Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:8])[CH2:3][CH2:4][C:5]([OH:7])=O.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C.Cl.[S:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[C:34]1[N:38]=[C:37]([CH:39]2[CH2:44][CH2:43][NH2+:42][CH2:41][CH2:40]2)[O:36][N:35]=1>ClCCl>[CH3:8][CH:2]([CH3:1])[CH2:3][CH2:4][C:5]([N:42]1[CH2:43][CH2:44][CH:39]([C:37]2[O:36][N:35]=[C:34]([C:30]3[S:29][CH:33]=[CH:32][CH:31]=3)[N:38]=2)[CH2:40][CH2:41]1)=[O:7]
Reactant: c1csc(-c2noc(C3CC[NH2+]CC3)n2)c1
Reactant: CC(C)CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)CCC(=O)N1CCC(c2nc(-c3cccs3)no2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 83.4 %

Procedure:
86 mg (2 eq.) of 4-methylvaleric acid, 141 mg (2 eq.) of 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride (EDCI) and 207 μl (4 eq.) of triethylamine were dissolved in 2 ml of dichloromethane. 100 mg (1 eq.) of 4-(3-thiophen-2-yl[1,2,4]oxadiazol-5-yl)piperidinium hydrochloride were then added to the reaction medium, which was then stirred at room temperature for 24 hours. The reaction medium was evaporated under reduced pressure and the residue was taken up in 20 ml of ethyl acetate. The organic phase was washed with aqueous 1N sodium hydroxide solution (3×30 ml), with aqueous 1N hydrochloric acid solution (3×30 ml) and with saturated aqueous NaCl solution (30 ml) and then dried over MgSO4 and concentrated under reduced pressure to give 102 mg (83%) of the expected compound.
Reaction SMILES: [C:1]([CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][O:17][C:18](=[O:29])[C@H:19]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)[NH2:20].O>[Pd].C1(OC)C=CC=CC=1>[CH3:16][O:17][C:18](=[O:29])[C@@H:19]([NH:20][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:1](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1
Reactant: O=C1CCCCC1C(=O)c1ccccc1
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Agent: [Pd]
Solvent: COc1ccccc1
Solvent: O
Product: COC(=O)[C@H](Cc1ccc(O)cc1)Nc1ccccc1C(=O)c1ccccc1
Temperature: 80 °C
Reaction time: 48 h
Yield: 59.3 %

Procedure:
A stirred mixture of 92 g (0.45 mol) 2-benzoyl-cyclohexanone, (Denny, W. A. et. al. J. Med. Chem. 1978, 21(5), 430-7) 78 g (0.40 mol) L-Tyrosine methyl ester, 17.0 g Palladium on activated carbon (10%) was refluxed for 2 h in 1 L anisole while the resulting water was removed by a Dean-Stark apparatus. The mixture was cooled to 80° C. and the Pd/C was filtered, and washed with 50 mL anisole three times. The mixture was cooled to 40° C., 1 L hexane was added and kept at −20° C. for 48 h. The solid was filtered, washed with 200 mL hexane five times to yield 89.0 g crude (S)-2-(2-Benzoyl-phenylamino)-3-(4-hydroxy-phenyl)-propionic acid methyl ester. This solid was mixed with 220 mL of MeOH, and the slurry was refluxed for 30 min. The mixture was cooled to 0° C., the product was filtered and washed with 50 mL cold (−20° C.) MeOH twice, then dried under reduced pressure to yield 67.4 g the of the title compound. mp 185-6° C.; low resolution MS (ESP+) m/e 376 (MH+).
Reaction SMILES: Cl[CH:2]([CH2:6][CH2:7][Cl:8])[C:3](=[O:5])[CH3:4].[C:9]([S-:11])#[N:10].[K+]>CC(C)=O>[S:11]([CH:2]([CH2:6][CH2:7][Cl:8])[C:3](=[O:5])[CH3:4])[C:9]#[N:10]
Reactant: CC(=O)C(Cl)CCCl
Reactant: N#C[S-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)C(CCCl)SC#N
Temperature: 25 °C
Reaction time: 4 h
Yield: 70 %

Procedure:
77.8 g (0.5 moles) of 3,5-dichloro-2-pentanone [prepared according to Acta Chim. Hung. 3, 157 (1953)] are added to the solution of 49.9 g (0.513 moles) of potassium rhodanide in 500 ml of acetone. The solution is boiled under stirring for 4 hours. The reaction mixture is cooled to room temperature and the precipitated potassium chloride is filtered off and washed with acetone. The filtrate is evaporated, the residue is dissolved in benzene and the benzene solution is washed 3 times with water. After drying with sodium sulphate, the benzene is distilled off. 62.2 g (93%) of 3-thiocyanato-5-chloro-2-pentanone are obtained in the form of a red oil. After distilling at a lower pressure a faint yellow oil is obtained, its boiling point is 112° C. at a pressure of 26.6 Pa, nD20 =1.5110. According to infrared spectrum it does not contain any isothiocyanate.
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]([I:20])[CH:17]=[CH:16][C:3]=1[NH:4][C:5]1[C:6]([C:13]([OH:15])=O)=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1.[NH2:21][O:22][CH2:23][CH2:24][OH:25].C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>CO.C1COCC1>[F:1][C:2]1[CH:19]=[C:18]([I:20])[CH:17]=[CH:16][C:3]=1[NH:4][C:5]1[C:6]([C:13]([NH:21][O:22][CH2:23][CH2:24][OH:25])=[O:15])=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1
Reactant: Cn1cc(C(=O)O)c(Nc2ccc(I)cc2F)cc1=O
Reactant: NOCCO
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CO
Solvent: C1CCOC1
Product: Cn1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)cc1=O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a mixture of 4-(2-fluoro-4-iodoanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylic acid (130 mg, 0.34 mmol) and 2-(aminooxy)ethanol [prepared by the literature procedure: Dhanak, D.; Reese, C. B., J. Chem. Soc., Perkin Trans. 1, 1987; 2829] (52 mg, 0.67 mmol) in MeOH/THF (1:1, 20 mL) was added DMT-MM (187 mg, 0.67 mmol) and the mixture stirred at R.T. for 15 h. The reaction solvent was removed under reduced pressure and the oily residue partitioned between water (100 mL) and EtOAc (100 mL). The EtOAc fraction was then washed with water (2×100 mL) and brine (100 mL), dried (Na2SO4) and the solvent removed under reduced pressure. This afforded a cream solid which was purified by recrystallisation from EtOAc/MeOH to give 4-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide as a white, crystalline solid (83 mg, 55%), m.p. (EtOAc/MeOH) 148-151° C. 1H NMR [(CD3)2SO, 400 MHz] δ 11.65 (v br s, 1H), 9.48 (br s, 1H), 8.13 (s, 1H), 7.74 (dd, J=10.2, 1.8 Hz, 1H), 7.58 (br d, J=8.6 Hz, 1H), 7.28 (t, J=8.5 Hz, 1H), 5.55 (s, 1H), 4.76 (v br s, 1H), 3.90 (t, J=4.9 Hz, 2H), 3.61 (t, J=4.9 Hz, 2H), 3.36 (s, 3H). Anal. Calcd for C15H15FIN3O4: C, 40.3; H, 3.4; N, 9.4. Found: C, 40.6; H, 3.6; N, 9.1.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[Cl:19][C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=1/[CH:27]=[CH:28]/[C:29](O)=[O:30]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:29](=[O:30])/[CH:28]=[CH:27]/[C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([Cl:26])[C:20]=3[Cl:19])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Reactant: O=C(O)/C=C/c1cccc(Cl)c1Cl
Product: CC(=O)c1ccc(Cn2cc(NC(=O)/C=C/c3cccc(Cl)c3Cl)cn2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and (E)-3-(2,3-dichloro-phenyl)-acrylic acid.
Reaction SMILES: Cl[CH2:2][C:3](=[O:5])[CH3:4].C([O-])(O)=O.[Na+].[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([SH:18])=[CH:14][CH:13]=1.O>CN(C=O)C>[C:12]1([CH3:11])[CH:17]=[CH:16][C:15]([S:18][CH2:2][C:3](=[O:5])[CH3:4])=[CH:14][CH:13]=1
Reactant: Cc1ccc(S)cc1
Reactant: CC(=O)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)CSc1ccc(C)cc1
Temperature: 55 °C
Reaction time: 1 h
Yield: 80.6 %

Procedure:
Chloroacetone (11.6 g, 125 mmol) and NaHCO3 (12.6 g, 150 mmol) were added to a solution of 4-methylthiophenol (10 g, 80.5 mmol) in dry DMF (50 mL). The mixture was stirred at 50-60° C. for 1 h. The cooled reaction mixture was poured into water (200 mL) and extracted with EtOAc (2×50 mL). The combined organic extracts were dried with K2CO3, evaporated to dryness and the residue was distilled (b.p. 145-148° C./12 mm) to give 11.7 g of 1-(p-tolyl sulfanyl)propan-2-one (81%).
Reaction SMILES: [SH:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]1C(=O)C2=CC=CC=C2C1=O>CN(C=O)C>[O:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[S:1][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH2:26]
Reactant: Sc1nc2ccccc2o1
Reactant: O=C1c2ccccc2C(=O)N1CCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NCCCCCCCCSc1nc2ccccc2o1
Temperature: 60 °C

Procedure:
To a round bottom flask with 2-mercaptobenzoxazole (2.14 g, 14.2 mmol) and DMF (100 mL) at room temperature was added K2CO3 (2.61 g, 18.9 mmol) followed by N-(8-bromooctyl)phthalimide (4.00 g, 11.8 mmol). The resulting solution was heated to 60° C. for 0.5 h and then cooled back to room temperature. At this point, the reaction mixture was quenched with H2O (100 mL) and then diluted with EtOAc (600 mL). The organic layer was washed with 1 N HCl (60 mL), sat. aq. NaHCO3 (60 mL), and brine (60 mL) and then dried (MgSO4). After concentration, the residue was purified by the Biotage Flash 40 apparatus (10 to 20% EtOAc/petroleum ether gradient) to afford the thioether intermediate.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][N:6]1[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:9]([OH:16])[C:8]([OH:17])=[C:7]1[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH3:2].Br[CH2:25][CH2:26][CH2:27]Br.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][N:6]1[C:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:8]2[O:17][CH2:25][CH2:26][CH2:27][O:16][C:9]2=[C:10]1[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH3:2]
Reactant: BrCCCBr
Reactant: CCOC(=O)Cn1c(C(=O)OCC)c(O)c(O)c1C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cn1c(C(=O)OCC)c2c(c1C(=O)OCC)OCCCO2
Temperature: 105 °C
Reaction time: 12 h
Yield: 83.3 %

Procedure:
To a 500-mL round-bottom flask containing a stir bar and an argon atmosphere was added diethyl 1-(2-ethoxy-2-oxoethyl)-3,4-dihydroxy-1H-pyrrole-2,5-dicarboxylate (48.00 g, 146 mmol), 1,3-dibromopropane (29.48 g, 146 mmol), anhydrous potassium carbonate (50.36 g, 364 mmol), and anhydrous dimethylformamide (DMF) (250 mL). The reaction was heated to 105° C. and became lime green after about 30 minutes. The reaction was stirred for 12 hours, during which, it became yellow, and was cooled to room temperature. The mixture was poured into DI water (500 mL), the solids were collected via vacuum filtration, and washed with several portions of DI water. The solids were recrystallized from hot methanol to yield 44.90 g (80%) of a yellow solid. mp 139.7-139.9° C.; 1H NMR (300 MHz, CDCl3): δ 5.43 (s, 2H), 4.30 (q, 4H, J=7.7 Hz), 4.22 (q, 2H, J=8.0 Hz), 4.20 (t, 6H, J=63 Hz), 2.25 (p, 2H, J=6.3 Hz), 1.34 (t, 6H, J=7.7 Hz), 1.28 (t, 3H, J=8.0 Hz); 13C NMR (75 MHz, CDCl3): δ 169.6, 161.0, 142.7, 114.1, 71.7, 61.5, 60.9, 48.0, 33.4, 14.5, 14.4; HRMS (EI): Calcd for C17H23NO8 ([M]+), 369.1424, found m/z, 369.1417; Anal. Calcd for C17H23NO8: C, 55.28; H3, 6.28; N, 3.79%, found: C, 55.29; H, 6.37; N, 3.80
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:24]C2CCCCC2)[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.[CH3:31][N:32]([CH3:44])[C:33]([C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1)=[O:34]>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].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>[NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:14](=[CH:13][CH:12]=[C:11]([C:38]4[CH:39]=[CH:40][C:35]([C:33]([N:32]([CH3:44])[CH3:31])=[O:34])=[CH:36][CH:37]=4)[CH:10]=3)[O:9][CH:8]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:7]2)[N:6]=1
Reactant: CN(C)C(=O)c1ccc(B(O)O)cc1
Reactant: NC1=NC2(CC(c3ccccc3)Oc3ccc(Br)cc32)C(=O)N1CC1CCCCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN(C)C(=O)c1ccc(-c2ccc3c(c2)C2(CC(c4ccccc4)O3)N=C(N)N(C)C2=O)cc1
Temperature: 120 °C
Yield: 33.7 %

Procedure:
Pd(PPh3)2Cl2 (10 mg) in a 10 mL tube under Ar was treated sequentially with 2′-amino-6-bromo-1′-(cyclohexylmethyl)-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 4-(dimethylcarbamoyl)phenylboronic acid (20.1 mg, 0.104 mmol). The mixture was heated at 120° C. in a microwave reactor for 0.5 h. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC to give pure 4-(2′-amino-1′-methyl-5′-oxo-2-phenyl-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)-N,N-dimethylbenzamide (7.97 mg, 34%). 1H-NMR (MeOD): 2.07 (m, 1H), 2.24 (m, 1H), 3.00 (m, 6H), 3.11 (m, 3H), 5.22 (d, 0.3H), 5.86 (d, 0.7H), 6.97 (m, 1H), 7.18 (m, 1H), 7.28 (m, 1H), 7.34 (m, 2H), 7.39 (m, 4H), 7.46 (m, 1H), 7.54 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([N:16](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[C@@H:13]([OH:31])[C@H:12]2[OH:32])=[C:4]([NH:33][CH2:34][CH:35]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:3]=1.[C:48]([OH:54])([C:50]([F:53])([F:52])[F:51])=[O:49]>C(Cl)Cl>[F:51][C:50]([F:53])([F:52])[C:48]([OH:54])=[O:49].[NH2:16][C@H:14]1[CH2:15][C@@H:11]([N:8]2[CH:7]=[N:6][C:5]3[C:9]2=[N:10][C:2]([Cl:1])=[N:3][C:4]=3[NH:33][CH2:34][CH:35]([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C@H:12]([OH:32])[C@@H:13]1[OH:31]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(1R,2S,3R,5S)-3-[2-Chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-5-(di-Boc-amino)-cyclopentane-1,2-diol (10.3 g, 15.50 mmol) is dissolved in DCM (50 mL). TFA (25 mL) is added and the reaction mixture is stirred at RT. The reaction is shown to be complete by LCMS after 2 hours. The solvent is removed in vacuo to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8](Br)[CH:9]=[C:10]([C:11]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:12])[N:6]2[N:5]=[CH:4][N:3]=1.[C:19]([O:23][C:24]([NH:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)=[O:25])([CH3:22])([CH3:21])[CH3:20].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[NH2:1][C:2]1[C:7]2=[C:8]([C:30]3[CH:29]=[CH:28][C:27]([NH:26][C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:25])=[CH:32][CH:31]=3)[CH:9]=[C:10]([C:11]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:12])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(B(O)O)cc1
Reactant: CCCCOC(=O)c1cc(Br)c2c(N)ncnn12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CN(C)C=O
Product: CCCCOC(=O)c1cc(-c2ccc(NC(=O)OC(C)(C)C)cc2)c2c(N)ncnn12
Temperature: 80 °C
Yield: 26.3 %

Procedure:
A mixture of butyl 4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazine-7-carboxylate (456.0 mg, 1.46 mmol), {4-[(tert-butoxycarbonyl)amino]phenyl}boronic acid (517.8 mg, 2.18 mmol), 2 M aqueous sodium carbonate solution (2.2 mL, 4.40 mmol), and tetrakis(triphenylphosphine)palladium(0) (168.3 mg, 0.15 mmol) in 1,2-dimethoxyethane (11 mL) was heated (80° C.) overnight. The reaction mixture was diluted with DMF and purified by HPLC using a gradient of 30-95% of MeCN in water to give 163.2 mg (26%) of the title compound as a white solid. 1H-NMR (DMSO-d6) δ 9.52 (s, 1 H), 8.08 (bs, 1 H), 8.06 (s, 1 H), 7.56 (d, J=8.6 Hz, 2 H), 7.35 (d, J=8.6 Hz, 2 H), 7.18 (s, 1 H), 5.67 (bs, 1 H), 4.25 (t, J=6.5 Hz, 2 H), 1.71-1.64 (m, 2 H), 1.47-1.37 (m, 2 H), 0.93 (t, J=7.4, 3 H); MS [M+H]+=426.2; LCMS RT=3.43 min.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[N:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.[CH2:17]([NH2:21])[CH2:18][CH2:19][CH3:20]>C(O)(C)(C)C>[CH2:17]([NH:21][C:3]([NH:2][CH3:1])=[N:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)[CH2:18][CH2:19][CH3:20]
Reactant: CCCCN
Reactant: CN=C=Nc1ccccc1N1CCOCC1
Solvent: CC(C)(C)O
Product: CCCCNC(=Nc1ccccc1N1CCOCC1)NC

Procedure:
A mixture of N-methyl-N'-(2-morpholinophenyl)carbodiimide (1 g), n-butylamine (0.5 g) and t-butanol (5 ml) was heated at 90°-95° C. for four hours. The solvent was removed by evaporation and the residue dissolved in dichloromethane (100 ml) and the resulting solution was washed with water, dried and filtered. Removal of the solvent gave 1-(n-butyl)-2-(2-morpholinophenyl)- 3-methylguanidine which was converted into its monofumarate salt (m.p. 178°-179° C..).
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[C:5](=[C:7]([C:19]#[N:20])[C:8]([CH3:18])=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10]=2[F:11])[N:6]=1.C(N(C(C)C)CC)(C)C.[NH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>ClCCl>[F:11][C:10]1[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:8]([CH3:18])[C:7]([C:19]#[N:20])=[C:5]2[C:4]=1[O:3][C:2]([N:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)=[N:6]2
Reactant: C1CCNCC1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(Cl)nc2c1C#N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(-c2ccccc2)c(F)c2oc(N3CCCCC3)nc2c1C#N
Yield: 89.5 %

Procedure:
2-Chloro-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-4-cabonitrile (I-130) (0.20 g, 0.70 mmol) was dissolved in dichloromethane (10 ml), and diisopropylethylamine (0.15 ml, 0.88 mmol) and piperidine (83.0 μl, 0.84 mmol) were added. This was heated under reflux for 3 hours, and diluted with dichloromethane. After washing with water and drying over anhydrous sodium sulfate, the solvent was evaporated away under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane) to obtain a colorless solid (0.21 g, 90%).
Reaction SMILES: [O:1]=[C:2]1[CH2:9][CH:8]2[CH:4]([CH2:5][C:6](C(OCC)=O)([C:10]([O:12][C:13](C)(C)[CH3:14])=[O:11])[CH2:7]2)[CH2:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:1]=[C:2]1[CH2:3][CH:4]2[CH:8]([CH2:7][CH:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:5]2)[CH2:9]1
Reactant: CCOC(=O)C1(C(=O)OC(C)(C)C)CC2CC(=O)CC2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1CC2CC(=O)CC2C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 2-tert-butyl 2-ethyl 5-oxohexahydropentalene-2,2(1H)-dicarboxylate (0.8 g, 2.70 mmol) in DCM (4 mL) was added TFA (2.080 mL) and the reaction mixture was stirred at rt for 4 h. The reaction mixture was evaporated to dryness and the residue was dissolved in pyridine (5 mL) and heated to reflux for 4 h until decarboxylation was complete. Pyridine was evaporated and the residue was purified by silica gel chromatography (10% EtOAC in DCM) to afford ethyl 5-oxooctahydropentalene-2-carboxylate (a mixture of endo/exo isomers) as a clear oil. 1H NMR (500 MHz, CDCl3) δ ppm 4.10-4.18 (2H, m), 2.85-3.02 (2H, m), 2.69-2.80 (1H, m), 2.44-2.56 (2H, m), 2.20-2.36 (2H, m), 2.10-2.20 (1H, m), 2.04 (1H, dd, J=19.45, 4.65 Hz), 1.66-1.80 (2H, m), 1.22-1.31 (3H, m).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[CH2:12]([O:14][C:15](=[O:22])[CH:16]=[C:17]([N:19]([CH3:21])[CH3:20])[NH2:18])[CH3:13]>C(O)C>[CH2:12]([O:14][C:15]([C:16]1[CH:7]([C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH:16]([C:15]([O:14][CH2:12][CH3:13])=[O:22])[C:17]([N:19]([CH3:20])[CH3:21])=[N:18][C:17]=1[NH2:18])=[O:22])[CH3:13]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: CCOC(=O)C=C(N)N(C)C
Solvent: CCO
Product: CCOC(=O)C1=C(N)N=C(N(C)C)C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1

Procedure:
After boiling a solution of 7.5 g of 3-nitrobenzaldehyde and 15.8 g of N,N-dimethyl-3,3-diaminoacrylic acid ethyl ester in 150 ml of ethanol for 4 hours, the solution was concentrated in vacuo. On triturating the resulting oil with ether, filtering off the crystals which separated out and crystallizing these from isopropanol, the yellow-orange colored crystals of 2-amino-6-dimethylamino-4-(3'-nitrophenyl)-4,5-dihydropyridine-3,5-dicarboxylic acid diethyl ester, of melting point 149° C, were obtained. Yield, 61% of theory.
Reaction SMILES: [CH3:1][NH:2][C:3](=[S:6])[NH:4][NH2:5].[C:7](O)(=O)[C:8]([CH3:11])([CH3:10])[CH3:9].P(Cl)(Cl)(Cl)=O.Cl>O1CCOCC1>[C:8]([C:11]1[S:6][C:3]([NH:2][CH3:1])=[N:4][N:5]=1)([CH3:10])([CH3:9])[CH3:7]
Reactant: CNC(=S)NN
Reactant: CC(C)(C)C(=O)O
Agent: Cl
Solvent: C1COCCO1
Solvent: O=P(Cl)(Cl)Cl
Product: CNc1nnc(C(C)(C)C)s1
Yield: 80 %

Procedure:
To a solution of 91.6 g of 4-methylthiosemicarbazide and 102.3 g of pivalic acid in 400 ml of dioxane at 90° is added slowly 160.5 g of phosphorus oxychloride at such a rate that the reaction temperature is maintained at 85°-90° C. without external heating. When the addition is complete, the mixture is heated at 85°-90° C until HCl evolution ceases (several hours), is cooled and the supernatant liquid decanted from the solid mass in the flask. The mass is broken up, slurried with 700 ml of water and made basic (pH 8-9) by the slow addition of sodium hydroxide pellets. The resulting precipitate is filtered, washed with water, air dried and recrystallized from hexane to give 119.4 g (80% yield) of 2-tert.butyl-5-methylamino-1,3,4-thiadiazole, m.p. 79°-81°.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Br:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][C:28]=1[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:31][CH:30]=1)[N:25](COCC[Si](C)(C)C)[N:24]=[C:23]2[NH:51][C:52](=[O:56])[CH2:53][CH2:54][CH3:55].C(OCC)(=O)C>O1CCCC1>[Br:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][C:28]=1[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:31][CH:30]=1)[NH:25][N:24]=[C:23]2[NH:51][C:52](=[O:56])[CH2:53][CH2:54][CH3:55]
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(-c3ccc(OCc4ccccc4)cc3)c(Br)cc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCC(=O)Nc1n[nH]c2cc(-c3ccc(OCc4ccccc4)cc3)c(Br)cc12
Yield: 32 %

Procedure:
20 cm3 of tetrabutylammonium fluoride as a 1M solution in tetrahydrofuran are added to 2 g of N-[5-bromo-6-[4-(phenylmethoxy)phenyl]-1-[[2-(trimethylsilyl)ethoxy]-methyl]-1H-indazol-3-yl]butanamide, described previously, in 60 μm3 of tetrahydrofuran, and the mixture is refluxed for 18 hours; after cooling, 75 cm3 of ethyl acetate are added and the organic phase is washed successively with 75 cm3 of saturated sodium hydrogen carbonate solution and with 75 cm3 of saturated sodium chloride solution. The organic phase is separated out after settling of the phases has taken place, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa; 50° C.) to give 2 g of crude product, which is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 3.5 cm), eluting with a cyclohexane/ethyl acetate mixture (70/30 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.) and the residue is taken up in 50 cm3 of diisopropyl ether, filtered off, washed with 2×10 cm3 of diisopropyl ether and dried (90 Pa; 45° C.) to give 500 mg of N-[5-bromo-6-[4-(phenylmethoxy)phenyl]-1H-indazol-3-yl]butanamide in the form of a solid melting at 20° C.
Reaction SMILES: [C:1]1(=[O:8])[O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:9]([OH:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[OH:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:16][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7]
Reactant: O=C1CCCCCO1
Reactant: OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: O=C(CCCCCO)OCc1ccccc1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A mixture of ε-caprolactone (a) (40 g), benzyl alcohol and p-toluenesulfonic acid monohydrate (0.7 g) was stirred at 100° C. for 16 hours. The reaction mixture was treated in the conventional manner and was distilled under reduced pressure (1 mmHg, 140°-154° C.) to give the title compound (b).