Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16]([F:20])([C:18]#[N:19])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO.Cl[Ni]Cl>[CH:1]([N:14]1[CH2:15][C:16]([CH2:18][NH2:19])([F:20])[CH2:17]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CC1(F)CN(C(c2ccccc2)c2ccccc2)C1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NCC1(F)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 14 h
Yield: 29.5 %

Procedure:
1-Benzhydryl-3-fluoroazetidine-3-carbonitrile (0.5 g, 1.88 mmol) was dissolved in methanol (25 mL). NaBH4 (0.49 g, 13.14 mmol) and NiCl2 (0.044 g, 0.34 mmol) were added at 0° C. and the reaction mixture was stirred at rt for 14 h. The solids formed were removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was purified by chromatography (0-5% methanol-DCM) to give 0.15 g of (1-benzhydryl-3-fluoroazetidin-3-yl)methanamine (30% yield). 1H NMR (400 MHz, CDCl3, ppm) δ=7.46-7.19 (m, 10H); 4.48 (s, 1H); 3.38-3.34 (t, 2H); 3.26-3.09 (m, 4H).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:32]=[CH:31][CH:30]=[CH:29][C:4]=1[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[N:17]=[CH:16][C:15]([C:18]3[CH:19]=[N:20][N:21]([CH2:23][C:24]([O:26]CC)=[O:25])[CH:22]=3)=[CH:14][N:13]=2)[CH2:8][CH2:7]1.[OH-].[Na+]>CO>[F:34][C:2]([F:1])([F:33])[C:3]1[CH:32]=[CH:31][CH:30]=[CH:29][C:4]=1[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[N:17]=[CH:16][C:15]([C:18]3[CH:19]=[N:20][N:21]([CH2:23][C:24]([OH:26])=[O:25])[CH:22]=3)=[CH:14][N:13]=2)[CH2:8][CH2:7]1
Reactant: CCOC(=O)Cn1cc(-c2cnc(N3CCC(Oc4ccccc4C(F)(F)F)CC3)nc2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)Cn1cc(-c2cnc(N3CCC(Oc4ccccc4C(F)(F)F)CC3)nc2)cn1
Temperature: 80 °C

Procedure:
Into a 10-mL flask equipped with a magnetic stirbar was added ethyl [4-(2-{4-[2-(trifluoromethyl)phenoxy]piperidin-1-yl}pyrimidin-5-yl)-1H-pyrazol-1-yl]acetate-(50 mg, 0.10 mmol), methanol (2 mL) and 1 M aqueous sodium hydroxide solution (0.52 mL, 0.53 mmol). The suspension was heated to 80° C. for 2 h. The reaction mixture was concentrated to remove the methanol and the residue was poured into a 125-mL separatory funnel containing saturated aqueous KH2PO4 solution (75 mL) and the mixture was extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and the solvent was evaporated under reduced pressure to give the desired product.
Reaction SMILES: C1(S(CC2C(C(OCC)=O)=C(O)C([C:23]3[CH:27]=[CH:26][O:25][CH:24]=3)=CC=2)(=O)=O)C=CC=CC=1.Br[C:29]1[C:30]([O:50][CH3:51])=[C:31]([C:36]([CH2:39][S:40]([C:43]2[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=2)(=[O:42])=[O:41])=[CH:37][CH:38]=1)[C:32]([O:34][CH3:35])=[O:33].O1C=CC(B(O)O)=C1>>[F:49][C:46]1[CH:47]=[CH:48][C:43]([S:40]([CH2:39][C:36]2[C:31]([C:32]([O:34][CH3:35])=[O:33])=[C:30]([O:50][CH3:51])[C:29]([C:23]3[CH:27]=[CH:26][O:25][CH:24]=3)=[CH:38][CH:37]=2)(=[O:42])=[O:41])=[CH:44][CH:45]=1
Reactant: COC(=O)c1c(CS(=O)(=O)c2ccc(F)cc2)ccc(Br)c1OC
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1O
Agent: OB(O)c1ccoc1
Product: COC(=O)c1c(CS(=O)(=O)c2ccc(F)cc2)ccc(-c2ccoc2)c1OC

Procedure:
Prepared by proceeding in a manner similar to Intermediate 36, starting from methyl 3-bromo-6-(4-fluorobenzenesulphonylmethyl)-2-methoxybenzoate (Intermediate 117) and furan-3-yl boronic acid.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:11])[NH:5]OCC(O)=O)[CH3:2].[NH2:12][C@@H:13]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:14]([N:16]([C@@H:28]([CH3:36])[CH:29]([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])[CH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1)=[O:15]>>[CH2:31]([O:30][CH:29]([O:33][CH2:34][CH3:35])[C@@H:28]([N:16]([CH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1)[C:14](=[O:15])[C@@H:13]([NH:12][C:29](=[O:30])[CH2:28][N:16]([CH3:14])[NH:5][C:4]([NH:3][CH2:1][CH3:2])=[O:11])[CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[CH3:36])[CH3:32]
Reactant: CCNC(=O)NOCC(=O)O
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@@H](N)Cc1ccccc1
Product: CCNC(=O)NN(C)CC(=O)N[C@@H](Cc1ccccc1)C(=O)N(Cc1cccc2ccccc12)[C@@H](C)C(OCC)OCC
Yield: 54.1 %

Procedure:
According to the procedure described in the synthesis method of Compound II-130, 2-(3-ethylureidooxy)acetic acid (Compound VI-13) 32 mg (0.18 mmol) was coupled with (S)-2-amino-N—((S)-1,1-diethoxypropan-2-yl)-N-(naphthalen-1-ylmethyl)-3-phenylpropanamide (Compound IV-27) 65 mg (0.15 mmol) to obtain the title compound 24 mg (27%).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2[C:12](=O)[C@H:11]([CH3:14])[NH:10][C:9](=O)[C@H:8]2[CH2:16][OH:17])=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2[CH2:12][C@H:11]([CH3:14])[NH:10][CH2:9][C@@H:8]2[CH2:16][OH:17])=[CH:4][CH:3]=1
Reactant: C[C@@H]1NC(=O)[C@@H](CO)N(Cc2ccc(F)cc2)C1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@H]1CN(Cc2ccc(F)cc2)[C@@H](CO)CN1
Temperature: 25 °C
Reaction time: 15 h
Yield: 89.5 %

Procedure:
To a suspension of (2R,5S)-1-(4-fluorobenzyl)-2-(hydroxy)methyl-5-methyl-piperazine-3,6-dione (2.0 g, 7.5 mmol) in anhydrous tetrahydrofuran (50 mL) under N2 at 0° C. was carefully added lithium aluminum hydride (2.2 g, 60 mmol). The resulting suspension was heated to reflux. After 15 hours, the mixture was cooled to ambient temperature and carefully quenched with water (2 mL), then 1 N aqueous KOH solution (6 mL). The resulting suspension was stirred at ambient temperature for 30 minutes, then filtered through Celite (ethyl acetate). The filtrate was concentrated in vacuo to afford 1.6 g (90% yield) of (2R,5S)-1-(4-fluorobenzyl)-2-(hydroxy)methyl-5-methylpiperazine, a compound of formula (S), as a white solid; NMR (CDCl3) 7.3 (dd, 2), 7.0 (dd, 2), 4.2-4.0 (m, 2), 3.5 (d, 1) 3.0 (m, 2), 2.7 (m, 2), 1.7 (m, 1), 1.0 (d, 3).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([B:10]2[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]2)=[CH:6][CH:5]=1)=[C:2]=[O:3].[N:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=1.C(N(CC)CC)C>C1COCC1>[N:19]1[CH:24]=[CH:23][C:22]([NH:25][C:2]([NH:1][C:4]2[CH:9]=[CH:8][C:7]([B:10]3[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]3)=[CH:6][CH:5]=2)=[O:3])=[CH:21][CH:20]=1
Reactant: CC1(C)OB(c2ccc(N=C=O)cc2)OC1(C)C
Reactant: Nc1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1(C)OB(c2ccc(NC(=O)Nc3ccncc3)cc2)OC1(C)C

Procedure:
2-(4-isocyanatophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1 g, 4.1 mmol) was dissolved in dry THF and stirred with pyridin-4-amine (460 mg, 4.9 mmol) and triethlyamine (1.13 ml, 8.2 mmol) at 60° C. for 3 hours. The mixture was cooled and then purified by flash chromatography (0-100% EtOAc in Petroleum ether 40-60, followed by 0-10% MeOH in EtOAc) to afford the title compound. (875 mg, 63%) uPLC (method D), (M+H+) 340, Rt=0.89 mins
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SC)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[N:34]1[CH:39]=[C:38]([CH2:40][NH2:41])[CH:37]=[N:36][CH:35]=1>>[F:1][C:2]([F:32])([F:33])[C:3]1[CH:27]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([NH:41][CH2:40][C:38]4[CH:39]=[N:34][CH:35]=[N:36][CH:37]=4)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: NCc1cncnc1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Product: O=C1N=C(NCc2cncnc2)SC1=Cc1ccc2c(cnn2Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c1

Procedure:
5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[(pyrimidin-5-ylmethyl)-amino]-thiazol-4-one was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and C-pyrimidin-5-yl-methylamine following General Procedure B.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([NH:15][C:16]1[S:20][C:19]([C:21]2[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=2[F:28])=[N:18][C:17]=1[C:29]([NH:31][C:32]1[C:33]([N:41]2[CH2:46][CH2:45][CH2:44][C@H:43]([NH:47]C(=O)OC(C)(C)C)[CH2:42]2)=[C:34]2[CH:40]=[CH:39][S:38][C:35]2=[N:36][CH:37]=1)=[O:30])=O)(C)(C)C>C(Cl)Cl>[NH2:15][C:16]1[S:20][C:19]([C:21]2[C:22]([F:28])=[CH:23][CH:24]=[CH:25][C:26]=2[F:27])=[N:18][C:17]=1[C:29]([NH:31][C:32]1[C:33]([N:41]2[CH2:46][CH2:45][CH2:44][C@H:43]([NH2:47])[CH2:42]2)=[C:34]2[CH:40]=[CH:39][S:38][C:35]2=[N:36][CH:37]=1)=[O:30]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)Nc1cnc2sccc2c1N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1sc(-c2c(F)cccc2F)nc1C(=O)Nc1cnc2sccc2c1N1CCC[C@H](N)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33.8 %

Procedure:
TFA (2.0 mL) was added to a solution of tert-butyl {(3S)-1-[5-({[5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazol-4-yl]carbonyl}amino)thieno[2,3-b]pyridin-4-yl]piperidin-3-yl}carbamate (230.7 mg, 0.3359 mmol) in DCM (2.0 mL). The mixture was stirred at room temperature for 30 min., and then concentrated under reduced pressure. The resulting residue was purified using RP-HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at flow rate of 30 mL/min.) to afford the title compound as a white solid (55.3 mg, 34%). LCMS calc. for C22H21F2N6OS2 (M+H)+: m/z=487.1. found 487.1. 1H NMR (500 MHz, DMSO-d6) δ 9.42 (s, 1H), 7.82 (d, J=6.1 Hz, 1H), 7.65 (s, 2H), 7.60 (d, J=6.2 Hz, 1H), 7.57-7.50 (m, 1H), 7.28 (t, J=8.7 Hz, 2H), 3.23-3.16 (m, 1H), 3.07-3.01 (m, 2H), 2.99-2.91 (m, 1H), 2.90-2.82 (m, 1H), 1.91-1.66 (m, 3H), 1.30-1.13 (m, 1H) ppm.
Reaction SMILES: C[O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH2:13][CH2:14][CH2:15][OH:16])[CH:5]=1.Cl>C1COCC1.[OH-].[Na+]>[OH:16][CH2:15][CH2:14][CH2:13][O:12][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[O:10][CH3:11])[C:3]([OH:17])=[O:2]
Reactant: COC(=O)c1ccc(OC)c(OCCCO)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)O)cc1OCCCO

Procedure:
A solution of 3-(3-hydroxy-propoxy)-4-methoxy-benzoic acid methyl ester (1.00 g, 4.16 mmol) in THF (3.0 mL) and 2N NaOH (3.1 mL) is stirred at room temperature over 6 hrs. The mixture is adjusted to pH 1 by addition of 2N aqueous HCl to afford a white suspension. The precipitate is filtered, washed with water and dried in vacuo at 50° C. to give the title compound as white solid. MS: 225.0 [M−H]+. 1H-NMR (CDCl3): δ 1.88 (m, 2H), 3.57 (m, 2H), 3.83 (s, 3H), 4.07 (m, 2H), 4.56 (s, br, 1H), 7.06 (dd, 1H), 7.46 (d, 1H), 7.57 (dd, 1H), 12.7 (s, br, 1H) ppm.
Reaction SMILES: [F-].C([N+](C[CH2:16][CH2:17][CH3:18])(CCCC)CCCC)CCC.C(OC1(O[Si](C)(C)C)CC1)C.C1(P(=[CH:49][C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)(=O)C1C=CC=CC=1>C1COCC1.C(OCC)C>[C:16]1(=[CH:49][C:50]([O:52][C:53]([CH3:54])([CH3:55])[CH3:56])=[O:51])[CH2:17][CH2:18]1
Reactant: CC(C)(C)OC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCOC1(O[Si](C)(C)C)CC1
Agent: O=C(O)c1ccccc1
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)C=C1CC1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
At room temperature, 55 ml (55 mmol) of a 1 M solution of tetra-n-butylammonium fluoride in THF were added dropwise to a solution of 9.65 g (55.34 mmol) of [(1-ethoxycyclopropyl)oxy](trimethyl)silane, 25 g (66.41 mmol) of tert-butyl (triphenyl-λ5-phosphanylidene)-acetate and 8.11 g (66.41 mmol) of benzoic acid in 240 ml of THF. After 1 h of stirring, the reaction mixture was heated to 80° C. and stirred at this temperature for 2 h. Using a rotary evaporator, the solvent was then distilled off (200 mbar, bath temperature 40° C.). The residue obtained was taken up in diethyl ether and the mixture was cooled to 4° C. and allowed to stand at this temperature for 1 h. The resulting precipitate (triphenylphosphane oxide) was filtered off. Using a rotary evaporator, the filtrate was then freed from the solvent. The crude product obtained was purified chromatographically on silica gel (mobile phase cyclohexane/ethyl acetate 20:1). This gave 3.58 g (42% of theory) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][NH:4][N:3]=1.C([O:14]/[CH:15]=[CH:16]/[C:17](OCC)=O)C.C(=O)([O-])[O-].[Cs+].[Cs+].CC(O)=O>CN(C=O)C>[OH:14][C:15]1[CH:16]=[CH:17][N:3]2[N:4]=[CH:5][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:2]2[N:1]=1
Reactant: CCOC(=O)c1c[nH]nc1N
Reactant: CCO/C=C/C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCOC(=O)c1cnn2ccc(O)nc12
Temperature: 110 °C

Procedure:
Ethyl 3-amino-1H-pyrazole-4-carboxylate (25.0 g, 161 mmol) and (E)-ethyl 3-ethoxyacrylate (35.8 ml, 242 mmol) were mixed in DMF (537 mL). Cesium carbonate (78.7 g, 242 mmol) was added and the mixture heated to 110° C. for 15 hours. The reaction mixture was cooled to ambient temperature and acidified with HOAc to pH 4. The resultant precipitate was filtered and washed with water and EtOAc, yielding the title compound as a fluffy white solid. Additional material was obtained by an aqueous workup. The filtrate was concentrated to remove the DMF, was diluted in EtOAc (500 mL) and washed with H2O. The resultant precipitate in the EtOAc layer was filtered and washed with water and EtOAc to obtain additional product. The solids were pooled and dried in vacuum to afford ethyl 5-hydroxypyrazolo[1,5-a]pyrimidine-3-carboxylate (33.3 g, 100% yield) as a fluffy white solid. MS (apci) m/z=206.2 (M−H).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]2[CH:16]=[CH:15][C:9]([O:10][CH2:11][CH:12]3[CH2:14][O:13]3)=[CH:8][CH:7]=2)[C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]1=2.[N:21]1([C:27]2[N:32]=[CH:31][CH:30]=[CH:29][N:28]=2)[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>C(O)C>[S:1]1[CH:5]=[C:4]([C:6]2[CH:16]=[CH:15][C:9]([O:10][CH2:11][C@H:12]([OH:13])[CH2:14][N:24]3[CH2:25][CH2:26][N:21]([C:27]4[N:28]=[CH:29][CH:30]=[CH:31][N:32]=4)[CH2:22][CH2:23]3)=[CH:8][CH:7]=2)[C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]1=2
Reactant: c1ccc2c(-c3ccc(OCC4CO4)cc3)csc2c1
Reactant: c1cnc(N2CCNCC2)nc1
Solvent: CCO
Product: O[C@@H](COc1ccc(-c2csc3ccccc23)cc1)CN1CCN(c2ncccn2)CC1
Temperature: 75 °C
Reaction time: 6 h
Yield: 0.1 %

Procedure:
Combine 2-(4-benzo[b]thiophen-3-yl-phenoxymethyl)-oxirane (200 mg, 0.708 mmol), 2-piperazin-1-yl-pyrimidine (465 mg, 2.83 mmol) and ethanol (4 mL). Apply heat (75° C.) to the homogeneous reaction mixtures and stir for 6 hours. Concentrate (in vacuo) and purify by column chromatography using a Waters Sep-Pak silica gel cartridge (10 g) and elution with graded solvent mixtures from 50% ethyl acetate in heptane to 100% ethyl acetate. Concentrate the appropriate fractions, dissolve in dichloromethane and re-evaporate under a stream of nitrogen. Dry the sample using medium heat and reduced pressure to give the title compound as a clear oil (0.285 mg, 90% Yield). Purity by LC/MS=99%, [M+H]+=447.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:10]2[O:14][N:13]=[C:12]([CH3:15])[N:11]=2)=[C:6]([CH2:8][OH:9])[CH:7]=1>C(Cl)Cl.O=[Mn]=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:10]2[O:14][N:13]=[C:12]([CH3:15])[N:11]=2)=[C:6]([CH:7]=1)[CH:8]=[O:9]
Reactant: Cc1noc(-c2ccc(Cl)cc2CO)n1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: Cc1noc(-c2ccc(Cl)cc2C=O)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 34.7 %

Procedure:
To a solution of [5-chloro-2-(3-methyl-1,2,4-oxadiazol-5-yl)-phenyl]-methanol (78 mg, 0.35 mmol) in CH2Cl2 (5.0 mL) is added MnO2 (125 mg, 1.22 mmol). The reaction mixture is stirred at room temperature for 16 hours and is filtered through diatomaceous earth. The filtrate is concentrated under reduced pressure and the residue is purified by silica gel flash column chromatography with 40% EtOAc in heptanes as the eluent to afford 5-chloro-2-(3-methyl-1,2,4-oxadiazol-5-yl)-benzaldehyde (27 mg, 35%).
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15]([C:20]([OH:22])=[O:21])[CH:14]=[CH:13]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C1(N=C=NC2CCCCC2)CCCCC1.[F:38][C:39]1[C:44](O)=[C:43]([F:46])[C:42]([F:47])=[C:41]([F:48])[C:40]=1[F:49]>C(OCC)(=O)C>[CH2:1]([O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15]([C:20]([O:22][C:44]1[C:43]([F:46])=[C:42]([F:47])[C:41]([F:48])=[C:40]([F:49])[C:39]=1[F:38])=[O:21])[CH:14]=[CH:13]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1ccc2cc(C(=O)O)ccc2c1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Product: CCCCCCCCOc1ccc2cc(C(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 110.3 %

Procedure:
To a suspension of 6-octyloxy-2-naphthoic acid (3.15 g, 10.5 mmol) and dicyclohexylcarbodiimide in ethyl acetate (25 ml) at 0° C. was added pentafluorophenol (2.12 g, 11.5 mmol). The mixture was stirred at 25° C. for a period of 18 h. The precipitate was removed by filtration. The filtrate was washed with water (2×150 ml) and brine and dried with magnesium sulfate. Removal of the ethyl acetate in vacuo gave 5.4 g of pentafluorphenyl 6-octyloxy-2-naphthoate as a solid: 1H NMR (400 MHz, CD3OD) δ0.88 (t, 3H, J=6.9 Hz), 4.10 (t, 2H, J=6.6 Hz), 7.16 (d, 1H), 7.21 (d, 1H), 7.80 (d, 1H), 7.87 (d, 1H), 8.08 (dd, 1H), 8.69 (d, 1H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[N:4][N:3]1[C:25](=[S:28])[NH:26][NH2:27].Br[CH2:30][C:31](OC)=[O:32]>CN(C)C=O>[O:32]=[C:31]1[CH2:30][S:28][C:25]([N:3]2[CH:2]([CH3:1])[CH2:8][C:7]3[CH:9]=[C:10]4[O:15][CH2:14][O:13][C:11]4=[CH:12][C:6]=3[C:5]([C:16]3[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=3)=[N:4]2)=[N:26][NH:27]1
Reactant: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1C(=S)NN)OCO3
Reactant: COC(=O)CBr
Solvent: CN(C)C=O
Product: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1C1=NNC(=O)CS1)OCO3
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 37.3 %

Procedure:
A mixture of 1.00 g (2.50 mmol) of the starting material XVIII, 20 ml of dimethylformamide and 0.94 g (6.14 mmol) of methyl bromoacetate was stirred at 70° C. for 1.5 h. After dilution with water the precipitated crystals were filtered off and purified by refluxing in ethyl acetate to yield 0.41 g (37%) of the title compound; Mp.: 294-295° C. (dec.).
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8](OCC)=[O:9])=[N:6][NH:5][C:4](=[S:13])[NH:3]1.[NH3:14]>C(O)C>[O:1]=[C:2]1[C:7]([C:8]([NH2:14])=[O:9])=[N:6][NH:5][C:4](=[S:13])[NH:3]1
Reactant: N
Reactant: CCOC(=O)c1n[nH]c(=S)[nH]c1=O
Solvent: CCO
Product: NC(=O)c1n[nH]c(=S)[nH]c1=O

Procedure:
In 5 mL of ethanol is dissolved 0.1 g of ethyl 5-oxo-3-thioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylate obtained according to the method described in literature (J. Am. Chem. Soc., 1956, 78, 1258-1259). At ambient temperature, gaseous ammonia is introduced into the solution for 30 minutes to saturate the solution with ammonia. After allowing the solution to stand at the same temperature as above for 15 hours, the resulting crystals are collected by filtration. The crystals thus collected are washed with three 5 mL portions of ethanol to obtain 0.05 g of 5-oxo-3-thioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide.
Reaction SMILES: [I:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](OC)=[O:7])=[CH:4][CH:3]=1.O.[NH2:13][NH2:14].O>C(O)C>[I:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:13][NH2:14])=[O:7])=[CH:4][CH:3]=1
Reactant: NN
Reactant: COC(=O)c1ccc(I)cc1
Solvent: O
Solvent: CCO
Product: NNC(=O)c1ccc(I)cc1
Temperature: 25 °C

Procedure:
To Methyl 4-iodobenzoate (30.0 g, 114 mmol) in ethanol (180.0 ml) was added hydrazine hydrate (30.0 g, 599 mmol). The reaction mixture was reflux for 22.5 hours. Heating was stopped and then water (300.0 ml) was added. After cooling down to room temperature, white solid was appeared. The white product solid was collected by filtration. The product was washed with water and dried under vacuum. Final white pure product was obtained in 26.0 g (86.7%). 1H NMR (400 MHz, DMSO-d6, δ): 9.84 (s, 1H, NH), 7.82 (d, J=8.4 Hz, 2H), 7.59 (d, J=8.4 Hz, 2H), 4.50 (s, 2H, NH2).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH:12]([CH3:21])[C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]=1[NH2:11])=[O:5])[CH3:2].[BH4-].[Na+]>CCO>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH:12]([CH3:21])[CH:13]([OH:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]=1[NH2:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnn(C(C)C(=O)c2ccccc2)c1N
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cnn(C(C)C(O)c2ccccc2)c1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.1 %

Procedure:
Compound 1 (0.7 g, 2.43 mmol) was dissolved in 34 mL EtOH. NaBH4 (0.18 g, 4.87 mmol) was added in one shot. The reaction stirred at room temperature for 0.5 h. The solution was quenched with sat. NH4Cl and extracted with CH2Cl2 (3 times). The organic layer was washed with brine, dried (MgSO4), concentrated to give a fluffy white solid 2 (0.69 g, 98% yield). MS: Calcd.: 289. Found: 290 (M+H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:24]C(=O)C)[S:5][C:6]=1[C:7]1[S:8][C:9]([S:12]([NH:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)(=[O:14])=[O:13])=[CH:10][CH:11]=1.Cl.CCO>>[NH2:24][C:4]1[S:5][C:6]([C:7]2[S:8][C:9]([S:12]([NH:15][CH2:16][CH2:17][N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)(=[O:14])=[O:13])=[CH:10][CH:11]=2)=[C:2]([CH3:1])[N:3]=1
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)NCCN3CCOCC3)s2)s1
Agent: Cl
Solvent: CCO
Product: Cc1nc(N)sc1-c1ccc(S(=O)(=O)NCCN2CCOCC2)s1
Temperature: 90 °C
Reaction time: 8 h
Yield: 111 %

Procedure:
To N-[4-methyl-5-(5-{[(2-morpholin-4-ylethyl)amino]sulfonyl}-2-thienyl)-1,3-thiazol-2-yl]acetamide (9) (240 mg; 0.56 mmol; 1 eq) is added hydrochloric acid 1.25 M in EtOH (8.9 ml; 1.25 M; 11.2 mmol; 20 eq). The mixture is stirred overnight at 90° C. The mixture is cooled down to room temperature. The resulting precipitate is filtrated and rinsed with cold EtOH, affording Compound (6) as a yellowish solid (241.5 mg; 94%).
Reaction SMILES: B.[CH3:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([CH3:12])[C:10]=1[OH:11])[C:6]#[N:7].[ClH:13]>O1CCCC1>[ClH:13].[NH2:7][CH2:6][C:5]1[CH:4]=[C:3]([CH3:2])[C:10]([OH:11])=[C:9]([CH3:12])[CH:8]=1
Reactant: Cc1cc(C#N)cc(C)c1O
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: Cc1cc(CN)cc(C)c1O
Temperature: 25 °C

Procedure:
A solution of borane in tetrahydrofuran (27.1 ml of a 1M solution, 27.1 mmol) was added dropwise to a solution of 3,5-dimethyl-4-hydroxybenzonitrile (1.0 g, 6.79 mmol) in tetrahydrofuran (70 ml) and the resulting solution heated to reflux under a nitrogen atmosphere for 16 hours. The reaction was cooled to room temperature and treated with 6N hydrochloric acid (20 ml) and refluxed for a further 30 minutes. The reaction mixture was cooled to room temperature and the solvent removed in vacuo. Purification using strong cation exchange resin, eluting biproducts with methanol followed by 2M ammonia in methanol to elute the product gave the title compound as an orange oil. The oil was treated with 1M hydrogen chrloide in methanol (20 ml) and the solvent removed in vacuo to give the title compound as a pale yellow solid (1.12 g).