Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N1C2C(=CC=CC=2)C(O)(CC(=O)C2C=CC=CN=2)C1=O)CCC.[CH2:25]([N:30]1[C:38]2[C:33](=[CH:34][C:35]([CH3:39])=[CH:36][CH:37]=2)[C:32](=[O:40])[C:31]1=[O:41])[CH2:26][CH:27]([CH3:29])[CH3:28].[NH:42]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:44]([C:51](=[O:53])[CH3:52])=[CH:43]1>>[NH:42]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:44]([C:51](=[O:53])[CH2:52][C:32]2([OH:40])[C:33]3[C:38](=[CH:37][CH:36]=[C:35]([CH3:39])[CH:34]=3)[N:30]([CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])[C:31]2=[O:41])=[CH:43]1
Reactant: CC(=O)c1c[nH]c2ccccc12
Reactant: Cc1ccc2c(c1)C(=O)C(=O)N2CCC(C)C
Agent: CCCCN1C(=O)C(O)(CC(=O)c2ccccn2)c2ccccc21
Product: Cc1ccc2c(c1)C(O)(CC(=O)c1c[nH]c3ccccc13)C(=O)N2CCC(C)C

Procedure:
This compound was made in a similar manner to 1-butyl-3-hydroxy-3-(2-oxo-2-(pyridin-2-yl)ethyl)indolin-2-one using 1-isopentyl-5-methylindoline-2,3-dione and commercially available 1-(1H-indol-3-yl)ethanone (purchased from Fisher Scientific). 1H-NMR δ 9.21 (bs, NH), 8.34 (m, 1H), 7.67 (d, 1H), 7.38 (m, 1H), 7.30-7.23 (m, 3H), 7.08 (d, 1H), 6.73 (d, 1H) 5.74 (bs, 1H), 3.68 (t, 2H), 3.49 (d, 1H), 3.21 (d, 1H), 2.27 (s, 3H), 1.67-1.49 (m, 3H), 0.95 (dd, 6H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[O:19]=[C:20]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[O:35][C:22]2([CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]2)[CH2:21]1.[CH:42](=[O:44])[CH3:43]>C1COCC1>[OH:44][CH:42]([CH:21]1[C:22]2([CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:26][CH2:27]2)[O:35][C:36]2[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:20]1=[O:19])[CH3:43]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1ccccc1O2
Reactant: CC=O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(O)C1C(=O)c2ccccc2OC12CCN(C(=O)OC(C)(C)C)CC2
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 63.2 %

Procedure:
To a solution of N-isopropylpropan-2-amine (0.57 mL, 4.1 mmol) in THF (3.5 mL) was added a solution of n-butyllithium in hexane (2.6 mL of 1.6 M, 4.1 mmol) dropwise at −78° C. under Ar. The solution was allowed to stir at −20° C. for 15 min and then cooled to −78° C. tert-Butyl 4-oxospiro[chromane-2,4′-piperidine]-1′-carboxylate (1.1 g, 3.5 mmol) in THF (3.5 mL) was added at −78° C. followed by the addition of acetaldehyde (0.22 mL, 3.9 mmol) in THF (3 mL). The reaction was quenched with saturated aqueous ammonium chloride at −78° C., warmed to 25° C. and extracted with ethyl acatate (2×). The combined organic layers were washed with brine, dried over MgSO4 and concentrated to dryness. Purification by silica gel chromatography (20-30% ethyl acetate in hexane) provided tert-butyl 3-(1-hydroxyethyl)-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate (0.80 g, 63%) as a colorless oil. ESI-MS m/z calc. 361.2. found 362.5 (M+1)+; Retention time: 1.79 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 7.87 (dd, J=7.8, 1.6 Hz, 1H), 7.55-7.48 (m, 1H), 7.06-6.96 (m, 2H), 4.33-4.23 (m, 1H), 4.10-3.93 (m, 1H), 3.88-3.67 (m, 1H), 3.41-3.27 (m, 1H), 3.07-2.94 (m, 1H), 2.62 (d, J=5.2 Hz, 1H), 2.45 (d, J=8.5 Hz, 1H), 2.20-2.00 (m, 2H), 1.85-1.76 (m, 1H), 1.58-1.49 (m, 1H), 1.46 (s, 9H), 1.26 (t, J=7.1 Hz, 1H) 1.13 (d, J=6.6 Hz, 3H).
Reaction SMILES: [N:1]([CH3:4])=[C:2]=[S:3].[NH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:16]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[C:17]3[C:22]([N:23]=2)=[CH:21][N:20]=[CH:19][N:18]=3)[CH2:10][CH2:9]1>O1CCCC1>[F:31][C:28]1[CH:27]=[CH:26][C:25]([CH2:24][N:16]2[C:15]([NH:14][CH:11]3[CH2:10][CH2:9][N:8]([CH2:7][CH2:6][NH:5][C:2]([NH:1][CH3:4])=[S:3])[CH2:13][CH2:12]3)=[N:23][C:22]3[C:17]2=[N:18][CH:19]=[N:20][CH:21]=3)=[CH:30][CH:29]=1
Reactant: CN=C=S
Reactant: NCCN1CCC(Nc2nc3cncnc3n2Cc2ccc(F)cc2)CC1
Solvent: C1CCOC1
Product: CNC(=S)NCCN1CCC(Nc2nc3cncnc3n2Cc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 29 %

Procedure:
A mixture of 0.7 parts of isothiocyanatomethane, 3.7 parts of N-[1-(2-aminoethyl)-4-piperidinyl]-9-[(4-fluorophenyl)methyl]-9H-purin-8-amine and 90 parts of tetrahydrofuran was stirred for 4 hours at room temperature. After evaporation, the residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (95:5 by volume) as eluent. The first fraction was collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 1.3 parts (29%) of N-[2-[4-[[9-[(4-fluorophenyl)methyl]-9H-purin-8-yl]amino]-1-piperidinyl]ethyl]-N'-methylthiourea; mp. 205.5° C. (compound 179).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[C:3]=12.C(=O)([O-])[O-].[K+].[K+].Br[C:30]1[CH:34]=[CH:33][S:32][CH:31]=1>CN(C=O)C.[Cu]>[CH:18]1([N:8]2[C:4]3=[N:5][CH:6]=[N:7][C:2]([NH2:1])=[C:3]3[C:10]([C:11]3[CH:12]=[CH:13][C:14]([O:17][C:30]4[CH:34]=[CH:33][S:32][CH:31]=4)=[CH:15][CH:16]=3)=[N:9]2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: Brc1ccsc1
Reactant: Nc1ncnc2c1c(-c1ccc(O)cc1)nn2C1CCCC1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccsc3)cc1)nn2C1CCCC1
Temperature: 153 °C
Yield: 22.3 %

Procedure:
A mixture of 4-(4-amino-1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenol (0.212 g, 0.718 mmol, 1 equiv), potassium carbonate (0.060 g, 0.43 mmol, 0.6 equiv), copper powder (0.015 g, 0.24 mmol, 0.33 equiv), and 3-bromothiophene (0.09 mL, 0.9 mmol, 1.3 equiv) in DMF (7.2 mL) was heated at 153° C. for 24 hr. The reaction mixture was allowed to cool to ambient temperature, concentrated, and the residue was purified by preparative RP-HPLC (Rainin C18, 8 μm, 300 Å, 25 cm; 10%-60% acetonitrile-0.1M ammonium acetate over 20 min, 21 mL/min). The acetonitrile was removed in vacuo and the aqueous mixture was lyopholyzed to give 1-cyclopentyl-3-[4-(3-thienyloxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine as a light brown solid (0.060 g, 0.16 mmol): 1H NMR (d6 DMSO, 400 MHz): δ H 9.77 (1H, s), 8.46 (1H, s), 8.41 (1H, s), 7.73-7.74 (1H, m), 7.57 (2H, d, J=4.5 Hz), 7.46-7.48 (1H, m), 7.15 (1H, d, J=5.2 Hz), 6.96 (2H, d, J=8.6 Hz), 5.24-5.30 (1H, m), 2.03-2.05 (4H, m), 1.89-1.93 (2H, m), 1.70-1.72 (2H, m). RP-HPLC (Delta Pak C18, 5 μm, 300 Å, 15 cm; 5%-85% acetonitrile-0.1M ammonium acetate over 20 min, 1 mL/min) Rt 18.76 min. MS: MH+ 378.
Reaction SMILES: Br[C:2]1[C:3]([NH:22][CH2:23][CH2:24][CH2:25][OH:26])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:27]1[CH:32]=[CH:31][CH:30]=[C:29](B(O)O)[CH:28]=1.C([O-])([O-])=O.[Na+].[Na+].CCO>COCCOC.O>[OH:26][CH2:25][CH2:24][CH2:23][NH:22][C:3]1[C:2]([C:29]2[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=2)=[CH:21][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)=[O:8])=[CH:5][N:4]=1
Reactant: OB(O)c1cccnc1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(NCCCO)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: COCCOC
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(NCCCO)c(-c2cccnc2)c1
Temperature: 25 °C

Procedure:
A mixture of 5-bromo-6-((3-hydroxypropyl)amino)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 161.1, 72 mg, 0.15 mmol), pyridin-3-ylboronic acid (18.6 mg, 0.15 mmol) and Na2CO3 (48 mg, 0.450 mmol) in a mixture of DME (3.2 mL), EtOH (0.43 mL) and water (0.64 mL) was flushed with argon for 5 min. Pd(PPh3)2Cl2 was added (5.3 mg, 0.0075 mmol) and the mixture subjected to MW irradiation at 125° C. for 20 min. The vial was cooled to RT and the RM was evaporated to dryness under reduced pressure to give a residue that was triturated with THF and filtered. The filtrate was evaporated to dryness under reduced pressure and the crude product was purified by preparative LC-MS. TFA was removed using a SPE PL-HCO3 (StratoSpheres™ VariPure IPE) cartridge to afford the title compound. UPLC-MS (Condition 8) tR=1.86 min, m/z=433.1 [M+H]+, m/z=431.1 [M−H]−.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][NH:5][CH3:6].C(N(C(C)C)CC)(C)C.[C:17](Cl)(=[O:20])[CH:18]=[CH2:19].I[C:23]1[C:31]2[C:26](=[CH:27][C:28]([CH:32]=[O:33])=[CH:29][CH:30]=2)[N:25]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[N:24]=1.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CC([O-])=O.CC([O-])=O.[Pd+2].CN(C=O)C.C(Cl)Cl>[CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][N:5]([CH3:6])[C:17](=[O:20])/[CH:18]=[CH:19]/[C:23]1[C:31]2[C:26](=[CH:27][C:28]([CH:32]=[O:33])=[CH:29][CH:30]=2)[N:25]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[N:24]=1
Reactant: C=CC(=O)Cl
Reactant: C[Si](C)(C)CCOCn1nc(I)c2ccc(C=O)cc21
Reactant: CNCCN(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(C)CCN(C)C(=O)/C=C/c1nn(COCC[Si](C)(C)C)c2cc(C=O)ccc12
Temperature: 25 °C
Yield: 36.3 %

Procedure:
A dry round-bottom flask was charged with N1,N1,N2-trimethylethane-1,2-diamine (0.32 mL, 2.50 mmol), diisopropylethylamine (0.87 mL, 5.00 mmol) and CH2Cl2 (12 mL) and the solution cooled with an ice-water bath. Acryloyl chloride (0.20 mL, 2.50 mmol) was added dropwise and the reaction allowed to warm to room temperature. After 3 hours the solvent was removed and the residue purified by column chromatography (silica gel, 88:10:2, CH2Cl2/MeOH/7M NH3 in MeOH) to give 50 mg of a crude oil to which was added 3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-6-carbaldehyde (105 mg, 0.262 mmol), DMF (5 mL) and diisopropylethylamine (0.091 mL, 0.524 mmol). The mixture was degassed by bubbling Argon through the solution for 15 min. Pd(OAc)2 (3.0 mg, 0.013 mmol) and P(o-tolyl)3 (12 mg, 0.039 mmol) were then added and the reaction heated to 110° C. for 18 hours. The mixture was cooled to room temperature, NaHCO3(sat.) (5 mL) was added, and the product extracted (3×) with EtOAc. The organic layer was washed with water (2×) and brine (2×), and then dried over MgSO4. After removal of solvent the residue was purified by column chromatography (silica gel, 93:6:1, CH2Cl2/MeOH/7M NH3 in MeOH) to give 41 mg, 41% of a red-orange oil. MS ESI 431.2 [M+H]+, calcd for [C22H34N4O3Si+H]+ 431.25.
Reaction SMILES: Br[C:2]1[CH:27]=[CH:26][C:5]2=[C:6]3[N:17]=[C:16]([C:18]4[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=4[Cl:25])[NH:15][C:7]3=[C:8]3[C:13]([C:12](=[O:14])[NH:11][CH:10]=[CH:9]3)=[C:4]2[CH:3]=1.[F:28][C:29]1[C:34](B(O)O)=[CH:33][CH:32]=[C:31]([F:38])[N:30]=1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>[Cl-].[Na+].O>[Cl:25][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]([F:24])[C:18]=1[C:16]1[NH:15][C:7]2=[C:8]3[C:13](=[C:4]4[CH:3]=[C:2]([C:34]5[C:29]([F:28])=[N:30][C:31]([F:38])=[CH:32][CH:33]=5)[CH:27]=[CH:26][C:5]4=[C:6]2[N:17]=1)[C:12](=[O:14])[NH:11][CH:10]=[CH:9]3
Reactant: O=c1[nH]ccc2c3[nH]c(-c4c(F)cccc4Cl)nc3c3ccc(Br)cc3c12
Reactant: OB(O)c1ccc(F)nc1F
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=c1[nH]ccc2c3[nH]c(-c4c(F)cccc4Cl)nc3c3ccc(-c4ccc(F)nc4F)cc3c12
Reaction time: 3 h

Procedure:
A sealed tube was charged with the intermediate from Example 1 Step E (230 mg, 0.52 mmol), (2,6-difluoropyridin-3-yl)boronic acid (580 mg, 3.6 mmol), and bis(triphenylphosphine)palladium(n) chloride (73 mg, 0.1 mmol). The tube was evacuated and backfilled with argon three times. Fully degassed toluene (3.0 mL) and ethanol (3.0 mL) were added, followed by the addition of 2.0M aqueous sodium carbonate solution (2.6 mL, 5.2 mmol). The tube was sealed, placed in an oil bath at 90° C., and stirred for 3 hours. The reaction mixture was then cooled and poured into a mixture of ethyl acetate and brine. The aqueous layer was extracted twice with ethyl acetate and the combined organics were dried over magnesium sulfate, filtered, concentrated in vacuo. Purification via flash chromatography (silica, 0-20% methanol/dichloromethane) was followed by purification via preparative chiral HPLC (AD column, 25% ethanol/heptane isocratic) to afford the title compound. 1H NMR (600 MHz, d6-DMSO) δ 11.75 (s, 1H), 10.57 (s, 1H), 8.49 (broad s, 1H), 8.43 (q, 1H), 7.92 (d, 1H), 7.72-7.69 (m, 1H), 7.62-7.61 (m, 2H), 7.58-7.52 (m, 1H), 7.37 (dd, 1H), 7.27 (broad s, 1H). Imidazole proton was not observed [M+H]+ 476. τR: 9.44 min (analytical chiral HPLC, AD column, 0.46 cm×25 cm, 25% ethanol/heptane, isocratic, flow rate=0.75 mL/min).
Reaction SMILES: [O-]CC.[Na+].Cl.[CH2:6]([NH:13][C:14]([NH2:16])=[NH:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=1[CH2:25][C:26](OC)=[O:27]>>[ClH:17].[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=1[CH2:25][C:26]([NH:15][C:14]([NH:13][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[NH:16])=[O:27]
Reactant: N=C(N)NCc1ccccc1
Reactant: COC(=O)Cc1c(Cl)cccc1Cl
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Product: N=C(NCc1ccccc1)NC(=O)Cc1c(Cl)cccc1Cl
Temperature: 25 °C
Yield: 128 %

Procedure:
To sodium ethoxide [prepared by reacting sodium (60 mg, 2.61 mmol) and anhydrous ethanol (5 ml)] benzylguanidine hydrochloride (580 mg, 3.12 mmol) was added and refluxed in an oilbath for 1 hour. The reaction mixture was cooled to room temperature and insoluble materials filtered. Methyl 2,6-dichlorophenylacetate (285 mg, 1.3 mmol) (CH3(C═O)CH2(2,6,-di-ClC6H3) was added to the filtrate and refluxed for 2 hours. After cooling to room temperature the reaction mixture was concentrated and converted to the hydrochloride salt by the addition of hydrogen chloride (1M in ether) to provide 310 mg of N-(2,6-dichlorophenylacetyl)-N′-benzylguanidine hydrochloride as a white solid, purity 89.3% (HPLC); 1H-NMR (CD3OD) δ 4.38 (s, 4H, CH2), 7.32–7.41 (m, 8H, Ar).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:14]([O-])=O)[CH:5]=[C:6]2[C:11]=1[N:10]([CH3:12])[C:9](=[O:13])[CH2:8][CH2:7]2.O.[Cl-].[NH4+].ClCCl>C(O)C.[Fe]>[NH2:14][C:4]1[CH:5]=[C:6]2[C:11](=[C:2]([F:1])[CH:3]=1)[N:10]([CH3:12])[C:9](=[O:13])[CH2:8][CH2:7]2
Reactant: CN1C(=O)CCc2cc([N+](=O)[O-])cc(F)c21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: CN1C(=O)CCc2cc(N)cc(F)c21
Temperature: 90 °C
Yield: 100 %

Procedure:
8-Fluoro-1-methyl-6-nitro-3,4-dihydro-1H-quinolin-2-one (Step 2, 2.28 g, 0.0102 mol) is heated in ethanol (75 ml) until dissolved. Water (25 ml) and ammonium chloride (5.46 g, 0.102 mol) are added and the mixture heated to 90° C. Iron powder (2.27 g, 0.0407 mol) is added portionwise and the mixture stirred and heated for 30 minutes. The reaction is cooled and dichloromethane (200 ml) added. The mixture is filtered and the organic layer separated, washed with saline, dried (MgSO4) and evaporated to give the title compound as a yellow solid (1.98 g, 99%); [M+H]+=195.
Reaction SMILES: [S:1]1[C:5]([C:6]2[C:14]3[C:9](=[CH:10][CH:11]=C(C#N)[CH:13]=3)[NH:8][N:7]=2)=[CH:4][C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]1=2.[C:21]([OH:24])(=[O:23])[CH3:22].O.S(=O)(=O)(O)O>C(OCC)(=O)C>[S:1]1[C:5]([C:6]2[C:14]3[C:9](=[CH:10][CH:11]=[C:22]([C:21]([OH:24])=[O:23])[CH:13]=3)[NH:8][N:7]=2)=[CH:4][C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]1=2
Reactant: N#Cc1ccc2[nH]nc(-c3cc4ccccc4s3)c2c1
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc2[nH]nc(-c3cc4ccccc4s3)c2c1
Temperature: 110 °C
Reaction time: 4 h

Procedure:
To 288 mg of 3-benzo[b]thiophen-2-yl-1H-5-indazolecarbonitrile were added 3 ml of glacial acetic acid, 1 ml of water and 0.8 ml of concentrated sulfuric acid, and the mixture was stirred at 110° C. for 4 hours. After standing to cool, the mixture was added with 120 ml of ethyl acetate, sequentially washed with water and brine, dried over anhydrous magnesium sulfate. After filtering the organic layer through a silica gel pat, the solvent was evaporated, to give 307 mg of the title compound as ocher yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[C:7](Cl)=[C:6]([Cl:9])[C:5]([Cl:10])=[C:4]([Cl:11])[C:3]=1[Cl:12].[SH-:13].[Na+].[OH-].[Na+].Cl>O.CN(C)C=O>[Cl:1][C:2]1[C:7]([SH:13])=[C:6]([Cl:9])[C:5]([Cl:10])=[C:4]([Cl:11])[C:3]=1[Cl:12]
Reactant: [SH-]
Reactant: Clc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Sc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Temperature: 85 °C
Reaction time: 0.17 h

Procedure:
Hexachlorobenzene (25.0 g, 0.088 mol) was added to 50 mL of dimethylformamide followed by the addition of 7.4 g (0.096 mol) of 73% sodium hydrosulfide and 7.9 mL (0.079 mol) of 40% aqueous sodium hydroxide. The stirred reaction mixture was heated to 85° C. for 3.0 hr, cooled to room temperature, and poured into 200 mL of water. After 10 min of stirring, the insoluble material was removed by filtration, and the filtrate acidified with 15 mL (0.18 mol) of concentrated aqueous hydrochloric acid. The resulting precipitate was collected by filtration, washed with 100 mL of water, and dried in vacuo giving 22.8 g, 92% of theoretical, of pentachlorothiophenol.
Reaction SMILES: [Cl:1][CH:2]([C:8](=O)[CH2:9][CH2:10][CH3:11])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C([O-])(=O)C.[NH4+:17]>CO>[NH2:17][C:8]([CH2:9][CH2:10][CH3:11])=[C:2]([Cl:1])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: [NH4+]
Reactant: CCCC(=O)C(Cl)C(=O)OCC
Agent: CC(=O)[O-]
Solvent: CO
Product: CCCC(N)=C(Cl)C(=O)OCC
Yield: 95.5 %

Procedure:
61.5 g (0.32 mol) of ethyl 2-chloro-3-oxohexanoate are reacted with 61.5 g (0.80 mol) of ammonium acetate in 120 ml of methanol and worked up in analogy to Example 2. Yield: 95.5% [GC]
Reaction SMILES: COC1CC2CC[C@H]3[C@H]4[C@@](CCC)(C(=O)CC4)CC[C@@H]3C=2CC=1.C([Mg]Br)C=C.[CH2:29]([C@@:32]1([OH:54])[C@:40]2([CH2:41][CH2:42][CH3:43])[C@H:35]([C@@H:36]3[CH2:51][CH2:50][C:49]4[CH2:48][C:47]([O:52]C)=[CH:46][CH2:45][C:44]=4[C@H:37]3[CH2:38][CH2:39]2)[CH2:34][CH2:33]1)[CH:30]=[CH2:31].Cl.C(O)(C)C.O>>[CH2:29]([C@@:32]1([OH:54])[C@:40]2([CH2:41][CH2:42][CH3:43])[C@H:35]([C@@H:36]3[CH2:51][CH2:50][C:49]4[C@H:44]([CH2:45][CH2:46][C:47](=[O:52])[CH:48]=4)[C@H:37]3[CH2:38][CH2:39]2)[CH2:34][CH2:33]1)[CH:30]=[CH2:31]
Reactant: C=CC[C@]1(O)CC[C@H]2[C@@H]3CCC4=C(CC=C(OC)C4)[C@H]3CC[C@@]21CCC
Agent: C=CC[Mg]Br
Agent: CCC[C@]12CC[C@@H]3C4=C(CC[C@H]3[C@@H]1CCC2=O)CC(OC)=CC4
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: C=CC[C@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@@]21CCC

Procedure:
Treat dl-3-methoxy-13-propylgona-2,5(10)-dien-17-one (2.0 g) with allyl magnesium bromide to obtain a glass that is a mixture of dl-17α-allyl-3-methoxy-13-propylgona-2,5(10)-dien-17-ol (minor component) and the Δ5(10) -3-keto and Δ4 -3-keto compounds (major component). Hydrolyze the mixture (in two portions) with hydrochloric acid-isopropanol-water, then chromatograph and crystallize the resultant crude product to obtain the title compound (22% from the starting material), m.p. 135°-137°; ultraviolet absorption peak at 241.5 mμ (ε17,470), infrared maxima at 2.95 μ (OH), 6.03 μ, 6.18 μ (α,β-unsaturated carbonyl), 10.93 μ (R-CH=CH2).
Reaction SMILES: [C:1]1([CH2:7][C:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16]([O:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([N+:28]([O-:30])=[O:29])[C:26]=1[OH:27])[CH:22]=O)[CH3:17].[NH2:31][C:32]([NH2:34])=[O:33].Cl>CCO>[CH2:16]([O:18][C:19]1[CH:20]=[C:21]([CH:22]2[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[C:8]([C:10]3[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=3)[NH:34][C:32](=[O:33])[NH:31]2)[CH:24]=[C:25]([N+:28]([O-:30])=[O:29])[C:26]=1[OH:27])[CH3:17]
Reactant: NC(N)=O
Reactant: O=C(Cc1ccccc1)c1ccncc1
Reactant: CCOc1cc(C=O)cc([N+](=O)[O-])c1O
Agent: Cl
Solvent: CCO
Product: CCOc1cc(C2NC(=O)NC(c3ccncc3)=C2c2ccccc2)cc([N+](=O)[O-])c1O
Yield: 45.6 %

Procedure:
A mixture of 2-phenyl-1-(pyridin-4-yl)ethanone (Intermediate 35) (60 mg, 0.30 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (58 mg, 0.28 mmol), urea (50 mg, 0.83 mmol), and concentrated HCl solution (0.02 mL, 0.28 mmol) in EtOH (5 mL) was refluxed overnight. The mixture was evaporated in vacuo and purified by preparative HPLC to give Compound 71 (55.17 mg, yield 46%). 1H NMR (DMSO-d6 400 MHz): δ 10.29 (br, 1H), 8.92 (s, 1H), 8.53 (d, J=5.6 Hz, 2H), 7.61 (s, 1H), 7.41 (d, J=1.6 Hz, 1H), 7.35 (d, J=1.6 Hz, 2H), 7.12-7.09 (m, 4H), 6.89 (d, J=7.6 Hz, 2H), 5.31 (d, J=2.8 Hz, 1H), 4.03 (q, J=7.2 Hz, 2H), 1.32 (t, J=7.2 Hz, 3H); MS (ESI): m/z 433.0 [M+1]+.
Reaction SMILES: [C:1]([NH2:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([O-:12])=[O:11]>>[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([NH:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:15][CH:14]=1)([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1ccccc1
Reactant: NC(=O)c1ccccc1
Product: O=C(Nc1ccc([N+](=O)[O-])cc1)c1ccccc1

Procedure:
This example illustrates the direct coupling of benzamide and nitrobenzene to give 4'-nitrobenzanilide.
Reaction SMILES: [N+]([O-])(O)=O.[CH:5]1([CH:11]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:12]2[C:16]([C:17]([O:19]C)=[O:18])=[CH:15][N:14]=[CH:13]2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[OH-].[Na+].O>C(O)(=O)C>[CH:21]1([CH:11]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:12]2[C:16]([C:17]([OH:19])=[O:18])=[CH:15][N:14]=[CH:13]2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: COC(=O)c1cncn1C(c1ccccc1)C1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=[N+]([O-])O
Solvent: CC(=O)O
Product: O=C(O)c1cncn1C(c1ccccc1)C1CCCCC1
Reaction time: 1 h
Yield: 30.8 %

Procedure:
A mixture of 8.7 parts of methyl 1-(cyclohexylphenylmethyl)-1H-imidazole-5-carboxylate mononitrate, 9 parts of a sodium hydroxide solution 50% and 45 parts of water was stirred for 1 hour at reflux temperature. 35 Parts of water were added. After cooling, the reaction mixture was neutralized with acetic acid. The product was extracted with 1,1'-oxybisethane. The extract was dried, filtered and evaporated. The residue was crystallized from a mixture of ethanol and acetonitrile. The product was filtered off (the filtrate was set aside) and dried in vacuo at 50° C., yielding a first fraction of 2.1 parts (30.8%) of 1-(cyclohexylphenylmethyl)-1H-imidazole-5-carboxylic acid; mp. 249.5° C. (compound 1.251).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([O:8][C:9]([C:11]1[NH:12][CH:13]=[C:14]([CH3:16])[CH:15]=1)=[O:10])[CH3:7].[OH-].[Na+].CN(C)[CH:21]=[O:22]>O>[CH2:6]([O:8][C:9]([C:11]1[NH:12][C:13]([CH:21]=[O:22])=[C:14]([CH3:16])[CH:15]=1)=[O:10])[CH3:7]
Reactant: CCOC(=O)c1cc(C)c[nH]1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cc(C)c(C=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
To the ice-cold solution of dimethylformamide (DMF) (3 mL, 39.2 mmol) was added phosphorus oxychloride (0.67 mL, 7.18 mmol) dropwise and the resultant mixture was stirred for 30 minutes. A solution of (1 g, 6.53 mmol) of 4-methyl-1H-pyrrole-2-carboxylic acid ethyl ester in 3 mL of DMF was added to the reaction. After 1 h, the reaction was warmed to room temperature for another 2.5 h. The reaction mixture was diluted with water (100 mL) and basified to pH=11 with 1N sodium hydroxide solution. The precipitate was removed by filtration, rinsing with water and dried to afford 0.8 g (68%) of 5-formyl-4-methyl-1H-pyrrole-2-carboxylic acid ethyl ester as a white solid.