Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]2[N:9]([CH:13]([C:15]3[O:16][C:17](=[O:31])[C:18]4[C:23]([C:24]=3[C:25]3[CH2:26][CH2:27][NH:28][CH2:29][CH:30]=3)=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH3:14])[N:10]=[C:11]([I:12])[C:4]=12.[CH3:32][N:33]([CH3:38])[CH2:34][C:35](O)=[O:36]>>[CH:17]([OH:31])=[O:16].[NH2:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]2[N:9]([CH:13]([C:15]3[O:16][C:17](=[O:31])[C:18]4[C:23]([C:24]=3[C:25]3[CH2:26][CH2:27][N:28]([C:35](=[O:36])[CH2:34][N:33]([CH3:38])[CH3:32])[CH2:29][CH:30]=3)=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH3:14])[N:10]=[C:11]([I:12])[C:4]=12
Reactant: CC(c1oc(=O)c2ccccc2c1C1=CCNCC1)n1nc(I)c2c(N)ncnc21
Reactant: CN(C)CC(=O)O
Agent: Cl
Product: CC(c1oc(=O)c2ccccc2c1C1=CCN(C(=O)CN(C)C)CC1)n1nc(I)c2c(N)ncnc21
Product: O=CO
Yield: 108.5 %

Procedure:
Title compound was prepared following the procedure used for the synthesis of Intermediate D25, from 3-(1-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-4-(1,2,3,6-tetrahydropyridin-4-yl)-1H-isochromen-1-one hydrochloride (Intermediate Intermediate D23, 0.200 g, 0.363 mmol) and 2-(dimethylamino)acetic acid (0.045 g, 0.436 mmol) to give the title compound (0.127 g, 0.197 mmol, 54.2% yield) as a white powder.
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH3:17])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.[CH2:18]([C@H:25]1[CH2:29][O:28][C:27](=[O:30])[N:26]1[C:31](=[O:46])[CH2:32][C@@H:33]([C:39]1[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=1)[C:34]1[CH:38]=[CH:37][O:36][N:35]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[CH2:14]([C:11]1[CH:12]=[CH:13][C:8]([C:5]2[S:4][C:3]([CH2:2][O:45][C:42]3[CH:43]=[CH:44][C:39]([C@@H:33]([C:34]4[CH:38]=[CH:37][O:36][N:35]=4)[CH2:32][C:31]([N:26]4[C@@H:25]([CH2:18][C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)[CH2:29][O:28][C:27]4=[O:30])=[O:46])=[CH:40][CH:41]=3)=[CH:7][CH:6]=2)=[CH:9][CH:10]=1)[CH2:15][CH2:16][CH3:17]
Reactant: O=C(C[C@@H](c1ccc(O)cc1)c1ccon1)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: CCCCc1ccc(-c2ccc(CCl)s2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1ccc(-c2ccc(COc3ccc([C@H](CC(=O)N4C(=O)OC[C@@H]4Cc4ccccc4)c4ccon4)cc3)s2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.2 %

Procedure:
A mixture of 60.5 (0.16 mmol), 7.5 (52 mg, 0.13 mmol), and Cs2CO3 (135 mg, 0.41 mmol) in DMF (1.6 mL) was stirred overnight at room temperature. The mixture was diluted with EtOAc, washed with water and brine, dried (Na2SO4), and concentrated. The crude product was chromatographed on silica gel (0-30% EtOAc/hexane) to afford 60.6 (26 mg, 32%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 8.29 (d, 1H), 7.48 (d, 2H), 7.28 (m, 5H), 7.19 (m, 4H), 7.14 (d, 1H), 7.04 (d, 1H), 6.96 (d, 2H), 6.13 (d, 1H), 5.17 (s, 2H), 4.75 (t, 1H), 4.61 (m, 1H), 4.13 (m, 2H), 4.02 (dd, 1H), 3.54 (dd, 1H), 3.20 (dd, 1H), 2.76 (dd, 1H), 2.62 (t, 2H), 1.61 (m, 2H), 1.37 (m, 2H), 0.94 (t, 3H).
Reaction SMILES: I[C:2]1[N:3](C)[N:4]=[C:5]2[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]=12.[CH:13]([Mg]Cl)(C)C.[CH2:18]([Sn:22]([CH2:28][CH2:29][CH2:30][CH3:31])([CH2:24][CH2:25][CH2:26][CH3:27])Cl)[CH2:19][CH2:20][CH3:21]>C1COCC1>[CH3:13][N:4]1[C:5]2[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:2]([Sn:22]([CH2:28][CH2:29][CH2:30][CH3:31])([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:18][CH2:19][CH2:20][CH3:21])=[N:3]1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: CC(C)[Mg]Cl
Reactant: Cn1nc2c(c1I)CCCCC2
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2c1CCCCC2
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 27.9 %

Procedure:
To a solution of 3-iodo-2-methyl-2,4,5,6,7,8-hexahydrocycloheptapyrazole (180 mg, 0.62 mmol) in THF (3 mL) at −10° C. (ice/acetone) was slowly added isopropylmagnesium chloride (2.0 M in THF, 0.37 mL, 0.74 mmol). The reaction mixture was stirred at −10° C. for 30 min then additional isopropylmagnesium chloride (2.0 M in THF, 0.10 mL, 0.20 mmol) was added. Stirring was continued at −10° C. for 20 min then tributylchlorostannane (0.20 mL, 0.74 mmol) was added dropwise. The reaction mixture was warmed to room temperature and stirred for 1 h then quenched with water and extracted with EtOAc (2×). The organics were dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography with 0% to 10% EtOAc/hexanes (0.5% Et3N spike in hexanes) to afford 76 mg (28%) of 1-methyl-3-tributylstannanyl-1,4,5,6,7,8-hexahydrocycloheptapyrazole as a colorless oil. 1H NMR (CDCl3, 400 MHz): δ (ppm) 3.82 (s, 3H), 2.66-2.76 (m, 2H), 2.50-2.60 (m, 2H), 1.80-1.89 (m, 2H), 1.61-1.74 (m, 4H), 1.51-1.61 (m, 6H), 1.29-1.41 (m, 6H), 1.04-1.12 (m, 6H), 0.91 (t, J=7.3 Hz, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]([CH3:12])[CH2:9][CH:8]([CH3:13])[NH:7]2.C([O:16][CH:17]=[C:18]([C:24](OCC)=O)[C:19]([O:21][CH2:22][CH3:23])=[O:20])C>O>[Cl:1][C:2]1[C:11]2[N:10]([CH3:12])[CH2:9][CH:8]([CH3:13])[N:7]3[CH:24]=[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:17](=[O:16])[C:5]([C:6]=23)=[CH:4][CH:3]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CC1CN(C)c2c(Cl)cccc2N1
Solvent: O
Product: CCOC(=O)c1cn2c3c(c(Cl)ccc3c1=O)N(C)CC2C

Procedure:
A mixture of 0.0765 mole (15 g) of 8-chloro-1,3-dimethyl-1,2,3,4-tetrahydroquinoxaline and 0.0765 mole (16.5 g) of diethyl ethoxymethylenemalonate is heated under a nitrogen atmosphere at 145° to 150° C. for about 75 minutes. The solution is cooled, 70 g of polyphosphoric acid are added and the mixture is heated under nitrogen at 110° to 120° C. for 45 minutes. The hot solution is poured into water with stirring and a white solid precipitates. The product is recrystallized from ethanol to provide ethyl 10-chloro-2,3-dihydro-1,3-dimethyl-7-oxo-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxylate, m.p. 259°-261° C. Analyis: Calculated for C16H17ClN2O3 : %C, 60.0, %H, 5.35; %H, 8.75; Found: %C, 60.0; %H, 5.3; %N, 8.9.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[N:8]=[C:7]([CH:9]=O)[CH:6]=[CH:5][CH:4]=1.[CH2:13]([NH2:15])[CH3:14]>C1COCC1>[CH2:13]([NH:15][CH2:9][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([C:2]([F:12])([F:11])[F:1])[N:8]=1)[CH3:14]
Reactant: CCN
Reactant: O=Cc1cccc(C(F)(F)F)n1
Solvent: C1CCOC1
Product: CCNCc1cccc(C(F)(F)F)n1

Procedure:
prepared by reaction of 6-trifluoromethyl-pyridin-2-carbaldehyde (Ashimori A. Chem. Pharm. Bull. 1990, 38, 9, 2446-2458) with 2M ethylamine in THF.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[CH2:5][C@@H:6]([C:8]([OH:10])=[O:9])[NH2:7].[CH2:14]=O.[ClH:16]>>[ClH:16].[OH:1][C:2]1[CH:3]=[C:4]2[C:11](=[CH:12][CH:13]=1)[CH2:14][NH:7][CH:6]([C:8]([OH:10])=[O:9])[CH2:5]2
Reactant: C=O
Reactant: N[C@@H](Cc1cccc(O)c1)C(=O)O
Agent: Cl
Product: O=C(O)C1Cc2cc(O)ccc2CN1

Procedure:
To a mixture of 100.0 g of 3-hydroxyphenylalanine in 820 ml of 5% hydrochloric acid were added 78 ml of formaldehyde (37% in water). The reaction mixture was heated at 90°-95° C. (external bath temperature) for 45 minutes. The mixture was cooled and concentrated in vacuo. Five hundred milliliters of ethanol were added and the mixture was again concentrated in vacuo, affording 115 g of the title intermediate as a pale white solid, used without purification in the next step.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[I:6][C:7]1[C:16](=O)[C:15]2[C:10](=[CH:11][C:12]([O:20][CH3:21])=[C:13]([O:18][CH3:19])[CH:14]=2)[NH:9][CH:8]=1>CN(C=O)C>[Cl:3][C:16]1[C:15]2[C:10](=[CH:11][C:12]([O:20][CH3:21])=[C:13]([O:18][CH3:19])[CH:14]=2)[N:9]=[CH:8][C:7]=1[I:6]
Reactant: COc1cc2[nH]cc(I)c(=O)c2cc1OC
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cc2ncc(I)c(Cl)c2cc1OC
Temperature: 100 °C
Reaction time: 2 h

Procedure:
Phosphorus oxychloride (6.743 g, 4.100 mL, 43.98 mmol) was added to a solution of 3-iodo-6,7-dimethoxyquinolin-4(1H)-one (13.237 g, 39.98 mmol) in DMF (100 mL). The mixture was stirred at 100° C. for 2 h then cooled to RT. The mixture was poured into ice water and the resulting precipitate was filtered and dried to afford 4-chloro-3-iodo-6,7-dimethoxyquinoline as a light brown solid. MS (ESI, pos. ion) m/z: 349.9 (M+H). Mass Calc'd for C11H9ClINO2: 349.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:9]2=[O:30])=[C:4]([OH:32])[CH:3]=1.FC(F)(F)C(O)=O>C([SiH](CC)CC)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH:17]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:9]2=[O:30])=[C:4]([OH:32])[CH:3]=1
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C1(O)c1ccc(Br)cc1O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=C1C(c2ccc(Br)cc2O)c2ccccc2N1C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 64 h
Yield: 79.2 %

Procedure:
To an ice cold stirred solution of 3-(4-bromo-2-hydroxyphenyl)-1-(diphenylmethyl)-3-hydroxy-1,3-dihydro-2H-indol-2-one (13.1 g, 27.1 mmol) in triethylsilane (25.0 mL) was added trifluoroacetic acid (25.0 mL). The solution was stirred at ambient temperature for 64 h, then concentrated in vacuo to dryness. Recrystallization from diethyl ether (25.0 mL) in a Branson ultrasonic bench top water bath afforded 3-(4-bromo-2-hydroxyphenyl)-1-(diphenylmethyl)-1,3-dihydro-2H-indol-2-one (10.1 g, 79%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 9.17 (s, 1H), 7.40-7.03 (m, 13H), 6.99-6.92 (m, 2H), 6.79-6.74 (m, 2H), 6.58-6.50 (m, 1H), 5.10 (s, 1H); MS (ES−) m/z 468.2 (M−1), 470.2 (M−1).
Reaction SMILES: [C:1]([NH:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[C:20]([N:39]1[CH:43]=[C:42]([CH2:44][CH2:45][CH2:46][C:47](O)=[O:48])[N:41]=[CH:40]1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[Cl-].[NH4+]>O1CCCC1>[C:1]([NH:5][C:6]([C:7]1[CH:12]=[CH:11][C:10]([C:47](=[O:48])[CH2:46][CH2:45][CH2:44][C:42]2[N:41]=[CH:40][N:39]([C:20]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:43]=2)=[CH:9][CH:8]=1)=[O:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NC(=O)c1ccc(Br)cc1
Reactant: O=C(O)CCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)c1ccc(C(=O)CCCc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
6.95 g of N-tert-butyl-p-bromobenzamide is dissolved in 175 ml of tetrahydrofuran at -70° under nitrogen and 20.1 ml of n-butyllithium (2.7M) is added dropwise. After 30 min, a solution of 5.35 g of 4-(1-trityl-4-imidazolyl)-butanoic acid in 10 ml of tetrahydrofuran is added slowly. The reaction mixture is allowed to warm slowly to room temperature and 20 ml of an aqueous ammonium chloride solution is added. The organic layer is separated, dried over sodium sulfate and evaporated to yield 1-(p-N-tert-butylaminocarbonylphenyl)-4-(1-trityl-4-imidazolyl)-1-butanone
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[Br:20][C:21]1[CH:22]=[C:23](F)[C:24]([N+:29]([O-:31])=[O:30])=[C:25]([CH:28]=1)[NH:26][CH3:27].CCN(CC)CC>CCOC(C)=O>[Br:20][C:21]1[CH:28]=[C:25]([NH:26][CH3:27])[C:24]([N+:29]([O-:31])=[O:30])=[C:23]([N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:19][CH:18]=2)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH:22]=1
Reactant: CNc1cc(Br)cc(F)c1[N+](=O)[O-]
Reactant: COc1ccc(CNCc2ccc(OC)cc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CNc1cc(Br)cc(N(Cc2ccc(OC)cc2)Cc2ccc(OC)cc2)c1[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 16 h

Procedure:
A mixture of bis-(4-methoxy-benzyl)-amine (346 mmol), 5-bromo-3-fluoro-N-methyl-2-nitroaniline (297 mmol) and Et3N (891 mmol) was stirred at 120° C. for 16 h. The mixture was then cooled. The crude was combined with another one obtained following the same procedure described above. The resulting mixture was diluted in EtOAc and washed (2×0.2 M HCl, H2O and sat. NaHCO3). The organic phase was dried (Na2SO4) and concentrated to afford the desired product.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][C@H:13]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]1.CCN(CC)CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH:12]([C@H:13]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]1)=[O:11]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CO)C1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@H](C=O)C1
Reaction time: 0.5 h

Procedure:
To a solution of oxalyl chloride (22.17 g, 0.176 mol) in CH2Cl2 (200 mL) was added dropwise a solution of DMSO (20.59 g, 0.264 mol) in CH2Cl2 (50 mL) at −78° C. The mixture was stirred for 0.5 hrs at this temperature. A solution of (S)-tert-butyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate (M6) (11.8 g, 58.7 mmol) in CH2Cl2 (50 mL) was added dropwise to the reaction mixture at −78° C. The mixture continued to stir for 1 hr at that temperature. Et3N (29.7 g, 0.294 mol) was added at −78° C. The resultant mixture was warmed to room temperature and stirred for 3 hrs. The mixture was poured into saturated aqueous NaHCO3 and shaken. The organic layer was separated, washed twice with water, dried and evaporated to give a residue, which was purified by column chromatography (P.E./EtOAc 5:1) to give (S)-tert-butyl 3-formylpyrrolidine-1-carboxylate (M7). 1H NMR (CDCl3, 300 MHz): δ 9.68 (d, J=1.8 Hz, 1H), 3.67-3.68 (m, 1H), 3.51-3.55 (m, 1H), 3.35-3.40 (m, 2H), 2.99-3.04 (m, 1H), 2.04-2.18 (m, 2H), 1.46 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[Br-].[Mg+2].[Br-].[Br:19][C:20]1[CH:21]=[C:22]([CH:25]=[O:26])[S:23][CH:24]=1>O1CCCC1.CCCCCC.ClCCl>[Br:19][C:20]1[CH:21]=[C:22]([CH:25]([OH:26])[C:2]2[CH:15]=[CH:14][CH:13]=[C:4]([O:5][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7])[CH:3]=2)[S:23][CH:24]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(Br)c1
Reactant: O=Cc1cc(Br)cs1
Agent: [Br-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)[Si](C)(C)Oc1cccc(C(O)c2cc(Br)cs2)c1
Temperature: -78 °C
Yield: 48.2 %

Procedure:
3-Bromophenoxy-tert-butyldimethylsilane (30.2 g, 0.105 mol), prepared as in Example 1, was dissolved in 300 mL of dry tetrahydrofuran under nitrogen and cooled to -78° C. A solution of 1.6M n-butylithium in hexane (66 mL, 0.105 mol) was added dropwise at a rate to maintain a temperature below -65° C. The reaction was stirred for thirty minutes after the addition was complete and the cold solution was transferred to another vessel containing a room temperature solution of magnesium bromide (20.2 g, 0.11 mol) in 400 mL of dry tetrahydrofuran under nitrogen. The resulting solution was allowed to warm to 15° C. while stirring. After one hour a solution of 4-bromo-2-thiophenecarboxaldehyde (20.0 g, 0.105 mol) in 100 mL of dry tetrahydrofuran was added slowly at a rate to maintain a temperature below 25° C. The resulting solution was stirred for three hours at room temperature, then washed three times with aqueous ammonium chloride, dried over sodium sulfate and evaporated to give a yellow oil. Chromatography on silica gel with dichloromethane:hexane/50:50 gave 20.23 g (48.2%) of α-(4-bromo-2-thienyl)-3-((tert-butyldimethylsilyl)-oxy)benzyl alcohol as a viscous yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=O.[CH2:11](Br)[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13].O>C(O)C>[C:12]([C:11]1[O:10][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:9][C:6]=2[CH:7]=1)(=[O:13])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: O=Cc1cc(Cl)ccc1O
Solvent: O
Solvent: CCO
Product: O=C(c1ccccc1)c1cc2cc(Cl)ccc2o1
Temperature: 80 °C
Reaction time: 1 h
Yield: 77.5 %

Procedure:
To a solution of 5-chloro-2-hydroxybenzaldehyde (2 g) and phenacyl bromide (1.85 g) in ethanol (10 ml) potassium carbonate (3.53 g) was added. The mixture was stirred at 80° C. for 1 h. Then the reaction mixture was poured into water (50 ml) and extracted with dichloromethane (3×20 ml). The combined organic layers were washed with brine (20 ml), dried (MgSO4), and concentrated under reduced pressure. The crude was purified by flash chromatography on silica gel (hexane/ethyl acetate 12:1) to give 2-benzoyl-5-chlorobenzofuran (1.85 g) as colourless solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[C:14](=[O:16])[CH3:15])=[O:4].C(O)CO.[OH-].[K+]>O1CCCC1>[C:14]([C:8]1[C:7]2[C:11](=[CH:12][CH:13]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=2)[NH:10][CH:9]=1)(=[O:16])[CH3:15]
Reactant: COC(=O)c1ccc2[nH]cc(C(C)=O)c2c1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: OCCO
Product: CC(=O)c1c[nH]c2ccc(C(=O)O)cc12
Temperature: 25 °C

Procedure:
0.686 g (3.16 mmol) methyl-3-acetylindole-5-carboxylate are dissolved under heat in 10 ml tetrahydrofurane and 10 ml ethylene glycol and mixed with 7.08 g (0.13 mol) potassium hydroxide. Having stirred under reflux for 30 minutes, the reaction mixture is cooled to room temperature. The tetrahydrofurane is removed on the rotary evaporator and the solution is acidified under ice cooling with 20 ml 6N hydrochloric acid. The precipitated light violet precipitate is sucked off and dried.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:14][C:13]([C:22]3[CH:23]=[N:24][C:25]([C:28]([OH:31])([CH3:30])[CH3:29])=[N:26][CH:27]=3)=[CH:12][C:10]=2[N:11]=1)=[O:5])[CH3:2].BrC1C=NC(C23OC2[CH2:43][O:42][CH2:41]C3)=NC=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O>[CH:30]12[O:31][C:28]1([C:25]1[N:26]=[CH:27][C:22]([C:13]3[CH:14]=[C:15]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=4)[C:9]4[S:8][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[N:11][C:10]=4[CH:12]=3)=[CH:23][N:24]=1)[CH2:29][CH2:43][O:42][CH2:41]2
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(C(C)(C)O)nc3)cc(-c3ccccn3)c2s1
Reactant: Brc1cnc(C23CCOCC2O3)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CCNC(=O)Nc1nc2cc(-c3cnc(C45CCOCC4O5)nc3)cc(-c3ccccn3)c2s1
Temperature: 80 °C
Yield: 57 %

Procedure:
Intermediate 1 (29 mg, 0.085 mmol), ii (20 mg, 78 mmol), Cs2CO3 (55 mg 0.17 mmol) and Pd(Ph3)2Cl2 (3 mg, 4 mmol) were dissolved in 1,4-dioxane:H2O (10:1, 10 mL). The mixture was degassed with a stream of N2 for 10 min, then heated in a microwave reactor at 80° C. for 1 h. The reaction was concentrated in vacuo, re-dissolved in a minimum quantity of DCM and purified by chromatography on silica (0-10% DCM-MeOH) yielding iii (23 mg 57%). MS: 475.0, [M+H]+.
Reaction SMILES: FC(F)(F)[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.[CH3:13][CH:14]([CH3:33])[CH:15]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:16]([NH:18][C@@H:19]1[C@@H:26]2[C@@H:22]([CH2:23][NH:24][CH2:25]2)[CH2:21][CH2:20]1)=[O:17].C1(C(C2CCCCC2)[C:41](N[C@@H]2[C@H]3[C@H](CNC3)CC2)=[O:42])CCCCC1>>[CH3:41][O:42][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][N:24]1[CH2:25][C@@H:26]2[C@@H:19]([NH:18][C:16](=[O:17])[CH:15]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:14]([CH3:33])[CH3:13])[CH2:20][CH2:21][C@@H:22]2[CH2:23]1
Reactant: O=C(N[C@H]1CC[C@H]2CNC[C@H]21)C(C1CCCCC1)C1CCCCC1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Reactant: CC(C)C(C(=O)N[C@H]1CC[C@@H]2CNC[C@@H]21)c1ccccc1
Product: COc1cccc(CN2C[C@H]3CC[C@H](NC(=O)C(c4ccccc4)C(C)C)[C@H]3C2)c1

Procedure:
The title compound was prepared by substituting 3-methoxybenzaldehyde for 3-(trifluoromethyl)benzaldehyde and 3-methyl-N-[(3aR,4S,6aS)-octahydrocyclopenta[c]pyrrol-4-yl]-2-phenylbutanamide from Example 83 Step A for 2,2-dicyclohexyl-N-[(3aS,4S,6aR)-octahydrocyclopenta[c]pyrrol-4-yl]acetamide in the procedure described for Example 54: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.61-8.54 (m, 1H), 7.63 (d, J=7.6, 2H), 7.36-7.24 (m, J=5.6, 12.0, 20.6, 4H), 7.17 (s, 0.5H), 7.11 (s, 0.5H), 7.06 (d, J=7.8, 0.5H), 7.00 (d, J=7.5, 0.5H), 6.95-6.88 (m, 1H), 4.42-4.29 (m, 1H), 3.72 (s, 1.5H), 3.70 (s, 1.5H), 3.60 (d, J=13.3, 0.5H), 3.52 (d, J=13.2, 0.5H), 3.48 (d, J=13.3, 0.5H), 3.36 (d, J=13.2, 0.5H), 3.23-3.19 (m, 1H), 2.93 (dd, J=2.7, 9.0, 0.5H), 2.68-2.61 (m, 1H), 2.58 (dd, J=3.0, 8.9, 1H), 2.52-2.46 (m, 1H), 2.45-2.20 (m, 3H), 2.18-2.11 (m, 1H), 1.91 (dd, J=6.0, 12.0, 0.5H), 1.87-1.80 (m, 0.5H), 1.78-1.64 (m, 1H), 1.48-1.26 (m, J=28.4, 35.4, 1.5H), 1.20 (t, J=6.7, 3H), 0.70 (dd, J=2.8, 6.7, 3H); MS (ESI+) m/z 407 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]=[O:12])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[H-].[Na+].CS(O[CH2:20][CH2:21][O:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=1)(=O)=O>CN(C)C=O>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH2:20][CH2:21][O:22][C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=2)[CH:11]=[O:12])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CS(=O)(=O)OCCOc1ccc2ccccc2c1
Reactant: CC(=O)c1ccc(NC=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(N(C=O)CCOc2ccc3ccccc3c2)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 62 %

Procedure:
A stirred mixture of N-(4-acetylphenyl)formamide (4.9 g) in dimethylformamide (50 mL) under argon was treated with 55% sodium hydride (1.31 g), stireed for 15 minutes and treated with 2-(2-naphthalenyloxy)ethyl methanesulfonate (7.6 g). The mixture was heated at 60° C. overnight and worked upas in Example 20. The material from dichloromethane extraction was purified by HPLC (dichloromethane-ethyl acetate; 20:1 ) and crystallized from dichloromethane-hexane to provide 5.9 g of N-(4-acetylphenyl)-N[2-(2-naphthalenyloxy)ethyl]formamide as a colorless solid, mp 115°-116° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([C:10]([CH3:18])([CH2:15][C:16]#[N:17])[C:11](OC)=[O:12])=[CH:4][CH:3]=1.[H][H]>N.CO.[Ni]>[Cl:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([C:10]2([CH3:18])[CH2:15][CH2:16][NH:17][C:11]2=[O:12])=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: COC(=O)C(C)(CC#N)c1ccc(Cl)nc1OC
Agent: [Ni]
Agent: N
Solvent: CO
Product: COc1nc(Cl)ccc1C1(C)CCNC1=O
Yield: 90.4 %

Procedure:
A Parr bottle was charged with a solution of methyl 2-(6-chloro-2-methoxypyridin-3-yl)-3-cyano-2-methylpropanoate (2.35 g, 8.73 mmol) in 7 M ammonia in MeOH and a slurry of Raney nickel (5.82 g, 67.9 mmol, washed 2× with water and 4× with MeOH) in 7 M ammonia in MeOH (99 mL total to charge both reagents, 690 mmol). The reaction was shaken with hydrogen (30 psi) for 6 h. The catalyst was filtered through a pad of Celite® under nitrogen rinsing with EtOH. The filtrate was then concentrated to give a light green oil/foam. Purification by silica gel column chromatography (80 g RediSep Gold column, 30-100% Ethyl acetate/Heptanes) provided 3-(6-chloro-2-methoxypyridin-3-yl)-3-methylpyrrolidin-2-one (1.9 g, 90%) as a white solid. 1H NMR (600 MHz, CDCl3) δ: 1.56 (s, 3H), 2.08 (ddd, 1H), 2.58 (dt, 1H), 3.37 (td, 1H), 3.40-3.46 (m, 1H), 3.97 (s, 3H), 5.86 (br. s., 1H), 6.89 (d, 1H), 7.61 (d, 1H); MS (ES+)(M+H) 241.