Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[NH:11])=[CH:4][CH:3]=1.[NH:20]1[C:28]2[C:23](=[CH:24][C:25](B(O)O)=[CH:26][CH:27]=2)[CH:22]=[CH:21]1>COCCOC.O.C(O)C.C([O-])(O)=O.[Na+].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:19][C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:10](=[NH:11])[CH:9]=[CH:8][C:5]2[CH:6]=[CH:7][C:2]([C:25]3[CH:24]=[C:23]4[C:28](=[CH:27][CH:26]=3)[NH:20][CH:21]=[CH:22]4)=[CH:3][CH:4]=2)=[CH:14][CH:15]=1
Reactant: N=C(C=Cc1ccc(Br)cc1)Nc1ccc(Cl)cc1
Reactant: OB(O)c1ccc2[nH]ccc2c1
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: CCO
Solvent: COCCOC
Solvent: O
Product: N=C(C=Cc1ccc(-c2ccc3[nH]ccc3c2)cc1)Nc1ccc(Cl)cc1
Yield: 44 %

Procedure:
A mixture of 0.075 g (0.22 mmol) of 3-(4-bromo-phenyl)-N-(4-chloro-phenyl)-acrylamidine, 0.042 g (0.26 mmol) of 5-indoleboronic acid, and 0.013 g (0.011 mmol) of Pd(PPh3)4 in 3 mL of DME/water/ethanol (4/2/1) in a sealed tube was heated under microwave (45 W, 5 min). The reaction was diluted with 10 mL of saturated NaHCO3, and extracted with three 10 mL portions of ethyl acetate. The combined organic extracts were washed with 10 mL of brine, dried over Na2SO4, filtered and concentrated. The residue was purified by preparative TLC eluting with 60% ethyl acetate in hexanes plus 1% NH4OH to give 0.036 g of N-(4-chloro-phenyl)-3-[4-(1H -indol-5-yl)-phenyl]-acrylamidine. Method M: To a stirred solution of 0.10 g (0.27 mmol) of N-(4-chloro-phenyl)-3-[4-(1H -indol-5-yl)-phenyl]-acrylamidine in 3 mL of DMF was added 0.011 g (0.28 mmol) of 60% NaH at 0° C. After 1 h, 0.018 mL (0.28 mmol) of iodomethane was introduced, the reaction was warmed to room temperature overnight and quenched with 10 mL of saturated NaHCO3. It was extracted with three 10 mL portions of dichloromethane. The combined organic extracts were washed with 10 mL of brine, dried over Na2SO4, filtered and concentrated. The residue was chromatographed eluting with 40% ethyl acetate in hexanes to give 0.028 g of N-(4-chloro-phenyl)-3-[4-(1-methyl-1H-indol-5-yl)-phenyl]-acrylamidine.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]([C:16]3[N:17]=[C:18]([CH2:21][CH2:22][C:23]([O:25]C)=[O:24])[O:19][CH:20]=3)[CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=2)=[CH:2]1.ClC1C=C(C2N=C(CCC(O)=O)OC=2)C=C(C(F)(F)F)C=1>>[S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]([C:16]3[N:17]=[C:18]([CH2:21][CH2:22][C:23]([OH:25])=[O:24])[O:19][CH:20]=3)[CH:9]=[C:10]([C:12]([F:13])([F:14])[F:15])[CH:11]=2)=[CH:2]1
Reactant: COC(=O)CCc1nc(-c2cc(-c3ccsc3)cc(C(F)(F)F)c2)co1
Agent: O=C(O)CCc1nc(-c2cc(Cl)cc(C(F)(F)F)c2)co1
Product: O=C(O)CCc1nc(-c2cc(-c3ccsc3)cc(C(F)(F)F)c2)co1
Yield: 77 %

Procedure:
The title compound was prepared from methyl 3-(4-(3-(thiophen-3-yl)-5-(trifluoromethyl)phenyl)oxazol-2-yl)propanoate (Reference Example 48) by a procedure similar to the one described for 3-(4-(3-chloro-5-(trifluoromethyl)phenyl)oxazol-2-yl)propanoic acid (Reference example 52) to provide 3-(4-(3-(thiophen-3-yl)-5-(trifluoromethyl)phenyl)oxazol-2-yl)propanoic acid (0.268 g, 77%) as a white solid.
Reaction SMILES: [NH:1]([C:3](=[O:24])[C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[CH2:18][CH2:17][C:16]([CH3:23])([C:19]([O:21][CH3:22])=[O:20])[CH2:15][CH2:14]2)=[N:11][CH:12]=1)=[O:5])[NH2:2].[F:25][C:26]1[CH:27]=[C:28]([N:33]=[C:34]=S)[CH:29]=[CH:30][C:31]=1[F:32].CCN=C=NCCCN(C)C.Cl.O>CN(C=O)C>[F:25][C:26]1[CH:27]=[C:28]([NH:33][C:34]2[O:24][C:3]([C:4]([NH:6][C:7]3[CH:8]=[CH:9][C:10]([N:13]4[CH2:14][CH2:15][C:16]([CH3:23])([C:19]([O:21][CH3:22])=[O:20])[CH2:17][CH2:18]4)=[N:11][CH:12]=3)=[O:5])=[N:1][N:2]=2)[CH:29]=[CH:30][C:31]=1[F:32]
Reactant: COC(=O)C1(C)CCN(c2ccc(NC(=O)C(=O)NN)cn2)CC1
Reactant: Fc1ccc(N=C=S)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C1(C)CCN(c2ccc(NC(=O)c3nnc(Nc4ccc(F)c(F)c4)o3)cn2)CC1
Temperature: 45 °C
Yield: 79.6 %

Procedure:
To a suspension of methyl 1-(5-{[hydrazino(oxo)acetyl]amino}pyridin-2-yl)-4-methylpiperidine-4-carboxylate (Intermediate 109; 250 mg, 0.75 mmol) in anhydrous DMF (3 mL) was added 3,4-difluorophenylisothiocyanate (154 mg, 0.89 mmol) in anhydrous DMF (1 mL) and the resulting suspension heated to 45° C. for 1 hr. EDAC.HCl (172 mg, 0.89 mmol) was added and the reaction mixture heated to 85° C. for 2 hrs and then allowed to cool to ambient temperature. Water (15 mL) was added and the suspension was filtered, washed with water (2×10 mL) and ether (15 mL) then dried to give the title product as a yellow solid (282 mg, 0.597 mmol, 79.6%);
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:22]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]=[C:14]([NH2:23])[C:13]=2[N:12]=[C:11]1[CH2:24][CH2:25][O:26][CH3:27].C(N(CC)CC)C.[C:35]1([S:41](Cl)(=[O:43])=[O:42])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[NH2:23][C:14]1[C:13]2[N:12]=[C:11]([CH2:24][CH2:25][O:26][CH3:27])[N:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][S:41]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)(=[O:43])=[O:42])[C:22]=2[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:15]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCCCCCCN
Solvent: CCN(CC)CC
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCCCCCCCNS(=O)(=O)c1ccccc1
Temperature: 25 °C
Yield: 42.9 %

Procedure:
Under a nitrogen atmosphere a solution of 1-(8-aminooctyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (1.0 g, 2.7 mmol) in didhloromethane (50 mL) was cooled to 0° C. Triethylamine (415 μL, 2.98 mmol) was added followed by benzenesulfonyl chloride (345 μL, 2.71 mmol). The reaction mixture was allowed to warm slowly to ambient temperature and then it was maintained overnight. The reaction mixture was washed with water, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography (50 g of silica gel eluting with 7.5% methanol in dichloromethane). The purified material was recrystallized from propyl acetate, triturated with hexanes, and then dried in a vacuum oven to provide 590 mg of N-{8-[4-amino-2-(2-methoxyetyl)-1H-imidazo[4,5-c]quinolin-1-yl]octyl}benzenesulfonamide as a yellow powder, m.p. 146-149° C. Analysis: Calculated for C27H35N5O3S: %C, 63.63; %H, 6.92; %N, 13.74; Found: %C, 62.96; %H, 7.03; %N, 13.09. Karl Fisher showed 0.16% or 0.045 mole water.
Reaction SMILES: [Mg].[CH3:2]I.[C:4]([C:8]1[CH:19]=[CH:18][C:11]([C:12]([CH3:17])=[C:13]([CH3:16])[CH:14]=[O:15])=[CH:10][CH:9]=1)([CH3:7])([CH3:6])[CH3:5].[Cl-].[NH4+]>CCOCC.O>[C:4]([C:8]1[CH:9]=[CH:10][C:11]([C:12]([CH3:17])=[C:13]([CH3:16])[CH:14]([OH:15])[CH3:2])=[CH:18][CH:19]=1)([CH3:7])([CH3:5])[CH3:6]
Reactant: CI
Reactant: CC(C=O)=C(C)c1ccc(C(C)(C)C)cc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Solvent: O
Product: CC(=C(C)C(C)O)c1ccc(C(C)(C)C)cc1
Temperature: 25 °C

Procedure:
A Grignard solution is prepared in the usual manner from 10.7 g of magnesium in 30 ml of absolute ether and 68.8 g of methyl iodide in 100 ml of absolute ether. To this solution are added dropwise at 20°-25° C. over a period of 15-20 minutes 56.1 g of p-tert.butyl-α,β-dimethyl-cinnamaldehyde. After cooling to room temperature, the mixture is cautiously poured on to 200 g of ice and 150 g of technical ammonium chloride in 500 ml of water are added. The organic phase is separated, washed with water and sodium bicarbonate solution, dried over sodium sulphate and concentrated. By distillation there is obtained pure 3-(p-tert.butyl-phenyl)-1,2,3-trimethyl-allyl alcohol of boiling point 143°-148° C./0.001 Torr.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([Cl:11])=[C:8]([OH:10])[CH:9]=1.Cl.Cl[CH2:14][CH2:15][N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1>CN(C=O)C>[Cl:11][C:7]1[CH:6]=[CH:5][C:4]([NH2:3])=[CH:9][C:8]=1[O:10][CH2:14][CH2:15][N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: ClCCN1CCCC1
Reactant: Nc1ccc(Cl)c(O)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ccc(Cl)c(OCCN2CCCC2)c1
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
To a stirring RT slurry of NaH (0.10 g of a 60% by weight oil dispersion, 2.5 mmol) in DMF (2 mL) was added 5-amino-2-chlorophenol (0.20 g, 1.4 mmol). The mixture was stirred for 10 min before adding 1-(2-chloroethyl-pyrrolidine hydrochloride (0.17 g, 1.0 mmol). The reaction was heated at 80° C. for 15 h. The reaction was quenched with water, treated with 1N NaOH, and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatography to yield title compound. MS: (MH+)=241.2; Calc'd 240.74 for C12H17ClN2O.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][CH2:6][C:7]1[CH:12]=[C:11]([C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:14])[CH:10]=[CH:9][C:8]=1[OH:27])[CH3:2].[Br:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]Br>>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][CH2:6][C:7]1[CH:12]=[C:11]([C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:14])[CH:10]=[CH:9][C:8]=1[O:27][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][Br:29])[CH3:2]
Reactant: BrCCCCCBr
Reactant: CCOC(=O)CCc1cc(C(=O)c2ccccc2CC(=O)OCC)ccc1O
Product: CCOC(=O)CCc1cc(C(=O)c2ccccc2CC(=O)OCC)ccc1OCCCCCBr
Yield: 74 %

Procedure:
Starting with 0.436 g (1.13 mmol) of 5-[[2-(2-ethoxy-2-oxoethyl)phenyl]carbonyl]-2-hydroxybenzenepropanoic acid ethyl ester, and 6.80 g (29.57 mmol) of 1,5-dibromopentane, the title compound was obtained as a pale yellow oil, in 74% yield, using the procedure of example 21.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.Cl[C:11]1[C:12]2[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[N:16]=1>>[N:20]1[CH:19]=[CH:18][C:17]([C:15]2[N:16]=[C:11]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=3)[C:12]3[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[S:23][C:13]=3[N:14]=2)=[CH:22][CH:21]=1
Reactant: O=[N+]([O-])c1cc2c(Cl)nc(-c3ccncc3)nc2s1
Reactant: NCc1ccc(F)cc1
Product: O=[N+]([O-])c1cc2c(NCc3ccc(F)cc3)nc(-c3ccncc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 4-fluorobenzylamine with 4-chloro-2-(pyridin-4-yl)-6-nitro-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-(4-fluorobenzylamino)-6-nitro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: CC1C=C(N2CCN(CC3C=CC(C(F)(F)F)=CC=3)C2=O)SC=1C(OCC)=O.[CH3:29][C:30]1[N:31]=[C:32]([N:40]2[CH2:44][CH2:43][N:42]([CH2:45][C:46]3[N:47]=[CH:48][O:49][C:50]=3[C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[C:41]2=[O:57])[S:33][C:34]=1[C:35]([O:37]CC)=[O:36]>>[CH3:29][C:30]1[N:31]=[C:32]([N:40]2[CH2:44][CH2:43][N:42]([CH2:45][C:46]3[N:47]=[CH:48][O:49][C:50]=3[C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[C:41]2=[O:57])[S:33][C:34]=1[C:35]([OH:37])=[O:36]
Reactant: CCOC(=O)c1sc(N2CCN(Cc3ncoc3-c3ccccc3)C2=O)nc1C
Agent: CCOC(=O)c1sc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)cc1C
Product: Cc1nc(N2CCN(Cc3ncoc3-c3ccccc3)C2=O)sc1C(=O)O
Yield: 20 %

Procedure:
Following the procedure as described in Example 14, making variations as required to replace ethyl 3-methyl-5-(2-oxo-3-(4-(trifluoromethyl)benzyl)imidazolidin-1-yl)thiophene-2-carboxylate with ethyl 4-methyl-2-(2-oxo-3-((5-phenyloxazol-4-yl)methyl)imidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained as a colorless solid in 20% yield: MS (ES+) m/z 385.1 (M+1).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[C:15]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:20]=[CH:19][C:18]([C:21](Cl)=[O:22])=[CH:17][CH:16]=1.C(N(CC)CC)C.C(OCC)(=O)C>ClCCl>[CH3:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:21]([C:18]1[CH:19]=[CH:20][C:15]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[CH:16][CH:17]=1)=[O:22]
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: Cc1ccc2[nH]cc(CCN)c2c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1ccc2[nH]cc(CCNC(=O)c3ccc(-c4ccccc4)cc3)c2c1
Yield: 72.8 %

Procedure:
N-(2-(5-Methyl-1H-indol-3-yl)ethyl)biphenyl-4-carboxamide was obtained following Method C starting from 2-(5-methyl-1H-indol-3-yl)ethanamine hydrochloride (0.080 g, 0.372 mmol), biphenyl-4-carbonyl chloride (0.0864 g; 0.391 mmol), and triethylamine (0.131 mL; 0.930 mmol) in dichloromethane (5 mL). Flash chromatography on silica gel eluting with 1 to 10% ethyl acetate in dichloromethane furnished 0.096 g (73%) of N-(2-(5-Methyl-1H-indol-3-yl)ethyl)biphenyl-4-carboxamide as a white solid.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:21][CH2:22][C:23]#[CH:24]>C(#N)C.O>[CH2:24]([N:11]1[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:13][CH2:12]1)[CH2:23][C:22]#[CH:21]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: C#CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: C#CCCN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 60 °C
Yield: 86.1 %

Procedure:
To a solution of 1-Boc-piperazine (0.5 g, 2.68 mmol) in acetonitrile (2.5 mL) was added K2CO3 (0.55 g, 4.02 mmol) followed by 4-bromo-1-butyne (0.39 g, 2.95 mmol). The mixture was heated at 60° C. for 6 h, allowed to come to room temperature, diluted with water and extracted with EtOAc (2×15 mL). The combined organic layers washed with water, brine, dried over Na2SO4 and concentrated under vacuo to afford the title compound (0.55 g, 86%); LCMS: m/z=239.10 (M+1). Method 2minLowp.
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)(O)[O-].[K+].[Cl:9][C:10]1[CH:26]=[CH:25][C:13]([O:14][C:15]2[CH:24]=[CH:23][C:18]([O:19][CH2:20][C:21]#[N:22])=[CH:17][CH:16]=2)=[CH:12][CH:11]=1>O.C(O)CCC>[ClH:9].[Cl:9][C:10]1[CH:26]=[CH:25][C:13]([O:14][C:15]2[CH:24]=[CH:23][C:18]([O:19][CH2:20][C:21](=[N:2][OH:3])[NH2:22])=[CH:17][CH:16]=2)=[CH:12][CH:11]=1
Reactant: N#CCOc1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCCCO
Solvent: O
Product: NC(COc1ccc(Oc2ccc(Cl)cc2)cc1)=NO
Yield: 157.8 %

Procedure:
A suspension of 5.37 g (0.0772 mol) of hydroxylamine hydrochloride and of 7.72 g (0.0772 mol) of potassium bicarbonate in 8 ml of water is added, all at once, to a suspension of 10 g (0.0385 mol) of 4-(4-chlorophenoxy)-phenoxy-acetonitrile prepared as indicated in Example 29a), in 24 ml of n-butanol. The mixture is heated to the reflux temperature for 1 hour, the butanol is driven off, the residue is taken up in water and the insoluble matter is extracted with diethyl ether. The organic phase is washed with water, dried over dry sodium sulphate and evaporated, and the residue obtained is purified by washing with hot diisopropyl ether to give 10 g of brilliant white needles.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([C:13]2[CH:14]=[C:15]([C:19](OCC)=[O:20])[CH:16]=[N:17][CH:18]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[C:7]1([C:13]2[CH:14]=[C:15]([CH2:19][OH:20])[CH:16]=[N:17][CH:18]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCOC(=O)c1cncc(-c2ccccc2)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: OCc1cncc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.8 %

Procedure:
Lithium aluminium hydride (1.45 g) was added to a solution of ethyl 5-phenyl-3-pyridinecarboxylate (8.60 g) in tetrahydrofuran (100 ml) at 0° C., which was stirred at room temperature for 30 minutes. Sodium sulfate decahydrate (13.40 g) was added to the reaction mixture, which was stirred at room temperature for 30 minutes. The precipitate was removed by filtration, and the filtrate was concentrated. The resulting colorless crystals were collected by filtration to obtain 5-phenyl-3-pyridylmethanol (4.82 g, yield 69%). This was recrystallized from ethyl acetate-hexane. Melting point: 71–72° C.
Reaction SMILES: C([O:3][C:4](=[O:20])[CH2:5][O:6][C:7]1[C:8]2[CH2:9][C:10]3[S:14][C:13]([SH:15])=[N:12][C:11]=3[C:16]=2[CH:17]=[CH:18][CH:19]=1)C.CS(O[CH2:26][CH:27]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(=O)=O>>[C:28]1([CH:27]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:26][S:15][C:13]2[S:14][C:10]3[CH2:9][C:8]4[C:7]([O:6][CH2:5][C:4]([OH:3])=[O:20])=[CH:19][CH:18]=[CH:17][C:16]=4[C:11]=3[N:12]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCOC(=O)COc1cccc2c1Cc1sc(S)nc1-2
Reactant: CS(=O)(=O)OCC(c1ccccc1)c1ccccc1
Product: O=C(O)COc1cccc2c1Cc1sc(SCC(c3ccccc3)c3ccccc3)nc1-2
Yield: 37 %

Procedure:
Using ethyl[(2-mercapto-8H-indeno[1,2-d]thiazol-7-yl)oxy]acetate and 2,2-diphenylethyl methanesulfonate, the procedure of Example 1 was otherwise repeated to synthesize the title compound. Yield 37%.
Reaction SMILES: O.[OH-].[Li+].C([O:6][P:7]([CH2:16][CH2:17][CH2:18][NH:19][CH2:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=1)([CH:9]([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])=[O:8])C>O.C(O)C>[Cl:28][C:23]1[CH:22]=[C:21]([CH:26]=[C:25]([Cl:27])[CH:24]=1)[CH2:20][NH:19][CH2:18][CH2:17][CH2:16][P:7]([CH:9]([O:10][CH2:11][CH3:12])[O:13][CH2:14][CH3:15])(=[O:6])[OH:8]
Reactant: CCOC(OCC)P(=O)(CCCNCc1cc(Cl)cc(Cl)c1)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOC(OCC)P(=O)(O)CCCNCc1cc(Cl)cc(Cl)c1
Temperature: 25 °C

Procedure:
A solution of 0.36 g of lithium hydroxide monohydrate in 7 ml of water is added to a solution of 1.61 g of 3-(3,5-dichlorobenzylamino)propyl(diethoxymethyl)-phosphinic acid ethyl ester in 3 ml of ethanol and heated at 60° for 24 hours. The mixture is then cooled to room temperature and the solvent is removed under reduced pressure. The evaporation residue is taken up in water and rendered neutral with phosphoric acid. A white precipitate is formed. The precipitate is filtered off and the filtrate is concentrated to dryness by evaporation. The white evaporation residue is dried under reduced pressure and crystallised from toluene/diethyl ether. Filtration with suction and drying yield 3-(3,5-dichlorobenzylamino)propyl(diethoxymethyl)phosphinic acid having a melting point of 160°-161°.
Reaction SMILES: C[O:2][C:3]1[C:8]2[C:9]([C:18]3[CH:19]=[C:20]([C:23]([O:25][CH3:26])=[O:24])[S:21][CH:22]=3)=[N:10][N:11]([CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:7]=2[CH:6]=[CH:5][N:4]=1.[I-].[Na+].Cl[Si](C)(C)C.O>C(#N)C>[O:2]=[C:3]1[C:8]2[C:9]([C:18]3[CH:19]=[C:20]([C:23]([O:25][CH3:26])=[O:24])[S:21][CH:22]=3)=[N:10][N:11]([CH:12]3[CH2:13][CH2:14][O:15][CH2:16][CH2:17]3)[C:7]=2[CH:6]=[CH:5][NH:4]1
Reactant: COC(=O)c1cc(-c2nn(C3CCOCC3)c3ccnc(OC)c23)cs1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COC(=O)c1cc(-c2nn(C3CCOCC3)c3cc[nH]c(=O)c23)cs1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 93.2 %

Procedure:
To a solution of methyl 4-(4-methoxy-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)thiophene-2-carboxylate (146 mg) in acetonitrile (10 mL) were added sodium iodide (117 mg) and chloro(trimethyl)silane (0.396 mL)(and the mixture was stirred at 60° C. for 30 min. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and the obtained solid was washed with ethyl acetate/diisopropyl ether to give the title compound (131 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]2[CH:20]([CH3:21])[CH2:19][CH2:18][CH:17]([OH:22])[CH2:16]2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23]I>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]2[CH:20]([CH3:21])[CH2:19][CH2:18][CH:17]([O:22][CH3:23])[CH2:16]2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: CC1CCC(O)CC1c1cccc(OCc2ccccc2)c1
Product: COC1CCC(C)C(c2cccc(OCc3ccccc3)c2)C1
Yield: 65 %

Procedure:
Using an analogous procedure to that described in Example 2, (1SR,3RS,4SR)-3-(3-benzyloxyphenyl)-4-methylcyclohexan-l-ol was reacted with methyl iodide to give (1SR,3RS,4SR)-3-(3-benzyloxyphenyl)-1-methoxy-4-methylcyclohexane in 65% yield as an oil.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:9]=[CH:10][CH:11]=1)[NH2:8])([CH3:4])([CH3:3])[CH3:2].[CH:12](=O)[CH2:13][CH2:14][CH3:15]>>[C:1]([C:5]1[CH:6]=[C:7]([CH:9]=[CH:10][CH:11]=1)[NH:8][CH2:12][CH2:13][CH2:14][CH3:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCC=O
Reactant: CC(C)(C)c1cccc(N)c1
Product: CCCCNc1cccc(C(C)(C)C)c1
Yield: 87.2 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 137, 3-tert-butylaniline (500 mg, 3.35 mmol) and butyraldehyde (300 μL, 3.35 mmol) were converted to the title compound (600 mg, 80%). 1H NMR (CDCl3) δ 7.15 (t, J=7.8 Hz, 1H), 6.79-6.74 (m, 1H), 6.66 (t, J=2.1 Hz, 1H), 6.47 (ddd, J=8.0, 2.3, 0.7 Hz, 1H), 3.61 (br s, 1H), 3.14 (t, J=7.0 Hz, 2H), 1.69-1.55 (m, 2H), 1.53-1.42 (m, 2H), 1.32 (s, 9H), 0.99 (t, J=7.3 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[CH2:4][C:5](=[O:8])[CH2:6][CH3:7].[CH2:10](O)[CH:11]=C>>[CH2:1]([O:2][C:3](=[O:9])[CH2:4][C:5](=[O:8])[CH2:6][CH3:7])[CH:10]=[CH2:11]
Reactant: CCC(=O)CC(=O)OC
Reactant: C=CCO
Product: C=CCOC(=O)CC(=O)CC
Reaction time: 24 h
Yield: 90 %

Procedure:
A mixture of 35 g of methyl-3-ketopentanoate and 36 mL of allyl alcohol are distilled to about 120° to 125° C., removing both methyl alcohol and allyl alcohol. Allyl alcohol (36 mL) is added to the reaction mixture, which is again distilled at 120°-125° C. This process is repeated for a total of four 36 mL portions of allyl alcohol over a 24 hour period. The remaining mixture is then vacuum distilled to yield 38.03 g of allyl-3-ketopentanoate (90% yield), bp 90°-95° C. under 10-14 mm Hg.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH:13]([NH:14][C:15]([CH:17]2[CH2:21][CH2:20][CH2:19][N:18]2[C:22](=[O:36])[CH:23]([NH:25][C:26](=[O:35])[C:27]2[CH:32]=[CH:31][C:30]([NH2:33])=[C:29]([Cl:34])[CH:28]=2)[CH3:24])=[O:16])[CH2:12][C:11](=[O:37])[O:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:38](Cl)(=[O:43])[C:39]([CH3:42])([CH3:41])[CH3:40]>>[CH2:1]([O:8][CH:9]1[CH:13]([NH:14][C:15]([CH:17]2[CH2:21][CH2:20][CH2:19][N:18]2[C:22](=[O:36])[CH:23]([NH:25][C:26](=[O:35])[C:27]2[CH:32]=[CH:31][C:30]([NH:33][C:38](=[O:43])[C:39]([CH3:42])([CH3:41])[CH3:40])=[C:29]([Cl:34])[CH:28]=2)[CH3:24])=[O:16])[CH2:12][C:11](=[O:37])[O:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCc1ccccc1
Reactant: CC(C)(C)C(=O)Cl
Product: CC(NC(=O)c1ccc(NC(=O)C(C)(C)C)c(Cl)c1)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.1 %

Procedure:
To a suspension of 98b (100 mg, 0.19 mmol) and poly(4-vinylpyridine) (200 mg) was added pivaloyl chloride (70 μL, 0.57 mmol). The resulting suspension was stirred overnight at room temperature the filtered and diluted with EtOAc (25 mL). The organic layer was washed with 10% NaHCO3 (2×25 mL), saturated NaCl (1×25 mL), dried (MgSO4), and evaporated to dryness to afford 98 mg of title compound (85% yield) after chromatography. 1H-NMR (500 MHz, 1:1 CDCl3:CD3OD) δ 1.10-1.55 (m, 3H), 1.38 (s, 9H), 1.65-2.40 (m, 4H), 2.60-3.10 (m, 2H), 3.46-3.88 (m, 2H), 4.20-4.95 (m, 5H), 5.62 (d, 0.8H), 5.78 (d, 0.2H), 7.15-8.30 (m, 8H). Analytical HPLC: 11.82 min. LC-MS (ES+): m/e=613.2 (M+H+).