Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:62])[NH:4][CH:5]([C:9]([N:11]1[CH:17]([C:18]2[NH:19][C:20]([C:23]3[CH:32]=[CH:31][C:30]4[C:25](=CC=[C:28]([C:33]5[CH:38]=[CH:37][C:36]([C:39]6[NH:40][C:41]([CH:44]7[CH:49]8[CH2:50][CH:46](CC8)[N:45]7[C:51](=[O:61])[CH:52]([NH:56][C:57]([O:59][CH3:60])=[O:58])[CH:53]([CH3:55])[CH3:54])=[N:42][CH:43]=6)=[CH:35][CH:34]=5)[CH:29]=4)[CH:24]=3)=[CH:21][N:22]=2)[CH2:16][C:13]2(C[CH2:14]2)[CH2:12]1)=[O:10])[CH:6]([CH3:8])[CH3:7].COC(=O)N[CH:67](C(N1CCCC1C1NC(C2C=CC3C(=CC=C(B4OC(C)(C)C(C)(C)O4)C=3)C=2)=CN=1)=O)[CH:68](C)C.COC(=O)NC(C(N1CC(=C)CC1C1NC(C2C=CC(Br)=CC=2)=CN=1)=O)C(C)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(=O)([O-])[O-].[K+].[K+]>>[CH3:60][O:59][C:57](=[O:58])[NH:56][CH:52]([C:51]([N:45]1[CH2:46][CH2:50][CH2:49][CH:44]1[C:41]1[NH:40][C:39]([C:36]2[CH:35]=[CH:34][C:33]3[C:38](=[CH:67][CH:68]=[C:29]([C:30]4[CH:25]=[CH:24][C:23]([C:20]5[NH:19][C:18]([CH:17]6[CH2:16][C:13](=[CH2:14])[CH2:12][N:11]6[C:9](=[O:10])[CH:5]([NH:4][C:3]([O:2][CH3:1])=[O:62])[CH:6]([CH3:8])[CH3:7])=[N:22][CH:21]=5)=[CH:32][CH:31]=4)[CH:28]=3)[CH:37]=2)=[CH:43][N:42]=1)=[O:61])[CH:53]([CH3:54])[CH3:55]
Reactant: COC(=O)NC(C(=O)N1CC2(CC2)CC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6C7CCC(C7)N6C(=O)C(NC(=O)OC)C(C)C)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(B4OC(C)(C)C(C)(C)O4)ccc3c2)[nH]1)C(C)C
Agent: C=C1CC(c2ncc(-c3ccc(Br)cc3)[nH]2)N(C(=O)C(NC(=O)OC)C(C)C)C1
Agent: O=C([O-])[O-]
Agent: O=P([O-])([O-])[O-]
Product: C=C1CC(c2ncc(-c3ccc(-c4ccc5cc(-c6cnc(C7CCCN7C(=O)C(NC(=O)OC)C(C)C)[nH]6)ccc5c4)cc3)[nH]2)N(C(=O)C(NC(=O)OC)C(C)C)C1
Yield: 5 %

Procedure:
This compound was prepared using the procedure used to prepare [1-(6-{5-[6-(4-{2-[2-(2-Methoxycarbonylamino-3-methyl-butyryl)-2-aza-bicyclo[2.2.1]hept-3-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester using [2-Methyl-1-(2-{5-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester (0.177 g, 0.324 mmol) and (1-{2-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-4-methylene-pyrrolidine-1-carbonyl]-2-methyl-propyl)-carbamic acid methyl ester (0.100 g, 0.216 mmol). Potassium phosphate (aqueous, 0.32 mL, 0.648 mmol) was substituted for potassium carbonate and the reaction was performed under an argon atmosphere. The crude reaction was purified by reverse phase HPLC (10-45% acetonitrile: water; 0.1% formic acid modifier), and lyophilized giving [1-(2-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-4-methylene pyrrolidin-2-yl]-3H-imidazol-4-yl]-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (0.009 g, 5%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.12-7.96 (m, 1H), 7.93-7.79 (m, 5H), 7.77-7.67 (m, 5H), 6.32 (s, 1H), 5.73-5.54 (m, 1H), 5.50-5.22 (m, 6H), 4.49-4.28 (m, 3H), 3.96-3.82 (m, 2H), 3.72 (s, 9H), 3.06-2.86 (m, 2H), 2.50-2.34 (m, 1H), 2.31-2.21 (m, 1H), 2.18-2.09 (m, 2H), 2.05-1.95 (m, 3H), 1.90 (s, 4H), 1.26 (s, 3H), 1.13-1.04 (m, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[S:10][C:9]([C:15]4[N:16]([CH:20]([CH3:22])[CH3:21])[N:17]=[CH:18][N:19]=4)=[N:8][C:7]=3[C:6]=2[CH:23]=1.C([O-])(=O)C.[K+].[O:29]=[C:30]1[NH:35][C:34](=[O:36])[C:33](B(O)O)=[CH:32][NH:31]1>CN(C)C=O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:20]([N:16]1[C:15]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:5]4[CH:4]=[CH:3][C:2]([C:33]5[C:34](=[O:36])[NH:35][C:30](=[O:29])[NH:31][CH:32]=5)=[CH:23][C:6]=4[C:7]=3[N:8]=2)=[N:19][CH:18]=[N:17]1)([CH3:22])[CH3:21]
Reactant: O=c1[nH]cc(B(O)O)c(=O)[nH]1
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(Br)cc1-2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(-c3c[nH]c(=O)[nH]c3=O)cc1-2
Temperature: 25 °C

Procedure:
9-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene from Example 6 (500 mg, 1.3 mmol) and potassium acetate (380 mg, 3.8 mmol) were suspended in N,N-dimethylformamide (5 mL) and water (5 mL) and degassed by bubbling N2 for 5 min. Charged with 2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-ylboronic acid (250 mg, 1.6 mmol) and then tetrakis(triphenylphosphine)palladium(0) (150 mg, 0.13 mmol). The reaction was microwaved at 300 watts, 140° C. for 20 minutes. Subsequently after cooling to r.t. and diluting with water (20 mL), the mixture was extracted with ethyl acetate. The combined organics portions were concentrated and purified by reverse phase HPLC to provide 506 as a white crystalline compound (70 mg, 10% yield). LC/MS (ESI+): m/z 423.1 (M+H). 1H NMR (500 MHz, DMSO) δ 1.22 (s, 2H), 8.71 (s, 1H), 8.11 (s, 1H), 7.65 (s, 1H), 7.48 (d, J=8.2 Hz, 1H), 7.06 (d, J=8.4 Hz, 1H), 5.92-5.81 (m, 1H), 4.38 (s, 2H), 3.45 (s, 2H), 1.55 (d, J=6.5 Hz, 4H)
Reaction SMILES: [CH2:1]([S:3]([CH2:5][S:6][CH2:7][CH3:8])=[O:4])[CH3:2].[H-].[Na+].Br[CH2:12][CH2:13][CH2:14][N:15]1[C:19](=[O:20])[C:18]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]2[C:16]1=[O:25]>O1CCCC1>[CH2:7]([S:6][CH:5]([S:3]([CH2:1][CH3:2])=[O:4])[CH2:12][CH2:13][CH2:14][N:15]1[C:19](=[O:20])[C:18]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]2[C:16]1=[O:25])[CH3:8]
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: CCSCS(=O)CC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCSC(CCCN1C(=O)c2ccccc2C1=O)S(=O)CC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 10 mmole of [((ethylsulfinyl)methyl)-thio]ethane in 20 ml of tetrahydrofuran is treated with 10 mmole of sodium hydride at 25° C for 2 hours after which 10 mmole of N-(3-bromopropyl)phthalimide in 5 ml of tetrahydrofuran is added. The reaction mixture is stirred overnight at 25° C then quenched with brine and extracted with chloroform. The organic phase is washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromotography on silica gel to give N-(4-ethylthio-4-ethylsulfinylbutyl)phthalimide. To a solution of 22 mmole of N-(4-ethylthio-4-ethylsulfinylbutyl)phthalimide in 20 ml of tetrahydrofuran is added under nitrogen at 0° C a solution of lithium diisopropylamide in 23 mmole of tetrahydrofuran. The reaction mixture is stirred for 30 minutes at 25° C then is saturated with difluorochloromethane. Stirring is continued for 2 hours at 40° C. After quenching with brine, the reaction mixture is extracted with ether. The organic phase is decanted, washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give N-(4-ethylthio-4-ethylsulfinyl-4-difluoro-methylbutyl)phthalimide. To a solution of 30 mole of N-(4-ethylthio-4-ethylsulfinyl-4-difluoromethylbutyl)-phthalimide in 33 ml of acetonitrile is added at 0° C 1.1 ml of a 70% aqueous solution of perchloric acid. After stirring for 2 hours at 0° C the reaction mixture is poured into 60 ml of water then extracted with chloromethane. The organic phase is washed with brine, dried, filtered and the filtrate concentrated under reduced pressure to afford difluoromethyl 3-phthalimidopropyl ketone.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9](=[CH:10][C:11](B4OC(C)(C)C(C)(C)O4)=[CH:12][CH:13]=3)[O:8][CH2:7][C:6]=2[CH:24]=1.Br[C:26]1[CH:27]=[CH:28][C:29]2[N:33]=[C:32]([C@@H:34]3[C@@H:39]4[CH2:40][C@@H:36]([CH2:37][CH2:38]4)[N:35]3[C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[NH:31][C:30]=2[CH:48]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.CN(C)C=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.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]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9](=[CH:10][C:11]([C:27]4[CH:26]=[CH:48][C:30]5[N:31]=[C:32]([C@H:34]6[CH:39]7[CH2:40][C@H:36]([CH2:37][CH2:38]7)[N:35]6[C:41]([O:43][C:44]([CH3:46])([CH3:45])[CH3:47])=[O:42])[NH:33][C:29]=5[CH:28]=4)=[CH:12][CH:13]=3)[O:8][CH2:7][C:6]=2[CH:24]=1
Reactant: CC(C)(C)OC(=O)N1[C@@H]2CC[C@@H](C2)[C@H]1c1nc2ccc(Br)cc2[nH]1
Reactant: CC1(C)OB(c2ccc3c(c2)OCc2cc(Cl)ccc2-3)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Pd]
Solvent: COCCOC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1[C@H]2CCC(C2)[C@@H]1c1nc2ccc(-c3ccc4c(c3)OCc3cc(Cl)ccc3-4)cc2[nH]1
Temperature: 85 °C
Yield: 24.8 %

Procedure:
To a solution of 2-(8-chloro-6H-benzo[c]chromen-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (750 mg, 2.18 mmol), (1R,3S,4S)-tert-butyl 3-(6-bromo-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (1.07 mg, 2.72 mmol), tetrakis(triphenylphosphine) palladium(0) (75 mg, 0.07 mmol) and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (96 mg, 0.13 mmol) in a mixture of 1,2-dimethoxyethane (10 mL) and dimethylformamide (2 mL) was added a solution of potassium carbonate (2M in water, 3.5 mL, 6.53 mmol). The resulting mixture was degassed and then heated to 85° C. under argon for 18 hours. After cooling to room temperature, the reaction was diluted with ethyl acetate. The organics were washed with water and brine, dried (Na2SO4), and concentrated. The crude residue was purified by flash chromatography to yield (1S,3R)-tert-butyl 3-(6-(8-chloro-6H-benzo[c]chromen-3-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (285 mg, 25%) LCMS-ESI+: calculated for C31H30ClN3O3: 528.06; observed [M+1]+: 528.36.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH2:10][CH2:11][OH:12])[C:5]([C:13]#[N:14])=[CH:4][C:3]=1[NH:15][C:16]1[N:21]=[C:20]([N:22]([CH:32]2[CH2:34][CH2:33]2)[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[C:19]2=[N:35][CH:36]=[C:37]([C:38]#[N:39])[N:18]2[N:17]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH2:10][CH:11]=[O:12])[C:5]([C:13]#[N:14])=[CH:4][C:3]=1[NH:15][C:16]1[N:21]=[C:20]([N:22]([CH:32]2[CH2:33][CH2:34]2)[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[C:19]2=[N:35][CH:36]=[C:37]([C:38]#[N:39])[N:18]2[N:17]=1
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)c(CCCCO)cc3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COc1ccc(CN(c2nc(Nc3cc(C#N)c(CCCC=O)cc3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 72.8 %

Procedure:
2-((2-chloro-5-cyano-4-(4-hydroxybutyl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (186 mg, 0.343 mmol) was taken up in DCM (3 mL) and cooled to 0° C. Dess-Martin periodinane (189 mg, 0.445 mmol) was added, and the reaction was stirred at room temperature for 1.5 h. The reaction mixture was quenched with 2M K3PO4 solution and extracted 2× with DCM. The organic layers were combined, dried over Na2SO4, filtered, and concentrated. The material was purified by flash column chromatography (0-60% EtOAc/IIex; 40 g column). 2-((2-chloro-5-cyano-4-(4-oxobutyl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (135 mg) was obtained as a yellow glass.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][NH:7][C:8]2=[O:13].I[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:22]=1[CH3:23].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:23][C:22]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1[N:7]1[CH2:6][CH2:5][C:4]2[C:9](=[CH:10][CH:11]=[CH:12][C:3]=2[C:2]([F:1])([F:14])[F:15])[C:8]1=[O:13]
Reactant: O=C1NCCc2c1cccc2C(F)(F)F
Reactant: Cc1ccncc1I
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCc2c(cccc2C(F)(F)F)C1=O
Yield: 24.2 %

Procedure:
Using analogous reaction conditions as described in Example 1, 5-trifluoromethyl-3,4-dihydro-2H-isoquinolin-1-one (I-22d: 0.090 g, 0.4186 mmol) was reacted with 3-iodo-4-methyl-pyridine (0.091 g, 0.4186 mmol), 1,4-dioxane (10 mL), copper iodide (0.007 g, 0.04186 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (0.017 g, 0.1255 mmol) and potassium phosphate (0.221 g, 1.0465 mmol) to afford the crude product. Purification by column chromatography on silica gel (60% ethylacetate in hexane) afforded 0.031 g of the product (24% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9]O)=[N:6][CH:7]=1.BrC1C=CC(CC[I:20])=CN=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][I:20])=[N:6][CH:7]=1
Reactant: OCCc1ccc(Br)cn1
Reactant: Brc1ccc(CCI)cn1
Product: Brc1ccc(CCI)nc1
Yield: 77 %

Procedure:
The title compound (3571 mg, 77%) was prepared from 2-(5-bromopyridin-2-yl)ethanol (Compound 6, Preparation 4) (3.0 g, 14.9 mmol) by a procedure analogous to that described for the preparation of 2-bromo-5-(2-iodoethyl)pyridine in Preparation 2, Step 1. MS (LCMS) m/z 312.0 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.24-3.36 (m, 2H) 3.41-3.56 (m, 2H) 7.06 (d, J=8.20 Hz, 1H) 7.74 (dd, J=8.20, 2.34 Hz, 1H) 8.60 (d, J=2.34 Hz, 1H).
Reaction SMILES: [C:1]([Si:5]([CH3:25])([CH3:24])[O:6][CH:7]([C:9]([CH3:23])([CH:21]=[CH2:22])[C:10](N1[C@@H](C(C)C)COC1=O)=[O:11])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[OH:26]O.O.[OH-].[Li+]>O1CCCC1.O>[C:1]([Si:5]([CH3:25])([CH3:24])[O:6][CH:7]([C:9]([CH3:23])([CH:21]=[CH2:22])[C:10]([OH:11])=[O:26])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=CC(C)(C(=O)N1C(=O)OC[C@@H]1C(C)C)C(C)O[Si](C)(C)C(C)(C)C
Reactant: OO
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C=CC(C)(C(=O)O)C(C)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 40.4 %

Procedure:
A cooled (0° C.) solution of (S)-3-{2-[1-(tert-butyl-dimethyl-silanyloxy)-ethyl]-2-methyl-but-3-enoyl}-4-isopropyl-oxazolidin-2-one (1.729 g, 4.677 mmol) in tetrahydrofuran/water (60 mL, 2:1) was subsequently treated with hydrogen peroxide (30% aqueous, 2.4 mL, 23.385 mmol) and lithium hydroxide monohydrate (392.4 mg, 9.355 mmol). After stirring for 2 days at room temperature, hydrogen peroxide (30% aqueous, 2.4 mL, 23.385 mmol) and lithium hydroxide monohydrate (400 mg, 9.535 mmol) were added at 0° C. After stirring at room temperature for 4 days, the reaction was quenched with solid sodium metabisulfite (18 g). After stirring for 1 h at room temperature, the pH was adjusted with hydrochloric acid (1 M) to pH 2 at 0° C. The aqueous layer was extracted with ethyl acetate (2×). The organics were combined, dried over anhydrous sodium sulfate, filtered and the volatiles were removed in vacuo. The residue was purified by silica gel chromatography using a 100 g Isolute cartridge eluted with a continuous gradient of iso-hexanes/diethyl ether 1:0 to 7:3 to afford the title compound (488.0 mg, 40%) as a yellow solid and as a single pair of enantiomers along with unreacted (S)-3-{2-[1-(tert-butyl-dimethyl-silanyloxy)-ethyl]-2-methyl-but-3-enoyl}-4-isopropyl-oxazolidin-2-one (431.5 mg, 25%, LCMS (m/z) 370.1 [M+H], Tr=3.93 min) as the other single pair of enantiomers as a colourless oil. 1H NMR (300 MHz, CDCl3) δ 0.12 (s, 6H), 0.92 (s, 9H), 1.18 (d, J=6.0 Hz, 3H), 1.34 (s, 3H), 3.99 (q, J=6.2 Hz, 1H), 5.18 (d, J=17.8 Hz, 1H), 5.28 (d, J=10.5 Hz, 1H), 6.22 (dd, J=17.6, 11.2 Hz, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:6]=1[N+:15]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:12])([F:13])[F:14])=[CH:7][C:6]=1[NH2:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)c1ccc(C(F)(F)F)cc1N

Procedure:
A solution of 2-t-butyl-5-trifluoromethylnitrobenzene (26.0 g, 105 mmol) in ethanol (95%, 100 mL) is treated with 10% Pd/C (2 g) and placed under a hydrogen atmosphere (40 psi) on a Parr apparatus for 1.5 h. The mixture is filtered, concentrated and purified by silica gel chromatography (7:1 hexane to ethyl acetate) to give 2-t-butyl-5-trifluoromethylaniline as an oil; yield: 20.2 g (89%).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:7]([O:14][C:15]1[CH:20]=[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:18]([Cl:29])=[CH:17][C:16]=1[C:30](=[O:33])[CH2:31]Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)=[O:40])([CH3:37])([CH3:36])[CH3:35]>CN(C)C=O>[C:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][N:44]([CH2:31][C:30]([C:16]2[CH:17]=[C:18]([Cl:29])[C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:20][C:15]=2[O:14][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:33])[CH2:43][CH2:42]1)=[O:40])([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(CBr)c1cc(Cl)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(CC(=O)c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)CC1
Reaction time: 2 h
Yield: 80.7 %

Procedure:
Cesium carbonate (2.95 g, 9 mmol) was added in three portions to a stirred solution of 1-(2,4-Bis-benzyloxy-5-chloro-phenyl)-2-bromo-ethanone (4.4 g, 9 mmol) and piperazine-1-carboxylic acid tert-butyl ester (1.74 g, 9 mmol) in dimethylformamide (20 ml). The suspension was stirred for 2 h then partitioned between water (200 ml) and ethyl acetate (3×50 ml). The combined organic extracts were washed with water (100 ml), dried over magnesium sulphate and concentrated to give 4-[2-(2,4-Bis-benzyloxy-5-chloro-phenyl)-2-oxo-ethyl]-piperazine-1-carboxylic acid tert-butyl ester as a yellow oil (4 g)
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[O:4]CC1.OS(O)(=O)=O.CCOC(C)=O>C1COCC1.O>[O:4]=[C:5]1[CH2:6][CH2:7][N:8]([C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)[CH2:9][CH2:10]1
Reactant: N#Cc1ccc(N2CCC3(CC2)OCCO3)cc1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(N2CCC(=O)CC2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 83.7 %

Procedure:
To 4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-benzonitrile (460 mg, 1.88 mmol, reference example 117) dissolved in THF (2 mL) was added 10% H2SO4 (4 mL) and the reaction was stirred for 24 h at room temperature. TLC (40% EtOAc in hexanes) shows a small amount of starting material, but mainly a more polar product. The reaction was diluted with water, extracted with dichloromethane (3×), washed with saturated aqueous NaCl solution, dried with Na2SO4, filtered and evaporated. The crude product was chromatographed on silica gel (20-40% EtOAc in hexanes) to afford the title compound (315 mg, 84%). 1H NMR (CDCl3): δ 7.52 (d, 2H), 6.88 (d, 2H), 3.72 (t, 4H), 2.57 (t, 4H). MS (ion spray) m/z 200 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15](B3OC(C)(C)C(C)(C)O3)[CH:16]=2)[N:11]([S:27]([C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[CH:10]=1.[CH3:37][N:38]([CH3:49])[C:39]([C:41]1[CH:46]=[C:45](Cl)[N:44]=[N:43][C:42]=1[NH2:48])=[O:40].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.C(=O)([O-])[O-].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCCC1.C(#N)C>[CH3:37][N:38]([CH3:49])[C:39]([C:41]1[CH:46]=[C:45]([C:15]2[CH:16]=[C:17]3[C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])=[CH:10][N:11]([S:27]([C:30]4[CH:31]=[CH:32][C:33]([CH3:36])=[CH:34][CH:35]=4)(=[O:28])=[O:29])[C:12]3=[N:13][CH:14]=2)[N:44]=[N:43][C:42]=1[NH2:48])=[O:40]
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: CN(C)C(=O)c1cc(Cl)nnc1N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1CCOC1
Solvent: CC#N
Product: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cc(C(=O)N(C)C)c(N)nn3)cc12
Temperature: 80 °C

Procedure:
3-(2-Methoxy-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (138.4 mg, 0.274 mmol), 3-amino-6-chloro-pyridazine-4-carboxylic acid dimethylamide (54.9 mg, 0.274 mmol), palladium acetate (3.0 mg, 0.013 mmol) and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (S-Phos) (11.2 mg, 0.0274 mmol) were combined under nitrogen. Acetonitrile (0.5 mL), tetrahydrofuran (0.5 mL) and 1 M aqueous potassium carbonate (0.822 mL, 0.822 mmol) were added and the vial was flushed with nitrogen, capped and heated at 80° C. for 15 h. The layers were separated. The organics were diluted with ethyl acetate and washed with brine (1×), dried over sodium sulfate and adsorbed onto silica gel. The material was purified by flash chromatography on silica gel using a gradient of ethyl acetate in hexanes to afford 3-amino-6-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-pyridazine-4-carboxylic acid dimethylamide. MS: m/z 543 (M+H+).
Reaction SMILES: [C:1]([C:4]1([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)[CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]1)(O)=[O:2].O1CCCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O>[OH:2][CH2:1][C:4]1([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)[CH2:5][CH2:6][C:7](=[O:10])[CH2:8][CH2:9]1
Reactant: O=C1CCC(C(=O)O)(c2cccc3ccccc23)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=C1CCC(CO)(c2cccc3ccccc23)CC1
Reaction time: 6 h
Yield: 99 %

Procedure:
A solution of 3.84 g. (0.0123 mole) of 4-carboxy-4-(1-naphthyl)cyclohexanone, ethylene ketal (prepared in Example 29) in 80 ml. of tetrahydrofuran is added to 0.5 g. (0.013 mole) of lithium aluminum hydride in 10 ml. of tetrahydrofuran. Following about 6 hours of heating at reflux the mixture is cooled in ice and treated successively with 0.5 ml. of water, 0.5 ml. of 15% sodium hydroxide solution and 1.5 ml. of water. The resulting inorganic gel is collected on a filter and rinsed with ether. The combined filtrates are evaporated to dryness to give 3.95 g. (99% yield) of 4-hydroxymethyl-4-(1-naphthyl)cyclohexanone, ethylene ketal as an amorphous gum.
Reaction SMILES: [Cl:1][C:2]1[C:10]([NH:11][S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:9]2[C:5]([CH:6]=[C:7]([C:20](=[S:22])[NH2:21])[NH:8]2)=[CH:4][CH:3]=1.Br[CH:24]([CH:27]=O)[CH:25]=[O:26].CN(C)C(=O)C>O>[Cl:1][C:2]1[C:10]([NH:11][S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:9]2[C:5]([CH:6]=[C:7]([C:20]3[S:22][C:24]([CH2:25][OH:26])=[CH:27][N:21]=3)[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=CC(Br)C=O
Reactant: NC(=S)c1cc2ccc(Cl)c(NS(=O)(=O)c3cccs3)c2[nH]1
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=S(=O)(Nc1c(Cl)ccc2cc(-c3ncc(CO)s3)[nH]c12)c1cccs1
Temperature: 90 °C
Reaction time: 3 h
Yield: 53.6 %

Procedure:
A mixture of 6-chloro-7-[(2-thienylsulfonyl)amino]-1H-indole-2-carbothioamide (0.75 g), bromomalonaldehyde (0.45 g) and N,N-dimethylacetamide (10 mL) was stirred at 90° C. for 3 hr. Water was added to the reaction mixture, and the obtained crystals were filtrated, washed with water and dried. To a mixture of the obtained crystals, tetrahydrofuran (10 mL) and methanol (5 mL) was added sodium borohydride (84 mg) at 0° C., and the mixture was stirred at the same temperature for 30 min. To the reaction mixture was added 10% aqueous citric acid solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography and the title compound (0.46 g, yield 55%) was obtained as pale-yellow crystals from a fraction eluted with tetrahydrofuran-hexane (3:1, volume ratio). melting point 197-199° C.