solid, m.p. 95-96° C., 21% yield
Reaction SMILES: [C:1]([O:6]CC)(=O)[CH:2]([CH3:4])[OH:3].[CH2:9]([CH:11]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:12][NH2:13])[CH3:10]>>[CH2:9]([CH:11]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:12][NH:13][C:1](=[O:6])[CH:2]([CH3:4])[OH:3])[CH3:10]
Reactant: CCCCC(CC)CN
Reactant: CCOC(=O)C(C)O
Product: CCCCC(CC)CNC(=O)C(C)O

Procedure:
N-(2-Ethylhexyl)lactamide was prepared in accordance with example 1 by amidation of ethyl lactate with 2-ethylhexylamine.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])(=[O:12])=[O:11])[CH2:7][N:6]1[C:23](=S)[CH2:24][C:25](=O)[CH3:26])=[O:4].Cl.[CH3:30][C:31]1[CH:32]=[C:33]([NH:37][NH2:38])[CH:34]=[CH:35][CH:36]=1>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:21])([F:22])[F:20])(=[O:11])=[O:12])[CH2:7][N:6]1[C:23]1[N:37]([C:33]2[CH:32]=[C:31]([CH3:30])[CH:36]=[CH:35][CH:34]=2)[N:38]=[C:25]([CH3:26])[CH:24]=1)=[O:4]
Reactant: Cc1cccc(NN)c1
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1C(=S)CC(C)=O
Agent: Cl
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1cc(C)nn1-c1cccc(C)c1

Procedure:
In analogy to the procedure described in example 192 h, (2S,4R)-1-(3-oxo-thiobutyryl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester (example 192 g) was reacted with 3-methylphenylhydrazine hydrochloride (CAS Reg. No. 637-04-7) to give the title compound as yellow solid. MS (ESI): m/z=508.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](Cl)=[O:5].[F:12][C:13]([F:23])([F:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][NH2:21].O>N1C=CC=CC=1>[F:12][C:13]([F:22])([F:23])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]([C:4](=[O:5])[C:3]1[C:7]([F:11])=[CH:8][CH:9]=[CH:10][C:2]=1[Cl:1])[NH2:21]
Reactant: NNc1ccccc1C(F)(F)F
Reactant: O=C(Cl)c1c(F)cccc1Cl
Solvent: c1ccncc1
Solvent: O
Product: NN(C(=O)c1c(F)cccc1Cl)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
71.7 g (0.37 mol) of 2-chloro-6-fluorobenzoyl chloride are slowly added dropwise to a solution, cooled to 5° C., of 65.4 g (0.37 mol) of o-trifluoromethylphenylhydrazine in 200 ml of pyridine in such a manner that the temperature of the reaction mixture does not exceed 5° C. The mixture is stirred at room temperature for a further 90 minutes and subsequently treated with 400 ml of water. The aqueous phase is extracted three times with 150 ml of diethyl ether each time and the combined organic phases are washed in sequence with 2N sodium hydroxide solution and concentrated sodium chloride solution. The organic phase is then dried over anhydrous sodium sulfate and evaporated under reduced pressure, the crude product being evaporated twice with a small amount of toluene in order to remove excess pyridine. After recrystallization from methylene chloride/n-hexane there is obtained N1 -(α,α,α-trifluoro-o-tolyl)-2-chloro-6-fluorobenzhydrazide, m.p. 147°-148° C.; mass spectrum: 332(19), 157(100).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1.Cl.[F:14][C:15]([F:26])([F:25])[C:16]1[N:20]2[CH2:21][CH2:22][NH:23][CH2:24][C:19]2=[N:18][N:17]=1.C(N(CC)C(C)C)(C)C>CN1C(=O)CCC1>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([N:23]1[CH2:22][CH2:21][N:20]3[C:16]([C:15]([F:26])([F:14])[F:25])=[N:17][N:18]=[C:19]3[CH2:24]1)=[N:3][N:4]=[CH:5]2
Reactant: FC(F)(F)c1nnc2n1CCNC2
Reactant: Clc1ccc2c(Cl)nncc2c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: FC(F)(F)c1nnc2n1CCN(c1nncc3cc(Cl)ccc13)C2

Procedure:
The title compound was prepared according to the method described in Example 19, using 1,6-dichlorophthalazine (400 mg, 2010 μmol), 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (Balsells, et. al. Org. Lett., 7:1039-1042 (2005), 689 mg, 3015 μmol) and N,N-diisopropylethylamine (702 μl, 4019 μmol) in NMP (5 mL). MS (ESI, pos. ion) m/z: 355 (M+1).
Reaction SMILES: [F:1][C@@H:2]1[C@@H:6]([CH2:7][OH:8])[O:5][C@@H:4]([N:9]2[C:19]3[N:18]=[C:16]([NH2:17])[NH:15][C:13](=[O:14])[C:12]=3[N:11]=[CH:10]2)[CH2:3]1.[C:20]([NH:30][C@H:31]([C:35]([O:37][CH2:38][CH:39]([CH2:44][O:45][C:46](=[O:62])[C@H:47]([CH:59]([CH3:61])[CH3:60])[NH:48][C:49]([O:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)=[O:50])[CH2:40][C:41](O)=[O:42])=[O:36])[CH:32]([CH3:34])[CH3:33])([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.CN(C=O)C>[F:1][C@@H:2]1[C@@H:6]([CH2:7][O:8][C:41](=[O:42])[CH2:40][CH:39]([CH2:44][O:45][C:46](=[O:62])[C@H:47]([CH:59]([CH3:61])[CH3:60])[NH:48][C:49]([O:51][CH2:52][C:53]2[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=2)=[O:50])[CH2:38][O:37][C:35](=[O:36])[C@H:31]([CH:32]([CH3:34])[CH3:33])[NH:30][C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[O:5][C@@H:4]([N:9]2[C:19]3[N:18]=[C:16]([NH2:17])[NH:15][C:13](=[O:14])[C:12]=3[N:11]=[CH:10]2)[CH2:3]1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)CC(=O)O
Reactant: Nc1nc2c(ncn2[C@H]2C[C@H](F)[C@@H](CO)O2)c(=O)[nH]1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)CC(=O)OC[C@H]1O[C@@H](n2cnc3c(=O)[nH]c(N)nc32)C[C@@H]1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2′,3′-dideoxy-3′-fluoroguanosine (1.35 g, 5 mmole), 3,3-bis (N-CBZ-L-valyloxymethyl)-propionic acid (3.6 g, 6 mmole), DMAP (0.061 g, 0.5 mmole) and HOBT (0.81 g, 6 mmole) was coevaporated two times with DMF and reduced to about 120 ml. DCC (1.24 g, 6 mmole) was added and the mixture was stirred overnight at room temperature. The mixture was filtered and the solution was evaporated under reduced pressure. Ethyl acetate (200 ml) was added and the organic phase washed twice with 5% acetic acid, 5% sodium hydrogen carbonate and water. The organic phase was dried with sodium sulfate and evaporated under reduced pressure. The product was isolated by silica gel column chromatography. Yield: 2.7 g
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[C:13]([F:23])=[C:14]4[C:18](=[CH:19][C:20]=3[F:21])[N:17]([CH3:22])[N:16]=[CH:15]4)=[CH:9][N:10]=2)[N:7]=1.[F-].[K+].[C:26]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)(=[O:28])[CH3:27]>CN1C(=O)CCC1.CCOC(C)=O>[F:23][C:13]1[C:12]([CH2:11][C:8]2[N:6]3[N:7]=[C:2]([N:32]4[CH2:33][CH2:34][N:29]([C:26](=[O:28])[CH3:27])[CH2:30][CH2:31]4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)=[C:20]([F:21])[CH:19]=[C:18]2[C:14]=1[CH:15]=[N:16][N:17]2[CH3:22]
Reactant: Cn1ncc2c(F)c(Cc3cnc4ccc(Cl)nn34)c(F)cc21
Reactant: CC(=O)N1CCNCC1
Agent: [F-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC(=O)N1CCN(c2ccc3ncc(Cc4c(F)cc5c(cnn5C)c4F)n3n2)CC1
Temperature: 180 °C
Reaction time: 3 h

Procedure:
6-chloro-3-((4,6-difluoro-1-methyl-1H-indazol-5-yl)methyl)imidazo[1,2-b]pyridazine (Intermediate T, 40.0 mg, 0.12 mmol), KF (34.8 mg, 0.6 mmol) and 1-acetylpiperazine (46.1 mg, 0.36 mmol) were suspended in NMP (0.3 mL). The RM was stirred at 180° C. for 3 h. The mixture was diluted with EtOAc and washed with NaHCO3 10% (2×) and water (4×). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography and afforded the title compound as a light brown foam (tR 3.72 min (conditions 5), MH+=426.3, 1H-NMR in DMSO-d6: 8.16 (s, 1H); 7.80 (d, 1H); 7.46 (d, 1H); 7.27 (s, 1H); 7.10 (d, 1H); 4.27 (s, 2H); 3.98 (s, 3H); 3.50 (s, 6H); 3.44 (m, 2H); 2.03 (s, 3H)).