Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH3:14])[NH:11][N:10]=2)[C:5]([Cl:15])=[CH:4][N:3]=1.[NH2:16][C:17]1[C:22]([F:23])=[CH:21][C:20]([CH:24]2[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH:26]([CH3:37])[CH2:25]2)=[C:19]([CH3:38])[CH:18]=1.Cl>CC(O)C>[Cl:15][C:5]1[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH3:14])[NH:11][N:10]=2)=[N:7][C:2]([NH:16][C:17]2[CH:18]=[C:19]([CH3:38])[C:20]([CH:24]3[CH2:29][CH2:28][NH:27][CH:26]([CH3:37])[CH2:25]3)=[CH:21][C:22]=2[F:23])=[N:3][CH:4]=1
Reactant: Cc1cc(Nc2nc(Cl)ncc2Cl)n[nH]1
Reactant: Cc1cc(N)c(F)cc1C1CCN(C(=O)OC(C)(C)C)C(C)C1
Agent: Cl
Solvent: CC(C)O
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNC(C)C4)cc3F)ncc2Cl)n[nH]1
Temperature: 130 °C

Procedure:
A mixture of 2,5-dichloro-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (346 mg, 1.42 mmol) and tert-butyl 4-(4-amino-5-fluoro-2-methylphenyl)-2-methylpiperidine-1-carboxylate (352 mg, 1.09 mmol) in 2-propanol (10 mL) was treated with conc. HCl (12N, 0.43 mL). The mixture was sealed and heated in a microwave at 130° C. for 45 min. The mixture was concentrated. The residue was purified by RP-HPLC to afford 5-Chloro-N2-(2-fluoro-5-methyl-4-(2-methylpiperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine as a white solid. ESMS m/z 430.1 (M+H+).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:11](=[O:37])[NH:12][CH:13]2[C:21]3[C:16](=[CH:17][C:18]([C:23]4[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([F:30])[C:24]=4[C:31]4[N:35]=[C:34]([CH3:36])[O:33][N:32]=4)=[CH:19][C:20]=3[F:22])[CH2:15][CH2:14]2)[CH2:10][CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>>[Cl:29][C:27]1[CH:26]=[C:25]([F:30])[C:24]([C:31]2[N:35]=[C:34]([CH3:36])[O:33][N:32]=2)=[C:23]([C:18]2[CH:17]=[C:16]3[C:21](=[C:20]([F:22])[CH:19]=2)[CH:13]([NH:12][C:11]([C:8]2([NH2:7])[CH2:10][CH2:9]2)=[O:37])[CH2:14][CH2:15]3)[CH:28]=1
Reactant: Cc1nc(-c2c(F)cc(Cl)cc2-c2cc(F)c3c(c2)CCC3NC(=O)C2(NC(=O)OC(C)(C)C)CC2)no1
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(-c2c(F)cc(Cl)cc2-c2cc(F)c3c(c2)CCC3NC(=O)C2(N)CC2)no1

Procedure:
In analogy to the procedure described for the preparation of intermediate A-11 [C], (1-{(rac)-5-[5-chloro-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-7-fluoro-indan-1-ylcarbamoyl}-cyclopropyl)-carbamic acid tert-butyl ester (example 31) has been treated with trifluoroacetic acid (90%) to give the title compound as light brown oil. MS: 445.1 (MH+, 1Cl).
Reaction SMILES: [C:1]([C:3]1[C:9]([F:10])=[CH:8][C:6]([NH2:7])=[C:5]([F:11])[CH:4]=1)#[N:2].[C:12](Cl)(Cl)=[S:13]>C1(C)C=CC=CC=1>[C:1]([C:3]1[C:9]([F:10])=[CH:8][C:6]([N:7]=[C:12]=[S:13])=[C:5]([F:11])[CH:4]=1)#[N:2]
Reactant: N#Cc1cc(F)c(N)cc1F
Reactant: S=C(Cl)Cl
Solvent: Cc1ccccc1
Product: N#Cc1cc(F)c(N=C=S)cc1F

Procedure:
10.0 g (65 mmol) of 4-cyano-2,5-difluoro-aniline are introduced into 100 ml of toluene and 8.2 g (71 mmol) of thiophosgene are slowly added to the mixture heated to 80° C. to 90° C. The reaction mixture is then refluxed for approximately 40 hours. Then, after the solvent has been carefully distilled off under reduced pressure, the product (4-cyano-2,5-difluoro-phenyl isothiocyanate) is obtained as an ochre colourant.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH:13]([CH3:17])[CH2:12]2)[S:5][C:6]=1[C:7]([O:9]C)=O.[CH:18]([NH2:20])=O>>[CH3:17][CH:13]1[CH2:12][N:11]([C:4]2[S:5][C:6]3[C:7](=[O:9])[N:20]=[CH:18][NH:1][C:2]=3[N:3]=2)[CH2:16][CH2:15][O:14]1
Reactant: COC(=O)c1sc(N2CCOC(C)C2)nc1N
Reactant: NC=O
Product: CC1CN(c2nc3[nH]cnc(=O)c3s2)CCO1
Temperature: 25 °C
Yield: 73 %

Procedure:
The solution of methyl 4-amino-2-(2-methylmorpholino)thiazole-5-carboxylate (1.4 g, 5.4 mmol) in formamide (5 mL) was stirred at 200° C. for 1.5 hours. The mixture was cooled to ambient temperature. The precipitate was collected through filtration and washed with water to give the desired product (1.0 g, 73%). 1H NMR (300 MHz, d6-DMSO) δ 12.42 (br, 1H), 8.09 (s, 1H), 3.93˜3.82 (m, 3H), 3.61-3.54 (m, 2H), 3.24 (m, 1H), 2.92 (m, 1H), 1.16 (m, 3H); LC-MS: 253 (MH+).
Reaction SMILES: [C:1]1([CH2:7][C:8](=[O:10])[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:11](OCC)=[O:12].[O-]CC.[Na+]>C1COCC1.O>[OH:12]/[CH:11]=[C:7](/[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)\[C:8]([CH3:9])=[O:10]
Reactant: CCOC=O
Reactant: CC(=O)Cc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)/C(=C\O)c1ccccc1

Procedure:
Phenylacetone (Aldrich Chem. Co. 13,538-0; Beilstein 7, 303), XXVIa (101 g, 0.75 mol) was combined with 100 g (1.35 mol) of ethyl formate was added all at once to a suspension of 50 g (0.75 mol) of sodium ethoxide in 500 ml of THF. After 3 hours at room temperature the brown solution was diluted with 400 ml of H2O. Following extraction with benzene to remove unreacted starting material, the aqueous phase was acidified with dilute HCl. The product was extracted with benzene, washed with H2O, dried over MgSO4, and concentrated to give an oil. Distillation gave 39 g (0.24 mol) of (Z)-1-hydroxymethylene-1-phenylacetone, XXVIIIa, as a colorless oil, bp 65- 69° C (0.3 mm).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([SH:12])=[CH:8][CH:7]=1)[CH3:2].N1C=CC=CC=1.Cl[CH2:21][O:22][CH2:23][CH3:24].Cl>C(#N)C.O>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][CH2:21][O:22][CH2:23][CH3:24])=[CH:8][CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(S)cc1
Reactant: CCOCCl
Agent: Cl
Solvent: CC#N
Solvent: c1ccncc1
Solvent: O
Product: CCOCSc1ccc(CC(=O)OCC)cc1
Temperature: 0 °C

Procedure:
A 100 mL 3-necked round bottom flask is charged with (4-mercapto-phenyl)-acetic acid ethyl ester (10 g, 0.0151 mol), followed by the addition of (20 mL) acetonitrile. The reaction mixture is cooled to 0° C. followed by the addition of 10 mL (0.13 mol) of pyridine and 5.30 g (0.056 mol) of chloromethylethyl ether in 10 mL of acetonitrile in a dropwise manner. The reaction mixture is brought to RT followed by heating at reflux for 24 h. The reaction is worked up by evaporating the solvent under vacuum. The residue thus obtained is diluted with water (20 mL) followed by addition of di lute aqueous hydrochloride solution. This is extracted with ethyl acetate (2×100 mL). The organic layer is washed with dilute aqueous hydrochloric acid solution, water and finally with brine. The organic layer is dried over sodium sulfate and evaporated under vacuum to give (4-ethoxymethylsulfanyl-phenyl)-acetic acid ethyl ester as yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:15][C:16](=[O:18])[CH3:17])[CH:7]=[C:8]([N:10]2[CH:14]=[CH:13][CH:12]=[CH:11]2)[CH:9]=1)([O-])=O.[Cl-].[Ca+2].[Cl-]>C(O)C.O.[Fe]>[NH2:1][C:4]1[CH:5]=[C:6]([NH:15][C:16](=[O:18])[CH3:17])[CH:7]=[C:8]([N:10]2[CH:11]=[CH:12][CH:13]=[CH:14]2)[CH:9]=1
Reactant: CC(=O)Nc1cc(-n2cccc2)cc([N+](=O)[O-])c1
Agent: [Fe]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: CC(=O)Nc1cc(N)cc(-n2cccc2)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
To a solution of N-(3-nitro-5-pyrrol-1-yl-phenyl)acetamide (7.51 g, 30.61 mmol) in ethanol (100 ml), were added iron powder (4.273 g, 76.53 mmol, 2.5 eq.) and a solution of calcium chloride (8.49 g, 76.53 mmol, 2.5 eq.) in water (100 ml). The mixture was stirred at 80° C. for 2 h and then filtered through a pad of celite. The celite pad was washed with ethyl acetate (200 ml) and the combined organic layer was washed with water (100 ml) and brine (25 ml). The solvent was evaporated and the residue was purified by column chromatography (20% ethyl acetate in hexanes) to give the compound in 87% yield (5.7 g). 1H NMR (300 MHz, DMSO-d6): δ 9.9 (s, 1H), 8.25 (s, 1H), 7.8 (d, 1H), 7.6 (s, 1H), 7.05 (d, 1H), 6.8 (s, 1H), 6.5 (m, 1H), 6.3 (m, 1H), 5.15 (s, 2H), 2.02 (s, 3H).
Reaction SMILES: [F:1][C:2]1[C:3]([C:22]([OH:24])=O)=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=2)=[N:11][CH:10]=1.[NH2:25][CH2:26][C:27]1([C:40]2[CH:44]=[C:43]([CH3:45])[O:42][N:41]=2)[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]1>>[F:1][C:2]1[C:3]([C:22]([NH:25][CH2:26][C:27]2([C:40]3[CH:44]=[C:43]([CH3:45])[O:42][N:41]=3)[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]2)=[O:24])=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=2)=[N:11][CH:10]=1
Reactant: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)O)c3F)s2)c1
Reactant: Cc1cc(C2(CN)CCN(C(=O)OC(C)(C)C)CC2)no1
Product: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)NCC4(c5cc(C)on5)CCN(C(=O)OC(C)(C)C)CC4)c3F)s2)c1

Procedure:
Following the amide bond forming procedure given in example 37, 3-fluoro-4-(2-(4-methylpyridin-2-ylamino)thiazol-5-ylthio)picolinic acid (intermediate B in example 1) and tert-butyl 4-(aminomethyl)-4-(5-methylisoxazol-3-yl)piperidine-1-carboxylate (amine intermediate “S”) were reacted to give the title compound. LC/MS (M+H)+: 640. Ret. time: 1.89 min. (Condition L).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH:4]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:5]([OH:7])[CH3:6].FS([C:21]([F:26])([F:25])C(O)=O)(=O)=O.O>C(#N)C.C(OCC)(=O)C.[Cu]I>[CH3:1][O:2][C:3](=[O:16])[CH:4]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:5]([O:7][CH:21]([F:26])[F:25])[CH3:6]
Reactant: COC(=O)C(NC(=O)OC(C)(C)C)C(C)O
Reactant: O=C(O)C(F)(F)S(=O)(=O)F
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: COC(=O)C(NC(=O)OC(C)(C)C)C(C)OC(F)F
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 36.1 %

Procedure:
To a mixture of 2-tert-butoxycarbonylamino-3-hydroxy-butyric acid methyl ester (630 mg, 2.70 mmol) and copper(I) iodide (105 mg, 0.55 mmol) in acetonitrile at 45° C. was added a solution of 2-(fluorosulfonyl)difluoroacetic acid (0.560 mL, 5.42 mmol) in acetonitrile (2 mL) by syringe pump over 45 minutes. The reaction was then stirred at 45° C. for 30 minutes. Another solution of 2-(fluorosulfonyl)difluoroacetic acid (0.560 mL, 5.42 mmol) in acetonitrile (2 mL) was added by syringe pump over 45 minutes at 45° C. The reaction was stirred for 30 minutes at 45° C. after the second syringe pump addition was complete. Water was carefully added to quench the reaction, and the mixture was diluted with ethyl acetate. The organic layer was separated, washed with water and brine, dried (MgSO4) and concentrated. The crude material was purified by flash chromatography (10% ethyl acetate/hexanes) to yield 2-tert-butoxycarbonylamino-3-difluoromethoxy-butyric acid methyl ester (276 mg, 36%). 1H-NMR: 400 MHz, (CDCl3: 6.16 (t, JHF=74.0 Hz, 1H), 5.23-5.16 (br, 1H), 4.86-4.80 (m, 1H), 4.40 (br d, J=9.8 Hz, 1H), 3.76 (s, 3H), 1.46 (br s, 9H), 1.36 (d, J=6.4 Hz, 3H) ppm.
Reaction SMILES: [S:1]1[C:5](B(O)O)=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.[Br:13][C:14]1[CH:19]=[CH:18][C:17](I)=[C:16]([F:21])[CH:15]=1.C([O-])(O)=O.[Na+]>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([C:5]2[S:1][C:2]3[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=3[CH:4]=2)=[C:16]([F:21])[CH:15]=1
Reactant: OB(O)c1cc2ccccc2s1
Reactant: Fc1cc(Br)ccc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Fc1cc(Br)ccc1-c1cc2ccccc2s1
Temperature: 80 °C
Yield: 12.8 %

Procedure:
A mixture of Benzo[b]thiophene-2-boronic acid (0.71 g, 4 mmol), 1-bromo-3-fluoro-4-iodobenzene (1 g, 3.3 mmol), bis(triphenylphospine)palladium(II) chloride (46 mg, 2 mol %), NaHCO3 (0.83 g, 9.9 mmol) in DME (4 mL) and H2O (4 mL) was heated to 80° C. under N2 for 72 h. The reaction mixture was partitioned between 1N HCl and EtOAc. The organic layer was washed with saturated NaHCO3, brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography (hexanes) to give the title compound as a white solid (0.13 g, 13%).
Reaction SMILES: [CH3:1][N:2]([CH:10]1[CH2:13][N:12]([C:14]2[C:15]3[N:16]([N:25]=[N:26][N:27]=3)[C:17]([C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)=[CH:18][N:19]=2)[CH2:11]1)C(=O)OC(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:1][NH:2][CH:10]1[CH2:11][N:12]([C:14]2[C:15]3[N:16]([N:25]=[N:26][N:27]=3)[C:17]([C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)=[CH:18][N:19]=2)[CH2:13]1
Reactant: CN(C(=O)OC(C)(C)C)C1CN(c2ncc(-c3cccs3)n3nnnc23)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC1CN(c2ncc(-c3cccs3)n3nnnc23)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 72.3 %

Procedure:
A 2 L round bottom flask was charged with tert-butyl methyl(1-(5-(thiophen-2-yl)tetrazolo[1,5-a]pyrazin-8-yl)azetidin-3-yl)carbamate (50 g, 0.13 mol) and dichloromethane (500 mL). To the solution was added trifluoroacetic acid (100 mL). The resulting slurry was stirred at room temperature for 2.5 h. Work-up: the reaction mixture was concentrated in vacuo. The residue was suspended in water (500 L) and treated with solid Na2CO3 (pH 10-11, there was un-dissolved Na2CO3 remaining). The solid was collected by filtration, re-suspended in water (500 mL×2) with stirring to remove Na2CO3. It was further washed with EtOH (500 mL), and dried to afford 27 g (73%) of the product as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ: 8.19 (s, 1H), 7.96 (dd, J=4.0, 0.8 Hz, 1H), 7.76 (dd, J=4.8, 0.8 Hz, 1H), 7.27 (dd, J=4.8, 4.0 Hz, 1H), 4.60 (br, 2H), 4.18 (br, 2H), 3.73 (m, 1H), 2.43 (br, 1H), 2.29 (s, 3H). MS m/z: 288 (M+H+).
Reaction SMILES: [OH:1][CH:2]([CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([NH:23][C:24]([O:26][CH2:27][CH:28]([CH3:30])[CH3:29])=[O:25])[CH2:19][CH2:18]1)[CH2:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=[O:15])[NH:10]2.[C:31](OC(=O)C)(=[O:33])[CH3:32]>N1C=CC=CC=1>[C:31]([O:1][CH:2]([CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([NH:23][C:24]([O:26][CH2:27][CH:28]([CH3:30])[CH3:29])=[O:25])[CH2:19][CH2:18]1)[CH2:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=[O:15])[NH:10]2)(=[O:33])[CH3:32]
Reactant: CC(C)COC(=O)NC1CCN(CC(O)COc2cccc3c2CCC(=O)N3)CC1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC(COc1cccc2c1CCC(=O)N2)CN1CCC(NC(=O)OCC(C)C)CC1

Procedure:
3,4-Dihydro-5-[2-hydroxy-3-(4-(isobutoxycarbonylamino)-1-piperidyl)propoxy]carbostyril (3 g) was dissolved in pyridine (30 mL) and acetic anhydride (0.9 mL) was added dropwise with stirring. After the addition, the mixture was stirred at room temperature for 12 hours, and the pyridine was then evaporated under reduced pressure. The residue was dissolved in chloroform (100 mL) and the organic solution was washed twice with water (50 mL each) and dried over sodium sulfate. The solvent was then evaporated and the residue recrystallized from isopropyl ether to yield 1.5 g of the title compound, 3,4-dihydro-5-[2-acetyloxy-3-(4-(isobutoxycarbonylamino)-1-piperidyl)propoxy]carbostyril, m.p. 120° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[N:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]2[CH:27]=[CH:26][C:22]3[N:23]=[CH:24][S:25][C:21]=3[CH:20]=2)[CH:13]=1.C(O)(=O)C.[CH:32]1([CH:38]=O)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CCOC(C)=O.ClCCCl>[S:25]1[C:21]2[CH:20]=[C:19]([NH:18][C:14]3[CH:13]=[C:12]([C:3]4[CH:4]=[CH:5][C:6]([C:8]([F:10])([F:11])[F:9])=[CH:7][C:2]=4[NH:1][CH2:38][CH:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)[N:17]=[CH:16][N:15]=3)[CH:27]=[CH:26][C:22]=2[N:23]=[CH:24]1
Reactant: Nc1cc(C(F)(F)F)ccc1-c1cc(Nc2ccc3ncsc3c2)ncn1
Reactant: O=CC1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: FC(F)(F)c1ccc(-c2cc(Nc3ccc4ncsc4c3)ncn2)c(NCC2CCCCC2)c1
Temperature: 0 °C

Procedure:
To a 5-mL, round-bottomed flask was added [6-(2-amino-4-trifluoromethylphenyl)pyrimidin-4-yl]benzothiazol-6-ylamine (0.060 g, 0.15 mmol), 1,2-dichloroethane (1 mL), acetic acid (0.018 mL, 0.31 mmol) and cyclohexanecarboxaldehyde (0.055 mL, 0.45 mmol, Aldrich). Sodium triacetoxy-borohydride (0.083 g, 0.39 mmol, Aldrich) was added to the mixture with stirring at 0° C. and the mixture was stirring for 17 h at room temperature. The reaction mixture was diluted with EtOAc (3 mL) and quenched with H2O (3 mL) and satd NaHCO3 (7 mL). The phases were separated and the aqueous phase was extracted with EtOAc (3×3 mL). The combined organic extracts were washed with brine, dried over Na2SO4 and concentrated in vacuo onto silica gel. Purification by silica gel chromatography with gradient from 20% to 50% solution of EtOAc in hexane afforded the title compound as a yellow solid. MS (ESI, pos. ion.) m/z: 484 (M+1).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23](=[O:31])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[CH3:30])=[CH:18][C:17]=2[O:32][CH3:33])=[CH:5][CH:6]=[C:7]2[C:12]=1[NH:11][C:10](=[O:13])[C:9]([CH3:15])([CH3:14])[NH:8]2.[CH3:34][O:35][C:36]1[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][C:37]=1O.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C1CCN(C(/N=N/C(N2CCCCC2)=O)=O)CC1>O1CCCC1>[CH3:33][O:32][C:17]1[CH:18]=[C:19]([O:22][C:23](=[O:31])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[CH:20]=[CH:21][C:16]=1[C:4]1[C:3]([CH2:2][O:1][C:37]2[CH:38]=[C:39]([N+:42]([O-:44])=[O:43])[CH:40]=[CH:41][C:36]=2[O:35][CH3:34])=[C:12]2[C:7]([NH:8][C:9]([CH3:14])([CH3:15])[C:10](=[O:13])[NH:11]2)=[CH:6][CH:5]=1
Reactant: COc1cc(OC(=O)c2ccccc2C)ccc1-c1ccc2c(c1CO)NC(=O)C(C)(C)N2
Reactant: COc1ccc([N+](=O)[O-])cc1O
Agent: CCCCP(CCCC)CCCC
Agent: O=C(/N=N/C(=O)N1CCCCC1)N1CCCCC1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COc1ccc([N+](=O)[O-])cc1OCc1c(-c2ccc(OC(=O)c3ccccc3C)cc2OC)ccc2c1NC(=O)C(C)(C)N2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 41.2 %

Procedure:
A mixture of 8-hydroxymethyl-7-[2-methoxy-4-(2-methylbenzoyloxy)phenyl]-3,3-dimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference Compound No. 23, 40.1 mg, 0.0898 mmol), 2-methoxy-5-nitrophenol (22.8 mg, 0.135 mmol), and tri n-butylphosphine (33.7 μL, 0.135 mmol) was dissolved in anhydrous tetrahydrofuran (1 mL), 1,1′-(azodicarbonyl)dipiperidine (34.0 mg, 0.135 mmol) was added thereto, and then the mixture was stirred at room temperature. After 20 minutes, 2-methoxy-5-nitrophenol (23.1 mg, 0.137 mmol), tri n-butylphosphine (33.7 μL, 0.135 mmol), and 1,1′-(azodicarbonyl)dipiperidine (33.9 mg, 0.134 mmol) were added thereto, and after 80 minutes, 2-methoxy-5-nitrophenol (22.9 mg, 0.135 mmol), tri-n-butylphosphine (33.7 μL, 0.135 mmol), and 1,1-(azodicarbonyl)dipiperidine (34.0 mg, 0.135 mmol) were added further. The stir was stopped 3 hours later and the reaction mixture was concentrated. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (22.1 mg) as a pale yellow amorphous product. (Yield 41%)
Reaction SMILES: I.[NH:2]([C:4](SC)=[NH:5])[NH2:3].[NH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1>CO>[N:8]1([C:4](=[NH:5])[NH:2][NH2:3])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: C1COCCN1
Reactant: CSC(=N)NN
Agent: I
Solvent: CO
Product: N=C(NN)N1CCOCC1
Temperature: 25 °C

Procedure:
To a solution of methyl hydrazinecarbimidothioate hydroiodide (0.100 g, 0.429 mmol) in MeOH (2 mL) was added morpholine (0.075 mL, 0.858 mmol) and refluxed overnight. Reaction was cool to RT and concentrated to get morpholine-4-carboximidhydrazide as a white solid in quantitative yield.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18](O)=[O:19])[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[NH:23]1[CH2:27][CH2:26][CH2:25][C@H:24]1[C:28]#[N:29]>>[NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([N:23]5[CH2:27][CH2:26][CH2:25][C@H:24]5[C:28]#[N:29])=[O:19])[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1
Reactant: N#C[C@@H]1CCCN1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Product: N#C[C@@H]1CCCN1C(=O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with (S)-pyrrolidine-2-carbonitrile (1.2 equiv) to give 137 (14.2 mg, M+1 392.1)
Reaction SMILES: [Li]CCCC.Br[CH2:7][C:8]1[CH:18]=[CH:17][CH:16]=[C:10]2[C:11]([NH:13][C:14](=[O:15])[C:9]=12)=[O:12]>COCCOC>[CH2:7]=[C:8]1[CH:18]=[CH:17][CH:16]=[C:10]2[C:11]([NH:13][C:14](=[O:15])[CH:9]12)=[O:12]
Reactant: O=C1NC(=O)c2c(CBr)cccc21
Agent: [Li]CCCC
Solvent: COCCOC
Product: C=C1C=CC=C2C(=O)NC(=O)C12
Temperature: -33 °C
Reaction time: 8 h
Yield: 105.5 %

Procedure:
The starting carborane, 1-C6H5-1,2-C2B10H11 1.00 g (4.53 mmol) dried in vacuum, was dissolved in DME (40 ml) in Schlenk-type flask under argon, and the resulting solution was cooled down to −33° C. and BuLi (2.5 M in hexane, Aldrich, 2.0 ml, 5.0 mmol) was added under stirring from a syringe through septum. The reaction slurry was stirred for 15 min. and then left to warm up to room temperature. The reaction mixture was again cooled down and bromomethyl phtalimide 1.20 g (Aldrich, 5.0 mmol) dissolved in v 15 ml of DME was added dropwise from a syringe. The reaction mixture was stirred for 15 min. −33° C. at and then left slowly to warm up to room temperature over 4 h period. After standing overnight, the solids were filtered off under argon, and washed under argon with two portions of DME (10 ml). Diluted acetic acid (3 M, 0.5 ml) was added to the combined DME extracts and volatiles were removed under reduced pressure. A solid residue was dissolved in benzene and poured atop of a silica gel column (3×25 cm). Elution with benzene led to isolation of the starting 1-Ph-carborane (240 mg), continued elution using benzene-CH3CN (4:1, b.v.) solvent mixture afforded the methylene-phtalimide substituted intermediate carborane 0.85 g (49%).
Reaction SMILES: N#N.C(OC([NH:10][C@@H:11]([C:14]([NH:16][CH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:15])[CH2:12][OH:13])=O)(C)(C)C.[ClH:26]>C(O)(=O)C>[ClH:26].[C:20]1([CH2:19][CH2:18][CH2:17][NH:16][C:14](=[O:15])[C@@H:11]([CH2:12][OH:13])[NH2:10])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CO)C(=O)NCCCc1ccccc1
Agent: Cl
Agent: N#N
Solvent: CC(=O)O
Product: N[C@H](CO)C(=O)NCCCc1ccccc1

Procedure:
A solution of N2 -(tert-butyloxycarbonyl)-N-(3-phenylpropyl)-D-serinamide (3.93 g.) in acetic acid saturated with hydrogen chloride (50 ml.) was stirred at room temperature for one half hour, then stripped of volatiles. The residue was purified by column chromatography on silica gel (100-200 mesh, 200 g.) using ethyl acetate-pyridine-acetic acid-water (200:54:16:30) as the eluant, affording N-(3-phenylpropyl)-D-serinamide hydrochloride (1.14 g., m.r. 97°-102° C.).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][S:14]([CH2:17][C:18](NC1N=NN(CCCCCCCCCCCC)N=1)=[O:19])(=[O:16])=[O:15])([CH3:3])[CH3:2].[C:38]1([CH:44]([NH2:51])[C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[CH:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]=1[NH:13][S:14]([CH2:17][C:18]([NH:51][CH:44]([C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:19])(=[O:16])=[O:15])([CH3:11])[CH3:12]
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: CCCCCCCCCCCCn1nnc(NC(=O)CS(=O)(=O)Nc2c(C(C)C)cccc2C(C)C)n1
Product: CC(C)c1cccc(C(C)C)c1NS(=O)(=O)CC(=O)NC(c1ccccc1)c1ccccc1

Procedure:
This compound was prepared in the same manner as for the title compound of Example 2, except that 2-DAT was replaced with diphenylmethylamine, mp 166°-167° C.