Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH:12]=[O:13])[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].[N+:25]([CH3:28])([O-:27])=[O:26].Cl>C1COCC1>[O:1]([C:9]1[CH:10]=[C:11]([C@@H:12]([OH:13])[CH2:28][N+:25]([O-:27])=[O:26])[CH:14]=[CH:15][C:16]=1[O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:19])[CH3:20])[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C=O)cc1O[Si](C)(C)C(C)(C)C
Reactant: C[N+](=O)[O-]
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1ccc([C@@H](O)C[N+](=O)[O-])cc1O[Si](C)(C)C(C)(C)C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
100 mg (0.26 mmol) of 3,4-di(t-butyldimethylsiloxy)benzaldehyde was dissolved in 10 ml of THF under the atmosphere of argon at −40° C., and 0.30 ml of rare earth metal complex solution A1 was mixed into the solution. After stirring for 30 minutes, 79.3 mg (1.3 mmol) of nitromethane was added dropwise to the mixture. After 67-hour reaction time, 2 ml of 1 N aqueous solution of hydrochloric acid was added to stop the reaction. Then, after 50 ml of ethyl accetate was added, the mixture was subjected to oil-water separation twice with 20 ml of saturated salt solution and once with 20 ml of water, and the ethyl accetate layer was dehydrated with sodium sulfate anhydride and concentrated with an evaporator, followed by the purification of the concentrate by silica gel chromatography (n-hexane/acetone=10/1), after which (R)-1-(3,4-di(t-butyldimethylsiloxy)phenyl)-2-nitroethanol with an optical purity of 92% e.e. was obtained in a yield of 93%.
Reaction SMILES: [CH:1]1([C:5]([O:7]CC)=O)[CH2:4][CH2:3][CH2:2]1.[CH3:10][C:11]([CH3:13])=[O:12]>CCOCC>[CH:1]1([C:5](=[O:7])[CH2:10][C:11](=[O:12])[CH3:13])[CH2:2][CH2:3][CH2:4]1
Reactant: CC(C)=O
Reactant: CCOC(=O)C1CCC1
Solvent: CCOCC
Product: CC(=O)CC(=O)C1CCC1
Reaction time: 4 h
Yield: 46.1 %

Procedure:
To a solution of NaNH2 (11.7 g, 91 mmol) in anhydrous ether (150 mL) under N2 at 30° C. was added dropwise a mixture of ethyl cyclobutanecarboxylate (19.2 g, 150 mmol) and acetone (21.75 g, 375 mmol). After addition, the reaction mixture was stirred for 4 h, then poured onto ice water with stirring. Ether was added and the unreacted components were extracted into the organic phase. The clear aqueous extract was acidified to pH 5.0 with 2 N HCl, and then to pH 7.5 with Na2CO3. The solution was extracted with ether. The combined organic layers were dried (Na2SO4), filtered, and concentrated to give the crude product of 1-cyclobutyl-1,3-butanedione (9.7 g, 76%), which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3-d3) δ 5.42 (s, 1H), 3.66 (s, 1H), 2.11-2.23 (m, 4H), 2.02 (s, 3H), 1.93-1.99 (m, 2H).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[CH:7]=[CH:8][C:9](O)=[C:10]([S:11]([OH:14])(=[O:13])=[O:12])[C:4]2=[CH:3][CH:2]=1.[NH3:16]>>[NH2:16][C:9]1[CH:8]=[CH:7][C:5]2[C:4](=[CH:3][CH:2]=[CH:1][CH:6]=2)[C:10]=1[S:11]([OH:14])(=[O:13])=[O:12]
Reactant: N
Reactant: O=S(=O)(O)c1c(O)ccc2ccccc12
Product: Nc1ccc2ccccc2c1S(=O)(=O)O

Procedure:
treating the resultant aqueous solution of the ammonium salt of oxy-Tobias acid, without increasing the concentration beforehand, with NH3 and concentrated (NH4)2SO3 or (NH4)HSO3 solution in the temperature range from 120° to 150° C. and at a pressure of 10 to 20 bar for 4 to 12 hours until the pH value is 9 to 12, to give the ammonium salt of 2-amino-1-naphthalenesulfonic acid (Tobias acid), and, after stripping off NH3 and removal of 2-naphthylamine by extraction with an aromatic hydrocarbon,
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([Cl:17])[CH:3]=1.[C:18]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)#[N:19]>>[Cl:17][C:4]1[CH:3]=[C:2]([C:23]2[CH:24]=[CH:25][C:20]([C:18]#[N:19])=[CH:21][CH:22]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: Cc1c2n(c3c(Br)cc(Cl)cc13)CCNC2=O
Reactant: N#Cc1ccc(B(O)O)cc1
Product: Cc1c2n(c3c(-c4ccc(C#N)cc4)cc(Cl)cc13)CCNC2=O

Procedure:
The title compound, off-white solid (75 mg, 89%), MS (ISP) m/z=336.4 [(M+H)+], mp 290° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-chloro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 12) (78.4 mg, 0.25 mmol) and commercially available 4-cyanophenylboronic acid (47.8 mg, 0.325 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]([NH:12][NH2:13])=[N:9]2)=[CH:4][CH:3]=1.[C:14](O)(=O)[CH3:15]>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]3[N:9]2[C:14]([CH3:15])=[N:13][N:12]=3)=[CH:4][CH:3]=1
Reactant: CC(=O)O
Reactant: NNc1cnc2ccc(Br)cc2n1
Product: Cc1nnc2cnc3ccc(Br)cc3n12
Yield: 90 %

Procedure:
A mixture of 7-bromo-2-hydrazinylquinoxaline (1 g, 4.18 mmol) in acetic acid (10 mL) was refluxed for 18 h. Half of the acetic acid was removed under vacuum and the residue was poured into ice-water. The precipitate was collected on a filter, washed with water, and dried under vacuo to afford crude 8-bromo-1-methyl-[1,2,4]triazolo[4,3-a]quinoxaline as a dark red solid (1 g, yield 90%) which was used in the next step without further purification. MS (m/z): 263 (M+H)+.
Reaction SMILES: [CH2:1]([N:4]1[C:13](=[O:14])[C:12]2[NH:11][C:10]([C:15]3[CH:16]=[N:17][C:18](Cl)=[CH:19][CH:20]=3)=[N:9][C:8]=2[N:7]([CH2:22][CH2:23]C)[C:5]1=[O:6])[CH2:2]C.[NH2:25][NH2:26]>C(O)C>[CH2:1]([N:4]1[C:13](=[O:14])[C:12]2[NH:11][C:10]([C:15]3[CH:16]=[N:17][C:18]([NH:25][NH2:26])=[CH:19][CH:20]=3)=[N:9][C:8]=2[N:7]([CH2:22][CH3:23])[C:5]1=[O:6])[CH3:2]
Reactant: CCCn1c(=O)c2[nH]c(-c3ccc(Cl)nc3)nc2n(CCC)c1=O
Reactant: NN
Solvent: CCO
Product: CCn1c(=O)c2[nH]c(-c3ccc(NN)nc3)nc2n(CC)c1=O
Temperature: 130 °C
Reaction time: 13 h

Procedure:
Compound 1 (500 mg, 1.44 mmol) and hydrazine (4 ml) were put in a pressure tube. Ethanol (30 ml) was added. The pressure tube was flushed with argon, sealed and stirred at 100-160° C. for 10-16 h. After cooling, the resulting solid was collected and washed with methanol and ether to give compound 138 (40 mg). The product was used in the next step without further purification.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([NH2:8])(=[O:7])=[O:6].C(Cl)CCl.[C:13]([O:17][C:18]([NH:20][CH2:21][CH2:22][N:23]([CH3:52])[C@@H:24]1[CH2:31][N:30]2[C:32]3[CH:33]=[C:34]([C:45](O)=[O:46])[CH:35]=[CH:36][C:37]=3[C:38]([CH:39]3[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]3)=[C:29]2[C:28]2[CH:48]=[CH:49][CH:50]=[CH:51][C:27]=2[O:26][CH2:25]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:13]([O:17][C:18](=[O:19])[NH:20][CH2:21][CH2:22][N:23]([C@@H:24]1[CH2:31][N:30]2[C:32]3[CH:33]=[C:34]([C:45]([NH:8][S:5]([CH2:4][CH2:3][CH2:2][Cl:1])(=[O:7])=[O:6])=[O:46])[CH:35]=[CH:36][C:37]=3[C:38]([CH:39]3[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]3)=[C:29]2[C:28]2[CH:48]=[CH:49][CH:50]=[CH:51][C:27]=2[O:26][CH2:25]1)[CH3:52])([CH3:16])([CH3:14])[CH3:15]
Reactant: NS(=O)(=O)CCCCl
Reactant: CN(CCNC(=O)OC(C)(C)C)[C@H]1COc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)O)cc3n2C1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CN(CCNC(=O)OC(C)(C)C)[C@H]1COc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)NS(=O)(=O)CCCCl)cc3n2C1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
3-chloropropane-1-sulfonamide (1.8 eq), DMAP (2.9 eq) and EDC (1.8 eq), were added to a solution of (7R)-7-[{2-[(tert-butoxycarbonyl)amino]ethyl}(methyl)amino]-14-cyclohexyl-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylic acid (prepared as described in Example 1, Step 7) (0.025 M) in DCM. The reaction was stirred under N2 at 40° C. for 2 h, before being allowed to cool. Volatiles were removed in vacuo to leave the crude product as a yellow gum which could be taken on without further purification. (ES+) m/z 687 (M+H)+; 689 (M+H)+
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1B(O)O.Br[C:14]1[CH:15]=[CH:16][C:17]([C:20]([NH2:22])=[O:21])=[N:18][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:14]1[CH:15]=[CH:16][C:17]([C:20]([NH2:22])=[O:21])=[N:18][CH:19]=1
Reactant: OB(O)c1cc2ccccc2o1
Reactant: NC(=O)c1ccc(Br)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(-c2cc3ccccc3o2)cn1
Yield: 0.3 %

Procedure:
2-Benzofuranboronic acid (3.1 mmol), 5-bromopyridine-2-carboxamide (3.7 mmol), 2M K2CO3 (aq., 6 mL) and Pd(dppf)Cl2 (0.31 mmol) were mixed and stirred at 80° C. in DMF for 2 h. The reaction mixture was filtered and washed with H2O and EtOAc. DMSO was added to the solid remains and filtered. The filtrate was collected and purified by reverse phase HPLC to afford the title compound as a white solid (2.5 mg). 1H NMR δ ppm 9.18 (d, 1 H) 8.46 (dd, 1 H) 8.13-8.19 (m, 2 H) 7.68-7.78 (m, 4 H) 7.43-7.30 (m, 2 H); MS m/z 239 (M+H).
Reaction SMILES: Cl[C:2]1[CH:17]=[C:6]2[C:7]3[C:12]([CH2:13][CH2:14][N:5]2[C:4](=[O:18])[N:3]=1)=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=3.[CH3:19][C:20]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:21]=1[NH2:22]>>[CH3:19][C:20]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:21]=1[NH:22][C:2]1[CH:17]=[C:6]2[C:7]3[C:12]([CH2:13][CH2:14][N:5]2[C:4](=[O:18])[N:3]=1)=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=3
Reactant: COc1ccc2c(c1)CCn1c-2cc(Cl)nc1=O
Reactant: Cc1cccc(C)c1N
Product: COc1ccc2c(c1)CCn1c-2cc(Nc2c(C)cccc2C)nc1=O

Procedure:
The title compound was prepared from 2-chloro-9-methoxy-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one (4) and 2,6-dimethyl-aniline as in Example 1 d. 1H-NMR as two isomeric mixture (400 MHz, d6-DMSO) δ 8.96 and 8.87 (br, 1H), 7.75 and 7.29 (d, 1H), 7.23-6.80 (5H), 6.37 and 5.33 (br, 1H), 3.96 and 3.92 (t, 2H), 3.84 and 3.78 (s, 3H), 2.95 (t, 2H) and 2.18 and 2.16 (s, 6H); MS (ESI) (M+H)+ 348.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:13])[C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[CH3:45][C:46]([CH3:50])=[CH:47][CH2:48]O>O1CCCC1>[CH3:45][C:46]([CH3:50])=[CH:47][CH2:48][O:1][C:2]1[C:3](=[O:13])[C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: CC(C)=CCO
Reactant: O=C1C=C(O)C(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)=CCOC1=CC(=O)c2ccccc2C1=O
Reaction time: 0.08 h
Yield: 59.7 %

Procedure:
To a stirred solution of 2-hydroxynaphthalene-1,4-dione (10.0 g, 57.4 mmol) and triphenylphosphine (15.1 g, 57.4 mmol) in dry tetrahydrofuran (150 ml) at 0° C. under an atmosphere of nitrogen was added diethyl azodicarboxylate (10.0 g, 57.4 mmol). After stirring for a further 5 minutes, a solution of 3-methylbut-2-enol (7.42 g, 86.1 mmol) in dry tetrahydrofuran (10 ml) was added dropwise and stirring was continued for 2 hours. The precipitate was collected, air-dried and recrystallised from aqueous methanol to yield the title compound (8.3 g) as a yellow crystalline solid with a melting point of 138° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[C:5](=O)[CH2:6][C:7]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:18])[C:13]1[N:19]([CH3:31])[C:20](=[O:30])[C:21]([C:23]3[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=3)=[CH:22][C:12]2=1)=O)[CH3:2].O.[NH2:35][NH2:36]>>[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[C:7]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH3:18])[C:13]2[N:19]([CH3:31])[C:20](=[O:30])[C:21]([C:23]4[CH:24]=[CH:25][C:26]([Br:29])=[CH:27][CH:28]=4)=[CH:22][C:12]3=2)[NH:36][N:35]=1)=[O:33])[CH3:2]
Reactant: CCOC(=O)C(=O)CC(=O)c1ccc2c(c1)c1cc(-c3ccc(Br)cc3)c(=O)n(C)c1n2C
Reactant: NN
Solvent: O
Product: CCOC(=O)c1cc(-c2ccc3c(c2)c2cc(-c4ccc(Br)cc4)c(=O)n(C)c2n3C)[nH]n1

Procedure:
The process is carried out as in Example 43 above, with compound A, 4-[3-(4-bromophenyl)-1,9-dimethyl-2-oxo-2,9-dihydro-1H-pyrido[2,3-b]indol-6-yl]-2,4-dioxobutyric acid ethyl ester and hydrazine monohydrate.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O)([O:3][CH3:4])=[O:2].O=S(Cl)Cl.N1C=CC=CC=1.[C:24]([NH:31][NH2:32])(=[O:30])/[CH:25]=[CH:26]\[C:27]([OH:29])=O>C(COC)OC.C(Cl)(Cl)Cl>[C:1]([C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([N:31]1[C:24](=[O:30])[CH:25]=[CH:26][C:27]([OH:29])=[N:32]1)=[O:9])([O:3][CH3:4])=[O:2]
Reactant: COC(=O)c1ccccc1C(=O)O
Reactant: NNC(=O)/C=C\C(=O)O
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: COCCOC
Product: COC(=O)c1ccccc1C(=O)n1nc(O)ccc1=O

Procedure:
Into a 100 ml round-bottomed flask fitted with a stirrer and reflux condenser there was charged 10.8 g (0.06 mole) of 2-carbomethoxybenzoic acid and 50 ml of chloroform. There was then added 7.8 g (0.066 mole) of SOCl2, followed by refluxing for 2 hr. The chloroform was then removed by distillation, followed by addition of 50 ml. of dimethoxyethane, 4.7 g (0.06 mole) of pyridine and 6.7 g (0.06 mole) of maleic hydrazide. The mixture was allowed to stir over night. The resulting reaction mixture was filtered to remove solids. Then the product was precipitated from the filtrate by addition of water and was recovered as a solid by filtration. The solid material was washed with hexane-ether solvent mixture and was filtered and dried. The yield was 6.6 g, m.p. 144°-145° C. Infrared and nuclear magnetic resonance spectra were consistent with the structure of the compound as named above.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])=[CH:7][N:6]=1)=[O:4].[OH-].[Li+]>>[F:19][C:13]([F:18])([C:14]([F:15])([F:16])[F:17])[CH2:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[N:6][CH:7]=1
Reactant: COC(=O)c1ccc(OCC(F)(F)C(F)(F)F)cn1
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)c1ccc(OCC(F)(F)C(F)(F)F)cn1

Procedure:
In a manner analogous to that described in example 17b), the hydrolysis of the 5-(2,2,3,3,3-pentafluoro-propoxy)-pyridine-2-carboxylic acid methyl ester with lithium hydroxide yielded the 5-(2,2,3,3,3-pentafluoro-propoxy)-pyridine-2-carboxylic acid as a white solid. MS (ISP): m/z=271 [M+H]+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH3:15][NH:16][CH:17]1[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]1.C([O-])(O)=O.[Na+]>C1COCC1>[CH3:15][N:16]([C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13])[CH:17]1[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Reactant: CNC1CCN(C)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCC(N(C)c2ccc(C(F)(F)F)cc2[N+](=O)[O-])CC1
Temperature: 25 °C

Procedure:
To a solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (7.5 g, 36 mmol) in THF (180 mL) was added N,1-dimethylpiperidin-4-amine (5.5 g, 43 mmol) and NaHCO3 (6.0 g, 71 mmol). The mixture was stirred at RT and monitored by LCMS for disappearance of starting material. The reaction was filtered, concentrated, and partitioned between H2O and CH2Cl2. The aqueous layer was extracted several times with CH2Cl2, and the organics combined. The organics were washed with brine, dried with MgSO4, filtered, and concentrated to afford the desired product.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([CH2:6][C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)=[N:2]1.C([N-]C(C)C)(C)C.[Li+].[C:23]1(=[O:28])[CH2:27][CH2:26][CH2:25][CH2:24]1.O>O1CCCC1>[OH:28][C:23]1([CH:6]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[C:3]2[N:4]=[CH:5][NH:1][N:2]=2)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C1CCCC1
Reactant: N#Cc1ccc(Cc2nc[nH]n2)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(C(c2nc[nH]n2)C2(O)CCCC2)cc1
Reaction time: 0.5 h
Yield: 99 %

Procedure:
5 g of 4-[1-(1,2,4-triazolyl)methyl]benzonitrile is dissolved in 100 ml of tetrahydrofuran and combined at -50° with 20 ml of 1.5-molar solution of lithium diisopropylamide in tetrahydrofuran, stirred for 0.5 hour, further stirred for 1 hour with 2.4 g of cyclopentanone at -70°, and heated to 25°. Then water is added, the mixture is extracted twice with ethyl acetate, washed neutral with water, dried over sodium sulfate, and concentrated to dryness under vacuum, thus obtaining 7.21 g of crude 4-[1-hydroxycyclopent-1-yl-1-(1,2,4-triazolyl)methyl]benzonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][CH2:5]2.Cl.[N:12]([O-])=[O:13].[Na+]>O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([N:12]=[O:13])[CH2:6][CH2:5]2
Reactant: O=N[O-]
Reactant: Clc1ccc2c(c1)CCN2
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=NN1CCc2cc(Cl)ccc21

Procedure:
A mixture of 77 g. (0.5 mole) of 5-chloroindoline, 80 ml. of concentrated hydrochloride acid and 500 ml. of crushed ice was stirred while a solution of 35 g. of sodium nitrite in 100 ml. of water was added over five minutes. The temperature was kept between 10°C. to 15°C. by addition of ice. The mixture was stirred for 1 hour and then filtered. Recrystallization of the product from benzene-isooctane gave 57 g. (68%) of product which melted at 120°-122°C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:15]([CH2:21][CH3:22])([CH3:20])[C:16]([OH:19])=[N:17][N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:23](=O)([O-])[O-].[K+].[K+].CI>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:15]([CH2:21][CH3:22])([CH3:20])[C:16]([O:19][CH3:23])=[N:17][N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC1(C)C(O)=NN=C1C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: CCC1(C)C(OC)=NN=C1C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 85 °C
Reaction time: 7 h

Procedure:
A suspension of 49 mg (0.15 mmol) of 1-tert-butoxycarbonyl-4-(4-ethyl-3-hydroxy-4-methyl-(4H)-pyrazol-5-yl)piperidine (from Step A), 50 mg (0.36 mmol) of potassium carbonate and 0.06 mL (0.96 mmol) of methyliodide in 0.3 mL of acetonitrile was stirred at rt for 17 hours and 85° C. for 7 hours. The reaction was partitioned between 25 mL of EtOAc and 25 mL of brine. After separating phases, the organic layer was dried over Na2SO4 and concentrated. The residue was purified by flash chromatography using 4:1 v/v of hexanes/acetone as the eluant to afford the title compound as a colorless film: RF: 0.21 (4:1 v/v hexanes/acetone); 1H-NMR (500 MHz) δ 0.65 (t, J=7.4, 3H), 1.21 (s, 3H), 1.45 (s, 9H), 1.57–1.66 (m, 2H), 1.73–1.81 (m, 4H), 2.37 (m, 1H), 2.73–2.78 (m, 2H), 3.27 (s, 3H), 4.15–4.20 (m, 2H); 13C-NMR (125 MHz) δ 54.4 (O—CH3).
Reaction SMILES: Cl[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Br:15])[CH:8]=2)[N:3]=1.[NH3:16]>>[NH2:16][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Br:15])[CH:8]=2)[N:3]=1
Reactant: N
Reactant: O=[N+]([O-])c1cc2cc(Br)ccc2nc1Cl
Product: Nc1nc2ccc(Br)cc2cc1[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 2.5 h

Procedure:
0.8 g of 2-chloro-6-bromo-3-nitroquinoline (compound C4) are dissolved in 12 ml of ethanolic ammonia solution and stirred at 120° C. for 2.5 h in an autoclave. Under cooling in an ice bath, 0.55 g of the title compound precipitate from the reaction mixture as red crystals.
Reaction SMILES: C(OC([N:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[C:11](=[O:22])[N:10]2[CH:23]=[C:24]([CH2:26][C:27]([O:29][CH3:30])=[O:28])[CH2:25][C@H:9]2[C@@H:8]1O)=O)C=C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1CCCC1.C(Cl)(Cl)Cl.CO>C(Cl)Cl.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>[CH3:19][O:18][C:16]1[C:15]([O:20][CH3:21])=[CH:14][C:13]2[N:7]=[CH:8][C@@H:9]3[CH2:25][CH:24]([CH2:26][C:27]([O:29][CH3:30])=[O:28])[CH2:23][N:10]3[C:11](=[O:22])[C:12]=2[CH:17]=1
Reactant: C=CCOC(=O)N1c2cc(OC)c(OC)cc2C(=O)N2C=C(CC(=O)OC)C[C@H]2[C@@H]1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNC1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)CC1C[C@H]2C=Nc3cc(OC)c(OC)cc3C(=O)N2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A catalytic amount of tetrakis(triphenylphosphine)palladium (44.0 mg, 38.0 μmol) was added to a stirred solution of the Alloc-protected carbinolamine 41 (0.66 g, 1.53 mmol), triphenylphosphine (20.0 mg, 77.0 μmol) and pyrrolidine (114 mg, 1.60 mmol) in CH2Cl2 (100 mL). After 2 hours stirring at room temperature under a nitrogen atmosphere, TLC (99% CHCl3/MeOH) revealed the complete consumption of starting material. The solvent was evaporated in vacuo and the crude residue was purified by flash chromatography (98% CHCl3/MeOH) to afford the PBD (42, AN-SJG, UP2065) as an orange glass which was repeatedly evaporated in vacuo with CHCl3 in order to provide the N10-C11 imine form (481 mg, 95%): [α]22D=+401.84° (c=1.00, CHCl3); 1H NMR (270 MHz, CDCl3) δ7.87-7.85 (m, 1H), 7.49 (s, 1H), 6.93 (s, 1H), 6.81 (s, 1H), 4.34-4.27 (m, 1H), 3.95 (s, 3H), 3.93 (s, 3H), 3.74 (s, 3H), 3.34 (d, 1H, J=16.85 Hz), 3.24 (s, 2H), 3.19-3.10 (m, 1H); 13C NMR (67.8 MHz, CDCl3) δ170.6, 162.7, 161.4, 151.8, 147.7, 140.4, 126.5, 119.0, 117.4, 111.5, 109.8, 56.2, 56.1, 53.8, 52.1, 37.4, 33.6; MS (EI), m/z (relative intensity) 332 (+. +2, 5), 331 (M+. +1, 9), 330 (M+., 41), 329 (28), 328 (100), 313 (18), 272 (8), 271 (24), 270 (14), 269 (27), 262 (7), 257 (12), 255 (5), 242 (6), 225 (7), 197 (4), 192 (16), 191 (16), 183 (6), 164 (14), 136 (11), 135 (9), 106 (9), 80 (17), 53 (5); IR (CHCl3) 3329 (br), 3112, 2952, 2842, 1737, 1626, 1602, 1512, 1453, 1436, 1381, 1356, 1246, 1213, 1173, 1096, 1069, 1008, 875, 840, 786, 666, 620, 574, 537 cm−1; exact mass calcd for C17H18N2O, m/e 330.1216, obsd m/e 330.1237.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[N:7]=[CH:8][NH:9][C:10]=1[CH3:11].[C:12]([NH:14][C:15](=[N:18][CH3:19])SC)#[N:13]>C(#N)C>[C:12]([NH:14][C:15]([NH:18][CH3:19])=[N:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[N:7]=[CH:8][NH:9][C:10]=1[CH3:11])#[N:13]
Reactant: Cc1[nH]cnc1CSCCN
Reactant: CN=C(NC#N)SC
Solvent: CC#N
Product: CNC(=NCCSCc1nc[nH]c1C)NC#N

Procedure:
A solution of 17.0 g of 4-(2-aminoethyl)thiomethyl-5-methylimidazole and 11.2 g of N-cyano-N',S-dimethylisothiourea in 500 ml of acetonitrile was refluxed for 24 hours. The mixture was concentrated and the residue was chromatographed on a column of silica gel with acetonitrile as eluant. The product obtained was recrystallized from acetonitrile-ether to give N-cyano-N'-methyl-N"-[2-(5-methyl-4-imidazolylmethylthio)ethyl]guanidine, m.p. 141°-142°.