Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[C:4]([F:12])[CH:3]=1.CCOCC.C([Li])CCC.CON(C)[C:26]([C@H:28]1[CH2:32][CH2:31][CH2:30][N:29]1[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[O:27]>C1COCC1>[F:12][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][C:5]=1[C:8]([F:11])([F:10])[F:9])[C:26]([C@H:28]1[CH2:32][CH2:31][CH2:30][N:29]1[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[O:27]
Reactant: CON(C)C(=O)[C@H]1CCCN1C(=O)OC(C)(C)C
Reactant: Fc1cc(Br)ccc1C(F)(F)F
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)c1ccc(C(F)(F)F)c(F)c1
Temperature: -78 °C
Yield: 35 %

Procedure:
To a solution of 4-bromo-2-fluoro-1-(trifluoromethyl)benzene (4.854 g, 19.98 mmol) and ether (50 mL) cooled to −78° C. was added butyl lithium (7.990 mL, 19.98 mmol) slowly over 10 min. The reaction was transferred via cannula to a solution of 74 (4.30 g, 16.65 mmol) in THF (50 mL) cooled to −78° C. The reaction was stirred for 10 min after all aryl lithium was added. The reaction was quenched with water and extracted with DCM. The organic layer was concentrated and the crude product purified by SiO2 chromatography eluting with an EtOAc/hexane (1 to 5% EtOAc). A close running impurity was not removed by this purification. A SiO2 column was run eluting with an Et2O/hexane gradient (1 to 3% Et2O). The impurity was still present and the compound was finally purified on a SP4 reverse phase column chromatography eluting with MeCN/water gradient (65 to 100% MeCN) to afford 2.105 g (33.2%) of (R)-tert-butyl 2-(3-fluoro-4-(trifluoromethyl)benzoyl)-pyrrolidine-1-carboxylate (76).
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:38])[CH:10]([CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)[N:11]1[C:15]2[CH:16]=[C:17]([F:21])[C:18]([F:20])=[CH:19][C:14]=2[N:13]=[C:12]1[C:22]1[C:23]([O:30][CH3:31])=[N:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.C(OC(=O)C)(=O)C.[N:50]([O-])=[O:51].[Na+]>>[CH2:1]([N:8]([N:50]=[O:51])[C:9](=[O:38])[CH:10]([CH:32]1[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]1)[N:11]1[C:15]2[CH:16]=[C:17]([F:21])[C:18]([F:20])=[CH:19][C:14]=2[N:13]=[C:12]1[C:22]1[C:23]([O:30][CH3:31])=[N:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=N[O-]
Reactant: COc1ccc(-c2nc3cc(F)c(F)cc3n2C(C(=O)NCc2ccccc2)C2CCCCC2)c(OC)n1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: COc1ccc(-c2nc3cc(F)c(F)cc3n2C(C(=O)N(Cc2ccccc2)N=O)C2CCCCC2)c(OC)n1
Temperature: 25 °C

Procedure:
To an ice-cold solution of 15 g (28.81 mmol) N-benzyl-2-cyclohexyl-2-[2-(2,6-dimethoxy-pyridin-3-yl)-5,6-difluoro-benzoimidazol-1-yl]-acetamide in 94 ml (1642 mmol) acetic acid and 198 ml (3486 mmol) acetic anhydride were added in 5 portions over 30 min. 9.94 g (144 mmol) sodium nitrite. The resulting solution was allowed to warm to room temperature overnight. The resulting yellow suspension was evaporated and the yellow slurry was taken up in 500 ml saturated aqueous sodium bicarbonate solution and 1500 ml ethyl acetate. The aqueous layer was extracted twice with 1500 ml ethyl acetate and once with 500 ml ethyl acetate. The combined organic layers were washed with water and brine. The remaining unsoluble material was filtered off and the filtrate dried over magnesium sulfate, filtered and evaporated until a suspension has formed. This suspensions was filtered and the filter cake washed twice with 50 ml ice-cold ethyl acetate and dried in high vacuum. Light yellow solid. MS (Turbo Spray): m/z=550.3 [M+H].
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:14]([CH3:18])=[C:15]([CH3:17])[N:16]=2)[CH:5]=[C:6]([C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9])[CH:7]=1.[Na+].[I-].C([O-])([O-])=O.[K+].[K+].[CH3:27][C:28]1[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[C:29]=1[CH2:30]Cl>C(O)(C)C.O>[CH3:27][C:28]1[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[C:29]=1[CH2:30][NH:1][C:2]1[C:3]2[N:4]([C:14]([CH3:18])=[C:15]([CH3:17])[N:16]=2)[CH:5]=[C:6]([C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9])[CH:7]=1
Reactant: Cc1cccc(C)c1CCl
Reactant: Cc1nc2c(N)cc(C(=O)OC(C)C)cn2c1C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Product: Cc1cccc(C)c1CNc1cc(C(=O)OC(C)C)cn2c(C)c(C)nc12
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 104.7 %

Procedure:
Isopropyl 8-amino-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxylate (9.85 kg, 1.0 equiv., 29.71 mol) was suspended in isopropanol (59 L); NaI (0.6 equiv., 2.68 kg, 17.88 mol) and is K2CO3 (2.5 equiv, 10.29 kg, 74.48 mol) were added and the mixture was heated to about 70° C. 2,6-Dimethylbenzyl chloride (1.1 equiv, 5.22 kg, 32.77 mol) was dissolved in isopropanol (˜60 L) and this solution was added to the reaction mixture. After the addition was complete, the temperature was kept at 60° C. for additional 1.5 hours. Additional K2CO3 was added (9.15 kg) and the resulting suspension was stirred for further 2 h at 60° C. Additional 2,6-dimethylbenzyl chloride (2.76 kg) in isopropanol (22L) was added slowly at an temperature of 60° C.; after the addition the reaction mixture was stirred for further 4 hours at this temperature. The suspension was diluted with water (124L), cooled, stirred and filtered. The filtercake was washed with water and then with cold isopropanol, dried under reduced pressure at 40° C. to give 11.37 kg wet material, yield: 90%.
Reaction SMILES: Cl.[OH:2][N:3]=[C:4]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:5]([NH:7][CH:8]([C:14](OCC)=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:6].CN(C)C.B>>[CH2:12]([O:11][C:9]([CH:8]1[NH:7][C:5](=[O:6])[CH:4]([CH2:19][CH:20]([CH3:22])[CH3:21])[N:3]([OH:2])[C:14]1=[O:15])=[O:10])[CH3:13]
Reactant: CCOC(=O)C(NC(=O)C(CC(C)C)=NO)C(=O)OCC
Agent: B
Agent: CN(C)C
Agent: Cl
Product: CCOC(=O)C1NC(=O)C(CC(C)C)N(O)C1=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 18.6 %

Procedure:
240 ml of 7N hydrochloric acid (an ethanolic solution) was dropwise added to 240 ml of an ethanolic solution containing 18.46 g of diethyl N-(2-hydroxyimino-4-methylpentanoyl)aminomalonate and 5.49 g of borane-trimethylamine, with ice-cooling. The mixture was stirred at room temperature for 15 hours. The reaction mixture was subjected to vacuum distillation at room temperature to remove the solvent. The residue was dissolved in dichloromethane. The resulting solution was washed with an aqueous solution saturated with sodium chloride and an aqueous solution saturated with sodium hydrogen carbonate in this order, then dried with anhydrous magnesium sulfate, and was subjected to distillation to remove the solvent. The resulting yellow oily substance was dissolved in 120 ml of toluene. The solution was refluxed for 1 hour and then subjected to distillation to remove the solvent. 19.02 g of the resulting orange oily substance was purified by silica gel column chromatography (eluant: dichloromethane/methanol =30/1) to obtain 2.94 g of 3-ethoxycarbonyl-1-hydroxy-6-isobutylpiperazine-2,5-dione as an orange oily substance.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.[S:36]1[CH:40]=[CH:39][CH:38]=[C:37]1[Sn](CCCC)(CCCC)CCCC.[F-].[Cs+]>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].O1CCOCC1>[CH3:14][N:11]1[CH2:12][CH2:13][N:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:37]3[S:36][CH:40]=[CH:39][CH:38]=3)[N:7]=2)[CH2:9][CH2:10]1
Reactant: CN1CCN(c2cccc(Cl)n2)CC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CN1CCN(c2cccc(-c3cccs3)n2)CC1
Temperature: 100 °C

Procedure:
To a vial was added 1-(6-chloro-pyridin-2-yl)-4-methyl-piperazine (27 mg, 0.13 mmol), Pd2(dba)3 (14 mg), 2-(di-t-butylphosphino)biphenyl (18 mg), 2-thienyltributylstannane (51 mg, 0.15 mmol), dioxane (1 mL) and CsF (39 mg, 0.26 mmol). The resulting mixture was heated at 100° C. for 24 hrs. The resulting mixture was extracted with EtOAc. The organic layer was dried and concentrated, and the residue was purified by preparative TLC (hexanes/EtOAc) to yield the title compound as a solid.
Reaction SMILES: Br[C:2]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[CH:6]=[CH:5][C:4]=2[CH:3]=1.[B:20](OC)([O:23]C)[O:21]C.O>CCCCCC.C1COCC1>[CH:19]1[C:14]2[C:13]3[C:12]4[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=4[CH:6]=[CH:5][C:4]=3[CH:3]=[C:2]([B:20]([OH:23])[OH:21])[C:15]=2[CH:16]=[CH:17][CH:18]=1
Reactant: Brc1cc2ccc3ccccc3c2c2ccccc12
Reactant: COB(OC)OC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: OB(O)c1cc2ccc3ccccc3c2c2ccccc12
Reaction time: 2 h

Procedure:
52 ml (130 mmol) of n-buthyllithium (2.5 M in n-hexane) are added dropwise to a suspension of 30.7 g (100 mmol) of 5-bromobenzo[c]phenanthrene in 1000 ml of THF at −78° C. with vigorous stirring, and the mixture is stirred for a further 2 h. 16.7 ml (150 mmol) of trimethyl borate are added to the red solution in one portion with vigorous stirring, the mixture is stirred at −78° C. for a further 30 min., then warmed to room temperature over the course of 3 h, 300 ml of water are added, and the mixture is stirred for 30 min. The organic phase is separated off and evaporated to dryness in vacuo. The solid is taken up in 100 ml of n-hexane, filtered off with suction, washed once with 100 ml of hexane and dried in vacuo. Yield: 24.8 g (91 mmol), 91%, purity about 90% (NMR) of boronic acid, with varying amounts of boronic anhydride and boronic acid. The boronic acid can be used in this form without further purification.
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]([CH3:13])[C:5]([C:7]1[CH:8]=[N:9][N:10]([CH3:12])[CH:11]=1)=[O:6].CN(C)CCN(C)CCN(C)C.[Li]C(C)(C)C.[C:31](=[O:33])=[O:32]>C1COCC1>[F:1][CH2:2][CH2:3][N:4]([CH3:13])[C:5]([C:7]1[CH:8]=[N:9][N:10]([CH3:12])[C:11]=1[C:31]([OH:33])=[O:32])=[O:6]
Reactant: O=C=O
Reactant: CN(CCF)C(=O)c1cnn(C)c1
Agent: CN(C)CCN(C)CCN(C)C
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CN(CCF)C(=O)c1cnn(C)c1C(=O)O
Temperature: -100 °C
Reaction time: 0.08 h
Yield: 50 %

Procedure:
In a 50 mL three-necked flask, N-(2-fluoroethyl)-N,1-dimethyl-1H-pyrazole-4-carboxamide (500 mg, 2.7 mmol) was combined with THF (10.0 ml) to give a colorless solution. 1,1,4,7,7-Pentamethyldiethylenetriamine (621 μl, 2.97 mmol) was added, and, after cooling down to −100° C., tBuLi (1.6 M in pentane, 2.53 ml, 4.05 mmol) was added dropwise. After stirring 30 min an excess of dry ice was carefully added. After 5 min, the cooling bath was removed and the mixture was allowed to warm up to RT. H2O was added and un-reacted starting material was removed by extraction with CH2Cl2. The aqueous layer was then acidified using 1 N HCl solution, and the acid was extracted using CH2Cl2. After drying over Na2SO4, filtration and concentration in vacuum, the viscous oil was dried in HV to yield 307 mg (50%) of product as a light brown viscous oil. MS: m/z=230.2 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:6](B2OC(C)(C)C(C)(C)O2)=[CH:5][CH:4]=[N:3]1.Br[C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[C:22](=[O:26])[N:21]([C@@H:27]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[CH:42]=1)[CH2:28][N:29]1[C:37](=[O:38])[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]1=[O:39])[CH2:20]2.C(N(CC)C(C)C)(C)C.O1CCOCC1.O>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:1][N:2]1[C:6]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[C:22](=[O:26])[N:21]([C@@H:27]([CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[CH:42]=2)[CH2:28][N:29]2[C:37](=[O:38])[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:30]2=[O:39])[CH2:20]3)=[CH:5][CH:4]=[N:3]1
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Reactant: O=C1c2ccccc2C(=O)N1C[C@H](Cc1cccc(F)c1)N1Cc2cc(Br)ccc2C1=O
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1COCCO1
Product: Cn1nccc1-c1ccc2c(c1)CN([C@@H](Cc1cccc(F)c1)CN1C(=O)c3ccccc3C1=O)C2=O
Temperature: 110 °C
Reaction time: 0.25 h
Yield: 65.3 %

Procedure:
A mixture of 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.557 g, 2.68 mmol), bis(tri-t-butylphosphine)palladium (0.114 g, 0.223 mmol), 2-[(2S)-2-(5-bromo-1-oxo-1,3-dihydro-2H-isoindol-2-yl)-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (1.10 g, 2.23 mmol) and N,N-diisopropylethylamine (1.16 mL, 6.69 mmol) in 1,4-dioxane (12 mL, 150 mmol) and water (0.60 mL, 33 mmol) was stirred under microwave at 110° C. for 15 minutes. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure. The residue was purified by combi-flash chromatography eluted with EtOAc/hexane (30-100%) to give 0.72 g (61% yield) of the desired product. LCMS found: 495.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2[S:9][CH:10]=[CH:11][C:12]=2[Br:13])[C:5]([Br:14])=[CH:4][C:3]=1[C:15]1[S:16][CH:17]=[CH:18][C:19]=1[Br:20].C1COCC1.C([N-]C(C)C)(C)C.[Li+].Cl[Si:35]([CH3:38])([CH3:37])[CH3:36]>O1CCCC1.CCCCCCC.C(C1C=CC=CC=1)C.O.CO>[Br:14][C:5]1[CH:4]=[C:3]([C:15]2[S:16][C:17]([Si:35]([CH3:38])([CH3:37])[CH3:36])=[CH:18][C:19]=2[Br:20])[C:2]([Br:1])=[CH:7][C:6]=1[C:8]1[S:9][C:10]([Si:35]([CH3:38])([CH3:37])[CH3:36])=[CH:11][C:12]=1[Br:13]
Reactant: C[Si](C)(C)Cl
Reactant: Brc1cc(-c2sccc2Br)c(Br)cc1-c1sccc1Br
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCCC
Solvent: CO
Product: C[Si](C)(C)c1cc(Br)c(-c2cc(Br)c(-c3sc([Si](C)(C)C)cc3Br)cc2Br)s1
Temperature: -78 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
A oven dried 1000 cm3 three neck flask is charged with 2,2′-(2,5-dibromobenzene-1,4-diyl)bis(3-bromothiophene) (12.00 g, 21.51 mmol) and anhydrous THF (430 cm3). The reaction is cooled down to −78° C. using a acetone dry ice bath, and then a 2.0M solution (22.0 cm3, 44.1 mmol) of lithium diisopropylamide in tetrahydrofuran/heptane/ethylbenzene is added dropwise. After the addition completion, the reaction mixture is kept at 78° C. for a hour, and then chlorotrimethylsilane (6.00 cm3, 47.3 mmol) is added quickly. The reaction is allowed to reach 23° C. overnight, and then methanol (100 cm3) and water (400 cm3) is added. The mixture is extracted with diethyl ether (3×300 cm3). The combined organic phases are washed with diluted aqueous chlorhydric acid (3×250 cm3) and water (300 cm3), dried over magnesium sulfate, and then the solvent removed in vacuo. The crude product is recrystallized in propan-2-ol to obtain the title product. (11.12 g, Yield: 74%). NMR (1H, 300 MHz, CDCl3): δ 7.68 (s, 2H); 7.16 (s, 2H); 0.36 (s, 18H). NMR (13C, 75 MHz, CDCl3): δ 142.52; 139.96; 136.60; 136.39; 136.25; 123.11; 112.71, −0.16.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH3:11])[N:9]=[CH:10][C:5]2=[C:4]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)[N:3]=1.[NH2:21][C:22]1[CH:27]=[CH:26][C:25](B2OC(C)(C)C(C)(C)O2)=[CH:24][N:23]=1>>[CH3:20][O:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[O:12][C:4]1[N:3]=[C:2]([C:25]2[CH:26]=[CH:27][C:22]([NH2:21])=[N:23][CH:24]=2)[N:7]=[C:6]2[N:8]([CH3:11])[N:9]=[CH:10][C:5]=12
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: COc1cccc(Oc2nc(Cl)nc3c2cnn3C)c1
Product: COc1cccc(Oc2nc(-c3ccc(N)nc3)nc3c2cnn3C)c1

Procedure:
6-Chloro-4-(3-methoxy-phenoxy)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (80 mg) was coupled to 2-aminopyridine-5-boronic acid pinacol ester via General Procedure A. The product was purified by reverse phase HPLC to yield 47.3 mg of 125. MS (Q1) 349.2 (M)+
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[O:28][C:13]3([CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=4)[CH2:15][CH2:14]3)[CH2:12][C:11](=[O:29])[C:10]=2[CH:30]=1)(=[O:4])=[O:3].N1C=CC=CC=1.[C:37](Cl)(=[O:39])[CH3:38]>C(Cl)Cl>[CH3:1][S:2]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[O:28][C:13]3([CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C:21]4[CH:22]=[CH:23][C:24]([NH:27][C:37](=[O:39])[CH3:38])=[CH:25][CH:26]=4)[CH2:15][CH2:14]3)[CH2:12][C:11](=[O:29])[C:10]=2[CH:30]=1)(=[O:3])=[O:4]
Reactant: CC(=O)Cl
Reactant: CS(=O)(=O)Nc1ccc2c(c1)C(=O)CC1(CCN(CCc3ccc(N)cc3)CC1)O2
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(CCN2CCC3(CC2)CC(=O)c2cc(NS(C)(=O)=O)ccc2O3)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 17.7 %

Procedure:
A suspension of 6-methanesulfonamido-3,4-dihydro-1'-(2-(4-aminophenyl)ethyl)-spiro[(2H)-1-benzopyran-2,4'-piperidine]-4-one (0.50 g, 1.2 mmol), and pyridine (0.09 mL, 1.2 mmol) in 25 mL of methylene chloride was cooled in an ice bath and treated dropwise with acetyl chloride (0.09 mL, 1.2 mmol). The mixture was stirred at 0° C. for 2 hours, and then filtered. The tan solid was washed with methylene chloride and dried in the air. The solid was found to be a mixture by thin layer analysis, and was chromatographed on silica gel using 10% methanol in methylene chloride eluant. The pure oil was dissolved in 20 mL of absolute ethanol and was treated with excess 4.8N ethanolic HCl. The solution was then concentrated to 10 mL. The resulting ivory colored solid was collected, washed with diethyl ether, and dried 3 hours at 100° C. under vacuum to give 0.10 g (18%) of product, mp 294° C. (dec).
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9]2)(=[O:5])=[O:4].[CH2:16]([O:18][C:19]([C:21]1[C:25]([CH2:26][CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[C:24]([CH:35]=O)[NH:23][C:22]=1[CH3:37])=[O:20])[CH3:17]>>[CH2:16]([O:18][C:19]([C:21]1[C:25]([CH2:26][CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[C:24]([CH:35]=[C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[C:6]([S:3](=[O:5])(=[O:4])[NH:2][CH3:1])[CH:7]=3)[NH:11][C:10]2=[O:15])[NH:23][C:22]=1[CH3:37])=[O:20])[CH3:17]
Reactant: CNS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Reactant: CCOC(=O)c1c(C)[nH]c(C=O)c1CCCN1CCOCC1
Product: CCOC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3ccc(S(=O)(=O)NC)cc32)c1CCCN1CCOCC1

Procedure:
2-Oxo-2,3-dihydro-1H-indole-5-sulfonic acid methylamide was stirred with 5-formyl-2-methyl-4-(3-morpholin-4-ylpropyl)-1H-pyrrole-3-carboxylic acid ethyl ester overnight at room temperature to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:16][CH2:17][O:18][CH3:19]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:16][CH2:17][O:18][CH3:19]
Reactant: Oc1ccccc1Br
Reactant: COCCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOc1ccccc1Br
Temperature: 90 °C
Yield: 59.9 %

Procedure:
To a solution of 2-bromophenol (500.0 mg, 2.89 mmol) in DMF (5 mL) was added cesium carbonate (2.82 g, 8.67 mmol). To this mixture was added 1-chloro-2-methoxyethane (0.26 mL, 2.89 mmol, Aldrich) and the mixture was heated at 90° C. for 4 h. After completion, the reaction mixture was diluted with water (3 mL) and extracted with ethyl acetate (2×10 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to get 1-bromo-2-(2-methoxyethoxyl)benzene (400 mg, 60.2%) as clear liquid that was used as such for next step without any purification. 1H NMR (400 MHz, DMSO) δ 7.57 (dd, J=7.9, 1.5 Hz, 1H), 7.39-7.24 (m, 1H), 7.13-7.05 (m, 1H), 6.89 (td, J=7.7, 1.2 Hz, 1H), 4.17 (t, J=4.6 Hz, 2H), 3.69 (t, J=4.6 Hz, 2H), 3.33 (s, 3H). MS (ESI, positive ion) m/z: 231.08 (M+1).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25](Br)=[CH:24][CH:23]=[C:22]([Cl:27])[N:21]=3)[C@H:14]2[CH3:28])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Cl:31][C:32]1[CH:33]=[CH:34][C:35]([O:41][CH3:42])=[C:36](B(O)O)[CH:37]=1.C([O-])([O-])=O.[K+].[K+].O>C1COCC1.[Pd](Cl)Cl.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2]>[F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:34]4[CH:33]=[C:32]([Cl:31])[CH:37]=[CH:36][C:35]=4[O:41][CH3:42])=[CH:24][CH:23]=[C:22]([Cl:27])[N:21]=3)[C@H:14]2[CH3:28])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1nc(Cl)ccc1Br
Reactant: COc1ccc(Cl)cc1B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(Cl)cc1-c1ccc(Cl)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1,1′-bis(di-t-butylphosphino)ferrocene palladium dichloride (0.263 g, 0.386 mmol) was added to a stirred, degassed mixture of INTERMEDIATE 9 (4.00 g, 7.73 mmol), 5-chloro-2-methoxy phenyl boronic acid (1.44 g, 7.73 mmol) and K2CO3 (4.27 g, 30.9 mmol) in THF (30 mL). The mixture was stirred at room temperature for 1 h. LCMS showed that no starting material was left. Water was added and the mixture was extracted with EtOAc (3×60 mL). The combined organic layers were washed with brine and dried (Na2SO4). The title compound was obtained as a colorless solid after flash chromatography using CH2Cl2/hexane (8:2) as the eluant.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH2:12][CH:13]([O:19][CH:20]([CH3:22])[CH3:21])[C:14]([O:16]CC)=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[Cl:23][C:24]1[CH:25]=[C:26]([N:30]=[C:31]=[O:32])[CH:27]=[CH:28][CH:29]=1>>[Cl:23][C:24]1[CH:25]=[C:26]([CH:27]=[CH:28][CH:29]=1)[NH:30][C:31]([O:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH2:12][CH:13]([O:19][CH:20]([CH3:21])[CH3:22])[C:14]([OH:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])=[O:32]
Reactant: CCOC(=O)C(Cc1ccc(OC)c(CCO)c1)OC(C)C
Reactant: O=C=Nc1cccc(Cl)c1
Product: COc1ccc(CC(OC(C)C)C(=O)O)cc1CCOC(=O)Nc1cccc(Cl)c1

Procedure:
Using ethyl 3-[3-(2-hydroxyethyl)-4-methoxyphenyl]-2-isopropoxypropanoate and 3-chlorophenylisocyanate, the title compound was obtained in the same manner as described in Example 148.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]([OH:13])(=[O:12])/[CH:9]=[CH:10]/[CH3:11]>C1(C)C=CC=CC=1>[C:2]1([NH:1][CH:10]([CH3:11])[CH2:9][C:8]([OH:13])=[O:12])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: C/C=C/C(=O)O
Solvent: Cc1ccccc1
Product: CC(CC(=O)O)Nc1ccccc1
Yield: 60.7 %

Procedure:
A mixture of aniline (3.0 g, 32 mmol) and crotonic acid (2.0 g, 23 mmol) in toluene (20 mL) was heated at reflux for 18 h. Removal of solvent and chromatography (silica gel, EtOAc/hexane, 9/1) of the crude material afforded 2.5 g (61%) of 3-phenylaminobutanoic acid. The acid was treated with PPA (20 mL) at 110° C. for 6 h and the reaction mixture was poured into ice water (50 mL) and then was neutralized with Na2CO3 to pH 7. Extraction with EtOAc (3×60 mL) followed by chromatography (silica gel, EtOAc/hexane, 4/6) afforded 1.0 g (44%) of 1,2,3,4-tetrahydro-2-methyl-4-quinolinone (structure 59A of Scheme XLVIII, where R1 =R3 =H, R2 =methyl) as a yellow solid. The quinolinone was treated with di-tert-butyl dicarbonate (2.2 g, 10 mmol) and DMAP (0.84 g, 6.8 mmol) in THF (15 mL) for 16 h followed by chromatography (silica gel, EtOAc/hexane, 2/8) to afford 1.1 g (68%) of 1-tert-butoxycarbonyl-1,2,3,4-tetrahydro-2-methyl-4-quinolinone as a yellow oil. Data for 1-tert-butoxycarbonyl-1,2,3,4-tetrahydro-2-methyl-4-quinolinone: 1H NMR (400 MHz, CDCl3) 7.99 (d, J=7.5, 1 H), 7.78 (d, J=7.5, 1 H), 7.50 (t, J=7.5, 1 H), 7.12 (t, J=7.5, 1 H), 5.10 (m, 1 H), 3.04 (dd, J=17.3, 5.8, 1 H), 2.57 (dd, J=17.3, 1.7, 1 H), 1.56 (s, 9 H), 1.22 (d, J=6.9, 3 H).