Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:15])=[C:4]([C:10]2[CH2:14][CH2:13][O:12][N:11]=2)[C:5]([S:8][CH3:9])=[CH:6][CH:7]=1.OO.[OH2:18].C(O)(=[O:21])C>O.O.[O-][W]([O-])(=O)=O.[Na+].[Na+]>[Cl:1][C:2]1[C:3]([CH3:15])=[C:4]([C:10]2[CH2:14][CH2:13][O:12][N:11]=2)[C:5]([S:8]([CH3:9])(=[O:21])=[O:18])=[CH:6][CH:7]=1
Reactant: CSc1ccc(Cl)c(C)c1C1=NOCC1
Reactant: CC(=O)O
Reactant: O
Agent: O=[W](=O)([O-])[O-]
Agent: OO
Agent: [Na+]
Product: Cc1c(Cl)ccc(S(C)(=O)=O)c1C1=NOCC1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
1.4 g (6.2 mmol) of 3-(3-chloro-2-methyl-6-methylthiophenyl)-4,5-dihydroisoxazole are dissolved in 3 ml of glacial acetic acid, and 30.7 mg of sodium tungstate dihydrate are added. At 25-40° C., 2.1 g (18.6 mmol) of hydrogen peroxide are added dropwise, and the reaction mixture is stirred for 3 h. The reaction mixture is then poured into 1.5 ml of water, the mixture is cooled to 0° C. and the resulting precipitate is filtered off with suction, washed five times with 10 ml of water and dried under reduced pressure. This gives 1.23 g of product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[NH:4][C@H:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]1[NH:17][CH:18]=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][C:28]=3[O:34][C:35]([F:38])([F:37])[F:36])=[CH:23][CH:22]=2)[N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].Cl[C:41](OC1C=CC([N+]([O-])=O)=CC=1)=[O:42].Cl.Cl.[CH:55]1([C:58]([N:60]2[CH2:65][CH2:64][CH:63]([N:66]3[CH2:71][CH2:70][NH:69][CH2:68][C@@H:67]3[CH3:72])[CH2:62][CH2:61]2)=[O:59])[CH2:57][CH2:56]1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[CH3:1][O:2][C:3](=[O:39])[NH:4][C@H:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]1[NH:17][CH:18]=[C:19]([C:21]2[CH:22]=[CH:23][C:24]([C:27]3[CH:32]=[CH:31][C:30]([NH:33][C:41]([N:69]4[CH2:70][CH2:71][N:66]([CH:63]5[CH2:64][CH2:65][N:60]([C:58]([CH:55]6[CH2:56][CH2:57]6)=[O:59])[CH2:61][CH2:62]5)[C@@H:67]([CH3:72])[CH2:68]4)=[O:42])=[CH:29][C:28]=3[O:34][C:35]([F:38])([F:36])[F:37])=[CH:25][CH:26]=2)[N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: C[C@H]1CNCCN1C1CCN(C(=O)C2CC2)CC1
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3ccc(N)cc3OC(F)(F)F)cc2)c[nH]1)C(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3ccc(NC(=O)N4CCN(C5CCN(C(=O)C6CC6)CC5)[C@@H](C)C4)cc3OC(F)(F)F)cc2)c[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20.7 %

Procedure:
A mixture of ((S)-1-{(S)-2-[4-(4′-amino-2′-trifluoromethoxy-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (20 mg, 0.04 mmol) and p-nitrophenyl chloroformate (8.9 mg, 0.04 mmol) in DMA (5 mL) was stirred at RT for 30 min and then cyclopropyl-[4-((S)-2-methyl-piperazin-1-yl)-piperidin-1-yl]-methanone 2 HCl (18 mg, 0.06 mmol; Preparation 6) was added followed by DIPEA (32 μL, 0.18 mmol). The reaction mixture was stirred at RT for 1 h, concentrated, dissolved in 1:1 acetic acid:water (1.5 mL), and purified by reverse phase HPLC to provide the di-TFA salt of the title product (6.8 mg, 20% yield) (m/z): [M+H]+ calcd for C42H53F3N8O6 823.40 found 823.6.
Reaction SMILES: [CH:1]1([C:5](=[O:10])[CH2:6][C:7](=O)[CH3:8])[CH2:4][CH2:3][CH2:2]1.[F:11][C:12]([F:24])([F:23])[C:13]1[CH:14]=[C:15]([NH:19][C:20]([NH2:22])=[O:21])[CH:16]=[CH:17][CH:18]=1.[C:25]([C:27]1[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=1)#[N:26]>O1CCCC1>[CH:1]1([C:5]([C:6]2[CH:31]([C:30]3[CH:33]=[CH:34][C:27]([C:25]#[N:26])=[CH:28][CH:29]=3)[NH:22][C:20](=[O:21])[N:19]([C:15]3[CH:16]=[CH:17][CH:18]=[C:13]([C:12]([F:23])([F:24])[F:11])[CH:14]=3)[C:7]=2[CH3:8])=[O:10])[CH2:4][CH2:3][CH2:2]1
Reactant: N#Cc1ccc(C=O)cc1
Reactant: CC(=O)CC(=O)C1CCC1
Reactant: NC(=O)Nc1cccc(C(F)(F)F)c1
Solvent: C1CCOC1
Product: CC1=C(C(=O)C2CCC2)C(c2ccc(C#N)cc2)NC(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
To a stirred suspension of 1-cyclobutylbutane-1,3-dione (69 mg, 0.49 mmol), N-[3-(trifluoromethyl)phenyl]urea (100 mg, 0.49 mmol) and 4-cyanobenzaldehyde (64.2 mg, 0.49 mmol) in tetrahydrofuran (250 ml) is added polyphosphoric acid ethyl ester (300 mg). The reaction mixture is stirred at reflux for 18 hours. After cooling to room temperature, the solvent is removed in vacuo and the crude product is purified by preparative HPLC (RP18 column; eluent: acetonitrile/0.1% aq. formic acid 10:90→90:10).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH:13]=[CH:14][NH:15]3)[CH:6]=1.C([OH:23])C.C(O)(=O)C.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>CC(O)(C)C.[Zn].O>[CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH2:13][C:14](=[O:23])[NH:15]3)[CH:6]=1
Reactant: COC(=O)Cc1cccc(-c2cccc3[nH]ccc23)c1
Reactant: CCO
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Solvent: CC(C)(C)O
Solvent: O
Product: COC(=O)Cc1cccc(-c2cccc3c2CC(=O)N3)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the suspension of [3-(1H-indol-4-yl)phenyl]-acetic acid methyl ester (3.72 g, 14 mmol) in t-BuOH: ethanol: acetic acid (93 mL: 56 mL: 67.2 mL) was added pyridinium tribromide (14.14 g, 44 mmol) portionwise. The mixture was stirred at room temperature for 3 hours, and then to the mixture was added acetic acid (60 mL). Water (2 mL) and zinc dust (14 g, excess) was added to the reaction mixture portionwise. After stirring at rt for one hour, any unreacted zinc was filtered off and most of the solvent was removed under reduced pressure. The residue was diluted with diluted with water (380 mL), extracted with ethyl acetate, washed with 0.5 N HCl (2×), 10% Na2CO3, (2×), brine (2×), water (1×), dried over Na2SO4, concentrated and triturated with ether to give [3-(2-oxo-2,3-dihydro-1H-indol-4-yl)phenyl]-acetic acid methyl ester.
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]=[C:11]([N:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH:22]([CH3:24])[CH3:23])=[CH:17][CH:16]=2)[CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:25]([O-])=O)[CH:9]=2)[N:4]=1.ClC1C2C(=CC=C([N+]([O-])=O)C=2)N=C(CCl)[N:30]=1.C(OC1C=CC(NC)=CC=1)(C)C.C(Cl)Cl>CC(O)C.Cl>[NH2:30][CH2:2][C:3]1[N:12]=[C:11]([N:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH:22]([CH3:24])[CH3:23])=[CH:17][CH:16]=2)[CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH2:25])[CH:9]=2)[N:4]=1
Reactant: O=[N+]([O-])c1ccc2nc(CCl)nc(Cl)c2c1
Reactant: CC(C)Oc1ccc(N(C)c2nc(CCl)nc3ccc([N+](=O)[O-])cc23)cc1
Agent: CNc1ccc(OC(C)C)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CC(C)O
Product: CC(C)Oc1ccc(N(C)c2nc(CN)nc3ccc(N)cc23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
(2-Chloromethyl-6-nitro-quinazolin-4-yl)-(4-isopropoxy-phenyl)-methyl-amine: A suspension of 4-chloro-2-chloromethyl-6-nitroquinazoline (200 mg, 0.77 mmol) and (4-isopropoxy-phenyl)-methyl-amine (140 mg, 0.84 mmol) in i-PrOH (1.5 mL) was treated with HCl (12 M, 6 drops) and stirred at rt overnight. CH2Cl2 was added and the reaction washed with 5% NaOH, dried (MgSO4), filtered and concentrated. The residue was purified by gradient MPLC (SiO2, EtOAc/hexanes, 0-100%) to provide 203 mg (71%) of the title compound. 1H NMR (DMSO-d6) δ 8.35 (dd, 1H), 7.86 (dd, 1H), 7.71 (dd, 1H), 7.32-7.40 (m, 2H), 7.08-7.12 (m, 2H), 4.78 (s, 2H), 4.71 (sept, 1H), 3.63 (s, 3H), 1.31 (d, 6H); LC-MS (ESI+; 387 ([M+H]+)).
Reaction SMILES: [F:1][C:2]1([F:17])[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2[N+:14]([O-])=O)[CH2:3]1.[C:18]([O:22][C:23]([NH:25][C:26]1[S:30][C:29]([C:31]2[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:32]=2[F:38])=[N:28][C:27]=1[C:39](O)=[O:40])=[O:24])([CH3:21])([CH3:20])[CH3:19]>>[F:38][C:32]1[CH:33]=[CH:34][CH:35]=[C:36]([F:37])[C:31]=1[C:29]1[S:30][C:26]([NH:25][C:23](=[O:24])[O:22][C:18]([CH3:20])([CH3:19])[CH3:21])=[C:27]([C:39](=[O:40])[NH:14][C:9]2[CH:10]=[N:11][N:12]([CH3:13])[C:8]=2[N:4]2[CH2:5][CH2:6][CH2:7][C:2]([F:17])([F:1])[CH2:3]2)[N:28]=1
Reactant: Cn1ncc([N+](=O)[O-])c1N1CCCC(F)(F)C1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2NC(=O)OC(C)(C)C)c1N1CCCC(F)(F)C1
Yield: 20 %

Procedure:
Following the procedure for Example 55, starting with 3,3-difluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperidine and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid, gave tert-butyl 2-(2,6-difluorophenyl)-4-(5-(3,3-difluoropiperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate as a cream solid (57 mg, 20%). 1H NMR (400 MHz, CDCl3) δ 10.33 (s, 1H), 8.67 (s, 1H), 7.71 (s, 1H), 7.41-7.32 (m, 1H), 7.11-7.01 (m, 2H), 3.76 (s, 3H), 3.32 (t, J=11.0 Hz, 2H), 3.19-3.13 (m, 2H), 2.10-1.97 (m, 2H), 1.94-1.85 (m, 2H), 1.53 (s, 9H).
Reaction SMILES: [CH3:1][N:2]([CH3:31])[C:3](=[O:30])[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24](OCC)=[O:25])[C:6]1=[O:29].[NH2:32][CH2:33][CH2:34][CH2:35][OH:36]>>[CH3:1][N:2]([CH3:31])[C:3](=[O:30])[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24]([NH:32][CH2:33][CH2:34][CH2:35][OH:36])=[O:25])[C:6]1=[O:29]
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N(C)C)c1=O
Reactant: NCCCO
Product: CN(C)C(=O)Cn1c(=O)c(C(=O)NCCCO)c(O)c2ncc(Cc3ccc(F)cc3)cc21

Procedure:
This compound was prepared from ethyl 1-[2-(dimethylamino)-2-oxoethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 3-amino-1-propanol employing methods similar to those described in Example 245 and was purified by reverse phase preparative HPLC (C-18 stationary phase; 10-100% CH3CN/water/0.1% formic acid mobile phase). The product was obtained as a white solid: 1H NMR (d6-DMSO) δ 10.56 (1H, br), 8.16 (1H, br s), 7.26 (3H, m), 7.10 (2H, t, J=8.8 Hz), 4.93 (2H, s), 4.50 (1H, br t), 3.99 (2H, s), 4.43 (2H, m), 3.27 (2H, m), 3.08 (3H, s), 2.78 (3H, s), 1.58 (2H, m, J=6 Hz); HRMS calcd for C23H25FN4O5+H+: 457.1887. Found: 457.1903.
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17][N:18]([CH2:30][CH2:31][CH2:32][CH2:33][N:34]1C(=O)C2C(=CC=CC=2)C1=O)[CH:19]1[C:28]2[N:27]=[C:26]([CH3:29])[CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21][CH2:20]1)=O)(C)(C)C.O.NN>C(O)C>[NH:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17][N:18]([CH:19]1[C:28]2[N:27]=[C:26]([CH3:29])[CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21][CH2:20]1)[CH2:30][CH2:31][CH2:32][CH2:33][NH2:34]
Reactant: Cc1ccc2c(n1)C(N(CCCCN1C(=O)c3ccccc3C1=O)Cc1nc3ccccc3n1C(=O)OC(C)(C)C)CCC2
Agent: NN
Solvent: O
Solvent: CCO
Product: Cc1ccc2c(n1)C(N(CCCCN)Cc1nc3ccccc3[nH]1)CCC2
Reaction time: 96 h
Yield: 58.7 %

Procedure:
To a solution of 2-{[[4-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-butyl]-(2-methyl-5,6,7,8-tetrahydroquinolin-8-yl)-amino]-methyl}-benzoimidazole-1-carboxylic acid tert-butyl ester (228 mg, 0.384 mmol) in ethanol (10 mL) at room temperature was added hydrazine hydrate (0.10 mL). The mixture was stirred for 4 days. The mixture was concentrated in vaccuo and the resultant material was purified by column chromatography on silica gel (1:1:10 MeOH: NH4OH: CH2Cl2) to provide the product as a colourless oil (82 mg, 59%): 1H NMR (CDCl3) δ 1.25-1.45 (m, 4H), 1.60-1.70 (m, 1H), 1.81-1.93 (m, 1H), 1.97-2.04 (m, 1H), 2.10-2.18 (m, 1H), 2.46-2.56 (m, 3H), 2.62-2.82 (m, 6H), 3.95-3.99 (m, 1H), 4.00 (d, 1H, J=17.1 Hz), 4.09 (d, 1H, J=17.1 Hz), 6.98 (d, 1H, J=7.8 Hz), 7.15-7.21 (m, 2H), 7.30 (d, 1H, J=7.8 Hz), 7.57-7.60 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][C@H:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][NH:8]1.Br[CH2:27][C:28](Br)=[O:29].[NH2:31][C@@H:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][C@@H:33]1[OH:41]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][C@H:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:27][C:28]([NH:31][C@@H:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][C@@H:33]1[OH:41])=[O:29]
Reactant: COc1ccc(C[C@@H]2NCCc3cc(OC)c(OC)cc32)cc1OC
Reactant: O=C(Br)CBr
Reactant: N[C@@H]1c2ccccc2C[C@@H]1O
Product: COc1ccc(C[C@H]2c3cc(OC)c(OC)cc3CCN2CC(=O)N[C@@H]2c3ccccc3C[C@@H]2O)cc1OC

Procedure:
prepared by reaction of (1S)-1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with (1R,2S)-1-amino-2-indanol
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29]Cl>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:25][C:26]3[CH:33]=[CH:32][CH:31]=[C:28]([CH3:29])[CH:27]=3)[N:13]=2)=[CH:23][CH:22]=1
Reactant: Cc1cccc(CCl)c1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Product: Cc1cccc(Cn2nc(-c3ccc(Cl)cc3)c3c2CCNCC3)c1

Procedure:
The title compound (0.004 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 59, Step C; 0.1 g) using 3-methylbenzyl chloride (0.6 mL) in place of benzyl chloride. MS (ESI): exact mass calculated for C21H22ClN3, 351.15; found, m/z 352.2 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.31-7.26 (m, 2H), 7.26-7.21 (m, 2H), 6.99 (t, J=7.5 Hz, 1H), 6.88 (d, J=7.1 Hz, 1H), 6.76 (s, 1H), 6.67 (d, J=7.1 Hz, 1H), 5.13 (s, 2H), 2.79-2.73 (m, 4H), 2.69-2.65 (m, 2H), 2.63-2.60 (m, 2H), 2.09 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:21])[N:5]([C:12]1([CH3:20])[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[Cl:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](Cl)=[O:27].CO>C1COCC1>[Cl:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26]([NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:21])[N:5]([C:12]1([CH3:20])[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11])=[O:27]
Reactant: CC1(N2C(=O)c3cccc(N)c3C2=O)CCC(=O)NC1=O
Reactant: O=C(Cl)c1cccc(Cl)c1
Solvent: CO
Solvent: C1CCOC1
Product: CC1(N2C(=O)c3cccc(NC(=O)c4cccc(Cl)c4)c3C2=O)CCC(=O)NC1=O
Reaction time: 0.25 h
Yield: 73.8 %

Procedure:
To a suspension of 4-amino-2-(3-methyl-2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione (0.10 g, 0.35 mmol) in THF (15 ml) was added 3-chlorobenzoyl chloride (0.12 g, 0.70 mmol) The mixture was heated to reflux for 18 h. The reaction mixture was allowed to cool and to the solution was added methanol (2 ml). The reaction mixture was stirred for an additional 15 minutes followed by solvent evaporation in vacuo. The resulting solid was slurried in diethyl ether (20 ml) and filtered to give 0.11 g (73%) of product as an off-white solid: mp 283-285° C.; 1H NMR (DMSO-d6) 11.06 (s, 1H), 10.43 (s, 1H), 8.48 (d, J=8.3 Hz, 1H), 7.98-7.61 (m. 6H), 2.80-2.51 (m, 3H), 2.11-2.01 (m, 1H), 1.92 (s, 3H), 1.61 (t, J=6.4 Hz, 2H), 1.29 (bs, 6H), 0.87 (t, J=6.3 Hz, 3H); 13C NMR (DMSO-d6) 171.72, 171.64, 168.53; 167.11, 163.55, 135.81, 135.75, 135.35, 133.59, 132.07, 131.03, 130.73, 127.03, 126.37, 125.58, 118.43, 118.06, 58.80, 28.90, 28.37, 20.84; Anal. Calcd. For C21H16ClN3O5: C, 59.23; H, 3.79; N, 9.87 Found: C, 59.00; H, 3.80; N, 9.70.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11]C(=O)OC(C)(C)C)[N:4]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][CH3:26])[CH:20]=2)[N:3]=1.[C:27](Cl)(=[O:30])[CH:28]=[CH2:29].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([C:19]3[CH:20]=[C:21]([N:25]([CH3:26])[C:27](=[O:30])[CH:28]=[CH2:29])[CH:22]=[CH:23][CH:24]=3)[N:3]=[C:2]([I:1])[C:10]=12
Reactant: CNc1cccc(-n2nc(I)c3c(NC(=O)OC(C)(C)C)ncnc32)c1
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CC(=O)N(C)c1cccc(-n2nc(I)c3c(N)ncnc32)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
To a stirred solution of tert-butyl 3-iodo-1-(3-(methylamino)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylcarbamate (46) (440 mg, 0.99 mmol) in DCM (8 mL) at 0° C. was added acryloyl chloride (103 mg, 1.13 mmol) dropwise. The resulting mixture was stirred at RT overnight before introducing TFA (8 mL). Stirring was continued for an additional 2 h. Solvents were removed and the residue was dissolved in sat. aquous NaHCO3. The product was extracted with 85% DCM/IPA (50 mL×3). The combined organic extracts were dried over Na2SO4, filtered and concentrated to provide N-(3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)phenyl)-N-methylacrylamide (50) (375 mg, 95%) as a white solid. LC-MS (ESI): m/z (M+1) 421.0.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]2[C:5]([C:6]([NH:24][C@H:25]([CH3:28])[CH2:26][OH:27])=[N:7][C:8]([S:12]([CH2:15][C:16]3C=C[CH:19]=[C:18](F)[C:17]=3F)(=O)=O)=[N:9]2)=[N:4][CH:3]=1.[S:29]1C=CC=C1S.CC(C)([O-])C.[K+]>CS(C)=O.C1COCC1>[NH2:1][C:2]1[N:11]=[C:10]2[C:5]([C:6]([NH:24][C@H:25]([CH3:28])[CH2:26][OH:27])=[N:7][C:8]([S:12][CH2:15][C:16]3[S:29][CH:19]=[CH:18][CH:17]=3)=[N:9]2)=[N:4][CH:3]=1
Reactant: C[C@H](CO)Nc1nc(S(=O)(=O)Cc2cccc(F)c2F)nc2nc(N)cnc12
Reactant: Sc1cccs1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: C[C@H](CO)Nc1nc(SCc2cccs2)nc2nc(N)cnc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of the product from Example 10, step (a) (0.18 g) and 2-thienylmercaptan (70 mg) in anhydrous DMSO (3 ml) was treated with potassium t-butoxide solution in THF (1.0 M, 0.44 ml) and stirred at room temperature for 1 hour. The solution was purified directly by preparative reversed phase HPLC on a Waters 19×50 mm Symmetry C8 silica column eluted with 0.1% aqueous ammonium acetate:acetonitrile (70:30) to give an off-white solid that was dried under reduced pressure at 40° (20 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].O1[CH2:15][CH2:14][O:13][CH2:12]C1.[OH-].[Na+].C(C1OC1)Cl>O.CCOCC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH2:15][CH:14]1[O:13][CH2:12]1
Reactant: COc1ccccc1O
Reactant: C1COCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCC1CO1
Solvent: O
Solvent: CCOCC
Product: COc1ccccc1OCC1CO1

Procedure:
To 2-methoxyphenol(76 g) dissolved in about 60 ml of water and 200 ml of dioxane containing 29 g of sodium hydroxide is slowly added a large excess of epichlorohydrin (80 g). The solution is stirred at reflux temperature for 3 hrs. The mixture is diluted with ether, washed with two portions of water and dried using anhydrous magnesium sulfate. Evaporation of the dried extract, followed by distillation of the residue produced the product, 1-(2-methoxyphenoxy)-2,3-epoxypropane.
Reaction SMILES: C=O.[C:3](O)(=O)C.[CH2:7]([NH:10][CH2:11][CH:12]=[CH2:13])[CH:8]=[CH2:9].[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[C:19]1[NH:20][C:21]([C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)=[CH:22][CH:23]=1>C(O)C>[CH2:7]([N:10]([CH2:3][C:22]1[CH:23]=[C:19]([C:15]2[S:14][CH:18]=[CH:17][CH:16]=2)[NH:20][C:21]=1[C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)[CH2:11][CH:12]=[CH2:13])[CH:8]=[CH2:9]
Reactant: CC(=O)O
Reactant: c1csc(-c2ccc(-c3cccs3)[nH]2)c1
Reactant: C=CCNCC=C
Agent: C=O
Solvent: CCO
Product: C=CCN(CC=C)Cc1cc(-c2cccs2)[nH]c1-c1cccs1
Temperature: 25 °C
Yield: 65.6 %

Procedure:
Paraformaldehyde (9.1 mg, 0.3 mmol) was added to a solution of acetic acid (0.33 mL, 0.71 mmol) and diallylamine (0.32 mmol) in 1 mL of ethanol. After stirring at room temperature for a few minutes, 2.5-dithienylpyrrole (0.3 mmol) was then added all at once. The reaction mixture was then allowed to stir at 60° for 19 hours. The reaction solvent was evaporated under reduced pressure, and the crude product was taken up with ethyl acetate. The organic layer was then washed with water (10 mL) and brine (10 mL). The aqueous layer was extracted with chloroform (10 mL). The combined organic layers were then dried over anhydrous magnesium sulfate, filtered and the solvent was removed under pressure. The crude product was purified on 50 g of silica gel. Elution with hexane-ethyl acetate (5:1), gave 67 mg (65%) of title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:13]=[CH:12][S:11][CH:10]=2)=[CH:4][CH:3]=1.C(Cl)(Cl)Cl.CO.[I:20]N1C(=O)CCC1=O>C(Cl)Cl>[I:20][C:10]1[S:11][CH:12]=[CH:13][C:9]=1[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Fc1ccc(Cc2ccsc2)cc1
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Fc1ccc(Cc2ccsc2I)cc1
Reaction time: 3 h
Yield: 95.2 %

Procedure:
To a solution of 3-(4-fluorophenylmethyl)thiophene (1.16 g, 6.04 mmol) in 1:1 CHCl3 /methanol was added N-iodosuccinimide (1.70 g, 7.53 mmol). The reaction mixture was stirred for 3 hours, and then was diluted with CH2Cl2. The organic phase was extracted with saturated aqueous NaHCO3 and brine, dried over MgSO4, filtered, and concentrated in vacuo to give 1.83 g of 2-iodo-3-(4fluorophenylmethyl)thiophene which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([S:9]([CH3:12])(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1Br.[CH2:14]([N:16]1[C:20]([OH:21])=[CH:19][CH:18]=[N:17]1)[CH3:15].[C]=O.[O:24]1CCOC[CH2:25]1>>[Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([S:9]([CH3:12])(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1[C:25]([C:19]1[CH:18]=[N:17][N:16]([CH2:14][CH3:15])[C:20]=1[OH:21])=[O:24]
Reactant: C1COCCO1
Reactant: Cc1c(S(C)(=O)=O)ccc(Br)c1Cl
Reactant: CCn1nccc1O
Agent: [C]=O
Product: CCn1ncc(C(=O)c2ccc(S(C)(=O)=O)c(C)c2Cl)c1O
Temperature: 150 °C
Reaction time: 9 h
Yield: 43 %

Procedure:
1.42 g of 2-chloro-4-methanesulfonyl-3-methylbromobenzene, 2.24 g of 1-ethyl-5-hydroxypyrazole, 10 ml of triethylamlne, 0.175 g of dichloro(bistriphenylphosphine)palladium and 50 ml of dry 1,4-dioxane were charged into a 100 ml stainless steel autoclave equipped with a rotary stirrer, and the interior of the autoclave was substituted by carbon monoxide. Then, carbon monoxide was injected under a pressure of 20 kg/cm2. Then, the reaction temperature was raised to 150° C. under stirring, and the reaction was continued for 9 hours. The reaction mixture was left to cool and treated in the same manner as in Example 2-1 to obtain 0.60 g of the desired product (yield: 43%).
Reaction SMILES: [C:1]1([S:7]([NH:10][C@@H:11]([CH2:15][OH:16])[C:12]([OH:14])=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=1[N:25]1[CH2:26][CH2:27][N:28]([C:12](=[O:14])[C@@H:11]([NH:10][S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:8])=[O:9])[CH2:15][OH:16])[CH2:29][CH2:30]1
Reactant: Cc1ccc(C)c(N2CCNCC2)c1
Reactant: O=C(O)[C@H](CO)NS(=O)(=O)c1ccccc1
Product: Cc1ccc(C)c(N2CCN(C(=O)[C@H](CO)NS(=O)(=O)c3ccccc3)CC2)c1

Procedure:
In analogy to example 2, (S)-2-benzenesulfonylamino-3-hydroxy-propionic acid was coupled with 1-(2,5-dimethylphenyl)-piperazine to give N-{(S)-2-[4-(2,5-dimethyl-phenyl)-piperazin-1-yl]-1-hydroxymethyl-2-oxo-ethyl}-benzenesulfonamide.