Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[C:3]1([C:5](=[CH:7][CH:8]=[CH:9][CH:10]=1)[OH:6])[OH:4].[C:11](Cl)(Cl)=[S:12]>>[O:4]1[C:3]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[O:6][C:11]1=[S:12]
Reactant: S=C(Cl)Cl
Reactant: Oc1ccccc1O
Agent: [Na+]
Agent: [OH-]
Product: S=c1oc2ccccc2o1

Procedure:
To 200 ml of aqueous sodium hydroxide (16.00 g, 0.400 mol) at 5° was added catechol (22.00 g, 0.200 mole). The resulting dark green solution was stirred magnetically and maintained at 5°-10° while thiophosgene (17 ml, 25.5 g, 0.22 mol) was added dropwise over 2 hours. The green color of the solution was discharged during the addition and an orange-brown precipitate formed. The mixture was filtered through a Buchner funnel into a saturated solution of aqueous sodium hydroxide to destroy any residual thiophosgene. The solid thus collected on the funnel was washed with 1.5 l of water and dried to give 27.41 (90 percent) of the crude 1,3-benzodioxole-2-thione (I): mp 151°-153° (sealed capillary; lit. mp 154°, 158°-158.5°). Sublimation twice at 150° (1 atm) gave white needles in 81 percent overall yield (lit. 25 percent): mp 158°-159.5° sealed capillary).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([O:9][S:10](=[O:12])(=[O:11])[C:4]2=[CH:3][CH:2]=1)=[O:8].[OH-:13].[Na+:14]>O>[Na+:14].[S:10]([C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][C:5]=1[C:7]([O-:13])=[O:8])([OH:9])(=[O:12])=[O:11]
Reactant: O=C1OS(=O)(=O)c2ccccc21
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: O=C([O-])c1ccccc1S(=O)(=O)O

Procedure:
20 g (108.6 mmoles) of 2-sulfobenzoic acid cyclic anhydride were added to a beaker containing 250 mL of water. After the reactant dissolved, 4.4 g (110 mmoles) of sodium hydroxide were added. After the water was removed, 22.9 g (94% of theory) of a white powder product, I-32, the title compound, were recovered.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[N:13]([C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)[N:12]=[CH:11][CH:10]=2)=[C:5]([CH3:22])[N:4]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)[C:3]1=[O:33].[B-](F)(F)(F)[F:35].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.Cl.C(OCC)(=O)C>C(#N)C>[CH3:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[N:13]([C:14]3[CH:15]=[CH:16][C:17]([C:18]#[N:19])=[CH:20][CH:21]=3)[N:12]=[CH:11][C:10]=2[F:35])=[C:5]([CH3:22])[N:4]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:30])([F:31])[F:32])[CH:24]=2)[C:3]1=[O:33]
Reactant: F[B-](F)(F)F
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)c(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Agent: Cl
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1c(-c2c(F)cnn2-c2ccc(C#N)cc2)c(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 22.9 %

Procedure:
To a solution of 4-(5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile (prepared in Example 1) (1.0 g) in acetonitrile (20 ml) was added Selectfluor (trade mark) (1.2 g) and the resulting mixture was stirred at 80° C. for four hours. To the reaction mixture was added 10% hydrochloric acid followed by an addition of ethyl acetate (20 ml×2) such the intended products were extracted into an organic layer. The organic layer was washed with saturated saline (20 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford 4-(5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-4-fluoro-1H-pyrazol-1-yl)benzonitrile (238 mg). UPLC/MS 470 (M+H)/1.023 min. (measurement condition 9)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH2:9]Br.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C(N(CC)CC)C.C(OC(=O)C)C>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH2:9][N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: C1COCCN1
Reactant: Clc1ccc(Br)c(CBr)c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Clc1ccc(Br)c(CN2CCOCC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
A mixture of 0.50 g (1.76 mmol) 1-Bromo-2-bromomethyl-4-chloro-benzene, 0.17 g (1.94 mmol) morpholine and 0.29 ml (210 mmol) triethylamine in 20 ml DMF was stirred overnight at room temperature. 200 ml of ethylacetate was added and the solution was extracted with sodium bicarbonate, water and brine. 0.47 g (1.62 mmol, 92%) of the title compound were obtained as a viscous oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].[N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1[CH:15]=O>>[N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1[CH2:15][NH:1][CH2:2][CH2:3][OH:4]
Reactant: NCCO
Reactant: O=Cc1ccc2ccccc2n1
Product: OCCNCc1ccc2ccccc2n1

Procedure:
prepared by reaction of 2-amino-ethanol with quinoline-2-carbaldehyde
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][CH2:5]2.Cl.Cl[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]Cl.C(=O)([O-])[O-].[K+].[K+]>ClC1C=CC=CC=1>[O:8]1[C:9]2[C:4](=[CH:3][C:2]([N:1]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[CH:11][CH:10]=2)[CH2:5][CH2:6][CH2:7]1
Reactant: ClCCNCCCl
Reactant: Nc1ccc2c(c1)CCCO2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Clc1ccccc1
Product: c1cc2c(cc1N1CCNCC1)CCCO2

Procedure:
A solution of 6-aminochroman from part 2 of this example (0.300 g, 2.013 mmol), bis-(2-choroethyl)amine hydrochloride (0.539 g, 3.020 mmol) and potassium carbonate (0.278 g, 2.013 mmol) in 10 mL chlorobenzene is heated at reflux for 24 h . The dark brown reaction mixture is then partitioned between 3N NaOH and methylene chloride. The organic layer is separated, dried over Mg2SO4, filtered and concentrated. Purification by flash column chromatography (5% methanol-methylene chloride) affords 0.157 g (36%) of 1-(chroman-6-yl) piperazine as a white solid, TLC Rf 0.35 (elution with 10% methanol-methylene chloride).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:18])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.[F:19][C:20]1[N:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]2=[N:22][C:21]=1[C:29](O)=[O:30]>>[Cl:17][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:29]([C:21]3[N:22]=[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]4[C:20]=3[F:19])=[O:30])[CH3:18])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: O=C(O)c1nc2ccccn2c1F
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1nc2ccccn2c1F

Procedure:
The title compound was prepared using the method of Example 34(d) starting from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (200 mg, 0.767 mmol) and 3-fluoroimidazo[1,2-a]pyridine-2-carboxylic acid (180 mg, 0.997 mmol). The product was triturated with acetonitrile. Yield 217 mg (67%). 1H-NMR (400 MHz; d6-DMSO): δ 1.15 (d, 3H), 4.31-4.44 (m, 2H), 4.47-4.55 (m, 1H), 6.95 (d, 1H), 7.06 (t, 1H), 7.37 (m, 1H), 7.55-7.58 (m, 1H), 7.85 (d, 1H), 7.97 (d, 1H), 8.08 (t, 1H), 8.31 (1H, d), 8.55 (d, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([CH2:15][O:14][C:13]3[CH:16]=[C:17]4[C:21](=[CH:22][C:12]1=3)[CH2:20][CH2:19][O:18]4)[C:5](=[O:11])[NH:6]2.N1C2C(=CC=CC=2)[C:25]2([CH2:35][O:34][C:33]3[CH:36]=C4C(=C[C:32]2=3)CCO4)C1=O.CC1C=CC(S(OC[C@H]2CCCO2)(=O)=O)=CC=1.BrCC1CCCCO1>>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([CH2:15][O:14][C:13]3[CH:16]=[C:17]4[C:21](=[CH:22][C:12]1=3)[CH2:20][CH2:19][O:18]4)[C:5](=[O:11])[N:6]2[CH2:36][C@H:33]1[CH2:32][CH2:25][CH2:35][O:34]1
Reactant: O=C1Nc2cccc(Br)c2C12COc1cc3c(cc12)CCO3
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Agent: BrCC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)OC[C@H]2CCCO2)cc1
Product: O=C1N(C[C@H]2CCCO2)c2cccc(Br)c2C12COc1cc3c(cc12)CCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 4′-bromo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and (R)-(tetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate to replace 2-(bromomethyl)tetrahydro-2H-pyran, 4′-bromo-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one was obtained (75%) as a colorless solid: mp 137-141° C.; 1H NMR (300 MHz, DMSO-d6) (diastereomers) δ7.30-7.10 (m, 3H), 6.42-6.37 (m, 1H), 6.32 (s, 1H), 4.88 (d, J=9.63 Hz, 1H), 4.70-4.63 (m, 1H), 4.46 (t, J=8.6 Hz, 2H), 4.18-4.05 (m, 1H), 3.85-3.52 (m, 4H), 2.93 (t, J=8.5 Hz, 2H), 2.01-1.67 (m, 3H), 1.64-1.49 (m, 1H); 13C NMR (75 MHz, DMSO-d6) δ177.5 (2), 162.2, 161.8, 145.7, 130.9, 130.2 (2), 126.6, 119.9 (2), 119.0 (2), 118.9 (2), 118.1, 92.5, 77.5, 76.3, 76.1, 72.5, 67.7 (2), 65.4, 58.7, 44.5, 29.0 (2), 28.7, 25.5; MS (ES+) m/z 443.9 (M+1), 445.9 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:4]=1[C:5](O)=O.Cl.Cl.[NH2:18][C:19]1[C:24]([NH2:25])=[CH:23][CH:22]=[C:21]([O:26][CH3:27])[N:20]=1>P(Cl)(Cl)(Cl)=O>[CH3:1][N:2]([CH3:15])[C:3]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:4]=1[C:5]1[NH:25][C:24]2[C:19]([N:18]=1)=[N:20][C:21]([O:26][CH3:27])=[CH:22][CH:23]=2
Reactant: COc1ccc(N)c(N)n1
Reactant: CN(C)c1cc([N+](=O)[O-])ccc1C(=O)O
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2[nH]c(-c3ccc([N+](=O)[O-])cc3N(C)C)nc2n1

Procedure:
An amount of 0.45 gm of 2-dimethylamino-4-nitro-benzoic acid is suspended in 15 ml of phosphorus oxychloride, and 0.45 gm of 2,3-diamino-6-methoxy-pyridine dihydrochloride are added. The mixture is refluxed for two hours and after cooling poured onto water. The aqueous solution is made ammoniacal with cooling, and the product precipitated is treated as in Example 4(b).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([NH:7][C:8]([C:10]2[CH:11]=[CH:12][CH:13]=[C:14]3[O:18][CH:17]=[CH:16][C:15]=23)=[O:9])[CH2:2]1.[C:19]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:20]([C:25](O)=[O:26])=[CH:21][CH:22]=[CH:23][CH:24]=1>>[C:19]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:20]([C:25]([N:1]2[CH2:6][CH2:5][CH2:4][C@@H:3]([NH:7][C:8]([C:10]3[CH:11]=[CH:12][CH:13]=[C:14]4[O:18][CH:17]=[CH:16][C:15]=34)=[O:9])[CH2:2]2)=[O:26])=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(O)c1ccccc1-c1ccccc1
Reactant: O=C(N[C@@H]1CCCNC1)c1cccc2occc12
Product: O=C(N[C@@H]1CCCN(C(=O)c2ccccc2-c2ccccc2)C1)c1cccc2occc12

Procedure:
prepared by reaction of (R)-benzofuran-4-carboxylic acid piperidin-3-ylamide with biphenyl-2-carboxylic acid acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:39][CH3:40])=[C:6]([CH2:8][C:9]2[N:13]3[N:14]=[C:15](Cl)[CH:16]=[CH:17][C:12]3=[N:11][C:10]=2[CH2:19][N:20]([CH2:34][CH2:35][CH:36]([CH3:38])[CH3:37])[C:21]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[C:24]=2[Cl:33])=[O:22])[CH:7]=1.[CH3:41][NH2:42].C1COCC1>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:39][CH3:40])=[C:6]([CH2:8][C:9]2[N:13]3[N:14]=[C:15]([NH:42][CH3:41])[CH:16]=[CH:17][C:12]3=[N:11][C:10]=2[CH2:19][N:20]([CH2:34][CH2:35][CH:36]([CH3:37])[CH3:38])[C:21]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[C:24]=2[Cl:33])=[O:22])[CH:7]=1
Reactant: CN
Reactant: COc1ccc(Br)cc1Cc1c(CN(CCC(C)C)C(=O)c2ccc(OC)c(OC)c2Cl)nc2ccc(Cl)nn12
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CNc1ccc2nc(CN(CCC(C)C)C(=O)c3ccc(OC)c(OC)c3Cl)c(Cc3cc(Br)ccc3OC)n2n1
Temperature: 150 °C
Yield: 24 %

Procedure:
A solution of 130 mg (0.2 mmol) N-({3-[(5-bromo-2-methoxyphenyl)methyl]-6-chloro(imidazolo[1,2-b]pyridazin-2-yl)}methyl)(2-chloro-3,4-dimethoxyphenyl)-N-(3-methylbutyl)carboxamide in DMSO (3 mL) is treated with 2M methyl amine in THF 1.5 mL (3.0 mmol). The reaction mixture is heated to 150° C. in a sealed tube for 18 hr and following cooling partitioned between ethyl acetate and water. The organic extract is washed with 5×10 mL water, dried over anhydrous MgSO4 and the solvent removed in vacuo to give the crude residue. The residue is prep-plate chromatographed (9% MeOH/CH2Cl2/0.5% NH4OH) to afford 31 mg (24%) of the title compound. Mass Spec m/z (M++1) 646.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.ClC1C=C(N2[C:23]([C:24]3[CH:29]=[C:28]([F:30])[CH:27]=[C:26](Cl)[CH:25]=3)=[CH:22][C:21]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=N2)C=CC=1F>>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:23]([C:24]3[CH:25]=[CH:26][CH:27]=[C:28]([F:30])[CH:29]=3)=[CH:22][C:21]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[N:10]2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccc(F)c(Cl)c2)n1
Reactant: NNc1ccc(Cl)cc1
Agent: Cl
Product: CCOC(=O)c1cc(-c2cccc(F)c2)n(-c2ccc(Cl)cc2)n1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 8A and 4-chlorophenylhydrazine hydrochloride in analogy to the synthesis of the compound of Example 21A. 43.4 g (87% of theory) of the title compound are obtained.
Reaction SMILES: [H-].[Na+].[CH2:3]([C@H:6]1[CH2:10][NH:9][C:8](=[O:11])[CH2:7]1)[CH2:4][CH3:5].[CH3:12][O:13][C:14](=[O:20])[C:15](C)(Br)[CH2:16][CH3:17]>O1CCCC1.O>[CH3:12][O:13][C:14](=[O:20])[CH:15]([N:9]1[CH2:10][C@H:6]([CH2:3][CH2:4][CH3:5])[CH2:7][C:8]1=[O:11])[CH2:16][CH3:17]
Reactant: CCC(C)(Br)C(=O)OC
Reactant: CCC[C@H]1CNC(=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCC[C@@H]1CC(=O)N(C(CC)C(=O)OC)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 84.1 %

Procedure:
A slurry of 60% sodium hydride suspension in mineral oil (0.94 g, 23.4 mmol) in tetrahydrofuran (30 mL) is cooled at 0° C. under a nitrogen atmosphere. A solution of substantially optically pure (R)-4-propyl-pyrrolidin-2-one (IIIa) (2 g, 15.7 mmol) in tetrahydrofuran (2 mL) is added over a 15 minutes period. The reaction mixture is stirred 10 min at 0° C. then a solution of methyl-2-bromo-butyric acid methyl ester (V) (3.69 g, 20.4 mmol) in tetrahydrofuran (2 mL) was added over a 20 minutes period. The reaction mixture is stirred at 0° C. until maximum conversion of starting material and the reaction mixture is then allowed to warm to room temperature and diluted with water (20 mL). Tetrahydrofuran is removed by evaporation and the residue is extracted with isopropyl acetate (20 ml+10 mL). The combined organic layers are dried on anhydrous magnesium sulfate and evaporated to afford 3 g (13.2 mmol, 86%) of a mixture of epimers of compound (VIa), as a mixture respectively of epimer (VIaa) and epimer (VIab).
Reaction SMILES: C([O-])(=O)C.[NH4+].[C:6]1([S:12]([N:15]2[C:23]3[C:18](=[CH:19][C:20]([CH:24]=O)=[CH:21][CH:22]=3)[C:17]3[CH:26]=[C:27]([Cl:30])[CH:28]=[N:29][C:16]2=3)(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[N+:31]([CH3:34])([O-:33])=[O:32]>>[C:6]1([S:12]([N:15]2[C:23]3[C:18](=[CH:19][C:20]([CH:24]=[CH:34][N+:31]([O-:33])=[O:32])=[CH:21][CH:22]=3)[C:17]3[CH:26]=[C:27]([Cl:30])[CH:28]=[N:29][C:16]2=3)(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccc2c(c1)c1cc(Cl)cnc1n2S(=O)(=O)c1ccccc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: O=[N+]([O-])C=Cc1ccc2c(c1)c1cc(Cl)cnc1n2S(=O)(=O)c1ccccc1
Reaction time: 2 h
Yield: 89.5 %

Procedure:
Solid ammonium acetate (121 mg, 1.1 equiv. 1.56 mmol) was added to solution of 9-benzenesulfonyl-3-chloro-9H-pyrido[2,3-b]indole-6-carbaldehyde (524 mg, 1.42 mmol) in nitromethane (5.5 mL). The mixture was vigorously stirred and boiled at 100° C. for 2 h. Then the mixture was cooled in an ice bath and concentrated under reduced pressure. Trituration of the crude residue from ethanol followed by filtration afforded 14 (528 mg, 89.5%), 1H-NMR (300 MHz, CDCl3): δ 8.81 (d, 1H, J=1.6 Hz), 8.70 (d, 1H, J=2.3 Hz), 8.65 (d, 1H, J=2.3 Hz), 8.42 (d, 1H, J=8.8 Hz), 8.25 (s, 2H), 8.17 (dd, 1H, J=1.6, 8.9 Hz), 8.09 (d, 1H, J=7.2 Hz), 8.09 (d, 1H, J=8.8 Hz), 7.71 (t, 1H, J=7.4 Hz), 7.60 (d, 1H, J=8.1 Hz), 7.58 (t, 1H, J=7.4 Hz); 13C-NMR (75 MHz, DMSO-d6): δ 148.7 (C), 146.0 (CH), 139.4 (C), 138.7 (CH), 137.9 (CH), 137.3 (C), 135.2 (CH), 130.9 (CH), 129.8 (2 CH), 129.5 (CH), 127.3 (C), 127.1 (2 CH), 126.5 (C), 123.8 (CH), 122.2 (C), 118.9 (C), 115.0 (CH), MS (ESI) m/z 414 [M+H+]
Reaction SMILES: [CH:1]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=2)[NH:11][N:10]=1)=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.N1C=CN=C1.[C:24]1([P:30](Cl)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>ClCCl>[CH:1](/[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][P:30]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:31])[CH:16]=2)[NH:11][N:10]=1)=[CH:2]\[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=P(Cl)(c1ccccc1)c1ccccc1
Reactant: Oc1ccc2[nH]nc(C=Cc3ccccc3)c2c1
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: O=P(Oc1ccc2[nH]nc(/C=C/c3ccccc3)c2c1)(c1ccccc1)c1ccccc1
Reaction time: 1.5 h

Procedure:
A solution of 70 mg of 3-styryl-1H-indazol-5-ol, 300 mg of imidazole and of 273 μl of diphenylphosphinyl chloride in 15 ml of dichloromethane is stirred at ambient temperature. After stirring for approximately 90 minutes, the medium is treated with 30 ml of distilled water. The aqueous phase is extracted twice with 30 ml of dichloromethane and the organic phases are then dried over magnesium sulfate, filtered, and concentrated under reduced pressure on a rotary evaporator. The crude is taken up with ethyl acetate. The solid is filtered through sintered glass, and rinsed with ethyl ether. The filtrate is concentrated under reduced pressure in a rotary evaporator, and purified by flash chromatography on silica 35-70 μm. Eluent: cyclohexane/ethyl acetate gradient of 80:20 to 70:30. 143 mg of a yellow solid are collected. This compound is purified by preparative LC/MS to obtain 47.3 mg of diphenylphosphinic acid 3-((E)-styryl)-1H-indazol-5-yl ester.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9](=[O:25])[NH:10][CH:11]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(C)(C)C.Cl>C(OCC)C>[ClH:24].[NH2:7][CH2:8][C:9]([NH:10][CH:11]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:25]
Reactant: CC(C)(C)OC(=O)NCC(=O)NC(c1ccccc1)c1ccc(Cl)cc1
Agent: Cl
Solvent: CCOCC
Product: NCC(=O)NC(c1ccccc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
6.6 mmol ({[(4-Chloro-phenyl)-phenyl-methyl]-carbamoyl}-methyl)-carbamic acid tert-butyl ester were treated with 30 ml of a saturated solution of hydrogen chloride in diethyl ether. The mixture was stirred at room temperature for 1 hour. Removal of the diethyl ether in the rotatory evaporator yields the title compound as a colorless solid. Yield=100%.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:10][N:9]1[C:28](=[O:35])[CH2:29][C:30]([O:32]CC)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:37][NH2:38].[C-]#N.[Na+].NN>CCO>[CH2:1]([C@H:8]1[CH2:13][N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:24][CH2:25][CH2:26][CH2:27]3)[CH:15]=2)[CH2:11][CH2:10][N:9]1[C:28](=[O:35])[CH2:29][C:30]([NH:37][NH2:38])=[O:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: CCOC(=O)CC(=O)N1CCN(c2ccc(OC)c(OC3CCCC3)c2)C[C@@H]1Cc1ccccc1
Agent: [C-]#N
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(N2CCN(C(=O)CC(=O)NN)[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Temperature: 60 °C
Yield: 72 %

Procedure:
A solution of (S)-Ethyl 3-(2-benzyl-4-(3-(cyclopentyloxy)-4-methoxyphenyl)piperazin-1-yl)-3-oxopropanoate (120 mg, 0.25 mmol) in EtOH (4 mL) was treated with hydrazine hydrate (24 μL, 0.50 mmol), a catalytic amount of sodium cyanide, and heated in a sealed tube at 50° C. for 24 hr after which time and additional amount of hydrazine was added (48 μL, 1.0 mmol) and the reaction mixture heated at 60° C. for 48 h. After this time the reaction mixture was evaporated, triturated with water and dissolved in EtOAc (2 mL), which was dried over MgSO4, filtered, and evaporated to afford the title compound as a foam (84 mg, 72%). LC/MS (Method B) 3.04 min, [M+1]+ 467.
Reaction SMILES: O.Br.C([NH:5][C:6](=[NH:8])[SH:7])C.[Cl:9][C:10]([SH:13])(Cl)Cl.[OH-].[Na+].[C:16](OC)(C)(C)[CH3:17]>>[CH2:16]([S:7][C:6]1[N:5]=[C:10]([Cl:9])[S:13][N:8]=1)[CH3:17]
Reactant: COC(C)(C)C
Reactant: CCNC(=N)S
Reactant: SC(Cl)(Cl)Cl
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCSc1nsc(Cl)n1

Procedure:
To 60 ml of water, 10.3 g of ehtylisothiourea hydrobromide, 10.4 g of perchloromethylmercaptan were added, followed the solution of 9.39 g of sodium hydroxide dissolved to 60 ml of water was added dropwise slowly at about 0° C. Then, t-butylmethylether was added to the reaction mixture, and extracted. The organic layer was dried by anhydrous sodium salfate, and concentrated. The residue obtaind was subjected to silica gel column chromatography (hexanne:ethylacetate=30:1) to obtain 2.54 g of 3-ethylthio-5-chloro-1,2,4-thiadiazole.
Reaction SMILES: [Zn:1].[CH3:2][S:3][C:4]1[N:9]=[C:8]([C:10]2[S:14][C:13]([S:15](Cl)(=[O:17])=[O:16])=[CH:12][CH:11]=2)[CH:7]=[CH:6][N:5]=1.O>C1COCC1.O>[CH3:2][S:3][C:4]1[N:9]=[C:8]([C:10]2[S:14][C:13]([S:15]([Zn:1])(=[O:17])=[O:16])=[CH:12][CH:11]=2)[CH:7]=[CH:6][N:5]=1
Reactant: [Zn]
Reactant: CSc1nccc(-c2ccc(S(=O)(=O)Cl)s2)n1
Solvent: C1CCOC1
Solvent: O
Product: CSc1nccc(-c2ccc(S(=O)(=O)[Zn])s2)n1
Reaction time: 22 h
Yield: 236.8 %

Procedure:
Zinc dust (106.5 mg, 1.63 mmol) in THF/H2O (2:1, 7.5 mL) was sonicated 15 minutes and 5-(2-Methylsulfanyl-pyrimidin-4-yl)-thiophene-2-sulfonyl chloride (500 mg, 1.63 mmol) was added all at once as a solid. After 22 hours, the mixture was concentrated to ¼ volume and a precipitate formed. Water was added and the suspension was sonicated for 1 minute. The solids were collected by filtration, washed with water and dried in vacuo to afford bis-5-(2-Methylsulfanyl-pyrimidin-4-yl)-thiophene-2-sulfonyl Zinc as a light yellow solid (1.3 g, >100%). This material was used in the next step. 1H NMR (500 MHz, DMSO-d6) δ 2.52 (s, 3H), 7.15 (d, J=3.5 Hz, 1H), 7.59 (d, J=5.5 Hz, 1H), 7.88 (d, J=3.5 Hz, 1H), 8.54 (d, J=5.5 Hz, 1H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[C:7]([CH3:12])[CH:6]=1)=[O:4].[C:13]1([P:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)(O)[O-].[Na+]>ClCCl.C1(C)C=CC=CC=1.O>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH:2]=[P:19]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:6][C:7]=1[CH3:12]
Reactant: Cc1cc(C(=O)CBr)ccc1Br
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Cc1cc(C(=O)C=P(c2ccccc2)(c2ccccc2)c2ccccc2)ccc1Br
Reaction time: 8 h

Procedure:
1300 mg of 2-Bromo-1-(4-bromo-3-methyl-phenyl)-ethanone (VIIa) (Journal of Organic Chemistry (1947), 12, 617-703) was stirred with 1300 mg of triphenylphosphine in 20 ml of dichloromethane at ambient temperature for 18 hours. The mixture was diluted with toluene and the separated phosphonium salt was filtered off. It was then suspended in 20 ml of dichloromethane and 20 ml of water. 800 mg (7.55 mmol) of sodium bicarbonate was then added in 20 ml of water and the mixture was stirred overnight. The organic layer was separated, dried and evaporated under reduced pressure. The residue was triturated with hexane giving 1.6 g (86%) of 1-(4-Bromo-3-methyl-phenyl)-2-(triphenylphosphanylidene)-ethanone (Va) as a solid. 1H-NMR (CDCl3, δ in ppm): 7.40-7.90 (m, 18H), 4.40 (m, 1H).