Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:6][C:5]2[C:7]3[CH:11]=[C:10](Br)[S:9][C:8]=3[C:13]3[CH:17]=[C:16](Br)[S:15][C:14]=3[C:4]=2[CH:3]=1.[CH:19]1[C:31]2[N:30]([C:32]3[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=3)[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]=2[CH:22]=[CH:21][CH:20]=1.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>CN(C=O)C.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>[CH:19]1[C:31]2[N:30]([C:32]3[CH:37]=[CH:36][C:35]([C:2]4[S:6][C:5]5[C:7]6[CH:11]=[C:10]([C:35]7[CH:34]=[CH:33][C:32]([N:30]8[C:29]9[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=9[C:23]9[C:31]8=[CH:19][CH:20]=[CH:21][CH:22]=9)=[CH:37][CH:36]=7)[S:9][C:8]=6[C:13]6[CH:17]=[C:16]([C:35]7[CH:36]=[CH:37][C:32]([N:30]8[C:29]9[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=9[C:23]9[C:31]8=[CH:19][CH:20]=[CH:21][CH:22]=9)=[CH:33][CH:34]=7)[S:15][C:14]=6[C:4]=5[CH:3]=4)=[CH:34][CH:33]=3)[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]=2[CH:22]=[CH:21][CH:20]=1
Reactant: Brc1cc2c(s1)c1cc(Br)sc1c1cc(Br)sc21
Reactant: OB(O)c1ccc(-n2c3ccccc3c3ccccc32)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc2c(c1)c1ccccc1n2-c1ccc(-c2cc3c(s2)c2cc(-c4ccc(-n5c6ccccc6c6ccccc65)cc4)sc2c2cc(-c4ccc(-n5c6ccccc6c6ccccc65)cc4)sc32)cc1
Temperature: 95 °C

Procedure:
Under a nitrogen atmosphere, 2,5,8-tribromobenzo[1,2-b:3,4-b′:5,6-b″]trithiophene (33) (500 mg, 1.04 mmol) obtained in Example 4, 4-(N-carbazolyl)phenyl boronic acid (1.34 g, 4.66 mmol) and tripotassium phosphate hydrate (3.96 g, 18.6 mmol) were suspended in DMF (40 mL) and degassed by Ar bubbling for 30 minutes. Pd(PPh3)4 (179 mg, 0.155 mmol) was added and heated at 90-100° C. for 18 hours. After completion of the reaction, water (30 mL) was added. A precipitated solid substance was obtained by filtration, washed with water (50 mL) and acetone (10 mL) and dried under reduced pressure. Vacuum sublimation purification was performed to obtain a light yellow substance (47.7 mg, 5%). MS (MALDI-TOF,1,8,9-trihydroxyanthracene matrix) m/z=966.34
Reaction SMILES: C[O:2][C:3](=[O:35])[C@@H:4]([NH:11][C:12](=[O:34])[CH:13]([C:24](=[O:33])[NH:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[NH:23])[NH2:22])=[CH:17][CH:16]=1)[CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.C(#N)C>O>[CH2:26]([NH:25][C:24]([CH:13]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([C:21](=[NH:22])[NH2:23])=[CH:19][CH:20]=1)[C:12]([NH:11][C@@H:4]([CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[C:3]([OH:35])=[O:2])=[O:34])=[O:33])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: COC(=O)[C@@H](NC(=O)C(Cc1ccc(C(=N)N)cc1)C(=O)NCc1ccccc1)C1CCCCC1
Solvent: CC#N
Solvent: O
Product: N=C(N)c1ccc(CC(C(=O)NCc2ccccc2)C(=O)N[C@H](C(=O)O)C2CCCCC2)cc1
Temperature: 25 °C

Procedure:
The above [2-(R,S)-benzylcarbamoyl-3-(4-carbamimidoyl-phenyl)-propionylamino]-(S)-cyclohexyl-acetic acid methyl ester was suspended in water/concentrated hydrochloric acid (1/1, 200 ml) and stirred at room temperature. After 8 days acetonitrile (100 ml) was added and stirred for 2 more days. The reaction mixture was filtered and poured into ice-water. The precipitate was collected by fractionized crystallization:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH3:12][S:13]([C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1)(=[O:15])=[O:14]>>[CH3:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([C:2]2[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=[N:4][CH:3]=2)=[CH:18][CH:17]=1)(=[O:15])=[O:14]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: COC(=O)c1cncc(Br)c1
Product: COC(=O)c1cncc(-c2ccc(S(C)(=O)=O)cc2)c1

Procedure:
4.5 g (20.8 mmol) of methyl 5-bromonicotinate and 5.0 g (25.0 mmol) of 4-(methylsulphonyl)phenylboronic acid were reacted according to the General Method 1A. Yield: 1.4 g (24% of theory)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].C(N(CC)CC)C.[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[C:18]([CH3:25])[CH:17]=1>ClCCl>[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([N:4]2[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]2)=[O:21])=[C:18]([CH3:25])[CH:17]=1
Reactant: O=C1CNCCN1
Reactant: Cc1cc(Cl)ccc1C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(Cl)ccc1C(=O)N1CCNC(=O)C1
Reaction time: 0.5 h

Procedure:
2-piperazinone (0.701 g, 7 mmol, commercially available from e.g. Sigma-Aldrich) was dissolved in dichloromethane (DCM) (30 mL), and to this was added triethylamine (1.171 mL, 8.40 mmol). The solution was then cooled to 0° C. before 4-chloro-2-methylbenzoyl chloride (I55) (1.456 g, 7.70 mmol) in Dichloromethane (DCM) (5 mL) was added dropwise. The solution was stirred, under argon, for 30 minutes before the solvent was evaporated in vacuo. The remaining residue was then dissolved in DCM (40 mL) and the solution was washed with water (20 mL), a saturated solution of sodium bicarbonate (20 mL) and brine (20 mL). The organic phase was then dried over anhydrous sodium sulphate, and the solid sodium sulphate was then filtered off. The solvent was then evaporated in vacuo, and the remaining solid was stirred in hexane, at 55° C., for 30 minutes. The solid was then filtered off and the remaining solid was further purified by flash chromatography (Biotage SP4, 40S cartridge) with a gradient of 0-10% MeOH in DCM. TLC confirmed product location and the solvent from the combined fractions was evaporated in vacuo to yield the product in 0.798 g.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][CH2:9][CH2:10][NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])(=O)=O.[N-:19]=[N+:20]=[N-:21].[Na+].O>CN(C)C=O>[N:19]([CH2:6][CH2:7][O:8][CH2:9][CH2:10][NH:11][C:12](=[O:13])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[N+:20]=[N-:21]
Reactant: CC(C)(C)OC(=O)NCCOCCOS(C)(=O)=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCOCCN=[N+]=[N-]
Temperature: 90 °C
Reaction time: 5 h
Yield: 100.8 %

Procedure:
A stirred solution of 2-{2-[(tert-butoxycarbonyl)amino]ethoxy}ethyl methanesulfonate (63.5 g, 0.224 mol) in 400 mL of N,N-dimethylformamide (DMF) was treated with NaN3 (16.1 g, 0.247 mol) and the reaction mixture was heated to 90° C. under N2. After 5 h, the solution was cooled to room temperature and treated with 500 mL of cold H2O. The reaction mixture was then extracted with Et2O (3×300 mL). The combined organic extracts were washed with H2O (4×100 mL) and brine (2×100 mL). The organic portion was dried over MgSO4 and concentrated to give 52.0 g of tert-butyl 2-(2-azidoethoxy)ethylcarbamate as a light brown oil.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:14][O:15][CH3:16])[CH2:11][C@H:10]2[C:17](=[N:19][OH:20])[NH2:18])=[O:8])=[CH:3][CH:2]=1.[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][C:42](O)=O)[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:2]=[CH:3][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:14][O:15][CH3:16])[CH2:11][C@H:10]2[C:17]2[N:18]=[C:42]([CH2:41][CH2:40][N:37]3[CH2:38][CH2:39][N:34]([C:32]([O:31][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:33])[CH2:35][CH2:36]3)[O:20][N:19]=2)=[O:8])=[CH:5][CH:6]=1
Reactant: CON=C1C[C@@H](C(N)=NO)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Reactant: CC(C)(C)OC(=O)N1CCN(CCC(=O)O)CC1
Product: CON=C1C[C@@H](c2noc(CCN3CCN(C(=O)OC(C)(C)C)CC3)n2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Yield: 70 %

Procedure:
Following the general method as outlined in Example 15, starting from (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide (Intermediate 8) and 3-[4-(tert-butoxycarbonyl)-1-piperazinyl]propanoic acid, the title compound was obtained in 70% yield (78% purity by HPLC).
Reaction SMILES: O.[NH2:2][NH2:3].[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH2:9]Cl>C(O)C>[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH2:9][NH:2][NH2:3]
Reactant: NN
Reactant: COc1cccc(CCl)c1
Solvent: CCO
Solvent: O
Product: COc1cccc(CNN)c1
Reaction time: 0.5 h

Procedure:
While a solution of hydrazine monohydrate (10 g, 0.2 mol) in ethanol (35 ml) was heated under reflux, a solution of 3-methoxybenzyl chloride (5.0 g, 32 m mol) in ethanol (15 ml) was added drop-wise thereto over a period of 30 minutes. After this mixture was further refluxed for 2 hours, the solvent was distilled off under reduced pressure. The oily residue was extracted with ether (2×30 ml). After the extract was dried, the solvent was distilled off under reduced pressure. The resulting residue was subjected to chromatography on silica gel (40 g) using chloroform-methanol (20:1), so that there was obtained a crude fraction containing the desired compound. Then, this crude fraction was distilled (120-123° C./1-2 mmHg) to obtain the desired compound (2.9 g, 60%) as a colorless oily material.
Reaction SMILES: Cl.[F:2][C:3]([F:29])([F:28])[C:4]1[CH:5]=[C:6]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:37][C:38]1[NH:39][C:40](=[O:43])[NH:41][N:42]=1>CN(C=O)C.O>[F:29][C:3]([F:2])([F:28])[C:4]1[CH:5]=[C:6]([CH:21]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:23]=1)[CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][N:12]([CH2:37][C:38]2[NH:39][C:40](=[O:43])[NH:41][N:42]=2)[CH2:11][C@H:10]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=c1[nH]nc(CCl)[nH]1
Reactant: FC(F)(F)c1cc(CO[C@H]2CCNC[C@H]2c2ccccc2)cc(C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1[nH]nc(CN2CC[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@H](c3ccccc3)C2)[nH]1
Temperature: 0 °C
Reaction time: 3 h
Yield: 29.3 %

Procedure:
To a mixed solution of the compound (0.15 g) obtained in Example 1 and potassium carbonate (0.047 g) in DMF (2 ml) and water (0.02 ml), 5-(chloromethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (0.046 g) synthesized by the method described in the document (e.g., Tetrahedron Letters, Vol. 41, pages 8661-8664) was added at 0° C., and the reaction mixture was stirred at 0° C. for 3 hours. The reaction mixture was poured into water, and then the product was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried, and then the solvent was evaporated under reduced pressure. The obtained residue was isolated and purified by silica gel column chromatography (ethyl acetate:methanol=20:1) to obtain the title compound as colorless crystals (0.050 g, 29%).
Reaction SMILES: C1C2C(COC([NH:18][C:19]([CH3:65])([C:21]([NH:23][C@H:24]([C:28]([N:30]([C@@H:32]([C@@H:61]([CH3:64])[CH2:62][CH3:63])[C@H:33]([O:59][CH3:60])[CH2:34][C:35]([N:37]3[CH2:41][CH2:40][CH2:39][C@H:38]3[C@H:42]([O:57][CH3:58])[C@@H:43]([CH3:56])[C:44]([NH:46][CH2:47][CH2:48][CH:49]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=[CH:50]3)=[O:45])=[O:36])[CH3:31])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22])[CH3:20])=O)C3C(=CC=CC=3)C=2C=CC=1.C(N(CC)CC)C>ClCCl>[CH3:20][C:19]([C:21]([NH:23][C@H:24]([C:28]([N:30]([C@@H:32]([C@@H:61]([CH3:64])[CH2:62][CH3:63])[C@H:33]([O:59][CH3:60])[CH2:34][C:35]([N:37]1[CH2:41][CH2:40][CH2:39][C@H:38]1[C@H:42]([O:57][CH3:58])[C@@H:43]([CH3:56])[C:44]([NH:46][CH2:47][CH2:48][CH:49]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=[CH:50]1)=[O:45])=[O:36])[CH3:31])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22])([CH3:65])[NH2:18]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)NCCC1C=CC=CC=C1)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)NCCC1C=CC=CC=C1)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)N)C(C)C
Reaction time: 2 h
Yield: 85.4 %

Procedure:
To a solution of #65 (540 mg, 0.603 mmol, 1 eq.) in dichloromethane (10 mL, 0.06 M) was added triethylamine (10 mL) and the reaction mixture was stirred for 2 hours. The mixture was concentrated in vacuo and the residue was purified by silica gel chromatography (Gradient: 0% to 10% methanol in dichloromethane) to give #66 (347 mg, 85%) as a colorless solid. HPLC (Protocol A at 45° C.): m/z 674.5 [M+H+], retention time=7.015 minutes. 1H NMR (400 MHz, DMSO-d6), presumed to be a mixture of rotamers, characteristic signals: δ [8.03 (br d, J=9 Hz) and 8.05 (br d, J=9 Hz), total 1H], [7.77 (br dd, J=5.5, 5.5 Hz) and 7.98 (br dd, J=5.5, 5.5 Hz), total 1H], 6.54-6.65 (m, 2H), 6.10-6.19 (m, 2H), 5.11-5.19 (m, 2H), [4.48 (dd, J=9, 8 Hz) and 4.54 (dd, J=9, 7.5 Hz), total 1H], 3.94-4.04 (br m, 1H), 3.26 and 3.29 (2 s, total 3H), 3.17 and 3.19 (2 s, total 3H), 2.93 and 3.06 (2 br s, total 3H), 1.20 and 1.21 (2 s, total 3H), 1.12 and 1.13 (2 s, total 3H), [1.04 (d, J=6.8 Hz) and 1.07 (d, J=6.7 Hz), total 3H].
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[NH:19][C:18](=[O:23])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]([O:28][C:29](=[O:32])[CH:30]=[CH2:31])([CH3:27])([CH3:26])[CH3:25].C(N(CC)CC)C>C(#N)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:24]([O:28][C:29](=[O:32])/[CH:30]=[CH:31]/[C:13]1[CH:12]=[CH:11][C:10]([N:16]2[CH2:17][C:18](=[O:23])[NH:19][S:20]2(=[O:22])=[O:21])=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:14]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: O=C1CN(c2ccc(I)cc2OCc2ccccc2)S(=O)(=O)N1
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)/C=C/c1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1
Temperature: 100 °C
Reaction time: 6 h

Procedure:
To a mixture of 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (2.0 g, 4.49 mmol), Pd(OAc)2 (100 mg) and acrylic acid t-butyl ester (0.78 mL, 5.8 mmol) in acetonitrile (15 mL) in a pressure vessel is added triethylamine (3.13, 22.5 mmol) and the mixture is stirred at 100° C. for 6 h. The solution is filtered through Celite, washed with acetonitrile and concentrated to give the title compound. This is used directly in the next step.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N].C(=O)([O-])[O-].[K+].[K+].IC.[NH:16]1[CH:21]=[CH:20][CH:19]=NC1=O.ClC1C=CC(CNC(C(=COC)C(OC)=O)=O)=CC=1>CC(C)=O>[N:1]1[C:2]2[C:3](=[CH:19][CH:20]=[CH:21][N:16]=2)[CH:4]=[CH:5][CH:6]=1
Reactant: [N]c1ccccn1
Reactant: O=c1nccc[nH]1
Agent: COC=C(C(=O)NCc1ccc(Cl)cc1)C(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: c1cnc2ncccc2c1

Procedure:
4,7-Dioxo-1,4,7,8-tetrahydro[1,8]naphthyridine-3-carboxamide. The preparation of specific examples of heterocycle W16.1 is described in Chart BE. 2-Amino-4-bromopyridine BE.1 is reacted with Boc-anhydride in dichloromethane to afford BE.2. The resulting Boc-protected amine is then oxidized with peroxybenzoic acid (Justus Liebigs Ann. Chem. 1972, 758, 111) to afford hydroxypyridine BE.3. The pyridyl nitrogen is then alkylated in the presence of potassium carbonate and iodomethane with acetone as solvent to afford BE.4. The Boc group is then removed under standard deprotection condition to afford BE.5. The pyrimidone BE.5 is. then cyclized with methyl 2-(((4-chlorobenzyl)amino)carbonyl)-3-methoxy-2-propenoate to afford naphthyridine BE.6. Reaction of BE.6 with an alkylating agent (e.g. iodomethane) in the presence of potassium carbonate with acetone as solvent affords compounds such as BE.7. Compound BE.7 is then coupled through a modified Sonogashira coupling (Linstrumelle, G.; et.al, Tetrahedron Lett, 1993, 34 6403) with an electron-rich acetylene (e.g. propargyl alcohol, Z=CH2OH) to afford the alkyne derivative BE.8. Saturation of the alkyne by hydrogenation catalyzed by palladium on carbon in alcoholic solvents affords alkyl derivatives of formula BE.9 (Z=CH2OH).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.Cl[C:12]1[N:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=[O:15]>O1CCOCC1>[OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:12]2[N:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14]([OH:16])=[O:15])[CH2:7][CH2:6]1
Reactant: OCCCN1CCNCC1
Reactant: O=C(O)c1cccnc1Cl
Solvent: C1COCCO1
Product: O=C(O)c1cccnc1N1CCN(CCCO)CC1

Procedure:
Grams 8.65 of 1-(3-hydroxypropyl)piperazine and 4.7 g of 2-chloronicotinic acid in 100 ml dioxane were refluxed for 6 hours. The reaction mixture was cooled and settled. The residual oil, crystallized from 95° ethanol, gave 2.3 g of 2-[4-(3-hydroxypropyl)piperazin-1-yl]nicotinic acid, melting at 222°-225° C. (with decomposition).
Reaction SMILES: Br[CH2:2][C:3]([C:5]([F:8])([F:7])[F:6])=O.[CH3:9][O:10][CH2:11][C:12]1[S:16][C:15]([NH2:17])=[N:14][N:13]=1.O>COCCOC>[CH3:9][O:10][CH2:11][C:12]1[S:16][C:15]2=[N:17][C:3]([C:5]([F:8])([F:7])[F:6])=[CH:2][N:14]2[N:13]=1
Reactant: O=C(CBr)C(F)(F)F
Reactant: COCc1nnc(N)s1
Solvent: COCCOC
Solvent: O
Product: COCc1nn2cc(C(F)(F)F)nc2s1
Temperature: 80 °C
Yield: 46.7 %

Procedure:
Bromotrifluoroacetone (478 g, 2.5 mol, 1.05 eq) is added on a suspension of 5-(methoxymethyl)-1,3,4-thiadiazol-2-amine a1 (346 g, 2.4 mol, 1 eq) in 1,2-dimethoxyethane (6 l) at 20° C. The reaction mixture is heated to 80° C. until maximum conversion (<24 h). Water (4 l) is added to the reaction mixture at 32° C. and the expected compound crystallized out of the reaction mixture. The crystalline suspension is cooled to 10° C. to complete the crystallization process, filtered and the crystalline precipitate is washed with water (1.5 l) to afford 266 g of pure 2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazole a2.
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[C:9]([O:12][CH3:13])([O:10][CH3:11])[CH2:8][CH2:7][N:6]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:5]1.[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl>CN(C=O)C>[CH2:21]([O:3][CH:4]1[C:9]([O:10][CH3:11])([O:12][CH3:13])[CH2:8][CH2:7][N:6]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:5]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC1(OC)CCN(C(=O)OC(C)(C)C)CC1O
Reactant: BrCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1(OC)CCN(C(=O)OC(C)(C)C)CC1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.7 %

Procedure:
Sodium hydride (55% content, 0.79 g, 18 mmol) was added to a solution of tert-butyl 3-hydroxy-4,4-dimethoxypiperidine-1-carboxylate (described in Tetrahedron Lett.; 46; 3; 2005; 447-450, 3.9 g, 15 mmol) in DMF (50 mL). Following stirring at room temperature for 30 minutes, benzyl bromide (2.82 g, 16.5 mmol) was added, and the mixture was stirred at room temperature for two hours. A 0.5 N aqueous hydrochloric acid solution was added to the reaction solution, followed by extraction with ethyl acetate. Then, the organic layer was washed with water (three times) and brine, and dried over anhydrous magnesium sulfate. Following concentration under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=10/1, 4/1, 2/1) to obtain 4.99 g of the title compound as a colorless solid (95%).
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:17]=2)[CH2:11][CH2:10][CH2:9][CH2:8][N:7]([CH2:12][CH2:13][OH:14])[C:6]1=[O:15])[CH3:4].[CH3:30]I>CN(C=O)C>[CH2:3]([C:5]1([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:17]=2)[CH2:11][CH2:10][CH2:9][CH2:8][N:7]([CH2:12][CH2:13][O:14][CH3:30])[C:6]1=[O:15])[CH3:4]
Reactant: CI
Reactant: CCC1(c2cccc(OCc3ccccc3)c2)CCCCN(CCO)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC1(c2cccc(OCc3ccccc3)c2)CCCCN(CCOC)C1=O
Reaction time: 16 h

Procedure:
Sodium hydride (0.017 g, 0.425 mmol) was added to a solution of 3-ethyl-1-(2-hydroxy-ethyl)-3-(3-benzyloxyphenyl)-azepan-2-one, as described in Example 54, Step C, (0.12 g, 0.327 mmol) in DMF (5 mL) at 0° C. with stirring. After 20 min CH3I (0.041 mL, 0.653 mmol) was added and stirring was continued at room temperature for 16 h. The reaction was quenched with H2O and the solvents removed in vacuo. The residue was partitioned between EtOAc and saturated NaHCO3 solution. The organic layer was separated, washed with brine and dried (MgSO4). Filtration and concentration gave the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[C:16]([Cl:24])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:13]([O-:15])=[O:14])=[C:9]([CH:12]=1)C=O.N1CCCCC1.[C:31](O)(=O)[CH2:32][C:33]([OH:35])=[O:34].Cl>N1C=CC=CC=1>[Cl:24][C:16]1[CH:17]=[C:18]([C:20]([F:22])([F:23])[F:21])[CH:19]=[C:2]([Cl:1])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:13]([O-:15])=[O:14])=[C:9]([CH:31]=[CH:32][C:33]([OH:35])=[O:34])[CH:12]=1
Reactant: O=Cc1cc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)C=Cc1cc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reaction time: 5 h
Yield: 66.7 %

Procedure:
270 g of 5-(2,6-dichloro-4-trifluoromethylphenoxy)-2-nitro-benzaldehyde and 6 g of piperidine were added, at 25° C., to 89.5 g of malonic acid in 570 ml of pyridine. The reaction mixture was stirred for 5 hours at 85° to 90° C. and was then heated for 90 minutes under reflux, after which it was poured onto water, the mixture was acidified with hydrochloric acid and the product was filtered off. The crystalline product was recrystallized from n-butanol. 200 g (66% of theory) of 3-(5-(2,6-dichloro-4-trifluoromethyl-phenoxy)-2-nitrophenyl)-propenoic acid, of melting point 192° C., were obtained in the form of yellow crystals.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].Cl.[F:12][C:13]1([F:19])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>>[F:12][C:13]1([F:19])[CH2:18][CH2:17][N:16]([C:2]2[N:6]([CH3:7])[N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:15][CH2:14]1
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Reactant: FC1(F)CCNCC1
Agent: Cl
Product: Cn1ncc([N+](=O)[O-])c1N1CCC(F)(F)CC1
Yield: 97 %

Procedure:
Reaction of 5-chloro-1-methyl-4-nitro-1H-pyrazole and 4,4 di-fluoropiperidine hydrochloride gave 4,4-difluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperidine as a white solid (289 mg, 97%). 1H NMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 3.79 (s, 3H), 3.36-3.31 (m, 4H), 2.22-2.09 (m, 4H)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.C([O-])(O)=O.[Na+].[N:14]#[C:15]Br>C(Cl)Cl.O>[OH:8][CH2:7][CH:4]1[CH2:5][CH2:6][N:1]([C:15]#[N:14])[CH2:2][CH2:3]1
Reactant: N#CBr
Reactant: OCC1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: N#CN1CCC(CO)CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of 4-piperidinemethanol (140 g, 1.22 mol) in CH2Cl2 (1 L) was treated with a slurry of NaHCO3 (205 g, 2.44 mol) in water (1.4 L) at 0° C. The mixture was stirred at 0° C. for 15 min, and then charged with a solution of cyanogen bromide in CH2Cl2, (1.34 mol) at 0° C. The reaction mixture was stirred and allowed to warm to ambient temperature, and stirred overnight. The aqueous layer was separated and extracted with CH2Cl2. The combined organic extracts were dried over Na2SO4, filtered, and the filtrate was concentrated. The crude product was combined with other batches made similarly and purified by chromatography on a silica gel column to give 300 g of 4-(hydroxymethyl)-1-piperidinecarbonitrile.