Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1.[C:13]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[OH:23])([CH3:16])([CH3:15])[CH3:14].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[C:13]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Reactant: CC(C)(C)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc([N+](=O)[O-])c(Oc2ccccc2C(C)(C)C)n1
Temperature: 80 °C
Yield: 79.8 %

Procedure:
A solution of 2-chloro-6-methoxy-3-nitropyridine (5.20 g, 27.6 mmol) in DMF (50 mL) was treated with 2-tert-butylphenol (4.9 mL, 31.7 mmol) and cesium carbonate (27.0 g, 82.8 mmol). The mixture was heated at 80° C. for 18 h. The reaction was allowed to cool to rt, the mixture was poured into water (500 mL) with stirring. The brown precipitate formed was filtered and washed with water, and recrystallized twice from ethanol to afford 2a as brown crystals (6.66 g, 80%). [M+H]+=303.2.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C@@:9]3([CH3:14])[C:11]([CH3:13])([CH3:12])[C@H:6]([CH2:7][CH2:8]3)[C:5]=2[C:4](=[O:15])[NH:3]1.Br[CH2:17][C:18]1[O:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=1>CN(C)C=O>[CH3:1][N:2]1[C:10]2[C@@:9]3([CH3:14])[C:11]([CH3:12])([CH3:13])[C@H:6]([CH2:7][CH2:8]3)[C:5]=2[C:4](=[O:15])[N:3]1[CH2:17][C:18]1[O:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=1
Reactant: FC(F)(F)c1ccc(CBr)o1
Reactant: Cn1[nH]c(=O)c2c1[C@]1(C)CC[C@H]2C1(C)C
Solvent: CN(C)C=O
Product: Cn1c2c(c(=O)n1Cc1ccc(C(F)(F)F)o1)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 110 °C
Yield: 78.3 %

Procedure:
A mixture of (4S,7R)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 19; 100 mg, 0.49 mmol) and 2-bromomethyl-5-trifluoromethyl-furan (144 mg, 0.63 mmol) in N,N-dimethylformamide (5 mL) was heated at 110° C. for 2 days. The reaction mixture was evaporated and the residue was dissolved in ethyl acetate (50 mL), washed with water (2×25 mL) and brine (25 mL), dried (magnesium sulfate), filtered, evaporated, and purified by flash chromatography, eluting with 2-3% methanol/dichloromethane to give (4S,7R)-1,7,8,8-tetramethyl-2-(5-trifluoromethyl-furan-2-ylmethyl)-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (136 mg, 78%) as a white solid. APCI-MS (M+H) 355.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](O)=[N:8][C:7]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[CH:6]2.O=P(Cl)(Cl)[Cl:21]>>[Cl:21][C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[CH:6]=[C:7]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2c(O)nc(N3CCCC3)cc2c1
Product: COc1ccc2c(Cl)nc(N3CCCC3)cc2c1
Temperature: 0 °C
Yield: 48.3 %

Procedure:
A solution of 6-methoxy-3-(pyrrolidin-1-yl)isoquinolin-1-ol (300 mg, 1.228 mmol) in POCl3 (8 mL) was refluxed for 4 h. After concentration, the residue was taken into a mixture of 100 mL of DCM and 50 mL of water, cooled to 0° C., neutralized with 3 N NaOH, dried over MgSO4, concentrated and purified via silica gel chromatography (5-20% EtOAc:Hex) to give 1-chloro-6-methoxy-3-(pyrrolidin-1-yl)isoquinoline (156 mg, 48.3% yield) as a yellow solid. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.95 (d, J=9.5 Hz, 1H), 6.85 (d, J=9.2 Hz, 1H), 6.80 (s, 1H), 6.43 (br. s., 1H), 3.89 (s, 3H), 3.56-3.49 (m, 4H), 2.08-2.03 (m, 4H); MS m/z 263.1 (M++1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([CH:13]=O)[CH2:11][S:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15][O:16][C:17](=[O:39])[C@H:18]([CH2:35][CH2:36][S:37][CH3:38])[NH:19][C:20](=[O:34])[C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][C:22]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH3:15][O:16][C:17](=[O:39])[C@H:18]([CH2:35][CH2:36][S:37][CH3:38])[NH:19][C:20](=[O:34])[C:21]1[CH:26]=[CH:25][C:24]([NH:27][CH2:13][C@@H:12]2[CH2:11][S:10][CH2:9][N:8]2[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[CH:23][C:22]=1[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CC(C)(C)OC(=O)N1CSC[C@H]1C=O
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(N)cc1-c1ccccc1
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(NC[C@@H]2CSCN2C(=O)OC(C)(C)C)cc1-c1ccccc1

Procedure:
N-tert-butoxycarbonyl-(R)-(−)thiazolidine-4-carboxaldehyde was reductively aminated with 4-amino-2-phenylbenzoyl methionine methyl ester (compound 8) according to the procedure of Example 158B.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-])=O)[N:4]([CH2:14][C:15]2[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=2)[C:18]([O:20][CH3:21])=[O:19])[N:3]=1.[NH4+].[Cl-]>CO.[Zn]>[NH2:11][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[CH:2]=[N:3][N:4]2[CH2:14][C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=1)[C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)c1cccc(Cn2nc(I)c3c([N+](=O)[O-])cccc32)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: COC(=O)c1cccc(Cn2ncc3c(N)cccc32)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 61.8 %

Procedure:
A suspension of methyl 3-((3-iodo-4-nitro-1H-indazol-1-yl)methyl)benzoate (1.00 g, 2.29 mmol) and MeOH (45 mL) was cooled to 0° C. Zinc dust (0.748 g, 11.4 mmol) was added followed by saturated aqueous NH4Cl (23 mL). The mixture was stirred at 0° C. for 2 hours, then warmed to ambient temperature with stirring for an additional 3 hours. The mixture was diluted with MeOH and filtered. To the filtrate was added saturated aqueous NH4OAc and the mixture was concentrated to remove bulk MeOH. The mixture was extracted with EtOAc and the combined organic extracts were washed with saturated aqueous NaHCO3 followed by brine, dried over Na2SO4, filtered and concentrated. The product was purified by column chromatography (25 to 100% EtOAc/hexane) to afford 0.398 g (61%) of the title compound as a sticky orange foam.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]([O:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][C:13]=1[C:22]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)=[O:23])([CH3:10])[CH3:9].Cl[C:31]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][N:32]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)CCC>[CH:8]([O:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:19])=[O:20])=[CH:14][C:13]=1[C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:31]2[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][N:32]=2)[CH2:26][CH2:25]1)=[O:23])([CH3:10])[CH3:9]
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Yield: 99.4 %

Procedure:
A solution of (2-isopropoxy-5-methanesulfonyl-phenyl)-piperazin-1-yl-methanone trifluoro-acetic acid (compound 2.4, 80 mg) 2-chloro-5-nitro-pyridine (29 mg), potassium carbonate (50 mg) in 1-butanol (3 mL) was stirred at 120° C. for 20 hours. After such time the solution was concentrated in vacuo, and purified by column chromatography (SiO2) to yield the title compound as white foam (81 mg). MS (m/e): 449.1 (M+H+, 100%).
Reaction SMILES: C([N:20]1[CH:24]=[CH:23][N:22]=[C:21]1[CH2:25]/[CH:26]=[CH:27]/[C:28]1[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[C:30]([C:38]2[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=2)[CH:29]=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)(=O)C.Cl>CO>[NH:20]1[CH:24]=[CH:23][N:22]=[C:21]1[CH2:25]/[CH:26]=[CH:27]/[C:28]1[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[C:30]([C:38]2[CH:39]=[CH:40][C:41]([F:44])=[CH:42][CH:43]=2)[CH:29]=1
Reactant: COC(=O)c1ccc(/C=C/Cc2nccn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1-c1ccc(F)cc1
Agent: Cl
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1ccc(/C=C/Cc2ncc[nH]2)cc1-c1ccc(F)cc1
Yield: 63 %

Procedure:
A solution of methyl 4-[(E)-3-(1-tritylimidazol-2-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzoate (5.78 g; 6.5 mmol), acetic acid (5 ml) and 12N HCl (5 ml) in methanol (100 ml) was refluxed for 1 hour 30 minutes. After evaporation to dryness, the residue was neutralised with aqueous NH4 OH, extracted with dichloromethane, evaporated and purified by flash chromatography, eluting with dichloromethane/ethanol (98/2) to give methyl 4-[(E)-3-(imidazol-2-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzoate. Yield: 63%
Reaction SMILES: Cl.[CH3:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([NH2:11])=[CH:9][CH:10]=1.[C:12]([SH:14])#[N:13].N.[Na]>>[CH2:3]([O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([NH2:13])=[S:14])=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOc1ccc(N)cc1
Reactant: N#CS
Agent: Cl
Agent: N
Agent: [Na]
Product: CCOc1ccc(NC(N)=S)cc1
Reaction time: 8 h

Procedure:
750 Parts of a 30% aqueous hydrochloric acid are placed into a reaction vessel, whereupon 822 parts of p-phenetidine, 479 parts of ammonium rhodanide and 31.2 parts of sodium hydrogenosulfite are introduced successively, while stirring. The reaction mixture is stirred for 15 hours at 80° C., thereafter for 8 hours at 95° C., and subsequently the precipitate having been formed is filtered off with suction, while hot, and washed with hot water until neutral. The dried product gives a yield of 1129 parts (corresponding to 96.0% of the theory) of p-ethoxyphenyl thiourea of the formula ##STR4## which product has a melting point of from 167° to 168° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:14]([CH:15]=2)[C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=2[S:11]3)=[CH:4][CH:3]=1.[CH2:20]([O:22][C:23](=[O:26])[CH2:24]Br)[CH3:21].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH2:20]([O:22][C:23]([CH2:24][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[N:14]([CH:15]=2)[C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=2[S:11]3)=[CH:6][CH:7]=1)=[O:26])[CH3:21]
Reactant: Oc1ccc(-c2cn3c(n2)sc2ccccc23)cc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)COc1ccc(-c2cn3c(n2)sc2ccccc23)cc1
Yield: 52.3 %

Procedure:
To 40 ml of methyl ethyl ketone were added 2.6 g of 2-(p-hydroxyphenyl)imidazo[2,1-b]benzothiazole, 1.7 g of monobromoacetic acid ethyl ester, and 1.5 g of potassium carbonate and the mixture was refluxed overnight. After the reaction was over, the reaction mixture was cooled, insoluble materials were filtered off, and the filtrate was concentrated under reduced pressure to provide solid materials, which were recrystallized from toluene-n-hexane to provide 1.8 g of 2-(p-ethoxycarbonylmethoxyphenyl)imidazo[2,1-b]benzothiazole.
Reaction SMILES: [C:1]([O:13][CH3:14])(=[O:12])[CH:2]1[CH2:11][CH:10]=[CH:9][CH2:8][CH:3]1[C:4]([O:6][CH3:7])=[O:5].[C:15](OC(=O)C)(=[O:17])[CH3:16].[Sn](Cl)(Cl)(Cl)Cl>O>[C:15]([C:9]1[CH2:8][CH:3]([C:4]([O:6][CH3:7])=[O:5])[CH:2]([CH2:11][CH:10]=1)[C:1]([O:13][CH3:14])=[O:12])(=[O:17])[CH3:16]
Reactant: COC(=O)C1CC=CCC1C(=O)OC
Reactant: CC(=O)OC(C)=O
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Product: COC(=O)C1CC=C(C(C)=O)CC1C(=O)OC

Procedure:
10 g of dimethyl 1,2,3,6-tetrahydro-phthalate (II) was treated at -5° C. with 25 ml of acetic anhydride in the presence of 9 ml of tin tetrachloride. The reaction mixture was poured into iced water and extracted with diethyl ether. The organic phase was washed with a saturated aqueous solution of sodium bicarbonate and then with water, and was then evaporated to dryness under vacuum. The obtained oil was dissolved in benzene, treated with a methanolic solution of hydrogen chloride. The solution was evaporated to dryness and the residue was purified by chromatography on column of silica gel to give 9 g of the title compound in 75% overall yield.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7](OC2C=C3C(=CC=2)OC(C2C=CC=CC=2)CC3)=[N:8][CH:9]=1)([O-:3])=[O:2].[Cl:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH:34]1[CH2:43][CH:42]([OH:44])[C:41]2[C:36](=[CH:37][CH:38]=[C:39]([OH:45])[CH:40]=2)[O:35]1>>[Cl:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH:34]1[CH2:43][CH:42]([OH:44])[C:41]2[C:36](=[CH:37][CH:38]=[C:39]([O:45][C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=3)[CH:40]=2)[O:35]1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Reactant: Oc1ccc2c(c1)C(O)CC(c1ccccc1Cl)O2
Product: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)C(O)CC(c2ccccc2Cl)O3)nc1

Procedure:
2-(2-Chlorophenyl)-6-(5-nitropyridin-2-yloxy)chroman-4-ol was prepared as described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) starting from 520 mg of 2-(2-chlorophenyl)chroman-4,6-diol (Example 68(b)). The product was recrystallised from 2-propanol. 1H NMR (300 MHz, d6-DMSO) δ: 9.04 (d, 1H, J 2.9 Hz), 8.61 (dd, 1H, J 9.1, 2.9 Hz), 7.68 (dd, 1H, J 7.6, 1.8 Hz), 7.51-7.40 (m, 3H), 7.27 (d, 1H, J 2.9 Hz), 7.23 (d, 1H, J 9.1 Hz), 7.04 (dd, 1H, J 8.8, 2.9 Hz), 6.92 (d, 1H, J 8.8 Hz), 5.59 (d, 1H, J 10.6 Hz), 5.02 (m, 1H), 2.40 (m, 1H), 1.93 (m, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]=[CH:13][N:14]([CH3:16])[CH:15]=3)[S:10][C:3]=12.[F:17][C:18]1[CH:38]=[C:37]([N+:39]([O-:41])=[O:40])[CH:36]=[CH:35][C:19]=1[O:20]C1C=CN=C2C=C(C3SC=CN=3)SC=12>>[F:17][C:18]1[CH:38]=[C:37]([N+:39]([O-:41])=[O:40])[CH:36]=[CH:35][C:19]=1[O:20][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]=[CH:13][N:14]([CH3:16])[CH:15]=3)[S:10][C:3]=12
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4nccs4)sc23)c(F)c1
Reactant: Cn1cnc(-c2cc3nccc(Cl)c3s2)c1
Product: Cn1cnc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)c1
Yield: 47 %

Procedure:
Starting from the chloride 175 and following the procedure described above for the synthesis of compound 11 (scheme 2, example 12), title compound 176 was obtained in 47% yield. LRMS (M+1) 371.0 (100%).
Reaction SMILES: [C:1]12([CH2:11][NH:12][C:13]([C:15]3[C:16]([C:20]([F:23])([F:22])[F:21])=[N:17][NH:18][CH:19]=3)=[O:14])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Cl[C:25]1[N:30]=[C:29]([NH2:31])[C:28]([F:32])=[CH:27][N:26]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN1C(=O)CCC1>[C:1]12([CH2:11][NH:12][C:13]([C:15]3[C:16]([C:20]([F:23])([F:22])[F:21])=[N:17][N:18]([C:25]4[N:30]=[C:29]([NH2:31])[C:28]([F:32])=[CH:27][N:26]=4)[CH:19]=3)=[O:14])[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: Nc1nc(Cl)ncc1F
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1c[nH]nc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Nc1nc(-n2cc(C(=O)NCC34CC5CC(CC(C5)C3)C4)c(C(F)(F)F)n2)ncc1F

Procedure:
A solution of 3-trifluoromethyl-1H-pyrazole-4-carboxylic acid (adamantan-1-ylmethyl)-amide (100 mg, 0.306 mmol), 2-chloro-5-fluoro-pyrimidin-4-ylamine (52 mg, 0.35 mmol) and Cs2CO3 (130 mg, 0.4 mmol) in NMP (1.0 mL) is heated in a microwave reactor at 150° C. for 1 h. The mixture is poured into H2O. The crude product is filtered out, dissolved in 10% MeOH in DCM, and dried over anhydrous Na2SO4. The title compound is purified by PTLC (eluted with 5% MeOH in DCM). 1H NMR (CD3OD): 8.96 (s, 1H), 8.11 (s, 1H), 3.0 (s, 2H), 1.98 (m, 3H), 1.78-1.68 (m, 6H), 1.58 (s, 611). MS (M+1)=439.29; RT=1.34 min. *IC50.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.C([Mg]Cl)(C)C.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:15]([CH3:14])(=[O:17])=[O:16])=[CH:4][N:3]=1
Reactant: Brc1ccc(Br)nc1
Reactant: CS(=O)(=O)Cl
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(Br)nc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 59 %

Procedure:
To a solution of 2,5-dibromopyridine (50 g, 211 mmol) in tetrahydrofuran (175 mL) at 0° C. was added 2.0 M isopropylmagnesium chloride (274 mmol) at a rate which maintained the temperature below 8° C. The reaction mixture was stirred at 0° C. for 45 minutes, then cooled to −15° C. A solution of methanesulfonyl chloride (32.2 g, 281 mmol) in tetrahydrofuran (40 mL) was added to the reaction mixture at a rate which maintained the temperature below 5° C. The reaction mixture was allowed to warm to room temperature and then quenched with water (500 mL) and tert-butylethylether (300 mL). The layers were separated, the aqueous layer was extracted twice with tert-butylethylether (2×200 mL). The combined organic extracts were washed with water (200 mL) and concentrated. The crude product was crystallized from toluene (110 mL) and the solids were filtered to afford 29.4 g (59% yield) of 2-bromo-5-(methanesulfonyl)-pyridine. Analytical data: 1H NMR (300 MHz, CDCl3) δ 3.13 (s, 3H), 7.73 (d, J=8.3 Hz, 1H), 8.07 (dd, J1=8.3 Hz, J2=2.7 Hz, 1H), 8.91 (d, J=2.5 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][C:6]1[NH:7][C:8](=[O:16])[C:9]([C:14]#[N:15])=[C:10](SC)[N:11]=1.[NH:20]1[CH2:25][CH2:24][CH:23]([CH2:26][CH2:27][OH:28])[CH2:22][CH2:21]1>C(#N)C>[OH:28][CH2:27][CH2:26][CH:23]1[CH2:24][CH2:25][N:20]([C:10]2[N:11]=[C:6]([CH2:5][C:4]3[CH:17]=[CH:18][CH:19]=[C:2]([CH3:1])[CH:3]=3)[NH:7][C:8](=[O:16])[C:9]=2[C:14]#[N:15])[CH2:21][CH2:22]1
Reactant: OCCC1CCNCC1
Reactant: CSc1nc(Cc2cccc(C)c2)[nH]c(=O)c1C#N
Solvent: CC#N
Product: Cc1cccc(Cc2nc(N3CCC(CCO)CC3)c(C#N)c(=O)[nH]2)c1
Temperature: 25 °C

Procedure:
0.1 g (0.37 mmol) of 2-(3-methylbenzyl)-4-(methylsulphanyl)-6-oxo-1,6-dihydro-5-pyrimidinecarbonitrile is heated with 0.142 g (1.16 mmol) of 2-(4-piperidinyl)ethan-1-ol in 3 ml of acetonitrile at 90° C. under argon for seven days. After cooling to room temperature, the crude product is purified by preparative HPLC. 0.047 g (36% of theory) of the title compound is obtained as a colourless solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]([CH:16]2[CH2:25][C:24]3[CH:23]=[C:22]([O:26][C:27]4[CH:32]=[CH:31][N:30]=[C:29]([C:33]([NH:35][CH3:36])=[O:34])[CH:28]=4)[CH:21]=[CH:20][C:19]=3[CH2:18][CH2:17]2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[N:37]([CH2:40][CH3:41])=[C:38]=[O:39]>C1COCC1.O>[CH2:40]([NH:37][C:38]([NH:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]([CH:16]2[CH2:25][C:24]3[CH:23]=[C:22]([O:26][C:27]4[CH:32]=[CH:31][N:30]=[C:29]([C:33]([NH:35][CH3:36])=[O:34])[CH:28]=4)[CH:21]=[CH:20][C:19]=3[CH2:18][CH2:17]2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1)=[O:39])[CH3:41]
Reactant: CNC(=O)c1cc(Oc2ccc3c(c2)CC(C(=O)Nc2cc(CN)cc(C(F)(F)F)c2)CC3)ccn1
Reactant: CCN=C=O
Solvent: O
Solvent: C1CCOC1
Product: CCNC(=O)NCc1cc(NC(=O)C2CCc3ccc(Oc4ccnc(C(=O)NC)c4)cc3C2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-{[7-({[3-(aminomethyl)-5-(trifluoromethyl)phenyl]amino}-carbonyl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}-N-methylpyridine-2-carboxamide (0.411 g, 0.824 mmol) and TEA (0.23 mL, 1.65 mmol) in THF (10 mL) was added isocyanatoethane (0.10 mL, 1.26 mmol) in THF (5 mL) dropwise. The reaction mixture was allowed to stir at rt overnight. The reaction mixture was diluted with water and extracted with DCM. The organic solutions were combined, washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography and then converted to the HCl salt of 4-{[7-({[3-({[(ethylamino)carbonyl]amino}methyl)-5-(trifluoromethyl)phenyl]amino}carbonyl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}-N-methylpyridine-2-carboxamide I-420. 1H NMR (400 MHz, d6-DMSO; HCl salt) δ: 10.42 (s, 1H), 8.84 (dd, 1H), 0.51 (dd, 1H), 8.03 (s, 1H), 7.68 (s, 1H), 7.41 (dd, 1H), 7.22-7.26 (m, 2H), 7.17 (dd, 1H), 7.01 (dd, 1H), 7.96 (dd, 1H), 4.23 (s, 2H), 3.01 (dd, 2H), 2.94 (dd, 2H), 2.80-2.90 (m, 3H), 2.77 (dd, 3H), 2.08-2.14 (m, 1H), 1.75-1.86 (m, 1H), and 0.98 (dd, 3H). LCMS: (FA) ES+ 570.7, ES− 568.4.
Reaction SMILES: [OH:1][CH:2]([C:23]1[C:32]2[O:31][CH2:30][C:29](=[O:33])[NH:28][C:27]=2[CH:26]=[C:25]([OH:34])[CH:24]=1)[CH2:3][NH:4][C:5]1([CH2:8][CH2:9][N:10]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[C:13]([CH3:21])([CH3:20])[O:12][CH:11]2[OH:22])[CH2:7][CH2:6]1.[H][H]>CO.[Pd]>[OH:1][CH:2]([C:23]1[C:32]2[O:31][CH2:30][C:29](=[O:33])[NH:28][C:27]=2[CH:26]=[C:25]([OH:34])[CH:24]=1)[CH2:3][NH:4][C:5]1([CH2:8][CH2:9][N:10]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[C:13]([CH3:21])([CH3:20])[O:12][C:11]2=[O:22])[CH2:6][CH2:7]1
Reactant: [H][H]
Reactant: CC1(C)OC(O)N(CCC2(NCC(O)c3cc(O)cc4c3OCC(=O)N4)CC2)c2ccccc21
Agent: [Pd]
Solvent: CO
Product: CC1(C)OC(=O)N(CCC2(NCC(O)c3cc(O)cc4c3OCC(=O)N4)CC2)c2ccccc21

Procedure:
1-(2-{1-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-ethylamino]-cyclopropyl}-ethyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-ol 590 mg (1.06 mmol) 1-(2-{1-[2-(6-benzyloxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-2-hydroxy-ethylamino]-cyclopropyl}-ethyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one are dissolved in 30 mL methanol and hydrogenated in the presence of palladium on charcoal (10%) at ambient temperature and 3 bar hydrogen pressure. Yield: 180 mg (36%); mass spectroscopy: [M+H]+=468.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:19]3[C:11](=[CH:12][C:13]4[S:17][CH:16]=[N:15][C:14]=4[C:18]=3[F:20])[NH:10][C:9]2=[O:21])=[C:4]([Cl:22])[CH:3]=1.C(N(CC)CC)C.[CH:30]1([S:33](Cl)(=[O:35])=[O:34])[CH2:32][CH2:31]1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:19]3[C:11](=[CH:12][C:13]4[S:17][CH:16]=[N:15][C:14]=4[C:18]=3[F:20])[N:10]([S:33]([CH:30]3[CH2:32][CH2:31]3)(=[O:35])=[O:34])[C:9]2=[O:21])=[C:4]([Cl:22])[CH:3]=1
Reactant: O=c1[nH]c2cc3scnc3c(F)c2n1-c1ccc(Br)cc1Cl
Reactant: O=S(=O)(Cl)C1CC1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=c1n(-c2ccc(Br)cc2Cl)c2c(F)c3ncsc3cc2n1S(=O)(=O)C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.5 %

Procedure:
To a solution of 5-(4-bromo-2-chlorophenyl)-4-fluoro-5H-imidazo[4′,5′:4,5]benzo[1,2-d]thiazol-6(7H)-one (100 mg, 0.25 mmol) in CH2Cl2 (10 mL) was added triethylamine (76 mg, 0.75 mmol) at 0° C. followed by cyclopropanesulfonyl chloride (53 mg, 0.38 mmol) and DMAP (10 mg). The mixture was stirred at room temperature for 1 h and washed with saturated NaHCO3 (aq.). The aqueous layer was extracted with CH2Cl2 (15 mL×2). The combined organic phase was washed with water (15 mL) and brine (20 mL) successively, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate, 5:1, v/v) to give the corresponding product (120 mg, 95.1% yield). 1H NMR (400 MHz, CDCl3): δ 8.67 (s, 1H), 7.99 (s, 1H), 7.91 (d, 1H), 7.73 (d, 1H), 7.50 (m, 1H), 3.37 (m, 1H), 1.70 (m, 2H), 0.93 (m, 2H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([O:6]C)=[O:5].[C:8](Cl)(=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10].Cl>[OH-].[Na+]>[CH3:10][C:9]([CH3:12])([CH3:11])[C:8]([NH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5])=[O:13]
Reactant: COC(=O)CCN
Reactant: CC(C)(C)C(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)C(=O)NCCC(=O)O
Reaction time: 4 h

Procedure:
558 mg (4.03 mmol) of methy 3-aminopropionate was dissolved in 20 ml of 1 N aqueous sodium hydroxide solution. 362 mg (3.00 mmol) of pivaloyl chloride was immediately added to the obtained solution, and they were stirred for 4 hours. 15 ml of 2 N aqueous hydrochloric acid was added to the reaction mixture. After extracting with ethyl acetate 3 times followed by drying under anhydrous sodium sulfate, the solvent was evaporated under reduced pressure to obtain the title compound.
Reaction SMILES: [OH:1][CH2:2][N:3]([N+:5]([O-:7])=[O:6])[CH3:4].FC(F)(F)C(O[CH2:13][N:14]([N+:16]([O-:18])=[O:17])[CH3:15])=O>C(#N)C>[N+:5]([N:3]([CH3:4])[CH2:2][O:1][CH2:13][N:14]([N+:16]([O-:18])=[O:17])[CH3:15])([O-:7])=[O:6]
Reactant: CN(CO)[N+](=O)[O-]
Reactant: CN(COC(=O)C(F)(F)F)[N+](=O)[O-]
Solvent: CC#N
Product: CN(COCN(C)[N+](=O)[O-])[N+](=O)[O-]
Reaction time: 2 h

Procedure:
1-Hydroxy-2-nitro-2-azapropane (0.52 g, 4.9 mmol) and acetonitrile (0.5 ml) were stirred under nitrogen at -20° C. as 2-nitro-2-azapropyl trifluoroacetate (1.09 g, 5.4 mmol) was added in one portion. The reaction flask was immediately connected to a vacuum pump and brought to 1-2 mm during several minutes. The reaction temperature was allowed to warm to ambient during 21/2 hours, a precipitate forming at about 10° C. After stirring an additional 11/2 hours, the vacuum was removed and cold ether (5 ml) was stirred with the solid mass 5 minutes before filtering bis(2-nitro-2-azapropyl) ether; yield: 0.83 g (87%); m.p. 30°-38.5° C. Recrystallization from ether gave bis(2-nitro-2-azapropyl) ether; yield: 0.55 g (58%); m.p. 38°-41° C. The analytical sample melted at 40.6°-42° C.