Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:12](=[O:25])(=[O:24])[NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)=[C:6]([CH2:8][C:9](O)=[O:10])[CH:7]=1.[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.O>CN(C=O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:12]([NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)(=[O:25])=[O:24])=[C:6]([CH2:8][C:9](=[O:10])[N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[CH:7]=1
Reactant: C1CCNC1
Reactant: Nc1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)c(CC(=O)O)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)c(CC(=O)N2CCCC2)c1
Reaction time: 16 h
Yield: 6.7 %

Procedure:
To a stirred solution of 2-(5-amino-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)acetic acid (360 mg, 1 mmol) and pyrrolidine (0.5 mL, 6 mmol) in 10 mL of DMF was added PyBOP (780 mg, 1.5 mmol) and TEA (0.5 mL, 3.56 mmol). The reaction mixture was stirred for 16 hours. After water was added, the reaction mixture was extracted with ethyl acetate and washed with water, 1N HCl and brine. The organic layer was dried over Na2SO4 and concentrated. The crude residue was purified by prep HPLC (SunFire Prep C18 OBD 5 uM 30×50 mm column) to give the desired product as a white powder (28 mg, yield 7%). MS calcd for (C19H22BN3O5S): 415.1. MS found (ESI negative): (M−H)−=414.1. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.77 (s, 1H), 9.17 (bs, 1H), 7.44 (m, 2H), 7.23 (d, J=8 Hz, 1H), 7.11 (dd, J=8, 2 Hz, 1H), 6.37 (m, 2H)), 4.87 (s, 2H), 3.82 (s, 2H), 3.32 (m, 4H), 1.81 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH2:38]([O:40][C:41]([N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)=[O:42])[CH3:39]>>[CH2:38]([O:40][C:41]([N:43]1[CH2:44][CH2:45][N:46]([C:21]2[N:20]=[C:19]([O:18][C:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:29]=[C:30]([N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)[CH:31]=[C:2]([F:1])[CH:3]=4)=[CH:9][CH:10]=3)[CH:24]=[CH:23][N:22]=2)[CH2:47][CH2:48]1)=[O:42])[CH3:39]
Reactant: CCOC(=O)N1CCNCC1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Product: CCOC(=O)N1CCN(c2nccc(Oc3ccc(NC(=O)c4cc(F)cc(N5CCOCC5)c4)c4ccccc34)n2)CC1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and piperazine-1-carboxylic acid ethyl ester according to conditions described in general procedure C. 1HNMR (400 MHz, CDCl3) δ 1.27 (t, J=7.6 Hz, 3 H), 3.27 (s, 4 H), 3.44 (m, 4 H), 3.64 (s, 4 H), 3.89 (m, 4 H), 4.12-4.17 (m, 2 H), 6.07-6.09 (m, 1H), 6.78-6.81 (m, 1 H), 7.10 (d, J=8.0 Hz, 1 H), 7.31-7.35 (m, 2 H), 7.51-7.61 (m, 2 H), 7.92-8.01 (m, 2 H), 8.19-8.24 (m, 2 H).
Reaction SMILES: [Cl:1][C:2]1[C:6]([CH2:7][CH3:8])=[C:5]([C:9]2[CH:10]=[C:11]([C:14]([OH:16])=O)[S:12][CH:13]=2)[N:4]([CH3:17])[N:3]=1.[NH2:18][C@@H:19]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39]([F:42])([F:41])[F:40])[CH2:20][N:21]1[C:29](=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]1=[O:31].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>ClCCl>[Cl:1][C:2]1[C:6]([CH2:7][CH3:8])=[C:5]([C:9]2[CH:10]=[C:11]([C:14]([NH:18][C@@H:19]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[C:39]([F:42])([F:40])[F:41])[CH2:20][N:21]3[C:29](=[O:30])[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:22]3=[O:31])=[O:16])[S:12][CH:13]=2)[N:4]([CH3:17])[N:3]=1
Reactant: CCc1c(Cl)nn(C)c1-c1csc(C(=O)O)c1
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCc1c(Cl)nn(C)c1-c1csc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.2 %

Procedure:
To a solution of 4-(3-chloro-4-ethyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (120 mg, 0.44 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (171 mg, 0.44 mmol)[prepared according to Preparation 6] and n,n-diisopropylethylamine (0.39 ml, 2.22 mmol) in Dichloromethane (4.6 ml) at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (228 mg, 0.49 mmol) in one portion. The solution stirred at 25° C. for 1 h and was then dry loaded onto silica and purified via column chromatography (silica, 30-70% EtOAc in hexanes) yielding 4-(3-chloro-4-ethyl-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-2-thiophenecarboxamide (190 mg, 0.30 mmol, 68% yield) as a white solid: LCMS (ES) m/e 601, 603 (M, M+2)+.
Reaction SMILES: [Mg].II.Br[C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1.[N:12]1[CH:17]=[CH:16][N:15]=[C:14]2[C:18]([O:20][C:21](=[O:22])[C:13]=12)=[O:19].Cl>C1COCC1>[F:11][C:8]1[CH:9]=[CH:10][C:5]([C:18]([C:14]2[C:13]([C:21]([OH:22])=[O:20])=[N:12][CH:17]=[CH:16][N:15]=2)=[O:19])=[CH:6][CH:7]=1
Reactant: O=C1OC(=O)c2nccnc21
Reactant: Fc1ccc(Br)cc1
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: O=C(O)c1nccnc1C(=O)c1ccc(F)cc1
Temperature: 25 °C

Procedure:
To a suspension of magnesium (4.2 g) in THF (20 ml) was added iodine (catalytic amount) while stirring at room temperature under argon atmosphere. To the mixture was then added dropwise a solution of 1-bromo-4-fluorobenzene (22.8 g) in THF (60 ml), and the mixture was stirred for 30 minutes. The mixture was added dropwise, while stirring at room temperature, to a solution of 2,3-pyrazinedicarboxylic anhydride (20.0 g) in THF (100 ml), followed by stirring for one hour. The reaction mixture was poured into dilute HCl (adjusting the pH to 4 to 5), followed by extraction with ethyl acetate. The extract solution was washed with water and dried, then the solvent was distilled off to give 3-(4-fluorobenzoyl)-2-pyrazinecarboxylic acid as a colorless oily product (25.8 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@@:8]2([CH3:17])[NH:13][C:12](=O)[CH2:11][S:10](=[O:16])(=[O:15])[CH2:9]2)[CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:28])=CC=1>O1CCOCC1.C([O-])(O)=O.[Na+]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@@:8]2([CH3:17])[NH:13][C:12](=[S:28])[CH2:11][S:10](=[O:16])(=[O:15])[CH2:9]2)[CH:7]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: C[C@@]1(c2cc(Br)ccc2F)CS(=O)(=O)CC(=O)N1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: C[C@@]1(c2cc(Br)ccc2F)CS(=O)(=O)CC(=S)N1
Temperature: 80 °C
Reaction time: 2 h
Yield: 103.6 %

Procedure:
To a solution of (R)-5-(5-bromo-2-fluoro-phenyl)-5-methyl-1,1-dioxo-1λ6-thio morpholin-3-one (3.11 g, 9.25 mmol, Eq: 1.00) in dioxane (72.3 ml) was added Lawesson's reagent (2.99 g, 7.4 mmol, Eq: 0.8) at 23° C. The mixture was stirred for 2 hours at 80° C. Diluted with sat. NaHCO3-sol., extracted with ethyl acetate, washed with brine, dried over Na2SO4 and filtered off. Removal of solvent in vacuum left a yellow oil (5.8 g), which was purified by flash chromatography on 50 g silica gel with 0-50% ethyl acetate in heptane to give the (R)-5-(5-bromo-2-fluoro-phenyl)-5-methyl-1,1-dioxo-1λ6-thio morpholin-3-thione (2.7 g, 7.67 mmol, 82.9% yield) as a light yellow foam. MS (ISN): m/z=350.1 [M−H]− and 352.2 [M+2−H]−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][C:8]2[O:9][CH:10]=[C:11]([C:13]([OH:15])=O)[N:12]=2)=[CH:5][CH:4]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([C:28]2([CH2:33][NH:34]C(C3N=C(CC4C=CC(OC)=CC=4)SC=3)=O)[CH2:32][CH2:31][CH2:30][CH2:29]2)[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]>>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([C:28]2([CH2:33][NH:34][C:13]([C:11]3[N:12]=[C:8]([CH2:7][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:17][CH:16]=4)[O:9][CH:10]=3)=[O:15])[CH2:29][CH2:30][CH2:31][CH2:32]2)[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]
Reactant: COc1ccc(Cc2nc(C(=O)O)co2)cc1
Reactant: COc1ccc(Cc2nc(C(=O)NCC3(c4ccc(OC)c(OC)c4)CCCC3)cs2)cc1
Product: COc1ccc(Cc2nc(C(=O)NCC3(c4ccc(OC)c(OC)c4)CCCC3)co2)cc1
Yield: 66 %

Procedure:
Starting from 2-(4-Methoxy-benzyl)-oxazole-4-carboxylic acid 25 g, 0.1 mmol) and [2-(3,4-Dimethoxy-phenyl)-2-methyl]-propylamine (47 mg, 0.2 mmol) following a similar procedure reported for the preparation of 2-(4-Methoxy-benzyl)-thiazole-4-carboxylic acid[1-(3,4-dimethoxy-phenyl)-cyclopentylmethyl]-amide, the amide (30 mg, 66%) was obtained as a white solid. ESI-MS m/Z calc. 450.5, found 451.2(M+1)+. Retention time of 3.51 minutes 1H NMR (400 MHz, CDCl3) δ1.68-2.19 (m, 8H), 3.50 (d, J=6.3 Hz, 2H), 3.81 (s, 3H), 3.88 (s, 3H), 3.92 (s, 3H), 4.00 (s, 2H), 6.73-6.88 (m, 6H), 7.20 (d, J=8.7 Hz, 2H), 8.07 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH2:9][C:10]([CH2:12][O:13][C:4]=2[CH:3]=1)=[O:11].[CH2:14]([O:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8]/[C:9](=[CH:27]\[C:26]3[CH:29]=[CH:30][C:23]([O:22][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:24][CH:25]=3)/[C:10](=[O:11])/[C:12](=[CH:27]/[C:26]3[CH:29]=[CH:30][C:23]([O:22][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:24][CH:25]=3)/[O:13][C:4]=2[CH:3]=1
Reactant: Cc1ccc2c(c1)OCC(=O)CO2
Reactant: CCCCCCCCOc1ccc(C=O)cc1
Product: CCCCCCCCOc1ccc(/C=C2\Oc3ccc(C)cc3O/C(=C\c3ccc(OCCCCCCCC)cc3)C2=O)cc1

Procedure:
Calone is reacted with 4-octyloxybenzaldehyde analogously to the reaction conditions of Example 1, giving 7-methyl-2,4-bis[1-(4-octyloxyphenyl)meth-(Z)-ylidene]benzo[b]-1,4-dioxepin-3-one.
Reaction SMILES: [Cl-].[Ce+3].[Cl-].[Cl-].[CH3:5][Mg]Br.[CH:8](=[C:15]1/[CH2:16][C:17]2([CH2:41][CH3:42])[C:23]3=[CH:24][C:25]4[CH:26]=[N:27][N:28]([C:31]5[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=5)[C:29]=4[CH:30]=[C:22]3[CH2:21][CH2:20][CH2:19][CH:18]2[CH2:38][C:39]/1=[O:40])/[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1COCC1>[CH:8](=[C:15]1/[CH2:16][C:17]2([CH2:41][CH3:42])[C:23]3=[CH:24][C:25]4[CH:26]=[N:27][N:28]([C:31]5[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=5)[C:29]=4[CH:30]=[C:22]3[CH2:21][CH2:20][CH2:19][CH:18]2[CH2:38][C:39]/1([CH3:5])[OH:40])/[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCC12C/C(=C\c3ccccc3)C(=O)CC1CCCc1cc3c(cnn3-c3ccc(F)cc3)cc12
Reactant: C[Mg]Br
Agent: [Ce+3]
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCC12C/C(=C\c3ccccc3)C(C)(O)CC1CCCc1cc3c(cnn3-c3ccc(F)cc3)cc12
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 55 %

Procedure:
THF (2 mL) was added to cerium(III) chloride (0.130 g, 0.527 mmol). The suspension was warmed to about 50° C. for about 30 min then cooled to about −78° C. A solution of methylmagnesium bromide (3.0 M solution in Et2O, 0.165 mL, 0.495 mmol) and THF (2 mL) was added dropwise and the reaction mixture was stirred for about 15 min. A solution of rac-(4aS,12bR,E)-2-benzylidene-12b-ethyl-9-(4-fluorophenyl)-1,4,4a,5,6,7,9,12b-octahydrobenzo[6,7]cyclohepta[1,2-f]indazol-3 (2H)-one (53, R1=4-Fluorophenyl, R2=Ethyl) (0.100 g, 0.215 mmol) and THF (2 mL) was added dropwise via syringe and the reaction was stirred at about −78° C. for about 1 h. Methylmagnesium bromide (3.0 M solution in Et2O, 0.16 mL, 0.48 mmol) was added. After about 1 h, methylmagnesium bromide (3.0 M solution in Et2O, 0.1 mL, 0.3 mmol) was added. After about 1 h, the reaction was quenched with MeOH (1 mL) maintaining an internal temperature of less than about −60° C. Sat. aq. NH4Cl (2 mL), water (2 mL), and EtOAc (20 mL) were added and the mixture was allowed to warm to rt. EtOAc (50 mL) and water (20 mL) were added. The layers were separated and the aqueous layer was extracted with EtOAc (20 mL). The combined organics were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified on silica gel (25 g) using a gradient of 0-10% EtOAc in heptane. The product fractions were combined and concentrated under reduced pressure to give rac-(3R,4aS,12bR,E)-2-benzylidene-12b-ethyl-9-(4-fluorophenyl)-3-methyl-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazol-3-ol (54, R1=4-Fluorophenyl, R2=Ethyl, R3=Methyl) (0.057 g. 55% yield); LC/MS, method 3, Rt=3.16 min.; MS m/z: 481 (M+H)+. 1H NMR (400 MHz, DMSO) δ 7.76-7.70 (m, 2H), 7.64 (s, 1H), 7.62-7.55 (m, 2H), 7.46 (s, 1H), 7.43-7.35 (m, 5H), 6.86 (s, 1H), 6.80 (s, 1H), 4.57 (s, 1H), 3.63-3.53 (m, 1H), 3.06-2.86 (m, 2H), 2.36-1.99 (m, 4H), 1.81-1.61 (m, 2H), 1.61-1.42 (m, 3H), 1.39 (s, 3H), 1.30-1.22 (m, 1H), 0.51 (t, J=7.3 Hz, 3H).
Reaction SMILES: CN(C)C=O.Cl[CH2:7][CH2:8][O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([O:20][C:21]3[C:22]([CH3:31])=[N:23][C:24]4[C:29]([CH:30]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:32][CH3:33].C(=O)([O-])[O-].[K+].[K+].[NH:40]1[CH2:45][CH2:44][CH:43]([C:46]([O:48][CH2:49][CH3:50])=[O:47])[CH2:42][CH2:41]1>O>[CH3:33][O:32][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:10]=1[O:9][CH2:8][CH2:7][N:40]1[CH2:45][CH2:44][CH:43]([C:46]([O:48][CH2:49][CH3:50])=[O:47])[CH2:42][CH2:41]1)[N:17]=[CH:16][CH:15]=[C:14]2[O:20][C:21]1[C:22]([CH3:31])=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=2
Reactant: CCOC(=O)C1CCNCC1
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1CCN(CCOc2cc3nccc(Oc4cc5ccccc5nc4C)c3cc2OC)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 73.5 %

Procedure:
N,N-Dimethylformamide (1 ml) was added to 7-(2-chloro-ethoxy)-6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinoline (compound 353) (50 mg), potassium carbonate (53 mg), and ethyl piperidine-4-carboxylate (60 mg), and the mixture was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (48 mg, yield 73%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([Cl:8])=[N:6][CH:7]=1.[CH3:10][C:11]([CH3:13])=O.FC(F)(F)C(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(OC(C)C)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:9][CH:11]([CH3:13])[CH3:10])[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Nc1cc(Br)cnc1Cl
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)OC(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Nc1cc(Br)cnc1Cl
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 102.6 %

Procedure:
5-bromo-2-chloropyridin-3-amine (1.889 g, 9.1 mmol) was dissolved in isopropyl acetate (20 ml) and acetone (0.81 ml, 11 mmol), trifluoroacetic acid (1.40 ml, 18 mmol), and sodium triacetoxyborohydride (2.34 g, 11 mmol) were added. The reaction was stirred under nitrogen at room temperature for almost 4.5 hours and then quenched with 10% sodium hydroxide in water (˜20 ml) to raise the pH to about 9. The layers were separated, and the aqueous phase was extracted with EtOAc. The organic extracts were combined, dried over sodium sulfate, filtered, concentrated, and dried under high vacuum to afford 5-bromo-2-chloro-N-isopropylpyridin-3-amine (2.33 g, 89% purity, 100% yield). MS (ESI pos. ion) m/z: 249 (MH+, 79Br), 251 (MH+, 81Br). Calculated exact mass for C8H10BrClN2 248 (79Br), 250 (81Br).
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5])[CH3:2].[C:10](OC(=O)C)(=[O:12])[CH3:11]>O>[C:10]([NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[CH:9][C:3]=1[CH2:1][CH3:2])(=[O:12])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: CCc1ccccc1N
Solvent: O
Product: CCc1ccccc1NC(C)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.9 %

Procedure:
commercial 2-ethylaniline (50 mL, 0.40 mol) was dissolved in acetic anhydride (160 mL, 1.70 mol) and stirred at room temperature for 2 h. Then the reaction mixture was poured into H2O, the whole was extracted with ethyl acetate (2×200 mL). The combined organic extracts were washed with 5% aqueous NaHCO3, brine, dried (K2CO3), filtered and concentrated to provide the title compound as a white solid (60.0 g, 92%).
Reaction SMILES: [C:1]([O:4][CH:5]([C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])[C:6](=O)[C:7]([CH3:10])([CH3:9])[CH3:8])(=O)[CH3:2].C([O-])(=O)C.[NH4+:22]>C(O)(=O)C.O.[OH-].[Na+]>[CH3:8][C:7]([C:6]1[N:22]=[C:1]([CH3:2])[O:4][C:5]=1[C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:10])[CH3:9]
Reactant: CC(=O)OC(C(=O)C(C)(C)C)C(=O)C(C)(C)C
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Cc1nc(C(C)(C)C)c(C(=O)C(C)(C)C)o1
Yield: 92.5 %

Procedure:
A solution of 4-(acetyloxy)-2,2,6,6-tetramethyl 3,5-heptanedione (22 g, 0.09 mol) in acetic acid (100 mL) is treated with ammonium acetate (44 g). The reaction mixture is heated at reflux overnight. The reaction mixture is diluted with water and neutralized (to pH 5) by the addition of aqueous sodium hydroxide. The product is extracted into ethyl acetate (3×150 mL) and the combined organic layers are washed with 0.1 N NaOH, water, and then brine. The organic layer is dried and evaporated. The residue is taken up in hexane (50 mL) and applied to a pad of silica gel (500 g). The silica pad is eluted with hexane (100 mL). Then the product is eluted from the silica with hexane/ethyl acetate (4:1) to give 18.6 g (91%) of 1-[4-(1,1-dimethylethyl)-2-methyl-5 oxazolyl]-2,2-dimethyl-1-propanone as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:10]([C:11]([OH:13])=[O:12])=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[Cl:14][C:15]1[C:16]([N:21]2[C:25]([C:26](O)=O)=[CH:24][C:23]([C:29]([F:32])([F:31])[F:30])=[N:22]2)=[N:17][CH:18]=[CH:19][CH:20]=1.N1C=CC=CC=1.CS(Cl)(=O)=O>C(#N)C>[Cl:14][C:15]1[C:16]([N:21]2[C:25]([C:26]3[O:12][C:11](=[O:13])[C:10]4[C:2](=[CH:3][CH:4]=[C:5]5[CH:6]=[CH:7][NH:8][C:9]5=4)[N:1]=3)=[CH:24][C:23]([C:29]([F:32])([F:30])[F:31])=[N:22]2)=[N:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Reactant: Nc1ccc2cc[nH]c2c1C(=O)O
Agent: CS(=O)(=O)Cl
Solvent: CC#N
Solvent: c1ccncc1
Product: O=c1oc(-c2cc(C(F)(F)F)nn2-c2ncccc2Cl)nc2ccc3cc[nH]c3c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24.4 %

Procedure:
To a suspension of 79 mg (0.45 mmol) of 6-amino-1H-indole-7-carboxylic acid in 7 mL of acetonitrile, is added 130 mg (0.45 mmol) of 2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid followed by 0.16 mL (2.06 mmol) of pyridine. The mixture is stirred at ambient temperature during 30 minutes. Then the suspension is cooled to 0° C. and 0.12 mL (1.57 mmol) of methanesulfonyl chloride is added dropwise. The mixture is stirred at 0° C. during 30 minutes and 2 hours at ambient temperature. After evaporation of the solvent, the residue is triturated with a minimum of cold water. The precipitate which is formed is filtrated and washed with cold water. The residue is then purified by column chromatography on silica gel with hexanes and ethyl acetate as eluents and 47.1 mg (0.11 mmol, 25%) of a yellowish solid are obtained; LC/MS:432/434 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:3](I)=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2.[C:15]([C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[C:20]([Cl:27])[CH:19]=1)([OH:17])=[O:16]>>[Cl:27][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][C:21]=1[C:3]1[C:2]([F:1])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:12][CH3:13])[CH:9]=2)[CH:4]=1)[C:15]([OH:17])=[O:16]
Reactant: COc1ccc2cc(I)c(F)cc2c1
Reactant: O=C(O)c1ccc(B(O)O)c(Cl)c1
Product: COc1ccc2cc(-c3ccc(C(=O)O)cc3Cl)c(F)cc2c1
Temperature: 90 °C
Yield: 70 %

Procedure:
Followed the coupling procedure described in Step 1 of Example 20, where the starting materials were 3-fluoro-2-iodo-6-methoxynaphthalene (Intermediate 6) and 4-carboxy-2-chlorophenylboronic acid and wherein the reaction was heated to 90° C. for 3 hours. The desired product (380 mg, yield 70%) was isolated as a solid after workup.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[F:11].[C:12]([CH:14]1[CH2:16][CH2:15]1)#[CH:13]>>[CH:14]1([C:12]#[C:13][C:2]2[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=2[F:11])[CH2:16][CH2:15]1
Reactant: O=[N+]([O-])c1ccc(F)c(Br)c1
Reactant: C#CC1CC1
Product: O=[N+]([O-])c1ccc(F)c(C#CC2CC2)c1

Procedure:
2-Bromo-1-fluoro-4-nitrobenzene and ethynylcyclopropane were reacted by method MA. The product with the molecular weight of 205.19 (C11H8FNO2) was obtained in this way; MS (ESI): 206 (M+H+).
Reaction SMILES: C1(OC2C=CC=CC=2)C=CC=CC=1.[C:14]([N:17]1[CH2:22][CH2:21][N:20]([C:23]2[N:28]=[C:27]([NH:29][CH:30]=[C:31]([C:37]([O:39]CC)=O)[C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:26]=[CH:25][N:24]=2)[CH2:19][CH2:18]1)(=[O:16])[CH3:15]>CCCCCC>[C:14]([N:17]1[CH2:18][CH2:19][N:20]([C:23]2[N:24]=[CH:25][C:26]3[C:37](=[O:39])[C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:30][NH:29][C:27]=3[N:28]=2)[CH2:21][CH2:22]1)(=[O:16])[CH3:15]
Reactant: CCOC(=O)C(=CNc1ccnc(N2CCN(C(C)=O)CC2)n1)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCCCCC
Product: CCOC(=O)c1c[nH]c2nc(N3CCN(C(C)=O)CC3)ncc2c1=O
Temperature: 25 °C
Yield: 86.1 %

Procedure:
To diphenyl ether (16 ml) kept at 250°-255° C. was added with stirring diethyl N-[2-(4-acetyl-1-piperazinyl)-4-pyrimidinyl]-aminomethylenemalonate (2.0 g). The mixture was gently refluxed for 10 minutes, and then allowed to cool to room temperature. To the mixture was added n-hexane (12 ml). The resulting precipitate was collected, washed with ethanol, and recrystallized from ethanol to yield ethyl 2-(4-acetyl-1-piperazinyl)-5,8-dihydro-5-oxopyrido[2,3-d]pyrimidine-6-carboxylate (1.52 g), m.p. 300°-302° C. (decomp.).