Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:17]1[CH:29]=[C:28]([NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH:27]=[C:26]2[C:18]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=1[C:25]2=[N:38]O)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Ni].C(O)C.O1CCCC1>[C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:17]1[CH:29]=[C:28]([NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH:27]=[C:26]2[C:18]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=1[CH:25]2[NH2:38])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cc2c(c(-c3nc4ccccc4n3C(=O)OC(C)(C)C)c1)-c1ccccc1C2=NO
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1cc(-c2nc3ccccc3n2C(=O)OC(C)(C)C)c2c(c1)C(N)c1ccccc1-2
Yield: 102.7 %

Procedure:
The procedure used in Example 6 is followed, but starting from 250 mg of 5-[1-(tert-butoxycarbonyl)benzimidazol-2-yl]-7-( tert-butoxycarbonyl-amino)-9H-fluoren-9-one oxime (Z,E), obtained in the previous stage, and 29 mg of Raney nickel in 4 ml of ethanol and 4 ml of tetrahydrofuran for 10 hours at 60° C. under an initial hydrogen pressure of one bar. After filtration of the catalyst, and purification by formation of a paste in diisopropyl ether, in this way we obtain 250 mg of 5-[1-(tert-butoxycarbonyl)benzimidazol-2-yl]-7-(tert-butoxycarbonylamino)-9H-fluoren-9(R,S)-ylamine, in the form of an orange powder which is used as it is in the following stage.
Reaction SMILES: [Br:1][C:2]1[CH:26]=[CH:25][C:5]2[C:6]([C:15](C)([CH3:23])[C:16](OC(C)(C)C)=O)=[N:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[C:12](Cl)[N:11]=[CH:10][CH:9]=3.C(O)(C(F)(F)F)=[O:28]>ClCCl>[Br:1][C:2]1[CH:26]=[CH:25][C:5]2[C:6]([CH:15]([CH3:23])[CH3:16])=[N:7][C:8]3[CH:9]=[CH:10][NH:11][C:12](=[O:28])[C:13]=3[C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)c1nc2ccnc(Cl)c2c2cc(Br)ccc12
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)c1nc2cc[nH]c(=O)c2c2cc(Br)ccc12
Reaction time: 12 h

Procedure:
To a stirred solution of tert-butyl 2-(9-bromo-1-chlorobenzo[c]-1,6-naphthyridin-6-yl)-2-methylpropanoate (3.32 g, 7.62 mmol) in dichloromethane (30 ml) was added TFA (30 ml). The solution was stirred for 12 hrs, then concentrated to a crude oil. EtOAc was added (20 mL), and the resulting solids were collected by vacuum filtration to afford 9-bromo-6-isopropylbenzo[c]-1,6-naphthyridin-1(2H)-one. The filtrate was concentrated, EtOAc was added, and a second crop of product was obtained by vacuum filtration. 1H NMR (500 MHz, DMSO-D6) δ 11.91 (br d, 1H), 10.28 (d, 1H), 8.41 (d, 1H), 7.89 (dd, 1H), 7.58 (t, 1H), 6.77 (d, 1H), 4.05 (septet, 1H), 1.36 (d, 6H). LRMS (ESI) calc'd for (C15H13BrN2O) [M+H]+, 317.0; found 317.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH2:14]OCC3CCCCC3)[C:11]3[CH:29]=[C:30]([F:34])[C:31]([F:33])=[CH:32][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[CH3:35][O:36][C:37](=[O:47])[C:38]1[CH:43]=[C:42]([CH3:44])[C:41]([OH:45])=[C:40]([CH3:46])[CH:39]=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>>[CH3:35][O:36][C:37](=[O:47])[C:38]1[CH:43]=[C:42]([CH3:44])[C:41]([O:45][CH2:14][CH:13]([N:12]2[C:11]3[CH:29]=[C:30]([F:34])[C:31]([F:33])=[CH:32][C:10]=3[N:9]=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]2)=[C:40]([CH3:46])[CH:39]=1
Reactant: COC(=O)c1cc(C)c(O)c(C)c1
Reactant: Fc1cc2nc(-c3ccc(Cl)cc3)n(C(COCC3CCCCC3)C3CCCCC3)c2cc1F
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Product: COC(=O)c1cc(C)c(OCC(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)c(C)c1

Procedure:
The title compound was prepared in analogy to Example 4, intermediate, from 2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethanol (Example 1, intermediate c), 4-hydroxy-3,5-dimethyl-benzoic acid methyl ester and replacing di-ethyl azodicarboxylate by di-tert-butyl azodicarboxylate and a reaction time of 18 h. Light yellow solid (12%). MS (Turbo Spray): m/z=553.3 [M+H].
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)=O.CCOC(C)=O.CCCCCC.[N+:24]([CH3:27])([O-:26])=[O:25]>>[N+:24]([CH:27]=[CH:1][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)([O-:26])=[O:25]
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccc2[nH]ccc2c1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=[N+]([O-])C=Cc1ccc2[nH]ccc2c1
Yield: 11 %

Procedure:
5-Formyl indole (14.5 g) was refluxed with NH4OAc (10.0 g) in nitromethane ((100 mL) for 3 hours. The mixture was cooled and evaporated under reduced pressure. The residue was recrystallized from isopropanol to give the first portion of intermediate and the mother liquid was purified by chromatograph (EtOAc:hexane=1:4 to 2:3) to the second portion intermediate of 5-(2-nitro-vinyl)-1H-indole (2.09 g combined, in 11% yield), which was treated with NaBH4 (1.85 g) in methanol (150 mL) at room temperature for 35 min then quenched with acetic acid (4 mL), concentrated and followed by chromatography purification (EtOAc:hexane=1:9) to afford 5-(2-nitro-ethyl)-1H-indole (1.37 g) in 65% yield. This nitro compound was hydrogenated with Pd—C (10%) under atmosphere hydrogen in methanol overnight to afford 2-(1H-indol-5-yl)-ethylamine in 99% yield. LC-MS showed the product had the expected M+H+ of 161.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:16])[C:5]([NH:8][CH2:9][CH2:10][O:11][C:12]([F:15])([F:14])[F:13])=[CH:6][CH:7]=1.[C:17]([CH2:21][C:22](Cl)=[O:23])([CH3:20])([CH3:19])[CH3:18]>C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][O:11][C:12]([F:13])([F:15])[F:14])=[C:4]([NH:16][C:22](=[O:23])[CH2:21][C:17]([CH3:20])([CH3:19])[CH3:18])[CH:3]=1
Reactant: CC(C)(C)CC(=O)Cl
Reactant: Nc1cc(Br)ccc1NCCOC(F)(F)F
Solvent: CCOC(C)=O
Product: CC(C)(C)CC(=O)Nc1cc(Br)ccc1NCCOC(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
To a solution of 4-bromo-N1-[2-(trifluoromethoxy)ethyl]benzene-1,2-diamine (step B, 752 mg, 2.51 mmol) in ethyl acetate (22 mL) was added tert-butylacetyl chloride (355 mg, 2.64 mmol) at room temperature. After stirring for 2 h at room temperature, the mixture was diluted with ethyl acetate. The organic solution was washed with saturated sodium hydrogencarbonate aqueous solution, brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=4:1 as eluent) to afford the title compound (728 mg, 73%) as a white solid.
Reaction SMILES: [OH-].[Na+].[C:3]1([C:9]2[N:10]=[CH:11][N:12]([C:14]3[C:19]([C:20]([O:22]CC)=[O:21])=[CH:18][CH:17]=[CH:16][N:15]=3)[CH:13]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>CO>[C:3]1([C:9]2[N:10]=[CH:11][N:12]([C:14]3[C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=[CH:16][N:15]=3)[CH:13]=2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1cccnc1-n1cnc(-c2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cccnc1-n1cnc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.9 %

Procedure:
15 m of a 2N NaOH solution were added to a solution of 2.0 g of ethyl 2-(4-phenyl-1H-imidazol-1-yl)pyridine-3-carboxylate (6.82 mmol) in 30 ml of methanol, and the mixture was then stirred at room temperature for 2 hours. The reaction mixture was subsequently evaporated to dryness, mixed with 10 ml of H2O and neutralized by adding 2N HCl. Filtration with suction and drying the precipitate formed resulted in 1.3 g of the acid as brown amorphous solid.
Reaction SMILES: [F:1][C:2]1([F:25])[CH2:4][CH:3]1[CH2:5][N:6]1[C:14]2[C:9](=[N:10][C:11]([C:15]3[CH2:16][CH:17]4[CH2:21][NH:20][CH2:19][CH:18]4[CH:22]=3)=[CH:12][CH:13]=2)[N:8]([CH3:23])[C:7]1=[O:24].[O:26]1[CH:30]=[CH:29][C:28]([C:31](O)=[O:32])=[N:27]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[F:25][C:2]1([F:1])[CH2:4][CH:3]1[CH2:5][N:6]1[C:14]2[C:9](=[N:10][C:11]([C:15]3[CH2:16][CH:17]4[CH2:21][N:20]([C:31]([C:28]5[CH:29]=[CH:30][O:26][N:27]=5)=[O:32])[CH2:19][CH:18]4[CH:22]=3)=[CH:12][CH:13]=2)[N:8]([CH3:23])[C:7]1=[O:24]
Reactant: O=C(O)c1ccon1
Reactant: Cn1c(=O)n(CC2CC2(F)F)c2ccc(C3=CC4CNCC4C3)nc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cn1c(=O)n(CC2CC2(F)F)c2ccc(C3=CC4CN(C(=O)c5ccon5)CC4C3)nc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1-[(2,2-Difluorocyclopropypmethyl]-5-(1,2,3,3a,4,6a-hexahydrocyclopenta-[c]pyrrol-5-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (14-2, 50 mg, 0.14 mmol, 1.0 equiv), isoxazole-3-carboxylic acid (2-6, 24.4 mg, 0.21 mmol, 1.5 equiv), DIPEA (0.076 mL, 0.43 mmol, 3.0 equiv) and HATU (82 mg, 0.21 mmol, 1.5 equiv) were added to anhydrous acetonitrile (3 mL). After stirring for 10 min at room temperature, LCMS showed consumption of starting material. Purification by reverse-phase HPLC (20-100% CH3CN:0.1% TFA in H2O) provided 14-3 as a white solid. MS m/z (M+H): calculated=442.1688; observed=442.1703.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:14]2([OH:21])[CH2:17][CH:16]([C:18](O)=[O:19])[CH2:15]2)[CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.CC[N:24]([CH:28]([CH3:30])C)[CH:25]([CH3:27])C.C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC.N1CCCC1>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:14]2([OH:21])[CH2:15][CH:16]([C:18]([N:24]3[CH2:25][CH2:27][CH2:30][CH2:28]3)=[O:19])[CH2:17]2)[CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=C(O)C1CC(O)(c2ccc(CN3CCCC3)c(F)c2)C1
Reactant: CCN(C(C)C)C(C)C
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: C1CCNC1
Solvent: C1CCOC1
Product: O=C(C1CC(O)(c2ccc(CN3CCCC3)c(F)c2)C1)N1CCCC1
Reaction time: 1.5 h

Procedure:
A 2-L 3-neck RB flask, equipped a mechanical stirrer, addition funnel and nitrogen gas inlet was charged with Intermediate 9, 3-[3-fluoro-4-(pyrrolidin-1-ylmethyl)phenyl]-3-hydroxycyclobutanecarboxylic acid (0.135 mol, crude material from the above intermediate), 500 mL of anhydrous THF and DIEA (34.8 g, 0.27 mol). The initially insoluble mixture was stirred for 1.5 h until a uniform suspension formed. Then 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (50% solution in EtOAc, 104.5 mL, 0.164 mol) was added and stirred for 5 min. (NOTE: exotherm was observed, reached ˜45-50° C.). Then pyrrolidine (28.2 mL, 24.0 g, 0.337 mol) was added. (NOTE: more exotherm was observed, reached ˜70-80° C. The mixture was stirring at RT for 12 h, then evaporated. The residue was mixed with 500 mL of sat. Na2CO3 and 200 mL of water. The mixture was extracted with DCM (5×300 mL), the extract was dried over Na2SO4, evaporated and dried to give 33.4 g (71% for two steps) of pure title compound (LCMS (M+H): 347.1. 1H NMR (300 MHz, CDCl3): δ 7.37 (t, J=7.37 Hz, 1H), 7.17-7.26 (m, 2H), 3.68 (s, 2H), 3.53 (t, J=6.78 Hz, 2H), 3.44 (t, J=6.58 Hz, 2H), 3.03-3.14 (m, 1H), 2.79-2.87 (m, 2H), 2.5-2.6 (m, 6H), 1.87-2.00 (m, 4H), 1.75-1.80 (m, 4H).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][C:13]([C@@H:16]([OH:23])[CH2:17][NH:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:12][CH:11]=1)[CH3:9])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[NH2:7][C@H:8]([C:10]1[CH:15]=[CH:14][C:13]([C@@H:16]([OH:23])[CH2:17][NH:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:12][CH:11]=1)[CH3:9]
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc([C@@H](O)CNC(C)(C)C)cc1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](N)c1ccc([C@@H](O)CNC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.4 %

Procedure:
78 mg of the compound [6-1] was dissolved in 2 mL of chloroform, then 2 mL of trifluoroacetic acid was added thereto, and the mixture was stirred for 1 hour at room temperature. The reaction mixture was concentrated under reduced pressure, dissolved in methanol, and passed through a weak ion exchange resin to remove the trifluoroacetic acid. The solvent was distilled off to obtain 55 mg of (1R)-1-{4-[(1S)-1-aminoethyl]phenyl}-2-(tert-butylamino)ethanol [11-3] as a white solid. The compound [11-3] (hereinafter, referred to as the compound [11-3]) was used in the subsequent reaction without further purification.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][NH:11][C:12](=O)[CH3:13].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>>[CH3:13][C:12]1[C:5]2[C:4](=[C:3]([C:2]([F:16])([F:15])[F:1])[CH:8]=[CH:7][CH:6]=2)[CH2:9][CH2:10][N:11]=1
Reactant: CC(=O)NCCc1ccccc1C(F)(F)F
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: CC1=NCCc2c1cccc2C(F)(F)F

Procedure:
In close analogy to the procedure described above, N-[2-(2-trifluormethyl-phenyl)-ethyl]-acetamide is reacted with phosphorus pentoxide to provide the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[O:17][C:16]([C:18]([O:20]CC)=[O:19])=[CH:15][C:14]=3[CH:23]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[OH-].[K+]>C(O)C>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[O:17][C:16]([C:18]([OH:20])=[O:19])=[CH:15][C:14]=3[CH:23]=2)=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(-c3ccc(C(C)=O)cc3)ccc2o1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(=O)c1ccc(-c2ccc3oc(C(=O)O)cc3c2)cc1

Procedure:
10A was treated with potassium hydroxide in ethanol to give 10, mp: 264°-266° C.
Reaction SMILES: C(OC(=O)[NH:10][CH:11]1[CH2:23][C:22]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:24][C:25]([F:28])([F:27])[F:26])[CH:20]=3)[N:15]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[N:31]=3)[C:14]=2[CH2:13][CH2:12]1)C1C=CC=CC=1.[H][H]>CCO.C1COCC1.[Pd]>[F:36][C:32]1[N:31]=[C:30]([CH2:29][N:15]2[C:14]3[CH2:13][CH2:12][CH:11]([NH2:10])[CH2:23][C:22]=3[C:21]3[C:16]2=[CH:17][CH:18]=[C:19]([O:24][C:25]([F:28])([F:26])[F:27])[CH:20]=3)[CH:35]=[CH:34][CH:33]=1
Reactant: O=C(NC1CCc2c(c3cc(OC(F)(F)F)ccc3n2Cc2cccc(F)n2)C1)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: NC1CCc2c(c3cc(OC(F)(F)F)ccc3n2Cc2cccc(F)n2)C1
Yield: 117.5 %

Procedure:
Dissolve [9-(6-fluoro-pyridin-2-ylmethyl)-6-trifluoromethoxy-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-carbamic acid benzyl ester (Preparation 45) (2.73 g, 5.32. mmol) in EtOH (100 mL) and THF (50 mL). Add 10% Pd/C (200 mg) and stir at room temperature under a balloon of hydrogen for 18 h. Filter the reaction through a pad of Celite®, rinse the pad with THF (50 mL), and concentrate the filtrate in vacuo to afford 2.37 g (90%) of the title compound as a dark brown oil. MS (ES): m/z 380 (M+1); HPLC (Method A): Rt=1.76 min (89%).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][N:7]1[CH2:14][C@@H:13]2[C@@H:9]([N:10]([C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([NH:23][C:24]4[N:29]=[C:28]([C:30]5[CH:31]=[N:32][N:33]6[CH2:38][CH2:37][CH2:36][CH2:35][C:34]=56)[CH:27]=[CH:26][N:25]=4)=[CH:17][C:16]=3[NH2:39])[CH2:11][CH2:12]2)[CH2:8]1>C1COCC1.C(Cl)Cl>[CH3:6][N:7]1[CH2:14][C@@H:13]2[C@@H:9]([N:10]([C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([NH:23][C:24]4[N:29]=[C:28]([C:30]5[CH:31]=[N:32][N:33]6[CH2:38][CH2:37][CH2:36][CH2:35][C:34]=56)[CH:27]=[CH:26][N:25]=4)=[CH:17][C:16]=3[NH:39][C:1](=[O:4])[CH:2]=[CH2:3])[CH2:11][CH2:12]2)[CH2:8]1
Reactant: C=CC(=O)Cl
Reactant: COc1cc(N2CC[C@@H]3CN(C)C[C@@H]32)c(N)cc1Nc1nccc(-c2cnn3c2CCCC3)n1
Solvent: C1CCOC1
Solvent: ClCCl
Product: C=CC(=O)Nc1cc(Nc2nccc(-c3cnn4c3CCCC4)n2)c(OC)cc1N1CC[C@@H]2CN(C)C[C@@H]21
Temperature: -15 °C
Reaction time: 1 h
Yield: 14.2 %

Procedure:
A solution of acryloyl chloride (26 mg, 0.29 mmol) in THF (1 mL) was added dropwise to a stirred solution of 4-[(3aR,6aR)-5-methyl-2,3,3a,4,6,6a-hexahydropyrrolo[3,4-b]pyrrol-1-yl]-6-methoxy-N-[4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl]benzene-1,3-diamine (Intermediate 132, 120 mg, 0.26 mmol) in THF (3 mL), which was cooled in an ice/methanol bath to approx −15° C. The mixture was stirred for 1 h, gradually warming to 0° C. The mixture was then diluted with CH2Cl2 (50 mL) and washed with sat. NaHCO3 (50 mL). The resulting aqueous wash solution was further extracted with CH2Cl2 (2×25 mL) and the combined organic solutions were then dried (MgSO4) and concentrated in vacuo onto silica. Part-purification was achieved by FCC, eluting with 0-5% 7N methanolic ammonia in CH2Cl2 and impure product containing fractions were combined and concentrated in vacuo. Purification by FCC, eluting with 0-2% 7N methanolic ammonia in CH2Cl2 and then eluting with 0-3% CH3OH in CH2Cl2 gave the title compound (19 mg, 14%) as a cream foam; 1H NMR (CDCl3): 1.82-1.97 (4H, m), 2.00-2.06 (2H, m), 2.13-2.24 (1H, s), 2.25-2.39 (1H, m), 2.29 (3H, s), 2.67-2.98 (4H, m), 3.17-3.26 (3H, m), 3.66 (1H, br s), 3.86 (3H, s), 4.18 (2H, t), 5.64-5.71 (1H, m), 6.30-6.47 (2H, m), 6.78 (1H, s), 6.81 (1H, d), 7.44 (1H, s), 8.06 (1H, s), 8.34 (1H, d), 9.24 (1H, s), 9.40 (1H, s); m/z: ES+ MH+ 515.15.
Reaction SMILES: [CH2:1]([C:3](=[CH2:14])[CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1I)[CH3:2].[F:15][C:16]([F:34])([F:33])[C:17](O)(CC1(C)C2C(=CC=CC=2)CCC1)[CH:18]=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.[Cu]I>[CH2:1]([C:3]1([CH2:14][C:17]([C:16]([F:34])([F:33])[F:15])=[CH2:18])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4]1)[CH3:2]
Reactant: C=C(CC)CCCc1ccccc1I
Reactant: CC1(CC(O)(C=O)C(F)(F)F)CCCc2ccccc21
Agent: [Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: C=C(CC1(CC)CCCc2ccccc21)C(F)(F)F
Temperature: 25 °C
Yield: 139.2 %

Procedure:
1-(4-Ethyl-4-penten-1-yl)-2-iodobenzene (Intermediate 11) (1.1 g, 3.66 mmole), tributyl[1-(trifluoromethyl)ethenyl]stannane (Intermediate 3) (1.4 g, 3.64 mmole), triphenyl phosphine (188 mg, 0.717 mmole), palladium acetate (82 mg, 0.365 mmole) and copper(I) iodide (69 mg, 0.362 mmole) were dissolved in dry DMF (60 ml). The solution was degassed by evacuating and filling the flask with nitrogen four times. The solution was then immediately immersed in a 110° C. oil bath, left to react for 3.5 h, cooled to room temperature then partitioned between water (100 ml) and cyclohexane (100 ml). The layers were separated and the aqueous layer was extracted with further cyclohexane (100 ml). The combined extracts were dried over anhydrous sodium sulphate and evaporated and the residue was applied to a silica Solid Phase Extraction (SPE) cartridge. Elution with cyclohexane gave the title compound (1.36 g) containing some residual impurities. This was used without additional purification.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:7]([N:21]2[CH2:32][CH2:31][N:30]3[C:23](=[CH:24][C:25]4[CH2:26][C:27]([CH3:34])([CH3:33])[CH2:28][C:29]=43)[C:22]2=[O:35])=[N:8][CH:9]=[CH:10][C:11]=1B1OC(C)(C)C(C)(C)O1)(=[O:3])[CH3:2].Br[C:37]1[CH:38]=[C:39]([NH:45][C:46]2[CH:50]=[CH:49][N:48]([CH3:51])[N:47]=2)[C:40](=[O:44])[N:41]([CH3:43])[CH:42]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>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].C(#N)C.O>[C:1]([O:4][CH2:5][C:6]1[C:7]([N:21]2[CH2:32][CH2:31][N:30]3[C:23](=[CH:24][C:25]4[CH2:26][C:27]([CH3:33])([CH3:34])[CH2:28][C:29]=43)[C:22]2=[O:35])=[N:8][CH:9]=[CH:10][C:11]=1[C:37]1[CH:38]=[C:39]([NH:45][C:46]2[CH:50]=[CH:49][N:48]([CH3:51])[N:47]=2)[C:40](=[O:44])[N:41]([CH3:43])[CH:42]=1)(=[O:3])[CH3:2]
Reactant: Cn1ccc(Nc2cc(Br)cn(C)c2=O)n1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: CC(=O)OCc1c(-c2cc(Nc3ccn(C)n3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 100 °C

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with {3-[(acetyloxy)methyl]-2-{4,4-dimethyl-9-oxo-1,10-diazatri-cyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}pyridin-4-yl}boronic acid 199e (595 mg, 1.5 mmol), 290a (282 mg, 1.0 mmol), K3PO4 (424 mg, 2.0 mmol), sodium acetate (164 mg, 2.0 mmol), 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II) (82 mg, 0.1 mmol), and acetonitrile/water (15/1 mL). After three cycles of vacuum/N2 flush, the mixture was heated at 100° C. for 1.5 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between dichloromethane (30 mL) and water (30 mL). The aqueous layer was extracted with dichloromethane (3×20 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The dark residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (80/1 to 50/1) to 290b (300 mg, 54%) as yellow solid. MS-ESI: [M+H]+ 556.1
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]=[CH:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)=[CH:7][C:6]=2[CH:20]=1>O1CCCC1.C(O)C.[Pt](=O)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)=[CH:7][C:6]=2[CH:20]=1
Reactant: COc1ccc(C=Cc2cc3cc(Br)ccc3o2)cc1
Agent: O=[Pt]=O
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(CCc2cc3cc(Br)ccc3o2)cc1
Reaction time: 4 h
Yield: 75.4 %

Procedure:
128 g of 5-bromo-2-[2-(4-methoxyphenyl)vinyl]benzofuran as a mixture of two stereoisomers was dissolved in a solvent mixture of 1.3 l of tetrahydrofuran and 0.7 l of ethanol. The resulting solution was mixed with 3.0 g of platinum dioxide and subjected to 4 hours of catalytic hydrogenation under normal pressure. Thereafter, the catalyst was removed by filtration, the resulting filtrate was concentrated, and crystals thus precipitated were collected by filtration and washed with ethanol. In this way, 97.08 g of 5-bromo-2-[2-(4-methoxyphenyl)ethyl]benzofuran was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:15]([NH:17][CH:18]2[CH:23]3[CH2:24][CH2:25][N:20]([CH2:21][CH2:22]3)[CH2:19]2)=[O:16])[C:5]2[O:10][CH:9]([CH3:11])[C:8](=[O:12])[N:7]([CH3:13])[C:6]=2[CH:14]=1.ClC1C=CC=C(C(OO)=[O:34])C=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:15]([NH+:17]([O-:34])[CH:18]2[CH:23]3[CH2:24][CH2:25][N:20]([CH2:21][CH2:22]3)[CH2:19]2)=[O:16])[C:5]2[O:10][CH:9]([CH3:11])[C:8](=[O:12])[N:7]([CH3:13])[C:6]=2[CH:14]=1
Reactant: CC1Oc2c(C(=O)NC3CN4CCC3CC4)cc(Cl)cc2N(C)C1=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CC1Oc2c(C(=O)[NH+]([O-])C3CN4CCC3CC4)cc(Cl)cc2N(C)C1=O
Reaction time: 0.5 h

Procedure:
To a solution of 5.0 g of 6-chloro-3,4-dihydro-2,4-dimethyl-3-oxo-N-(3-quinuclidinyl)-2H-1,4-benzoxazine-8-carboxamide in 150 ml of chloroform is added portionwise 3.7 g of metachloroperbenzoic acid under cooling and stirring. After 0.5 hour, ammonia gas is bubbled through the reaction solution under stirring and the precipitate is filtered off. The mother liquor is distilled off under reduced pressure followed by recrystallizing the residue from ethanol-isopropyl ester to give 6-chloro-3,4-dihydro-2,4-dimethyl-3-oxo-N-(3-quinuclidinyl)-2H-1,4-benzoxazine-8-carboxamide N-oxide, melting at 188°-190° C. with decomposition.
Reaction SMILES: [CH2:1]([N:3]1[C:8]2[N:9]=[C:10](S(C)=O)[N:11]=[CH:12][C:7]=2[CH:6]=[C:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:4]1=[O:22])[CH3:2].[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][N:33]([C:36]2[CH:41]=[CH:40][C:39]([NH2:42])=[CH:38][C:37]=2[F:43])[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>>[CH2:1]([N:3]1[C:8]2[N:9]=[C:10]([NH:42][C:39]3[CH:40]=[CH:41][C:36]([N:33]4[CH2:34][CH2:35][N:30]([C:28]([O:27][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:29])[CH2:31][CH2:32]4)=[C:37]([F:43])[CH:38]=3)[N:11]=[CH:12][C:7]=2[CH:6]=[C:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:4]1=[O:22])[CH3:2]
Reactant: CCn1c(=O)c(-c2ccccc2)cc2cnc(S(C)=O)nc21
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cc2F)CC1
Product: CCn1c(=O)c(-c2ccccc2)cc2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)c(F)c3)nc21
Yield: 21.1 %

Procedure:
8-ethyl-2-(methylsulfinyl)-6-phenylpyrido[2,3-d]pyrimidin-7(8H)-one (120 mg, 0.38 mmol) and 4-(4-amino-2-fluorophenyl)piperazine-1-carboxylic acid tert-butyl ester (113 mg, 0.38 mmol) were stirred at 120° C. for 3 h. The reaction mixture was purified by silica gel column chromatography using hexane:ethyl acetate (3:2). The isolated product was recrystallized from isopropanol to give the title compound (45 mg, 0.08 mmol, 21%) as a pale yellow solid. ESMS m/z 545 (M+H)+.