Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][C:7]2[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][CH:19]([CH2:22][N:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[C:4]([F:30])[CH:3]=1.[C@]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[F:46][C:47]1[CH:52]=[CH:51][C:50]([CH2:53][C:54]([N:56]=[C:57]=[S:58])=[O:55])=[CH:49][CH:48]=1.C(OCC)C>C(O)C.C1(C)C=CC=CC=1.CCCCCC>[F:30][C:4]1[CH:3]=[C:2]([NH:1][C:57]([NH:56][C:54](=[O:55])[CH2:53][C:50]2[CH:51]=[CH:52][C:47]([F:46])=[CH:48][CH:49]=2)=[S:58])[CH:29]=[CH:28][C:5]=1[O:6][C:7]1[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][CH:19]([CH2:22][N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH2:18][CH2:17]2)=[O:15])[CH:8]=1
Reactant: O=C(Cc1ccc(F)cc1)N=C=S
Reactant: Nc1ccc(Oc2cc(NC(=O)N3CCC(CN4CCCC4)CC3)ncn2)c(F)c1
Agent: CC1(C)C2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Solvent: CCOCC
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: O=C(Cc1ccc(F)cc1)NC(=S)Nc1ccc(Oc2cc(NC(=O)N3CCC(CN4CCCC4)CC3)ncn2)c(F)c1
Reaction time: 0.08 h

Procedure:
4-(Pyrrolidin-1-ylmethyl)piperidine-1-carboxylic acid [6-(4-amino-2-fluorophenoxy)pyrimidin-4-yl]amide (100 mg) was dissolved in ethanol (1.0 ml) under a nitrogen atmosphere, and then (S)-(+)-10-camphorsulfonic acid (56 mg) was added thereto, followed by stirring for 5 min. A 0.25 M solution of 2-(4-fluorophenyl)acetyl isothiocyanate in toluene (1.45 ml) was added thereto, followed by stirring for 1 hr. The reaction mixture was partitioned between ethyl acetate (30 ml) and a saturated aqueous solution of sodium hydrogencarbonate (20 ml). The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (20 ml), water (20 ml), brine (20 ml) in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (FUJI Silysia NH, eluent; heptane:ethyl acetate=1:3). Fractions containing the target compound were concentrated to give a residue, to which diethyl ether (1.5 ml) and hexane (2.0 ml) were then added to suspend. The solid was filtered off, and dried under aeration to provide the titled compound (32.7 mg) as pale yellow powder.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[O:3]1.[N:17]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=1)=[C:18]=[O:19]>>[CH3:8][C:6]1([CH3:7])[C:2]([CH3:16])([CH3:1])[O:3][B:4]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:18]([NH:17][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[CH:21]=3)=[O:19])=[CH:11][CH:10]=2)[O:5]1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Product: CC1(C)OB(c2ccc(NC(=O)Nc3cccc(C(F)(F)F)c3)cc2)OC1(C)C

Procedure:
Intermediate 19 was prepared in analogy to GP 3 by reaction of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine with 1-isocyanato-3-trifluoromethylbenzene.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][CH:30]=1)[C:6]([NH:8][C:9]1[C:10]([NH:16][C:17](=[O:27])[C:18]2[CH:23]=[CH:22][C:21]([CH:24]([CH3:26])[CH3:25])=[CH:20][CH:19]=2)=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=1)=[O:7])#[N:2].Cl.[NH2:32][OH:33].C(N(CC)CC)C>CCO>[NH2:2][C:1](=[N:32][OH:33])[C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][CH:30]=1)[C:6]([NH:8][C:9]1[C:10]([NH:16][C:17](=[O:27])[C:18]2[CH:23]=[CH:22][C:21]([CH:24]([CH3:26])[CH3:25])=[CH:20][CH:19]=2)=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=1)=[O:7]
Reactant: NO
Reactant: CC(C)c1ccc(C(=O)Nc2cc(O)ccc2NC(=O)c2cccc(C#N)c2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)c1ccc(C(=O)Nc2cc(O)ccc2NC(=O)c2cccc(C(N)=NO)c2)cc1
Temperature: 80 °C
Yield: 49.5 %

Procedure:
To a mixture of N1-(3-cyanobenzoyl)-N2-(4-isopropylbenzoyl)-4-hydroxy-1,2-benzenediamine (445 mg, 1.11 mmol) and absolute EtOH (30 mL) was added hydroxylamine hydrochloride (125 mg, 1.80 mmol) followed by triethylamine (0.3 mL, 2.15 mmol). The resulting mixture was heated to 80° C. for 2 h, cooled to room temperature, and filtered to give the title compound as a solid (238 mg, 0.55 mmol, 50%); NMR(300 MHz, d6-DMSO): δ9.92 (s, 1H), 9.76 (s, 1H), 9.69 (s, 1H), 9.53 (s, 1H), 8.23 (s, 1H), 7.84 (m, 4H), 7.49 (m, 1H), 7.29 (m, 4H), 6.65 (d, J=9.0, 1H), 5.85 (s, 2H), 2.92 (m, 1H), 1.19 (s, 3H), 1.17 (s, 3H); MS(FD): 432.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH:12]=[CH2:13])=[CH:5][CH:4]=1.ClC1C=C(C=CC=1)C(OO)=[O:19]>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH:12]2[CH2:13][O:19]2)=[CH:5][CH:4]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCCCc1ccc(OC)cc1
Solvent: ClCCl
Product: COc1ccc(CCCC2CO2)cc1

Procedure:
5-(4-Methoxyphenyl)pent-1-ene (18.9 g, 0.107 mol) and 3-chloroperoxybenzoic acid (22.3 g of 85%, 0.11 mol) in dichloromethane (250 ml) was stirred at room temperature for 25 minutes. Dichloromethane (150 ml) was added and the resulting solution was washed with saturated aqueous sodium hydrogen carbonate solution (3×300 ml) and dried (MgSO4). The solvent was evaporated off under reduced pressure to yield an oil which was purified by column chromatography (silica gel, chloroform) to yield [3-(4-methoxyphenyl)propyl]oxirane as a colourless oil having the following structural characteristics:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[C:7]([F:15])[CH:6]=1)(=[O:3])[CH3:2].[CH3:16][NH2:17]>ClCCl.C1COCC1>[F:15][C:7]1[CH:6]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:10]=[CH:9][C:8]=1[S:11](=[O:13])(=[O:12])[NH:17][CH3:16]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)c(F)c1
Reactant: CN
Solvent: C1CCOC1
Solvent: ClCCl
Product: CNS(=O)(=O)c1ccc(NC(C)=O)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
The above prepared 4-acetylamino-2-fluorobenzenesulfonyl chloride (2 g, 7.9 mmol) was dissolved in dichloromethane and methylamine (9.9 mL of a 2M solution in THF, 19.9 mmol) was added. The reaction was stirred at room temperature for 2 hrs. The solvent was then evaporated under reduced pressure and the resulting solid was suspended in 50 mL of water. The solid was isolated by filtration and dried to yield 1.55 g (79%) of N-(3-fluoro-4-methylsulfamoylphenyl)acetamide which was used in the subsequent step without further purification.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2].C[Si]([N-][Si](C)(C)C)(C)C.[K+].Br[CH2:27][CH:28]1[CH2:30][CH2:29]1.[NH4+].[Cl-]>C1COCC1>[C:1]([C:3]1([CH2:27][CH:28]2[CH2:30][CH2:29]2)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2]
Reactant: BrCC1CC1
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C#N)(CC2CC2)CC1
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl 4-cyanopiperidine-1-carboxylate I-1 (1.0 g, 4.8 mmol) in THF (20 mL) at room temperature was treated with KHMDS (9.6 mL of a 1.0 M solution in TBF, 9.6 mmol). After 30 min, (bromomethyl)cyclopropane (0.47 mL, 4.8 mmol) was added dropwise and the mixture was stirred until LCMS indicated the reaction was complete. The reaction mixture was poured into saturated aqueous NH4Cl (50 nil) and extracted with EtOAc (3×50 mL), and the combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure to afford tert-butyl 4-cyano-4-(cyclopropyl-methyl)piperidine-1-carboxylate (I-2, M+H+=265.2). This material was used in subsequent reactions without further purification.
Reaction SMILES: [CH3:1][Si:2]([CH3:15])([CH3:14])[C:3]#[C:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N+:11]([O-])=O>CO.[Pd]>[CH3:14][Si:2]([CH3:1])([CH3:15])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH2:11]
Reactant: C[Si](C)(C)C#Cc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: C[Si](C)(C)CCc1ccccc1N
Reaction time: 12 h
Yield: 42.4 %

Procedure:
10.9 g (50 mmol) of trimethyl-(2-nitrophenylethynyl)silane were dissolved in 200 ml of methanol, and 0.5 g of palladium-on-carbon (5%) were added. The mixture was then hydrogenated in an autoclave at 4 bar for 12 h. Removal of the solvent and column-chromatographic purification on silica gel 60 (mobile phase: methylene chloride) gave 4.1 g of 2-(2-trimethylsilylethyl)phenylamine [log P (pH 2.3)=2.58].
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[OH:16][C:17]1[CH:18]=[C:19]([CH:26]=[CH:27][C:28]=1[OH:29])[CH2:20][C@@H:21]([C:23]([OH:25])=[O:24])[NH2:22]>>[C:23]([C@@H:21]([NH:22][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:20][C:19]1[CH:26]=[CH:27][C:28]([OH:29])=[C:17]([OH:16])[CH:18]=1)([OH:25])=[O:24]
Reactant: N[C@@H](Cc1ccc(O)c(O)c1)C(=O)O
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Product: O=C(O)c1cc2cc(Cl)ccc2nc1N[C@@H](Cc1ccc(O)c(O)c1)C(=O)O
Yield: 50 %

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with 3,4-dihydroxy-L-phenylalanine to provide the title compound in 50% yield as yellow needles (recrystallization from acetone/toluene).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[C:12]2[C:7](=[CH:8][C:9]([CH:13]=O)=[CH:10][CH:11]=2)[CH2:6][CH2:5]1.C[O-].[Na+].Cl.[CH3:19][N:20]([CH3:33])[CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30](=[O:32])[CH3:31])=[CH:26][CH:25]=1>CO.O>[CH3:1][O:2][N:3]=[C:4]1[C:12]2[C:7](=[CH:8][C:9](/[CH:13]=[CH:31]/[C:30]([C:27]3[CH:28]=[CH:29][C:24]([O:23][CH2:22][CH2:21][N:20]([CH3:19])[CH3:33])=[CH:25][CH:26]=3)=[O:32])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1
Reactant: CON=C1CCc2cc(C=O)ccc21
Reactant: CC(=O)c1ccc(OCCN(C)C)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CON=C1CCc2cc(/C=C/C(=O)c3ccc(OCCN(C)C)cc3)ccc21
Temperature: 25 °C
Yield: 82.1 %

Procedure:
A solution of the product of Example 1 Step 2 (1.06 g, 5.6 mmol), sodium methoxide (0.750 g, 13.9 mmol) and 1-[4-(2-dimethylaminoethoxy) phenyl]ethanone hydrochloride (1.36 g, 5.6 mmol) (J. H. Short et al., J. Med. Chem. 1965, 8, 223) in methanol (30 ml) and water (1 ml) was heated under reflux for 5 hours. After cooling to room temperature the solid was collected, washed with cold methanol and diethyl ether and dried to give the title compound (1.74 g, 83%); MS(ES+) m/e 378 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[CH:4][CH:3]=1.S(Cl)([Cl:16])=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([Cl:16])=[O:13])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CCCc1ccc(F)cc1
Product: O=C(Cl)CCCc1ccc(F)cc1
Yield: 101.4 %

Procedure:
A mixture of 4-(4-fluorophenyl)butyric acid (68.2 g, 0.37 mol) and thionyl chloride (155 g, 1.3 mol) was refluxed for 1.25 h. The mixture was concentrated in vacuo to give 75.3 g (100%) of 4-(4-fluorophenyl)butyryl chloride)
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6]Br)(=[O:3])[CH3:2].[CH3:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([O:19][CH3:20])=[C:15]([OH:18])[CH:16]=2)[C:11]([C:21]2[N:29]([S:30]([C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=3)(=[O:32])=[O:31])[C:24]3=[N:25][CH:26]=[CH:27][CH:28]=[C:23]3[CH:22]=2)=[CH:10]1>>[CH3:20][O:19][C:14]1[CH:13]=[C:12]2[C:17](=[CH:16][C:15]=1[O:18][CH2:6][CH2:5][O:4][C:1](=[O:3])[CH3:2])[N:9]([CH3:8])[CH:10]=[C:11]2[C:21]1[N:29]([S:30]([C:33]2[CH:34]=[CH:35][C:36]([CH3:39])=[CH:37][CH:38]=2)(=[O:32])=[O:31])[C:24]2=[N:25][CH:26]=[CH:27][CH:28]=[C:23]2[CH:22]=1
Reactant: COc1cc2c(-c3cc4cccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1O
Reactant: CC(=O)OCCBr
Product: COc1cc2c(-c3cc4cccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OCCOC(C)=O

Procedure:
2-[5-Methoxy-6-(2-acetyloxyethoxy)-1-methyl-1H-indol-3-yl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine is prepared by following the procedure described in example 147d, but using 0.246 ml of 2-bromoethyl acetate and 0.5 g of 2-[1-methyl-5-methoxy-6-hydroxyl-1H-indol-3-yl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine. After purification by flash-pack chromatography (silica, 40/60 by volume ethyl acetate/cyclohexane as eluents), 0.506 g of 2-[5-methoxy-6-(2-acetyloxyethoxy)-1-methyl-1H-indol-3-yl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine is obtained, the characteristics of which are as follows:
Reaction SMILES: [F:1][C:2]1[C:3]([O:19][C:20]2[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=2[O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:23]#[N:24])=[N:4][C:5](F)=[C:6]([F:17])[C:7]=1[O:8][CH2:9][CH:10]1[CH2:14][O:13][C:12]([CH3:16])([CH3:15])[O:11]1.C([O-])([O-])=O.[Cs+].[Cs+].[OH:42][C:43]1[CH:44]=[C:45]([C:49]2[N:50]([CH3:54])[CH2:51][CH2:52][N:53]=2)[CH:46]=[CH:47][CH:48]=1>CS(C)=O>[F:1][C:2]1[C:3]([O:19][C:20]2[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=2[O:28][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:23]#[N:24])=[N:4][C:5]([O:42][C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([C:49]3[N:50]([CH3:54])[CH2:51][CH2:52][N:53]=3)[CH:44]=2)=[C:6]([F:17])[C:7]=1[O:8][CH2:9][CH:10]1[CH2:14][O:13][C:12]([CH3:16])([CH3:15])[O:11]1
Reactant: CN1CCN=C1c1cccc(O)c1
Reactant: CC1(C)OCC(COc2c(F)c(F)nc(Oc3cc(C#N)ccc3OCc3ccccc3)c2F)O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CN1CCN=C1c1cccc(Oc2nc(Oc3cc(C#N)ccc3OCc3ccccc3)c(F)c(OCC3COC(C)(C)O3)c2F)c1
Temperature: 55 °C
Reaction time: 24 h
Yield: 66.7 %

Procedure:
To 3-[[3,5,6-trifluoro-4-[(2,2-dimethyldioxolan-4-yl)methoxy]pyridin-2-yl]oxy]-4-(benzyloxy)benzonitrile (1.0 g, 2.1 mmol) in DMSO (6 mL) was added Cs2CO3 -(0.7 g, 2.1 mmol) and 2-(3-hydroxyphenyl)-1-methylimidazoline (0.4 g, 2.2 mmol). After stirring in an oil bath at 55° C. for 24 hours, the reaction was partitioned with water and ethyl acetate. The layers were separated, washed with water and brine, dried (Na2SO4), and the solvent was removed in vacuo. The residue was chromatographed on silica with CH2Cl2/MeOH/NH4OH (240/10/1) to give 3-[[3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-[(2,2-dimethyldioxolan-4-yl)methoxy]pyridin-2-yl]oxy]-4-(benzyloxy)benzonitrile (0.9 g).
Reaction SMILES: Cl[C:2]1[N:3]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[N:4]=[C:5]2[C:10]=1[CH:9]=[CH:8][C:7]([F:11])=[CH:6]2.[CH:19]1([NH2:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>CN1CCCC1=O>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([N:3]2[C:2]([NH:25][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[C:10]3[C:5]([CH:6]=[C:7]([F:11])[CH:8]=[CH:9]3)=[N:4]2)=[CH:13][CH:14]=1
Reactant: NC1CCCCC1
Reactant: Fc1ccc2c(Cl)n(-c3ccc(Cl)cc3)nc2c1
Solvent: CN1CCCC1=O
Product: Fc1ccc2c(NC3CCCCC3)n(-c3ccc(Cl)cc3)nc2c1

Procedure:
In analogy to the procedure described in example 4.1, 3-chloro-2-(4-chloro-phenyl)-6-fluoro-2H-indazole was reacted with cyclohexylamine ([108-91-8]) in N-methyl 2-pyrrolidone for 72 h at 150° C. in a sealed tube to give the title compound as yellow solid. MS: m/e=344.5 [M+H+].
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18]#[N:19].C(O)(=O)C[C:22](CC(O)=O)(C(O)=O)[OH:23]>O1CCCC1.O>[C:18]([C:14]1[S:13][C:17]([CH:22]=[O:23])=[CH:16][CH:15]=1)#[N:19]
Reactant: N#Cc1cccs1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)NC(C)C
Product: N#Cc1ccc(C=O)s1
Reaction time: 0.08 h
Yield: 55.3 %

Procedure:
A solution of diisopropylamine (35.3 ml, 0.251 moles) in tetrahydrofuran (500 ml) was cooled to −78° C. under a nitrogen blanket. To this was added 1.6M n-butyllithium in hexanes (157 ml, 0.251 moles) and allowed to stir for 5 min. Then slowly added thiopene-2-carbonitrile (21.33 ml, 0.229 moles) in tetrahydrofuran (115 ml) and allowed to stir. After 45 min. was added NN-dimethylformamide (88.66 ml, 1.145 moles) at −78° C. Citric acid (40 g) was added after 2 h. followed by water (240 ml) and stirred for 18 h. The reaction was concentrated in vacuo, transferred to a separatory funnel, diluted with brine, and extracted twice with ether. The combined ether layers were washed with brine, dried over magnesium sulfate, filtered, and the solvent removed in vacuo. Chromatography yielded 15.8 g (50%) of 2-cyano-5-formylthiophene (EX-55A) as a brown solid: 1H NMR (300 MHZ, CDCl3) d 10.02 (s, 1H), 7.79 (m, 1H), 7.30 (m, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:10]([N:13](CC2C=CC(OC)=CC=2OC)[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=2)(=[O:12])=[O:11])[CH:6]=[CH:7][C:8]=1F)#[N:2].[Cl:32][C:33]1[CH:40]=[C:39]([OH:41])[CH:38]=[C:37]([Cl:42])[C:34]=1[C:35]#[N:36]>>[C:1]([C:3]1[CH:4]=[C:5]([S:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=2)(=[O:11])=[O:12])[CH:6]=[CH:7][C:8]=1[O:41][C:39]1[CH:38]=[C:37]([Cl:42])[C:34]([C:35]#[N:36])=[C:33]([Cl:32])[CH:40]=1)#[N:2]
Reactant: COc1ccc(CN(c2ccc(F)cn2)S(=O)(=O)c2ccc(F)c(C#N)c2)c(OC)c1
Reactant: N#Cc1c(Cl)cc(O)cc1Cl
Product: N#Cc1cc(S(=O)(=O)Nc2ccc(F)cn2)ccc1Oc1cc(Cl)c(C#N)c(Cl)c1

Procedure:
The title compound was prepared according to the method described for Method Variation 5 using 3-cyano-N-(2,4-dimethoxybenzyl)-4-fluoro-N-(5-fluoropyridin-2-yl)benzenesulfonamide (Preparation 18) and 2,6-dichloro-4-hydroxybenzonitrile, and then purified using preparative HPLC.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([C:17]1[O:18][C:19]2[CH:25]=[CH:24][C:23]([CH:26]=[CH2:27])=[CH:22][C:20]=2[CH:21]=1)=[O:16])([CH3:4])([CH3:3])[CH3:2].B1C2CCCC1CCC2.[OH-:38].[Na+]>C1COCC1.O>[C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([C:17]1[O:18][C:19]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][OH:38])=[CH:22][C:20]=2[CH:21]=1)=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=Cc1ccc2oc(C(=O)Nc3ccccc3NC(=O)OC(C)(C)C)cc2c1
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1cc2cc(CCO)ccc2o1
Reaction time: 2 h
Yield: 6.3 %

Procedure:
A solution of 114 mg (o.30 mmol) {2-[(5-Vinyl-benzofuran-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester (57), 5 ml THF and 1.4 ml of a 0.5M solution of 9-BBN in THF was stirred at rt for 4 h. A solution of 86 mg NaOH in 0.6 ml water was added and stirring was continued for further 2 h. The reaction mixture was washed with brine and the organic phase dried over sodium sulfate, the solvent was evaporated and the residue subjected to silica gel chromatography (petrolether/ethylacetate 1:1) to give 54 mg (0.136 mmol) (2-{[5-(2-Hydroxy-ethyl)-benzofuran-2-carbonyl]-amino}-phenyl)-carbamic acid tert-butyl ester (58).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:16]3[CH2:17][CH2:18][CH2:19][CH:12]2[CH:13]([CH2:21][CH3:22])[C:14](=[O:20])[CH2:15]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CO[CH:25](OC)[N:26]([CH3:28])[CH3:27]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH:12]3[CH2:19][CH2:18][CH2:17][CH:16]2[C:15](=[CH:25][N:26]([CH3:28])[CH3:27])[C:14](=[O:20])[CH:13]3[CH2:21][CH3:22])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CCC1C(=O)CC2CCCC1N2S(=O)(=O)c1ccc(Cl)cc1
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CCC1C(=O)C(=CN(C)C)C2CCCC1N2S(=O)(=O)c1ccc(Cl)cc1
Temperature: 110 °C

Procedure:
To a stirring mixture of 9-(4-chloro-benzenesulfonyl)-2-ethyl-9-aza-bicyclo[3.3.1]nonan-3-one (180 mg, 0.52 mmol) in DMF (1 mL,) was added N,N-dimethylformamide dimethyl acetal (1 mL). The resulting mixture was heated to 110° C. for 2 h after which the reaction mixture was concentrated under reduced pressure to give the desired product as a brown oil. This crude product was directly taken to the next reaction without any further purification. Retention time (min)=2.365 min, Method [1], MS (ESI) 370 (M-NMe2+OH+H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7](Cl)=[C:8]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:9]=1)(=[O:3])[CH3:2].[CH3:15][NH:16][CH3:17]>C(O)C>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([N:16]([CH3:17])[CH3:15])=[C:8]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(Cl)c(S(N)(=O)=O)c1
Reactant: CNC
Solvent: CCO
Product: CC(=O)c1ccc(N(C)C)c(S(N)(=O)=O)c1

Procedure:
A mixture of 5-acetyl-2-chloro-benzenesulphonamide (0.5 g) in ethanol (10 ml) and dimethylamine in ethanol (33%, 5 ml) was heated in a closed vessel on a steam bath for 16 hours. The solvents were removed under reduced pressure and the residue crystallised from ethanol to give the product 0.31 g, m.p. 184°-185°.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[C:6](B(O)O)=[CH:5][N:4]=1.I[C:15]1[N:16]=[N:17][CH:18]=[CH:19][CH:20]=1.C([O-])([O-])=O.[Na+].[Na+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(O)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[C:6]([C:15]2[N:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:5][N:4]=1
Reactant: COc1ncc(B(O)O)c(OC)n1
Reactant: Ic1cccnn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCCO
Product: COc1ncc(-c2cccnn2)c(OC)n1
Yield: 33.7 %

Procedure:
2,4-Dimethoxy-pyrimidine-5-boronic acid (2.05 g, 11.21 mmol) was dissolved in degassed n-PrOH (80 ml) and then 3-iodo-pyridazine (Prep 119, 2.1 g, 10.19 mmol), Na2CO3 (3.24 g, 30.57 mmol), PPh3 (890 mg, 3.40 mmol) and Pd(OAc)2 (180 mg, 0.8 mmol) were added. The suspension was stirred at reflux for 5 hours. The solvent was evaporated under vacuum and the crude was partitioned between water and ethyl acetate. The organic phase washed with brine, dried (Na2SO4) and evaporated. The residue was triturated with iPrOH to afford 750 mg of the title compound as a white powder (34% yield).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([N:18]1[CH2:23][CH2:22][CH:21]([CH2:24][CH2:25][CH2:26][OH:27])[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH2:11]([N:18]1[CH2:23][CH2:22][CH:21]([CH2:24][CH2:25][CH:26]=[O:27])[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OCCCC1CCN(Cc2ccccc2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=CCCC1CCN(Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of 0.93 mL of oxalyl chloride in 20 mL of CH2Cl2 at −78° C. was added 1.13 mL of DMSO in 0.1 mL of CH2Cl2 dropwise. After stirring 5 min, a solution of 3-(1-benzyl-piperidin)yl)propan-1-ol (form Step C) in 8 mL of CH2Cl2 was added dropwise. After stirring 15 minutes, 0.75 mL of diisopropylethylamine was added. The reaction was warmed to 0° C. and stirred for 20 min. After quenching with H2O, the reaction was diluted with 50 mL of CH2Cl2. The aqueous layer was extracted with 2×50 mL Of CH2Cl2. The combined organic phases were dried over MgSO4 and concentrated to give 612 mg the title compound, which was used for the next step without further purification
Reaction SMILES: [CH3:1][NH:2][C:3]1[NH:7][N:6]=[N:5][N:4]=1.[NH2:8][C:9]([CH3:50])([CH:47]([CH3:49])[CH3:48])[CH2:10][O:11][C@@H:12]1[C@@:19]2([CH3:44])[C@@H:20]3[CH2:21][CH2:22][C@H:23]4[C:32]([C@@:15]3([CH2:16][O:17][CH2:18]2)[CH2:14][C@H:13]1OC)=[CH:31][CH2:30][C@:29]1([CH3:33])[C@:24]4([CH3:43])[CH2:25][CH2:26][C@@:27]([C@H:38]([CH3:42])[CH:39]([CH3:41])[CH3:40])([CH3:37])[C@H:28]1[C:34]([OH:36])=[O:35]>>[NH2:8][C:9]([CH3:50])([CH:47]([CH3:49])[CH3:48])[CH2:10][O:11][C@@H:12]1[C@@:19]2([CH3:44])[C@@H:20]3[CH2:21][CH2:22][C@H:23]4[C:32]([C@@:15]3([CH2:16][O:17][CH2:18]2)[CH2:14][C@H:13]1[N:5]1[N:6]=[N:7][C:3]([NH:2][CH3:1])=[N:4]1)=[CH:31][CH2:30][C@:29]1([CH3:33])[C@:24]4([CH3:43])[CH2:25][CH2:26][C@@:27]([C@H:38]([CH3:42])[CH:39]([CH3:40])[CH3:41])([CH3:37])[C@H:28]1[C:34]([OH:36])=[O:35]
Reactant: CNc1nnn[nH]1
Reactant: CO[C@@H]1C[C@@]23COC[C@](C)([C@@H]2CC[C@H]2C3=CC[C@@]3(C)[C@H](C(=O)O)[C@@](C)([C@H](C)C(C)C)CC[C@]23C)[C@H]1OCC(C)(N)C(C)C
Product: CNc1nnn([C@@H]2C[C@@]34COC[C@](C)([C@@H]3CC[C@H]3C4=CC[C@@]4(C)[C@H](C(=O)O)[C@@](C)([C@H](C)C(C)C)CC[C@]34C)[C@H]2OCC(C)(N)C(C)C)n1

Procedure:
Employing a procedure analogous that described in the preceding Examples, but using N-methyl-1H-tetrazol-5-amine, the title compound was prepared from (1S,4aR,6aS,7R,8R,10aR,10bR,12aR,14R,15R)-15-(2-amino-2,3-dimethylbutoxy)-8-[(1R)-1,2-dimethylpropyl]-14-methoxy-1,6,6a,7,8,9,10,10a,10b,11,12,12a-dodecahydro-1,6a,8,10a-tetramethyl-4H-1,4a-propano-2H-phenanthro[1,2-c]pyran-7-carboxylic acid (prepared as described for Intermediate 6, but as a ˜1:1 mixture of diastereomers).