Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][C:9]([Cl:15])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Cl-].[NH4+].O>CO.[Fe]>[NH2:12][C:11]1[C:2]([Br:1])=[C:3]([CH:8]=[C:9]([Cl:15])[CH:10]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(Cl)cc([N+](=O)[O-])c1Br
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: COC(=O)c1cc(Cl)cc(N)c1Br
Temperature: 70 °C
Reaction time: 3 h
Yield: 51.8 %

Procedure:
To a solution of methyl 2-bromo-5-chloro-3-nitrobenzoate (4.0 g, 14 mmol) in methanol (130 ml) at room temperature was added ammonium chloride (7.13 g, 136 mmol) followed by deionized water (65 ml). The mixture was heated to 70° C. in air before the addition of iron (4.55 g, 81.5 mmol). The reaction was stirred at 70° C. for 3 hours, allowed to cool to room temperature and filtered through Kieselgel. The filter pad was washed with MeOH (65 ml) and the filtrate concentrated under reduced pressure. The residue was dissolved in saturated NaHCO3 (50 ml) and EtOAc (100 ml). The phases were separated and the organic phase was washed with saturated NaHCO3(aq) (3×50 ml) before being dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by FCC (50 g silica, Isolute cartridge, gradient of eluents; 95:5 Heptane:EtOAc to 7:3 Heptane:EtOAc) to give 1.92 g (48%) of the title compound as a colourless oil. LC-MS 92%, m/z=268.8/265.8/267.6, 1H NMR (500 MHz, Chloroform-d) δ 7.08 (1H, d, J=2.36 Hz), 6.86 (1H, d, J=2.36 Hz), 4.34-4.49 (2H, m), 3.93 (3H, s).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[C:18]([Cl:23])[CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:17]=1[NH:16][CH:15]=[C:14]2[CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2c[nH]c3c(Cl)cccc23)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1cccc2c(C3CCNCC3)c[nH]c12
Yield: 146.2 %

Procedure:
4-(7-Chloro-1H-indol-3-yl)-piperidine-1-carboxylic acid tert-butyl ester (3.4 g, 10.2 mmol) was set stirring in 1:1 TFA/CH2Cl2. After 45 min the mixture was evaporated and the golden oil brought up in Et2O. A solid formed and was filtered, washed with Et2O and air dried to give 3.5 g (97%) of a white solid. MS (electrospray): exact mass calculated for C12H15ClN2, 234.09; m/z found, 235.1 [M++H].
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[CH:5]=[CH:6][C:7]([OH:9])=[O:8].CO>O.[C].[Pd]>[OH:1][C:2]1[CH:3]=[C:4]([CH2:5][CH2:6][C:7]([OH:9])=[O:8])[CH:10]=[CH:11][C:12]=1[O:13][CH3:14]
Reactant: COc1ccc(C=CC(=O)O)cc1O
Agent: [Pd]
Solvent: O
Solvent: CO
Product: COc1ccc(CCC(=O)O)cc1O
Temperature: 50 °C
Reaction time: 5 h
Yield: 99.3 %

Procedure:
3-Hydroxy-4-methoxycinnamic acid (15.0 g, 77.2 mmo) and 10% palladium carbon in the water content of 50% (2.26 g) were added to a mixed solvent (330 ml) of methanol and water (mixing ratio of 10:1 v/v), and the mixture was stirred under hydrogen atmosphere of normal pressure (0.1 MPa) at 50° C. for 5 hours for reaction. The reaction solution was filtrated to remove the catalyst, and the filtrate was concentrated under reduced pressure to solidification to obtain 3-(3-hydroxy-4-methoxyphenyl) propionic acid (15.1 g, 76.7 mmol, yield: 99%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[CH:8]1[N:14]([CH3:17])[CH2:15][CH2:16][C:7]21[CH3:18])([O-])=O.[C:19]([O:22][CH2:23][CH3:24])(=[O:21])C>O=[Pt]=O>[CH2:23]([O:22][C:19]([NH:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[CH:8]1[N:14]([CH3:17])[CH2:15][CH2:16][C:7]21[CH3:18])=[O:21])[CH3:24]
Reactant: CCOC(C)=O
Reactant: CN1CCC2(C)c3cc([N+](=O)[O-])ccc3N(C)C12
Agent: O=[Pt]=O
Product: CCOC(=O)Nc1ccc2c(c1)C1(C)CCN(C)C1N2C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1,2,3,3a,8,8a-Hexahydro-5-nitro-1,3a,8-trimethylpyrrolo[2,3-b]indole (1.0 g) was dissolved in ethyl acetate (100 ml) and hydrogenated in a Parr apparatus at 45 psi using PtO2 (100 mg) as a catalyst. The reduction was complete within 2 hours. The reduction mixture was filtered directly into a nitrogen flushed flask. 4-Dimethylaminopyridine (50 mg) and triethylamine (0.14 g) were added, the mixture was cooled to 0° C. and a solution of ethylchloroformate (0.44 g) in ethyl acetate (70 ml) was added over a period of 1.5 hours. The mixture was washed with water (2×100 ml), dried (Na2SO4), concentrated and purified by flash chromatography on silica gel (eluting with 15% MeOH/EtOAc). The pure fractions were concentrated to give 5-ethoxycarbonylamino-1,2,3,3a,8,8a-hexahydro-1,3a,8-trimethylpyrrolo[2,3-b]indole (0.6 g). The oxalate salt was prepared by dissolving the free base in ether (200 ml) and a minimum amount of MeOH (20 ml) and adding a solution of oxalic acid in ether.
Reaction SMILES: [OH:1][C:2]1[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=2)[CH2:5][C:4](=[O:18])[C:3]=1[C:19](=O)[CH2:20][CH3:21].[CH2:23]([O:25][NH2:26])[CH3:24]>CO>[CH2:23]([O:25][N:26]=[C:19]([C:3]1[C:4](=[O:18])[CH2:5][CH:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=2)[CH2:7][C:2]=1[OH:1])[CH2:20][CH3:21])[CH3:24]
Reactant: CCON
Reactant: CCC(=O)C1=C(O)CC(c2ccc(C(=O)OC)cc2)CC1=O
Solvent: CO
Product: CCON=C(CC)C1=C(O)CC(c2ccc(C(=O)OC)cc2)CC1=O
Temperature: 0 °C
Reaction time: 15 h

Procedure:
Into 20 ml of methanol was dissolved 2.5 g of 3-hydroxy-5-(4-methoxycarbonylphenyl)-2-propionyl-2-cyclohexen-1-one and to the solution was added 0.7 g of ethoxyamine. The mixture was kept for 15 hours at room temperature and it was poured into ice water. The crystal sedimented was collected with a filtering step and recrystallized with mixture solvent of methanol-water. Thus, 1.9 g of the desired compound which was in the form of colorless crystals having a melting point of 75°-76° C. was obtained.
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([F:37])[CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl[CH2:40][C:41]([N:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1)=O>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:40][CH2:41][N:43]2[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]2)=[C:32]([F:37])[CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: O=C(CCl)N1CCCCC1
Reactant: CCN(C(=O)c1ccc(O)c(F)c1)c1cc(OC)ccc1[C@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(Cc1ccc(OCCN2CCCCC2)c(F)c1)c1cc(OC)ccc1[C@H]1CCc2cc(O)ccc2C1
Yield: 3.9 %

Procedure:
Synthesized from pivalic acid (S)-6-{2-[ethyl(3-fluoro-4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 2-chloro-1-piperidin-1-ylethanone (13 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (0.8 mg) was obtained.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Br:15]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:15][C:8]1[CH:9]=[C:4]([C:1](=[O:3])[CH3:2])[CH:5]=[CH:6][C:7]=1[NH:10][S:11]([CH3:14])(=[O:12])=[O:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)c1ccc(NS(C)(=O)=O)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)c1ccc(NS(C)(=O)=O)c(Br)c1
Temperature: 80 °C

Procedure:
A mixture of 2.13 g (10 mmol) of N-(4-acetylphenyl)methanesulfonamide, 1.78 g (10 mmol) of N-bromosuccinimide and 0.28 g of dibenzoyl peroxide in 100 ml of carbon tetrachloride is heated for 16 hrs at 80° C. (oil bath). The resulting product is concentrated and extracted with methylene chloride. The extract is deposited on silica gel and chromatographed with 1% methanol-methylene chloride to give a product which is recrystallized from methylene chloride-pet. ether; m.p. 124°-126° C. MW 292.17.
Reaction SMILES: Cl.[NH2:2][OH:3].[Na].[C:5]([C:7]1[CH:12]=[CH:11][N:10]=[C:9]([N:13]([CH3:15])[CH3:14])[CH:8]=1)#[N:6]>CO>[CH3:14][N:13]([CH3:15])[C:9]1[CH:8]=[C:7]([C:5](=[N:2][OH:3])[NH2:6])[CH:12]=[CH:11][N:10]=1
Reactant: NO
Reactant: CN(C)c1cc(C#N)ccn1
Agent: Cl
Agent: [Na]
Solvent: CO
Product: CN(C)c1cc(C(N)=NO)ccn1
Temperature: 25 °C
Yield: 134.8 %

Procedure:
To a solution of hydroxylamine hydrochloride (0.47 g, 7.0 mmol) in methanol (10 mL) was added sodium metal (0.16 g, 7.0 mmol) portionwise. After all the sodium metal had dissolved 4-cyano-2-dimethylaminopyridine (1.0 g, 7.0 mmol) was added and the reaction was heated to reflux for 4 hours. The reaction was cooled to room temperature, filtered to remove precipitated sodium chloride and the filtrate was evaporated to dryness. The residue was dissolved in ethanol in order to crystallise the product but this was unsuccessful, so the solvent was removed in vacuo to give the title compound as a white solid (1.7 g), which was contaminated with ethanol.
Reaction SMILES: [CH2:1]([C:8]1[S:9][CH:10]=[C:11]([CH2:13][OH:14])[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[O-2].[O-2].[Mn+4].C1C=CC=CC=1>[CH2:1]([C:8]1[S:9][CH:10]=[C:11]([CH:13]=[O:14])[N:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1csc(Cc2ccccc2)n1
Agent: [Mn+4]
Agent: [O-2]
Solvent: c1ccccc1
Product: O=Cc1csc(Cc2ccccc2)n1
Temperature: 20 °C
Reaction time: 20 h
Yield: 60.6 %

Procedure:
2.1 g of manganese dioxide were added to a mixture of 0.5 g of (2-benzyl-4-thiazolyl)-methanol and 10 ml of benzene and the mixture was stirred at 20° C. for 20 hours and was filtered. The filtrate was evaporated to dryness and the residue was chromatographed over silica gel.Elution with a 7-3 hexane-ethyl acetate mixture yielded 0.3 g of (2-benzyl-4-thiazolyl)-methanal melting at 78° C.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:12][CH3:13])[O:4][CH2:3]1.[CH3:14][C:15]([CH3:17])=O.[BH3-]C#N.[Na+]>C(O)(=O)C.CO>[CH:15]([NH:1][C@@H:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:12][CH3:13])[O:4][CH2:3]1)([CH3:17])[CH3:14]
Reactant: COc1cccc2c1C[C@@H](N)CO2
Reactant: CC(C)=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1cccc2c1C[C@@H](NC(C)C)CO2
Reaction time: 72 h

Procedure:
(R)-3-Amino-5-methoxychroman (1.0 g; 6 mmol) and acetone (2.5 g; 40 mmol) were mixed with methanol (820 ml), acetic acid (0.4 g; 6.6 mmol) and NaCNBH3 (1.2 g; 19 mmol), pH was adjusted to 6.0 with acetic acid. Stirring was continued at room temperature for 3 days. The mixture was evaporated and the residue was made alkaline and extracted with CH2Cl2. After drying (Na2SO4) and evaporation the title compound as base was transformed to the HCl-salt. Yield: 1.1 g (83%). Mp: 289° dec. [α]D25 =-29° (C=0.015; MeOH)
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][C:7]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[NH:11][N:10]=[C:9]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])[S:8]1)=[N+:2]=[N-:3].C(N(CC)CC)C.[C:33](Cl)(=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35]>C(Cl)Cl>[N:1]([CH2:4][CH2:5][CH2:6][C:7]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:11]([C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])[N:10]=[C:9]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])[S:8]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCCCC1(c2ccccc2)NN=C(c2cc(F)ccc2F)S1
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)N1N=C(c2cc(F)ccc2F)SC1(CCCN=[N+]=[N-])c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.5 %

Procedure:
To a cooled (0° C.) solution of 2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazole (100 mg, 0.278 mmol) in DCM (5 mL) was added triethylamine (50.4 μL, 0.362 mmol) followed by pivaloyl chloride (45 μL, 0.362 mmol). After warming slowly to room temperature and stirring for 16 hours, the mixture was partitioned between DCM (10 mL) and saturated NaHCO3 (10 mL). The aqueous layer was extracted with DCM (10 mL) and the combined organics were washed with brine (10 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was chromatographed (19:1 hexanes/ethyl acetate) to provide the product as a pale yellow oil (114 mg, 92%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16](=[O:31])[N:17]3[C:22](=[C:23]([C:25]([OH:27])=O)[CH:24]=2)[C:21]2[S:28][CH:29]=[CH:30][C:20]=2[CH:19]=[CH:18]3)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=S(Cl)Cl.CN(C=O)C.[CH:41]1([CH2:44][NH:45][CH2:46][CH2:47][O:48][CH3:49])[CH2:43][CH2:42]1>C1(C)C=CC=CC=1.ClCCl.C(N(CC)CC)C>[CH:41]1([CH2:44][N:45]([CH2:46][CH2:47][O:48][CH3:49])[C:25]([C:23]2[CH:24]=[C:15]([C:12]3[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:10][CH:11]=3)[C:16](=[O:31])[N:17]3[C:22]=2[C:21]2[S:28][CH:29]=[CH:30][C:20]=2[CH:19]=[CH:18]3)=[O:27])[CH2:43][CH2:42]1
Reactant: COCCNCC1CC1
Reactant: O=C(O)c1cc(-c2ccc(OCc3ccccc3)cc2)c(=O)n2ccc3ccsc3c12
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: COCCN(CC1CC1)C(=O)c1cc(-c2ccc(OCc3ccccc3)cc2)c(=O)n2ccc3ccsc3c12

Procedure:
From 8-[p-(benzyloxy)phenyl]-7-oxo-7H-thieno[2,3-a]quinolizine-10-carboxylic acid with SOCl2 and DMF in toluene. Then treatment with triethylamine and cyclopropylmethyl-(2-methoxy-ethyl)-amine in dichloromethane.
Reaction SMILES: [CH3:1][C:2]([N:6]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[N:8]=[CH:7]1)([CH3:5])[CH:3]=O.[F:14][C:15]([F:19])([F:18])[CH2:16][NH2:17]>>[CH3:1][C:2]([N:6]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[N:8]=[CH:7]1)([CH3:5])[CH2:3][NH:17][CH2:16][C:15]([F:19])([F:18])[F:14]
Reactant: CC(C)(C=O)n1cnc([N+](=O)[O-])c1
Reactant: NCC(F)(F)F
Product: CC(C)(CNCC(F)(F)F)n1cnc([N+](=O)[O-])c1

Procedure:
2-Methyl-2-(4-nitro-imidazol-1-yl)-propionaldehyde was reacted with 2,2,2-trifluoro-ethyl amine to provide the title compound: H1 NMR (400 MHz, CDCl3) 1.59 (s, 6H), 2.98 (s, 2H), 3.10 (m, 2H), 7.56 (s, 1H), 7.90 (s, 1H) MS m/z267.3 (M+1).
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.O.N([O-])=O.[Na+].[C:14](=[S:19])([O:16][CH2:17][CH3:18])[S-:15].[K+]>Cl.C(OCC)(=O)C>[C:14](=[S:15])([O:16][CH2:17][CH3:18])[S:19][C:2]1[CH:7]=[N:6][C:5]([Cl:8])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)nc1
Reactant: CCOC(=S)[S-]
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=S)Sc1ccc(Cl)nc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 21 %

Procedure:
In 1N hydrochloric acid (10 ml) was dissolved 5-amino-2-chloropyridine (643 mg, 3.00 mmol). A water (1 ml) solution of sodium nitrite (207 mg, 3.00 mmol) was added dropwise to the resulting solution at −5° C. After the reaction mixture was stirred at 60° C. for 30 minutes, a water (1 ml) solution of potassium O-ethyl dithiocarbonate (481 mg, 3.00 mmol) was added dropwise thereto at the same temperature. The reaction mixture was then stirred at 80° C. for 1 hour, followed by cooling to room temperature. Ethyl acetate was added, and the resulting mixture was washed with a saturated aqueous solution of sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was subjected to flash chromatography on a silica gel column, and the fraction obtained from the hexane:ethyl acetate=49:1 eluate was concentrated under reduced pressure, whereby the title compound (148 mg, 0.63 mmol, 21%) was obtained as a yellow oil.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:13])(=[O:3])[CH3:2].[C:14]([C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19](O)=[O:20])#[N:15].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:19]([OH:20])[C:18]2[CH:22]=[CH:23][CH:24]=[C:16]([C:14]#[N:15])[CH:17]=2)[C:5]1=[O:13])(=[O:3])[CH3:2]
Reactant: N#Cc1cccc(C(=O)O)c1
Reactant: CC(=O)N1C(=O)Cc2ccccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(=O)N1C(=O)C(=C(O)c2cccc(C#N)c2)c2ccccc21

Procedure:
Prepared from 1-acetyl-2-indolinone and 3-cyano-benzoic acid in dry DMF in the presence of TBTU, HOBT and Huinig's base (35° C., for 2 hours) and final purification by column chromatography on silica gel with CH2Cl2 /MeOH (10:1) as eluant.
Reaction SMILES: [OH-].[Na+].[CH3:3][NH:4][C:5]1[N:10]=[C:9]([CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C@H:21]([C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)[CH2:22][C:23]([O:25]CC)=[O:24])=[CH:16][CH:15]=2)[CH:8]=[CH:7][CH:6]=1.Cl>O1CCOCC1.O.C(Cl)Cl>[CH3:3][NH:4][C:5]1[N:10]=[C:9]([CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C@H:21]([C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)[CH2:22][C:23]([OH:25])=[O:24])=[CH:16][CH:15]=2)[CH:8]=[CH:7][CH:6]=1
Reactant: CCOC(=O)C[C@H](Cc1ccc(OCCc2cccc(NC)n2)cc1)c1cccnc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: CNc1cccc(CCOc2ccc(C[C@@H](CC(=O)O)c3cccnc3)cc2)n1
Temperature: 50 °C
Reaction time: 18 h
Yield: 92.4 %

Procedure:
2.0 M NaOH (15 mL, 30 mmole) was added to a solution of ethyl (S)-4-[4-[2-[6-(methylamino)pyridin-2-yl]ethoxy]phenyl]-3-(pyridin-3-yl)butanoate (9.2 g, 22 mmole) in dioxane/H2O (100 mL), and the mixture was heated at 50° C. After 18 hr, the reaction was cooled to RT, acidified with 10% HCl (25 mL), and concentrated to 1/3 volume to precipitate a gum. The supernatant was decanted and the gum was partitioned between H2O and CHCl3. The layers were separated and the aqueous layer was extracted with CHCl3 (3×). The combined organic layers were dried (MgSO4)and concentrated, and the residue was taken up in H2O and 2 M NaOH (30 mL). The solution was washed with Et2O (3×), and the Et2O extracts were discarded. The aqueous solution was acidified with 10% HCl (50 mL), concentrated to 1/3 volume, and extracted with CHCl3 (3×). The organic layers were combined, dried (MgSO4), and concentrated to leave a foam. This foam was taken up in CH2Cl2, and the solution was diluted with hexanes and concentrated. This process was repeated three times. The resulting solid was dried in vacuo at 65° C. to afford the title compound (7.96 g, 92%): 1H NMR (400 MHz, MeOH-d4) δ 88.28 (narrow m, 1 H), 8.21 (d, J=1.7 Hz, 1 H), 7.68 (narrow m, 1 H), 7.48 (dd, J=8.5, 7.3 Hz, 1 H), 7.30 (dd, J=7.9, 4.9 Hz, 1 H), 6.91 (d, J=8.6 Hz, 2 H), 6.72 (d, J=8.6 Hz, 2 H), 6.56 (d, J=7.3 Hz, 1 H), 6.44 (d, J=8.5 Hz, 1 H), 4.20 (t, J=6.6 Hz, 2 H), 3.31-3.42 (m, 1 H), 3.02 (t, J=6.6 Hz, 2 H), 2.97 (dd, J=13.6, 6.5 Hz, 1 H), 2.87 (s, 3 H), 2.77 (dd, J=13.6, 8.9 Hz, 1 H), 2.71 (dd, J=15.6, 6.4 Hz, 1 H), 2.62 (dd, J=15.6, 8.9 Hz, 1 H); MS (ES) m/e 392 (M+H)+. Anal. Calcd for C23H25N3O3.0.1H2O: C, 70.25; H, 6.46; N, 10.68. Found: C, 70.32; H, 6.50; N, 10.32.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].[Br:14][C:15]1[S:23][C:22]2[C:21](=[O:24])[NH:20][C:19]([CH2:25]Cl)=[N:18][C:17]=2[CH:16]=1>CN(C)C=O>[Br:14][C:15]1[S:23][C:22]2[C:21](=[O:24])[NH:20][C:19]([CH2:25][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[N:18][C:17]=2[CH:16]=1
Reactant: O=c1[nH]c(CCl)nc2cc(Br)sc12
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1[nH]c(CN2CCCC2)nc2cc(Br)sc12
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
To a mixture of pyrrolidine (2.2 mL), potassium carbonate (2.5 g), sodium iodide (134 mg) and N,N-dimethylformamide (40 mL) was added 6-bromo-2-(chloromethyl)thieno[3,2-d]pyrimidin-4(3H)-one (2.5 g), and the mixture was stirred at 70° C. for 30 min. Insoluble material was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was washed with a small amount of ethyl acetate to give the title compound (1.5 g) as a pale-yellow solid. The filtrate was purified by basic silica gel column chromatography (methanol/ethyl acetate) to give the title compound (0.87 g) as a pale-yellow solid. The total yield of the title compound was 2.37 g.
Reaction SMILES: [CH:1]1([C:4]([C:6]2[C:7]([CH3:25])=[N:8][C:9]3[S:10][C:11]4[CH2:12][NH:13][CH2:14][CH2:15][C:16]=4[C:17]=3[C:18]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:5])[CH2:3][CH2:2]1>C1(C=CC2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH:1]1([C:4]([C:6]2[C:7]([CH3:25])=[N:8][C:9]3[S:10][C:11]4[C:16]([C:17]=3[C:18]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:15][CH:14]=[N:13][CH:12]=4)=[O:5])[CH2:2][CH2:3]1
Reactant: Cc1nc2sc3c(c2c(-c2ccccc2)c1C(=O)C1CC1)CCNC3
Agent: [Pd]
Agent: C(=Cc1ccccc1)c1ccccc1
Product: Cc1nc2sc3cnccc3c2c(-c2ccccc2)c1C(=O)C1CC1
Temperature: 150 °C
Yield: 7.7 %

Procedure:
To a stirred solution of 0.46 g (1.32 mmol) cyclopropyl-(2-methyl-4-phenyl-5,6,7,8-tetrahydro-9-thia-1,7-diaza-fluoren-3-yl)-methanone in 7 ml diphenylethylene was added 230 mg palladium on charcoal 10%. The mixture was stirred over night at 150° C., and then poured onto ethyl acetate (about 150 ml), and extracted three times aqueous HCl (1M). The combined aqueous phases were basified with K2CO3 until ph=8, and then the product was extracted with ethyl acetate. The combined organic phase were dried over sodium sulfate and concentrated in vacuo. Flash chromatography (heptane/ethyl acetate 1:1) afforded 35 mg (8%) cyclopropyl-(2-methyl-4-phenyl-9-thia-1,7-diaza-fluoren-3-yl)-methanone as a light yellow solid. ES-MS m/e (%): 345 (M+H+, 100).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:12]([CH2:14][N:15]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]([CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[CH2:18][C@@H:17]([NH:32][C:33]([NH:35][C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([O:44]C(C)(C)C)=[O:43])[CH:37]=2)=[O:34])[C:16]1=[O:49])=[O:13])([CH3:11])([CH3:10])[CH3:9]>C(Cl)Cl>[C:8]([C:12]([CH2:14][N:15]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]([CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[CH2:18][C@@H:17]([NH:32][C:33](=[O:34])[NH:35][C:36]2[CH:37]=[C:38]([CH:39]=[CH:40][CH:41]=2)[C:42]([OH:44])=[O:43])[C:16]1=[O:49])=[O:13])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)c1cccc(NC(=O)N[C@@H]2CN(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)C(=O)CN1C(=O)[C@H](NC(=O)Nc2cccc(C(=O)O)c2)CN(C2CCCCC2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
Trifluoroacetic acid (40 ml) was added to a solution of (R)-(−)-1-(1-tert-butylcarbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-tert-butoxycarbonylphenyl)urea (8 g) in methylene chloride (40 ml), the mixture was stirred for one hour at room temperature. The reaction mixture was concentrated under reduced pressure, a mixed solvent (32 ml) of diisopropyl ether and ethanol (15:1) was added to the residue for crystallization, collected by filtration, to thereby obtain 6.35 g of the title compound (Yield 88%).
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].[Na].[C:10](#[N:13])[CH:11]=[CH2:12].O>C(O)C>[NH2:13][C:10]1[CH2:11][CH2:12][N:1]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=2)[N:2]=1
Reactant: NNc1ccccn1
Reactant: C=CC#N
Agent: [Na]
Solvent: O
Solvent: CCO
Product: NC1=NN(c2ccccn2)CC1

Procedure:
2-Hydrazinopyridine (0.545 g) was added to a solution of sodium (50 mg; 0.43 atoms) in dry absolute ethanol (2 ml) in a nitrogen atmosphere. Acrylonitrile (0.265 g; 0.32 ml; 1 mol) was added dropwise and the resulting solution heated for 4 hours on the steam bath. The reaction mixture was cooled, giving some crystals, and treated with water (10 ml) to give a suspension of a solid. The solid was collected and washed with water. Recrystallisation from ethanol (ca. 5 ml) gave the title compound m.p. 168°-169.5°. Thin Layer Chromatography: On Al2O3 in CHCl3 gave a single spot Rf 0.18.