Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14](=[O:29])[CH2:15][NH:16][C:17](=[O:28])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[CH2:9]1.[C:30](O)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.CCN(CC)CC.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl.CCOC(C)=O>[C:30]([NH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14](=[O:29])[CH2:15][NH:16][C:17](=[O:28])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:26])([F:27])[F:25])[CH:19]=2)[CH2:9]1)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(O)c1ccccc1
Reactant: N[C@H]1CCCC[C@H]1N1CC[C@@H](NC(=O)CNC(=O)c2cccc(C(F)(F)F)c2)C1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCN([C@@H]2CCCC[C@@H]2NC(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.9 %

Procedure:
To a stirred solution of N-(2-{[(3R)-1-(cis-2-aminocyclohexyl)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide (0.48 g, 0.6 mmol) and benzoic acid (0.088 g, 0.72 mmol) in CH2Cl2 (5 mL) was added Et3N (0.25 mL, 1.8 mmol) followed by EDC (0.138 g, 0.72 mmol) and HOBt (0.097 g, 0.72 mmol). The mixture was stirred at room temperature overnight. Then the reaction mixture was diluted with EtOAc and washed with saturated Na2CO3 and brine. The organic layer was dried (MgSO4), concentrated and flash chromatographed (EtOAc to 10% MeOH/EtOAc) to give 0.13 g of the title compound. MS (EI) calcd: (M+H)+=517.2; found: 517.3.
Reaction SMILES: [C:1]([CH2:4][C@@H:5]1[CH2:17][C:16]2[C:15]3[C:14]([O:18][CH:19]4[CH2:24][CH2:23][CH:22]([NH:25]C(=O)OC(C)(C)C)[CH2:21][CH2:20]4)=[N:13][CH:12]=[N:11][C:10]=3[S:9][C:8]=2[CH2:7][CH2:6]1)(=[O:3])[NH2:2].[ClH:33]>ClCCl>[ClH:33].[NH2:25][CH:22]1[CH2:23][CH2:24][CH:19]([O:18][C:14]2[C:15]3[C:16]4[CH2:17][C@@H:5]([CH2:4][C:1]([NH2:2])=[O:3])[CH2:6][CH2:7][C:8]=4[S:9][C:10]=3[N:11]=[CH:12][N:13]=2)[CH2:20][CH2:21]1
Reactant: CC(C)(C)OC(=O)NC1CCC(Oc2ncnc3sc4c(c23)C[C@@H](CC(N)=O)CC4)CC1
Agent: Cl
Solvent: ClCCl
Product: NC(=O)C[C@H]1CCc2sc3ncnc(OC4CCC(N)CC4)c3c2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed tert-butyl N-(4-[[(12S)-12-(carbamoylmethyl)-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraen-3-yl]oxy]cyclohexyl)carbamate (80 mg, 0.17 mmol, 1.00 equiv) in dichloromethane (5 mL) at 0° C. Then hydrochloric acid (6 M, 0.5 mL) was added and the resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum to give 86 mg (crude) of 2-[(12S)-3-[(4-aminocyclohexyl)oxy]-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraen-12-yl]acetamide hydrochloride as a yellow solid. The crude hydrochloride dissolved in 5 mL of methanol was added HCHO (37%, 1 mL) and AcOH (0.5 mL). After stirring for 30 min, NaCNBH3 (34 mg, 0.54 mmol, 2.50 equiv) was added and the resulting mixture was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The crude product (80 mg) was purified by preparative HPLC under the following conditions (Waters): column: X bridge Prep C18 5 um, 19*150 mm; mobile phase: water with 0.05% NH4HCO3 and CH3CN (5.0% CH3CN up to 41.0% in 9 min, up to 95.0% in 2 min, down to 5.0% in 2 min); flow rate: 20 mL/min; UV detection at 220/254 nm. This resulted in 21.5 mg (26%) of 2-[(12S)-3-[[4-(dimethylamino)cyclohexyl]oxy]-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraen-12-yl]acetamide as a white solid. MS: m/z 389 (M+H)+. 1H NMR (400 MHz, CDCl3): δ 8.51 (s, 1H), 5.47-5.40 (d, 2H), 5.25-5.19 (m, 1H), 3.31-3.25 (m, 1H), 2.92-2.90 (m, 2H), 2.61-2.55 (m, 1H), 2.41-2.29 (m, 11H), 2.20-2.15 (m, 1H), 2.13-2.00 (m, 2H), 1.69-1.56 (m, 6H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C@@H:8]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=1)[C@H:9]([OH:25])[CH2:10][NH:11][C:12]1([C:15]2[CH:20]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:18]=[CH:17][N:16]=2)[CH2:14][CH2:13]1)([CH3:4])([CH3:3])[CH3:2].[CH3:35][O:36][C:37](=[O:55])[C:38]1[CH:43]=[C:42]([CH3:44])[N:41]=[C:40]([O:45][CH2:46][CH2:47][CH2:48][CH2:49]OS(C)(=O)=O)[CH:39]=1>>[CH3:35][O:36][C:37](=[O:55])[C:38]1[CH:43]=[C:42]([CH3:44])[N:41]=[C:40]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][O:33][C:29]2[CH:30]=[CH:31][CH:32]=[C:27]([CH2:26][C@H:8]([NH:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:34])[C@H:9]([OH:25])[CH2:10][NH:11][C:12]3([C:15]4[CH:20]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:18]=[CH:17][N:16]=4)[CH2:14][CH2:13]3)[CH:28]=2)[CH:39]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccc(O)c1)[C@H](O)CNC1(c2cc(C(C)(C)C)ccn2)CC1
Reactant: COC(=O)c1cc(C)nc(OCCCCOS(C)(=O)=O)c1
Product: COC(=O)c1cc(C)nc(OCCCCOc2cccc(C[C@H](NC(=O)OC(C)(C)C)[C@H](O)CNC3(c4cc(C(C)(C)C)ccn4)CC3)c2)c1

Procedure:
The product is prepared according to the method described in example 43 (step a), starting from [(1S,2R)-3-[1-(4-tert-butyl-pyridin-2-yl)cyclopropylamino]-2-hydroxy-1-(3-hydroxy-benzyl)-propyl]-carbamic acid tert-butyl ester (building block C16) and 2-(4-methanesulfonyloxy-butoxy)-6-methyl-isonicotinic acid methyl ester (building block E1).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH:7]=[O:8].[C:9]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])[CH:10]=[CH2:11].C(=O)([O-])[O-].[K+].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:7]([C:6]1[CH:5]=[CH:4][S:3][C:2]=1/[CH:11]=[CH:10]/[C:9]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:8]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: O=Cc1ccsc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)/C=C/c1sccc1C=O
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A suspension of 1 g of 2-bromothiophene-3-carbaldehyde, 3.8 ml of tert-butyl acrylate, 120 mg of palladium acetate, 420 mg of tetra-n-butylammonium bromide, and 610 mg of potassium carbonate in 10 ml of DMF was stirred at 100° C. overnight. After leaving to be cooled, the insoluble material was filtered through Celite, and to the filtrate were added water and ethyl acetate to carry out a layer separation operation. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 660 mg of tert-butyl (2E)-3-(3-formyl-2-thienyl)acrylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]([CH2:13][C:14](OC)=[O:15])[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[N:4]=[C:5]([CH2:13][CH:14]=[O:15])[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: COC(=O)Cc1nc(OC)cc2ccccc12
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: COc1cc2ccccc2c(CC=O)n1
Reaction time: 1 h

Procedure:
To 1 part of methyl 3-methoxy-2-azanaphthaleneacetate in 25 parts by volume of toluene at -78° C. is slowly added 0.33 part of diisobutylaluminum hydride in toluene. The reaction is stirred for 1 hour and allowed to come to room temperature. The reaction is quenched with ethylacetate followed by ice water. The organic layer is washed with saturated sodium chloride, dried with anhydrous sodium sulfate, and 3-methoxy-2-azanaphthaleneacetaldehyde is isolated.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][NH:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[NH2:24][CH2:25][CH2:26][N:27]1[CH2:31][CH2:30][CH2:29][C:28]1=[O:32]>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][NH:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:24][CH2:25][CH2:26][N:27]2[CH2:31][CH2:30][CH2:29][C:28]2=[O:32])=[O:21])=[CH:17][N:16]=1
Reactant: Cc1onc(-c2ccccc2)c1CNc1ccc(C(=O)O)cn1
Reactant: NCCN1CCCC1=O
Product: Cc1onc(-c2ccccc2)c1CNc1ccc(C(=O)NCCN2CCCC2=O)cn1
Yield: 83 %

Procedure:
As described for example 162b, 6-[(5-methyl-3-phenyl-isoxazol-4-ylmethyl)-amino]-nicotinic acid (200 mg, 0.65 mmol) was converted using 1-(2-amino-ethyl)-pyrrolidin-2-one instead of ethanolamine to the title compound (trituration with tert-butylmethylether, 224 mg, 83%) which was obtained as a white solid. MS: m/e=420.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([CH2:32][CH3:33])=[CH:28][CH:27]=2)=[CH:4][C:5]([C@H:14]2[C@H:19]([OH:20])[C@@H:18]([OH:21])[C@H:17]([OH:22])[C@@H:16]([CH2:23][OH:24])[O:15]2)=[C:6]([CH:13]=1)[CH2:7][O:8][CH2:9][C:10](=[O:12])[CH3:11].[BH4-].[Na+].CO>C1COCC1>[Cl:1][C:2]1[C:3]([CH2:25][C:26]2[CH:27]=[CH:28][C:29]([CH2:32][CH3:33])=[CH:30][CH:31]=2)=[CH:4][C:5]([C@H:14]2[C@H:19]([OH:20])[C@@H:18]([OH:21])[C@H:17]([OH:22])[C@@H:16]([CH2:23][OH:24])[O:15]2)=[C:6]([CH2:7][O:8][CH2:9][CH:10]([OH:12])[CH3:11])[CH:13]=1
Reactant: CCc1ccc(Cc2cc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c(COCC(C)=O)cc2Cl)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1ccc(Cc2cc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c(COCC(C)O)cc2Cl)cc1
Temperature: 25 °C
Yield: 67.5 %

Procedure:
To a solution of 1-(5-chloro-4-(4-ethylbenzyl)-2-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)benzyloxy)propan-2-one (compound K) (3.7 mg, 0.0077 mmol) in dry THF (0.5 mL) was added NaBH4 (1.76 mg, 0.0045 mmol) with stirring under argon at room temperature. After the mixture was stirred for 20 min, anhydrous methanol was added dropwise, and the resulting mixture was stirred at 20° C. for 2 h, then quenched by addition of sat. NH4Cl. The mixture was extracted with EtOAc and the combined organic layers were washed with water, brine, dried over Na2SO4, filtered and concentrated to provide the crude product, which was purified by preparative TLC to yield 2.5 mg of the product. 1H-NMR (CD3OD, 300 MHz) δ 7.45 (s, 1H), 7.43 (s, 1H), 7.08 (s, 4H), 4.75-4.56 (m, 1H), 4.47 (dd, J=9.3 Hz, 3.3 Hz, 1H), 4.10 (d, J=14.8 Hz, 1H), 4.05 (d, J=14.8 Hz, 1H), 3.93-3.83 (m, 2H), 3.68-3.66 (m, 1H), 3.47-3.37 (m, 6H), 2.60 (q, J=7.8 Hz, 2H), 1.21 (t, J=7.8 Hz, 3H), 1.15 (d, J=7.8 Hz, 3H); LC-MS (m/z) 481 [(M+1)+], 525 [(M+45)−].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].O=[C:10]1[CH2:14][CH2:13][CH2:12][CH:11]1[C:15]#[N:16].[Cl-].[Ca+2].[Cl-]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:10]2[CH2:14][CH2:13][CH2:12][C:11]=2[C:15]#[N:16])[CH:6]=[CH:7][CH:8]=1
Reactant: N#CC1CCCC1=O
Reactant: Nc1cccc(Cl)c1
Agent: [Ca+2]
Agent: [Cl-]
Product: N#CC1=C(Nc2cccc(Cl)c2)CCC1

Procedure:
3-Chloro-aniline (Aldrich Chemicals) (5.1 g, 40.0 mmol), cyano-ketone (Example 11) (4.4 g, 40.4 mmol) and calcium chloride (5.0 g, 45.0 mmol) in T.H.F. (60 ml) were heated under reflux for 17 hours. After cooling, the mixture was filtered and the solvent evaporated. Kugelrohr distillation (150° C., 0.2 mmHg) gave the product as light yellow powder.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:3]=1[CH2:22][C:23]([O:25][CH3:26])=[O:24].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>ClC1C=CC=CC=1Cl>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:3]=1[CH2:22][C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Clc1ccccc1Cl
Product: COC(=O)Cc1c(C)nc2sc3ccccc3c2c1-c1ccc(C)cc1
Yield: 56.1 %

Procedure:
A suspension of methyl [2-methyl-4-p-tolyl-5,6,7,8-tetrahydro[1]benzothieno [2,3-b]pyridin-3-yl]acetate (0.225 mg; 0.616 mmol) and 2,3-Dichloro-5,6-Dicyanobenzoquinone (0.351 mg; 1.546 mmol) in 1,2-dichlorobenzene (2 mL) was placed in a sealed tube and was irradiated in a microwave oven at 190° C. for 10 minutes. The reaction mixture was then evaporated to dryness under reduced pressure. The residue was suspended in dichloromethane and the solid was filtered through celite. The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate (10-30%) in heptane to afford 0.125 g (56%) of the title compound as a pink solid.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([OH:16])=O)=[CH:11][CH:12]=2)[C@H:7]([O:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2].Cl.C1C=CC2N(O)N=[N:38][C:36]=2C=1.CN>ClCCl.O>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([NH:38][CH3:36])=[O:16])=[CH:11][CH:12]=2)[CH:7]([O:17][C:18]2[CH:19]=[CH:20][C:21]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[CH:22][CH:23]=2)[CH2:6][CH:5]1[CH3:30])(=[O:3])[CH3:2]
Reactant: On1nnc2ccccc21
Reactant: CC(=O)N1c2ccc(C(=O)O)cc2[C@H](Oc2ccc(N3CCOCC3)cc2)C[C@@H]1C
Agent: CN
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CNC(=O)c1ccc2c(c1)C(Oc1ccc(N3CCOCC3)cc1)CC(C)N2C(C)=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
48.6 mg of (2S,4R)-1-acetyl-2-methyl-4-(4-morpholinophenoxy)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid, 27.2 mg of WSCD.HCl, and 24.6 mg of HOBt.H2O were dissolved in 1 mL of dichloromethane, and the solution was stirred for 1.5 hours at room temperature. 178 μL of monomethylamine (2.0 M tetrahydrofuran solution) was added to the reaction liquid, and the mixture was stirred for another 1.5 hours at room temperature. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted three times with chloroform. The extraction product was washed with saturated brine, dehydrated over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by using silica gel chromatography (chloroform:methanol=10:1), and then was recrystallized from chloroform-hexane. Thus, 27.2 mg (53.3%, cis:trans=15:1) of the title compound was obtained as a white crystalline powder.
Reaction SMILES: Cl[C:2]1[N:24]=[C:5]2[C:6]([NH:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:25][N:26]1[CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([NH2:35])[CH:32]=2)[CH2:27]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:23][N:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][NH:10][C:6]1[C:5]2[N:4]([N:3]=[C:2]([NH:35][C:31]3[CH:32]=[C:33]4[C:28](=[CH:29][CH:30]=3)[CH2:27][N:26]([CH3:25])[CH2:34]4)[N:24]=2)[CH:9]=[CH:8][CH:7]=1)[S:19]([CH3:22])(=[O:21])=[O:20]
Reactant: CN(c1ccccc1CNc1cccn2nc(Cl)nc12)S(C)(=O)=O
Reactant: CN1Cc2ccc(N)cc2C1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1Cc2ccc(Nc3nc4c(NCc5ccccc5N(C)S(C)(=O)=O)cccn4n3)cc2C1

Procedure:
N-Methyl-N-(2-{[2-(2-methyl-2,3-dihydro-1H-isoindol-5-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino]-methyl}-phenyl)-methanesulfonamide was prepared from N-{2-[(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-methyl]-phenyl}-N-methyl-methanesulfonamide (75.0 mg, 0.205 mmol) and 2-methyl-2,3-dihydro-1H-isoindol-5-ylamine (34.0 mg, 0.229 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a tan foam (0.052 g, 53%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.82 (d, J=6.6 Hz, 1H), 7.55-7.50 (m, 2H), 7.37-7.28 (m, 4H), 7.13 (d, J=7.9 Hz, 1H), 6.70-6.65 (m, 2H), 6.37 (d, J=7.7 Hz, 1H), 5.23 (t, J=5.7 Hz, 1H), 4.73 (d, J=6.3 Hz, 2H), 3.94 (s, 2H), 3.88 (s, 2H), 3.31 (s, 3H), 3.01 (s, 3H), 2.60 (s, 3H). MS=478 (MH)+.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[NH:5][C:6]([Br:9])=[CH:7][N:8]=1.[CH3:10][Si:11]([CH3:18])([CH3:17])[CH2:12][CH2:13][O:14][CH2:15]Cl.C(OCC)(=O)C>CN(C)C=O>[Br:3][C:4]1[N:5]([CH2:15][O:14][CH2:13][CH2:12][Si:11]([CH3:18])([CH3:17])[CH3:10])[C:6]([Br:9])=[CH:7][N:8]=1
Reactant: Brc1cnc(Br)[nH]1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1c(Br)cnc1Br
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 41 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.212 g, 5.30 mmol) was added in portions to a 0° C. solution of 2,5-dibromo-1H-imidazole (0.600 g, 2.67 mmol) in N,N-dimethylformamide (4 mL), and the resulting mixture stirred for 30 min at 0° C. A solution of 2-(trimethylsilyl)ethoxymethyl chloride (0.665 g, 4.01 mmol) in N,N-dimethylformamide (0.5 mL) was added at 0° C., and the resulting solution stirred for an additional 2.5 h at room temperature. The reaction mixture was poured into ethyl acetate (20 mL), washed with brine (3×5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified via column chromatography on silica gel (eluting with 10:1, ethyl acetate/petroleum ether) to afford 2,5-dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (0.390 g, 41%) as light yellow oil. MS (ESI, pos. ion) m/z 357, 355, 359 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[O:12]=[C:13]1[C:18]2=[CH:19][NH:20][C:21]([CH:22]=O)=[C:17]2[CH2:16][CH2:15][O:14]1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[CH:22][C:21]3[NH:20][CH:19]=[C:18]4[C:13](=[O:12])[O:14][CH2:15][CH2:16][C:17]=34)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: O=Cc1[nH]cc2c1CCOC2=O
Product: O=C1Nc2cc(Cl)ccc2C1=Cc1[nH]cc2c1CCOC2=O

Procedure:
6-Chloro-1,3-dihydro-indol-2-one was condensed with 4-oxo-2,4,6,7-tetrahydro-pyrano[3,4-c]pyrrole-1carbaldehyde to give the title compound. MS m/z 315.2 [M++1].
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]([C:11]1[CH:12]=[C:13]([CH:19]=[C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:21]=1[OH:22])[CH:14]=[CH:15][C:16]([OH:18])=O)([CH3:10])[CH3:9].[CH3:27][C:28]([N:31]([C:33]([OH:35])=[O:34])[NH2:32])([CH3:30])[CH3:29]>C(Cl)Cl.CN(C)C=O>[CH3:27][C:28]([N:31]([C:33]([OH:35])=[O:34])[NH:32][C:16](=[O:18])[CH:15]=[CH:14][C:13]1[CH:12]=[C:11]([C:8]([CH3:7])([CH3:10])[CH3:9])[C:21]([OH:22])=[C:20]([C:23]([CH3:25])([CH3:24])[CH3:26])[CH:19]=1)([CH3:30])[CH3:29]
Reactant: CC(C)(C)N(N)C(=O)O
Reactant: CC(C)(C)c1cc(C=CC(=O)O)cc(C(C)(C)C)c1O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(C=CC(=O)NN(C(=O)O)C(C)(C)C)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.6 %

Procedure:
Oxalyl chloride (2.9 g, 0.023 mole) is added dropwise to a stirred 0° C. solution of 3,5-bis(1,1-dimethylethyl)-4-hydroxycinnamic acid (4.3 g, 0.016 mole) in methylene chloride (30 ml) and N,N-dimethylformamide (0.5 ml). After one hour the solvent is removed in vacuo. The residue is dissolved in methylene chloride (30 ml) and added dropwise to a stirred 0° C. solution of 1,1-dimethylethyl hydrazinecarboxylic acid (4.5 g, 0.034 mole). After the addition is complete, the mixture is allowed to warm to room temperature and stir 18 hours. The mixture is concentrated in vacuo and the residue dissolved in methylene chloride (50 ml) and washed with aqueous 2M HCl, saturated aqueous NaCl, and dried MgSO4. Filtration and concentration gives a solid which was recrystallized from ethyl acetate/isopropyl ether to provide 4.6 g (6.1 g theor., 76% ) of 1,1-dimethylethyl 2- [3- [3,5-bis (1,1-dimethylethyl)-4-hydroxyphenyl]-1-oxo-2-propenyl]hydrazinecarboxylic acid, mp 184° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:19][CH:18]=3)[CH:10]=2)=[C:4]([CH3:32])[CH:3]=1.[CH2:33]([S:35][CH2:36][CH2:37]O)[CH3:34].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.C(OCC)C>[CH2:33]([S:35][CH2:36][CH2:37][O:1][C:2]1[CH:3]=[C:4]([CH3:32])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])=[CH:19][CH:18]=3)[CH:10]=2)=[C:6]([CH3:8])[CH:7]=1)[CH3:34]
Reactant: Cc1cc(O)cc(C)c1-c1cccc(COc2ccc(CCC(=O)OC(C)(C)C)cc2)c1
Reactant: CCSCCO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCSCCOc1cc(C)c(-c2cccc(COc3ccc(CCC(=O)OC(C)(C)C)cc3)c2)c(C)c1
Yield: 68.8 %

Procedure:
To a solution of tert-butyl 3-{4-[(4′-hydroxy-2′,6′-dimethylbiphenyl-3-yl)methoxy]phenyl}propanoate (1.69 g, 3.91 mmol), 2-(ethylthio)ethanol (0.46 mL, 4.30 mmol) and tributylphosphine (1.46 mL, 5.86 mmol) in tetrahydrofuran (33 mL) was added 1,1′-(azodicarbonyl)dipiperidine (1.48 g, 5.86 mmol) at room temperature with stirring. The reaction mixture was stirred at room temperature for 16 hrs., and an equivalent amount of the aforementioned reagents (2-(ethylthio)ethanol, tributylphosphine and 1,1′-(azodicarbonyl)dipiperidine) were added at the same temperature and the mixture was further stirred for 16 hrs. Diethyl ether was added to the reaction mixture and insoluble material was filtered off. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-hexane/ethyl acetate=4/1) to give the title compound (1.40 g, yield 69%) as a colorless oil.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.C([Mg]Br)C.[C:21]1([S:27]([N:30]2[C:34]3=[N:35][CH:36]=[CH:37][CH:38]=[C:33]3[C:32]([CH:39]=[O:40])=[CH:31]2)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[C:21]1([S:27]([N:30]2[C:34]3=[N:35][CH:36]=[CH:37][CH:38]=[C:33]3[C:32]([CH:39]([C:2]3[N:6]4[N:7]=[C:8]([C:11]5[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=5)[CH:9]=[CH:10][C:5]4=[N:4][CH:3]=3)[OH:40])=[CH:31]2)(=[O:28])=[O:29])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=Cc1cn(S(=O)(=O)c2ccccc2)c2ncccc12
Reactant: Cn1cc(-c2ccc3ncc(Br)n3n2)cn1
Agent: CC[Mg]Br
Solvent: C1CCOC1
Product: Cn1cc(-c2ccc3ncc(C(O)c4cn(S(=O)(=O)c5ccccc5)c5ncccc45)n3n2)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-Bromo-6-(1-methyl-1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazine (Example 8.1, 150 mg, 0.539 mmol) was dissolved in THF (15 mL) under Nitrogen. Ethylmagnesium bromide solution (3 M, 0.360 mL) was added and the mixture was stirred at rt for 30 min. Then 1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (Stage 199.2, 173 mg, 0.539 mmol) in THF (2 mL) was slowly added and the mixture was stirred at rt for 3.5 h. The mixture was quenched with 10% NH4Cl solution. It was extracted with EtOAc twice. The combined organic layers was washed with brine, dried over Na2SO4, filtered and evaporated. The title compound was obtained as a yellow solid (tR 1.4 min (conditions 1), MH+=486).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][CH:3]=1.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C(Cl)Cl>[CH3:18][S:19]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][NH:10][C:11]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:17])=[CH:6][CH:7]=1)(=[O:21])=[O:20]
Reactant: CC(C)(C)OC(=O)NCCc1ccc(O)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCc1ccc(OS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.5 %

Procedure:
tert-Butyl [2-(4-hydroxyphenyl)ethyl]carbamate (3.45 g, 14.54 mmol) was dissolved in dry DCM (70 mL) and cooled in an ice-water bath. Methanesulfonyl chloride (1.99 g, 17.45 mmol) was added followed by TEA (2.21 g, 21.80 mmol). The reaction mixture was stirred at rt for 2 h. The reaction mixture was washed with saturated aqueous NaHCO3, and the organic phase was dried with MgSO4, filtered and evaporated. Column chromatography of the crude product (ISOLUTE SI, (20 g), eluated with Heptane/EtOAc (90:10), Heptane/EtOAc (70:30)) afforded the title compound (4.06 g, 88.5%). 1H NMR (500 MHz, CD3OD): δ 1.43 (s, 9H), 2.80 (t, 2H), 3.20 (s, 3H), 3.29 (q, 2H), 7.25 (d, 2H), 7.31 (d, 2H).