Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([C:13]([F:16])([F:15])[F:14])=[CH:6][C:5]=1[N:17]=[C:18]=[O:19].[CH3:21][S:22]([NH:25][NH2:26])(=[O:24])=[O:23].[OH-].[Na+].Cl>C1COCC1>[N+:10]([C:8]1[CH:9]=[C:4]2[C:5](=[CH:6][C:7]=1[C:13]([F:16])([F:15])[F:14])[NH:17][C:18](=[O:19])[N:26]([NH:25][S:22]([CH3:21])(=[O:24])=[O:23])[C:3]2=[O:2])([O-:12])=[O:11]
Reactant: CS(=O)(=O)NN
Reactant: COC(=O)c1cc([N+](=O)[O-])c(C(F)(F)F)cc1N=C=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc(C(F)(F)F)c([N+](=O)[O-])cc2c1=O
Reaction time: 1 h
Yield: 81.7 %

Procedure:
To a solution of 2-isocyanato-5-nitro-4-trifluoromethyl-benzoic acid methyl ester (110 mg, 0.379 mmol) in dry THF (1.7 mL) was added a solution of CH3SO2NHNH2 (41.7 mg, 0.379 mmol) in dry THF (0.6 mL) at r.t. The resultant mixture turned into a white suspension that was stirred for one hour. A 1 M aq NaOH solution (0.379 mL) was added and stirring of the clear solution was continued for 4 h. After addition of 2 M HCl solution (0.472 mL) and evaporation of the THF, the precipitate was filtered and dried at 50° C./0.1 mm yielding N-(6-nitro-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (114 mg, 81%) as a slightly yellow powder, m.p. 220-232° C. (decomp.). 1H-NMR (DMSO-d6, 400 MHz): 3.15 (s, 3H), 7.66 (s, 1H), 8.62 (s, 1H), 10.50 (s, 1H), 12.41 (s, 1H).
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[CH2:19][CH2:18][CH2:17][CH:16]([C:21]([NH2:23])=[O:22])[C:15]=2[C:14]2[C:9]1=[C:10]([F:26])[CH:11]=[CH:12][C:13]=2[O:24][CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCOCC1>[CH2:1]([N:8]1[C:9]2[C:10]([F:26])=[CH:11][CH:12]=[C:13]([O:24][CH3:25])[C:14]=2[C:15]2[C:20]1=[CH:19][CH:18]=[CH:17][C:16]=2[C:21](=[O:22])[NH2:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(F)c2c1c1c(n2Cc2ccccc2)CCCC1C(N)=O
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: COc1ccc(F)c2c1c1c(C(N)=O)cccc1n2Cc1ccccc1
Yield: 99.4 %

Procedure:
A solution of 0.458 g of 9-benzyl-5-methoxy-8-fluoro-1,2,3,4-tetrahydrocarbazole-4-carboxamide in 13 ml of dry dioxane under nitrogen was treated with 0.59 g of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone and refluxed for one hour. The reaction mixture was cooled and filtered and the precipitate was washed with 15 ml of dioxane. The filtrate and washing were poured into saturated sodium bicarbonate solution and extracted three times with ethyl acetate. The extracts were washed with saturated sodium bicarbonate, with water and then with brine; dried over magnesium sulfate and concentrated. This residue was chromatographed on silica gel using dichloromethane/0-2% methanol to afford 0.45 g of subtitle compound. ESIMS m/e 349 (M++1)
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]([C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[N:19]=[C:20]=S.[Cl:22][C:23]1[C:24]([N:32]2[CH2:37][CH2:36][CH:35]([C:38]([F:41])([F:40])[F:39])[CH2:34][CH2:33]2)=[CH:25][C:26]([NH:30][CH3:31])=[C:27]([CH:29]=1)[NH2:28].CC(C)N=C=NC(C)C>CN(C=O)C>[F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]([C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[NH:19][C:20]1[N:30]([CH3:31])[C:26]2[CH:25]=[C:24]([N:32]3[CH2:37][CH2:36][CH:35]([C:38]([F:40])([F:41])[F:39])[CH2:34][CH2:33]3)[C:23]([Cl:22])=[CH:29][C:27]=2[N:28]=1
Reactant: CNc1cc(N2CCC(C(F)(F)F)CC2)c(Cl)cc1N
Reactant: O=C(NCc1ccc(F)c(N=C=S)c1)C1(C(F)(F)F)CC1
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: Cn1c(Nc2cc(CNC(=O)C3(C(F)(F)F)CC3)ccc2F)nc2cc(Cl)c(N3CCC(C(F)(F)F)CC3)cc21

Procedure:
The title compound was prepared in analogy to the procedure in Example 76 using N-(4-fluoro-3-isothiocyanatobenzyl)-1-(trifluoromethyl)cyclopropane carboxamide (191 mg; 0.60 mmol), 5-chloro-2-methylamino-4-(4-trifluoromethyl-piperidin-1-yl)aniline (185 mg; 0.60 mmol), DIC (76 mg; 0.60 mmol) and DMF (3 mL).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[S:7][C:8]2[CH:14]=[C:13]([O:15][C:16]3[CH:17]=[CH:18][C:19]([CH3:36])=[C:20]([NH:22][C:23](=[O:35])[C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]5([C:33]#[N:34])[CH2:32][CH2:31]5)[CH:25]=4)[CH:21]=3)[CH:12]=[CH:11][C:9]=2[N:10]=1)=[O:4].C(N(CC)CC)C.[CH3:44][N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1>O1CCCC1.C(OCC)(=O)C>[C:33]([C:30]1([C:26]2[CH:25]=[C:24]([CH:29]=[CH:28][CH:27]=2)[C:23]([NH:22][C:20]2[CH:21]=[C:16]([O:15][C:13]3[CH:12]=[CH:11][C:9]4[N:10]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:48]5[CH2:49][CH2:50][N:45]([CH3:44])[CH2:46][CH2:47]5)[S:7][C:8]=4[CH:14]=3)[CH:17]=[CH:18][C:19]=2[CH3:36])=[O:35])[CH2:32][CH2:31]1)#[N:34]
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)CCl)sc3c2)cc1NC(=O)c1cccc(C2(C#N)CC2)c1
Reactant: CN1CCNCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(Oc2ccc3nc(NC(=O)CN4CCN(C)CC4)sc3c2)cc1NC(=O)c1cccc(C2(C#N)CC2)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 36 %

Procedure:
N-[5-({2-[(Chloroacetyl)amino]-1,3-benzothiazol-6-yl}oxy)-2-methylphenyl]-3-(1-cyanocyclopropyl)benzamide synthesized above was dissolved in tetrahydrofuran (5.0 mL), triethylamine (188 μL, 1.36 mmol) and 1-methylpiperazine (152 μL, 1.36 mmol) were added, and the mixture was stirred at 60° C. for 8 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (100 mL), washed with water (100 mL) and saturated brine (100 mL), successively, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=50/50→0/100), and the obtained solution was concentrated under reduced pressure. The obtained residue was triturated with ethyl acetate/hexane to give the title compound (141 mg, 36%) as a colorless solid.
Reaction SMILES: [C:1]([O:4][CH:5]1[C@@H:9]2[CH2:10][C:11](=[O:12])[N:8]2[CH:7]([C:13]([O:15]C(C2C=CC=CC=2)C2C=CC=CC=2)=[O:14])[CH:6]1[CH3:29])(=[O:3])[CH3:2].C(Cl)(Cl)Cl>[Pd].C(OCC)(=O)C>[C:1]([O:4][CH:5]1[C@@H:9]2[CH2:10][C:11](=[O:12])[N:8]2[CH:7]([C:13]([OH:15])=[O:14])[CH:6]1[CH3:29])(=[O:3])[CH3:2]
Reactant: CC(=O)OC1C(C)C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C[C@@H]12
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(=O)OC1C(C)C(C(=O)O)N2C(=O)C[C@@H]12
Reaction time: 1 h
Yield: 99.9 %

Procedure:
Benzhydryl 1-acetoxy-2-methylcarbapenam-3-carboxylate (26 mg.) was dissolved in 3 ml. of ethyl acetate. Hydrogenation catalyst (10% palladium on carbon, 26 mg.) was added and the reaction mixture hydrogenated at room temperature and atmospheric pressure for 1 hour, at which time tlc (4:1 chloroform:ethyl acetate) indicated no starting material remained. The catalyst was recovered by filtration and the filtrate evaporated in vacuo to yield 1-acetoxy-2-methylcarbapenam-3-carboxylic acid [15 mg.; Rf 0.0 (4:1 chloroform:ethyl acetate); ir (CH2Cl2) 1770, 1730 cm-1 ].
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3].[CH2:14]([NH:16][CH2:17][CH3:18])[CH3:15].Cl>C(Cl)Cl>[CH2:14]([N:16]([CH2:17][CH3:18])[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3])[CH3:15]
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Reactant: CCNCC
Agent: Cl
Solvent: ClCCl
Product: CCN(CC)S(=O)(=O)c1cccc(C(=O)O)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 3-(chlorosulfonyl)benzoic acid (1.02 g, 4.62 mmol) in CH2Cl2 (100 mL) at 0° C. was added diethylamine (2.4 mL, 23 mmol). The resulting mixture was stirred at 0° C. for 3 h then worked up by adding 2N aqueous HCl and extracting 3× with EtOAc. The combined organic was washed with brine then dried over MgSO4 and concentrated under reduced pressure. The residue was used without further purification.
Reaction SMILES: C(C1C=C(/[C:10](/[CH:37]=[CH:38]/[CH:39]=[C:40]2\[C:41]([CH3:59])([CH3:58])[C:42]3[C:43](=[N:57]\2)[N:44]([CH2:49][CH2:50][CH2:51][CH2:52][S:53]([O-:56])(=[O:55])=[O:54])[CH:45]=[C:46]([Cl:48])[CH:47]=3)=[CH:11]\[CH:12]=[CH:13]\[C:14]2[C:22]([CH3:24])([CH3:23])[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([S:25]([O-:28])(=[O:27])=[O:26])[CH:20]=3)[N+:15]=2[CH2:29][CH2:30][CH2:31][CH2:32][S:33]([O-:36])(=[O:35])=[O:34])C=CC=1)(O)=O.[Na+:60].[Na+].B([C:65]1[CH:66]=[C:67]([CH2:71][CH2:72][CH2:73][C:74]([OH:76])=[O:75])[CH:68]=[CH:69][CH:70]=1)(O)O>>[C:74]([CH2:73][CH2:72][CH2:71][C:67]1[CH:66]=[C:65](/[C:10](/[CH:37]=[CH:38]/[CH:39]=[C:40]2\[C:41]([CH3:59])([CH3:58])[C:42]3[C:43](=[N:57]\2)[N:44]([CH2:49][CH2:50][CH2:51][CH2:52][S:53]([O-:56])(=[O:55])=[O:54])[CH:45]=[C:46]([Cl:48])[CH:47]=3)=[CH:11]\[CH:12]=[CH:13]\[C:14]2[C:22]([CH3:24])([CH3:23])[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([S:25]([O-:28])(=[O:26])=[O:27])[CH:20]=3)[N+:15]=2[CH2:29][CH2:30][CH2:31][CH2:32][S:33]([O-:36])(=[O:34])=[O:35])[CH:70]=[CH:69][CH:68]=1)([OH:76])=[O:75].[Na+:60].[Na+:60]
Reactant: CC1(C)C2=CC(Cl)=CN(CCCCS(=O)(=O)[O-])C2=N/C1=C/C=C/C(=C/C=C/C1=[N+](CCCCS(=O)(=O)[O-])c2ccc(S(=O)(=O)[O-])cc2C1(C)C)c1cccc(C(=O)O)c1
Reactant: O=C(O)CCCc1cccc(B(O)O)c1
Agent: [Na+]
Product: CC1(C)C2=CC(Cl)=CN(CCCCS(=O)(=O)[O-])C2=N/C1=C/C=C/C(=C/C=C/C1=[N+](CCCCS(=O)(=O)[O-])c2ccc(S(=O)(=O)[O-])cc2C1(C)C)c1cccc(CCCC(=O)O)c1

Procedure:
Compound 44 is prepared analogously to compound 43, except with 4-(3-boronophenyl)butanoic acid as a starting material.
Reaction SMILES: CC[N:3]([C:6]1C=C[CH:9]=[CH:10][CH:11]=1)[CH2:4][CH3:5].P(Cl)(Cl)(Cl)=O.CC(C)([O-])C.[K+].[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1>C1COCC1>[N:3]1[CH:6]=[CH:11][C:10]([C:9]#[C:28][C:27]2[CH:30]=[CH:31][C:24]([F:23])=[CH:25][CH:26]=2)=[CH:5][CH:4]=1
Reactant: CCN(CC)c1ccccc1
Reactant: O=Cc1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O=P(Cl)(Cl)Cl
Product: Fc1ccc(C#Cc2ccncc2)cc1
Reaction time: 16 h

Procedure:
4-pyridyl-hydroxymethyldiphenylphosphonate (6) (15.3 g, 46 mmol), diethylaniline (4 mL), and phosphorous oxychloride (50 mL) were warmed to 90° C. for 16 h. The reaction was quenched by pouring the reaction mixture over ice (400 g). Potassium carbonate was added until a pH of 8 was obtained for the solution followed by extraction with methylene chloride (3×200 mL). After drying ( MgSO4), the reaction was concentrated to afford crude 4-pyridyl-chloromethyldiphenylphosphonate (7) as a solid which was used in the next step without further purification: Mass Spectrum (CI) 360 (MH+). Potassium t-butoxide (3.30 g, 29.2 mmol) was added as a solid to 4-pyridyl-chloromethyldiphenylphosphonate (7) (5.00 g, 13.9 mmol), 4-fluorobenzaldehyde (8) (2.00 g, 15.3 mmol), and THF (70 mL) at 23° C. under argon. After 16 h, the reaction was quenched by adding to water (200 mL) over 3 min. After adjusting the pH of the solution to 7 with 1N HCl, the mixture was extracted with ethyl acetate (3×350 mL), and dried (MgSO4). After concentration in vacuo, the residue was purified by flash chromatography (ethyl acetate:methylene chloride 1:1) to afford 1-(4-pyridyl)-2-(4-fluorophenyl)ethyne (1) as a solid: Mass Spectrum (CI) 198 (MH+).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:15]=[C:14]([F:16])[CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][N:11]2[C:17]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)([CH2:22][CH3:23])[C:18]([O:20][CH3:21])=[O:19].CN1CCOCC1>C(Cl)Cl>[Cl:30][C:27]1[CH:26]=[CH:25][C:24]([C:17]([N:11]2[C:12]3[C:8](=[C:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[CH:15]=[C:14]([F:16])[CH:13]=3)[CH:9]=[CH:10]2)([CH2:22][CH3:23])[C:18]([O:20][CH3:21])=[O:19])=[CH:29][CH:28]=1
Reactant: CCC(C(=O)OC)(c1ccc(Cl)cc1)n1ccc2c(N)cc(F)cc21
Reactant: CS(=O)(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCC(C(=O)OC)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cc(F)cc21
Reaction time: 0.5 h

Procedure:
Methanesulfonyl chloride (0.23 g, 2 mmol) was added to a stirred solution of methyl 2-(4-amino-6-fluoro-1H-indol-1-yl)-2-(4-chlorophenyl)butanoate (0.6 g, 1.7 mmol) and 4-methylmorpholine (0.25 g, 2.5 mmol) in DCM (8 mL) at 0° C. After 30 min, an additional portion of methanesulfonyl chloride (0.1 g, 1 mmol) was added. After 1 h, the reaction mixture was partitioned between DCM and saturated aqueous ammonium chloride. The layers were separated and the aqueous layer was extracted with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography (PE:EA=2:1) to afford the title compound. LC/MS m/z=439.1 [M+H]+.
Reaction SMILES: C[Si](C)(C)Br.C(OC([N:11]([CH2:18][CH:19]([O:29]C1CCCCO1)[CH2:20][P:21](=[O:28])([O:25]CC)[O:22]CC)[O:12]C(OCC)=O)=O)C>C(Cl)Cl>[OH:29][CH:19]([CH2:18][NH:11][OH:12])[CH2:20][P:21](=[O:22])([OH:28])[OH:25]
Reactant: CCOC(=O)ON(CC(CP(=O)(OCC)OCC)OC1CCCCO1)C(=O)OCC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: O=P(O)(O)CC(O)CNO
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 35.5 %

Procedure:
Trimethylbromosilane (122 g.) was added dropwise to a solution of diethyl 3-(N-ethoxycarbonyl-N-ethoxycarbonyloxyamino)-2-(tetrahydro-2H-pyran-2-yloxy)propylphosphonate (79.4 g.) in methylene chloride (160 ml.) under ice-cooling with stirring over a period of 15 minutes. The mixture was further stirred for an hour at 0°-5° C. and for additional 2.5 hours at ambient temperature, and then evaporated under reduced pressure. The oily residue was dissolved in water (500 ml.) stirred at ambient temperature for an hour, and then washed twice with chloroform (200 and 200 ml. portions) to remove off bis(trimethylsilyl)ether. The combined chloroform washings were back extracted once with water (50 ml.). The combined aqueous layers were evaporated under reduced pressure. The dark brown oily residue was dissolved in water (300 ml.) washed twice with chloroform (each 150 ml. portion) and ethyl acetate (100 ml.) successively, treated with activated charcoal (2.5 g.), and evaporated under reduced pressure. The oily residue was dissolved in 1 N hydrochloric acid (750 ml.) treated with activated charcoal (2.5 g.) and then heated to reflux for 13.5 hours. The mixture was evaporated under reduced pressure. The oily residue was dissolved in a mixture of water (50 ml.) and methanol (100 ml.) adjusted to pH about 4 with propylene oxide, and diluted with ethanol (300 ml.). The oily precipitates were collected by decantation, and dissolved in water (60 ml.). This aqueous solution was diluted with methanol (120 ml.) under heating at 60° C., and then allowed to stand overnight at ambient temperature. The precipitates were collected by filtration, washed twice with 80% aqueous methanol (each 20 ml. portion) and methanol (20 ml.), and then dried on phosphorus pentoxide to give 2-hydroxy-3-(N-hydroxyamino)propylphosphonic acid (10.60 g.). M.p. 153°-155° C.
Reaction SMILES: [N:1]([C:4]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]([F:34])([F:33])[F:32])[CH:25]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:22])[F:21])[CH:14]=1)[C@H:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[OH:6])=[N+]=[N-]>CO.[Pd]>[NH2:1][C:4]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:21])([F:22])[F:23])[CH:14]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]([F:33])([F:34])[F:32])[CH:25]=1)[C@H:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[OH:6]
Reactant: [N-]=[N+]=NC(c1cccc(OC(F)(F)F)c1)(c1cccc(OC(F)(F)F)c1)[C@@H](O)c1ccccc1
Agent: [Pd]
Solvent: CO
Product: NC(c1cccc(OC(F)(F)F)c1)(c1cccc(OC(F)(F)F)c1)[C@@H](O)c1ccccc1
Reaction time: 8 h
Yield: 87.8 %

Procedure:
A slurry of (S)-2-azido-1-phenyl-2,2-bis(3-(trifluoromethoxy)phenyl)ethanol (64 mg, 0.132 mmol) and 10% Pd on C (40 mg) in methanol (2 mL) was subjected to balloon hydrogenation overnight at rt. The reaction mixture was filtered through celite and the filtrate was concentrated to give (S)-2-amino-1-phenyl-2,2-bis(3-(trifluoromethoxy)phenyl)ethanol as a light yellow oil (53 mg, 87% yield). HPLC: RT=3.40 min (Phenomenex Luna C18 5 u column, eluting with 10-90% MeOH/H2O containing 0.1% phosphoric acid over a 4 minute gradient, monitoring at 220 nm). LCMS: [M+H] 458.1 (Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]#[N:14].[CH2:15]([SH:19])[CH2:16][CH2:17][CH3:18].CCN(C(C)C)C(C)C>>[CH2:15]([S:19][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]#[N:14])[CH2:16][CH2:17][CH3:18]
Reactant: N#Cc1cnc2ccc(I)cc2c1Cl
Reactant: CCCCS
Solvent: CCN(C(C)C)C(C)C
Product: CCCCSc1c(C#N)cnc2ccc(I)cc12

Procedure:
Similar procedure as described in example 39a was used, starting from 4-chloro-6-iodo-quinoline-3-carbonitrile (example 14c), butane-1-thiol and DIEA to give 4-butylsulfanyl-6-iodo-quinoline-3-carbonitrile. LC-MS m/e 369 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C:7](=[O:12])[CH2:6][CH2:5]2.[CH2:13](O)[CH2:14][OH:15]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:14]1[O:15][C:7]2([CH2:6][CH2:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=3)[CH2:8]2)[O:12][CH2:13]1
Reactant: O=C1CCc2cc(Br)ccc2C1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Brc1ccc2c(c1)CCC1(C2)OCCO1
Temperature: 25 °C
Yield: 93.2 %

Procedure:
6-bromo-2-tetralone (2.0 g, 8.89 mmol) was dissolved in toluene (50 mL) and treated with excess ethylene glycol (4.88 mL, 88.9 mmol) and catalytic p-toluenesulfonic acid (15 mg). The solution was stirred at reflux 16 hours, and water was removed from the reaction mixture using a Dean-Stark condenser. After cooling to ambient temperature, the toluene solution was washed 2×1N NaOH, 1×water, 1×brine, dried over Na2SO4 and concentrated in vacuo to give 2.23 g (93%) of 6-bromo-2-tetralone ethylene ketal as a brown oil which was used without further purification.
Reaction SMILES: [CH:1]1([N:10]2[C:18](=[O:19])[NH:17][C:16]3[C:11]2=[N:12][C:13]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][Si](C(C)C)(C(C)C)C(C)C)[CH:25]=2)=[N:14][C:15]=3[C:20]([O:22]C)=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[NH2:41]C1C(C(OC)=O)=NC(C2C=CC=C(O[Si](C(C)C)(C(C)C)C(C)C)C=2)=NC=1NC1C2C(=CC=CC=2)CC1>ClCCl>[CH:1]1([N:10]2[C:18](=[O:19])[NH:17][C:16]3[C:11]2=[N:12][C:13]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=2)=[N:14][C:15]=3[C:20]([NH2:41])=[O:22])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1nc(-c2cccc(O[Si](C(C)C)(C(C)C)C(C)C)c2)nc2c1[nH]c(=O)n2C1CCc2ccccc21
Reactant: COC(=O)c1nc(-c2cccc(O[Si](C(C)C)(C(C)C)C(C)C)c2)nc(NC2CCc3ccccc32)c1N
Solvent: ClCCl
Product: NC(=O)c1nc(-c2cccc(O)c2)nc2c1[nH]c(=O)n2C1CCc2ccccc21
Yield: 85 %

Procedure:
Methyl 9-(2,3-dihydro-1H-inden-1-yl)-8-oxo-2-(3-(triisopropylsilyloxy)phenyl)-8,9-dihydro-7H-purine-6-carboxylate. Methyl 5-amino-6-(2,3-dihydro-1H-inden-1-ylamino)-2-(3-(triisopropylsilyloxy)phenyl)pyrimidine-4-carboxylate (0.192 g, 0.360 mmol) and 1,1′-1,1′-carbonyldiimidazole (0.467 g, 2.88 mmol) in dichloromethane (15 mL) were reacted according to General Procedure F and purified using biotage chromatography (0 to 45% EtOAc in hexanes) to afford the title compound (0.171 g, 85%). 1H NMR (400 MHz, DMSO-d6) δ 11.85 (s, 1H), 7.76 (d, J=7.99, 1H), 7.64 (s, 1H), 7.36 (d, J=7.59, 1H), 7.32 (t, J=7.99, 1H), 7.24 (m, 1H), 7.12 (s, 1H), 7.11 (s, 1H), 6.92 (dd, J=7.99, 2.39, 1H), 6.05 (t, J=7.19, 1H), 3.94 (s, 3H), 3.33 (s, 9H), 3.06 (m, 1H), 2.67 (m, 1H), 1.23 (m, 3H), 1.08 (m, 18H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:13]4[C:18]([C:19]=3[CH:20]=2)=[CH:17][CH:16]=[CH:15][CH:14]=4)=[CH:4][CH:3]=1.[CH3:27][C:28]1([CH3:42])[C:40]2[CH:39]=[C:38]([NH2:41])[CH:37]=[CH:36][C:35]=2[C:34]2[C:29]1=[CH:30][CH:31]=[CH:32][CH:33]=2>C1(C)C=CC=CC=1>[CH3:27][C:28]1([CH3:42])[C:40]2[CH:39]=[C:38]([NH:41][C:2]3[CH:3]=[CH:4][C:5]([C:8]4[CH:9]=[CH:10][C:11]5[N:12]([C:21]6[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=6)[C:13]6[C:18]([C:19]=5[CH:20]=4)=[CH:17][CH:16]=[CH:15][CH:14]=6)=[CH:6][CH:7]=3)[CH:37]=[CH:36][C:35]=2[C:34]2[C:29]1=[CH:30][CH:31]=[CH:32][CH:33]=2
Reactant: Ic1ccc(-c2ccc3c(c2)c2ccccc2n3-c2ccccc2)cc1
Reactant: CC1(C)c2ccccc2-c2ccc(N)cc21
Solvent: Cc1ccccc1
Product: CC1(C)c2ccccc2-c2ccc(Nc3ccc(-c4ccc5c(c4)c4ccccc4n5-c4ccccc4)cc3)cc21
Temperature: 25 °C
Yield: 96.4 %

Procedure:
50 g (112 mmol) 3-(4-Iodo-phenyl)-9-phenyl-9H-carbazole and 23.5 g (112 mmol) 9,9-Dimethyl-9H-fluoren-2-ylamine are dissolved in 500 ml toluene and 21.5 g sodium-tert-butylat is added. The reaction mixture is carefully degassed and 80 mg bis(diphenylphosphino)ferrocendichloro-Pd(II) (Pd(dppf)) complex is added. The solution is refluxed for 6 h. The reaction mixture is then cooled to room temperature and 250 ml water are added. The layers are separated. The water phase is extracted three times with toluene, and then the organic layers is washed twice with water dried over magnesium sulphate, filtrated and the solvent is removed under vacuum. The residue is recrystallized from butanole, to yield 57 g (108 mmol) (96%) of a white solid with a purity of 99.5%.
Reaction SMILES: [CH3:1][N:2]1[CH2:24][CH2:23][C:5]2[N:6]([CH2:13][C:14]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)(O)[CH3:15])[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[OH-].[K+]>S(Cl)(Cl)=O>[CH3:1][N:2]1[CH2:24][CH2:23][C:5]2[N:6](/[CH:13]=[C:14](/[C:17]3[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=3)\[CH3:15])[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: CN1CCc2c(c3ccccc3n2CC(C)(O)c2ccncc2)C1
Agent: [K+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Product: C/C(=C\n1c2c(c3ccccc31)CN(C)CC2)c1ccncc1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
1-(1,2,3,4-Tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-2-(pyridin-4-yl)propan-2-ol (600 mg, 1.86 mmol) was dissolved in thionyl chloride (8 mL) and the solution was stirred for 1 h. Excess thionyl chloride was removed under reduced pressure and the residue was dissolved in N-methyl-2-pyrrolidone (3 mL) and the solution was stirred for 5 min. at RT. Powdered KOH (690 mg, 12.32 mmol) was added and the reaction mixture was heated at 100° C. for 1-2 h. The reaction mixture was cooled to RT, diluted with ice water and extracted with EtOAc. The organic layer washed with water, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 2% MeOH-DCM. 1H NMR (CD3OD, HCl salt) δ (ppm): 8.85 (d, 2H), 8.40 (d, 2H), 7.82 (d, 1H), 7.60 (d, 1H), 7.30 (m, 2H), 7.20 (m, 1H), 4.80 (d, 1H), 4.40 (d, 1H), 3.90 (m, 1H), 3.60 (m, 2H), 3.20 (m, 1H), 3.10 (s, 3H), 2.20 (s, 3H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([N+:9]([O-])=O)=[CH:7][CH:6]=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:4]=1.C(O)C>[Pd].O1CCOCC1>[NH2:9][C:8]1[C:3]([NH:2][CH3:1])=[N:4][C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:7]=1
Reactant: CNc1nc(-c2ccccc2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Solvent: C1COCCO1
Product: CNc1nc(-c2ccccc2)ccc1N
Yield: 98.9 %

Procedure:
A procedure similar to that described in Example 6 was repeated, except that 5.7 g of 2-methylamino-3-nitro-6-phenylpyridine (prepared as described in Preparation 108) were hydrogenated in 200 ml of a 1:1 by volume mixture of ethanol and 1,4-dioxane in the presence of 1.14 g of 10% w/w palladium-on-charcoal. After working up the product as described in Example 6, 4.9 g of the title compound having Rf=0.08 (on silica gel thin layer chromatography using a 1:5 by volume mixture of ethyl acetate and hexane as the developing solvent) were obtained.