Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[C:39]([C:41]1[CH:42]=[C:43](B(O)O)[CH:44]=[C:45]([O:47][CH3:48])[CH:46]=1)#[N:40].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[CH3:48][O:47][C:45]1[CH:46]=[C:41]([CH:42]=[C:43]([C:2]2[C:10]3[C:9]([NH:11][C@H:12]([C:14]4[N:19]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:18](=[O:26])[C:17]5=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]5[N:15]=4)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=3[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=2)[CH:44]=1)[C:39]#[N:40]
Reactant: COc1cc(C#N)cc(B(O)O)c1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1cc(C#N)cc(-c2cn(COCC[Si](C)(C)C)c3ncnc(N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)c23)c1
Yield: 43 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (100 mg, 0.17 mmol) was treated with (3-cyano-5-methoxyphenyl)boronic acid (74 mg, 0.42 mmol), sodium carbonate (45 mg, 0.42 mmols), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (41 mg, 0.05 mmol) and 4 ml 1,2-dimethoxyethane and 1 ml water as a solvents according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 50% hexane-ethyl acetate) to obtain 54 mg (43% yield, 87% purity) of the title compound.
Reaction SMILES: ICCCCCI.[C:8]12([S:18][C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH2:30]C[CH2:28][CH2:27][CH2:26]4)=[CH:21][CH:20]=3)[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2>>[C:8]12([S:18][C:19]3[CH:20]=[CH:21][C:22]([N:25]4[CH2:26][CH2:27][CH2:28][CH2:30]4)=[CH:23][CH:24]=3)[CH2:17][CH:12]3[CH2:11][CH:10]([CH2:16][CH:14]([CH2:13]3)[CH2:15]1)[CH2:9]2
Reactant: c1cc(N2CCCCC2)ccc1SC12CC3CC(CC(C3)C1)C2
Agent: ICCCCCI
Product: c1cc(N2CCCC2)ccc1SC12CC3CC(CC(C3)C1)C2

Procedure:
In a similar manner, usng 1,5-diiodopentane, 1-(p-1-adamantylthiophenyl)piperidine can be prepared.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C(OC([N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[CH2:25][CH2:24][NH:23][C:22]2=[O:26])[CH2:17][CH2:16]1)=O)(C)(C)C>ClCCl>[NH:15]1[CH2:16][CH2:17][CH:18]([N:21]2[CH2:25][CH2:24][NH:23][C:22]2=[O:26])[CH2:19][CH2:20]1.[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCNC2=O)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1NCCN1C1CCNCC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Trifluoroacetic acid (0.5 mL) was added to a solution of 1-(1-t-butoxycarbonylpiperidin-4-yl)imidazolidin-2-one (30 mg, 0.11 mmol) in dichloromethane (2 mL) and the reaction stirred at room temperature for 5 h. The reaction was concentrated in vacuo to give the title compound as its trifluoroacetic acid salt (18 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].N1C=CN=C1.[CH:15]([Si:18](Cl)([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])([CH3:17])[CH3:16]>CN(C)C=O.O>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([O:9][Si:18]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[CH:15]([CH3:17])[CH3:16])=[C:2]([Cl:1])[CH:7]=1
Reactant: Oc1ccc(Cl)cc1Cl
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)[Si](Oc1ccc(Cl)cc1Cl)(C(C)C)C(C)C
Reaction time: 3 h
Yield: 81.7 %

Procedure:
To a mixture of 2,4-dichlorophenol (3.20 g) and imidazole (2.67 g) in dimethylformamide (30 ml) was added triisopropylsilyl chloride (3.97 g) in water bath under nitrogen atmosphere, and the mixture was stirred for 3 hours under the same condition. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (n-hexane) to give 1,3-dichloro-4-triisopropylsilyloxybenzene (5.12 g).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.[Br:12][C:13]1[CH:14]=[C:15]([CH:23]=[CH:24][CH:25]=[O:26])[CH:16]=[C:17]([O:21][CH3:22])[C:18]=1[O:19][CH3:20].N1CCOCC1>>[Br:12][C:13]1[CH:14]=[C:15]([CH:23]2[C:11]3[C:2](=[C:3]4[CH:4]=[CH:5][N:6]=[CH:7][C:8]4=[CH:9][CH:10]=3)[O:1][CH:25]([OH:26])[CH2:24]2)[CH:16]=[C:17]([O:21][CH3:22])[C:18]=1[O:19][CH3:20]
Reactant: COc1cc(C=CC=O)cc(Br)c1OC
Reactant: Oc1cccc2cnccc12
Solvent: C1COCCN1
Product: COc1cc(C2CC(O)Oc3c2ccc2cnccc32)cc(Br)c1OC
Yield: 29 %

Procedure:
The title compound was prepared following the procedure in Example 18 from 5-hydroxyisoquinoline (9 mg; 0.062 mmol) and 3-(3-bromo-4,5-dimethoxyphenyl)-propenal (30 mg; 0.11 mmol) using morpholine as a base (10 μl; 0.11 mmol) (yield: 29%). 1H NMR (acetone-d6): 9.16 (s, 1H), 8.50 and 8.49 (d each, J=5.7 Hz; 1H), 7.95 (d, J=6.4 Hz) and 7.94 (d, J=5.9 Hz) (1H), 7.51 (d, J=8.4 Hz) and 7.49 (d, J=7.0 Hz) (1H), 6.98-7.07 (m, 3H), 6.65 (d, J=6.6 Hz) and 6.59 (d, J=3.9 Hz) (1H), 5.91-5.93 (m) and 5.74-5.77 (m) (1H), 4.46-4.54 (overlapping dd, J=6.2, 10.5 Hz; 1H), 3.84, 3.81 and 3.80 (s each, 6H), 2.54 (ddd, J=2.1, 6.4, 13.3 Hz) and 2.19-2.38 (m) (2H).
Reaction SMILES: Br.Cl.C[O:4][C:5]1[CH:6]=[CH:7][C:8]2[O:21][CH2:20][C@H:12]3[N:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH2:16][C@@H:11]3[C:9]=2[CH:10]=1>>[OH:4][C:5]1[CH:6]=[CH:7][C:8]2[O:21][CH2:20][C@H:12]3[N:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH2:16][C@@H:11]3[C:9]=2[CH:10]=1
Reactant: CCCN1CCC[C@@H]2c3cc(OC)ccc3OC[C@H]21
Agent: Br
Agent: Cl
Product: CCCN1CCC[C@@H]2c3cc(O)ccc3OC[C@H]21

Procedure:
A mixture of 21.6 l of 47-49% hydrobromic acid and 2.27 kg of trans-9-methoxy-4-propyl-1,2,3,4a,5,10b-hexahydro-4H-[1]-benzopyrano[3,4-b]pyridine hydrochloride is stirred and heated at 105°-110° for 2 hours. Most of the hydrobromic acid is then removed by distillation (125°/3 mmHg), a solution of 10.5 l of methanol and 9.5 l of water is added and the suspension heated to 75°. The hot mixture is cautiously treated with 2.2 l of 4N sodium hydroxide solution to pH 8, cooled to 10° and filtered. The collected solids are washed five times with 1 l of water each and dried (68°/3 mmHg) to yield trans-9-hydroxy-4-propyl-1,2,3,4a,5,10b-hexahydro-4H-[1]-benzopyrano[3,4-b]pyridine, m.p. 194°-196°.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([Cl:13])[C:8]=1[F:14])=O.S(Cl)([Cl:22])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:3]=1[C:4]([Cl:22])=[N:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([Cl:13])[C:8]=1[F:14]
Reactant: O=C(Nc1ccnc(Cl)c1F)c1c(Cl)cccc1Cl
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: Fc1c(N=C(Cl)c2c(Cl)cccc2Cl)ccnc1Cl
Temperature: 25 °C

Procedure:
A mixture of 2,6-dichloro-N-(2-chloro-3-fluoropyridin-4-yl)benzamide (1.12 g, 3.5 mmol) and thionyl chloride (10 mL) was heated under reflux for 18 hours then cooled to ambient temperature. The reaction mixture was diluted with toluene (10 mL) and concentrated under reduced pressure to afford the title compound as a pale brown solid (1.23 g, quant. yield). 1H NMR (400 MHz, CDCl3): δ 8.23 (d, J=5.1 Hz, 1H), 7.45-7.44 (m, 2H), 7.38 (dd, J=9.4, 6.5 Hz, 1H), 6.98 (t, J=5.1 Hz, 1H).
Reaction SMILES: [C:1]([C:4]1[N:5]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[C:6]2[C:11]([C:12]=1[C:13]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[C:19]([F:24])[CH:18]=1)=[O:14])=[CH:10][CH:9]=[C:8]([O:25][CH:26]([CH3:28])[CH3:27])[CH:7]=2)(=O)[CH3:2].[OH:36][NH2:37].Cl.N1C=CC=CC=1>CO>[F:24][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][C:20]=1[F:23])[CH2:16][NH:15][C:13]([C:12]1[C:11]2[C:6](=[CH:7][C:8]([O:25][CH:26]([CH3:27])[CH3:28])=[CH:9][CH:10]=2)[N:5]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[C:4]=1/[C:1](=[N:37]/[OH:36])/[CH3:2])=[O:14]
Reactant: CC(=O)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(OC(C)C)cc2n1Cc1ccccn1
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: C/C(=N\O)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(OC(C)C)cc2n1Cc1ccccn1
Temperature: 65 °C
Reaction time: 20 h

Procedure:
General Procedure Q. To a solution of 2-acetyl-N-(3,4-difluorobenzyl)-6-isopropoxy-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide (Compound 109, 18 mg, 0.038 mmol) in MeOH (3 ml) was added HONH2.HCl (8.0 mg, 0.11 mmol) and pyridine (30 μl, 0.38 mmol). The reaction was stirred at 65° C. for 20 h and the solvent was removed in vacuo. The residue was purified by PTLC (75% EtOAc-hexanes) to yield the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([O:12][C:13]1[CH:14]=[C:15]([CH:22]=[C:23]([CH3:25])[CH:24]=1)[O:16][CH2:17][CH2:18][CH2:19][O:20][NH2:21])(=[O:11])=[O:10].Cl.[N:27]1([C:32](N)=[NH:33])C=CC=N1>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([O:12][C:13]1[CH:14]=[C:15]([CH:22]=[C:23]([CH3:25])[CH:24]=1)[O:16][CH2:17][CH2:18][CH2:19][O:20][NH:21][C:32]([NH2:33])=[NH:27])(=[O:11])=[O:10]
Reactant: COc1ccccc1S(=O)(=O)Oc1cc(C)cc(OCCCON)c1
Reactant: N=C(N)n1cccn1
Agent: Cl
Solvent: CN(C)C=O
Product: COc1ccccc1S(=O)(=O)Oc1cc(C)cc(OCCCONC(=N)N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
A solution of 3-[3-(2-methoxyphenylsulfonyloxy)-5-methylphenoxy]propoxyamine (74 mg, 0.20 mmol, prepared in the preceding step) and 1H-pyrazole-1-carboxamidine hydrochloride (60 mg, 0.41 mmol) in anhydrous N,N-dimethylformamide (2 mL) was stirred at ambient temperature overnight. Additional 1H-pyrazole-1-carboxamidine hydrochloride (30 mg, 0.20 mmol) was added, and the reaction was stirred at ambient temperature for 3 days. N,N-Dimethylformamide was removed in vacuo, then the residue was treated with acetonitrile. The mixture was filtered to remove excess 1H-pyrazole-1-carboxamidine hydrochloride, and the filtrate was concentrated in vacuo. The residual oil was partitioned between diethyl ether (10 mL) and water (10 mL). The aqueous layer was washed with diethyl ether (2×10 mL), adjusted to pH 8 with 2N NaOH, and extracted with ethyl acetate (2×10 mL). The ethyl acetate extracts were washed with pH 7 buffer (2×15 mL) and brine (15 mL), dried over Na2SO4, filtered, and evaporated to give the title compound (64 mg, 78%) as a colorless oil. 1H-NMR (300 MHz, DMSO-d6) δ7.76 (ddd, 1H, J=8.4, 7.4, 1.8 Hz), 7.69 (dd, 1H, J=7.9, 1.6 Hz), 7.37 (d, 1H, J=7.7 Hz), 7.09 (dt, 1H, J=7.9, 1.0 Hz), 6.69 (s, 1H), 6.47 (s, 1H), 6.33 (t, 1H, J=2.1 Hz), 4.00 (s, 3H), 3.92 (t, 2H, J=6.5 Hz), 3.70 (t, 2H, J=6.1 Hz), 2.20 (s, 3H), 1.88 (pentet, 2H, J=6.3 Hz). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C18H23N3O6S: 410.1 (M+H), 432.1 (M+Na). Found: 410.1, 432.6.
Reaction SMILES: Br[CH:2]1[CH2:8][CH2:7][O:6][C:5]2[CH:9]=[CH:10][C:11]([Br:13])=[CH:12][C:4]=2[C:3]1=O.[NH2:15][NH:16][C:17]([NH2:19])=[S:18]>>[Br:13][C:11]1[CH:10]=[CH:9][C:5]2[O:6][CH2:7][CH2:8][C:2]3[S:18][C:17]([NH:16][NH2:15])=[N:19][C:3]=3[C:4]=2[CH:12]=1
Reactant: O=C1c2cc(Br)ccc2OCCC1Br
Reactant: NNC(N)=S
Product: NNc1nc2c(s1)CCOc1ccc(Br)cc1-2

Procedure:
Following the procedure for 449, Step 2, 4,7-dibromo-3,4-dihydro-2H-benzo[b]oxepin-5-one was reacted with thiosemicarbazide to afford the title compound as a beige solid. LCMS (Method E): RT=3.85 min, [M+H]+=312 and 314. 1H NMR (DMSO-d6): 10.13 (2 H, bs), 9.80 (1 H, bs), 8.49 (1 H, d, J=2.6 Hz), 7.37 (1 H, dd, J=8.6, 2.6 Hz), 6.97 (1 H, d, J=8.6 Hz), 4.29 (2 H, t, J=5.0 Hz), 3.21 (2 H, t, J=5.0 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[NH:9][C:8]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.N1CCC[C@H]1C(O)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[CH:33]=[C:34]([C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=1)[CH3:35]>CN(C=O)C.[Cu]I>[Cl:1][C:2]1[C:10]2[N:9]([CH2:35][C:34]([C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=3)=[CH2:33])[C:8]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCc2[nH]c3c(Cl)cccc3c2C1
Reactant: CC(=CBr)c1ccc(F)cc1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: C=C(Cn1c2c(c3cccc(Cl)c31)CN(C)CC2)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
6-Chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (200 mg, 0.909 mmol) was dissolved in DMF (4 mL). Copper (I) iodide (14 mg, 0.089 mmol), L-proline (20 mg, 0.173 mmol) and K3PO4 (380 mg, 1.79 mmol) were added and the reaction mixture was stirred for 10 min at RT. 1-(1-Bromoprop-1-en-2-yl)-4-fluorobenzene (250 mg, 1.17 mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated at 85° C. overnight (prolonged heating in some cases was required). DMF was evaporated under reduced pressure, the residue was diluted with water, and the solid was filtered. The solid material was purified by silica gel chromatography (100-200 mesh) eluting with 0-5% MeOH-DCM. 1H NMR (CD3OD, oxalate salt) δ (ppm): 7.60 (m, 2H), 7.45 (d, 1H), 7.20-7.05 (m, 4H), 5.50 (s, 2H), 5.30 (s, 1H), 4.55 (m, 2H), 4.05 (s, 1H), 3.70 (m, 2H), 3.18 (m, 2H), 3.10 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:4][CH:3]=1.[CH2:16]([S:18](Cl)(=[O:20])=[O:19])[CH3:17]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[S:18]([CH2:16][CH3:17])(=[O:20])=[O:19])=[CH:6][CH:7]=1
Reactant: Brc1ccc(NCc2cccnc2)cc1
Reactant: CCS(=O)(=O)Cl
Product: CCS(=O)(=O)N(Cc1cccnc1)c1ccc(Br)cc1

Procedure:
Using the procedure of Example 343 using N-(4-bromophenyl)pyridin-3-ylmethylamine and ethanesulfonyl chloride (Aldrich) and purifying via preparative HPLC eluting with 90:10 to 70:30 DCM/ethyl acetate gave the title compound. Anal Calcd for C14H15BrN2O2S: C, 47.33; H, 4.26; N, 7.88. Found: C, 47.24; H, 4.23; N, 7.79. MS found 354.0, 355.9 FD.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[CH3:18][C:19]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][C:20]=1[NH2:21].Cl.[OH-].[Na+]>O.C(O)C>[CH3:18][C:19]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][C:20]=1[NH:21][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Reactant: Cc1ccc([N+](=O)[O-])cc1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1ccc([N+](=O)[O-])cc1Nc1cc(C(F)(F)F)nc(-c2cccnc2)n1
Yield: 18.8 %

Procedure:
A mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (500 mg, 1.93 mmol), 2-methyl,5-nitroaniline (441 mg, 2.90 mmol), and 2N HCl (1.5 ml) in water:ethanol (1:1, 100 ml) was refluxed for 48 h. The mixture was cooled to room temperature and basified with aqueous 2N NaOH to pH 10–12. The resulting precipitate was filtered, washed with water and water:ethanol (2:1). The product was dried under vacuo and then washed with chloroform to give a yellow solid (136 mg, 19%). 1H NMR (DMSO-d6): 9.84 (s, 1H), 9.41 (s, 1H), 8.99 (s, 1H), 8.73 (d, J=4.2 Hz, 1H), 8.57 (d, J=7.8 Hz, 1H), 8.02 (dd, J=1.8, 7.8, 1H), 7.61 (d, J=8.1 Hz, 1H), 7.58–7.54 (m, 1H), 7.39 (s, 1H), 2.45 (s, 3H).
Reaction SMILES: [C:1]1([C:7]2[N:16]=[C:15]([C:17]([O:19]CC)=O)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:22][CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C([Li])CCC>CCCCCC.O1CCCC1>[CH3:22][CH:23]1[CH2:28][CH2:27][N:26]([C:17]([C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:16]=2)=[O:19])[CH2:25][CH2:24]1
Reactant: CCOC(=O)c1nc(-c2ccccc2)nc2ccccc12
Reactant: CC1CCNCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC1CCN(C(=O)c2nc(-c3ccccc3)nc3ccccc23)CC1

Procedure:
The procedure of Example 24 is followed using ethyl 2-phenylquinazoline-4-carboxylate (3 g), 4-methylpiperidine (2.95 ml), a 1.6M solution of butyllithium in hexane (15 ml) and tetrahydrofuran (20 ml) as the starting materials. After recrystallisation from ethanol, 4-methyl-1-[(2-phenylquinazolin-4-yl)-carbonyl]-piperidine (1 g), melting at 138° C., is obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([NH2:11])=[S:10].Br[C:13]1([C:17](OCC)=[O:18])[CH2:16][CH2:15][CH2:14]1>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[S:10][C:13]2([C:17](=[O:18])[N:11]=1)[CH2:16][CH2:15][CH2:14]2
Reactant: CCOC(=O)C1(Br)CCC1
Reactant: Cc1ccccc1NC(N)=S
Product: Cc1ccccc1NC1=NC(=O)C2(CCC2)S1

Procedure:
Synthesis was performed from N-(2-methylphenyl)thiourea and ethyl 1-bromocyclobutanecarboxylate according to Method D.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]([O:12][CH3:13])(=[O:11])[CH:9]=[CH2:10].C(O)(=O)C>CCCCCC>[C:2]1([NH:1][CH2:10][CH2:9][C:8]([O:12][CH3:13])=[O:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: C=CC(=O)OC
Solvent: CC(=O)O
Solvent: CCCCCC
Product: COC(=O)CCNc1ccccc1

Procedure:
A mixture of 20 ml of aniline, 22 ml of methyl acrylate and 2 ml of acetic acid is refluxed for 8 hours. After concentrating the reaction mixture under vacuum, the resulting oil is distilled off under reduced pressure (b.p.=132° C. at 333.3 Pa and then b.p.=110° C. at 6.66 Pa). The product obtained is taken up in hexane and the precipitate formed is filtered off by suction. 25 g of the expected product are obtained.
Reaction SMILES: Cl[Si:2](Cl)([CH3:4])[CH3:3].[Na+].[S:7]([CH2:11][CH2:12][OH:13])([O-:10])(=[O:9])=[O:8]>>[CH3:3][Si:2]1([CH3:4])[O:10][S:7](=[O:9])(=[O:8])[CH2:11][CH2:12][O:13]1
Reactant: C[Si](C)(Cl)Cl
Reactant: O=S(=O)([O-])CCO
Agent: [Na+]
Product: C[Si]1(C)OCCS(=O)(=O)O1
Reaction time: 20 h
Yield: 67 %

Procedure:
To 25 mL of dichlorodimethylsilane in a 100 mL r.b. flask was added 10 g of isethionic acid sodium salt and the mixture was heated to reflux with stirring for 20 hrs. The excess dichlorodimethylsilane was distilled and the residue transferred to a short-path distillation tube with a CH2Cl2 rinse. The residue was distilled at 145-175° C., 0.2 mm pressure, to give 8.25 g (67%) of a viscous liquid.
Reaction SMILES: C[C:2]1[C:3]([NH2:21])=[C:4]([Cl:20])[C:5]([C:17]([OH:19])=[O:18])=[N:6][C:7]=1[O:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([Cl:16])[CH:10]=1.[OH-].[Na+]>CO>[NH2:21][C:3]1[CH:2]=[C:7]([O:8][C:9]2[CH:10]=[C:11]([Cl:16])[CH:12]=[C:13]([Cl:15])[CH:14]=2)[N:6]=[C:5]([C:17]([OH:19])=[O:18])[C:4]=1[Cl:20]
Reactant: Cc1c(Oc2cc(Cl)cc(Cl)c2)nc(C(=O)O)c(Cl)c1N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1cc(Oc2cc(Cl)cc(Cl)c2)nc(C(=O)O)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.5 %

Procedure:
To Methyl 4-amino-3-chloro-6-(3,5-dichlorophenoxy)pyridine-2-carboxylic acid (0.0.720 g, 2.07 mmol) in 20 mL of methanol was added 1N NaOH (2.07 mL) and stirred at RT for 1 hr. The reaction mixture was concentrated to dryness in vacuo and 100 mL each of diethyl ether and H2O added. The aqueous layer acidified with 1N HCl until pH=2. Methylene chloride was added and the aqueous phase was extracted with additional CH2Cl2 (2×100 mL). The combined extracts were dried (MgSO4) and concentrated to dryness in vacuo to give 0.390 g of white solid 4-amino-3-chloro-6-(3,5-dichlorophenoxy)pyridine-2-carboxylic acid (Compound 47); mp 196° C.
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH2:9][C@@H:3]([C:4](OCC)=[O:5])[CH2:2]1.[NH3:12]>>[NH:1]1[CH2:11][CH2:10][CH2:9][C@@H:3]([C:4]([NH2:12])=[O:5])[CH2:2]1
Reactant: N
Reactant: CCOC(=O)[C@@H]1CCCNC1
Product: NC(=O)[C@@H]1CCCNC1
Reaction time: 72 h

Procedure:
To 14.7 g (93.5 mmol) of (R)-ethyl nipecotate in a 300 ml round-bottomed flask were added 200 ml of concentrated aqueous ammonia at room temperature, and the mixture was allowed to stand for 3 days at room temperature. The reaction mixture was distilled off at a water bath temperature of lower than 40° C. to obtain (R)-nipecotamide as a pale yellow oil. To this were added 100 ml of methylene chloride and 50 ml of ethanol at room temperature, and 15.6 ml (1.2 eg.) of triethylamine were added while cooling with ice. To this reaction mixture were gradually added dropwise 11.1 ml (1 eg.) of benzyl bromide under cooling with ice. After dropwise addition, the mixture was stirred for 10 minutes under cooling with ice and further for 4 hours after returned to room temperature, which was allowed to stand overnight. The reaction mixture was distilled off under reduced pressure and the residue obtained was dissolved into 200 ml of methylene chloride, which was washed with 1N sodium hydroxide and saturated aqueous solution of sodium chloride in turn. The aqueous layer was extracted with methylene chloride (50 ml×3) and, after washed with saturated aqueous solution of sodium chloride, these were combined with previous organic layer and dried over anhydrous sodium sulfate. Solvent was distilled off under reduced pressure and the residue thus obtained was recrystallized to obtain 8.61 g (yield 42 %) of title compound.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8]([O:10]CC)=[O:9].[OH-].[Na+]>O>[O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8]([OH:10])=[O:9]
Reactant: CCOC(=O)C1CCCCC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C1CCCCC1=O
Temperature: 0 °C
Reaction time: 12 h

Procedure:
Ethyl 2-oxocyclohexanecarboxylate (2 g, 11.7 mmol) was dissolved in water (2 mL), cooled to 0° C. and 5N aqueous .NaOH (5 mL) was added, cooled to room temperature and stirred for 12 h. The reaction mixture was cooled to 0° C., acidified with conc. (pH=2) and used in the next step without any purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:14]([O-:16])=[O:15])[CH:7]=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10])([O-])=O>[Pd].CO>[NH2:1][C:4]1[CH:5]=[C:6]([CH:7]=[C:8]([C:9]([O:11][CH3:12])=[O:10])[CH:13]=1)[C:14]([OH:16])=[O:15]
Reactant: COC(=O)c1cc(C(=O)[O-])cc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(N)cc(C(=O)O)c1
Reaction time: 3 h

Procedure:
A suspension of mono-methyl 5-nitro-isophthalate (22.5 g, 100 mmol) and palladium on carbon (5%, 2.00 g) in methanol (100 mL) is shaken in a hydrogenation apparatus under hydrogen (50 psi) for 3 hours. The mixture is then filtered through diatomaceous earth and concentrated to give the title compound, NMR (300 MHz, CDCl3) delta 7.67, 7.41, 7.40 and 3.83; MS (ESI−) for C9H9NO4 m/z (M−H)−=194.