Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:35]2[CH2:47][CH2:46][N:38]3[C:39]4[CH2:40][CH2:41][CH2:42][CH2:43][C:44]=4[CH:45]=[C:37]3[C:36]2=[O:48])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[O:26])=[CH:21][N:20]=2)[C:15](=[O:33])[N:14]([CH3:34])[N:13]=1)(=O)C.[OH-].[Li+].O>C(O)(C)C.C1COCC1.O>[OH:4][CH2:5][C:6]1[C:7]([N:35]2[CH2:47][CH2:46][N:38]3[C:39]4[CH2:40][CH2:41][CH2:42][CH2:43][C:44]=4[CH:45]=[C:37]3[C:36]2=[O:48])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[O:26])=[CH:21][N:20]=2)[C:15](=[O:33])[N:14]([CH3:34])[N:13]=1
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(C(=O)N4CCOCC4)cn3)c(=O)n(C)n2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Solvent: C1CCOC1
Product: Cn1nc(-c2ccnc(N3CCn4c(cc5c4CCCC5)C3=O)c2CO)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Yield: 61.4 %

Procedure:
A mixture of 227a (131 mg, 0.20 mmol) and lithium hydroxide.1 water (120 mg, 2.0 mmol) in i-propanol/THF/water (4 mL/4 mL/2 mL) was stirred at 35° C. for 0.5 h. The mixture was evaporated in vacuo and the residue was extracted with dichloromethane (3×10 mL). The combined dichloromethane extract was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 227 as a white solid (75 mg, 62%). MS-ESI: [M+H]+ 611.2. 1H NMR (500 MHz, DMSO-d6) δ 9.75 (s, 1H), 8.64 (s, 1H), 8.54 (d, J=5.0 Hz, 1H), 8.36 (d, J=2.0 Hz, 1H), 7.79-7.77 (m, 1H), 7.59 (d, J=8.5 Hz, 1H), 7.43 (d, J=5.0 Hz, 1H), 6.58 (s, 1H), 4.82 (s, 1H), 4.60-4.57 (m, 1H), 4.38-4.36 (m, 1H), 4.29-4.19 (m, 2H), 4.10-4.05 (m, 1H), 3.93-3.90 (m, 1H), 3.80 (s, 3H), 3.60-3.50 (m, overlap, 8H), 2.66-2.54 (m, 2H), 2.48-2.46 (m, 2H), 1.81-1.66 (m, 4H).
Reaction SMILES: C[C:2]1[O:3]C(=O)C2SC=C[C:6]=2[N:7]=1.[NH2:12][C:13]1C(C)=CC=CC=1>C(O)(=O)C>[CH3:2][N:7]([C:13]([N:12]=[N:12][C:2]([N:7]([CH3:6])[CH3:13])=[O:3])=[O:3])[CH3:6]
Reactant: Cc1nc2ccsc2c(=O)o1
Reactant: Cc1ccccc1N
Solvent: CC(=O)O
Product: CN(C)C(=O)N=NC(=O)N(C)C
Yield: 45.9 %

Procedure:
2-Methyl-thieno[3,2-d][1,3]oxazin4-one (12.7 g, 76 mmol) and o-toluidine (16.2 mL, 152 mmol) were combined in acetic acid (175 mL) and refluxed for 3 hours. The reaction was concentrated and the residue was partitioned between ethyl acetate and water. The two phase mixture was treated with sodium bicarbonate until the aqueous layer was basic and the phases were then separated. The aqueous phase was extracted with ethyl acetate and the combined organic layer was washed with water and brine, dried over sodium sulfate and concentrated to leave a black oil. This residue was purified by flash chromatography on silica gel (60×200 mm). Elution with 20% ethyl acetate/hexane gave 16.2 g of impure product and 3 g of uncyclized diamide biproduct. The impure product was chromatographed a second time as above but with 10% and 15% ethyl acetate/hexane elution. In this fashion 9.2 g (47%) of 2-methyl-3-(2-methylphenyl)-3H-thieno[3,2-d]pyrimidin-4-one was isolated as a light yellow solid. NMR δ7.70 (d, J=5.3 Hz, 1H), 7.39-7.30 (m, 3H), 7.29 (d, J=5.3 Hz, 1H), 7.13 (d, J=7.8 Hz, 1H), 2.15 (s, 3H), 2.10 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][NH2:13]>C1COCC1.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:13][CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: CN
Solvent: O
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1ccc(Br)cc1

Procedure:
A solution of 4-bromobenzenesulphonyl chloride (2.0 g) in THF (5 ml) was treated in two portions with aqueous methylamine (40%; 6 ml). The resulting exothermic reaction-was allowed to subside and the solution was diluted with water (10 ml) and extracted with dichloromethane (2×50 ml). The dried extract was evaporated to give the title compound as a white solid (2.0 g).
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:15]=[O:16]>C(O)CCC>[C:1]1([C@@H:7]([N:9]([CH2:10][Si:11]([CH3:13])([CH3:12])[CH3:14])[CH2:15][O:16][CH2:6][CH2:1][CH2:2][CH3:3])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@H](NC[Si](C)(C)C)c1ccccc1
Reactant: C=O
Solvent: CCCCO
Product: CCCCOCN(C[Si](C)(C)C)[C@@H](C)c1ccccc1

Procedure:
The title compound was prepared from (S)-(-)-N-1-phenylethyl-N-trimethylsilylmethylamine by reaction with n-butanol and aqueous formaldehyde following the procedure of Example 2 to give the crude acetal (85% pure) as a colourless oil (7.1 g, 80%) δC (CD2Cl2)-1.09 (SiMe3), 14.35, 20.16, 24.72, 67.38 (OBu), 19.57 (CMe), 40.30 (NCH2Si), 62.30 (CH), 84.73 (NCH2O), 127.01, 128.15, 128.51, 146.15 (Ph).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:20]=1[O:21][CH3:22])[C:16](=[O:17])[O:15][CH2:14]2>ClCCl>[Br:1][CH:14]1[C:13]2[C:18](=[CH:19][C:20]([O:21][CH3:22])=[C:11]([O:10][CH3:9])[CH:12]=2)[C:16](=[O:17])[O:15]1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc2c(cc1OC)C(=O)OC2
Solvent: ClCCl
Product: COc1cc2c(cc1OC)C(Br)OC2=O

Procedure:
12 mmol of N-bromosuccinimide are added to 10 mmol of 5,6-dimethoxyphthalide dissolved in dichloromethane and then the reaction mixture, illuminated with a halogen lamp, is heated at reflux for 5 hours. The mixture is then brought to ambient temperature and filtered, and the filtrate is subsequently evaporated, toluene is added, the suspension obtained is filtered and the filtrate is evaporated. The residue obtained is filtered through silica to yield the expected product.
Reaction SMILES: [OH-].[Na+].[N:3]1([C:8]2[CH:31]=[CH:30][C:11]3[N:12]([C:15]4[CH:16]=[C:17]([NH:26]C(=O)C)[CH:18]=[C:19]([N:21]5[CH:25]=[CH:24][CH:23]=[CH:22]5)[CH:20]=4)[CH:13]=[N:14][C:10]=3[CH:9]=2)[CH:7]=[CH:6][CH:5]=[N:4]1>C(O)C.C(OCC)(=O)C>[N:3]1([C:8]2[CH:31]=[CH:30][C:11]3[N:12]([C:15]4[CH:16]=[C:17]([CH:18]=[C:19]([N:21]5[CH:25]=[CH:24][CH:23]=[CH:22]5)[CH:20]=4)[NH2:26])[CH:13]=[N:14][C:10]=3[CH:9]=2)[CH:7]=[CH:6][CH:5]=[N:4]1
Reactant: CC(=O)Nc1cc(-n2cccc2)cc(-n2cnc3cc(-n4cccn4)ccc32)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1cc(-n2cccc2)cc(-n2cnc3cc(-n4cccn4)ccc32)c1
Yield: 85 %

Procedure:
A mixture of 10% NaOH (5 ml) and the compound of Example 96 (1.45 g, 3.79 mmol) in 25 ml ethanol was heated at 100° C. for 2 h. The mixture was diluted with ethyl acetate (100 ml) and the organic layer was washed with water (50 ml) and brine (25 ml). The solvent was removed under reduced pressure and the residue was purified by column chromatography over silica gel to give the product in 85% yield (1.1 g).
Reaction SMILES: [O:1]1[C:5]2[CH2:6][N:7]([C:11](=[O:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:8][CH2:9][CH2:10][C:4]=2[CH:3]=[CH:2]1.[CH3:24][NH:25][CH3:26].[CH2:27]=O>C(O)(=O)C>[CH3:24][N:25]([CH2:27][C:2]1[O:1][C:5]2[CH2:6][N:7]([C:11](=[O:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:8][CH2:9][CH2:10][C:4]=2[CH:3]=1)[CH3:26]
Reactant: O=C(CCCCCc1ccccc1)N1CCCc2ccoc2C1
Reactant: CNC
Reactant: C=O
Solvent: CC(=O)O
Product: CN(C)Cc1cc2c(o1)CN(C(=O)CCCCCc1ccccc1)CCC2
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.216 g (0.694 mmol) of 1-(4,5,6,8-tetrahydrofuro[2,3-c]azepin-7-yl)-6-phenylhexan-1-one in 20 ml of acetic acid, 75 mg (0.83 mmol) of 50% aqueous dimethylamine and 68 mg (0.83 mmol) of 37% aqueous formaldehyde were added, followed by stirring at 100° C. for 30 minutes. After the solvent was distilled off under reduced pressure, the residual solution was alkalified with aqueous sodium hydroxide and extracted with dichloromethane 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (ethyl acetate to ethyl acetate/methanol=4/1) to yield the desired product.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[C:9]([O:12][CH3:13])[CH:8]=[CH:7][CH:6]=2.[CH:14]([Mg]Cl)([CH3:16])[CH3:15].[CH:19]1(C)CC[CH:22](C(C)C)[CH:21]([S:28]([O-])=[O:29])[CH2:20]1.[NH4+].[Cl-]>C1COCC1>[CH3:15][C:14]1[CH:16]=[CH:22][C:21]([S:28]([C:2]2[CH:3]=[N:4][C:5]3[C:10]([CH:11]=2)=[C:9]([O:12][CH3:13])[CH:8]=[CH:7][CH:6]=3)=[O:29])=[CH:20][CH:19]=1
Reactant: COc1cccc2ncc(Br)cc12
Reactant: CC1CCC(C(C)C)C(S(=O)[O-])C1
Reactant: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cccc2ncc(S(=O)c3ccc(C)cc3)cc12
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To a solution 3-bromo-5-methoxyquinoline (2.37, 10 mmol) prepared in stage B in dried THF (35 mL) is added a solution of isopropylmagnesium chloride (16.6 mL, 30 mmol) at −78° C. The solution is stirred at −78° C. under nitrogen atmosphere for 3 hours. Menthyl sulfinate (8.8 g, 30 mmol) is added and the resulting solution is stirred for a further 24 hours. The reaction mixture is then hydrolysed with saturated aqueous NH4Cl solution. After extraction of the aqueous phase, the combined organic layers are dried (MgSO4), evaporated giving the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([OH:11])[CH:10]=1)[C:5]([OH:7])=[O:6].[CH2:12](O)[CH:13]=[CH2:14].C[Si](Cl)(C)C>>[CH2:14]([O:6][C:5](=[O:7])[C:4]1[CH:3]=[C:2]([OH:1])[CH:10]=[C:9]([OH:11])[CH:8]=1)[CH:13]=[CH2:12]
Reactant: O=C(O)c1cc(O)cc(O)c1
Reactant: C=CCO
Agent: C[Si](C)(C)Cl
Product: C=CCOC(=O)c1cc(O)cc(O)c1
Temperature: -20 °C
Reaction time: 16 h

Procedure:
To 1.5 g of 3,5-dihydroxybenzoic acid in screw-capped vial was added 10 g of allyl alcohol and the vial was closed and cooled to −20° C. To the cold contents of the reaction vial was added 5 mL of trimethylsilyl chloride via syringe through a septum. The reaction vial was allowed to warm to room temperature and agitated for 16 hours. The vial was opened carefully and its contents transferred to a round-bottomed flask. The solvent was removed under reduced pressure and the residual solid was dried under reduced pressure over potassium hydroxide pellets for 12 h. The semisolid product was used in the subsequent synthetic steps without further purification. The product was analyzed by HPLC and had a retention time of 3.65 on 5 cm C18 reversed phase column with flow rate of 2.5 mL/min of pure acetonitrile (for solvent A) and 0.1% aqueous trifluroacetic acid (for solvent B). The product was characterized by 1H NMR (DMSO-d6, 350 MHz): δ=6.87 (s, 2H, aromatic); 6.44 (s, 1H, aromatic); 5.85-5.96 (m, 1H); 5.16-5.33 (m, 2H); 4.65-4.67(dd, 2H).
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[CH:8]2)#[N:4].C[N:15]1C(=O)CCC1>>[C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([NH2:15])[CH:9]=[CH:8]2)#[N:4]
Reactant: N#Cc1ccc2[nH]ccc2c1
Reactant: CN1CCCC1=O
Agent: [H-]
Agent: [Na+]
Product: N#Cc1ccc2c(ccn2N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 16 %

Procedure:
NaH (60%, 60 mmol) is portion-wise added to a solution of 5-cyano-1H-indole (20 mmol) in NMP (35 mL), and the reaction mixture is 0° C. for 1 h. A solution of HOSA (60 mmol) in NMP (14 mL) is added drop-wise at 0° C. The reaction mixture is warmed to rt and stirred overnight, then quenched with water and extracted with EtOAc. The organic layer is separated, washed with water three times and with brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 20-40% EtOAc in heptane to afford 5-cyano-indole-1-ylamine (531 mg, 16%) as a solid. 1H NMR (300 MHz, CDCl3): δ 4.88 (br, 2N—H), 6.53 (d, H), 7.32 (d, H), 7.54 (q, 2H), 7.98 (d, H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2C3C([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=4[CH:21]=2)=CC=CC=3)[CH:5]=[CH:6][CH:7]=1.[CH3:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].C([Li])CCC.[B:33](OC(C)C)([O:38]C(C)C)[O:34]C(C)C.Cl>ClCCl.C1COCC1>[CH:15]1[C:20]2[CH:21]=[C:8]([C:24]3[CH:23]=[C:22]([B:33]([OH:38])[OH:34])[CH:27]=[CH:26][CH:25]=3)[C:4]3[C:3](=[CH:2][CH:7]=[CH:6][CH:5]=3)[C:19]=2[CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CCCCCC
Reactant: Brc1cccc(-c2cc3ccccc3c3ccccc23)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: ClCCl
Product: OB(O)c1cccc(-c2cc3ccccc3c3ccccc23)c1
Temperature: -60 °C
Yield: 67 %

Procedure:
Under an argon gas atmosphere, a mixture of 15.45 g (46.4 mmol) of 9-(3-bromophenyl)phenanthrene and 150 mL of dehydrated THF was cooled down to −60 degrees C., and added with 35.9 mL (55.6 mmol) of hexane solution of 1.55M n-butyllithium in drops while being stirred. Then, the reaction mixture was stirred for two hours at −60 degrees C. The reaction solution was added with 26.2 g (139 mol) of triisopropyl borate in drops at −60 degrees C. Subsequently, the reaction mixture was warmed up to room temperature, and stirred for one hour. Then, the reaction mixture was left for a night. The solvent was distilled away under reduced pressure, such that the reaction mixture was condensed. The reaction mixture was cooled down to 0 degree C. to be further added with solution of hydrochloric acid, and then stirred for one hour at room temperature. After the reaction, the reaction mixture was further added with dichloromethane, so that aqueous phase thereof was eliminated. After organic phase thereof was dried with magnesium sulfate, the solvent was distilled away under reduced pressure. Residue thereof was refined by silica-gel column chromatography, such that 13.4 g of 3-(9-phenanthrenyl)phenylboronic acid was obtained with an yield of 67%.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([NH:9][C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:17])=[NH:8])=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].Br[CH2:24][C:25](=O)[C:26]([O:28][CH2:29][CH3:30])=[O:27]>C(O)(C)C>[CH2:29]([O:28][C:26]([C:25]1[N:8]=[C:7]([C:5]2[S:6][C:2]([Br:1])=[CH:3][CH:4]=2)[N:9]([C:10]2[C:11]([Cl:17])=[CH:12][CH:13]=[CH:14][C:15]=2[Cl:16])[CH:24]=1)=[O:27])[CH3:30]
Reactant: N=C(Nc1c(Cl)cccc1Cl)c1ccc(Br)s1
Reactant: CCOC(=O)C(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CCOC(=O)c1cn(-c2c(Cl)cccc2Cl)c(-c2ccc(Br)s2)n1
Temperature: 95 °C
Reaction time: 17 h
Yield: 67.2 %

Procedure:
A stirred mixture of 5-bromo-N-(2,6-dichlorophenyl)-thiophene-2-carboxamidine (3.9 g, 11 mmol) and sodium bicarbonate (1.85 g, 22 mmol) in isopropanol (55 mL) was charged with ethyl bromopyruvate (2.5 mL 20 mmol) and then heated at 95° C. After 17 h the reaction mixture was allowed to cool to ambient temperature, filtered and the solids rinsed with EtOAc. The combined filtrates were concentrated under reduced pressure and purified by chromatography (silica, EtOAc/Hex, 15:85 to 65:35) to give the title compound (3.3 g, 67%) as a tacky yellow solid, which was used in the next step without further purification. 1H-NMR (DCM-d2): δ 7.60 (s, 1H), 7.49-7.59 (m, 3H), 6.89 (d, 1H), 6.56 (d, 1H), 4.37 (q, 2H), 1.38 (t, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]=[CH:11][CH:12]1[NH:18][C:17](=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13]1)([O-:3])=[O:2].F[B-](F)(F)F.[CH3:25][O+](C)C>C(Cl)Cl>[CH3:25][O:19][C:17]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]([CH:11]=[CH:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])[N:18]=1
Reactant: O=C1CCCCC(C=Cc2ccccc2[N+](=O)[O-])N1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COC1=NC(C=Cc2ccccc2[N+](=O)[O-])CCCC1

Procedure:
The product of Example 155 is reacted with trimethyloxonium tetrafluoroborate in CH2Cl2 by the method of Example 3 to produce the title material.
Reaction SMILES: CO.[OH-].[K+].O.C([O:25][CH2:26]/[CH:27]=[C:28](/[CH2:30][CH2:31]/[CH:32]=[C:33](\[CH3:45])/[CH2:34][CH2:35]/[CH:36]=[C:37](/[CH2:39][CH2:40][CH:41]=[C:42]([CH3:44])[CH3:43])\[CH3:38])\[CH3:29])(=O)CCCCCCCCCCCCCCCCC>CCCCCC>[CH2:35]([CH2:34][C:33](=[CH:32][CH2:31][CH2:30]/[C:28](=[CH:27]/[CH2:26][OH:25])/[CH3:29])[CH3:45])/[CH:36]=[C:37](/[CH2:39][CH2:40][CH:41]=[C:42]([CH3:44])[CH3:43])\[CH3:38]
Reactant: CCCCCCCCCCCCCCCCCC(=O)OC/C=C(\C)CC/C=C(\C)CC/C=C(\C)CCC=C(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CCCCCC
Product: CC(C)=CCC/C(C)=C/CCC(C)=CCC/C(C)=C/CO
Temperature: 50 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
250 g of methanol, 4.7 g of potassium hydroxide and 10 g of water were added to 23.0 g of geranylgeranyl stearate (containing 22.08 g of geranylgeranyl stearate and 0.37 g of geranylneryl stearate) obtained as a cake in Example 2. The reaction mixture was stirred at 50° C. for 1 hour and cooled down to room temperature, to which 130 g of hexane was added. The resulting organic phase was separated, and the aqueous phase (lower phase) was washed twice with 120 g of hexane. Thereafter, the hexane washings were combined to the organic phase, followed by washing twice with 100 g of a 50% aqueous methanol. The resultant organic phase was concentrated under reduced pressure to give 12 g of crude geranylgeraniol. This crude product was subjected to simple distillation (137° C., 0.3 mmHg) to give 8.2 g of a main fraction. The results of the analysis of the obtained fraction with gas chromatography revealed that it contained geranylgeraniol with a purity of 98.1% and geranylnerol with a purity of 1.2%.
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8]([C:31](=[O:35])[C:32]([NH2:34])=[O:33])=[C:9]([CH2:28][CH2:29][CH3:30])[N:10]2[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>[OH-].[Na+].CO>[NH2:34][C:32](=[O:33])[C:31]([C:8]1[C:7]2[C:11](=[CH:12][CH:13]=[CH:14][C:6]=2[O:5][CH2:4][C:3]([OH:36])=[O:2])[N:10]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:9]=1[CH2:28][CH2:29][CH3:30])=[O:35]
Reactant: CCCc1c(C(=O)C(N)=O)c2c(OCC(=O)OC)cccc2n1Cc1ccccc1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCc1c(C(=O)C(N)=O)c2c(OCC(=O)O)cccc2n1Cc1ccccc1-c1ccccc1
Reaction time: 0.75 h
Yield: 88319032 %

Procedure:
A mixture of 440 mg (0.9 nmol) of [[3-(2-amino-1,2-dioxoethyl)-1-([1,1′-biphenyl]-2-ylmethyl)-2-propyl-1H-indol-4-yl]oxy]acetic acid methyl ester in 5 mL of 1N NaOH and 15 mL of MeOH was stirred for 0.75 hours, concentrated at reduced pressure and the residue taken up in EtOAc/water. The aqueous layer was separated, made acidic with 1N HCl to pH 2-3 and extracted with EtOAc. The EtOAc solution was dried (MgSO4) and evaporated to give 374 mg (88% yield) of [[3-(2-amino-1,2-dioxoethyl)-1-([1,1′-biphenyl]-2-ylmethyl)-2-propyl-1H-indol-4-yl]oxy]acetic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](C)([CH3:12])[C:10]#N)[CH:5]=[CH:6][C:7]=1[Cl:8].C[Mg]I.CC[O:19][CH2:20][CH3:21]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([CH3:12])([CH3:10])[C:20](=[O:19])[CH3:21])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCOCC
Reactant: CC(C)(C#N)c1ccc(Cl)c(Cl)c1
Agent: C[Mg]I
Product: CC(=O)C(C)(C)c1ccc(Cl)c(Cl)c1
Temperature: 95 °C
Reaction time: 18 h

Procedure:
A solution of 2-(3,4-dichlorophenyl)-2-methylpropionitrile (12.8 g) in ether (100 ml) was added dropwise at −10° C. under nitrogen over 20 minutes to stirred ethereal methylmagnesium iodide solution (3M; 30 ml), then the mixture was stirred at reflux temperature for 2 hour and at ambient temperature for 18 hours. The resulting solid was collected by filtration, washed well with ether, and added in portions to a mixture of ice-cold water (100 ml) and concentrated hydrochloric acid (50 ml). The resulting mixture was heated at 95° C. with occasional stirring for 1 hour, then cooled to ambient temperature. The product was extracted into dichloromethane (3×100 ml), then the combined extracts were dried (CaCl2), and the solvents were removed in vacuo to give 3-(3,4-dichlorophenyl)-3-methylbutan-2-one as a pale brown oil (9.07 g) which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:6]([OH:10])=[CH:5][C:3]=1[NH2:4].Cl.[CH2:12]([O:19][C:20]1[CH:29]=[C:28]2[C:23]([C:24]([Cl:30])=[N:25][CH:26]=[N:27]2)=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CC(O)CCC>[ClH:30].[CH2:12]([O:19][C:20]1[CH:29]=[C:28]2[C:23]([C:24]([NH:4][C:3]3[CH:5]=[C:6]([OH:10])[C:7]([CH3:9])=[CH:8][C:2]=3[F:1])=[N:25][CH:26]=[N:27]2)=[CH:22][CH:21]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Clc1ncnc2cc(OCc3ccccc3)ccc12
Reactant: Cc1cc(F)c(N)cc1O
Agent: Cl
Solvent: CCCC(C)O
Product: Cc1cc(F)c(Nc2ncnc3cc(OCc4ccccc4)ccc23)cc1O
Temperature: 120 °C
Reaction time: 2 h
Yield: 80.4 %

Procedure:
2-Fluoro-5-hydroxy-4-methylaniline (170 mg, 1.2 mmol), (prepared as described for the starting material in Example 13), was added to a solution of 7-benzyloxy-4-chloroquinazoline hydrochloride (307 mg, 1 mmol) in 2-pentanol (5 ml) and the mixture stirred at 120° C. for 2 hours. The mixture was allowed to cool and the resulting precipitate was collected by filtration, washed with isopropanol and then ether and dried under vacuum at 70° C. to give 7-benzyloxy-4-(2-fluoro-5-hydroxy-4-methylanilino)quinazoline hydrochloride (331 mg, 80%).
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][NH:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8].Cl[Sn]Cl.O.[CH3:15][CH2:16][O:17]C(C)=O>ClCCCl>[C:16]([C:6]1[C:2]([Cl:1])=[C:3]([C:7]([O:9][CH3:10])=[O:8])[NH:4][CH:5]=1)(=[O:17])[CH3:15]
Reactant: CCOC(C)=O
Reactant: COC(=O)c1[nH]ccc1Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: ClCCCl
Product: COC(=O)c1[nH]cc(C(C)=O)c1Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 26 %

Procedure:
A solution of methyl 3-chloro-1H-pyrrole-2-carboxylate (0.100 g, 0.627 mmol) in DCE (3 mL) was added to a suspension of SnCl2 (0.238 g, 1.25 mmol) and methyl 3-chloro-1H-pyrrole-2-carboxylate (0.100 g, 0.627 mmol) in DCE (3 mL) at 0° C. The reaction was stirred for 10 min. at 0° C. then warmed to room temp over 2 hours. The reaction mixture was poured into water and EtOAc. The organic layer was separated, washed with 1N sodium hydroxide, dried over MgSO4, filtered and evaporated to a residue. Purification was accomplished on silica with EtOAc and hexanes to afford the title compound (0.034 g, 26%) as a solid, along with methyl 4-acetyl-3-chloro-1H-pyrrole-2-carboxylate (0.047 g, 37%) as a solid. 1H NMR (400 MHz, CDCl3) δ ppm 10.19 (br. s., 1H), 7.34-7.84 (m, 1H), 3.90 (s, 3H), 2.52 (s, 3 H). LCMS: m/z 200.0 (M−1).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.CCN(CC)CC.Cl[C:17]1[S:21][N:20]=[C:19]([CH3:22])[N:18]=1>CCO>[CH3:22][C:19]1[N:18]=[C:17]([N:2]2[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]2)[S:21][N:20]=1
Reactant: Cc1nsc(Cl)n1
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1nsc(N2CCC(=O)CC2)n1
Yield: 8.6 %

Procedure:
To a mixture of piperidin-4-one HCl salt (C3) (4.08 g, 30 mmol) and Et3N (20 mL, 78.6 mmol) in EtOH (50 mL) was added 5-chloro-3-methyl-1,2,4-thiadiazole (4.05 g, 30 mmol). The mixture was heated to reflux for 1.5 h and then concentrated to dryness. The residue was dissolved in EtOAc. The solution was washed with water (30 mL×3) and brine (30 mL), dried over Na2SO4, and concentrated to dryness. The residue was recrystallized from ether to give 1-(3-methyl-1,2,4-thiadiazol-5-yl)piperidin-4-one (D1) (510 mg). 1H-NMR (300 MHz, CDCl3) δ 3.86 (t, J=6.3 Hz, 4H), 2.62 (t, J=6.3, Hz, 4H), 2.44 (s, 3H).