Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[H-].[Na+].Br[CH:16]1[CH2:21][CH2:20][CH2:19][CH:18]=[CH:17]1>CN(C=O)C>[Cl:1][C:2]1[N:3]([CH:21]2[CH2:20][CH2:19][CH2:18][CH:17]=[CH:16]2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: O=Cc1c(Cl)[nH]c2ccccc12
Reactant: BrC1C=CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1c(Cl)n(C2C=CCCC2)c2ccccc12
Temperature: 40 °C
Reaction time: 0.33 h
Yield: 39.2 %

Procedure:
To a solution of 2-chloro-1H-indole-3-carbaldehyde (2.00 g, 11.1 mmol) in DMF (15 ml) was added sodium hydride (468 mg, 11.7 mmol, 60% dispersion in mineral oil). Under an argon atmosphere, the suspension was stirred at 40° C. for 20 min and then allowed to cool to room temperature. After the addition of 3-bromocyclohexene (2.56 ml, 22.3 mmol) the reaction mixture was stirred at room temperature for 1 h. The mixture was then quenched with water and extracted with EA. The organic layer was separated, dried over sodium sulfate, filtered and evaporated. The residue was and purified by silica gel chromatography (EA/HEP 1:10). 1.13 g of the title compound were obtained.
Reaction SMILES: C(OC([NH:8][C:9]([NH:32]C(OC(C)(C)C)=O)=[N:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[C:22]([CH2:23][O:24][Si](C(C)(C)C)(C)C)=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:12]=1)=O)(C)(C)C.[ClH:40]>ClCCl.O1CCOCC1>[ClH:40].[ClH:40].[OH:24][CH2:23][C:22]1[C:17]([C:13]2[CH:12]=[C:11]([NH:10][C:9]([NH2:32])=[NH:8])[CH:16]=[CH:15][CH:14]=2)=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)NC(=Nc1cccc(-c2ncccc2CO[Si](C)(C)C(C)(C)C)c1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: N=C(N)Nc1cccc(-c2ncccc2CO)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of N,N′-bis(tert-butoxycarbonyl)-N″-(3-(3-tert-butyldimethylsilyloxymethylpyridin-2-yl)phenyl)guanidine (300 mg) in dichloromethane (3 ml) was added a solution of hydrogen chloride in 1,4-dioxane (4N, 6 ml), and the mixture was stirred at room temperature for 24 hours. The solvent was evaporated under reduced pressure. To the residue was added 5% ethanol in ethyl acetate (100 ml), and the precipitate was collected by filtration and dried under reduced pressure to give 3-(3-hydroxymethylpyridin-2-yl)-phenylguanidine dihydrochloride (1I40 mg).
Reaction SMILES: [Cl:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]([NH:6][C@@H:7]2[CH2:11][C@H:10]([CH2:12][OH:13])[CH:9]=[CH:8]2)=[C:4]([N+:17]([O-])=O)[CH:3]=1.O.[CH2:21](O)C>[Fe].O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Fe+2]>[Cl:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]2[N:6]([C@@H:7]3[CH2:11][C@H:10]([CH2:12][OH:13])[CH:9]=[CH:8]3)[CH:21]=[N:17][C:4]=2[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)cc1N[C@H]1C=C[C@@H](CO)C1
Reactant: CCO
Agent: [Fe+2]
Agent: [Fe]
Agent: O=S(=O)([O-])[O-]
Solvent: O
Product: OC[C@@H]1C=C[C@H](n2cnc3cc(Cl)c(Cl)cc32)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 82 %

Procedure:
(±)-cis-[4-(4,5-Dichloro-2-nitroanilino)-2-cyclopenten-1-yl]methanol (5.00 g, 16.5 mmol) in ethanol (100 mL)-water (35 mL) was heated while iron powder (325 mesh, 99.9%, Aldrich, 9.2 g, 0.165 equiv) and iron(II) sulfate heptahydrate (Aldrich, 98+%, 2.3 g, 8.2 mequiv) were added. The mixture was refluxed 1.75 hours. Solids were filtered off and the ethanol filtrate-wash concentrated to an oil. Triethylorthoformate (75 mL) and methanesulfonic acid (0.05 mL) were added to the oil and the resulting solution stirred at ambient temperature for 18 hours. Concentration in vacuo left an oil which was redissolved in 1N hydrochloric acid (25 mL)-dioxane(5 mL). After 3 hours, the pH was adjusted to 7 with 1N sodium hydroxide and the solution extracted with chloroform (3×50 mL). The contents of the dried (sodium sulfate) chloroform solution was chromatographed on silica gel. Title compound was eluted with 5% methanol-chloroform and crystallized from ethyl acetate-hexanes to give white crystals (3.85 g, 82%), m.p. 166°-169° C.; 1H-NMR(DMSO-d6) and mass spectrum(CI) consistent with structure.
Reaction SMILES: C(N[C:6]1[CH:7]=[C:8]([CH:10]=[CH:11][CH:12]=1)[NH2:9])(=O)CC.[C:13](NC1C=C(C=CC=1)N)(=[O:17])CCC.C(NC1C=C(C=CC=1)N)(=O)C1C=CC=CC=1>>[NH2:9][C:8]1[CH:7]=[C:6]([O:17][CH3:13])[CH:12]=[CH:11][CH:10]=1
Reactant: CCCC(=O)Nc1cccc(N)c1
Reactant: CCC(=O)Nc1cccc(N)c1
Agent: Nc1cccc(NC(=O)c2ccccc2)c1
Product: COc1cccc(N)c1

Procedure:
m-propionylaminoaniline, m-butyrylaminoaniline or m-benzoylaminoaniline;
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[S:13][CH:14]=[C:15]([CH3:17])[N:16]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Br:18]N1C(=O)CCC1=O>CN(C)C=O>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:7][CH2:8][C@H:9]([C:12]2[S:13][C:14]([Br:18])=[C:15]([CH3:17])[N:16]=2)[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)[C@H]1CC[C@H](c2nc(C)cs2)CC1
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H]1CC[C@H](c2nc(C)c(Br)s2)CC1

Procedure:
A solution of cis/trans-4-(4-methyl-thiazol-2-yl)-cyclohexanecarboxylic acid ethyl ester (1:5) (319 mg, 1.26 mmol) and N-bromosuccinimide (247 mg, 1.38 mmol) in N,N-dimethylformamide (1.6 ml) was stirred for 1 h at room temperature. The reaction mixture was partitioned between tert-butyl methyl ether (25 ml) and 0.1 M aqueous sodium hydroxide solution (25 ml). The layers were separated. The aqueous layer was extracted with two 25-ml portions of tert-butyl methyl ether. The combined organic layers were washed with two 25-ml portions of water, dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude title compound (371 mg, 89%) as light yellow solid, which was used in the next step without further purification. MS m/e: 334 ([M+H]+)
Reaction SMILES: [C:1]1([C:7]2[CH:13]=[C:12](Br)[CH:11]=[CH:10][C:8]=2[NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15]([O:19][C:20](=[O:24])[CH2:21][CH:22]=[CH2:23])([CH3:18])([CH3:17])[CH3:16].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(C(C)C)CC)(C)C>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:9][C:8]1[CH:10]=[C:11](/[CH:23]=[CH:22]/[CH2:21][C:20]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:24])[CH:12]=[CH:13][C:7]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=CCC(=O)OC(C)(C)C
Reactant: Nc1ccc(Br)cc1-c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C/C=C/c1ccc(-c2ccccc2)c(N)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 78.8 %

Procedure:
2-Phenyl-4-bromoaniline (564.7 mg, 2.28 mmol) was dissolved in N,N-dimethylformamide (25 mL) and, at room temperature, thereto were added tert-butyl-3-butenoate (582.5 mg, 4.10 mmol), tri-(o-tolyl)phosphine (1.87 g, 6.16 mmol), and diisopropylethylamine (0.78 mL, 4.56 mmol). The reaction mixture was deaerated, palladium acetate (67.4 mg, 0.30 mmol) was added, and the mixture was deaerated again. After stirring at 90° C. overnight, the reaction mixture was filtered through celite and washed with ethyl acetate (120 mL). The organic layer was washed with a saturated aqueous solution of sodium chloride (50 mL), thereafter dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by a silica gel column to obtain tert-butyl (3E)-4-(3-amino-4-phenylphenyl)-3-butenoate (555.8 mg).
Reaction SMILES: [C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16](OC(C)C)=[O:17])=[CH:15][C:10]=3[N:9]=[CH:8]2)[CH:2]=1.[H-].C([Al+]CC(C)C)C(C)C.[Cl-].[NH4+]>C1(C)C=CC=CC=1>[C:1]1([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([CH2:16][OH:17])=[CH:15][C:10]=3[N:9]=[CH:8]2)[CH:2]=1
Reactant: CC(C)OC(=O)c1ccc2c(c1)ncn2-c1cccc(-c2ccccc2)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: Cc1ccccc1
Product: OCc1ccc2c(c1)ncn2-c1cccc(-c2ccccc2)c1
Reaction time: 1.5 h

Procedure:
To a solution of 1-(3-biphenylyl)-5-isopropoxycarbonylbenzimidazole (0.52 g, 1.6 mmol) in dry toluene (5 ml) under nitrogen at a temperature of -70° C. was added diisobutylaluminum hydride (1.1 ml of an 1.5M solution in toluene). After 1.5 h at -70° the reaction mixture was allowed to reach room temperature and was then poured in a slurry of 2M aqueous ammonium chloride and ice. After extractive workup with toluene the product was purified by chromatography on silica gel. Yield: 60 mg, 0.2 mmol, 12%. mp 130°-131° C.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:10]([NH:17][CH2:18][CH2:19][O:20][C:21]1[CH:29]=[C:25]([C:26]([NH2:28])=[O:27])[C:24]([OH:30])=[CH:23][CH:22]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(O)(C)C>[CH2:10]([N:17]([CH2:9][C@H:7]([OH:8])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:18][CH2:19][O:20][C:21]1[CH:22]=[CH:23][C:24]([OH:30])=[C:25]([C:26](=[O:27])[NH2:28])[CH:29]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NC(=O)c1cc(OCCNCc2ccccc2)ccc1O
Reactant: c1ccc([C@@H]2CO2)cc1
Solvent: CC(C)O
Product: NC(=O)c1cc(OCCN(Cc2ccccc2)C[C@H](O)c2ccccc2)ccc1O

Procedure:
A solution of 7.2 g of (R)-2-phenyl-oxirane and 14.3 g of 5-(2-benzylamino-ethoxy)-salicylamide in 100 ml of isopropanol is refluxed for 22-24 hours. The solution is concentrated by evaporation to yield (R)-α-[N-benzyl-N-[2-(3-carbamoyl-4-hydroxy-phenoxy)-ethyl]-aminomethyl]-benzyl alcohol, which is further processed in this form.
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[CH2:3][CH2:4][OH:5].[C:7](Cl)(=[O:10])[CH:8]=[CH2:9].C(N(CC)CC)C>ClCCl>[C:7]([O:5][CH2:4][CH2:3][CH:2]([CH3:6])[CH3:1])(=[O:10])[CH:8]=[CH2:9]
Reactant: C=CC(=O)Cl
Reactant: CC(C)CCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)OCCC(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.4 %

Procedure:
To a stirred solution of 3-methyl butanol (2.0 g, 22.6 mmol) and acryloyl chloride (2.05 g, 22.6 mmol) in dichloromethane (5 ml) at 0° C. is added dropwise triethylamine (3.2 ml, 22.7 mmol). The solution is stirred for 30 minutes at room temperature and then concentrated to a residue. The residue is washed with hexanes (2×10 ml) and the resultant combined organics are concentrated and filtered through a plug of silica to give 3.0 g of 3-methylbutyl acrylate as an oil, 93% yield.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[C:11]([C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=O)=[CH:15][CH:14]=1)#[N:12].N>>[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([C:3]2[N:10]=[C:17]([C:16]3[CH:20]=[CH:21][C:13]([C:11]#[N:12])=[CH:14][CH:15]=3)[O:1][N:2]=2)[CH:5]=1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: NC(=NO)c1cccnc1
Agent: N
Product: N#Cc1ccc(-c2nc(-c3cccnc3)no2)cc1

Procedure:
The title compound was prepared according to the procedure of Example 1 using N′-hydroxynicotinimidamide (Aldrich) and 4-cyanobenzoyl chloride (Aldrich). 1H NMR (300 MHz, CD3OD) δ 7.65 (ddd, J=8.0, 4.9, 1.0 Hz, 1H), 8.02 (d, J=8.8 Hz, 2H), 8.42 (d, J=8.8 Hz, 2H), 8.57 (dt, J=8.1, 1.9 Hz, 1H), 8.75 (dd, J=4.7, 1.7 Hz, 1H), 9.31 (dd, J=2.2, 0.8 Hz, 1H) ppm; MS (DCl/NH3) m/z 249 (M+H)+.
Reaction SMILES: OC(C(F)(F)F)=O.[F:8][C:9]1[CH:26]=[CH:25][C:12]([CH2:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[O:24])[NH:16][N:15]=2)=[CH:11][C:10]=1[C:27]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)=[O:28].[CH3:35][C:36]([CH3:43])([CH3:42])[C:37](=[O:41])[C:38](O)=[O:39].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:8][C:9]1[CH:26]=[CH:25][C:12]([CH2:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[O:24])[NH:16][N:15]=2)=[CH:11][C:10]=1[C:27]([N:29]1[CH2:34][CH2:33][N:32]([C:38](=[O:39])[C:37](=[O:41])[C:36]([CH3:43])([CH3:42])[CH3:35])[CH2:31][CH2:30]1)=[O:28]
Reactant: CC(C)(C)C(=O)C(=O)O
Reactant: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)C(=O)N1CCN(C(=O)c2cc(Cc3n[nH]c(=O)c4ccccc34)ccc2F)CC1
Temperature: 25 °C
Reaction time: 44 h
Yield: 48.2 %

Procedure:
4-(4-fluoro-3-(piperazine-1-carbonyl)benzyl)phthalazin-1(2H)-one TFA salt (310 mg, 0.65 mmol), 3,3-dimethyl-2-oxobutanoic acid [1.37 g (60%), 6.3 mmol], DIPEA (2 ml, 11.6 mmol), and HATU (1030 mg, 2.72 mmol) were mixed in DMF (50 ml), the resulting reaction mixture was stirred at room temperature for 44 h until the reaction finished (monitored by TLC). The reaction mixture was then partitioned between DCM and water (100 ml each, the water phase was extracted with DCM (100 ml). The combined organic phase was washed with water, sat. aqueous sodium bicarbonate, and brine, dried over sodium sulphate, filtered, and concentrated to yield the crude product. Then the crude product was firstly purified by column chromatography on silica gel (DCM:MeOH=100:1) and re-purified by preparative TLC (DCM:MeOH=40:1) to afford the desired product (150 mg, 46.9%) as a off white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][N:3]=1.Br[CH2:9][CH2:10][Cl:11].BrCCBr>O1CCCC1>[CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([CH2:9][CH2:10][Cl:11])[N:3]=1.[CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][N:3]=1
Reactant: ClCCBr
Agent: Cc1cc(C)[nH]n1
Solvent: C1CCOC1
Solvent: BrCCBr
Product: Cc1cc(C)n(CCCl)n1

Procedure:
When an equivalent amount of 3,5-dimethylpyrazole is substituted for 1-ethoxycarbonyl-2H-indazolin-3-one and 2-bromochloroethane is substituted for 1,2-dibromoethane in the procedure of Example 19 using tetrahydrofuran as solvent, 2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl chloride is isolated after column chromatography (3,5-dimethylpyrazole, Aldrich, 24%, C).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[CH:6]=[CH:7][C:8]=1[CH:9]([CH3:12])[C:10]#[CH:11].ClS([N:24]=[C:25]=[O:26])(=O)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:14]=[CH:15][C:16]([O:19][C:25](=[O:26])[NH2:24])=[CH:17][CH:18]=2)[CH:6]=[CH:7][C:8]=1[CH:9]([CH3:12])[C:10]#[CH:11]
Reactant: C#CC(C)c1ccc(-c2ccc(O)cc2)cc1OC
Reactant: O=C=NS(=O)(=O)Cl
Solvent: ClCCl
Product: C#CC(C)c1ccc(-c2ccc(OC(N)=O)cc2)cc1OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67.7 %

Procedure:
To a 25 mL flame dried flask with stir bar cooled to room temperature was added alkyne 20 (0.115 g, 0.46 mmol) dissolved in anhydrous CH2Cl2. The reactant was cooled to 0° C. and chlorosulfonyl isocyanate (0.08 mL, 0.92 mmol) was added dropwise. After 15 min, the reaction mixture was brought to room temperature and followed by TLC. The reaction was quenched with water and extracted with ether. The organic extracts were washed with brine, dried over MgSO4, and filtered. The filtrate was concentrated and purified by flash column chromatography (SiO2, 7 g, 25% EtOAc/hexanes) to give the terminal acetylene 23 as a white solid (0.092 g, 68% yield): TLC Rf=0.1 (25% EtOAc/hexanes); mp 113.6-115.3° C.; 1H NMR (500 MHz, CDCl3) δ 7.61 (d, J=7.8 Hz, 1H), 7.56 (d, J=8.5 Hz, 2H), 7.19 (d, J=8.5 Hz, 2H), 7.15 (dd, J=7.8, 1.4 Hz, 1H), 7.01 (d, J=1.7 Hz, 1H), 4.21 (qd, J=7.0, 2.3 Hz, 1H), 3.88 (s, 3H), 2.23 (d, J=2.4 Hz, 1H), 1.47 (d, J=7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 189.2, 156.4, 155.6, 150.3, 140.6, 138.9, 133.1, 130.3, 128.3, 128.2, 122.1, 119.7, 109.6, 87.7, 69.6, 60.6, 55.7, 25.3, 22.8, 21.2, 14.4; IR (neat cm−1) 3423, 3308, 3268, 3199, 2969, 2341, 2105, 1698, 1606, 1494, 1378, 1213, 586; HRMS (DART, M++H) m/z 296.1300 (calculated for C18H18NO3, 296.1287).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([C:13]([NH:15][C@@H:16]([CH3:20])[C:17]([OH:19])=[O:18])=[O:14])[N:3]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([SH:28])=[CH:24][CH:23]=1>CN1CCCC1=O>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([OH:12])=[C:4]([C:13]([NH:15][C@@H:16]([CH3:20])[C:17]([OH:19])=[O:18])=[O:14])[N:3]=2)=[CH:24][CH:23]=1
Reactant: C[C@H](NC(=O)c1nc(Br)c2ccccc2c1O)C(=O)O
Reactant: Sc1ccc(Cl)cc1
Solvent: CN1CCCC1=O
Product: C[C@H](NC(=O)c1nc(Sc2ccc(Cl)cc2)c2ccccc2c1O)C(=O)O
Temperature: 210 °C
Yield: 6.1 %

Procedure:
To a solution of 250 mg of (S)-2-{[1-bromo-4-hydroxy-isoquinoline-3-carbonyl]-amino}-propionic acid in 0.7 ml of 1-methyl-2-pyrrolidinone was added 433 mg of 4-chloro-benzenethiol. The solution was heated at 210° C. for 30 min. using a CEM Discover microwave reactor. The solution was concentrated under vacuum. The resultant residue was crystallized from methanol to yield 18 mg of a tan solid; MS (−): m/z 401.10 (M−1)
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:4][CH:3]=1.[Br:11]Br>C(O)(=O)C>[Br:11][CH2:9][C:8]([C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=1)=[O:10]
Reactant: CC(=O)c1cccc(Br)n1
Reactant: BrBr
Solvent: CC(=O)O
Product: O=C(CBr)c1cccc(Br)n1
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
A solution of 1-(6-bromopyridin-2-yl)ethanone (9.2 g, 46.0 mmol) in acetic acid (25 mL) was heated to 70° C. and bromine (2.4 mL, 46.0 mmol) was added dropwise over 30 minutes. After 75 minutes, the solution was cooled to room temperature and a yellow solid precipitated which was collected by filtration and washed with acetic acid (3×10 mL) The solid was then dissolved in a mixture of ethyl acetate (150 mL), hexanes (50 mL), and saturated aqueous sodium bicarbonate (75 mL). The layers were separated and the organic layer was washed with brine (30 mL), dried over sodium sulfate, filtered, and concentrated. The crude residue was purified by silica gel chromatography (10-50% dichloromethane/hexanes) to give the title compound as a white solid.
Reaction SMILES: C(OC([N:8]1[C:46]2[C:41](=[CH:42][CH:43]=[C:44]([Cl:47])[CH:45]=2)[C:10]2([CH:15]([C:16]3[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=3[O:23][CH2:24][C:25]3([C:30]#[N:31])[CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:14][C:13](=[O:32])[NH:12][CH:11]2[C:33]2[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=2[CH3:40])[C:9]1=[O:48])=O)(C)(C)C>FC(F)(F)C(O)=O>[Cl:47][C:44]1[CH:45]=[C:46]2[NH:8][C:9](=[O:48])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][CH2:24][C:25]4([C:30]#[N:31])[CH2:29][CH2:28][CH2:27][CH2:26]4)[CH2:14][C:13](=[O:32])[NH:12][CH:11]3[C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[CH3:40])[C:41]2=[CH:42][CH:43]=1
Reactant: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OCC2(C#N)CCCC2)C12C(=O)N(C(=O)OC(C)(C)C)c1cc(Cl)ccc12
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OCC2(C#N)CCCC2)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.4 %

Procedure:
racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-cyano-cyclopentyl-methoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl)-2,3-dihydro-2,6′-dioxo spiro[indole-3,3′-piperidine]-1-carboxylic acid tert-butyl ester (100 mg) was dissolved in trifluoroacetic acid (5 mL). After stirred at room temperature for 0.5 h, the reaction mixture was concentrated and the residue was purified by recrystallization to give the title compound as a yellow solid (38 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH3:13])[CH2:11][CH2:10][C@H:9]1[C:14](O)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].B.CSC.CO>O1CCCC1>[OH:15][CH2:14][C@@H:9]1[CH2:10][CH2:11][C@H:12]([CH3:13])[N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7]
Reactant: C[C@H]1CC[C@@H](C(=O)O)N1C(=O)OC(C)(C)C
Agent: B
Solvent: C1CCOC1
Solvent: CO
Solvent: CSC
Product: C[C@H]1CC[C@@H](CO)N1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 4 h
Yield: 92.6 %

Procedure:
To a solution of (2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidine-2-carboxylic acid (5.91 g, 25.8 mmol) in tetrahydrofuran at 0° C., was added borane in dimethylsulfide (1.0 M, 3.4 mL, 34 mmol) dropwise. The reaction was stirred for 4 hours at 0° C. then 18 hours at room temperature. The mixture was then cooled to 0° C. and methanol (70 mL) was added dropwise. The reaction was warmed to room temperature and the solvents were removed in vacuo. The residue was taken up in dichloromethane (200 mL) and extracted with saturated sodium bicarbonate. The organic layer was dried with sodium sulfate and the solvent was removed in vacuo to yield (2S,55)-tert-butyl 2-(hydroxymethyl)-5-methylpyrrolidine-1-carboxylate as a clear oil (5.15 g, 23.9 mmol, 93%) and was used directly in the following step.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=CC=CC=1.[C:10]([OH:14])(=[O:13])[CH:11]=[CH2:12]>>[C:10]([O:14][C:1](=[O:8])[CH:2]=[CH2:7])(=[O:13])[CH:11]=[CH2:12]
Reactant: C=CC(=O)O
Reactant: O=C(Cl)c1ccccc1
Product: C=CC(=O)OC(=O)C=C

Procedure:
Moreover, in the case of benzoyl chloride, the resulting mixed anhydride is more reactive than benzoyl chloride. Thus, the carboxylate ion of acrylic acid preferentially reacts with the mixed anhydride to give acrylic anhydride and the benzoate ion, which subsequently reacts with unreacted benzoyl chloride to give benzoic anhydride, according to reaction scheme I.
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([C:10]2[CH:11]=[C:12]([NH2:16])[CH:13]=[CH:14][CH:15]=2)[N:9]=1)[C:2]([NH2:4])=[NH:3].[CH2:17](OC(OCC)OCC)C>FC(F)(F)C(O)=O>[NH:1]([C:5]1[S:6][CH:7]=[C:8]([C:10]2[CH:11]=[C:12]([NH:16][CH3:17])[CH:13]=[CH:14][CH:15]=2)[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: N=C(N)Nc1nc(-c2cccc(N)c2)cs1
Reactant: CCOC(OCC)OCC
Solvent: O=C(O)C(F)(F)F
Product: CNc1cccc(-c2csc(NC(=N)N)n2)c1
Temperature: 0 °C

Procedure:
A mixture of 9.3 g (0.04 mole) of 3-(2-guanidino-4-thiazolyl)benzeneamine, 20 ml of triethylorthoformate, and 2 drops of trifluoroacetic acid is stirred at reflux for 5 hours after which it is concentrated in vacuo. The residue is dissolved in 20 ml of ethanol, the solution cooled to 0° C. and then treated with excess sodium borohydride. The mixture is allowed to warm to room temperature, then stirred at reflux for 4 hours. Upon concentration in vacuo the residue is partitioned between water and dichloromethane.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]([CH2:19][CH2:20][OH:21])=[CH:6]2)[CH3:2].[Na]>CCO>[CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C@@H:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C@H:7]([CH2:19][CH2:20][OH:21])[CH2:6]2)[CH3:2]
Reactant: CCc1ccc2nc(-c3ccccc3)c(CCO)cc2c1
Agent: [Na]
Solvent: CCO
Product: CCc1ccc2c(c1)C[C@@H](CCO)[C@H](c1ccccc1)N2

Procedure:
As described under b.), 0.80 g (2.88 mmol) of 7 were reacted with 0.66 g (28.8 mmol, 10 eq) of sodium in EtOH (10 ml) to give compound trans-8 as a colourless solid and compound cis-8, likewise as a colourless solid.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]([C:14]([O:16]CC)=O)[C:11]([NH:12][NH2:13])=[C:6]2[CH:5]=[N:4]1)[CH3:2].C(O[CH:22]=[N:23][C:24]#[N:25])C>O1CCOCC1>[CH2:1]([N:3]1[C:7]2[N:8]=[CH:9][C:10]3[C:14](=[O:16])[NH:25][C:24]4[N:12]([N:13]=[CH:22][N:23]=4)[C:11]=3[C:6]=2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCOC=NC#N
Reactant: CCOC(=O)c1cnc2c(cnn2CC)c1NN
Solvent: C1COCCO1
Product: CCn1ncc2c1ncc1c(=O)[nH]c3ncnn3c12
Temperature: 25 °C

Procedure:
249 g. of 1-ethyl-4-hydrazino-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid, ethyl ester (1 mol.) are refluxed in 1.5 liters of dry dioxane together with 98 g. of ethoxymethylene cyanamide for 12 hours. After cooling to room temperature, the precipitated 8-ethyl-4H-pyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidin-5(8H)-one is filtered off and recrystallized from dimethylformamide, yield 135 g. (53%); m.p. 355°-356°.
Reaction SMILES: C([N:8]([C@@H:17]([CH3:27])[C@@H:18]([CH3:26])[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@@H](C)C1C=CC=CC=1)C1C=CC=CC=1>CCO.[OH-].[OH-].[Pd+2]>[C:22]([O:21][C:19](=[O:20])[C@H:18]([CH3:26])[C@@H:17]([NH2:8])[CH3:27])([CH3:24])([CH3:23])[CH3:25]
Reactant: C[C@@H](C(=O)OC(C)(C)C)[C@H](C)N(Cc1ccccc1)[C@@H](C)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: C[C@H](N)[C@@H](C)C(=O)OC(C)(C)C
Reaction time: 48 h
Yield: 79.4 %

Procedure:
A mixture of tert-butyl (2R,3S,αS)-3-(N-benzyl-N-α-methylbenzylamino)-2-methyl-butyrate (458 mg, 1.25 mmol) and 20% Pd(OH)2 on carbon (200 mg) in EtOH (10 mL) was stirred under H2 atmosphere (1 atm) for 48 h, then filtered through a pad of Celite. The filtrate was concentrated to give 172 mg of the title compound, which was used in the next step without purification. 1H NMR (CDCl3, 200 MHz): δ=8.4 (broad), 3.45-3.65 (m, 1H), 2.70-2.80 (m, 1H), 1.46 (s, 9H), 1.42 (d, 3H, J=7.0 Hz), 1.29 (d, 3H, J=7.0 Hz).