Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:18]4[CH2:19][C:20]5[S:21][C:22]([C:25]6[CH:26]=[CH:27][C:28]([NH2:31])=[N:29][CH:30]=6)=[CH:23][C:24]=5[C:17]=4[N:16](COCC[Si](C)(C)C)[N:15]=3)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[ClH:40]>CO>[ClH:40].[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]3[C:18]4[CH2:19][C:20]5[S:21][C:22]([C:25]6[CH:26]=[CH:27][C:28]([NH2:31])=[N:29][CH:30]=6)=[CH:23][C:24]=5[C:17]=4[NH:16][N:15]=3)=[CH:12][CH:13]=2)[CH2:4][CH2:3]1
Reactant: CN1CCN(c2ccc(-c3nn(COCC[Si](C)(C)C)c4c3Cc3sc(-c5ccc(N)nc5)cc3-4)cc2)CC1
Agent: Cl
Solvent: CO
Product: CN1CCN(c2ccc(-c3n[nH]c4c3Cc3sc(-c5ccc(N)nc5)cc3-4)cc2)CC1
Temperature: 100 °C
Yield: 48.8 %

Procedure:
5-[6-[4-(4-Methyl-piperazin-1-yl)-phenyl]-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-2-yl]-pyridin-2-ylamine (0.45 g, 0.8 mmol) was dissolved in MeOH and treated with concentrated HCl (0.25 mL, 8 mmol). The reaction mixture was heated at 100° C. for 4 hr. The solution was cooled to room temperature and the resultant precipitate was filtered, washed with MeOH and concentrated under reduced pressure to provide the corresponding 5-{6-[4-(4-Methyl-piperazin-1-yl)-phenyl]-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-2-yl}-pyridin-2-ylamine hydrochloride (0.18 g, 0.39 mmol) as yellow solid in 49% yield.
Reaction SMILES: C[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[CH2:9](NCCCC)[CH2:10][CH2:11]C>>[CH3:11][C:10]1[N:8]=[C:4]2[CH:3]=[CH:2][CH:7]=[CH:6][N:5]2[CH:9]=1
Reactant: CCCCNCCCC
Reactant: Cc1ccnc(N)c1
Product: Cc1cn2ccccc2n1

Procedure:
4-Methyl-2-aminopyridine (1.4 g, 12.5 mmol) was reacted with β-bromo-α-keto-(4-chloropropoxy)propiophenone as described in Example 8. The resulting product was reacted with dibutylamine as described in Example 8 to produce 2.9 g (75% yield) of the free base of the title compound which was converted to the HCl salt, mp 210° C. to 212° C. IR(KBr): 3460, 2640, 1650 cm-1. MS: 421 (M+). 1H NMR (CD3OD): δ8.89 (s, 1H), 8.77 (d, J=7.5 Hz, 2H), 8.12 (d, J=8.9 Hz, 2H), 7.77 (s, 1H), 7.48 (d, J=7.5 Hz, 2H), 7.20 (d, J=8.9 Hz, 2H), 4.30 (t, J=5.7 Hz, 2H), 3.38-3.16 (m, 6H), 2.65 (s, 3H), 2.35 (m, 2H), 1.81-1.34 (m, 8H), 1.02 (m, 6H).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][NH:18]3)=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:10])(=[O:9])[N:8]=1.C(N(CC)CC)C.[CH3:30][CH:31]([CH3:36])[CH2:32][C:33](O)=[O:34].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][N:18]3[C:33](=[O:34])[CH2:32][CH:31]([CH3:36])[CH3:30])=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:9])(=[O:10])[N:8]=1
Reactant: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCCN3)c21
Reactant: CC(C)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)CC(=O)N1CCCC[C@@H]1COc1cccc2c1C(N)=NS(=O)(=O)N2
Temperature: 25 °C
Reaction time: 18 h
Yield: 12.9 %

Procedure:
To a solution of (R)-4-amino-5-(piperidin-2-ylmethoxy)-1H-benzo[c][1,2,6]thiadiazine 2,2-dioxide hydrochloride (Example 15a, 500 mg, 1.44 mmol) in DMF (12 mL) was added triethylamine (399 uL, 2.88 mmol), 3-methylbutanoic acid (159 uL, 1.44 mmol), EDCI-HCl (276 mg, 1.44 mmol), and HOBt (220 mg, 1.44 mmol). The reaction mixture was stirred at room temperature, under nitrogen for 18 hrs, then was filtered and purified by HPLC (10-90% acetonitrile in water). The pure fractions were combined, concentrated and crystallized from ethanol and water to give the title compound as a white solid (73 mg, 13% yield). 1H NMR (400 MHz, DMSO-d6, 80° C.) δ 0.89 (d, J=6.8 Hz, 6H), 1.37 (m, 1H), 1.51-1.70 (m, 4H), 1.78 (d, J=12.8 Hz, 1H), 2.01 (m, 1H), 2.13-2.27 (m, 2H), 3.02 (br s, 1H), 3.89 (br s, 1H), 4.18 (br s, 1H), 4.48 (t, J=9.2 Hz, 1H), 5.02 (br s, 1H), 6.63 (d, J=8.0 Hz, 1H), 6.83 (d, J=8.8 Hz, 1H), 7.42 (t, J=8.4 Hz, 1H), 7.82 (br s, 2H), 10.63 (s, 1H). MS 395 (MH+).
Reaction SMILES: [C:1]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=O)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:34][C:35]1[CH:43]=[CH:42][C:38]([C:39]([OH:41])=[O:40])=[C:37]([NH:44][C:45]([O:47][CH:48]([CH3:50])[CH3:49])=[O:46])[CH:36]=1>O1CCCC1>[C:45]([NH:44][C:37]1[CH:36]=[C:35]([NH:34][C:13](=[O:15])[C@@H:12]2[CH2:16][CH2:17][CH2:18][N:11]2[C:1]([O:3][CH2:4][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2])[CH:43]=[CH:42][C:38]=1[C:39]([OH:41])=[O:40])([O:47][CH:48]([CH3:50])[CH3:49])=[O:46]
Reactant: CC(C)OC(=O)Nc1cc(N)ccc1C(=O)O
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)OC(=O)Nc1cc(NC(=O)[C@@H]2CCCN2C(=O)OCc2ccccc2)ccc1C(=O)O
Temperature: -15 °C
Reaction time: 0.03 h

Procedure:
A solution was prepared by dissolving 249 mg of N-carbobenzoxy-L-proline and 101.0 mg of N-methylmorpholine in 5 ml of dry tetrahydrofuran and cooling to a temperature of -15° C. The solution was mixed with 136.6 mg of isobutyl chloroformate and the mixture was stirred at a temperature of -15° C. to -10° C. for 2 minutes. Then, a solution of 238 mg of 4-amino-2-carboisopropoxyaminobenzoic acid and 101.2 mg of N-methylmorpholine in 2 ml of dry tetrahydrofuran was added dropwise to the above-mentioned mixture. The resultant reaction mixture was stirred at a temperature of -15° C. to -10° C. for one hour, gradually heated to room temperature, and then stirred at room temperature for 18 hours. The resultant deposit generated in the reaction mixture was removed by filtration, the filtrate was concentrated under a reduced pressure, and an oily yellow substance was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([Mg]Br)=[CH:14][CH:13]=1>C(OCC)C>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]([OH:5])[C:15]1[CH:16]=[CH:17][C:12]([Cl:11])=[CH:13][CH:14]=1
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: O=Cc1ccc(Cl)cc1Cl
Solvent: CCOCC
Product: OC(c1ccc(Cl)cc1)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 73 %

Procedure:
To a stirred solution of 2,4-dichlorobenzaldehyde (286 mmol) in diethyl ether (500 mL) was added 4-chlorophenylmagnesium bromide (1.0 M in diethyl ether, 286 mmol) dropwise at 0° C. over a period of 1 hour. The reaction was allowed to warm to ambient temperature, and stirred for 3 h. The reaction mixture was quenched with saturated ammonium chloride solution (500 mL) and extracted with diethyl ether (2×500 mL), the extracts were washed with water and brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by trituration with iso-hexane (500 mL) to yield the product as a white solid (60.0 g, 73%).
Reaction SMILES: C(O[CH:5]([CH:18]([CH3:20])[CH3:19])[C:6]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1)=[O:7])(=O)C.Cl.OC(C(C)C)C(C1C2C(=CC=CC=2)C=CC=1)=O.OC(C1C2C(=CC=CC=2)C=CC=1)C(=O)C(C)C.[N:56]#[C:57][NH2:58]>C(O)C>[NH2:58][C:57]1[O:7][C:6]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)=[C:5]([CH:18]([CH3:20])[CH3:19])[N:56]=1
Reactant: N#CN
Reactant: CC(=O)OC(C(=O)c1cccc2ccccc12)C(C)C
Agent: CC(C)C(=O)C(O)c1cccc2ccccc12
Agent: CC(C)C(O)C(=O)c1cccc2ccccc12
Agent: Cl
Solvent: CCO
Product: CC(C)c1nc(N)oc1-c1cccc2ccccc12
Temperature: 115 °C

Procedure:
A mixture of 2-acetoxy-3-methyl-1-(naphth-1-yl)butan-1-one (8.4 g), IMS (200 ml) and hydrochloric acid (1M; 100 ml) were boiled under reflux for 4 hours. The mixture was cooled, evaporated in vacuo and partitioned between dichloromethane and brine. The organic layer was separated, dried with sodium sulphate, filtered and evaporated in vacuo to afford a mixture of crude 2-hydroxy-3-methyl-1-naphthalen-1-yl-butan-1-one and 1-hydroxy-3-methyl-1-naphthalen-1-yl-butan-2-one (F) (7.4 g). Cyanamide (1.3 g) and anhydrous ethanol (50 ml) were added and the resulting mixture was boiled under reflux for 96 hours. After cooling the volatiles were removed in vacuo and the residue heated at 115° C. for a further 48 hours. The mixture was cooled, triturated with chloroform (80 ml) and filtered. The filtrate was washed with water, dried with sodium sulphate, filtered and evaporated in vacuo. The title compound (7) was obtained (0.26 g; m.p. 127-129° C.) following silica gel column chromatography of the residue in 33% ethyl acetate in petroleum ether and re-crystallisation from dichloromethane/petroleum ether.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH:13]=[N:12]2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:31][C:32]1[CH:36]=[CH:35][N:34]([CH2:37][C:38]([CH3:41])([OH:40])[CH3:39])[N:33]=1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH:13]=[N:12]2)[C:8]([NH:31][C:32]2[CH:36]=[CH:35][N:34]([CH2:37][C:38]([OH:40])([CH3:39])[CH3:41])[N:33]=2)=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: O=C(O)C(CC1CCCC1)n1ncc(Oc2ccccc2N2CCCCC2)cc1=O
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCCC2)n2ncc(Oc3ccccc3N3CCCCC3)cc2=O)n1
Yield: 55 %

Procedure:
Using the method described in Example 17, 3-cyclopentyl-2-[6-oxo-4-(2-piperidin-1-yl-phenoxy)-6H-pyridazin-1-yl]-propionic acid (Intermediate 52) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-[6-oxo-4-(2-piperidin-1-yl-phenoxy)-6H-pyridazin-1-yl]-propionamide as a white solid (0.79 g, 55%); ES+-HRMS m/e calcd for C30H40N6O4 [M+H+] 549.3184 found 549.3186. 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.05 (s, 3H), 1.06 (s, 3H), 1.08 (m, 1H), 1.32 (m, 1H), 1.40 (br.s., 8H), 1.49-1.71 (m, 5H), 1.93 (m, 1H), 2.31 (m, 1H), 2.89 (m, 4H), 3.89 (s, 2H), 4.67 (s, 1H), 5.52 (dd, J=3.9, J=11.4 Hz, 1H), 5.71 (d, J=2.8 Hz, 1H), 6.39 (d, J=2.3 Hz, 1H), 7.09 (m, 1H), 7.13 (dd, Jo=8.1 Hz, Jm=1.3 Hz, 1H), 7.21 (dd, Jo=7.9 Hz, Jm=1.5 Hz, 1H), 7.28 (m, 1H), 7.52 (d, J=2.3 Hz, 1H), 8.01 (d, J=2.8 Hz, 1H), 10.73 (s, 1H).
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][N:4]=1.[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1>>[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:2][C:3]2[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][N:4]=2)=[CH:15][CH:14]=1
Reactant: Cc1ccc(O)cc1
Reactant: O=[N+]([O-])c1cccnc1CBr
Product: Cc1ccc(OCc2ncccc2[N+](=O)[O-])cc1
Yield: 85 %

Procedure:
In accordance with the same procedures as in Step 3 of Preparation 1, except for using 2-bromomethyl-3-nitropyridine prepared in Step 2 of Preparation 1 and 4-methylphenol, the titled compound was obtained as yellow solid. (Yield: 85%)
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4]>CC(C)=O>[CH3:2][C:3]1([CH3:5])[O:4][C@@H:3]([C@H:5]2[O:6][C@@H:11]3[O:12][C:9]([CH3:11])([CH3:7])[O:10][C@@H:9]3[C@H:7]2[OH:8])[CH2:2][O:1]1
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: CC(C)=O
Product: CC1(C)O[C@H]2O[C@H]([C@H]3COC(C)(C)O3)[C@H](O)[C@H]2O1

Procedure:
The process of claim 1 where the 1,2:5,6-di-O-isopropylidene-3-amino-3-deoxy-α-D-allofuranose is prepared by reacting D-glucose with acetone to produce 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose, oxidizing the glucofuranose to produce 1,2:5,6-di-O-isopropylidene-α-D-ribo-hexofuranose-3-ulose, subjecting the hexofuranose to oximization to produce 1,2:5,6-di-O-isopropylidene-α-D-ribo-hexofuranose-3-ulose oxime, and reducing the oxime to produce said 1,2:5,6-di-O-isopropylidene-3-amino-3-deoxy-α-D-allofuranose.
Reaction SMILES: [OH:1][C:2]1[C:19]([CH:20]=[O:21])=[CH:18][C:17]2[C@@H:16]3[C@H:7]([C@H:8]4[C@@:12]([CH2:14][CH2:15]3)([CH3:13])[C:11](=[CH2:22])[CH2:10][CH2:9]4)[CH2:6][CH2:5][C:4]=2[CH:3]=1.[H][H]>CCOC(C)=O.[Pd]>[OH:1][C:2]1[C:19]([CH:20]=[O:21])=[CH:18][C:17]2[C@@H:16]3[C@H:7]([C@H:8]4[C@@:12]([CH2:14][CH2:15]3)([CH3:13])[C@@H:11]([CH3:22])[CH2:10][CH2:9]4)[CH2:6][CH2:5][C:4]=2[CH:3]=1
Reactant: [H][H]
Reactant: C=C1CC[C@H]2[C@@H]3CCc4cc(O)c(C=O)cc4[C@H]3CC[C@]12C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: C[C@H]1CC[C@H]2[C@@H]3CCc4cc(O)c(C=O)cc4[C@H]3CC[C@]12C
Yield: 76.2 %

Procedure:
To a solution of 3-hydroxy-17-methyleneestra-1,3,5(10)-triene-2-carboxaldehyde (23, 0.401 g, 1.35 mmol) in EtOAc (10 mL) was added 10 palladium on carbon (0.060 g). The reaction mixture was stirred for 4 h under the hydrogen atmosphere at room temperature. After the catalyst was filtered, the solvent was evaporated at reduced pressure. The residue was purified by column chromatography (silica gel) using n-hexane:EtOAc (10:1→2:1, v/v) to afford 0.307 g of 27 (76% yield).
Reaction SMILES: Cl[CH:2]=[C:3]([CH2:9][CH2:10][CH3:11])[C:4](=O)[CH:5]([CH3:7])[CH3:6].C([O:14][C:15](=[O:18])[CH2:16][SH:17])C>>[CH:5]([C:4]1[C:3]([CH2:9][CH2:10][CH3:11])=[CH:2][S:17][C:16]=1[C:15]([OH:18])=[O:14])([CH3:7])[CH3:6]
Reactant: CCCC(=CCl)C(=O)C(C)C
Reactant: CCOC(=O)CS
Product: CCCc1csc(C(=O)O)c1C(C)C
Yield: 30.5 %

Procedure:
1-Chloro-4-methyl-2-propyl-pent-1-en-3-one (29.7 g, 170 mmol) is reacted with mercaptoacetic acid ethyl ester (40.9 g, 340 mmol) in analogy to the procedure given for Intermediate A7 to give 3-isopropyl-4-propyl-thiophene-2-carboxylic acid (11.0 g) as colourless crystals; 1H NMR (CD3OD): δ 7.21 (s, 1H), 3.83 (hept, J=7.0 Hz, 1H), 2.60 (t, J=7.6 Hz, 2H), 1.70-1.56 (m, 2H), 1.33 (d, J=7.6 Hz, 6H), 0.99 (t, J=7.6 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([S:13]C(=O)C)[CH2:10][C@@H:9]1[CH2:17][O:18][CH2:19][C:20]1[CH:25]=[C:24]([F:26])[C:23]([F:27])=[CH:22][C:21]=1[F:28])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>CCO>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([SH:13])[CH2:10][C@H:9]1[CH2:17][O:18][CH2:19][C:20]1[CH:25]=[C:24]([F:26])[C:23]([F:27])=[CH:22][C:21]=1[F:28])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)S[C@H]1C[C@H](COCc2cc(F)c(F)cc2F)N(C(=O)OC(C)(C)C)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1C[C@H](S)C[C@H]1COCc1cc(F)c(F)cc1F
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 97.2 %

Procedure:
A solution of 0.126 g (0.3 mmol) (2R,4S)-4-acetylsulfanyl-2-(2,4,5-trifluoro-benzyloxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester in 12 ml EtOH (degased with Ar) was treated at 0° C. with 0.9 ml 1N LiOH, warmed up to room temperature and stirred for 4.5 h. The reaction was recooled to 0° C. and quenched with aqueous 10% KHSO4. The reaction was extracted with aqueous 10% KHSO4/EtOAc (3×) and the organic phase was washed with aqueous 10% NaCl, dried over Na2SO4 and evaporated to give 0.11 g (97%) (2S,4R)-4-mercapto-2-(2,4,5-trifluoro-benzyloxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester, MS: 378 (MH+).
Reaction SMILES: C[O:2][CH:3](Cl)Cl.[Sn](Cl)(Cl)(Cl)Cl.[F:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1>ClCCl>[F:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH:3]=[O:2])=[CH:14][CH:13]=1
Reactant: COC(Cl)Cl
Reactant: Fc1cccc2ccccc12
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: O=Cc1ccc(F)c2ccccc12
Reaction time: 0.25 h
Yield: 100.7 %

Procedure:
19.9 g Dichloromethyl methyl ether and 45.7 g tin chloride were dissolved in 70 ml dichloromethane. The solution was cooled to +5° C. and 20.0 g fluoronapthalene in dichloromethane (49 ml) was added over a 60 min period, while keeping the temperature at 5° C. The reaction was brought to room temperature after the addition. After 4 h the reaction was quenched by slowly pouring it into an ice/water mixture. This mixture was stirred for 15 min and left standing overnight. The dichloromethane layer was washed with water, dried (sodium sulfate), filtered through celite and concentrated in vacuo to obtain 24.0 g of 4-fluoro-naphthalene-1-carbaldehyde as an off white solid.
Reaction SMILES: CC(C)([O-])C.[K+].[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([CH3:15])[C:9]=1[F:16].[Cl:17][C:18]1[CH:23]=[C:22](Cl)[CH:21]=[CH:20][N:19]=1>CC(N(C)C)=O>[Cl:17][C:18]1[CH:23]=[C:22]([O:14][C:11]2[CH:12]=[CH:13][C:8]([NH2:7])=[C:9]([F:16])[C:10]=2[CH3:15])[CH:21]=[CH:20][N:19]=1
Reactant: Cc1c(O)ccc(N)c1F
Reactant: Clc1ccnc(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cc1c(Oc2ccnc(Cl)c2)ccc(N)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.2 %

Procedure:
Potassium tert-butoxide (3.5 g, 31 mmol) was added to a solution of 4-amino-3-fluoro-2-methyl-phenol (4.2 g, 30 mmol) in dimethylacetamide. The mixture was stirred at RT for 30 min. A solution of 2,4-dichloropyridine (4.38 g, 30 mmol) in dimethylacetamide was added and the mixture was heated at 100° C. overnight. The reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (200 mL) and filtered through silica gel. The filter cake was washed with ethyl acetate, the combined filtrates were concentrated in vacuo and purified by silica gel chromatography to give 4-(2-chloro-pyridin-4-yloxy)-2-fluoro-3-methyl-phenylamine (3.2 g, 42% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.21 (d, J=6.4 Hz, 1H), 6.84 (d, J=2.0 Hz, 1H), 6.81 (dd, J=5.6, 2.4 Hz, 1H), 6.67-6.65 (m, 2H), 5.13 (s, 2H), 1.91 (s, 3H); MS (ESI): m/z 253.2 [M+H]+.
Reaction SMILES: FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C([SiH](CC)CC)C.[CH2:20]([N:27]1[CH2:32][CH2:31][O:30][C:29]([C:34]2[O:38][N:37]=[C:36]([CH3:39])[CH:35]=2)(O)[CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:20]([N:27]1[CH2:32][CH2:31][O:30][CH:29]([C:34]2[O:38][N:37]=[C:36]([CH3:39])[CH:35]=2)[CH2:28]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: Cc1cc(C2(O)CN(Cc3ccccc3)CCO2)on1
Agent: CC[SiH](CC)CC
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Solvent: ClCCl
Product: Cc1cc(C2CN(Cc3ccccc3)CCO2)on1
Temperature: 80 °C

Procedure:
Trimethylsilyl trifluoromethanesulfonate (2.9 g, 13 mmol) and triethylsilane (2.6 g, 22 mmol) were added to a solution of 4-benzyl-2-(3-methyl-1,2-oxazol-5-yl)morpholin-2-ol (C36) (1.2 g, 4.4 mmol) in dichloromethane (15 mL), and the reaction mixture was heated at 80° C. for 2 hours. The reaction mixture was then adjusted to a pH of 5 to 6 via addition of saturated aqueous sodium bicarbonate solution. After extraction with dichloromethane (3×20 mL), the combined organic layers were washed with saturated aqueous sodium chloride solution (25 mL), dried over sodium sulfate, filtered, and concentrated. Purification via silica gel chromatography (Gradient: 0% to 50% ethyl acetate in petroleum ether) afforded the product as a yellow oil. Yield: 500 mg, 1.9 mmol, 43%. LCMS m/z 258.9 [M+H+]. 1H NMR (400 MHz, CDCl3) δ 7.27-7.37 (m, 5H), 6.07 (s, 1H), 4.75 (dd, J=9.7, 2.3 Hz, 1H), 3.96 (ddd, J=11.3, 2.8, 2.4 Hz, 1H), 3.81 (ddd, J=11.3, 10.8, 2.5 Hz, 1H), 3.52-3.61 (m, 2H), 3.02 (br d, J=11.4 Hz, 1H), 2.68-2.75 (m, 1H), 2.29 (s, 3H), 2.27-2.37 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:14]([F:17])([F:16])[F:15].[CH3:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=1)=O>CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=3)[CH3:18])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:14]([F:15])([F:17])[F:16]
Reactant: COc1ccc(C(C)=O)cc1OC
Reactant: FC(F)(F)c1cc(N2CCNCC2)ccc1Cl
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Solvent: CO
Product: COc1ccc(C(C)N2CCN(c3ccc(Cl)c(C(F)(F)F)c3)CC2)cc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A quantity of 0.17 g (0.6 mmole, 1 eq) of 1-(4-chloro-3-trifluoromethyl-phenyl)-piperazine and 0.1 g (0.6 mmole, 1 eq) of 3,4-dimethoxyacetophenone and 2 mL of Ti(OiPr)4 are warmed to 70° C. for 2 hours. The reaction solution is cooled to room temperature and 20 mL of anhydrous methanol is added followed by 1.0 g of NaBH and the resulting solution is stirred at room temperature for 2 hours. The reaction is quenched by the addition of 1 N NaOH and extracted with CH2Cl2. The CH2Cl2 extracts are dried over anhydrous MgSO4 and concentrated in vacuo. The residue is chromatographed on SiO2 with ethyl to afford 1-[4-chloro-3-(trifluoromethyl)phenyl]-4-[1-(3,4-dimethoxyphenyl)ethyl]piperazine (compound 2). Analysis 1H NMR (400 MHz, CDCl3): 7.31 (1H, d), 7.19 (1H, m), 6.90 (4H, m), 3.89 (6H, d), 3.38 (1H, m), 3.20 (4H, m), 2.61 (4H, m). MS (LC-MS): Calculated for C21H24ClF3N2O2 428.88. Found 429.30 (M+).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4](C)[C:3]=1[S:9]([Cl:12])(=[O:11])=[O:10].[F:13][C:14]([F:26])([F:25])C1C=CC=CC=1S(Cl)(=O)=O.N1C=CC=CC=1.C(Cl)Cl>O>[F:13][C:14]([F:26])([F:25])[C:5]1[CH:4]=[C:3]([S:9]([Cl:12])(=[O:10])=[O:11])[CH:2]=[CH:7][CH:6]=1
Reactant: Cc1cccc(Cl)c1S(=O)(=O)Cl
Reactant: O=S(=O)(Cl)c1ccccc1C(F)(F)F
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Chloro-6-methylbenzenesulfonyl chloride (8, 7.82 g, 34.8 mmol) was added to a solution of 7 (8.83 g, 31.6 mmol) in pyridine (7.67 ml, 95.0 mmol) and the reaction mixture was stirred at room temperature overnight. CH2Cl2 and H2O were added to the reaction mixture and the organic phase was separated, washed with water and sat. NaCl solution, dried over Na2SO4 and concentrated to obtain the product 9, which was employed directly as such in the next stage.
Reaction SMILES: Cl[C:2]12[O:8][CH:7]1[CH2:6][CH2:5][C:4]([Cl:10])([F:9])[CH2:3]2.[Br:11]C1(Cl)CCCC(Cl)(F)C1O.[OH-].[Na+]>O>[Br:11][C:2]12[O:8][CH:7]1[CH2:6][CH2:5][C:4]([Cl:10])([F:9])[CH2:3]2
Reactant: FC1(Cl)CCC2OC2(Cl)C1
Reactant: OC1C(F)(Cl)CCCC1(Cl)Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: FC1(Cl)CCC2OC2(Br)C1
Yield: 80 %

Procedure:
The same procedure was followed as for the production of 2e in Example 17: it was performed with 0.20 g (0.75 mmol) of alcohol 1i, 3 cm3 of water and 0.12 g (3 mmol) of sodium hydroxide. Reaction time: 1 h 15 min; ether extraction (4×7 cm3). After treatment, 0.15 g of epoxide 2g were obtained (macrobore GC purity>97.5%), having a yield of 80%.
Reaction SMILES: N1(C2CCCCCCCCCC2)CCCN=CCCCCC1.[CH3:23][N:24]1[N:33]=[N:32][C:31]2[N:27]([CH:28]=[N:29][C:30]=2[C:34]([NH2:36])=[O:35])[C:25]1=[O:26].BrC[C:39](=[O:42])[CH2:40][CH3:41].Cl>C(#N)C>[O:26]=[C:25]1[N:24]([CH2:23][C:39](=[O:42])[CH2:40][CH3:41])[N:33]=[N:32][C:31]2=[C:30]([C:34]([NH2:36])=[O:35])[N:29]=[CH:28][N:27]12
Reactant: Cn1nnc2c(C(N)=O)ncn2c1=O
Reactant: CCC(=O)CBr
Agent: C1=NCCCN(C2CCCCCCCCCC2)CCCCC1
Agent: Cl
Solvent: CC#N
Product: CCC(=O)Cn1nnc2c(C(N)=O)ncn2c1=O
Reaction time: 8 h
Yield: 33.2 %

Procedure:
1,8-Diazabicycloundec-7-ene (DBU) (150 μL, 1.00 mmol, 1.4 eq.) was added dropwise to a suspension of the hydroxymethyl derivative of temozolomide (150 mg, 0.71 mmol) and 1-bromo-2-butanone (90%, stabilized with CaCO3) (330 μL, 2.91 mmol, 4.1 eq.) in acetonitrile (4 mL). The resulting green suspension became homogeneous and was stirred overnight. The reaction was acidified with 1 N HCl and the yellow solution was extracted four times with ethyl acetate. The combined organic extracts were washed with water and then dried over MgSO4. The solvent was removed under vacuum and the pale yellow solid was triturated with diethyl ether to remove the excess of 1-bromo-2-butanone. The precipitate was filtered and washed with diethyl ether and 59 mg of a pale yellow/green solid were obtained (33% crude). LCMS: crude product (99.5% pure); m/z: 523.4 (2M+Na)+, 273.2 (M+Na)+, 251.3 ((MH+)+, 100). 1H NMR (d6 DMSO): 8.90 (s, 1H), 7.90 (s, 1H), 7.75 (s, 1H), 5.37 (s, 2H), 2.67-2.72 (q, 2H, J=7.2 Hz), 0.99-1.03 (t, 3H, J=7.2 Hz).