Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][S:21]([O-:24])(=[O:23])=[O:22].[Na+]>CN(C)C=O>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][S:21]([OH:24])(=[O:23])=[O:22])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: O=S(=O)([O-])CCCCCCBr
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(=O)(O)CCCCCCN1CCN(Cc2ccccc2)CC1
Temperature: 180 °C
Reaction time: 16 h
Yield: 64.5 %

Procedure:
1-Benzylpiperazine (3.5 g), sodium 6-bromohexylsulfonate (16.2 g) and dry dimethylformamide (150 ml) are added to a flask and the mixture is heated and stirred at 180° C. for 16 hours. Precipitated crystals are collected by filtration and recrystallized from ethanol-diethyl ether to give 6-(4-benzyl-1-piperazinyl)hexylsulfonic acid (4.36 g, 63.5%) as colorless prisms. mp. 228°-230° C.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C@@H:18]3[CH2:20][O:19]3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:21]([Mg]Cl)=[CH2:22]>C1COCC1.[Cu]I>[C:1]1([C:7]2[N:8]=[C:9]([C@@H:18]([OH:19])[CH2:20][CH:21]=[CH2:22])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=C[Mg]Cl
Reactant: c1ccc(-c2nc([C@@H]3CO3)oc2-c2ccccc2)cc1
Agent: [Cu]I
Solvent: C1CCOC1
Product: C=CC[C@H](O)c1nc(-c2ccccc2)c(-c2ccccc2)o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2S)-2-(4,5-diphenyloxazol-2-yl)oxirane (12 g) and CuI (0.19 g) in THF (240 ml) was dropwise added a solution of vinylmagnesium chloride in THF (1.0M solution, 101 ml) at −78° C. under N2. The mixture was stirred for 1 hour at room temperature and partitioned between ethyl acetate and water. The organic layer was washed with 1N-HCl, water, sat. NaHCO3 and brine. The dried solvent was evaporated in vacuo and the residue was purified by chromatography on silica gel to give (4S)-4-(4,5-diphenyloxazol-2-yl)-4-hydroxy-1-butene (9.2 g).
Reaction SMILES: [CH:1]1([CH:7]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([N:28]([CH3:36])[CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])=[O:27])=[CH:22][CH:21]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCCCCC.C(O)C.C(O)C.[OH-].[Na+]>O1CCCC1>[CH:1]1([CH:7]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]([N:28]([CH3:36])[CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[O:27])=[CH:24][CH:25]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(F)cc3c2C)C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCO
Product: Cc1c(C(Nc2ccc(C(=O)N(C)CCC(=O)O)cc2)C2CCCCC2)oc2ccc(F)cc12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Ethyl 3-{[(4-{[cyclohexyl (5-fluoro-3-methyl-1-benzofuran-2-yl)methyl]amino}phenyl) carbonyl](methyl)amino}propanoate (564 mg) synthesized above was fractionated by high performance liquid chromatography (column: CHIRALPAK AD (50 mm ID×500 mL, manufactured by Daicel Chemical Industries, Ltd., mobile phase: hexane/ethanol (400/600), flow rate: 60 mL/min, column temperature: 30° C.). The fraction containing an optically active form having a shorter retention time under the above-mentioned high performance liquid chromatography conditions was concentrated to give an amorphous form (274 mg, 99.9% ee). To a mixture of the obtained amorphous form, ethanol (5 mL) and tetrahydrofuran (5 mL) was added 1N aqueous sodium hydroxide solution (1.00 mL), and the mixture was stirred at room temperature for 1.5 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (1.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (249 mg, 47%, 99.9% ee) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]#[N:29])[CH:23]=3)[C:12]3[C:17]([CH:18]=2)=[C:16]([O:19][CH3:20])[CH:15]=[CH:14][CH:13]=3)=[O:9])=[CH:4][CH:3]=1.[ClH:32].[NH3:33]>>[ClH:32].[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28](=[NH:33])[NH2:29])[CH:23]=3)[C:12]3[C:17]([CH:18]=2)=[C:16]([O:19][CH3:20])[CH:15]=[CH:14][CH:13]=3)=[O:9])=[CH:30][CH:31]=1
Reactant: COc1cccc2c1cc(C(=O)NCc1ccc(O)cc1)n2Cc1cccc(C#N)c1
Reactant: N
Agent: Cl
Product: COc1cccc2c1cc(C(=O)NCc1ccc(O)cc1)n2Cc1cccc(C(=N)N)c1
Yield: 79 %

Procedure:
This compound was prepared from 1-(3-cyano-benzyl)-4-methoxy-1H-indole-2-carboxylic acid 4-hydroxy-benzyl amide (200 mg, 0.49 mmol), hydrogen chloride, and liquid ammonia analogously to example 19/3. Purification by reversed phase chromatography on RP18 material with water/ethanol/acetic acid 7:3:0.1 and lyophilization gave 179 mg of the desired product (79%). M.p. 202° C. (dec.). MS: 429.2 (100%; M+H+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][C:17]([OH:19])=O)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][N:23]=1.CN(C)CCCN=C=NCC>ClCCl.CN(C)C1C=CN=CC=1>[C:1]([O:5][C:6](=[O:20])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][C:17]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][N:23]=2)=[O:19])[N:15]=1)([CH3:8])[CH3:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CC(=O)O)cs1
Reactant: Nc1ccc(Br)cn1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CC(=O)Nc2ccc(Br)cn2)cs1
Temperature: 25 °C
Reaction time: 6 h
Yield: 92.6 %

Procedure:
{2-[(2-tert-Butoxy-1,1-dimethyl-2-oxoethyl)thio]-1,3-thiazol-4-yl}acetic acid (16 g) obtained in Example 3 and 2-amino-5-bromopyridine (8.7 g) were dissolved in dichloromethane (100 mL), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (EDC) hydrochloride (14.5 g) and 4-dimethylaminopyridine (DMAP) (9.2 g) was successively added, and the mixture was stirred at room temperature for 6 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=2:1) to give the title compound (22 g) as a white solid.
Reaction SMILES: Cl.[Br:2][C:3]1[C:4]([O:10][CH3:11])=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[N:12]([O-])=O.[Na+].[CH2:16]([O:18][C:19](=[O:24])[CH2:20][C:21]([CH3:23])=[O:22])[CH3:17].C(=O)(O)[O-].[Na+]>Cl.CO>[Br:2][C:3]1[C:4]([O:10][CH3:11])=[C:5]([NH:6][N:12]=[C:20]([C:21](=[O:22])[CH3:23])[C:19]([O:18][CH2:16][CH3:17])=[O:24])[CH:7]=[CH:8][CH:9]=1
Reactant: COc1c(N)cccc1Br
Reactant: CCOC(=O)CC(C)=O
Reactant: O=N[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)C(=NNc1cccc(Br)c1OC)C(C)=O

Procedure:
To a solution of 3-bromo-2-methoxyaniline hydrochloride (10 g) prepared as in Example 15, in hydrochloric acid (13.5 mL of concentrated hydrochloric acid in 136.5 mL of water) was added a solution of sodium nitrite (3.47 g in 10 mL of water) at about −5° C. to about 5° C. under stirring. The reaction mixture was stirred for about 1 hour at about −5° C. to about 5° C. Then ethylacetoacetate (6.55 g) was added to the reaction mixture and stirred for about 3 hours at about −5° C. to about 5° C. Sodium bicarbonate and methanol was then added to the reaction mixture. The reaction mixture was stirred at about −5° C. to about 5° C. for about 1 hour. The mixture was filtered to give a solid, which was washed with water and dried at about 50° C. to about 55° C. Yield: 13.3 g
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([Cl:9])=[CH:4][N:3]=1.[C:10]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C.CC(=O)OCC>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:10])[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: Oc1cc(Cl)ncc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cc(Cl)ncc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 47 %

Procedure:
To a solution of 2,5-dichloro-4-hydroxypyridine (1.43 g, 8.73 mmol) in DMF (15 mL), K2CO3 (2.41 g, 17.5 mmol) followed by methyl iodide (1.48 g, 8.73 mmol) is added. The mixture is stirred at rt for 24 h before it is diluted with EA (200 mL), washed with water (2×100 mL), dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 1:1 to give 2,5-dichloro-4-methoxy-pyridine (0.73 g) as a white solid; LC-MS: tR=0.85 min; [M+1]+=177.90.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:16]=[C:11]2[CH:10]=[C:9]1[C:25]([OH:27])=[O:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:30]I>CN(C)C=O>[CH3:30][O:26][C:25]([C:9]1[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:12]2=[N:13][CH:14]=[C:15]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:16]=[C:11]2[CH:10]=1)=[O:27]
Reactant: CC(C)(C)OC(=O)n1c(C(=O)O)cc2cc(OCc3ccccc3)cnc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc2cc(OCc3ccccc3)cnc2n1C(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 92 %

Procedure:
The solution of 0.2 g (0.54 mmol) 5-benzyloxy-pyrrolo[2,3-b]pyridine-1,2-dicarboxylic acid 1-tert-butyl ester in 2 ml N,N-dimethylformamide was cooled down to 0° C. and 26 mg (0.54 mmol; 55% dispersion in mineral oil) sodium hydride were added. After 15 min., 38 μl (85 mg, 0.6 mmol) methyl iodide were added and the cooling bath was removed. After 5 hours the reaction mixture was poured on water and was extracted five times with dichloromethane. The organic layers were dried over magnesium sulfate, filtered and evaporated to give 0.19 g (93%) the compound as a light yellow oil which was pure enough for the subsequent steps without further purification.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[CH:3]([O:7][C:8](=[O:12])[C:9]([CH3:11])=[CH2:10])[C:4]([OH:6])=[O:5].C1CCC(N=C=NC2CCCCC2)CC1.[F:30][C:31]([F:35])([F:34])[CH2:32]O.Cl>CN(C1C=CN=CC=1)C.ClCCl.C(OCC)(=O)C>[C:8]([O:7][CH:3]([C:4](=[O:6])[O:5][CH2:32][C:31]([F:35])([F:34])[F:30])[C:2]([F:13])([F:14])[F:1])(=[O:12])[C:9]([CH3:11])=[CH2:10]
Reactant: C=C(C)C(=O)OC(C(=O)O)C(F)(F)F
Reactant: OCC(F)(F)F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C=C(C)C(=O)OC(C(=O)OCC(F)(F)F)C(F)(F)F
Temperature: 0 °C
Reaction time: 3 h
Yield: 60.1 %

Procedure:
Under a nitrogen atmosphere, 3.18 g (15 mmol) of 3,3,3-trifluoro-2-(methacryloyloxy)propionic acid was added to 60 mL of a solution of 6.8 g (16.5 mmol) of DCC and 0.37 g (0.003 mol) of DMAP in dichloromethane, and 1.78 g (18 mmol) of 2,2,2-trifluoroethanol was added thereto at 0° C. The temperature of the mixture was equilibrated to the room temperature, and the mixture was stirred for 3 hrs. After disappearance of the raw material was confirmed by TLC, the reaction liquid was cooled to 0° C., and the reaction was stopped by adding 1 N hydrochloric acid. Thereafter, ethyl acetate was added to the reaction liquid and extraction was carried out three times, and the organic layer thus obtained was washed with water twice. Thereafter, purification by column chromatography gave 2.65 g of intended 1,1,1-trifluoro-3-oxo-3-(2,2,2-trifluoroethoxy)propan-2-yl methacrylate (M-6) (yield: 60%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:47])[CH:4]([NH:16][C:17](=[O:46])[CH:18]([NH:33][S:34]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[N+:43]([O-:45])=[O:44])(=[O:36])=[O:35])[CH2:19][CH2:20][CH2:21][NH:22][C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1.Br[CH:49](Br)[CH3:50].C(=O)([O-])[O-].[K+].[K+].OS([O-])(=O)=O.[K+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:47])[CH:4]([N:16]1[CH2:50][CH2:49][N:33]([S:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[N+:43]([O-:45])=[O:44])(=[O:36])=[O:35])[CH:18]([CH2:19][CH2:20][CH2:21][NH:22][C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[C:17]1=[O:46])[CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1
Reactant: COC(=O)C(Cc1ccc2ccccc2c1)NC(=O)C(CCCNC(=O)OCc1ccccc1)NS(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: CC(Br)Br
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1ccc2ccccc2c1)N1CCN(S(=O)(=O)c2ccccc2[N+](=O)[O-])C(CCCNC(=O)OCc2ccccc2)C1=O
Temperature: 55 °C
Reaction time: 18 h

Procedure:
A mixture of 2-[5-benzyloxycarbonylamino-2-(2-nitro-benzenesulfonylamino)-pentanoylamino]-3-naphthalen-2-yl-propionic acid methyl ester, 40, (2.4 g, 3.63 mmol), dibromoethane (3.8 mL, 4.36 mmol), potassium carbonate (5.0 g, 36.3 mmol) in DMF (50 mL) is stirred at 55° C. for 18 hours. The reaction mixture is cooled to room temperature, treated with 1M KHSO4 and the resulting solution is extracted with ethyl acetate. The crude product is purified over silica (sequential elution with EtOAc/hexanes mixtures 1:2, 1:1, 100% EtOAc, then EtOAc with 5% MeOH) to afford 2.76 g of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([CH:21]=2)=[N:19][CH:18]=[CH:17][CH:16]=3)([NH2:11])[CH2:9][NH2:10])=[CH:4][CH:3]=1.CO[C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]#N)[CH:27]=1)=[NH:25].C(Cl)(Cl)Cl>CO>[C:24]([C:26]1[CH:27]=[C:28]([C:32]2[NH:10][CH2:9][C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)([C:12]3[CH:13]=[N:14][C:15]4[C:20]([CH:21]=3)=[N:19][CH:18]=[CH:17][CH:16]=4)[N:11]=2)[CH:29]=[CH:30][CH:31]=1)#[N:25]
Reactant: NCC(N)(c1ccc(F)cc1)c1cnc2cccnc2c1
Reactant: COC(=N)c1cccc(C#N)c1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: N#Cc1cccc(C2=NC(c3ccc(F)cc3)(c3cnc4cccnc4c3)CN2)c1
Temperature: 25 °C
Reaction time: 19 h
Yield: 33.8 %

Procedure:
To a solution of 1-(4-fluorophenyl)-1-(1,5-naphthyridin-3-yl)-1,2-ethanediamine (17 mg) in methanol (1 mL) was added 3-cyanobenzeneimidic acid methyl ester (23 mg), and the mixture was stirred at room temperature for 19 hrs. To the reaction mixture was added chloroform and insolubles were removed by filtration, followed by concentration of the filtrate in vacuo. The residue was purified by preparative thin-layer chromatography (100% ethyl acetate) to give the objective compound (8.0 mg).
Reaction SMILES: [NH2:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[Cl:11].C(OC(=O)C)(=O)C.C([O-])(=O)C.[K+].[N:24](OCCC(C)C)=O>C(Cl)(Cl)Cl>[Cl:11][C:3]1[CH:4]=[C:5]([C:6]#[N:7])[CH:8]=[C:9]2[C:2]=1[NH:1][N:24]=[CH:10]2
Reactant: CC(C)CCON=O
Reactant: Cc1cc(C#N)cc(Cl)c1N
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)OC(C)=O
Product: N#Cc1cc(Cl)c2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-amino-3-chloro-5-methylbenzonitrile (3.00 g, 18.0 mmol) in CHCl3 (50 mL) was added acetic anhydride (3.9 mL, 41.4 mmol). The mixture was stirred at room temperature overnight and then heated at reflux for 5 hours. The reaction mixture was cooled to room temperature and potassium acetate (530 mg, 5.40 mmol) and isoamyl nitrite (5.28 mL, 39.6 mmol) were added. The mixture was heated at reflux for 3 days. The reaction mixture was washed with saturated aqueous NaHCO3, dried over Na2SO4 and concentrated. To this was added methanol followed by water (25 mL) and 38% HCl (25 mL). The mixture was stirred at room temperature overnight. The reaction mixture was concentrated and the pH was adjusted to about 7. The solids were isolated by filtration and then washed with water (2×30 mL) and heptane (2×30 mL). Purify by Biotage chromatography (CH2Cl2-heptane (1:1)/MeOH gradient to afford 7-chloro-1H-indazole-5-carbonitrile was isolated as a white solid (585 mg, 18%).
Reaction SMILES: [CH3:1][C:2]([CH3:12])([CH2:4][C:5](=O)[CH2:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH3:3].[C:13](O)(=O)C.[CH:17]([NH2:19])=[NH:18]>C(O)CCC>[C:2]([C:4]1[C:5]([CH2:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[N:18][CH:17]=[N:19][CH:13]=1)([CH3:12])([CH3:3])[CH3:1]
Reactant: N=CN
Reactant: CC(C)(C)CC(=O)CC(C)(C)C
Reactant: CC(=O)O
Solvent: CCCCO
Product: CC(C)(C)Cc1ncncc1C(C)(C)C
Temperature: 130 °C
Reaction time: 24 h
Yield: 40.4 %

Procedure:
A 100 mL reaction flask is charged with 2,2,6,6-tetramethyl-heptan-4-one (10 g, 0.06 mol), formamidine acetate (33 g, 0.3 mol), and butanol (50 mL). The reaction mixture is heated to 130° C. and stirred for 24 hours. The crude mass is washed once with aqueous sulfuric acid (10%, 100 mL) followed by twice with brine (30 mL). Butanol is recovered by roto-evaporation. The crude product is further purified with liquid chromatography (Biotage® system) and then crystallized. Product 5-tert-butyl-4-(2,2-dimethyl-propyl)-pyrimidine (˜5 g) is obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15](C)=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:19]#[C:20][C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:22]=3)[CH:5]=[CH:4][C:3]1=2.[CH3:33]C1(C)CC=C(OS(C(F)(F)F)(=O)=O)C2C=C(C#CC3C=CC(C(OCC)=O)=CC=3)C=CC1=2>>[CH3:1][C:2]1([CH3:32])[CH2:11][CH:10]=[C:9]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=2[CH3:33])[C:8]2[CH:7]=[C:6]([C:19]#[C:20][C:21]3[CH:22]=[CH:23][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:30][CH:31]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(C)cc2)=CCC3(C)C)cc1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(OS(=O)(=O)C(F)(F)F)=CCC3(C)C)cc1
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccccc2C)=CCC3(C)C)cc1

Procedure:
Employing the same general procedure as for the preparation of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(4-methylphenyl)-2-naphthalenyl)ethynyl]benzoate (Compound 1), 200.0 mg (0.418 mmol) of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(trifluoromethylsulfonyl)oxy-2-naphthalenyl)ethynyl]benzoate (Compound G) was converted into the title compound (colorless solid) using 199.4 mg (1.463 mmol) of zinc chloride, 24 mg (0.02 mmol) of tetrakis(triphenylphosphine)palladium(0) in 4.0 ml of THF, and 2-methylphenyl lithium (prepared by adding 133.9 mg (1.23 ml, 2.09 mmol) of tert-butyllithium (1.7M solution in pentane) to a cold solution (-78° C.) of 178.7 mg (1.045 mmol) of 2-methylbromobenzene in 2.0 ml of THF). 1H NMR (CDCl3): δ7.97 (2H, d, J=8.4 Hz), 7.50 (2H, d, J=8.4 Hz), 7.49-7.19 (6H, m), 6.81 (1H, d, J=1.6 Hz), 5.89 (1H, t, J=4.5 Hz), 4.36 (2H, q, J=7.1 Hz), 2.43-2.14 (2H, dq, J=3.7, 5.4 Hz), 2.15 (3H, s), 1.39-1.34 (9H, m).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH2:7]([O:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][C:16]=1[F:24])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Br[C:26]1[C:27]([NH2:32])=[N:28][CH:29]=[CH:30][CH:31]=1>COCCOC.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>[CH2:7]([O:14][C:15]1[CH:20]=[CH:19][C:18]([C:26]2[C:27]([NH2:32])=[N:28][CH:29]=[CH:30][CH:31]=2)=[CH:17][C:16]=1[F:24])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: OB(O)c1ccc(OCc2ccccc2)c(F)c1
Reactant: Nc1ncccc1Br
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: [Na+]
Solvent: O
Solvent: COCCOC
Product: Nc1ncccc1-c1ccc(OCc2ccccc2)c(F)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A mixture of sodium carbonate (7.18 g), tetrakis(triphenylphosphine)palladium(0) (1.957 g), 4-(benzyloxy)-3-fluorophenylboronic acid (10 g), and 3-bromopyridin-2-amine (5.86 g) in DME (120 mL) and water (24 mL) was stirred at 80° C. overnight. The mixture was added with silica gel, concentrated in vacuo, and purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (9.97 g) as a pale yellow solid.
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:4][C:5]([CH3:8])=[N:6][N:7]=1.[C:9](Cl)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>N1C=CC=CC=1>[CH3:1][N:2]([C:3]1[S:4][C:5]([CH3:8])=[N:6][N:7]=1)[C:9](=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CNc1nnc(C)s1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: Cc1nnc(N(C)C(=O)c2ccccc2)s1

Procedure:
2-(N-Methyl-amino)-5-methyl-1,3,4-thiadiazole (6 g, 0.046 mole) in pyridine (190 ml) was refluxed for 6 hours with benzoyl chloride (9.7 g, 0.069 mole) and the pyridine then evaporated off under reduced pressure. The residue was treated with water, made alkaine with sodium hydroxide solution and extracted with chloroform. The chloroform was washed with a saturated solution of sodium bicarbonate and and a saturated solution of sodium chloride, dried, filtered and evaporated to yield title product which was recrystallised from ethanol.
Reaction SMILES: [CH3:1]C1(C)CCCNC1=O.[CH3:10][C:11]1([CH3:18])[NH:16][C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1.[H-].[Na+].CI>C1COCC1>[CH3:1][N:16]1[C:11]([CH3:18])([CH3:10])[CH2:12][CH2:13][CH2:14][C:15]1=[O:17]
Reactant: CC1(C)CCCNC1=O
Reactant: CC1(C)CCCC(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CN1C(=O)CCCC1(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
To a solution of a 3 to 1 mixture of 3,3-dimethylpiperidin-2-one and 6,6-dimethylpiperidine-2-one (4.72 g, 37.1 mmol) in 60 ml of THF was added 60% sodium hydride suspension (1.93g, 48.2 mmol). The grey reaction mixture was stirred at room temperature for 30 minutes. Then methyl iodide (3.02 ml, 48.2 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with water, and worked up with ethyl acetate/water. The orange oil was chromatographed over a prepacked 70 g silica column After elution with a 50% to 100% ethyl acetate in heptane gradient, the fractions containing the desired product were collected to yield 2.46 g (47%) of the title compound as a light yellow solid; and 0.91 g (17%) of isomeric 1,3,3-trimethyl-piperidin-2-one as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([CH:13]=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1.[CH2:20]([Mg]Cl)[CH:21]([CH3:23])[CH3:22].CCOCC>[NH4+].[Cl-]>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([C@@H:13]([OH:14])[CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([C@H:13]([OH:14])[CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](C=O)C1
Reactant: CC(C)C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)C[C@@H](O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Product: CC(C)C[C@H](O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: -78 °C

Procedure:
(S)-3-Formylpyrrolidine-1-carboxylic acid t-butyl ester (6.0 g, 30.1 mmol) and THF (60 mL, 700 mmol) were combined under nitrogen, and the resulting solution was cooled to −78° C. 2.0M Isobutylmagnesium chloride in ether (18.1 mL, 36.1 mmol) was then added dropwise over 10 minutes. The mixture was allowed to warm to room temperature slowly overnight. Then aqueous saturated NH4Cl (100 mL) was added dropwise to quench the reaction. The resulting mixture was extracted with EtOAc (2×100 mL), and the combined organic layers were washed with saturated aqueous NaHCO3 (1×100 mL) and saturated aqueous NaCl (1×100 mL), then dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography (80 g SiO2, ethyl ether) to yield (S)-3-((S)-1-hydroxy-3-methylbutyl)pyrrolidine-1-carboxylic acid t-butyl ester (1.6 g) and (S)-3-((R)-1-hydroxy-3-methylbutyl)pyrrolidine-1-carboxylic acid t-butyl ester (2.2 g) as oils.