Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:23]1[C:32]2[C:27](=[CH:28][C:29]([C:33]([F:36])([F:35])[F:34])=[CH:30][CH:31]=2)[N:26]=[CH:25][C:24]=1[C:37]([O:39][CH2:40][CH3:41])=[O:38].Cl>CN(C=O)C.O>[CH2:40]([O:39][C:37]([C:24]1[CH:25]=[N:26][C:27]2[C:32]([C:23]=1[N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[S:9]([C:12]1[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)(=[O:11])=[O:10])=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)=[O:38])[CH3:41]
Reactant: COc1ccc(S(=O)(=O)NCc2ccccc2)cc1
Reactant: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85.6 %

Procedure:
To a solution of 1.85 g (6.67 mmol) of N-benzyl 4-methoxyphenyl-sulphonamide in 15 mL of DMF was added, in one portion, 0.267 g (6.67 mmol) of 60% sodium hydride and the resulting mixture was stirred at room temperature under nitrogen for 15 min. Ethyl 4-chloro-7-trifluoromethyl-3-quinolinecarboxylate (2.02 g, 6.67 mmol) was then added to the solution in one portion and the resulting mixture was heated at 85° C. for 24 h. The reaction mixture was then cooled to room temperature, poured into a mixture of water (300 mL) and HCl (1N, aqueous, 100 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was then chromatographed on silica gel eluting with 15%-50% ethyl acetate/hexane to give 3.11 g (88%) of the desired product. Electrospray Mass Spec 545.1 (M+H)+.
Reaction SMILES: O[C:2]([CH:5]([CH2:10][CH2:11][CH2:12]/[CH:13]=[C:14](\[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)/[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[C:6]([O:8][CH3:9])=[O:7])([CH3:4])[CH3:3].N1C=CC=CC=1.C(=O)([O-])O.[Na+]>ClCCl>[CH3:4][C:2]([CH:5]([CH2:10][CH2:11][CH2:12]/[CH:13]=[C:14](\[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)/[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[C:6]([O:8][CH3:9])=[O:7])=[CH2:3]
Reactant: COC(=O)C(CCC/C=C(\c1ccccc1)c1cccnc1)C(C)(C)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=C(C)C(CCC/C=C(\c1ccccc1)c1cccnc1)C(=O)OC
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 83.7 %

Procedure:
Methyl (E)-2-(1-hydroxy-1-methylethyl)-7-phenyl-7-(3-pyridyl)-6-heptenoate (0.3 g, 0.89 mmole) was dissolved in dichloromethane (10 ml), and the solution was cooled at -10° C. Thionyl chloirde (0.15 ml) was added to the solution, followed by adding pyridine (0.4 ml) and stirring for 10 minutes under the same reaction conditions. After the completion of the reaction, aqueous sodium hydrogencarbonate (5 ml) was added, and the product was extracted with ethyl acetate. The organic layer was worked up in the usual procedure, and the crude product was chromatographed on silica gel, followed by elution with isopropyl ether:ethyl acetate (1:1) to yield methyl (E)-2-(1-methylethenyl)-7-phenyl-7-(3-pyridyl)-6-heptenoate (5-e) (0.25 g, 70%).
Reaction SMILES: Cl[CH2:2][O:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1.[F:12][C:13]1[CH:14]=[N:15][C:16](=[O:19])[NH:17][CH:18]=1>>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][O:3][CH2:2][N:17]2[CH:18]=[C:13]([F:12])[CH:14]=[N:15][C:16]2=[O:19])=[CH:6][CH:7]=1
Reactant: O=c1ncc(F)c[nH]1
Reactant: ClCOCc1ccc(Cl)cc1
Product: O=c1ncc(F)cn1COCc1ccc(Cl)cc1
Reaction time: 6 h
Yield: 70 %

Procedure:
was prepared as described in Example 3 from 4-chlorobenzyl chloromethyl ether (see Preparation 5a and 5b) (4 mmol) and 5-fluoropyrimidin-2-one (4 mmol) by allowing the reaction to proceed for 6 hours at room temperature; yield 70% (0.75 g), m.p. 103° C. 1H NMR (CDCl3): δ4.62 (CH2Ph), 5.30 (CH2N), 7.17 (Ph), 7.63 and 8.53 (H-4, H-6). IR(KBr): 1670 cm-1 (CO).
Reaction SMILES: C([O:4][CH2:5][CH:6]([N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[CH2:7][O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1)(=O)C.[OH-].[K+]>CO.O>[N:19]1([CH:6]([CH2:7][O:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][CH:10]=2)[CH2:5][OH:4])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CC(=O)OCC(COc1cccc2ccccc12)N1CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: OCC(COc1cccc2ccccc12)N1CCCCC1

Procedure:
A suspension of 2-piperidino-3-(1-naphthyloxy)-1-propanol acetate (6.4 g), 15% KOH in methanol (10 ml), methanol (10 ml) and water (20 ml) is heated at reflux for one hour. The reaction mixture is concentrated to dryness. The residue is taken up in diethyl ether. The ether extract is washed with water and concentrated to give the title compound as an oil, γmaxEtOH 319 nm (ε=1780), 350 nm (ε=3330), 288 nm (ε=6340), 230 nm (ε=30,600), 212 nm (ε=44,180).
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:18][CH2:17][CH:16]([CH:19]=O)[CH2:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1>>[N:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[NH:21][CH2:19][CH:16]1[CH2:17][CH2:18][N:13]([C:10]2[CH:11]=[CH:12][C:7]([CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:8][CH:9]=2)[CH2:14][CH2:15]1
Reactant: O=CC1CCN(c2ccc(CN3CCCC3)cc2)CC1
Reactant: Nc1ccccn1
Product: c1ccc(NCC2CCN(c3ccc(CN4CCCC4)cc3)CC2)nc1

Procedure:
Prepared from the product of Example 16 and 2-aminopyridine.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][N:9]=2)[S:4][C:3]=1[C:11]([NH:13][C:14]1[CH:19]=[C:18]([NH:20][C:21](=[O:33])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([C:31]#[N:32])([CH3:30])[CH3:29])[CH:23]=2)[CH:17]=[CH:16][C:15]=1[CH3:34])=[O:12].[CH2:35]([Sn](CCCC)(CCCC)C=C)[CH2:36]CC>C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:31]([C:28]([C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[C:21]([NH:20][C:18]1[CH:17]=[CH:16][C:15]([CH3:34])=[C:14]([NH:13][C:11]([C:3]2[S:4][C:5]3=[N:6][CH:7]=[CH:8][N:9]=[C:10]3[C:2]=2[CH:35]=[CH2:36])=[O:12])[CH:19]=1)=[O:33])([CH3:30])[CH3:29])#[N:32]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1NC(=O)c1sc2nccnc2c1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: C=Cc1c(C(=O)Nc2cc(NC(=O)c3cccc(C(C)(C)C#N)c3)ccc2C)sc2nccnc12
Yield: 10.1 %

Procedure:
A solution of 7-bromo-N-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)thieno[2,3-b]pyrazine-6-carboxamide 42 (22 mg, 0.041 mmol), bis(triphenylphosphine)palladium(II) chloride (1.445 mg, 2.058 μmol) and tributyl(vinyl)tin (0.024 mL, 0.082 mmol) in toluene (1 mL) was stirred for 30 min at 110° C. in microwave. After filtration, diluted with toluene and washed with water, brine, dried and evaporated. Purification by HPLC gave the title compound N-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)-7-vinylthieno[2,3-b]pyrazine-6-carboxamide 43c (2 mg, 10.09%). NMR (400 MHz, DMSO-d6) 2.27 (s, 3H), 5.76 (dd, J=12.0 and 2.3 Hz, 1H), 8.85-8.91 (dd, J=17.6 and 1.9 Hz, 1H), 7.28-7.38 (m, 2H), 7.58-7.68 (m, 2H), 7.76 (d, J=7.8 Hz, 1H), 7.91 (d, J=1.9 Hz, 1H), 7.96 (d, J=7.8 Hz, 1H), 8.05 (t, J=1.9 Hz, 1H), 8.80 (d, J=2.3, 1H), 8.94 (d, J=2.3 Hz, 1H), 10.37 (s, 1H), 10.38 (s, 1H). (m/z)=482 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2([C:16]([O:18]CC)=[O:17])[CH2:15][CH2:14][CH2:13]2)=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.O.[OH-].[K+].[K].Cl>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2([C:16]([OH:18])=[O:17])[CH2:15][CH2:14][CH2:13]2)=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCOC(=O)C1(C(=O)Nc2cc(Cl)cc(Cl)c2)CCC1
Agent: Cl
Agent: [K+]
Agent: [K]
Solvent: O
Product: O=C(O)C1(C(=O)Nc2cc(Cl)cc(Cl)c2)CCC1

Procedure:
A 2.0 gram (0.006 mole) portion of ethyl 1-(3,5-dichlorophenylaminocarbonyl)cyclobutanecarboxylate prepared in Example X (Compound 130) was hydrolyzed in the presence of water (0.114 gram, 0.006 mole) and ethanolic potassium hydroxide (0.355 gram, 0.006 mole). The potassium salt of the acid was then acidified with 25% HCl solution and worked up in a manner similar to that described in Example VII to give 0.92 gram (0.003 mole) of 1-(3,5-dichlorophenylaminocarbonyl)cyclobutanecarboxylic acid as a beige-colored solid having a melting point of 159° C.-160° C.
Reaction SMILES: C([Li])CCC.O1CCCC1.[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CN(C)[C:28](=[O:39])[C:29]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:30]=1[O:37][CH3:38]>Cl>[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([C:28]([C:29]2[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:30]=2[O:37][CH3:38])=[O:39])=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Brc1ccc(OCc2ccccc2)cc1
Reactant: COc1ccc(OC)c(C(=O)N(C)C)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(OC)c(C(=O)c2ccc(OCc3ccccc3)cc2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Butyllithium (2.0M in hexanes, 6.6 ml, 13.2 mmol) was added dropwise under nitrogen, at −78° C. to a stirred tetrahydrofuran (20 ml) solution of 4-benzyloxy-bromobenzene (3.15 g, 11.97 mmol) to give a yellow coloured suspension, which was stirred for 10 minutes. A tetrahydrofuran (10 ml) solution of N,N-dimethyl 2,5-dimethoxybenzamide (2.09 g, 9.99 mmol) was then added slowly, and the resulting mixture warmed to room temperature over 20 h. The mixture was diluted with 50ml of 1M hydrochloric acid and the product extracted into dichloromethane (4×50 ml). The combined extracts were washed with brine, dried over sodium sulfate and evaporated to a yellow coloured solid. This crude product was purified by column chromatography on silica gel 60, using 4:1 petrol/ethyl acetate as the eluent. This gave the product as a colourless solid, which was recrystallised from hot ethanol (25 ml) to give the product as colourless platelets which were vacuum dried.
Reaction SMILES: [C:1]([CH:5]1[CH2:15][CH2:14][C:8]2([O:12][CH2:11][C:10](=[O:13])[CH2:9]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].[H][H]>CO>[C:1]([CH:5]1[CH2:15][CH2:14][C:8]2([O:12][CH2:11][CH:10]([OH:13])[CH2:9]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)C1CCC2(CC1)CC(=O)CO2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)C1CCC2(CC1)CC(O)CO2
Temperature: 25 °C
Yield: 98679.1 %

Procedure:
To an ice cooled solution of 8-t-butyl-1-oxaspiro(4,5)decane-3-one (44.1 g, 0.21 mmol) in methanol (300 ml) was added sodium borohydride (10.8 g, 0.285 mol) in portions. After the evolution of hydrogen ceased the cooling bath was removed and the mixture was stirred at room temperature over night. The solvent was evaporated in vacuo and the residue was taken up in toluene/diluted hydrochloric acid. The organic layer was washed twice with water (200 ml), dried (MgSO4) and evaporated in vacuo to yield a colourless oil (44 g) which was recrystallised from light petroleum. 30 g of colourless crystals were obtained which melted at 82°-84° C. TLC and NMR-analysis indicated a single diastereoisomer only (cis).
Reaction SMILES: [ClH:1].CO.[CH2:4]([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18]2[N:23]=[CH:22][C:21](/[CH:24]=[CH:25]/[C:26]([NH:28][O:29]C3CCCCO3)=[O:27])=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CO>[ClH:1].[ClH:1].[CH2:4]([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18]2[N:23]=[CH:22][C:21](/[CH:24]=[CH:25]/[C:26]([NH:28][OH:29])=[O:27])=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=C(/C=C/c1ccc(NC2CCN(Cc3ccccc3)CC2)nc1)NOC1CCCCO1
Agent: Cl
Solvent: CO
Product: O=C(/C=C/c1ccc(NC2CCN(Cc3ccccc3)CC2)nc1)NO
Temperature: 20 °C
Reaction time: 2 h

Procedure:
A solution of 10% HCl-MeOH solution (0.5 ml) was added to a mixture of (2E)-3-{6-[(1-benzyl-4-piperidyl)amino]-3-pyridyl}-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (180 mg) in MeOH (5 ml) and stirred at 15-25° C. for 2 hours. The reaction mixture was evaporated in vacuo and the residue was triturated with small amount MeOH and acetone and the precipitate was collected by filtration to give (2E)-3-{6-[(1-benzyl-4-piperidyl)amino]-3-pyridyl}-N-hydroxyacrylamide dihydrochloride (120 mg)
Reaction SMILES: [CH:1]1([C@@:7]([OH:47])([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:8]2[N:12]=[CH:11][N:10]([CH2:13][CH:14]3[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][N:30]5C(=O)C6C(=CC=CC=6)C5=O)=[CH:24][CH:23]=4)[CH2:16][CH2:15]3)[N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.NN>C(O)C>[NH2:30][CH2:29][CH2:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][CH2:20][N:17]2[CH2:16][CH2:15][CH:14]([CH2:13][N:10]3[CH:11]=[N:12][C:8]([C@@:7]([CH:41]4[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46]4)([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[OH:47])=[N:9]3)[CH2:19][CH2:18]2)=[CH:27][CH:26]=1
Reactant: O=C1c2ccccc2C(=O)N1CCc1ccc(CCN2CCC(Cn3cnc([C@](O)(c4ccccc4)C4CCCCC4)n3)CC2)cc1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCc1ccc(CCN2CCC(Cn3cnc([C@](O)(c4ccccc4)C4CCCCC4)n3)CC2)cc1
Temperature: 25 °C
Yield: 81 %

Procedure:
2-[2-(4-{2-[4-({3-[(R)-cyclohexyl(hydroxy)phenylmethyl]-1H-1,2,4-triazol-1-yl}methyl)piperdin-1-yl]ethyl}phenyl)ethyl]-1H-isoindole-1,3(2H)-dione (Preparation 12, 3.4 g, 5.38 mmol) was suspended in ethanol (20 ml) and hydrazine monohydrate (2.61 ml, 53.8 ml) added. After stirring at reflux for 2 hours, the reaction was cooled to room temperature and the precipitate collected by filtration and washed with ethanol (200 ml). The filtrate was concentrated in vacuo to furnish the title compound as a white solid, in 81% yield, 2.57 g.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C@H:12]([NH:14][C:15]([C@@H:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:34])[C@@H:24]([NH:26][C:27](=[O:33])[C@@H:28]([OH:32])[CH:29]([CH3:31])[CH3:30])[CH3:25])[NH:18]3)=[O:16])[CH3:13])=[N:9]2)=[CH:4][CH:3]=1.[CH:35]([C:37]1([C:44]([OH:46])=[O:45])[CH2:43][O:42][CH2:41][CH2:40][O:39][CH2:38]1)=[CH2:36].C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[OH:32][C@@H:28]([CH:29]([CH3:31])[CH3:30])[C:27]([NH:26][C@@H:24]([CH3:25])[C:23]([N:19]1[CH2:20][CH2:21][CH2:22][C@@H:17]([C:15]([NH:14][C@@H:12]([C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][C:2](/[CH:36]=[CH:35]/[C:37]4([C:44]([OH:46])=[O:45])[CH2:43][O:42][CH2:41][CH2:40][O:39][CH2:38]4)=[CH:3][CH:4]=3)[N:9]=2)[CH3:13])=[O:16])[NH:18]1)=[O:34])=[O:33]
Reactant: C=CC1(C(=O)O)COCCOC1
Reactant: CC(C)[C@H](O)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)N[C@H](C)c2ccc3ccc(Br)cc3n2)N1
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(C)[C@H](O)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)N[C@H](C)c2ccc3ccc(/C=C/C4(C(=O)O)COCCOC4)cc3n2)N1
Temperature: 50 °C

Procedure:
A mixture of (S)-1-[(S)-2-((S)-2-hydroxy-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid [(R)-1-(7-bromo-quinolin-2-yl)-ethyl]-amide (68 mg, 0.128 mmol), 6-vinyl-[1,4]dioxepane-6-carboxylic acid (22 mg, 0.128 mmol), triethylamine (39 mg, 54 μL, 0.384 mmol) and tri(o-tolyl)phosphine (8 mg, 0.026 mmol) in 1,4-dioxane (2 mL) was deoxygenated by bubbling nitrogen through for 5 minutes and then warmed to 50° C. under nitrogen with stirring. Tris(dibenzylideneacetone)dipalladium(0) (12 mg, 0.013 mmol) was added and the mixture was refluxed for 40 minutes and then allowed to cool. The suspension was filtered and the filtrate was evaporated to give crude title compound which was used directly in the next stage. LCMS (m/z) 626.2 [M+H], Tr=1.67 min.
Reaction SMILES: O.O[N:3]1[C:7]2C=CC=[CH:11][C:6]=2N=N1.Cl.CN(C)CCCN=C=NCC.[C:24]1([C:30]2([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH2:38][C:37]3[NH:36][N:35]=[C:34]([C:39](O)=[O:40])[C:33]=3[CH:32]=[CH:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.N1CCC1>ClCCl.C(N(CC)CC)C>[N:3]1([C:39]([C:34]2[C:33]3[CH:32]=[CH:31][C:30]([C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=4)([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:38][C:37]=3[NH:36][N:35]=2)=[O:40])[CH2:11][CH2:6][CH2:7]1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1n[nH]c2c1C=CC(c1ccccc1)(c1ccccc1)C2
Agent: C1CNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1n[nH]c2c1C=CC(c1ccccc1)(c1ccccc1)C2)N1CCC1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 65.9 %

Procedure:
0.256 g of 1-hydroxybenzotriazole hydrate and 0.364 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride are added to 0.5 g of 6,6-diphenyl-6,7-dihydro-1H-indazole-3-carboxylic acid in suspension in 100 cm3 of dichloromethane. After stirring for 30 minutes at a temperature in the region of 20° C., a solution of 0.114 g of azetidine and 0.303 g of triethylamine in 10 cm3 of dichloromethane is added to the reaction mixture. After stirring at a temperature in the region of 20° C. for about 20 hours, the reaction mixture is diluted with 300 cm3 of dichloromethane and then washed with 3 times 100 cm3 of water. The resulting organic phase is dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (13 kPa). The residue is purified by flash chromatography on a column of silica [eluent: dichloromethane/methanol (95/5 by volume)] to give 0.37 g of azetidin-1-yl(6,6-diphenyl-6,7-dihydro-1H-indazol-3-yl)methanone, in the form of a white powder, the characteristics of which are as follows:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH2:16][CH2:17]O)=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-:3])=[O:2].S(Cl)([Cl:21])=O>ClCCl>[Cl:21][CH2:17][CH2:16][CH2:15][NH:14][C:13]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[CH:5][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1NCCCO
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: O=[N+]([O-])c1cnc2ccccc2c1NCCCCl
Temperature: 25 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
A round bottom flask was charged with a magnetic stir bar, 3-[(3-nitroquinolin-4-yl)amino]propan-1-ol (20.75 g, 83.93 mmol), thionyl chloride (15.0 g, 125.89 mmol), and dichloromethane (420 mL). The bright yellow, homogeneous solution was stirred at ambient temperature for 2 hours at which time the starting material was completely consumed. The volatiles were removed under reduced pressure and the resulting solid stirred in water (400 mL) made basic (pH 10) with solid sodium carbonate. A bright yellow solid was collected by filtration to afford N-(3-chloropropyl)-3-nitroquinolin-4-amine (21.63 g, 81.41 mmol) which was used without further purification.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][N:11]=[CH:12][C:13]1[O:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=1.[N+](C1OC(C=O)=CC=1)([O-])=O.N(C1SC2C=C([F:42])C=CC=2N=1)N>>[F:42][C:7]1[CH:8]=[CH:9][C:4]2[N:3]=[C:2]([NH:10][N:11]=[CH:12][C:13]3[O:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=3)[S:1][C:5]=2[CH:6]=1
Reactant: NNc1nc2ccc(F)cc2s1
Reactant: O=[N+]([O-])c1ccc(C=NNc2nc3ccccc3s2)o1
Agent: O=Cc1ccc([N+](=O)[O-])o1
Product: O=[N+]([O-])c1ccc(C=NNc2nc3ccc(F)cc3s2)o1

Procedure:
The compound 3k was prepared according procedure described for 3a by employing 5-nitrofuran aldehyde (157 mg, 1 mmol) and 2-hydrazino-6-fluoro-benzothiazole (183 mg, 1 mmol) at 70° C. for 2 h (yield 230 mg, 75%).
Reaction SMILES: [N:1]([CH:4]1[CH2:10][C:9]([CH3:12])([CH3:11])[C:8]2[CH:13]=[CH:14][C:15]([N+:17]([O-:19])=[O:18])=[CH:16][C:7]=2[NH:6][C:5]1=[O:20])=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1COCC1.O>>[NH2:1][CH:4]1[CH2:10][C:9]([CH3:12])([CH3:11])[C:8]2[CH:13]=[CH:14][C:15]([N+:17]([O-:19])=[O:18])=[CH:16][C:7]=2[NH:6][C:5]1=[O:20]
Reactant: CC1(C)CC(N=[N+]=[N-])C(=O)Nc2cc([N+](=O)[O-])ccc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)CC(N)C(=O)Nc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3-Azido-5,5-dimethyl-8-nitro-1,3,4,5-tetrahydro-1-benzazepin-2-one (3.10 g, 10.3 mmol), Triphenylphosphine Resin (12 g, 11.55 mmol), THF (120 mL, 1400 mmol) and Water (0.9 mL, 50 mmol) were combined and stirred at rt for 16 h. The reaction mixture was filtered. Product isolated as a beige solid. (HPLC purity >98%)
Reaction SMILES: [CH:1]([Mg]Cl)([CH3:3])[CH3:2].[Cl:6][C:7]1[C:15]2[N:14]=[C:13]3[N:16]([C:20]4[C:21]([CH3:28])=[N:22][C:23](Cl)=[N:24][C:25]=4[CH3:26])[CH2:17][CH2:18][CH2:19][N:12]3[C:11]=2[C:10]([CH:29]([O:34][CH:35]([F:37])[F:36])[C:30]([F:33])([F:32])[F:31])=[CH:9][CH:8]=1.FC(F)(F)C(O)=O>O1CCCC1.[Cl-].[NH4+].Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:6][C:7]1[C:15]2[N:14]=[C:13]3[N:16]([C:20]4[C:25]([CH3:26])=[N:24][C:23]([CH:1]([CH3:3])[CH3:2])=[N:22][C:21]=4[CH3:28])[CH2:17][CH2:18][CH2:19][N:12]3[C:11]=2[C:10]([CH:29]([O:34][CH:35]([F:36])[F:37])[C:30]([F:33])([F:32])[F:31])=[CH:9][CH:8]=1
Reactant: Cc1nc(Cl)nc(C)c1N1CCCn2c1nc1c(Cl)ccc(C(OC(F)F)C(F)(F)F)c12
Reactant: CC(C)[Mg]Cl
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(C(C)C)nc(C)c1N1CCCn2c1nc1c(Cl)ccc(C(OC(F)F)C(F)(F)F)c12
Temperature: 25 °C
Reaction time: 14 h

Procedure:
i-Propylmagnesium chloride (1.0 M solution in tetrahydrofuran, 0.76 mL, 0.760 mmol) was added dropwise to a stirred suspension of 9-chloro-1-(2-chloro-4,6-dimethylpyrimidin-5-yl)-6-[1-(difluoromethoxy)-2,2,2-trifluoroethyl]-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole (189 mg, 0.381 mmol) and [1,3-bis(diphenylphosphino)propane]dichloronickel (20.7 mg, 0.0381 mmol) in tetrahydrofuran (1.5 mL) at 0° C., and the mixture was stirred at room temperature for 14 hr. The mixture was diluted with aqueous ammonium chloride and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 50-100% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was purified by preparative HPLC to give a mixture containing an intermediate of the title compound as the trifluoroacetic acid salt. The mixture was washed with aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give the solid, which was recrystallized from ethyl acetate/n-hexane to give the title compound as a colorless crystal (19.1 mg, 0.0379 mmol, 10%).
Reaction SMILES: [OH-].[Na+].CO.C([O:7][C:8]([C:10]1[C:14]([CH:15]=[CH:16][C:17]2[CH:22]=[CH:21][C:20]([CH:23]([CH3:25])[CH3:24])=[CH:19][C:18]=2[Cl:26])=[CH:13][S:12][C:11]=1[N:27]1[C:35](=[O:36])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]1=[O:37])=[O:9])C.Cl>O>[Cl:26][C:18]1[CH:19]=[C:20]([CH:23]([CH3:25])[CH3:24])[CH:21]=[CH:22][C:17]=1[CH:16]=[CH:15][C:14]1[C:10]([C:8]([OH:9])=[O:7])=[C:11]([N:27]2[C:35](=[O:36])[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]2=[O:37])[S:12][CH:13]=1
Reactant: CCOC(=O)c1c(C=Cc2ccc(C(C)C)cc2Cl)csc1N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)c1ccc(C=Cc2csc(N3C(=O)c4ccccc4C3=O)c2C(=O)O)c(Cl)c1

Procedure:
To a solution of NaOH (1.4 mmol) in a 1:1 mixture of methanol:H2O (6 mL) is added 4-[2-(2-chloro-4-isopropylphenyl)vinyl]-2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-thiophene-3-carboxylic acid ethyl ester (0.7 mmol, Example 31, Part C). The mixture is heated to reflux for 90 min, then diluted with water (12 mL), chilled in an ice bath, and acidified with concentrated HCl. The product that precipitates is collected by filtration, washed with water, and dried, affording the desired compound.