Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:3]=1.Cl[S:13]([OH:16])(=[O:15])=[O:14].CO>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[CH:6][C:7]=1[S:13]([OH:16])(=[O:15])=[O:14]
Reactant: O=S(=O)(O)Cl
Reactant: CC(C)(C)c1cccc(Br)c1
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)c1ccc(S(=O)(=O)O)c(Br)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90.8 %

Procedure:
To a cooled (0° C.) solution of commercially available 1-bromo-3-tert-butylbenzene (42.6 g; 199 mmol) in anhydrous dichloromethane (800 mL) was added chlorosulfonic acid (15.9 mL; 239.0 mmol) dropwise. After addition was complete, the reaction was stirred at 0° C. for an additional 30 minutes, allowed to gradually warm to room temperature and further stirred overnight. The reaction mixture was concentrated under reduced pressure to about 500 mL and washed with aqueous hydrochloric acid (20 mL; 20N). The organic layer was separated and dried over magnesium sulfate which resulted in formation of a white precipitate. Methanol (200 mL) was added to dissolve the precipitate. The organic solution was filtered and concentrated under reduced pressure to yield the title product as a white solid (53.0 g).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([CH2:20][NH:21][CH:22]3[CH2:27][CH2:26][CH:25]([N:28]([CH3:36])[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:24][CH2:23]3)[CH:13]=2)=[CH:8][CH:7]=1)(=[O:4])=[O:3].[Cl:37][C:38]1[C:39]2[C:49]([F:50])=[CH:48][CH:47]=[C:46]([F:51])[C:40]=2[S:41][C:42]=1[C:43](Cl)=[O:44]>>[Cl:37][C:38]1[C:39]2[C:49]([F:50])=[CH:48][CH:47]=[C:46]([F:51])[C:40]=2[S:41][C:42]=1[C:43]([N:21]([CH2:20][C:14]1[CH:13]=[C:12]([C:9]2[CH:10]=[CH:11][C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:7][CH:8]=2)[CH:17]=[CH:16][C:15]=1[O:18][CH3:19])[CH:22]1[CH2:27][CH2:26][CH:25]([N:28]([CH3:36])[C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])[CH2:24][CH2:23]1)=[O:44]
Reactant: O=C(Cl)c1sc2c(F)ccc(F)c2c1Cl
Reactant: COc1ccc(-c2ccc(NS(C)(=O)=O)cc2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Product: COc1ccc(-c2ccc(NS(C)(=O)=O)cc2)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Biaryl amine 202 (42 mg, 81 mmol) is treated with acid chloride 8 (24 mg, 89 μmol) using Method D to give the title compound.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1([CH3:25])[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]=[CH:13][C:12]=2[C:23]#[N:24])[CH2:5]1.[O:26]=[C:27]1[CH2:32][S:31][C:30]2[CH:33]=[CH:34][C:35]([CH:37]=O)=[N:36][C:29]=2[NH:28]1>CO.C(Cl)Cl>[CH3:25][C:4]1([CH2:3][NH:2][CH2:37][C:35]2[CH:34]=[CH:33][C:30]3[S:31][CH2:32][C:27](=[O:26])[NH:28][C:29]=3[N:36]=2)[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]=[CH:13][C:12]=2[C:23]#[N:24])[CH2:5]1
Reactant: COc1ccc2ncc(C#N)c(CCN3CCC(C)(CN)C3)c2c1
Reactant: O=Cc1ccc2c(n1)NC(=O)CS2
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: COc1ccc2ncc(C#N)c(CCN3CCC(C)(CNCc4ccc5c(n4)NC(=O)CS5)C3)c2c1
Reaction time: 24 h
Yield: 25.8 %

Procedure:
To a solution of the HCl salt of 4-{2-[3-(aminomethyl)-3-methyl-1-pyrrolidinyl]ethyl}-6-(methyloxy)-3-quinolinecarbonitrile (50 mg) in MeOH (2 mL) and DCM (2 mL) were added NaHCO (130 mg, 1.6 mmol) followed by 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carbaldehyde (30 mg, 0.18 mmol). After 24 h at 25° C., NaBH (10 mg, 0.27 mmol) was added. After 1 h, the reaction was concentrated and the residue was partitioned between DCM-H O. The aqueous phase was extracted several times with DCM and the combined organic fractions were dried over MgSO, concentrated and purified via column chromatography (silica, 4% MeOH in DCM (1% NH OH)) yielding the title compound (20 mg) as a brown oil: LC/MS (ES) m/e 503 (M+H) 1H NMR (CDCl3, 400 MHz) δ 8.85 (s, 1H), 8.22 (d, J=9.0 Hz, 1H), 7.58 (d, J=7.8 Hz, 1H), 7.55 (d, J=9.0 Hz, 1H), 7.35 (s, 1H), 6.95 (d, J=7.8 Hz, 1H), 4.12 (s, 3H), 3.83 (s, 2H), 3.51 (m, 3H), 2.9-2.5 (m, 6H), 2.3 (m, 1H), 1.85 (m, 1H), 1.55 (m, 1H), 1.1 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([O:49][CH3:50])=[C:7]2[CH2:12][N:13]1[C:19](=[O:20])[C@@H:18]([NH:21][C:22](=[O:34])[C@@H:23]([N:25](C)[C:26](=O)OC(C)(C)C)[CH3:24])[C@H:17]([CH3:35])[N:16]([C:36](=[O:42])[CH2:37][S:38]([CH3:41])(=[O:40])=[O:39])[C:15]2[CH:43]=[C:44]([C:47]#[N:48])[CH:45]=[CH:46][C:14]1=2.[C:51]([OH:57])([C:53]([F:56])([F:55])[F:54])=[O:52]>C(Cl)Cl>[F:54][C:53]([F:56])([F:55])[C:51]([OH:57])=[O:52].[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([O:49][CH3:50])=[C:7]2[CH2:12][N:13]1[C:19](=[O:20])[C@@H:18]([NH:21][C:22](=[O:34])[C@@H:23]([NH:25][CH3:26])[CH3:24])[C@H:17]([CH3:35])[N:16]([C:36](=[O:42])[CH2:37][S:38]([CH3:41])(=[O:40])=[O:39])[C:15]2[CH:43]=[C:44]([C:47]#[N:48])[CH:45]=[CH:46][C:14]1=2
Reactant: COc1ccc2c(Br)cccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)[C@H](C)N(C(=O)CS(C)(=O)=O)c2cc(C#N)ccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN[C@@H](C)C(=O)N[C@@H]1C(=O)N(Cc2c(OC)ccc3c(Br)cccc23)c2ccc(C#N)cc2N(C(=O)CS(C)(=O)=O)[C@H]1C
Temperature: 25 °C
Reaction time: 6 h
Yield: 93 %

Procedure:
To a rt solution of tert-butyl(S)-1-((3S,4S)-1-((5-bromo-2-methoxynaphthalen-1-yl)methyl)-7-cyano-4-methyl-5-(2-(methylsulfonyl)acetyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (32 mg, 41.5 μmol) in CH2Cl2 (166 μl) was added TFA (41.5 μl). The reaction was stirred at rt for 6 h, then concentrated, taken up in H2O, and lyophilized to provide (S)-N-((3S,4S)-1-((5-bromo-2-methoxynaphthalen-1-yl)methyl)-7-cyano-4-methyl-5-(2-(methylsulfonyl)acetyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-2-(methylamino)propanamide 2,2,2-trifluoroacetate (30.3 mg, 93%) as a white solid. MS m/z 670/672 (MNa)+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[S:19][CH:18]=[CH:17][N:5]2[C:6](=[O:16])[C:7]=1C1C=CC(C#N)=CC=1.[F:20][C:21]([F:32])([F:31])[C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+].FC1C=C(C2C(=O)N3C=CSC3=NC=2C)C=C(F)C=1>C1(C)C=CC=CC=1.O.C(O)C>[CH3:1][C:2]1[N:3]=[C:4]2[S:19][CH:18]=[CH:17][N:5]2[C:6](=[O:16])[C:7]=1[C:25]1[CH:26]=[CH:27][C:22]([C:21]([F:32])([F:31])[F:20])=[CH:23][CH:24]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: Cc1nc2sccn2c(=O)c1-c1ccc(C#N)cc1
Agent: Cc1nc2sccn2c(=O)c1-c1cc(F)cc(F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: Cc1nc2sccn2c(=O)c1-c1ccc(C(F)(F)F)cc1
Yield: 159.8 %

Procedure:
The title compound was prepared by coupling reaction of Step 2 intermediate from Intermediate 4 (10.9 g, 37.312 mmol) with 4-(trifluoromethyl)phenyl boronic acid (9.9 g, 52.241 mmol) in the presence of Pd[(C6H5)3P]4 (1.72 g, 1.491 mmol) and sodium carbonate (23.7 g, 223.891 mol) in a mixture of toluene, ethanol and water according to the procedure described in Intermediate 3, step 3 yielded 18.5 g of the desired compound as a light yellow solid; 1H NMR (300 MHz, DMSO-d6) δ 2.18 (s, 3H), 7.53-7.59 (m, 4H), 7.58-7.80 (m, 1H), 8.01 (d, J=4.8 Hz, 1H); ESI-MS (m/z) 311.28 (M+H)+.
Reaction SMILES: [C:1]1([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([CH3:32])([S:28]([CH3:31])(=[O:30])=[O:29])[C:17]([NH:19][O:20]C(OC)CCCC)=[O:18])=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.Cl.CO>C(Cl)Cl>[C:1]1([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([CH3:32])([S:28]([CH3:31])(=[O:30])=[O:29])[C:17]([NH:19][OH:20])=[O:18])=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CCCCC(OC)ONC(=O)C(C)(CCc1ccc(C2=CCCCCC2)cc1)S(C)(=O)=O
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CC(CCc1ccc(C2=CCCCCC2)cc1)(C(=O)NO)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
4-(4-Cyclohept-1-en-1-ylphenyl)-N-[(1-methoxypentyl)oxy]-2-methyl-2-(methylsulfonyl)butanamide (205 mg, 0.36 mmol) was dissolved in methylene chloride (4 mL) at ambient temperature. To this solution was added HCl (4M in 1,4-dioxane, 1.82 mL, 7.30 mmol) and the solution was stirred at rt for 20 minutes. Methanol (500 uL) was added followed by silica gel and the mixture was concentrated to dryness. The crude material was purified via silica gel chromatography eluting with methylene chloride/methanol to afford 4-(4-cyclohept-1-en-1-ylphenyl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide as a solid. 91.5 mg. LCMS: (M+1) 366.2.
Reaction SMILES: C(O[CH:5]([C:28]1[CH:29]=[CH:30][C:31]2[N:35]=[C:34]3[S:36][CH:37]=[CH:38][N:33]3[C:32]=2[CH:39]=1)[C:6]1(Br)[C:12](=[O:13])[N:11]2[C@@H:7]1[S:8][CH:9]=[C:10]2[C:14]([O:16]CC1C=CC([N+]([O-])=O)=CC=1)=[O:15])(=O)C.[H][H]>C1COCC1.P([O-])([O-])([O-])=O>[O:13]=[C:12]1[N:11]2[C@H:7]([S:8][CH:9]=[C:10]2[C:14]([OH:16])=[O:15])/[C:6]/1=[CH:5]\[C:28]1[CH:29]=[CH:30][C:31]2[N:35]=[C:34]3[S:36][CH:37]=[CH:38][N:33]3[C:32]=2[CH:39]=1
Reactant: [H][H]
Reactant: CC(=O)OC(c1ccc2nc3sccn3c2c1)C1(Br)C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CS[C@@H]21
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Product: O=C(O)C1=CS[C@@H]2/C(=C\c3ccc4nc5sccn5c4c3)C(=O)N12
Yield: 9.3 %

Procedure:
4-nitrobenzyl (5R)-6-[(acetyloxy)([1,3]thiazolo[3,2-a]benzimidazol-6-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (630 mg, 1 mmol) was suspended in 20 ml THF and 20 ml pH=6.5 aqueous phosphate buffer. The mixture was then subjected to 45 psi hydrogen for two hours. Then it was filtered through a pad of celite and concentrated in vacuo to remove most of the THF. The solution was then cooled to zero degree and basified to pH=8 with 1 N sodium hydroxide. Then it was purified via reverse phase HPLC using 1 liter of water followed by 5%˜25% acetonitrile and water. Water was then removed through concentrate in vacuo and 33 mg of product (Yield 8%) was collected. MP: >250° C.;
Reaction SMILES: [CH2:1]([C:4]1[CH:20]=[C:19]([C:21]([O:30][CH2:31][O:32][CH3:33])([C:26]([F:29])([F:28])[F:27])[C:22]([F:25])([F:24])[F:23])[CH:18]=[CH:17][C:5]=1[O:6][C:7]1[CH:8]=[CH:9][C:10]([CH:15]=[CH2:16])=[C:11]([CH:14]=1)[C:12]#[N:13])[CH2:2][CH3:3].C(=O)([O-])[OH:35].[Na+].ClC1C=C(C=CC=1)C(OO)=O.S([O-])([O-])=O.[Na+].[Na+]>ClCCl>[O:35]1[CH2:16][CH:15]1[C:10]1[CH:9]=[CH:8][C:7]([O:6][C:5]2[CH:17]=[CH:18][C:19]([C:21]([O:30][CH2:31][O:32][CH3:33])([C:22]([F:23])([F:24])[F:25])[C:26]([F:28])([F:27])[F:29])=[CH:20][C:4]=2[CH2:1][CH2:2][CH3:3])=[CH:14][C:11]=1[C:12]#[N:13]
Reactant: C=Cc1ccc(Oc2ccc(C(OCOC)(C(F)(F)F)C(F)(F)F)cc2CCC)cc1C#N
Reactant: O=C([O-])O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1Oc1ccc(C2CO2)c(C#N)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 37.5 %

Procedure:
5-[2-Propyl-4-(2,2,2-trifluoro-1-methoxymethoxy-1-trifluoromethyl-ethyl)-phen oxy]-2-vinyl-benzonitrile (14 mg, 0.030 mmol) was dissolved in dichloromethane (300 μL). The resultant mixture was added with sodium hydrogen carbonate (7.5 mg, 0.089 mmol) and 3-chloroperoxybenzoic acid (8.5 mg, 0.030 mmol) under ice-cold conditions and stirred at room temperature for 1.5 hours. Subsequently, the resultant mixture was further added with sodium hydrogen carbonate (7.5 mg, 0.089 mmol) and 3-chloroperoxybenzoic acid (8.5 mg, 0.030 mmol) under ice-cold conditions and stirred at room temperature overnight. The reaction solution was added with a saturated aqueous solution of sodium sulfite and a saturated aqueous solution of sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and brine, dried over sodium sulfate, and concentrated in vacuo. The obtained residue was purified using silica-gel column chromatography (hexane/ethyl acetate), and 2-oxiranyl-5-[2-propyl-4-(2,2,2-trifluoro-1-methoxymethoxy-1-trifluoromethyl-ethyl)-phenoxy]-benzonitrile (5.5 mg, yield 38%) was obtained as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[O:8][C:9]2[C:10](=[C:12]([C:16]([OH:18])=O)[CH:13]=[CH:14][CH:15]=2)[N:11]=1.Cl.Cl.[NH2:21][CH:22]1[CH2:29][CH:28]2[N:30]([CH3:31])[CH:24]([CH2:25][CH2:26][CH2:27]2)[CH2:23]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C.ClCCl>[CH3:31][N:30]1[CH:24]2[CH2:25][CH2:26][CH2:27][CH:28]1[CH2:29][CH:22]([NH:21][C:16]([C:12]1[CH:13]=[CH:14][CH:15]=[C:9]3[O:8][C:7]([C:3]4[S:4][CH:5]=[CH:6][C:2]=4[CH3:1])=[N:11][C:10]=13)=[O:18])[CH2:23]2
Reactant: CN1C2CCCC1CC(N)C2
Reactant: Cc1ccsc1-c1nc2c(C(=O)O)cccc2o1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccsc1-c1nc2c(C(=O)NC3CC4CCCC(C3)N4C)cccc2o1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68.4 %

Procedure:
A mixture of 2-(3-methylthiophen-2-yl)benzoxazole-4-carboxylic acid (87 mg, 0.34 mmol), 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride (93 mg, 0.41 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (130 mg, 0.68 mmol) and 1-hydroxybenzotriazole (92 mg, 0.68 mmol) in DMF (5 mL) was stirred at room temperature for 10 min, then triethylamine (0.24 mL, 1.7 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane (30 mL), and then washed with a saturated solution of sodium bicarbonate. The aqueous layer was further extracted with dichloromethane (2×30 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:9:1 ethyl acetate/methanol/concentrated ammonium hydroxide) to afford N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(3-methylthiophen-2-yl)benzoxazole-4-carboxamide (92 mg, 69%) as an off-white solid: 1H NMR (500 MHz, CDCl3) δ 8.99 (d, J=7.0 Hz, 1H), 8.19 (dd, J=8.0, 1.0 Hz, 1H), 7.66 (dd, J=8.5, 1.0 Hz, 1H), 7.51 (d, J=5.0 Hz, 1H), 7.43 (t, J=7.5 Hz, 1H), 7.06 (d, J=5.0 Hz, 1H), 4.55-4.51 (m, 1H), 3.18-3.09 (m, 2H), 2.79 (s, 3H), 2.68-2.60 (m, 2H), 2.55 (s, 3H), 2.08-1.98 (m, 3H), 1.65-1.42 (m, 3H), 1.16-1.11 (m, 2H); MS (ESI+) m/z 396 (M+H); HPLC=98.4% (AUC), tR=12.84 min.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=O)[CH3:10].[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH2:20][CH2:21][C:22](=[O:25])[NH:23][N:24]=2)=[CH:15][CH:14]=1>>[OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[N:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH2:20][CH2:21][C:22](=[O:25])[NH:23][N:24]=2)=[CH:15][CH:14]=1)[CH3:10]
Reactant: Nc1ccc(C2=NNC(=O)CC2)cc1
Reactant: CC(=O)c1ccc(O)cc1O
Product: CC(=Nc1ccc(C2=NNC(=O)CC2)cc1)c1ccc(O)cc1O
Temperature: 140 °C

Procedure:
A mixture containing 0.91 g (0.006 mol) of 2',4'-dihydroxyacetophenone and 0.95 g (0.005 mol) of 6-(4-aminophenyl)-4,5-dihydropyridazin-3(2H)one was heated for 4 h at 140° C. in a stream of nitrogen gas. The product was triturated with boiling ethanol and filtered. Yield 0.88 g (54%), m.p. 350° C. (decomp).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]#[N:26])[CH:20]=2)[C:7]2[C:12]([C:13]=1[C:14]([O:16][CH3:17])=[O:15])=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4].[SH2:27]>>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25](=[S:27])[NH2:26])[CH:20]=2)[C:7]2[C:12]([C:13]=1[C:14]([O:16][CH3:17])=[O:15])=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4]
Reactant: COC(=O)c1c(C(=O)OC)n(Cc2cccc(C#N)c2)c2ccccc12
Reactant: S
Product: COC(=O)c1c(C(=O)OC)n(Cc2cccc(C(N)=S)c2)c2ccccc12

Procedure:
The starting material 1-(3-thiocarbamoylphenyl)methyl-1H-indole-2,3-dicarboxylic acid dimethyl ester was prepared analogously to example 13/1 by reacting 1-(3-cyano-benzyl)-1H-indole-2,3-dicarboxylic acid dimethyl ester (example 11/1) with hydrogen sulfide. It was crystallized from ether/hexane to give yellow crystals with m.p. 176-178° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([NH2:15])[NH:13][CH:14]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:16][O:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20]Cl.C([O-])([O-])=O.[Cs+].[Cs+].[Cl-].[Na+]>CN(C)C=O>[CH3:16][O:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20][N:13]1[CH:14]=[C:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[N:11]=[C:12]1[NH2:15]
Reactant: COc1ccccc1CCl
Reactant: Nc1nc(-c2ccc([N+](=O)[O-])cc2)c[nH]1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccccc1Cn1cc(-c2ccc([N+](=O)[O-])cc2)nc1N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 4-(4-nitrophenyl)-1H-imidazole-2-ylamine (0.9 g, 4.4 mmol), 2-methoxybenzyl chloride (0.69 g, 4.4 mmol), and Cs2CO3 (1.6 g, 4.9 mmol) in dimethylformamide was stirred for 18 hr at room temperature. The batch was combined with 50% sodium chloride solution and extracted with ethyl acetate. The organic phase was washed several times with water and saturated sodium chloride solution and concentrated, and the residue was purified on silica gel using methylene chloride/methanol 50:1 (100 mg of a red solid).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C:25]3[CH:26]=[C:27]([CH:40]=[CH:41][CH:42]=3)[CH2:28][N:29]3C(=O)C4C(=CC=CC=4)C3=O)=[N:9][C:10]=2[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:12]=2)[CH:5]=[CH:6][N:7]=1>C(Cl)Cl>[NH2:29][CH2:28][C:27]1[CH:26]=[C:25]([C:8]2[N:4]3[CH:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]3=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:12]=3)[N:9]=2)[CH:42]=[CH:41][CH:40]=1
Reactant: Nc1nccn2c(-c3cccc(CN4C(=O)c5ccccc5C4=O)c3)nc(-c3cccc(OCc4ccccc4)c3)c12
Solvent: ClCCl
Product: NCc1cccc(-c2nc(-c3cccc(OCc4ccccc4)c3)c3c(N)nccn23)c1
Reaction time: 17 h
Yield: 42.9 %

Procedure:
To a solution of 2-{3-[8-amino-1-(3-benzyloxyphenyl)-imidazo[1,5-a]pyrazin-3-yl]-benzyl}-isoindole-1,3-dione (328 mg, 0.594 mmol) in CH2Cl2 (4 mL), N2H4 (56 μL, 57 mg, 1.78 mmol) was added and the reaction was vortexed at rt for 17 h, under N2 atmosphere. Additional N2H4 (40 μL, 41 mg, 1.27 mmol) and CH2Cl2 (10 mL) were added and vortexing was continued for 3 d. The suspension was filtered, the solid was washed extensively with CH2Cl2, and the filtrate was concentrated in vacuo. The crude material (273 mg) was purified by chromatography on silica gel [Jones Flashmaster, 5 g/25 mL cartridge, eluting with MeOH (7N NH3):CH2Cl2 5%→10%], affording 107.4 mg (43%, 0.255 mmol) of the title compound, as a yellow solid, containing 0.18 eq. of DMF. Mixed fractions were also collected, giving an additional 67.4 mg (max. 16%, 0.159 mmol) of the title compound, as a yellow solid, containing 0.8 eq. of DMF; 1H NMR (CDCl3, 400 MHz) δ 1.88 (s, br, —NH2), 3.97 (s, 2H), 5.15 (s, 4H), 7.05-7.09 (m, 1H), 7.10 (d, J=4.8 Hz, 1H), 7.29-7.47 (m, 9H), 7.51 (t, J=7.8 Hz, 1H), 7.63 (d, J=5.2 Hz, 1H), 7.69 (d, J=7.6 Hz, 1H), 7.81 (s, 1H); MS (ES+): m/z 422.0 (14) [MH+].
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[NH:10][CH2:11][C:12]([NH2:14])=[O:13].[C:15](=O)([O-])[O-].[K+].[K+].CI>CO>[CH3:15][N:10]([CH:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1]1)[CH2:11][C:12]([NH2:14])=[O:13]
Reactant: O=C([O-])[O-]
Reactant: NC(=O)CNC1Cc2ccccc2C1
Agent: [K+]
Solvent: CO
Solvent: CI
Product: CN(CC(N)=O)C1Cc2ccccc2C1
Reaction time: 0.25 h

Procedure:
2-(2-indanylamino)acetamide (0.016 moles, 3.00 g) is dissolved in methanol (60 ml), and potassium carbonate (0.016 moles, 2.18 g) is added under stirring. Methyl iodide (0.028 moles, 4.14 g) is dropped therein at r.t. in 15 minutes. The mixture is reacted for 4 hours at r.t., then evaporated under vacuum. The resulting solid is taken up into water (100 ml), the aqueous solution is extracted with ethyl acetate (3×150 ml). The organic solution is dried over sodium sulfate, then evaporated under vacuum to obtain an oil which is chromatographed under medium pressure through silica gel (eluent chloroform:methanol=90:10) Yield: 1.31 g (40%)--m.p.=122-123° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[C:11]([NH2:15])([CH3:14])([CH3:13])[CH3:12]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:6]
Reactant: CC(C)(C)N
Reactant: O=C(Cl)c1cccc(Br)c1
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1cccc(Br)c1
Reaction time: 4 h

Procedure:
A solution of 3-bromo-benzoyl chloride (0.83 g, 3.8 mmol) in DCM (10 mL) was chilled to zero degrees and treated with tert-butylamine (1.2 mL, 11.3 mmol). Reaction was allowed to come to room temperature and stir for 4 h. Mixture was then poured onto water and washed once. Organic phase then washed with brine, dried over sodium sulfate, filtered and evaporated to amber oil (0.9 g, 94%).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[S:20][C:19]3[C:18]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[N:17][C:16](SC)=[N:15][C:14]=3[CH:13]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[CH3:29][NH:30][C:31]1[N:36]=[CH:35][C:34]([Sn](CCCC)(CCCC)CCCC)=[CH:33][N:32]=1>COCCOC.C(OCC)(=O)C.CSC.[Cu]Br.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:29][NH:30][C:31]1[N:36]=[CH:35][C:34]([C:16]2[N:17]=[C:18]([N:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)[C:19]3[S:20][C:12]([CH2:11][N:8]4[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][CH2:7]4)=[CH:13][C:14]=3[N:15]=2)=[CH:33][N:32]=1
Reactant: CSc1nc(N2CCOCC2)c2sc(CN3CCN(S(C)(=O)=O)CC3)cc2n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc(NC)nc1
Agent: [Cu]Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: CSC
Solvent: CCOC(C)=O
Product: CNc1ncc(-c2nc(N3CCOCC3)c3sc(CN4CCN(S(C)(=O)=O)CC4)cc3n2)cn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 6-(4-methanesulfonyl-piperazin-1-ylmethyl)-2-methylsulfanyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (80 mg) in 1,2-dimethoxyethane (10 mL) was added methyl-(5-tributylstannyl-pyrimidin-2-yl)-amine (143 mg) and copper(I)bromide-dimethyl sulfide (74 mg) and the reaction mixture was stirred at room temperature for 10 minutes. Tetrakis(triphenylphosphine)palladium (0) (10 mg) was then added and the reaction mixture was heated at reflux for 16 h. After cooling to room temperature, the mixture was diluted with ethyl acetate (20 mL) and washed with water (2×20 mL) and brine (2×20 mL). The organic phase was dried (MgSO4), reduced in vacuo and purified by column chromatography to give 417. NMR: (CDCl3): 2.59-2.61 (4H, m), 2.73 (3H, s, Me), 3.01 (3H, d, J 5.1, Me), 3.21-3.24 (4H, m), 3.78-3.81 (6H, m), 3.93-3.96 (4H, m), 7.22 (1H, s, Ar) and 9.21 (2H, s, Ar) MS: (ESI+): MH+=505.20