Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:25][CH:26]([CH3:28])[CH3:27])=[C:13]([C:15]2[NH:24][C:18]3=[N+:19]([O-])[CH:20]=[CH:21][CH:22]=[C:17]3[N:16]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:29]([N:31](CC)CC)C.C[Si](C#N)(C)C>C(#N)C.O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:25][CH:26]([CH3:28])[CH3:27])=[C:13]([C:15]2[NH:24][C:18]3=[N:19][C:20]([C:29]#[N:31])=[CH:21][CH:22]=[C:17]3[N:16]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)Oc1ccc(OCc2ccccc2)cc1-c1nc2ccc[n+]([O-])c2[nH]1
Reactant: CCN(CC)CC
Agent: C[Si](C)(C)C#N
Solvent: CC#N
Solvent: O
Product: CC(C)Oc1ccc(OCc2ccccc2)cc1-c1nc2ccc(C#N)nc2[nH]1
Yield: 69 %

Procedure:
A solution (10 ml) of 2-[5-(benzyloxy)-2-isopropoxyphenyl]-3H-imidazo[4,5-b]pyridine 4-oxide, triethylamine (0.11 g) and trimethylsilyl cyanide (0.22 g) in acetonitrile was heated under reflux for 5 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated. The obtained crude crystals were washed with diethyl ether to give the title compound (0.15 g, yield 69%) as colorless crystals. melting point 214-215° C. purity 93%. M+H: 385. 1H NMR (CDCl3) δ: 1.53 (6H, d, J=6.0 Hz), 4.77-4.85 (1H, m), 5.16 (2H, s), 7.06 (1H, d, J=9.0 Hz), 7.12-7.18 (1H, m), 7.32-7.50 (5H, m), 7.66 (1H, d, J=8.1 Hz), 8.12 (1H, d, J=8.1 Hz), 8.20 (1H, d, J=3.0 Hz).
Reaction SMILES: O1C2C(=CC=CC=2)C=CC1=O.C(N(CC)CC)C.[OH:19][C:20]1[CH:29]=[C:28]2[C:23]([C:24]([CH3:31])=[CH:25][C:26](=[O:30])[O:27]2)=[CH:22][CH:21]=1.[C:32](Cl)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1COCC1>[C:32]([O:19][C:20]1[CH:29]=[C:28]2[C:23]([C:24]([CH3:31])=[CH:25][C:26](=[O:30])[O:27]2)=[CH:22][CH:21]=1)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: Cc1cc(=O)oc2cc(O)ccc12
Reactant: O=C(Cl)c1ccccc1
Agent: O=c1ccc2ccccc2o1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(=O)oc2cc(OC(=O)c3ccccc3)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The route shown in Scheme 1 exemplifies synthesis of the coumarin compounds of the present invention. Triethylamine is added to a solution of 7-hydroxy-4-methyl-chromen-2-one (i) and a benzoyl chloride (ii) in THF at room temperature. The reaction mixture is stirred at room temperature overnight and filtered. The filtrate is concentrated to afford a 7-benzoyloxy-4-methyl-coumarin (iii). A mixture of compound (iii) and finely powdered aluminum chloride is heated at 170° C. for 2 hours to afford an 8-benzoyl-7-hydroxy-4-methyl-chromen-2-one (iv). A mixture of compound (iv), 2-bromoacetophenone (v), and K2CO3 in CH3CN is refluxed overnight. The reaction mixture is filtered and the filtrate is concentrated. The residue is purified by column chromatography to afford a pure 8-benzoyl-4-methyl-9-phenyl-furo[2,3-h]chromen-2-one (vi).
Reaction SMILES: [C:1]([C:3]1([CH3:17])[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1)#[CH:2].Br[C:19]1[S:23][C:22]2[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=2[CH:20]=1>>[S:23]1[C:19]([C:2]#[C:1][C:3]2([CH3:17])[CH2:8][CH2:7][C:6]3[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=3[O:4]2)=[CH:20][C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]1=2
Reactant: C#CC1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Reactant: Brc1cc2ccccc2s1
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C#Cc1cc3ccccc3s1)O2

Procedure:
Reaction of rac-3,4-dihydro-2-ethynyl-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol with 2-bromobenzo[b]-thiophene under the conditions described in example 16 gave after chromatographic isolation and crystallization from ether/hexane colorless crystals with m.p. 120°-123° C.
Reaction SMILES: [CH2:1](N(CC)CC)C.C(OCC)(=O)CC(OCC)=O.[Cl-].[Mg+2].[Cl-].[Cl:22][C:23]1[N:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26]>C1(C)C=CC=CC=1>[Cl:22][C:23]1[C:24]([C:25](=[O:26])[CH3:1])=[CH:28][CH:29]=[CH:30][N:31]=1
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: CCN(CC)CC
Agent: [Cl-]
Agent: [Mg+2]
Solvent: Cc1ccccc1
Solvent: CCOC(=O)CC(=O)OCC
Product: CC(=O)c1cccnc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.2 %

Procedure:
Triethylamine (7.4 g, 73 mmol) was added to a solution of diethyl malonate (5.6 g, 35 mmol) and anhydrous magnesium chloride (1.9 g, 20 mmol) in toluene (15 ml) under inert atmosphere. After stirring for 1 hr at room temperature, a solution of 2-chloro nicotinoyl chloride (5.2 g, 29 mmol) in toluene (5 ml) was added and the reaction mixture was stirred at room temperature for a further 1 hr. The reaction was quenched with ice cold 2N hydrochloric acid (20 ml), and the organic layer was separated and concentrated to dryness. The resultant residue was dissolved in a mixture of 3:2 DMSO-water and heated at 120-130° C. for 6 hr. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (100 ml). The organic layer was washed once with bicarbonate solution, then several times with water, and finally with brine. The organic layer was then dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to yield 1-(2-chloro-pyridin-3-yl)ethanone (1 g, 25%) as oil.
Reaction SMILES: [O:1]=[C:2]1[O:7][CH2:6][C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[N:3]1[CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:30]=[CH:29][C:21]([C:22](OC(C)(C)C)=[O:23])=[CH:20][CH:19]=2)[CH2:14][CH2:13]1.Cl.[NH2:32][C@H:33]([C:38]([NH2:40])=[O:39])[CH2:34][CH:35]([CH3:37])[CH3:36]>>[NH2:40][C:38]([C@@H:33]([NH:32][C:22](=[O:23])[C:21]1[CH:29]=[CH:30][C:18]([N:15]2[CH2:16][CH2:17][CH:12]([N:3]3[C:4]4[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=4[CH2:6][O:7][C:2]3=[O:1])[CH2:13][CH2:14]2)=[CH:19][CH:20]=1)[CH2:34][CH:35]([CH3:37])[CH3:36])=[O:39]
Reactant: CC(C)(C)OC(=O)c1ccc(N2CCC(N3C(=O)OCc4ccccc43)CC2)cc1
Reactant: CC(C)C[C@H](N)C(N)=O
Agent: Cl
Product: CC(C)C[C@H](NC(=O)c1ccc(N2CCC(N3C(=O)OCc4ccccc43)CC2)cc1)C(N)=O

Procedure:
The title compound was prepared from the product of example 161 step (i) (0.06 g) and (S)-leucinamide hydrochloride (0.056 g) using the method of example 161 step (ii). Purification was by chromatography eluting with (5:1) ethyl acetate/dichloromethane. Yield 0.01 g as a solid.
Reaction SMILES: [Cl-].[Mg+2].[Cl-].Cl[P:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=CC=CC=2)[CH:20]=1>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.CN(C)C=O>[CH2:18]([P:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:19]1[CH:28]=[CH:27][CH:26]=[CH:21][CH:20]=1
Reactant: Cc1ccc2ccccc2c1
Reactant: ClP(c1ccccc1)c1ccccc1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CN(C)C=O
Product: c1ccc(CP(c2ccccc2)c2ccccc2)cc1
Temperature: 35 °C
Reaction time: 3 h
Yield: 83 %

Procedure:
An electrolysis cell as described in Example 1 is used. The electrolyte comprises 70 ml of dimethylformamide (max. 0.1% of water), 0.4 g of anhydrous magnesium chloride and 6.62 g (0.030 mol) of chlorodiphenylphosphine. The electrolysis is carried out as described in Example 1. The electrolysis temperature is 25° C. After an amount of charge of 0.96 Ah, the electrolysis is ended. 4.64 g (0.025 mol) of benzyltrimethylammonium chloride are then introduced into the electrolyte with exclusion of air and the mixture is stirred at 35° C. After 3 h the reaction mixture contains, according to analysis by gas chromatography (internal standard: 2-methylnaphthalene), 5.72 g of benzyldiphenylphosphine (yield 83%, based on benzyltrimethylammonium chloride used) which can be isolated by workup as described in Example 1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[SH:9].CS(O[CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)(=O)=O.C([O-])([O-])=O.[K+].[K+].O>C(#N)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: Fc1ccc(S)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Sc2ccc(F)cc2F)CC1
Temperature: 80 °C
Yield: 100 %

Procedure:
A mixture of 2,4-difluorobenzenethiol (0.810 mL, 7.15 mmol), tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (1.816 g, 6.5 mmol), and K2CO3 (1.348 g, 9.75 mmol) in ACN (16.25 mL) was heated at 80° C. overnight. The reaction mixture was poured into water and extracted twice with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to afford tert-butyl 4-((2,4-difluorophenyl)thio)piperidine-1-carboxylate (2.141 g) as a yellow oil, which was carried forward without purification.
Reaction SMILES: [CH2:1]([N:4]1[CH2:12][CH:11]2[C:6]([C:22]3[S:23][C:24]([F:27])=[CH:25][CH:26]=3)([N:7]=[C:8]([NH:13][C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[S:9][CH2:10]2)[CH2:5]1)[CH:2]=[CH2:3]>CO.C(Cl)(Cl)Cl>[F:27][C:24]1[S:23][C:22]([C@:6]23[CH2:5][N:4]([CH2:1][CH:2]=[CH2:3])[CH2:12][C@H:11]2[CH2:10][S:9][C:8]([NH:13][C:14](=[O:21])[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[N:7]3)=[CH:26][CH:25]=1
Reactant: C=CCN1CC2CSC(NC(=O)c3ccccc3)=NC2(c2ccc(F)s2)C1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: C=CCN1C[C@H]2CSC(NC(=O)c3ccccc3)=N[C@@]2(c2ccc(F)s2)C1

Procedure:
Racemic N-[6-allyl-7a-(5-fluoro-2-thienyl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide (4.71 g, 11.73 mmol) is dissolved in 1:1 MeOH/CHCl3 (20 mg/mL) and separated into its constituent enantiomers by chiral HPLC (Column: Chiralcel OD 8×32 cm (20 μM); mobile phase: 60:40 IPA/heptane; flow rate 385 mL/min at UV 290 nm; 0.320 g/injection). Analysis of the second eluting isomer (Column: Chiralcel OD-H 4.6×150 mm; mobile phase: 60:40 IPA/heptane; flow rate 0.6 mL/min at UV 290 nm) gave the title compound, Rt=8.2 minutes (2.01 g, 43%, 96.1% ee). ES/MS (m/e): 402.0 (M+H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[C:5]([O:23][CH3:24])[CH:4]=1.[CH2:25]([N:32]1[CH:36]=[C:35]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[C:34]([OH:42])=[N:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:25]([N:32]1[CH:36]=[C:35]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[C:34]([O:42][CH2:2][C:3]2[CH:22]=[CH:21][C:6]([O:7][CH2:8][C:9]3[N:10]=[C:11]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[O:12][C:13]=3[CH3:14])=[C:5]([O:23][CH3:24])[CH:4]=2)=[N:33]1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COc1cc(CCl)ccc1OCc1nc(-c2ccccc2)oc1C
Reactant: CCOC(=O)c1cn(Cc2ccccc2)nc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)c(OC)c1
Temperature: 80 °C
Reaction time: 15 h
Yield: 91.9 %

Procedure:
A mixture of 4-(4-chloromethyl-2-methoxyphenoxy)methyl-5-methyl-2-phenyl-1,3-oxazole (2.30 g), ethyl 1-benzyl-3-hydroxy-1H-pyrazole-4-carboxylate (1.50 g), potassium carbonate (0.84 g) and N,N-dimethylformamide (50 mL) was stirred at 80° C. for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give ethyl 1-benzyl-3-({3-methoxy-4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyl}oxy)-1H-pyrazole-4-carboxylate (3.10 g, yield 92%) as colorless crystals. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 154-155° C.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8](C(=O)C(F)(F)F)[CH2:9]2)=[CH:4][CH:3]=1.[CH3:18][C:19]1[CH:24]=[CH:23][C:22](OB(O)O)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C>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.C1(C)C=CC=CC=1>[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[CH:11]=[C:10]3[C:5]([CH2:6][CH2:7][NH:8][CH2:9]3)=[CH:4][CH:3]=2)=[CH:21][CH:20]=1
Reactant: Cc1ccc(OB(O)O)cc1
Reactant: O=C(N1CCc2ccc(Br)cc2C1)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1ccc(-c2ccc3c(c2)CNCC3)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.3 %

Procedure:
To 7-bromo-2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinoline (8.1 g), 4-methylphenylboric acid (3.9 g), a 2 M aqueous solution of potassium carbonate (40 ml) and ethanol (40 ml) was added toluene (100 ml), and the resulting mixture was stirred at room temperature under an argon atmosphere for 30 minutes. Thereto was added tetrakis(triphenylphosphine)palladium (1.26 g), and the resulting mixture was refluxed under an argon atmosphere for 4.5 hours. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with water and an aqueous saturated solution of sodium chloride, and was then dried with anhydrous magnesium sulfate. After evaporation of the solvent under reduced pressure, methanol (200 ml) and a 2 M aqueous solution of potassium carbonate (50 ml) were added to the residue, and the resulting mixture was stirred overnight at room temperature. After concentration, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and was then back-extracted with 1 N hydrochloric acid. The aqueous layer was made alkaline with a 1 N aqueous solution of sodium hydroxide, was then saturated with sodium chloride and was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with anhydrous magnesium sulfate. The resulting organic layer was evaporated under reduced pressure to remove the solvent to obtain 7-(4-methylphenyl)-1,2,3,4-tetrahydroisoquinoline (4.2 g) as colorless crystals.
Reaction SMILES: COC(CCC([O:9][C:10]1[C:11]([CH3:27])=[C:12]([CH3:26])[C:13]2[O:17][CH:16]([CH2:18][CH2:19][C:20](OC)=[O:21])[S:15][C:14]=2[C:24]=1[CH3:25])=O)=O.[NH3:28]>CO>[OH:9][C:10]1[C:11]([CH3:27])=[C:12]([CH3:26])[C:13]2[O:17][CH:16]([CH2:18][CH2:19][C:20]([NH2:28])=[O:21])[S:15][C:14]=2[C:24]=1[CH3:25]
Reactant: N
Reactant: COC(=O)CCC(=O)Oc1c(C)c(C)c2c(c1C)SC(CCC(=O)OC)O2
Solvent: CO
Product: Cc1c(C)c2c(c(C)c1O)SC(CCC(N)=O)O2

Procedure:
4.9 g of methyl 3-[5-(3-methoxycarbonylpropionyloxy)-4,6,7-trimethyl-1,3-benzoxathiole-2-yl]propionate (prepared as described in Example 31) was dissolved in 60 ml of methanol, and 17 g of 28% w/v aqueous ammonia was added to the solution. The reaction mixture was then allowed to react for 5 days at room temperature. At the end of this time, the solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate. The resulting solution was washed with water and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure. The resulting crude product was subjected to silica gel column chromatography, and the title compound, melting at 160°-161° C., was obtained from the fraction eluted with a 3:7 by volume mixture of benzene and ethyl acetate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][OH:10].Cl[C:12]1[CH:13]=[C:14]2[N:21]([CH3:22])[CH:20]([CH3:23])[CH2:19][N:15]2[C:16](=[O:18])[N:17]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][O:10][C:12]1[CH:13]=[C:14]2[N:21]([CH3:22])[CH:20]([CH3:23])[CH2:19][N:15]2[C:16](=[O:18])[N:17]=1
Reactant: CC1Cn2c(cc(Cl)nc2=O)N1C
Reactant: OCc1ccc(F)cc1F
Product: CC1Cn2c(cc(OCc3ccc(F)cc3F)nc2=O)N1C

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from (2,4-difluorophenyl)methanol and 7-chloro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17](O)=[O:18])=[CH:14][CH:15]=3)[C:10]([C:20]([CH:22]3[C:24]([CH3:26])([CH3:25])[C:23]3([CH3:28])[CH3:27])=[O:21])=[CH:9]2)[CH2:3][CH2:2]1.[C:29](N1C=CN=C1)([N:31]1C=CN=C1)=O.CN>CCOC(C)=O.C1COCC1>[CH3:29][NH:31][C:17]([C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:7][CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)[CH:9]=[C:10]2[C:20]([CH:22]1[C:23]([CH3:28])([CH3:27])[C:24]1([CH3:25])[CH3:26])=[O:21])=[O:18]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC1(C)C(C(=O)c2cn(CC3CCOCC3)c3ccc(C(=O)O)cc23)C1(C)C
Agent: CN
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNC(=O)c1ccc2c(c1)c(C(=O)C1C(C)(C)C1(C)C)cn2CC1CCOCC1
Yield: 14 %

Procedure:
A mixture 1-(tetrahydro-2H-pyran-4-ylmethyl)-3-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]-1H-indole-5-carboxylic acid (0.10 g, 0.26 mmol, the minor product of Example 114B), 1,1′-carbonyldimidazole (55 mg, 0.34 mmol) and methylamine (2 M solution in THF, 0.2 mL, 0.4 mmol) in 4 mL of EtOAc and 3 mL of THF was processed as described in Example 93 to provide the title compound (14 mg, 0.035 mmol, 14% yield). 1H NMR (DMSO-d6, 300 MHz) δ ppm 1.27 (s, 12H), 1.30-1.46 (m, 4H), 2.03-2.17 (m, 1H), 2.22 (s, 1H), 2.79 (d, J=4.7 Hz, 3H), 3.22 (dt, J=11.4, 3.1 Hz, 2H), 3.80-3.88 (m, 2H), 4.17 (d, J=7.5 Hz, 2H), 7.63-7.77 (m, 2H), 8.32-8.37 (m, 1H), 8.38 (s, 1H), 8.74 (d, J=1.4 Hz, 1H); MS (DCI/NH3) m/z 397 (M+H)+; Anal. Calculated for C24H32N2O2.0.3H2O: C, 71.72; H, 8.18; N, 6.97. Found: C, 71.96; H, 8.19; N, 6.69.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8](=[O:15])[N:9]([CH2:11][CH:12]([CH3:14])[CH3:13])[N:10]=[C:4]2[C:3]=1I.[Cl:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:2]2[CH:7]=[CH:6][N:5]3[C:8](=[O:15])[N:9]([CH2:11][CH:12]([CH3:14])[CH3:13])[N:10]=[C:4]3[C:3]=2[C:21]2[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=2)=[CH:20][CH:19]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CC(C)Cn1nc2c(I)c(Br)ccn2c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)Cn1nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)ccn2c1=O
Temperature: 200 °C
Yield: 40.8 %

Procedure:
To a stirring, degassed mixture of 7-bromo-8-iodo-2-isobutyl-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (50 mg, 0.13 mmol), 4-chlorophenylboronic acid (40 mg, 0.28 mmol), and tetrakis(triphenylphosphine)palladium (7 mg, 0.006 mmol) in dioxane (1.0 mL) at 20° C. was added K2CO3 (40 mg, 0.25 mmol) in water (0.3 mL). The resulting reaction mixture was heated in a microwave reactor at 200° C. for 10 min under argon. Analysis by HPLC/MS indicated that starting material had been consumed. The reaction mixture was brought to room temperature and was concentrated under reduced pressure. The crude product was purified by reverse phase preparative HPLC (acetonitrile-water-TFA) to isolate the title compound (22 mg, 0.053 mmol) as a light yellow solid. MS: [M+H]+=412.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[OH:17])=O.[NH2:18][CH2:19][CH2:20][CH:21]([OH:23])[CH3:22]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[N:18][CH2:19][CH2:20][CH:21]([OH:23])[CH3:22])[C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[OH:17]
Reactant: CC(O)CCN
Reactant: O=C(c1cc(Cl)ccc1O)c1ccccc1Cl
Product: CC(O)CCN=C(c1cc(Cl)ccc1O)c1ccccc1Cl

Procedure:
The enantiomers of this compound were prepared in the same manner by a reaction between (2-chlorophenyl)-(5-chloro-2-hydroxyphenyl)-methanone and the enantiomers of 4-aminobutan-2-ol.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>CC(C)=O>[CH2:20]([O:19][C:17](=[O:18])[CH2:16][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[I:1])[CH3:21]
Reactant: CCOC(=O)CBr
Reactant: Oc1ccccc1I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1ccccc1I
Temperature: 25 °C
Reaction time: 1 h

Procedure:
9.10 g (41.4 mmol) of o-iodophenol was dissolved in 102 ml of acetone and treated subsequently at 0° C. with 14.8 g (1.1 eq.) of cesium carbonate and 4.57 ml (1.0 eq.) of ethyl bromoacetate. After vigorous stirring for 1 h at ambient temperature and filtration, the bulk of solvent was evaporated and the residue redissolved in EtOAc. Washing with water, drying over magnesium sulfate, and evaporation of the solvents finally produced 12.66 g of pure title compound as colorless oil, MS: 306.0 (M)+.
Reaction SMILES: [N:1]([C:4]1[C:21](=[O:22])[CH2:20][CH2:19][C@@:18]2([CH3:23])[C:5]=1[CH2:6][CH2:7][C@@H:8]1[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]1[CH2:10][CH2:11][C@@H:12]2[O:24][CH:25]1[CH2:27][CH2:26]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCCC1>O>[NH2:1][C:4]1[C:21](=[O:22])[CH2:20][CH2:19][C@@:18]2([CH3:23])[C:5]=1[CH2:6][CH2:7][C@@H:8]1[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]1[CH2:10][CH2:11][C@@H:12]2[O:24][CH:25]1[CH2:26][CH2:27]1
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=C(N=[N+]=[N-])C(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2OC1CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: C[C@]12CC[C@H]3[C@@H](CCC4=C(N)C(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2OC1CC1
Yield: 43.1 %

Procedure:
A stirred solution of 4-azido-17β-(cyclopropyloxy)androst-4-en-3-one (1.32 q, 3.57 mM), triphenylphosphine (1.14 g, 4.97 mM), tetrahydrofuran (25 ml) and water (8 ml) was heated to reflux for 15 hours. The reaction was cooled and most of the solvent was evaporated. The residue was dissolved in dichloromethane, loaded onto a column of SiO2 and flash chromatographed (toluene--10% ethyl acetate) to give 4-amino-17β-(cyclopropyloxy)androst-4-en-3-one (0.53 g 43.1%), mp 85°-88° C. IR 3446, 3363, 1672, 1584 cm-1 ; MS (CI) m/z 344 (100%, M+ +1), 1H NMR (CDCl3), 0.38-0.61 (4H, m, 2×cyclopropyl (CH2 's), 0.74 (s, C18 -Me), 1.15 (s, C19 -Me), 3.25-3.33 (m, OCH), 3.44 (t+br s, C17 α-H+NH 2), 13C NMR (CDCl3), 88.95, 132.87, 138.90, 194.33. This compound has the following structure:
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:20]2[C:19]([CH3:21])=[C:18]([CH3:22])[N:17]=[C:16]([NH2:23])[C:15]=2[N:14]=[C:13]1[CH3:24].[C:25](Cl)(=[O:29])[CH:26]([CH3:28])[CH3:27]>C(Cl)(Cl)Cl>[NH2:23][C:16]1[C:15]2[N:14]=[C:13]([CH3:24])[N:12]([CH2:11][CH2:10][CH2:9][NH:8][C:25](=[O:29])[CH:26]([CH3:28])[CH3:27])[C:20]=2[C:19]([CH3:21])=[C:18]([CH3:22])[N:17]=1
Reactant: Cc1nc(N)c2nc(C)n(CCCN)c2c1C
Reactant: CC(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1nc(N)c2nc(C)n(CCCNC(=O)C(C)C)c2c1C
Reaction time: 0.25 h
Yield: 25.3 %

Procedure:
Triethylamine (0.78 mL, 5.6 mmol) was added to a solution of 1-(3-aminopropyl)-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-4-amine (1.00 g, 4.3 mmol) in chloroform (50 mL). The solution was cooled in an ice bath and then isobutyryl chloride (0.49 mL, 4.7 mmol) was added. The reaction mixture was stirred for 15 minutes then the ice bath was removed and the reaction mixture was stirred for an additional 15 minutes. The reaction mixture was diluted with chloroform to a volume of 150 mL. Water (50 mL) was added then the pH was adjusted to 11 with solid potassium carbonate and then to pH 14 with 50% sodium hydroxide. The resulting precipitate was isolated by filtration and dried to provide 0.33 g of N-[3-(4-amino-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-1-yl)propyl]-2-methylpropanamide as a white solid, m.p. 178.1-178.8° C.