Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[OH:8][C:9]1[C:10]([CH3:40])=[C:11]2[C:16](=[C:17]([CH3:20])[C:18]=1[CH3:19])[O:15][C:14]([CH2:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=1)([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:13][CH2:12]2.N1C=CC=CC=1.C1C=CC=CC=1>O>[C:1]([O:8][C:9]1[C:10]([CH3:40])=[C:11]2[C:16](=[C:17]([CH3:20])[C:18]=1[CH3:19])[O:15][C:14]([CH2:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=1)([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:13][CH2:12]2)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCCCCC1(COc2ccc([N+](=O)[O-])cc2)CCc2c(C)c(O)c(C)c(C)c2O1
Solvent: O
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CCCCCCCCC1(COc2ccc([N+](=O)[O-])cc2)CCc2c(C)c(OC(C)=O)c(C)c(C)c2O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.2 g of acetic anhydride was added to a mixture of 3.5 g of 6-hydroxy-5,7,8-trimethyl-2-(4-nitrophenoxymethyl)-2-octylchroman (prepared as described in Preparation 15), 10 ml of pyridine and 10 ml of benzene, and the mixture was stirred for 2hours at room temperature. The reaction mixture was then poured into water and extracted with benzene. The extract was washed with 5% w/v aqueous hydrochloric acid and water, successively in that order, and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, to give the title compound.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][CH2:6][C:7](Cl)=[O:8].[CH3:10][N:11]1[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[CH2:20][CH2:21][C:22](=[O:23])[C:12]1=2>C(Cl)Cl>[Cl:5][CH2:6][C:7]([C:16]1[CH:17]=[CH:18][C:19]2[N:11]([CH3:10])[C:12]3[C:22](=[O:23])[CH2:21][CH2:20][C:13]=3[C:14]=2[CH:15]=1)=[O:8]
Reactant: O=C(Cl)CCl
Reactant: Cn1c2c(c3ccccc31)CCC2=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Cn1c2c(c3cc(C(=O)CCl)ccc31)CCC2=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 53.1 %

Procedure:
Aluminum chloride (8.5 g) was suspended in CH2Cl2 (20 ml) at 0° C., chloroacetyl chloride (7.2 g) was slowly added and the mixture was stirred for 5 minutes. This mixture was added dropwise to a stirred solution of 1,4-dihydro-4-methylcyclopent[b]indol-3(2H)-one (6.0 g) in 100 ml CH2Cl2 at 0° C. The mixture was stirred at 0° C. for 45 minutes and thereafter an additional equivalent of preformed solution of aluminum chloride and chloroacetyl chloride in methylene chloride was introduced in a dropwise manner. After 30 minutes the reaction mixture was slowly poured into a stirred ice/water mixture. The layers were separated and the CH2Cl2 layer was washed with NaHCO3, dried (Na2SO4) and concentrated to an oil. Purification by flash chromatography on silica gel eluting with hexane/acetone provided 7-chloroacetyl-1,4-dihydro-4-methylcyclopent[b]indol-3(2H)-one (4.5 g).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:11]2=[N:12][CH:13]=[N:14][C:15]([O:16][C:17]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=3)=[C:10]2[CH:9]=[N:8]1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32]([C:34]2([C:37](O)=[O:38])[CH2:36][CH2:35]2)=[O:33])=[CH:27][CH:26]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>C(OCC)(=O)C.CN(C=O)C>[F:24][C:25]1[CH:26]=[CH:27][C:28]([NH:31][C:32]([C:34]2([C:37]([NH:23][C:20]3[CH:21]=[CH:22][C:17]([O:16][C:15]4[N:14]=[CH:13][N:12]=[C:11]5[N:7]([CH:2]6[CH2:3][CH2:4][CH2:5][CH2:6][O:1]6)[N:8]=[CH:9][C:10]=45)=[CH:18][CH:19]=3)=[O:38])[CH2:36][CH2:35]2)=[O:33])=[CH:29][CH:30]=1
Reactant: Nc1ccc(Oc2ncnc3c2cnn3C2CCCCO2)cc1
Reactant: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(F)cc1)C1(C(=O)Nc2ccc(Oc3ncnc4c3cnn4C3CCCCO3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.9 %

Procedure:
To a round bottom flask equipped with a magnetic stir bar was added 4-[1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-phenylamine (0.199 g, 0.63 mmol, 1.0 eq.), 1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid (0.213 g, 0.95 mmol, 1.5 eq), HATU (0.607 g, 1.6 mmol, 2.5 eq), triethylamine (0.26 ml, 1.9 mmol, 3 eq), and anhydrous DMF (5 ml). The mixture was stirred at room temperature for 1 hour. The mixture was diluted with ethyl acetate, washed with (2×) H2O (50 ml), sat'd NaHCO3 (2×), 5% LiCl (3×), sat'd NaCl (1×), dried (Na2SO4), and concentrated in vacuo to give N-(4-fluorophenyl)-N′-(4-{[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]oxy}phenyl)cyclopropane-1,1-dicarboxamide as a white solid (0.312 g, 95% yield). 1H NMR (400 MHz, CDCl3): 9.21 (s, 1H), 8.82 (bs, 1H), 8.56 (s, 1H), 7.96 (s, 2H), 7.65 (dd, 2H), 7.48 (m, 2H), 7.21 (m, 2H), 7.05 (t, 2H), 6.05 (dd, 1H), 3.78 (m, 1H), 2.61 (m, 1H), 2.16 (m, 1H), 2.14 (s,1H), 1.99 (m, 1H), 1.81 (m, 2H), 1.69 (m, 4H), 1.60 (s, 1H); MS (ESI) for C27H25FN7O4: 517 (MH+).
Reaction SMILES: [CH:1]1([CH2:7][C:8]2[S:12][C:11]([NH2:13])=[N:10][C:9]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([O:35][CH3:36])[C:32]=1[O:33][CH3:34])[C:27](Cl)=[O:28]>>[CH:1]1([CH2:7][C:8]2[S:12][C:11]([NH:13][C:27](=[O:28])[C:26]3[CH:25]=[C:24]([O:23][CH3:22])[C:32]([O:33][CH3:34])=[C:31]([O:35][CH3:36])[CH:30]=3)=[N:10][C:9]=2[C:14]2[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: COc1ccc(-c2nc(N)sc2CC2CCCCC2)cc1
Product: COc1cc(C(=O)Nc2nc(-c3ccc(O)cc3)c(CC3CCCCC3)s2)cc(OC)c1OC
Yield: 60.1 %

Procedure:
A procedure similar to that in Example 4 was used. 5-cyclohexylmethyl-4-(4-methoxy-phenyl)-thiazol-2-ylamine prepared in Example 47 and 3,4,5-trimethoxy-benzoyl chloride prepared in the step 1 of Example 37 were used as starting materials, allowed to react at room temperature overnight, followed by post-treatment to give a crude product, which was purified by a silica gel column chromatography eluted with a gradient of dichloromethane and ethyl acetate (20:1) to obtain a product as a white solid in a yield of 60.1%, mp: 193-194└. 1H-NMR (CDCl3, 400 MHz) δ: 0.85˜0.98 (2H, m), 1.05˜1.28 (3H, m), 1.58˜1.88 (6H, m), 2.75 (2H, d, J=7.28 Hz, CHCH2Ar), 3.74 (3H, s, OCH3), 3.77 (3H, s, OCH3), 3.79 (3H, s, OCH3), 3.97 (3H, s, OCH3), 6.77 (2H, d, J=8.44 Hz, ArH), 6.98 (2H, s, ArH), 7.29 (2H, d, J=8.44 Hz, ArH); EI-MS m/e (%): 496.1 (M+, 64), 413.1 (48), 195.1 (100); HREI-MS Calcd. for C27H32N2O5S: 496.2032. found: 496.2040. Anal. Calcd. for C27H32N2O5S: C, 65.30; H, 6.49; N, 5.64. found: C, 65.11; H, 6.55; N, 5.70.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6](=O)[N:7](C2C=CC=CC=2)[CH:8]=1)[CH3:2].[CH2:16]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[CH3:17]>C(O)(=O)CCCCCCC/C=C\CCCCCCCC>[NH2:20][C:6]1[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][N:7]=1.[CH2:16]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[CH3:17]
Reactant: CCc1ccc(=O)n(-c2ccccc2)c1
Agent: CCCCCCCC/C=C\CCCCCCCC(=O)O
Agent: CCc1cccnc1
Product: CCc1ccc(N)nc1

Procedure:
In said first reaction scheme, we have found that 5-ethyl-1-phenyl-2-(1H)-pyridone can be made from 3-ethyl pyridine (available from Sigma-Aldrich Corporation, St. Louis, Mo.) which is reacted with NaNH2 in presence of a small amount of oleic acid as a catalyst to speed up the reaction. A general reaction scheme for obtaining 2-amino-5-ethyl pyridine isomer from 3-ethylpyridine is provided in U.S. Pat. No. 5,003,069 to McGill et al, “Chichibabin Reaction,” at Example 12. U.S. Pat. No. 5,003,069 is herein incorporated by reference as if fully set forth herein. In this reaction 3-ethyl pyridine (I) is converted to 2-amino-5-ethylpyridine (II) as well as 2-amino-3-ethylpyridine(III).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([CH3:14])([CH3:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)C(C)C)C.[NH2:74][CH:75]1[CH2:80][CH2:79][N:78]([CH3:81])[CH2:77][CH2:76]1>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([CH3:13])([CH3:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:74][CH:75]5[CH2:80][CH2:79][N:78]([CH3:81])[CH2:77][CH2:76]5)=[O:27])=[CH:24][CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1CCC(N)CC1
Reactant: CN1C(=O)C(C)(C)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3)ncc21
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCCC3)CC(C)(C)C(=O)N4C)cc2)CC1
Reaction time: 0.25 h
Yield: 49.7 %

Procedure:
To a suspension of 0.0293 g (0.000072 mole) of 4-(9-cyclopentyl-5,7,7-trimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-benzoic acid (I-50a) in 3 mL of dimethylformamide was added 0.0156 g (0.00012 mole) of 1-hydroxybenzotriazole, 0.043 g (0.00011 mole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium 3-oxide hexafluorophosphate and 0.08 mL (0.0005 mole) of ethyldiisopropylamine. The mixture was stirred for 15 minutes and then 0.0129 g (0.00011 mole) of 4-amino-1-methylpiperidine was added. The mixture was stirred for an additional 2.5 hours and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed successively with 1 M sodium hydroxide, brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-methanol (98:2-85:15) to give 0.0181 g of 4-(9-cyclopentyl-5,7,7-trimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-methyl-piperidin-4-yl)-benzamide (I-50).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[C@H:18]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:17][CH2:16]3)=[N:6][CH:7]=1.[H-].[Na+].[NH4+].[Cl-].[CH3:32]N(C=O)C>>[Br:1][C:2]1[CH:7]=[N:6][C:5]([N:8]([CH3:32])[CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[C@H:18]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:17][CH2:16]3)=[N:4][CH:3]=1
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCNc3ncc(Br)cn3)ccc21
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCCN(C)c3ncc(Br)cn3)ccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 21 %

Procedure:
To a solution of ethyl ((1S)-5-{3-[(5-bromo-2-pyrimidinyl)amino]propoxy}2,3-dihydro-1H-inden-1-yl)acetate (Example 281, 500 mg, 1.15 mmol) in DMF (10 mL) was added NaH [H2 evolution], followed by Mel (180 mg, 1.27 mmol) added over 5 min. The reaction mixture was stirred at rt for 4 h, NH4Cl (10% aqueous solution) was added, after which the mixture was concentrated under reduced pressure. The residue was taken up in EtOAc, then washed with water and brine successively. The organic phase was dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to provide the product (600 mg, 21%) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 1.29 (t, 3H), 1.71-1.81 (m, 1H), 2.05-2.13 (m, 2H), 2.34-2.45 (m, 2H), 2.73 (dd, 1H), 2.73-2.94 (m, 2H), 3.14 (s, 3H), 3.49-3.56 (m, 1H), 3.77 (t, 2H), 3.97 (t, 2H), 4.18 (q, 2H), 6.74 (dd, 1H), 6.75 (d, 1H), 7.05 (d, 1H), 8.24 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:24])[C:5]2[CH:11]=[C:10](Br)[C:9](=[O:13])[N:8]([C@H:14]3[CH2:19][CH2:18][C@@H:17]([O:20][CH2:21][CH2:22][OH:23])[CH2:16][CH2:15]3)[C:6]=2[N:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][N:34]=1>[Pd](Cl)Cl>[NH2:1][C:2]1[N:3]=[C:4]([CH3:24])[C:5]2[CH:11]=[C:10]([C:36]3[CH:35]=[N:34][C:33]([O:32][CH3:31])=[CH:38][CH:37]=3)[C:9](=[O:13])[N:8]([C@H:14]3[CH2:19][CH2:18][C@@H:17]([O:20][CH2:21][CH2:22][OH:23])[CH2:16][CH2:15]3)[C:6]=2[N:7]=1
Reactant: Cc1nc(N)nc2c1cc(Br)c(=O)n2[C@H]1CC[C@@H](OCCO)CC1
Reactant: COc1ccc(B(O)O)cn1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(-c2cc3c(C)nc(N)nc3n([C@H]3CC[C@@H](OCCO)CC3)c2=O)cn1
Temperature: 100 °C

Procedure:
A mixture of 2-amino-6-bromo-8-(cis-4-(2-hydroxyethoxy)cyclohexyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one (50 mg, 0.13 mmol), potassium carbonate (52 mg, 0.38 mmol), and 2-methoxy-5-pyridine boronic acid (38 mg, 0.25 mmol) in 5:1 dimethylformade:water (1.3 mL) was bubbled with argon for 5 minutes. To the mixture was added bis(tripehnylphosphine) palladium (II) chloride (9 mg, 0.13 mmol) and the microwave vial was immediately sealed and the mixture was bubbled again with argon. After heating for 20 min at 100° C. in the microwave, the mixture was concentrated in vacuo. The residue was dissolved in CHCl3 (60 mL) and washed with water (10 mL) and brine (10 mL). The organic layer was dried (Na2SO4), filtered and concentrated. The crude product was purified by flash chromatography eluting with chloroform/7 N ammonia in methanol (0-5%) to afford the title compound (50 mg, 93%).
Reaction SMILES: O[C:2]1([C:12]2[C:20]([OH:21])=[CH:19][C:15]3[O:16][CH2:17][O:18][C:14]=3[CH:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:11].C([SiH](CC)CC)C.CCCCCCC>COC(C)(C)C>[OH:21][C:20]1[C:12]([CH:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[NH:4][C:3]2=[O:11])=[CH:13][C:14]2[O:18][CH2:17][O:16][C:15]=2[CH:19]=1
Reactant: O=C1Nc2ccccc2C1(O)c1cc2c(cc1O)OCO2
Agent: CC[SiH](CC)CC
Solvent: CCCCCCC
Solvent: COC(C)(C)C
Product: O=C1Nc2ccccc2C1c1cc2c(cc1O)OCO2
Temperature: 10.5 °C
Reaction time: 1 h
Yield: 77.7 %

Procedure:
A 1600 L reactor was charged with 3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one (113.1 kg, 396 mol), evacuated and filled with nitrogen. Trifluoroacetic acid (679 kg) was added in two portions over 20 minutes and the internal temperature was lowered to 10° C. over 1 h. Triethylsilane (69.2 kg, 595 mol) was added over 2 h 05 min at 10-11° C. and the mixture was stirred for a further 0.5 h at 10-11° C. A 1000 L reactor was charged with heptane (524 kg) and tert-butyl methyl ether (63 kg). The contents of the 1000 L reactor were transferred to the 1600 L reactor over 13 minutes at an internal temperature of 10-11° C. The resultant yellow-orange suspension was allowed to warm to 23° C. over 1 h. The solid was collected by filtration, washed with heptane (464 kg) followed by tert-butyl methyl ether (57 kg) and dried at 50° C. under a reduced pressure of 58 to 7 mbar over a period of 25 h to afford 3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one (82.8 kg, 75%) as an off-white solid: purity (HPLC-UV at 300 nm) 98.0% a/a; 1H NMR (300 MHz, DMSO-d6) δ 10.40 (s, 1H), 9.25 (s, 1H), 7.17-7.10 (m, 1H), 6.95-6.81 (m, 3H), 6.55 (s, 1H), 6.43 (s, 1H), 5.92-5.85 (m, 2H), 4.66 (s, 1H); 13C NMR (75 MHz, DMSO-d6) δ177.9, 150.1, 146.6, 142.7, 139.6, 130.9, 127.4, 123.8, 121.2, 115.9, 109.5, 109.0, 100.7, 97.8, 55.0.
Reaction SMILES: [C:1]1([S:7]([N@:10]2[CH2:12][CH:11]2[C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=3[CH3:28])[CH2:17][CH2:16]2)=[O:14])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-].[Na+].[C:31]1([N:37]=[C:38]=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[C:1]1([S:7]([N:10]2[CH2:12][C@@H:11]([C:13]([N:15]3[CH2:16][CH2:17][N:18]([C:21]4[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=4[CH3:28])[CH2:19][CH2:20]3)=[O:14])[N:37]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:38]2=[O:39])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(C)c(N2CCN(C(=O)C3C[N@@]3S(=O)(=O)c3ccccc3)CC2)c1
Reactant: O=C=Nc1ccccc1
Agent: [I-]
Agent: [Na+]
Product: Cc1ccc(C)c(N2CCN(C(=O)[C@@H]3CN(S(=O)(=O)c4ccccc4)C(=O)N3c3ccccc3)CC2)c1

Procedure:
In analogy to example 2, ((S)-1-benzenesulfonyl-aziridin-2-yl)-[4-(2,5-dimethyl-phenyl)-piperazin-1-yl]-methanone was reacted with sodium iodide and phenylisocyanate to give the title compound as a colorless solid. MS: 519.3 ([M+H]+)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[S:11][C:12]([CH2:15][CH2:16][OH:17])=[N:13][N:14]=2)[CH:5]=1.[O:19]1[CH:24]=[CH:23][CH2:22][CH2:21][CH2:20]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCOC(C)=O>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[S:11][C:12]([CH2:15][CH2:16][O:17][CH:20]3[CH2:21][CH2:22][CH2:23][CH2:24][O:19]3)=[N:13][N:14]=2)[CH:5]=1
Reactant: COC(=O)c1cccc(-c2nnc(CCO)s2)c1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(-c2nnc(CCOC3CCCCO3)s2)c1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
A mixture of 3-[5-(2-hydroxy-ethyl)-[1,3,4]thiadiazol-2-yl]-benzoic acid methyl ester (1.86 g), dihydropyrane (0.95 mL) and p-toluenesulfonic acid hydrate (0.13 g) in AcOEt (25 mL) was stirred at 20° C. for 1 h. The solution was diluted with AcOEt, washed with 5% NaHCO3 solution and with brine, dried and evaporated in vacuum. The residual oil was purified by chromatography on silica gel using AcOEt/hexane (1:2) as eluent to give 3-{5-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-[1,3,4]thiadiazol-2-yl]-benzoic acid methyl ester (1.60 g) as a pale-yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([C:15]([OH:18])([CH3:17])[CH3:16])=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:19]([NH2:21])=[O:20])=[CH:4][CH:3]=1.[I:22]N1C(=O)CCC1=O.N1C=CC=CC=1>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([C:15]([OH:18])([CH3:17])[CH3:16])=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:19]([NH2:21])=[O:20])=[CH:4][C:3]=1[I:22]
Reactant: O=C1CCC(=O)N1I
Reactant: CC(C)(O)c1ccc2c(c1)[nH]c1c(C(N)=O)ccc(Br)c12
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)(O)c1ccc2c(c1)[nH]c1c(C(N)=O)cc(I)c(Br)c12
Yield: 23 %

Procedure:
A mixture of 4-bromo-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide [synthesized according to the procedure described in U.S. Pat. No. 8,084,620, Example 73-2] (2.00 g, 5.76 mmol), N-iodosuccinimide (1.69 g, 7.49 mmol), and pyridine (1.9 mL, 23.0 mmol) in DMF (20 mL) was heated at 65° C. for 2 days. The cooled mixture was diluted with EtOAc, washed twice with 10% aqueous LiCl and then with brine. The aqueous layers were extracted with EtOAc. The combined organic layers were dried and concentrated, and the residue was purified by column chromatography on silica gel, eluting with EtOAc-hexanes (gradient from 50%-65%), to provide 4-bromo-7-(2-hydroxypropan-2-yl)-3-iodo-9H-carbazole-1-carboxamide as a yellow solid (0.609 g, 23% yield). Mass spectrum m/z 473, 475 (M+H—H2O)+. 1H NMR (500 MHz, DMSO-d6) δ 11.66 (s, 1H), 8.49 (d, J=8.6 Hz, 1H), 8.38 (s, 1H), 8.26 (br. s., 1H), 7.94 (d, J=1.1 Hz, 1H), 7.58 (br. s., 1H), 7.40 (dd, J=8.6, 1.4 Hz, 1H), 5.09 (s, 1H), and 1.51 (s, 6H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([C:10]2[C:19]3[C:14](=[CH:15][C:16]([S:20]([N:23]([CH2:30][C:31]4[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=4)[C:24]4[CH:29]=[CH:28][N:27]=[CH:26][N:25]=4)(=[O:22])=[O:21])=[CH:17][CH:18]=3)[CH:13]=[CH:12][N:11]=2)=[CH:4][CH:3]=1.[F:39][C:40]1[CH:41]=[C:42](B(O)O)[CH:43]=[CH:44][C:45]=1[F:46].C(=O)([O-])[O-].[K+].[K+]>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>[F:39][C:40]1[CH:41]=[C:42]([C:2]2[N:7]=[C:6]([O:8][CH3:9])[C:5]([C:10]3[C:19]4[C:14](=[CH:15][C:16]([S:20]([N:23]([CH2:30][C:31]5[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=5)[C:24]5[CH:29]=[CH:28][N:27]=[CH:26][N:25]=5)(=[O:22])=[O:21])=[CH:17][CH:18]=4)[CH:13]=[CH:12][N:11]=3)=[CH:4][CH:3]=2)[CH:43]=[CH:44][C:45]=1[F:46]
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc3c(-c4ccc(Cl)nc4OC)nccc3c2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc3c(-c4ccc(-c5ccc(F)c(F)c5)nc4OC)nccc3c2)cc1

Procedure:
A microwave vial was charged with 1-(6-chloro-2-methoxypyridin-3-yl)-N-(4-methoxybenzyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (Intermediate EEEEE; 0.052 g, 0.095 mmol), (3,4-difluorophenyl)boronic acid (0.022 g, 0.142 mmol), potassium carbonate (0.039 g, 0.285 mmol), and Pd(Ph3P)4 (10.96 mg, 9.49 μmol). The vial was flushed with Ar (g), then Dioxane (0.712 mL) and Water (0.237 mL) were added. The reaction was microwaved at 90° C. for one hour. The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (RediSep Gold 12 g, gradient elution 0-50% EtOAc:Heptane) to afford 1-(6-(3,4-difluorophenyl)-2-methoxypyridin-3-yl)-N-(4-methoxybenzyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide. The material was dissolved in DCM and TFA (0.1 mL, 1.298 mmol) was added. The reaction was stirred overnight at room temperature. Triflic acid (0.050 mL, 0.563 mmol) was added and the reaction was stirred for one hour. The reaction was concentrated and the material was purified via column chromatography (RediSep Gold 12 g, gradient elution 0-10% MeOH:DCM) to afford 1-(6-(3,4-difluorophenyl)-2-methoxypyridin-3-yl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ=8.78-8.71 (m, 2H), 8.59 (s, 1H), 8.33-8.28 (m, 1H), 8.28-8.23 (m, 2H), 8.13 (br. s., 1H), 8.02 (d, J=1.9 Hz, 1H), 7.98 (d, J=7.6 Hz, 2H), 7.88 (d, J=7.9 Hz, 2H), 7.62 (td, J=8.6, 10.4 Hz, 1H), 7.03 (d, J=6.0 Hz, 1H), 3.91 (s, 3H). m/z (ESI) 506.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11]2[C:12](=[O:27])[N:13]([CH3:26])[CH2:14][C:15]3[N:16]([CH:17]=[N:18][C:19]=3[C:20]3[N:24]=[C:23]([CH3:25])[O:22][N:21]=3)[C:10]=2[CH:9]=[CH:8][CH:7]=1)=[O:5])[CH3:2].C(O)C[OH:30]>S(=O)(=O)(O)O>[OH:30][CH2:2][CH2:1][O:3][C:4]([C:6]1[C:11]2[C:12](=[O:27])[N:13]([CH3:26])[CH2:14][C:15]3[N:16]([CH:17]=[N:18][C:19]=3[C:20]3[N:24]=[C:23]([CH3:25])[O:22][N:21]=3)[C:10]=2[CH:9]=[CH:8][CH:7]=1)=[O:5]
Reactant: OCCO
Reactant: CCOC(=O)c1cccc2c1C(=O)N(C)Cc1c(-c3noc(C)n3)ncn1-2
Agent: O=S(=O)(O)O
Product: Cc1nc(-c2ncn3c2CN(C)C(=O)c2c(C(=O)OCCO)cccc2-3)no1
Temperature: 130 °C
Reaction time: 24 h

Procedure:
7-Ethoxycarbonyl-5,6-dihydro-5-methyl-3-(5-methyl-1,2,4-oxadiazol-3-yl)-6-oxo-4H-imidazo(1,5-a)(1,4)benzodiazepine (500 mg) was dissolved in ethylene glycol (20 ml) and 3 drops of concentrated sulphuric acid were added. The solution was then stirred at 130° C. for 24 hours, cooled and partitioned between water (150 ml) and CHCl3 (150 ml). The organic phase was separated, dried over Na2SO4, and evaporated to give the title compound as white crystals.