Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1)#[CH:2].[C:10]1([CH3:19])[CH:15]=[CH:14][CH:13]=[C:12]([N:16]=[C:17]=[O:18])[CH:11]=1>C1COCC1>[C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH:7][C:17]([NH:16][C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([CH3:19])[CH:11]=2)=[O:18])=[CH:5][CH:4]=1)#[CH:2]
Reactant: C#Cc1ccc(N)cc1
Reactant: Cc1cccc(N=C=O)c1
Solvent: C1CCOC1
Product: C#Cc1ccc(NC(=O)Nc2cccc(C)c2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-ethynylaniline (1.308 g, 11.18 mmol, 1 eq) in anhydrous THF (20 mL) under nitrogen atmosphere at room temperature was added dropwise m-tolyl isocyanate (1.684 mL, 1.2 eq). The yellow reaction solution was stirred at room temperature for 3 hours. The reaction was then partitioned between EtOAc and aq NH4Cl. The organic layer was isolated, washed with saturated aq NaHCO3, brine, and dried with anhydrous sodium sulfate. The upper solvent layer was decanted and concentrated. The resulting solid residue was chromatographed initially with EtOAc-Hex from 1:100 to 1:4 and then continued with an eluent from dichloromethane to MeOH-DCM 1:10. The product fractions were collected, concentrated, and the white solid was triturated with EtOAc-Hex (2:1) at room temperature for 18 h. Upon filtration, 1-(4-ethynylphenyl)-3-(3-methylphenyl)urea was obtained as white solid in amount of 2.134 g.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7](B2OC(C)(C)C(C)(C)O2)[CH:6]=[CH:5][C:4]=1[N:18]1[CH2:22][CH2:21][C@@H:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:19]1)=[O:2].C(=O)([O-])[O-].[K+].[K+].[C:37]([N:41]1[C:45](=[O:46])[CH:44]=[C:43](Cl)[S:42]1(=[O:49])=[O:48])([CH3:40])([CH3:39])[CH3:38].ClCCl>O1CCOCC1.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]>[C:37]([N:41]1[C:45](=[O:46])[CH:44]=[C:43]([C:7]2[CH:6]=[CH:5][C:4]([N:18]3[CH2:22][CH2:21][C@@H:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:28])[CH3:29])[CH2:19]3)=[C:3]([CH:1]=[O:2])[CH:8]=2)[S:42]1(=[O:49])=[O:48])([CH3:40])([CH3:39])[CH3:38]
Reactant: CC(C)(C)N1C(=O)C=C(Cl)S1(=O)=O
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2C=O)C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ccc(C3=CC(=O)N(C(C)(C)C)S3(=O)=O)cc2C=O)C1
Temperature: 80 °C
Yield: 73 %

Procedure:
Boronic ester 22-B in dioxane (1 mL) was treated with potassium carbonate (124 mg, 0.901 mmol), heterocycle 9-A (48 mg, 0.21 mmol) and [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (17.6 mg, 0.0216 mmol). The solution was degassed, placed under nitrogen and heated to 80° C. for 48 hours. The solution was allowed to cool to ambient temperature, diluted with ethyl acetate (10 mL) and washed with water (10 mL). The organics were separated, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography (30 ethyl acetate/hexanes) to afford a yellow solid 22-C (63 mg, 73%). 1H NMR (500 MHz, CD3OD): δ 10.05 (s, 1H), 8.25 (d, J=1.95 Hz, 1H), 7.87 (dd, J=11.22 Hz, 1H), 7.06 (d, J=9.27 Hz, 1H), 6.84 (s, 1H), 4.24 (m, 1H), 3.70 (m, 2H), 3.65 (m, 1H), 3.19 (m, 1H), 2.28 (m, 1H), 2.26 (m, 1H), 1.72 (s, 9H), 1.46 (s, 9H); LCMS found for C23H31N3O6S (M+H)+: m/z=478.
Reaction SMILES: Br[C:2]1[C:6]([CH3:7])=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14]C)=[C:10]([F:16])[CH:9]=2)[S:4][C:3]=1[CH:17]1[O:21]CCO1.C[O:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[C:26]([CH3:33])[CH:25]=1>>[F:16][C:10]1[CH:9]=[C:8]([C:5]2[S:4][C:3]([CH:17]=[O:21])=[C:2]([C:27]3[CH:28]=[CH:29][C:24]([OH:23])=[CH:25][C:26]=3[CH3:33])[C:6]=2[CH3:7])[CH:13]=[CH:12][C:11]=1[OH:14]
Reactant: COc1ccc(-c2sc(C3OCCO3)c(Br)c2C)cc1F
Reactant: COc1ccc(B(O)O)c(C)c1
Product: Cc1cc(O)ccc1-c1c(C=O)sc(-c2ccc(O)c(F)c2)c1C
Yield: 37.7 %

Procedure:
Starting from 2-[3-bromo-5-(3-fluoro-4-methoxyphenyl)-4-methylthien-2-yl]-1,3-dioxolane (0.90 g, 2.4 mmol, made in Example 8, Step 1) and substituting 4-methoxy-2-methylphenylboronic acid (0.44 g, 2.7 mmol) in place of 4-methoxyphenylboronic acid (Step 2), the title compound (0.31 g, 76%, m.p. 227-30° C.) was synthesized in essentially the same manner as described in Example 1, Steps 2-4.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[F:12][C:13]1[C:18](O)=[C:17]([F:20])[C:16]([F:21])=[C:15]([F:22])[C:14]=1[F:23]>>[F:12][C:13]1[C:18]([O:8][C:7](=[O:9])[C:6]2[CH:10]=[CH:11][C:3]([CH2:2][Br:1])=[CH:4][CH:5]=2)=[C:17]([F:20])[C:16]([F:21])=[C:15]([F:22])[C:14]=1[F:23]
Reactant: O=C(O)c1ccc(CBr)cc1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Product: O=C(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc(CBr)cc1
Yield: 56.4 %

Procedure:
Starting from 4-(bromomethyl)benzoic acid (5.0 g, 23.25 mmol) and pentafluorophenol (4.3 g, 23.25 mmol), applying the same procedure described in Preparation 2, 4-(bromomethyl)benzoic acid pentafluorophenyl ester (5.0 g, 56%) was obtained as an off white solid.
Reaction SMILES: Br[CH:2]([CH3:12])[C:3]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[CH3:11])=O.[NH2:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([C:23](=[S:25])[NH2:24])=[CH:19][CH:18]=1)(=[O:16])=[O:15]>>[CH3:12][C:2]1[S:25][C:23]([C:20]2[CH:19]=[CH:18][C:17]([S:14]([NH2:13])(=[O:15])=[O:16])=[CH:22][CH:21]=2)=[N:24][C:3]=1[C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[CH3:11]
Reactant: NC(=S)c1ccc(S(N)(=O)=O)cc1
Reactant: Cc1ccncc1C(=O)C(C)Br
Product: Cc1ccncc1-c1nc(-c2ccc(S(N)(=O)=O)cc2)sc1C
Yield: 56.8 %

Procedure:
By the reaction in the same manner as in Example 25-iii) using 2-bromo-1-(4-methylpyridin-3-yl)propan-1-one hydrobromate (510 mg) and 4-(aminosulfonyl)benzenecarbothioamide (355 mg), the title compound (322 mg) was obtained as colorless powder crystals.
Reaction SMILES: C([O:8][CH2:9][CH:10]=[C:11]([CH3:30])[CH2:12][CH2:13][CH:14]=[C:15]([CH3:29])[CH2:16][CH2:17][CH:18]=[C:19]([CH3:28])[CH2:20][CH2:21][CH:22]=[C:23]([CH3:27])[C:24]([OH:26])=[O:25])C1C=CC=CC=1.[Li].C=CC=C.CO>O1CCCC1>[OH:8][CH2:9][CH:10]=[C:11]([CH3:30])[CH2:12][CH2:13][CH:14]=[C:15]([CH3:29])[CH2:16][CH2:17][CH:18]=[C:19]([CH3:28])[CH2:20][CH2:21][CH:22]=[C:23]([CH3:27])[C:24]([OH:26])=[O:25]
Reactant: CC(=CCCC(C)=CCOCc1ccccc1)CCC=C(C)CCC=C(C)C(=O)O
Agent: C=CC=C
Agent: [Li]
Solvent: CO
Solvent: C1CCOC1
Product: CC(=CCO)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)O
Reaction time: 0.5 h
Yield: 84.6 %

Procedure:
In 50 ml of tetrahydrofuran was dissolved 5 g of the 16-benzyloxy-2,6,10,14-tetramethyl-2,6,10,14-hexadecatetraenoic acid obtained as described in the previous (a) section. This solution was added dropwise to the above-prepared lithium solution over a period of 30 min. The mixture was stirred for 30 min., and 1,3-butadiene was introduced into the mixture until the color of the mixture (blue) faded. To the resulting yellow colored solution was added methanol until the yellow faded. Subsequently, this was left standing to reach room temperature. The solid product thus obtained was collected on a filter, and then dissolved in water. The aqueous solution was made weakly-acidic by addition of 1 N hydrochloric acid under ice-cooling, and then extracted with hexane. The extract was washed successively with water and a saturated aqueous sodium chloride solution, and then dried over magnesium sulfate. The dried extract was concentrated, and the thus-obtained concentrate was purified over a silica gel column to give 3.3 g of 16-hydroxy-2,6,10,14-tetramethyl-2,6,10,14-hexadecatetraenoic acid.
Reaction SMILES: Br[C:2]1[C:3](=[O:21])[O:4][C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][C:7]=1[OH:8].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([SH:29])=[C:25]([CH:30]([CH3:32])[CH3:31])[CH:24]=1.N1CCCCC1>ClCCl>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([S:29][C:2]2[C:3](=[O:21])[O:4][C:5]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:6][C:7]=2[OH:8])=[C:25]([CH:30]([CH3:32])[CH3:31])[CH:24]=1
Reactant: O=C1OC(c2ccccc2)(c2ccccc2)CC(O)=C1Br
Reactant: CC(C)c1cc(Cl)ccc1S
Solvent: ClCCl
Solvent: C1CCNCC1
Product: CC(C)c1cc(Cl)ccc1SC1=C(O)CC(c2ccccc2)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared as described in General Method 6 from 2.0 mmol of 3-bromo-5,6-dihydro-4-hydroxy-6,6-diphenyl-2H-pyran-2-one (prepared in example AAA), 2.1 mmol of 4-chloro-2-isopropylbenzenethiol, and 2.1 mmol of piperidine in 30 mL of dichloromethane. The product was chromatographed on silica gel, eluting first with chloroform and then with 5% methanol in chloroform (m.p. 95°-96° C.). 1H NMR (DMSO-d6) δ1.16 (d, 6H), 3.23 (m, 1H), 3.73 (bs, 2H), 5.60 (d, 1H), 6.45 (d, 1H), 7.14 (d, 1H), 7.32-7.48 (m, 10H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:5]=1[N:11]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:14])=[O:13].Br[CH2:32][C:33]1[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=1>>[CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:32][C:33]2[CH:34]=[CH:35][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:41][CH:42]=2)[C:5]=1[N:11]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:13])=[O:14]
Reactant: COC(=O)c1cccc(O)c1N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Reactant: COC(=O)c1ccc(CBr)cc1
Product: COC(=O)c1ccc(COc2cccc(C(=O)OC)c2N(Cc2ccccc2)S(=O)(=O)c2ccc(OC)cc2)cc1
Yield: 86.9 %

Procedure:
In the same manner as described in Example 38, 0.275 g (0.644 mmol) of the product of Example 37 and 0.295 g (1.288 mmol) of methyl 4-(bromomethyl)benzoate provided 0.322 g (87%) of the desired product as a white solid. Electrospray Mass Spec: 576.2 (M+H)+
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[CH:25]([NH2:28])([CH3:27])[CH3:26]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:28][CH:25]([CH3:27])[CH3:26])=[O:21])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2]
Reactant: CC(C)N
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)NC(C)C)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and isopropylamine 1H NMR (400 MHz, DMSO-d6) δ ppm 1.20 (d, J=6.57 Hz, 6 H) 2.44 (s, 3 H) 4.13 (dd, J=14.15, 6.57 Hz, 1 H) 7.66 (dd, J=8.08, 1.52 Hz, 1 H) 7.74 (s, 1 H) 7.75-7.85 (m, 1 H) 8.07-8.28 (m, 1 H) 8.45 (dd, J=19.70, 6.82 Hz, 3 H) 8.84-8.98 (m, 1 H) 12.97-13.37 (m, 1 H). MS m/z [M+H]+ 362.2.
Reaction SMILES: COC(C1C=C(OC2C=CC(Cl)=CC=2[Cl:21])C=CC=1[N+]([O-])=O)=O.[C:23]([Cl:31])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[Cl:21][C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][CH:27]=1)[C:23]([Cl:31])=[O:30]
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)c1cc(Oc2ccc(Cl)cc2Cl)ccc1[N+](=O)[O-]
Product: O=C(Cl)c1cccc(Cl)c1

Procedure:
In the commercial process for producing herbicidal bifenox, i.e., methyl 2-nitro-5-(2'4'-dichlorophenoxy)-benzoate, preparation of a reaction precursor involves the chlorination of benzoyl chloride to obtain m-chlorobenzoyl chloride. This material is then reacted with methanol to produce the corresponding methyl chlorobenzoate.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[S:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][NH:9][CH2:8][CH2:7]1.C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([N:9]1[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[S:6][CH2:7][CH2:8]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: c1ccc2c(c1)CNCCS2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCSc2ccccc2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of methanesulphonyl chloride (3.3 g) in dichloromethane (15 ml) was added dropwise at room temperature to a stirred solution of 2,3,4,5-tetrahydro-1,4-benzothiazepine (4.8 g, prepared as described in the first paragraph of Example 6 above) and triethylamine (2.9 g) in dichloromethane (100 ml). The reaction mixture was stirred at room temperature for one hour, washed with water, dried and the solvent was removed by evaporation. Purification of the residue by flash chromatography using dichloromethane as eluent gave 4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine which was recrystallised from hexane. Yield 3 g. (m.p. 98°-100° C.).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.Cl.[F:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]([OH:41])[CH:28]([NH2:40])[CH2:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=2)=[CH:23][CH:22]=1.C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C.O.CN(C)C=O>[F:20][C:21]1[CH:22]=[CH:23][C:24]([CH:27]([OH:41])[CH:28]([NH:40][C:10](=[O:12])[CH2:9][CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=2)=[CH:25][CH:26]=1
Reactant: O=C(O)CCCc1ccccc1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(CCCc1ccccc1)NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.3 %

Procedure:
To a solution of 4-phenylbutyric acid (141 mg, 0.86 mmol) in tetrahydrofuran (5 ml) were added oxalyl chloride (0.15 ml, 1.72 mmol) and N,N-dimethylformamide (0.01 ml), and the mixture was stirred at room temperature for 30 min. The reaction solution was evaporated under reduced pressure. To a solution of the residue in ethyl acetate (5 ml) were added (1RS,2SR)-1-(4-fluorophenyl)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)-2-propylamine hydrochloride (200 mg, 0.57 mmol) and saturated aqueous sodium hydrogen carbonate (5 ml), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (50 ml) and extracted with ethyl acetate (50 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1-1:1) and recrystallized from ethyl acetate-hexane to give the title compound (179 mg, 68%).
Reaction SMILES: [NH2:1][C:2]1[C:7](C(O)=O)=[C:6]([CH3:11])[N:5]=[C:4]2[S:12][C:13]([Br:23])=[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=3)[C:3]=12.N1C2C(=CC=CC=2)C=CC=1>[Cu]>[Br:23][C:13]1[S:12][C:4]2[N:5]=[C:6]([CH3:11])[CH:7]=[C:2]([NH2:1])[C:3]=2[C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1
Reactant: COc1cccc(-c2c(Br)sc3nc(C)c(C(=O)O)c(N)c23)c1
Agent: [Cu]
Solvent: c1ccc2ncccc2c1
Product: COc1cccc(-c2c(Br)sc3nc(C)cc(N)c23)c1
Temperature: 180 °C
Reaction time: 0.5 h
Yield: 60.3 %

Procedure:
A mixture of 4-amino-2-bromo-6-methyl-3-[3-(methyloxy)phenyl]thieno[2,3-b]pyridine-5-carboxylic acid (400 mg, 1.017 mmol) (Description 16), copper (194 mg, 3.05 mmol) and quinoline (3 mL, 25.3 mmol) was heated in a microwave at 180° C. for 30 min and then 190° C. for 30 min. After cooling to RT, the mixture was purified by chromatography on silica gel, eluting with a gradient of 40-60% ethyl acetate in cyclohexane, to give the title compound (214 mg). LCMS (A) m/z: 349/351 [M+1]+, Rt 1.08 min (acidic).
Reaction SMILES: [O:1]=[C:2]1[C:11]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C@H:21]([CH2:26][C:27]3[CH:28]=[C:29]4[C:33](=[C:34]([CH3:36])[CH:35]=3)[NH:32][N:31]=[CH:30]4)[C:22]([O:24]C)=[O:23])=[O:19])[CH2:14][CH2:13]2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.O.[OH-].[Li+]>CO.O1CCCC1.O>[CH3:36][C:34]1[CH:35]=[C:27]([CH2:26][C@@H:21]([O:20][C:18]([N:15]2[CH2:14][CH2:13][CH:12]([C:11]3[C:2](=[O:1])[NH:3][C:4]4[C:9]([CH:10]=3)=[CH:8][CH:7]=[CH:6][CH:5]=4)[CH2:17][CH2:16]2)=[O:19])[C:22]([OH:24])=[O:23])[CH:28]=[C:29]2[C:33]=1[NH:32][N:31]=[CH:30]2
Reactant: COC(=O)[C@@H](Cc1cc(C)c2[nH]ncc2c1)OC(=O)N1CCC(c2cc3ccccc3[nH]c2=O)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(c3cc4ccccc4[nH]c3=O)CC2)C(=O)O)cc2cn[nH]c12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of (R)-1-methoxy-3-(7-methyl-1H-indazol-5-yl)-1-oxopropan-2-yl 4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxylate (1.20 g, 2.46 mmol) in methanol (10 mL) and tetrahydrofuran (10 mL) at 0° C. was added a precooled solution of lithium hydroxide monohydrate (309 mg, 3.0 equiv) in water (10 mL). After 2 h, the reaction was concentrated under high vaccuum (<25° C.). The resulting residue was dissolved in water (20 mL), cooled to 0° C., and acidified to ca. pH 2 with 1 N hydrochloric acid. The suspension was maintained at 0° C. for 1 h, filtered, and the solid washed with cold water. The resulting white solid was air dried and then dried under high vacuum overnight to give 1.04 g (89%) as a white solid. Mass spec.: 475.30 (MH)+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][OH:5].[CH2:6]=[C:7]1[O:11][C:9](=[O:10])[CH2:8]1>C(N(CC)CC)C>[C:9]([O:5][CH2:4][CH2:3][CH2:2][Cl:1])(=[O:10])[CH2:8][C:7]([CH3:6])=[O:11]
Reactant: C=C1CC(=O)O1
Reactant: OCCCCl
Solvent: CCN(CC)CC
Product: CC(=O)CC(=O)OCCCCl
Yield: 81.6 %

Procedure:
3-Chloropropanol (47.3 g, 0.50 mole) and a catalytic amount of triethylamine at 65° were treated dropwise with 42 g (0.50 mole) of diketene. After the addition was complete, the reaction was stirred at 65° for an additional hour. Distillation of the residue furnished 72.9 g (82%) of product as a clear liquid, b.p. 78°-85° at 150 mm.
Reaction SMILES: [C:1]([C:3]1([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1)#[N:2]>[Ni]>[NH2:2][CH2:1][C:3]1([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1
Reactant: CCOC(=O)C1(C#N)CCOCC1
Agent: [Ni]
Product: CCOC(=O)C1(CN)CCOCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.1 %

Procedure:
A mixture of the compound (8.09 g) obtained in step 1, Raney-nickel (containing water (50%), 5.18 g) washed with ethanol and ammonia (0.5% ethanol solution, 200 mL) was stirred under a hydrogen atmosphere (1 atm) at room temperature for 3 hr. The mixture was filtered, and concentrated under reduced pressure to give ethyl 4-(aminomethyl)tetrahydro-2H-pyran-4-carboxylate (6.79 g, 82%) as a yellow oil.
Reaction SMILES: Cl.[CH2:2]([C:4]1[C:5]2[N:6]([C:11]([CH2:14][CH2:15][C:16]3[N:20]([CH3:21])[N:19]=[C:18]([N:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)[N:17]=3)=[N:12][N:13]=2)[C:7]([CH3:10])=[N:8][CH:9]=1)[CH3:3]>CO>[CH2:2]([C:4]1[C:5]2[N:13]([N:12]=[C:11]([CH2:14][CH2:15][C:16]3[N:20]([CH3:21])[N:19]=[C:18]([N:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)[N:17]=3)[N:6]=2)[C:7]([CH3:10])=[N:8][CH:9]=1)[CH3:3]
Reactant: CCc1cnc(C)n2c(CCc3nc(N4CCCC4)nn3C)nnc12
Agent: Cl
Solvent: CO
Product: CCc1cnc(C)n2nc(CCc3nc(N4CCCC4)nn3C)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.9 %

Procedure:
1.25 N HCl in methanol (57.3 μl, 71.7 μmol) was added to a solution of 8-ethyl-5-methyl-3-(2-(1-methyl-3-(pyrrolidin-1-yl)-1H-1,2,4-triazol-5-yl)ethyl)-[1,2,4]triazolo[4,3-c]pyrimidine (24.4 mg, 71.7 μmol) in methanol (2 mL). The reaction mixture was stirred at room temperature for 2 h. Additional 1.25 N HCl in methanol (57.3 μl, 71.7 μmol) was added and the mixture was stirred for 15 min. The solvent was evaporated. The crude product was purified with preparative HPLC to afford the desired product (20 mg, 82%) as a white solid. MS: m/z=341.2 (M+H+)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11](=O)[CH:12]=[C:13]([CH3:15])[CH3:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].O.[NH2:18][NH2:19]>CCO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH2:12][C:13]([CH3:15])([CH3:14])[NH:19][N:18]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: NN
Reactant: COc1ccc(C(=O)C=C(C)C)cc1OC
Solvent: CCO
Solvent: O
Product: COc1ccc(C2=NNC(C)(C)C2)cc1OC
Temperature: 80 °C
Yield: 100 %

Procedure:
A 100 mL round bottom flask equipped with a stir bar, Vigreux column and nitrogen inlet was charged with 1-(3,4-dimethoxy-phenyl)-3-methyl-but-2-en-1-one (1.4 g, 10 mmol), EtOH (40 mL) and hydrazine monohydrate (0.58 mL, 12 mmol). The mixture was heated at 80° C. for 2 h. LC-MS and TLC analysis showed consumption of SM. The solvent was evaporated under reduced pressure and trace hydrazine and EtOH was removed under high vacuum for 30 min. The material was used as in the next step. Amount obtained: 2.3 g, 10 mmol, 100% yield. LC-MS (ESI) m/e 235 (M+H). Step 3
Reaction SMILES: C([O:5][C:6](=[O:39])[CH2:7][O:8][CH2:9][C:10]1([CH2:14][O:15][C:16]2[C:17]3[C:24]([C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=4)=[C:23]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[O:22][C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:13][CH2:12][CH2:11]1)(C)(C)C.Cl>O1CCOCC1>[CH3:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([C:24]2[C:17]3[C:16]([O:15][CH2:14][C:10]4([CH2:9][O:8][CH2:7][C:6]([OH:39])=[O:5])[CH2:11][CH2:12][CH2:13]4)=[N:21][CH:20]=[N:19][C:18]=3[O:22][C:23]=2[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:26][CH:27]=1
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(OCC4(COCC(=O)OC(C)(C)C)CCC4)c23)cc1
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(OCC4(COCC(=O)O)CCC4)c23)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Dissolve 237 mg (0.45 mmol) of {[1-({[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}methyl)cyclobutyl]methoxy}acetic acid tert-butyl ester in 1 ml of dioxane, add 2 ml of 4 N hydrogen chloride in dioxane and stir at RT for 16 h. After concentrating the reaction solution under reduced pressure, purify the residue by means of preparative RP-HPLC (gradient: water/acetonitrile). 180 mg (85% of theory) of the desired product are obtained.
Reaction SMILES: CCC(C)[BH-](C(C)CC)C(C)CC.[Li+].[CH3:15][C@H:16]1[CH2:44][O:43][C@@:19]2([O:23][C@H:22]3[CH2:24][C@H:25]4[C@@H:30]5[CH2:31][CH2:32][C@@H:33]6[CH2:39][C:37](=[O:38])[CH2:36][CH2:35][C@:34]6([CH3:40])[C@H:29]5[CH2:28][CH2:27][C@:26]4([CH3:41])[C@H:21]3[C@@H:20]2[CH3:42])[CH2:18][CH2:17]1>O1CCCC1>[CH3:15][C@H:16]1[CH2:44][O:43][C@@:19]2([O:23][C@H:22]3[CH2:24][C@H:25]4[C@@H:30]5[CH2:31][CH2:32][C@@H:33]6[CH2:39][C@@H:37]([OH:38])[CH2:36][CH2:35][C@:34]6([CH3:40])[C@H:29]5[CH2:28][CH2:27][C@:26]4([CH3:41])[C@H:21]3[C@@H:20]2[CH3:42])[CH2:18][CH2:17]1
Reactant: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@@H]5CC(=O)CC[C@]5(C)[C@H]4CC[C@]3(C)[C@H]1[C@@H]2C
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@@H]5C[C@@H](O)CC[C@]5(C)[C@H]4CC[C@]3(C)[C@H]1[C@@H]2C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
L-Selectride® (527 ml; 1M in tetrahydrofuran) was added to a solution of smilagenone (156 g) in tetrahydrofuran (obtained by hydrogenation of diosgenone) at ca. −10° C. under an atmosphere of nitrogen. The reaction mixture was stirred at this temperature for 30 minutes, allowed to warm to ambient temperature and stirred overnight. The mixture was quenched by addition to a mixture of aqueous citric acid (311 g in 3800 ml water) and dichloromethane (2200 ml), maintaining the internal temperature below 30° C. The aqueous phase was separated and re-extracted with dichloromethane (400 ml). The combined organic extracts were washed with aqueous citric acid (160 g in 2200 ml water) and distilled to low volume. 2-Propanol (3000 ml) was added and the mixture redistilled to ca. ½ volume. Additional 2-propanol (1500 ml) was added and the mixture distilled to ca. ½ volume. The mixture was heated to reflux and allowed to cool. The mixture was further cooled to 0-10° C. and filtered. The solid was dried in a vacuum oven at 60-65° C. to afford smilagenin. The yield is 94.0 g.