Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].N1CC(C2C=CC3C4C(CCOC=3C=2)=CN(C2N(C3C=CC(F)=CC=3F)N=CN=2)N=4)C1.C(OC([N:40]1[CH2:43][CH:42]([C:44]2[CH:65]=[CH:64][C:47]3[C:48]4[N:52]([CH2:53][CH2:54][O:55][C:46]=3[CH:45]=2)[CH:51]=[C:50]([C:56]2[N:57]([CH:61]([CH3:63])[CH3:62])[N:58]=[CH:59][N:60]=2)[N:49]=4)[CH2:41]1)=O)(C)(C)C>>[ClH:1].[NH:40]1[CH2:41][CH:42]([C:44]2[CH:65]=[CH:64][C:47]3[C:48]4[N:52]([CH2:53][CH2:54][O:55][C:46]=3[CH:45]=2)[CH:51]=[C:50]([C:56]2[N:57]([CH:61]([CH3:62])[CH3:63])[N:58]=[CH:59][N:60]=2)[N:49]=4)[CH2:43]1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CN(C(=O)OC(C)(C)C)C3)cc1OCC2
Agent: Cl
Agent: Fc1ccc(-n2ncnc2-n2cc3c(n2)-c2ccc(C4CNC4)cc2OCC3)c(F)c1
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CNC3)cc1OCC2

Procedure:
8-Azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene hydrochloride was prepared similarly to 8-azetidin-3-yl-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene hydrochloride from 3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-azetidine-1-carboxylic acid tert-butyl ester. LCMS: RT=2.44 min, M+H+ =351
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([NH2:11])[C:7]=1[C:8]([OH:10])=[O:9].[F:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:14]=1[C:15](Cl)=O.C(NC1C=CC2N=C(C3C(F)=CC=CC=3F)OC(=O)C=2C=1)(=O)C>C(N(CC)CC)C.C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]2[C:8](=[O:10])[O:9][C:15]([C:14]3[C:13]([F:12])=[CH:21][CH:20]=[CH:19][C:18]=3[F:22])=[N:11][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc(Cl)c1C(=O)O
Reactant: O=C(Cl)c1c(F)cccc1F
Agent: CC(=O)Nc1ccc2nc(-c3c(F)cccc3F)oc(=O)c2c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=c1oc(-c2c(F)cccc2F)nc2cccc(Cl)c12

Procedure:
6-Chloroanthranilic acid (0.566 g), 2,6-difluorobenzoyl chloride (0.93 mL) and triethyl amine/toluene (1/1) (18 mL) were reacted as described under (10). Reaction time 2 days. Extraction between ethyl acetate (100 mL) and HCl (2N, 100 mL), followed by separation of the organic layer, drylng over MgSO4, filtering and evaporation gave a crude product which was dissolved in warm THF (20 mL) and precipitated with hexane. The resulting mixture was further purified on a silicagel column using dichloromethane as eluent. The isolated fraction was dissolved in warm THF (20 mL) and precipitated with hexane, ylelding 5-chloro-2-(2,6-difluoro-phenyl)-benzo[d][1,3]oxazin-4-one (0.65 g) mp. 176 C, MS m/e: 293/295 M+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[CH2:17]([NH2:22])[CH2:18][CH:19]([CH3:21])[CH3:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:16]=[CH:15][C:12]([CH2:13][NH:22][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])=[CH:11][CH:10]=2)=[N:6][CH:7]=1
Reactant: O=Cc1ccc(Oc2ccc(Br)cn2)cc1
Reactant: CC(C)CCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)CCNCc1ccc(Oc2ccc(Br)cn2)cc1

Procedure:
As shown in scheme 7, 4-Hydroxybenzaldehyde is treated with potassium carbonate and 2,5-dibromopyridine in DMAC to afford 4-(5-bromo-pyridin-2-yloxy)-benzaldehyde (35). The aldehyde 35 is combined with isoamylamine, sodium triacetoxyborohydride, acectic acid, and dichloromethane to yield the reductive amination product [4-(5-bromo-pyridin-2-yloxy)-benzyl]-(3-methyl-butyl)-amine (36). The resulting aryl bromide 36 is treated with acetamide, copper iodide, and 1,2 diaminocyclohexane in dioxane to yield the target compound 37.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+].Br[CH:15]([CH3:17])[CH3:16]>CO>[CH:15]([N:5]1[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]1)([CH3:17])[CH3:16]
Reactant: CC(C)Br
Reactant: OC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)N1CCC(O)CC1
Temperature: 25 °C
Yield: 79.7 %

Procedure:
4-Hydroxypiperidine (2.13 g, 21.1 mmol), K2CO3 (5.83 g, 2 eq.), 2-bromopropane (11.2 g, 91 mmol, 4.3 eq.) and MeOH (21.3 ml) were refluxed together overnight. The reaction was allowed to cool to room temperature and quenched with 2M HCl solution (40 ml) and extracted with TBME (40 ml). The aqueous phase was basified to pH 14 with 2M NaOH solution and extracted with DCM (9×50 ml). The combined organic extracts were dried over MgSO4, filtered, washed with DCM and concentrated in vacuo to give 1-isopropyl-4-hydroxypiperidine (2.41 g, 80%) as a pale yellow oil.
Reaction SMILES: O=C1C2C3C(C(OC)=O)=CC=CC=3NC=2CNC1.[C:19](Cl)(=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21].C1(C([N:31]2[CH2:43][C:42]3[NH:41][C:40]4[CH:39]=[CH:38][CH:37]=[C:36]5[C:44](=[O:47])[NH:45][N:46]=[C:33]([C:34]=3[C:35]=45)[CH2:32]2)=O)CC1>>[C:19]([N:31]1[CH2:43][C:42]2[NH:41][C:40]3[CH:39]=[CH:38][CH:37]=[C:36]4[C:44](=[O:47])[NH:45][N:46]=[C:33]([C:34]=2[C:35]=34)[CH2:32]1)(=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21]
Reactant: O=C1NN=C2CN(C(=O)C3CC3)Cc3[nH]c4cccc1c4c32
Reactant: CC(C)(C)C(=O)Cl
Agent: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CNC3
Product: CC(C)(C)C(=O)N1CC2=NNC(=O)c3cccc4[nH]c(c2c34)C1

Procedure:
Compound 51 was prepared from methyl 4-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-5-carboxylate and pivaloyl chloride according to the procedures similar to those for Compound 47. 1H NMR (DMSO-d6) δ 9.63 (s, 1H), 7.27-7.47 (m, 2H), 6.96 (s, 1H), 4.89 (s, 2H), 4.33 (s, 2H), and 1.24 (s, 9H). MS (ESI) m/e [M+1]+ 311.
Reaction SMILES: [F:1][C:2]1([F:11])[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=O)[CH2:4][CH2:3]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C(=O)(O)[O-].[Na+].[NH:31]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N:33]=[C:32]1[C:40]1[C:48]2[C:43](=[CH:44][CH:45]=[C:46]([NH2:49])[CH:47]=2)[N:42]([CH:50]2[CH2:55][CH2:54][CH2:53][CH2:52][O:51]2)[N:41]=1>CN(C=O)C>[NH:33]1[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[N:31]=[C:32]1[C:40]1[C:48]2[C:43](=[CH:44][CH:45]=[C:46]([NH:49][C:8]([CH:5]3[CH2:4][CH2:3][C:2]([F:1])([F:11])[CH2:7][CH2:6]3)=[O:10])[CH:47]=2)[N:42]([CH:50]2[CH2:55][CH2:54][CH2:53][CH2:52][O:51]2)[N:41]=1
Reactant: O=C(O)C1CCC(F)(F)CC1
Reactant: Nc1ccc2c(c1)c(-c1nc3ccccc3[nH]1)nn2C1CCCCO1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(Nc1ccc2c(c1)c(-c1nc3ccccc3[nH]1)nn2C1CCCCO1)C1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 46.3 %

Procedure:
4,4-Difluorocyclohexanecarboxylic acid (8 mg, 0.048 mmol), HOBt (9 mg, 0.066 mmol), EDC (13 mg, 0.068 mmol) and sodium bicarbonate (4 mg, 0.047 mmol) was added to a solution of 3-(1H-benzo[d]imidazol-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (15 mg, 0.045 mmol) in DMF (5 mL). The reaction mixture was stirred at room temperature for 24 h, and then the solvent was removed in vacuo. Purification by flash chromatography (6% CH3OH/CH2Cl2) afforded the title compound (10 mg). 1H NMR (400 MHz, CD3OD): δ 8.51 (s, 1H), 7.74 (m, 2H), 7.66 (m, 2H), 7.28 (m, 2H), 5.92 (d, 1H, J=8.8 Hz), 4.01 (m, 1H), 3.84 (m, 1H), 2.66 (m, 1H), 2.54-2.44 (m, 2H), 2.17 (m, 3H), 2.01-1.70 (m, 9H).
Reaction SMILES: CC(C)([O-])C.[K+].C(O)(C)(C)C.[CH2:12]([O:14][C:15](=[O:21])[CH2:16][C:17](=[O:20])[CH2:18][CH3:19])[CH3:13].Br[CH2:23][C:24]1[CH:36]=[CH:35][C:27]([C:28]([NH:30][CH:31]2[CH2:34][CH2:33][CH2:32]2)=[O:29])=[CH:26][C:25]=1[Cl:37]>O1CCCC1.O>[CH2:12]([O:14][C:15](=[O:21])[CH:16]([CH2:23][C:24]1[CH:36]=[CH:35][C:27]([C:28](=[O:29])[NH:30][CH:31]2[CH2:34][CH2:33][CH2:32]2)=[CH:26][C:25]=1[Cl:37])[C:17](=[O:20])[CH2:18][CH3:19])[CH3:13]
Reactant: CCOC(=O)CC(=O)CC
Reactant: O=C(NC1CCC1)c1ccc(CBr)c(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc(C(=O)NC2CCC2)cc1Cl)C(=O)CC
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A suspension of potassium tert-butoxide (0.34 g) in anhydrous tetrahydrofuran (15 mL) at 0° C. was treated with a mixture of tert-butanol (1.0 mL) and 3-oxopentanoic acid ethyl ester (038 mL). The mixture was stirred at 0° C. for 45 minutes and then a solution of 4-bromomethyl-3-chloro-N-cyclobutylbenzamide (0.67 g) in tetrahydrofuran (5.0 mL) was added and the resulting mixture heated at 70° C. for 24 hours. The mixture was cooled to room temperature, diluted with water and the tetrahydrofuran removed under reduced pressure. The residue was extracted with ethyl acetate and the combined extracts washed With saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane (1:5 by volume) to afford title compound, 0.44 g.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10](Cl)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH:14]([NH:17][CH2:18][CH2:19][CH2:20][NH2:21])([CH3:16])[CH3:15]>>[CH3:15][CH:14]([NH:17][CH2:18][CH2:19][CH2:20][NH:21][S:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)(=[O:12])=[O:11])[CH3:16]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: CC(C)NCCCN
Product: CC(C)NCCCNS(=O)(=O)c1cccc([N+](=O)[O-])c1

Procedure:
Following the procedure of Example 1, m-nitrobenzenesulfonyl chloride was reacted with N-isopropyl propane-1,3-diamine to provide the free base, m.r. 57°-59° C., converted to the hydrochloride salt, m.r. 184°-188° C.
Reaction SMILES: [CH3:1][C:2]1([C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([N:25]5[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]5)[CH:20]=4)[N:17]=3)[NH:12][CH:11]=2)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>N1C=CC=CC=1>[CH3:31][S:32]([N:28]1[CH2:29][CH2:30][N:25]([C:21]2[CH:20]=[C:19]([C:16]3[N:17]=[C:18]4[C:10]([C:8]([C:2]5([CH3:1])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]5)=[O:9])=[CH:11][NH:12][C:13]4=[N:14][CH:15]=3)[CH:24]=[CH:23][CH:22]=2)[CH2:26][CH2:27]1)(=[O:34])=[O:33]
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C(=O)c2c[nH]c3ncc(-c4cccc(N5CCNCC5)c4)nc23)CCCCC1
Solvent: c1ccncc1
Product: CC1(C(=O)c2c[nH]c3ncc(-c4cccc(N5CCN(S(C)(=O)=O)CC5)c4)nc23)CCCCC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 22.7 %

Procedure:
A solution of (1-methyl-cyclohexyl)-[2-(3-piperazin-1-yl-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-methanone (135 mg, 0.33 mmol) in pyridine (3 ml), at 0° C., was treated with methane sulfonyl chloride (0.03 ml, 0.367 mmol). The reaction mixture was allowed to stir at 0° C. for 1.5 hours, and then room temperature for 16 hours. The reaction mixture was poured onto ice cold 1N HCl and extracted with DCM. The organic layers were collected, dried over MgSO4, filtered and concentrated giving a yellow film. The crude product was purified by preparative thin layer chromatography using 3% [5% NH4OH:MeOH]/DCM as eluant providing 36 mg (22%) of {2-[3-(4-methanesulfonyl-piperazin-1-yl)-phenyl]-5H-pyrrolo[2,3-b]pyrazin-7-yl}-(1-methyl-cyclohexyl)-methanone as an off white solid. MP 230-231° C., M+H=482.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:25]1([N:30]2[CH2:40][C:39]([CH3:42])([CH3:41])[C:38](=[O:43])[N:37]([CH3:44])[C:36]3[C:31]2=[N:32][C:33]([NH:45][C:46]2[CH:54]=[CH:53][C:49]([C:50]([OH:52])=O)=[CH:48][C:47]=2[O:55][CH3:56])=[N:34][CH:35]=3)[CH2:29][CH2:28][CH2:27][CH2:26]1.CCN(C(C)C)C(C)C.Cl.Cl.[NH2:68][CH:69]1[CH2:74][CH2:73][CH2:72][N:71]([CH3:75])[CH2:70]1>CC(N(C)C)=O>[CH:25]1([N:30]2[CH2:40][C:39]([CH3:41])([CH3:42])[C:38](=[O:43])[N:37]([CH3:44])[C:36]3[C:31]2=[N:32][C:33]([NH:45][C:46]2[CH:54]=[CH:53][C:49]([C:50]([NH:68][CH:69]4[CH2:74][CH2:73][CH2:72][N:71]([CH3:75])[CH2:70]4)=[O:52])=[CH:48][C:47]=2[O:55][CH3:56])=[N:34][CH:35]=3)[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: CN1CCCC(N)C1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(C)(C)C(=O)N2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)NC2CCCN(C)C2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(C)(C)C(=O)N2C
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.4 %

Procedure:
A solution of HATU (126 mg, 0.33 mmol) in DMA (5 mL) was added to a mixture of the 4-[(2-cyclopentyl-4,4,6-trimethyl-5-oxo-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-10-yl)amino]-3-methoxy-benzoic acid (Example 242 132 mg, 0.3 mmol), DIPEA (261 uL, 1.5 mmol) and 3-amino N-methylpiperidine dihydrochloride (71 mg, 0.375 mmol) in DMA (5 mL). The resulting mixture was stirred at room temperature for 2 hours, then partially purified by SCX. The compound was eluted from the SCX column using 7N ammonia in methanol, then concentrated in vacuo, and further purified by column chromatography, eluting with 0-10% ammonia (7N in methanol) in DCM. The pure material was recovered as an orange oil, which foamed and solidified under high vacuum. Trituration under ether gave the title compound as a pale yellow amorphous solid (65 mg, 41%)
Reaction SMILES: C([O:5][C:6](=[O:34])[C@@H:7]([NH:9][C@H:10]([C:26](=[O:33])[NH:27][C:28]1[NH:32][N:31]=[N:30][N:29]=1)[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=2[Cl:25])=[CH:14][CH:13]=1)[CH3:8])(C)(C)C.C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>C(Cl)Cl>[Cl:25][C:19]1[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:18]=1[C:15]1[CH:14]=[CH:13][C:12]([CH2:11][C@H:10]([NH:9][C@@H:7]([CH3:8])[C:6]([OH:34])=[O:5])[C:26](=[O:33])[NH:27][C:28]2[NH:32][N:31]=[N:30][N:29]=2)=[CH:17][CH:16]=1
Reactant: C[C@H](N[C@@H](Cc1ccc(-c2cc(Cl)ccc2Cl)cc1)C(=O)Nc1nnn[nH]1)C(=O)OC(C)(C)C
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](N[C@@H](Cc1ccc(-c2cc(Cl)ccc2Cl)cc1)C(=O)Nc1nnn[nH]1)C(=O)O
Reaction time: 8 h

Procedure:
To a solution of (S)-2-[(S)-2-(2′,5′-dichloro-biphenyl-4-yl)-1-(1H-tetrazol-5-ylcarbamoyl)-ethylamino]-propionicacid tert-butyl ester (103 mg, 0.204 mmol) in DCM (2 mL) were added TFA (1 mL) and triethylsilane (0.098 mL, 0.611 mmol). After stirred for 8 hours, the reaction mixture was concentrated under reduced pressure. The residue was purified by reverse phase HPLC (Sunfire C-18 column, eluent: 0.1% TFA in H2O/CH3CN) to give (S)-2-[(S)-2-(2′,5′-dichloro-biphenyl-4-yl)-1-(1H-tetrazol-5-ylcarbamoyl)-ethylamino]-propionic acid. 1H NMR (400 MHz, DMSO-d6+TFA-d) δ 1.49 (d, 3H, J=7.1 Hz), 3.29 (dd, 1H, J=7.6, 13.9 Hz), 3.42 (dd, 1H, J=7.1, 14.2 Hz), 4.13 (dd, 1H, J=7.1, 14.0 Hz), 4.62 (dd, 1H, J=7.3, 7.3 Hz), 7.37 (d, 1H, J=2.5 Hz), 7.37-7.43 (m, 2H), 7.40 (d, 2H, J=4.3 Hz), 7.48 (dd, 1H, J=2.5, 8.6 Hz), 7.59 (d, 1H, J=8.6 Hz), 14.89 (bs, 1H); HPLC Retention time 1.25 minutes (condition A); MS: m/z (MH+) 449.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[O:28]1[CH:33]=[CH:32][CH2:31][CH2:30][CH2:29]1>C(OCC)C>[O:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH:29]1[O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Product: O=C(O)c1ccc(OC2CCCCO2)cc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To an ice-cooled mixture of 4-hydroxybenzoic acid (13.81 g) in 250 ml of diethylether containing 1.98 g of pyridinium p-toluenesulphonic acid, 3,4-dihydro-2H-pyran (16 g) was drop wise added. After complete addition stirring was continued at temperature below +8° C. for 4 h and the white precipitate was filtered off, washed twice with 100 ml of +4° C. pre-cooled diethylether and dried to give nearly pure 4-(tetrahydro-2H-pyran-2-yloxy)benzoic acid as white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH2:10][O:11][CH3:12])[C:4]=1[O:13][CH3:14].C([Li])CCC.C(O[B:24]1[O:28][C:27]([CH3:30])([CH3:29])[C:26]([CH3:32])([CH3:31])[O:25]1)(C)C>C(OCC)C>[CH3:14][O:13][C:4]1[C:5]([O:9][CH2:10][O:11][CH3:12])=[C:6]([B:24]2[O:28][C:27]([CH3:30])([CH3:29])[C:26]([CH3:32])([CH3:31])[O:25]2)[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: COCOc1cccc(OC)c1OC
Agent: [Li]CCCC
Solvent: CCOCC
Product: COCOc1c(B2OC(C)(C)C(C)(C)O2)ccc(OC)c1OC
Temperature: -78 °C
Reaction time: 2 h

Procedure:
The MOM-protected phenol 1 (10 g; 0.0505 mol) was dissolved 1000 ml of dry diethyl ether and cooled to −78° C. A solution of n-butyl lithium (22.2 ml of 2.5 M) was then added via syringe. The cooling bath was removed and the solution was allowed to warm to room temperature. After stirring the solution at room temperature for two hours, a yellow precipitate was observed. The mixture was cooled to −78° C., and 15 ml of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.080 mol) was added via syringe. The cooling bath was removed after two hours. Stirring was continued for four hours at room temperature. The mixture was then poured into 300 ml of water and extracted several times with diethyl ether (3×300 ml), dried (Na2SO4), and concentrated to a yellow oil (12.37 g, 76%) that was used without further purification: 1H NMR: (300 MHz, CDCl3): 7.46 (d, 1H, J=8.4 Hz); 6.69 (d, 1H, J=8.4 Hz); 5.15 (s, 2H); 3.87 (s, 3H); 3.83 (s, 3H); 1.327 (s, 12H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][CH:7]([CH2:13][CH2:14][CH3:15])[C:8]2=[O:12])=[CH:4][C:3]=1[O:16][CH3:17].[H-].[Na+].Cl[CH2:21][CH:22]=[C:23]([Cl:25])[CH3:24]>C1(C)C=CC=CC=1.CN(C)C=O>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH2:21][CH:22]=[C:23]([Cl:25])[CH3:24])([CH2:13][CH2:14][CH3:15])[C:8]2=[O:12])=[CH:4][C:3]=1[O:16][CH3:17]
Reactant: CCCC1Cc2cc(OC)c(Cl)c(Cl)c2C1=O
Reactant: CC(Cl)=CCCl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCCC1(CC=C(C)Cl)Cc2cc(OC)c(Cl)c(Cl)c2C1=O
Temperature: 30 °C
Reaction time: 0.5 h
Yield: 80.2 %

Procedure:
6,7-Dichloro-2,3-dihydro-5-methoxy-2-propyl-1H-inden-1-one (13.66 g, 0.05 mole) dissolved in toluene (80 ml) was added over 15 minutes with stirring under N2 to a suspension of 56% sodium hydride (2.36 g, 0.055M) in dimethylformamide (65 ml) and toluene (15 ml) at 25°. The mixture was stirred without external heat for 11/2 hours, at 50° C. for 1/2 hour and then cooled to 30° C. A solution of 1,3-dichloro-2-butene (7.81 g, 0.0625 mole) in toluene (10 ml) was added, and the mixture was heated at 50°-55° for 2 hours, poured into ice water, and extracted with diethyl ether. The organic extracts were washed with water, dried over MgSO4, concentrated under vacuum and chromatographed on silica with elution with 1/1 hexane/methylene chloride to obtain 14.5 g of product as an oil which was a mixture of cis-trans isomers.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([CH:13]1[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH2:16][CH2:15][CH2:14]1)(=[O:12])=[O:11].[Br:24]N1C(=O)CCC1=O>ClC1C=CC=CC=1.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:24][CH:16]1[CH2:15][CH2:14][CH:13]([S:10](=[O:11])(=[O:12])[NH:9][C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17]1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C1=CCCCC1S(=O)(=O)Nc1ccc(F)cc1F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: Clc1ccccc1
Product: CCOC(=O)C1=CC(Br)CCC1S(=O)(=O)Nc1ccc(F)cc1F
Temperature: 90 °C
Reaction time: 7 h
Yield: 22 %

Procedure:
To a solution -of ethyl 6-(N-(2,4-difluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate (100 mg) obtained in Example 3 in chlorobenzene (2 ml), N-bromosuccinimide (56.7 mg) and 2,2′-azobisisobutyronitrile (0.5 mg) were added and the mixture was stirred at 90° C. for 7 hours. The reaction mixture was combined with an ice-water (20 ml), extracted with ethyl acetate (20 ml), washed with saturated brine (20 ml) and dried over anhydrous sodium sulfate. The solvent was distilled off and the resultant residue was purified by flash column chromatography on silica gel (eluent: ethyl acetate/hexane=1/20→ethyl acetate/hexane=1/10) and crystallized from hexane to yield ethyl 3-bromo-6-[N-(2,4-difluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate (Compound 85, 27 mg) as colorless powdery crystals.
Reaction SMILES: [H-].[Na+].FC(F)(F)[C:5]([N:7]([CH2:9][CH2:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1)C)=O.O.Cl>CO.C1COCC1>[CH3:5][NH:7][CH2:9][CH2:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1
Reactant: COC(=O)c1ccc(CCN(C)C(=O)C(F)(F)F)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CNCCc1ccc(C(=O)OC)cc1
Temperature: 22 °C
Reaction time: 36 h

Procedure:
A solution of 0.80 g (5.5 mmol) of sodium hydride (60% mineral oil dispersion) dissolved in 20 mL of methanol was prepared and added to a separate solution of 1.05 g (3.64 mmol) of methyl 4-(2-(2,2,2-trifluoro-N-methylacetamido)ethyl)benzoate dissolved in 12 mL of THF at 0° C. The solution was warmed to 22° C. and stirred for about 36 h. Water was added (100 mL) and the solution was acidified to pH 1 with 1 N HCl. The mixture was washed with DCM (2×100 mL) and then basified with 1 N NaOH to pH 8-9. The aqueous solution was extracted with DCM (3×100 mL) and the organic extracts dried (Na2SO4) and evaporated to give 2b as a white solid which was used without further purification in the subsequent transformation.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:14]([O:16]C(C)C)=[O:15])[CH:7]=[N:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12].C(Cl)Cl>CO>[Cl:3][C:4]1[CH:5]=[C:6]([C:14]([OH:16])=[O:15])[CH:7]=[N:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12]
Reactant: CC(C)OC(=O)c1cnc(OC(C)C)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CC(C)Oc1ncc(C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium hydroxide (29.1 ml, 58.2 mmol) was added to a solution of 1-methylethyl 5-chloro-6-[(1-methylethyl)oxy]-3-pyridinecarboxylate (D30) (3 g, 11.64 mmol) in methanol (25 ml) and stirred at room temperature overnight. The solvent was evaporated before neutralising with 2M HCl and extracting with ether. It was then dried over magnesium sulfate and evaporated to give an impure white solid. Trituration with DCM gave the title compound as a pure white solid. MS (ES) C9H10ClNO3 requires 215, found 216 [M+H]+
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([CH3:13])[CH3:12])[C:5]=1[NH2:6])([CH3:3])[CH3:2].[Br:14][CH2:15][C:16](Br)=[O:17]>>[CH:11]([C:7]1[CH:8]=[CH:9][CH:10]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]=1[NH:6][C:16](=[O:17])[CH2:15][Br:14])([CH3:13])[CH3:12]
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: O=C(Br)CBr
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CBr

Procedure:
2,6-diisopropylaniline and bromoacetyl bromide were used to produce the above compound in the same way as Reference Example 8.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[N:11]3[N:12]=[C:13]([CH3:21])[CH:14]=[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:10]3=[N:9][C:8]=2[CH3:22])=[C:4]([Cl:23])[CH:3]=1.[Br-].[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[Zn+]>CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:23][C:4]1[CH:3]=[C:2]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=2)[S:6][C:5]=1[C:7]1[N:11]2[N:12]=[C:13]([CH3:21])[CH:14]=[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:10]2=[N:9][C:8]=1[CH3:22]
Reactant: [Zn+]c1ccccn1
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(Br)cc3Cl)c(C)nc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Br-]
Solvent: CCOC(C)=O
Product: CCC(CC)c1cc(C)nn2c(-c3sc(-c4ccccn4)cc3Cl)c(C)nc12
Temperature: 65 °C
Yield: 59 %

Procedure:
To a flask containing 3-(5-bromo-3-chloro-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.25 g, 0.61 mmol) and PdCl2(dppf) (0.022 g, 0.030 mmol) is added a 0.5 M solution of 2-pyridylzinc bromide (2.40 mL, 1.21 mmol) and the solution heated at 65° C. overnight, diluted with EtOAc (30 mL), washed with sat. NH4Cl (2×30 mL), dried over MgSO4, filtered and concentrated. The residue is purified by ISCO column chromatography (20%-40% EtOAc/hexane gradient) followed by recrystallization from CH3CN furnish the title compound (0.15 g, 0.36 mmol, 60%). 1H NMR (CDCl3) δ 0.88 (d, J=7.5 Hz, 6H), 1.73-1.93 (m, 4H), 2.52 (s, 3H), 2.53 (s, 3H), 3.29-3.38 (m, 1H), 6.70 (s, 1H), 7.17-7.23 (m, 1H), 7.56 (s, 1H), 7.66 (d, J=7.9 Hz, 1H), 7.70-7.76 (m, 1H), 8.59 (d, J=4.7 Hz, 1H). LC/MS (m/z): calcd. for C22H23ClN4S (M+H)+: 412.0; found: 412.4.