Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH:20]([CH3:22])[CH3:21])[CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[F:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([C:34](O)=[O:35])=[CH:26][CH:25]=1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([C:34]([NH:1][CH:2]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH:20]([CH3:22])[CH3:21])[CH:14]=2)[CH:3]([C:5]2[CH:6]=[CH:7][C:8]([F:11])=[CH:9][CH:10]=2)[OH:4])=[O:35])=[CH:26][CH:25]=1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Reactant: CC(C)Oc1cccc(CC(N)C(O)c2ccc(F)cc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: CC(C)Oc1cccc(CC(NC(=O)c2ccc(F)c3ccccc23)C(O)c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[3-(isopropyloxy)phenyl]-1-propanol (0.46 g, 1.5 mmol) and 4-fluoronaphthalene-1-carboxylic acid (0.34 g, 1.8 mmol) in acetonitrile (20 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.36 g, 2.1 mmol) and 1-hydroxybenzotriazole hydrate (0.32 g, 2.1 mmol), and the mixture was stirred at room temperature for 5 hrs. To the reaction solution was added water (100 ml), and the mixture was extracted with ethyl acetate (100 ml×2). The extract was washed with water, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel chromatography (chloroform:ethyl acetate=10:1) to give the objective substance (0.65 g, 91%) as crystals.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C@H:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:8]1.Br[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)[N:24]=1>>[CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C@H:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH2:18][N:17]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)[N:24]=2)[CH2:16][CH2:15]3)[CH2:8]1
Reactant: Brc1cccc(N2CCCC2)n1
Reactant: C[C@H]1CCCN1[C@H]1CCN(c2ccc3c(c2)CCNC3)C1
Product: C[C@H]1CCCN1[C@H]1CCN(c2ccc3c(c2)CCN(c2cccc(N4CCCC4)n2)C3)C1

Procedure:
The title compound was synthesized in substantially the same way as Example 1 by condensation of 6-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-1,2,3,4-tetrahydro-isoquinoline with 2-bromo-6-pyrrolidin-1-yl-pyridine.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[C:8]([NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([CH2:30][CH3:31])([CH3:29])[CH3:28])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[N:7]([CH3:32])[N:6]=1.[H-].[Na+].CC(N(C)C)=O.[Br:41][C:42]1[CH:43]=[N:44][C:45](Cl)=[N:46][CH:47]=1>O1CCCC1.O>[Br:41][C:42]1[CH:43]=[N:44][C:45]([O:1][CH2:2][CH2:3][O:4][C:5]2[C:9]([C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=3)=[C:8]([NH:17][S:18]([C:21]3[CH:22]=[CH:23][C:24]([C:27]([CH2:30][CH3:31])([CH3:28])[CH3:29])=[CH:25][CH:26]=3)(=[O:19])=[O:20])[N:7]([CH3:32])[N:6]=2)=[N:46][CH:47]=1
Reactant: Clc1ncc(Br)cn1
Reactant: CCC(C)(C)c1ccc(S(=O)(=O)Nc2c(-c3ccc(C)cc3)c(OCCO)nn2C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Solvent: O
Product: CCC(C)(C)c1ccc(S(=O)(=O)Nc2c(-c3ccc(C)cc3)c(OCCOc3ncc(Br)cn3)nn2C)cc1
Reaction time: 0.02 h
Yield: 80.5 %

Procedure:
To N-[3-(2-hydroxyethoxy)-1-methyl-4-(4-methylphenyl)-1H-pyrazol-5-yl]-4-(tert-pentyl)benzenesulfonamide (Example 8) (270 mg) in tetrahydrofuran (4 ml) at room temperature under an atmosphere of nitrogen was added sodium hydride (60% dispersion in oil, 50 mg) and the mixture was stirred for 1 minute. To the mixture was added dimethyl acetamide (0.5 ml) followed by 5-bromo-2-chloropyrimidine (171 mg). The mixture was stirred for 2 hours at room temperature and then diluted with water (20 ml) and extracted with ether (2×20 ml). The organic fractions were combined, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica (35 g) eluted with hexane:ethyl acetate (2:1 to 1:2) to yield the title compound as an orange oil (292 mg).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([NH2:12])=[O:11])#[CH:2].Cl[C:14]1[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][N:17]=[C:16]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([CH:31]3[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]3)=[CH:27][C:26]=2[O:44][C:45]([F:48])([F:47])[F:46])[N:15]=1.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:12][C:10](=[O:11])[CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:1]#[C:2][C:18]1[C:19]([C:20]([F:21])([F:23])[F:22])=[CH:14][N:15]=[C:16]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([CH:31]3[CH2:32][CH2:33][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:35][CH2:36]3)=[CH:27][C:26]=2[O:44][C:45]([F:46])([F:47])[F:48])[N:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)c(OC(F)(F)F)c2)CC1
Reactant: C#Cc1ccccc1CC(N)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(C#Cc4ccccc4CC(N)=O)n3)c(OC(F)(F)F)c2)CC1
Temperature: 120 °C
Yield: 73 %

Procedure:
To a nitrogen de-gassed solution of 2-(2-ethynylphenyl)acetamide (I41) (0.029 g, 0.18 mmol) and tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-(trifluoromethoxy)phenyl)piperidine-1-carboxylate (I48) (0.082 g, 0.15 mmol) in dry DMF (4 mL) were added triethylamine (0.085 mL, 0.61 mmol), triphenylphosphine (6.0 mg, 0.023 mmol), trans-dichlorobis (triphenylphosphine)palladium (II) (0.011 g, 0.015 mmol) and Cu(I)I (4.0 mg, 0.023 mmol). The reaction mixture was heated under microwave irradiation at 120° C. for 20 minutes, concentrated to dryness in vacuo and purified by silica gel chromatography (12 g Si cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.) to give the title compound (I49) (0.073 g, 73% yield) as a pale yellow solid; 1H NMR (400 MHz, d6-DMSO) δ 10.11 (s, 1H), 8.74 (s, 1H), 7.58 (dd, J=7.7, 6.2 Hz, 2H), 7.53-7.47 (m, 1H), 7.42-7.27 (m, 5H), 6.99 (s, 1H), 4.14-4.03 (m, 2H), 3.67 (s, 2H), 2.87-2.72 (m, 3H), 1.79 (d, J=12.8 Hz, 2H), 1.50 (qd, J=12.5, 4.1 Hz, 2H), 1.42 (s, 9H). LCMS Method C: rt 6.63 min; m/z 564.0 [M-Boc+2H]+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[CH:5][C:4]([NH2:8])=[N:3]1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+].[CH:57]1([N:60]([CH:79]2[CH2:81][CH2:80]2)[C:61]([C:63]2[N:76]([CH2:77][CH3:78])[C:66]3=[N:67][C:68](I)=[C:69]4[N:73]=[CH:72][N:71]([CH3:74])[C:70]4=[C:65]3[CH:64]=2)=[O:62])[CH2:59][CH2:58]1>COCCOC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:79]1([N:60]([CH:57]2[CH2:58][CH2:59]2)[C:61]([C:63]2[N:76]([CH2:77][CH3:78])[C:66]3=[N:67][C:68]([NH:8][C:4]4[CH:5]=[C:6]([CH3:7])[N:2]([CH3:1])[N:3]=4)=[C:69]4[N:73]=[CH:72][N:71]([CH3:74])[C:70]4=[C:65]3[CH:64]=2)=[O:62])[CH2:81][CH2:80]1
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(I)nc21
Reactant: Cc1cc(N)nn1C
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: COCCOC
Product: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Nc3cc(C)n(C)n3)nc21
Temperature: 90 °C
Yield: 31.7 %

Procedure:
To a vial containing 1,5-dimethyl-1H-pyrazol-3-amine (13.60 mg, 0.122 mmol), Pd2(dba)3 (4.67 mg, 5.10 μmol), Xantphos (5.90 mg, 10.20 μmol), and cesium carbonate (100 mg, 0.306 mmol) was added N,N-dicyclopropyl-6-ethyl-4-iodo-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (45.8 mg, 0.102 mmol) in DME (1020 μL). The reaction mixture was sparged with argon for 5 min, the vial was capped, and the reaction mixture was heated at 90° C. 1 h. The reaction mixture was diluted with dichloromethane and vacuum filtered through Celite. The filtrate was concentrated in vacuo. The crude residue was purified via flash column chromatography using an ISCO 12 g column eluting with 1-10% MeOH/CH2Cl2). N,N-Dicyclopropyl-4-(1,5-dimethyl-1H-pyrazol-3-ylamino)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (14 mg, 31.7% yield) was isolated as an off-white solid.
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[CH:10]=[C:11]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)[CH3:12].N1CCC[C@H]1C(O)=O.[CH2:27]([N:30]1[CH2:43][CH2:42][C:33]2[NH:34][C:35]3[CH:36]=[CH:37][C:38]([Cl:41])=[CH:39][C:40]=3[C:32]=2[CH2:31]1)[CH:28]=[CH2:29]>C(Cl)Cl.[Cu](I)I.CO.CN(C=O)C>[CH2:27]([N:30]1[CH2:43][CH2:42][C:33]2[N:34]([CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[CH3:12])[C:35]3[CH:36]=[CH:37][C:38]([Cl:41])=[CH:39][C:40]=3[C:32]=2[CH2:31]1)[CH:28]=[CH2:29]
Reactant: CC(=CBr)c1ccncc1
Reactant: C=CCN1CCc2[nH]c3ccc(Cl)cc3c2C1
Agent: I[Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C=CCN1CCc2c(c3cc(Cl)ccc3n2C=C(C)c2ccncc2)C1
Temperature: 120 °C
Yield: 25.7 %

Procedure:
In a 100 mL screw-cap bottle, potassium phosphate tribasic (1.75 g, 8.25 mmol) was taken. 4-(2-Bromo-1-methyl-vinyl)-pyridine (1.1 g, 5.55 mmol) was added under nitrogen at RT. DMF (15 mL) was added and nitrogen was purged into it for 1-2 min. L-proline, (140 mg, 1.21 mmol), copper Iodide (235 mg, 1.21 mmol), and 2-allyl-8-chloro-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (1 g, 4.06 mmol) were added one by one with nitrogen purging. The screw-cap bottle was closed tightly and the contents heated to 120° C. for 12 h. The reaction was monitored by TLC. The reaction mixture was cooled at RT. DMF was evaporated under vacuum, residue diluted with water (100 mL) and the compound extracted with EtOAc (3×50 mL). The combined organic layers were washed with water (200 mL×3), dried over anhydrous sodium sulfate and concentrated under vacuum to obtain the crude, which was subjected to chromatography (100-200 mesh silica gel and 3% MeOH in DCM as eluent) and recrystallized in ether:hexane (10:90 ratio) to obtain 380 mg of 2-Allyl-8-chloro-5-(2-pyridin-4-yl-propenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (CD3OD, HCl salt) δ (ppm): 8.84 (d, 2H), 8.38 (d, 2H), 7.82 (s, 1H), 7.60 (s, 1H), 7.24 (s, 2H), 6.10 (m, 1H), 5.70 (m, 2H), 4.75 (m, 2H), 4.40 (m, 1H), 4.05 (d, 2H), 4.0 (m, 1H), 3.60 (m, 1H), 3.25 (m, 1H), 2.18 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:12][N:13]3[CH:17]=[C:16]([C:18]([OH:20])=O)[CH:15]=[N:14]3)[CH:8]=2)[N:3]=1.[Na+].[Cl-].CCN=C=NCCCN(C)C.Cl.C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.[NH2:52][CH2:53][C:54]1[CH:55]=[CH:56][C:57]([NH2:61])=[N:58][C:59]=1[CH3:60]>CN(C=O)C.CO.C(#N)C>[NH2:61][C:57]1[N:58]=[C:59]([CH3:60])[C:54]([CH2:53][NH:52][C:18]([C:16]2[CH:15]=[N:14][N:13]([CH2:12][C:7]3[CH:8]=[C:9]4[C:4](=[CH:5][CH:6]=3)[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10]4)[CH:17]=2)=[O:20])=[CH:55][CH:56]=1
Reactant: Cc1ccc2cc(Cn3cc(C(=O)O)cn3)ccc2n1
Reactant: Cc1nc(N)ccc1CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CC#N
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1ccc2cc(Cn3cc(C(=O)NCc4ccc(N)nc4C)cn3)ccc2n1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a suspension of 1-((2-methylquinolin-6-yl)methyl)-1H-pyrazole-4-carboxylic acid (incl. NaCl) (100 mg, 0.337 mmol), EDC.HCl (84 mg, 0.438 mmol) and HOAt (59.6 mg, 0.438 mmol) in DMF (1 ml) was added N-methylmorpholine (0.185 ml, 1.684 mmol). The reaction mixture was stirred for 1 h at 50° C., then 5-(aminomethyl)-6-methylpyridin-2-amine (70.7 mg, 0.337 mmol) was added. Stirring continued at 50° C. for 18 h. Reaction mixture was diluted with methanol, then applied onto a PL-SO3H cartridge (500 mg/6 ml by VARIAN) to catch the desired amine product, washed the cartridge with DMF, DCM and MeOH to remove all impurities, then the product was released from the cartridge by washing with 2M NH3 in MeOH. The basic filtrate was evaporated to give the crude material, which was treated with 0.2 ml of MeOH and 1 ml of ACN in ultrasonic bath. The precipitate formed was filtered, washed with 1 ml of ACN and dried under high vacuum for 4 days to yield the title compound. HPLC (Method J) Rt=2.373 min, MS (Method V) [M+H]+=387.1.
Reaction SMILES: [CH2:1]([C:4]1[N:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]2=[C:6]([C:13]([OH:15])=O)[N:5]=1)[CH2:2][CH3:3].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.[C:37]12([NH2:47])[CH2:46][CH:41]3[CH2:42][CH:43]([CH2:45][CH:39]([CH2:40]3)[CH2:38]1)[CH2:44]2>CN(C=O)C.C(OCC)(=O)C>[C:37]12([NH:47][C:13]([C:6]3[N:5]=[C:4]([CH2:1][CH2:2][CH3:3])[N:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=34)=[O:15])[CH2:44][CH:43]3[CH2:42][CH:41]([CH2:40][CH:39]([CH2:45]3)[CH2:38]1)[CH2:46]2
Reactant: CCCc1nc(C(=O)O)c2ccccn12
Reactant: NC12CC3CC(CC(C3)C1)C2
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1nc(C(=O)NC23CC4CC(CC(C4)C2)C3)c2ccccn12
Reaction time: 0.17 h
Yield: 78.8 %

Procedure:
To a solution of 3-propyl-imidazo[1,5-a]pyridine-1-carboxylic acid (114 mg, 0.44 mmol) in DMF (5 mL) was added EDC (161 mg, 0.84 mmol), HOBt, (90 mg, 0.67 mmol) and Et3N (0.23 mL, 1.68 mmol). The mixture was allowed to stir for 10 min. and adamantylamine (93 mg, 0.62 mmol) was added. The mixture was stirred for 15 h. then diluted with ethyl acetate (30 mL) and washed with water (50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica to yield the title compound (117 mg, 79%). 1H NMR (DMSO-d6) δ 8.31 (1H), 8.02 (1H), 7.04 (1H), 6.93 (1H), 6.81 (1H), 2.97 (2H), 2.07 (9H), 1.76 (2H), 1.67 (6H), 0.96 (3H); m/z (M+H)=338.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([S:25]([CH2:28][CH2:29][CH2:30][C:31]([O:33]C(C)(C)C)=[O:32])(=[O:27])=[O:26])[C:10]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[C:14]3[S:22][CH:23]=[CH:24][C:13]=23)=[O:11])=[CH:5][CH:4]=1.C(Cl)Cl>FC(F)(F)C(O)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]([S:25]([CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])(=[O:26])=[O:27])[C:10]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[C:14]3[S:22][CH:23]=[CH:24][C:13]=23)=[O:11])=[CH:7][CH:8]=1
Reactant: COc1ccc(N(C(=O)c2c3ccccc3nc3sccc23)S(=O)(=O)CCCC(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(N(C(=O)c2c3ccccc3nc3sccc23)S(=O)(=O)CCCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 104.8 %

Procedure:
80 mg (0.13 mmol) N-(4-Methoxy-phenyl)-N-(tert-butyl-oxycarbonylpropyl-sulfonyl)-thieno-[2,3-b]quinoline-4-carboxamide 16 were dissolved in 1.2 mL trifluoroacetic acid and stirred for 30 minutes at room temperature. 50 mg of silica gel and 10 mL of methylene chloride were added and the solvent was removed under reduced pressure. The residue was purified by chromatography on silica gel (eluent: methylene chloride/diethylether 6:4+0.1% trifluoroacetic acid). Evaporation of the appropriate fractions gave 66 mg of the desired product 17.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH2:9]([N:11]=[C:12]=[O:13])[CH3:10].O>CN1CCCC1=O>[CH2:9]([NH:11][C:12]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1)=[O:13])[CH3:10]
Reactant: CCN=C=O
Reactant: Nc1ccc(O)cc1
Solvent: O
Solvent: CN1CCCC1=O
Product: CCNC(=O)Nc1ccc(O)cc1
Reaction time: 2 h
Yield: 55 %

Procedure:
10 g of 4-aminophenol (Mw=109.13; 0.0916 mol) are suspended in 100 cm3 of anhydrous N-methylpyrrolidone, under an inert atmosphere. 6.5 g of ethyl isocyanate (Mw=71.08; 0.0914 mol) are then added dropwise. The reaction mixture is brought to a temperature of 60° C. with stirring for two hours. The mixture is poured into one litre of water and the precipitate is then filtered off and dried. After recrystallization from ethanol, 9 g of a white powder are obtained, which corresponds to a yield of 55%. The melting point of the product obtained is 173.4° C. The 200 MHz 1H NMR spectrum and the elemental analysis are in accordance with the expected product.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9]([CH2:11][N:12]3[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[N:14]([CH:21]([CH2:26][CH2:27][CH3:28])[CH2:22][C:23]([OH:25])=O)[C:13]3=[O:29])=[CH:8][S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:42]1([S:48]([NH2:51])(=[O:50])=[O:49])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.N12CCCN=C1CCCCC2.Cl>C1COCC1.O>[CH3:1][C:2]1[C:10]2[C:9]([CH2:11][N:12]3[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[N:14]([CH:21]([CH2:26][CH2:27][CH3:28])[CH2:22][C:23]([NH:51][S:48]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)(=[O:50])=[O:49])=[O:25])[C:13]3=[O:29])=[CH:8][S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCCC(CC(=O)O)n1c(=O)n(Cc2csc3cccc(C)c23)c2ccccc21
Reactant: NS(=O)(=O)c1ccccc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: CCCC(CC(=O)NS(=O)(=O)c1ccccc1)n1c(=O)n(Cc2csc3cccc(C)c23)c2ccccc21
Temperature: 55 °C
Reaction time: 0.5 h
Yield: 82.2 %

Procedure:
3-[3-(4-Methyl-benzo[b]thiophen-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-hexanoic acid (56 mg, 0.14 mmol) is dissolved in dry THF (1.0 mL) and 1,1′-carbonyl diimidazole (50 mg, 0.29 mmol) is added into it at room temperature. The mixture is stirred for 30 min and then it is heated at 55° C. for 1 hr. After the mixture is cooled down to room temperature, benzenesulfonamide (46 mg, 0.29 mmol) is added and after 10 min, 1,8-diazabicyclo[5,4,0]undec-7-ene (0.044 mL, 0.29 mmol) is added. The mixture is stirred for 3 hr at room temperature. Then 1.0 M HCl (3 mL) is added followed by water (30 mL). The mixture is extracted with EtOAc (3×50 mL) and the organic layers are combined, dried and concentrated to give crude product. Purification by preparative TLC using 2% MeOH in CH2Cl2 affords 63 mg (84%) of N-{3-[3-(4-Methyl-benzo[b]thiophen-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]hexanoyl}-benzenesulfonamide. LCMS (ESMS): m/z 548.11 (M+H+).
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([C:19]5[O:23][C:22]([NH:24]CC6C=CC(OC)=CC=6)=[N:21][N:20]=5)[CH:17]=4)[N:12]([S:34]([C:37]4[CH:43]=[CH:42][C:40]([CH3:41])=[CH:39][CH:38]=4)(=[O:36])=[O:35])[CH:11]=3)[CH:7]=[N:6][CH:5]=2)[CH2:3][CH2:2]1>C(O)(C(F)(F)F)=O>[CH:1]1([C:4]2[N:9]=[C:8]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([C:19]5[O:23][C:22]([NH2:24])=[N:21][N:20]=5)[CH:17]=4)[N:12]([S:34]([C:37]4[CH:38]=[CH:39][C:40]([CH3:41])=[CH:42][CH:43]=4)(=[O:36])=[O:35])[CH:11]=3)[CH:7]=[N:6][CH:5]=2)[CH2:2][CH2:3]1
Reactant: COc1ccc(CNc2nnc(-c3ccc4c(c3)c(-c3cncc(C5CC5)n3)cn4S(=O)(=O)c3ccc(C)cc3)o2)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cncc(C4CC4)n3)c3cc(-c4nnc(N)o4)ccc32)cc1
Yield: 68.6 %

Procedure:
An orange-brown solution of 5-(3-(6-cyclopropylpyrazin-2-yl)-1-tosyl-1H-indol-5-yl)-N-(4-methoxybenzyl)-1,3,4-oxadiazol-2-amine (69.7 mg, 0.118 mmol) in TFA (0.5 mL) was heated at 120° C. (microwave for 10 min. TFA was removed in vacuo, and the resulting brown oil was partitioned between DCM (30 mL) and 0.5 N NaOH (10 mL). The organic layer was separated and concentrated onto silica gel. Chromatographic purification (silica gel, 0-100% EtOAc/Hex) furnished 5-(3-(6-cyclopropylpyrazin-2-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazol-2-amine (38.3 mg, 0.081 mmol, 69%) as a white solid: MS (ESI, pos. ion) m/z: 473.1 (M+1).
Reaction SMILES: B(Br)(Br)Br.[F:5][C:6]1[CH:22]=[CH:21][C:9]2[C:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=3)=[N:11][O:12][C:8]=2[CH:7]=1.CO>ClCCl.C(O)(C)C>[F:5][C:6]1[CH:22]=[CH:21][C:9]2[C:10]([C:13]3[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=3)=[N:11][O:12][C:8]=2[CH:7]=1
Reactant: COc1ccc(-c2noc3cc(F)ccc23)cc1
Agent: BrB(Br)Br
Solvent: CC(C)O
Solvent: CO
Solvent: ClCCl
Product: Oc1ccc(-c2noc3cc(F)ccc23)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.4 %

Procedure:
Add a 1.0 M solution of boron tribromide (2.31 L, 2.31 mol) in dichloromethane (1.87 L) to a cold (0° C.) solution of 6-fluoro-3-(4-methoxy-phenyl)-benzo[d]isoxazole (187.2 g, 0.77 mol) in dichloromethane, over ˜2 hours. Warm to room temperature overnight. Cool reaction mixture to ˜3° C. and add methanol (4 L) over a period of time of 1 hour, keeping the temperature of the reaction mixture at 3-10° C. Gas evolution occurs. Concentrate (40-50° C., 50 torr) reaction mixture to give a gray solid. Heat to dissolve the gray solid in isopropyl alcohol (550 mL) at reflux. Cool (room temperature), followed by 0-5° C. for 1 hour. Filter off the solid and wash filter cake with cold (0° C.) isopropyl alcohol (265 mL) and dry to air. Subsequently dry the solid in the oven (60° C., 50 torr) overnight to give the title compound (147.2 g, 83% Yield): 1H NMR (DMSO-d6, 200 MHz) δ 7.0 (d, 2H), 7.4 (t, 1H), 7.8 (d, 1H), 7.84 (d, 2H), 8.18 (m, 1H). Purity by LC/MS (APCl)=100% area, [M+H]+=230 m/e.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([NH:6][CH2:7][CH2:8][CH2:9][CH3:10])=[C:4]([N+:13]([O-])=O)[CH:3]=1.O.O.[Sn](Cl)Cl.Cl.C([O-])(O)=O.[Na+].[OH-].[Na+]>C(O)(C)C>[Br:1][C:2]1[CH:3]=[C:4]([NH2:13])[C:5]([NH:6][CH2:7][CH2:8][CH2:9][CH3:10])=[CH:11][CH:12]=1
Reactant: CCCCNc1ccc(Br)cc1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Solvent: CC(C)O
Solvent: O
Product: CCCCNc1ccc(Br)cc1N

Procedure:
A mixture of Example 166A (1.82 g, 6.66 mmol) and tin(II) chloride dihydrate (3.76 g, 16.6 mmol), and concentrated HCl (22 mL) in isopropanol (30 mL) at room temperature was stirred for 90 minutes, adjusted to pH 6.5-7.5 using NaHCO3 and 6M NaOH, and filtered. The filter cake was washed with water and ethyl acetate, and the filtrate was separated. The aqueous phase was extracted with ethyl acetate (3×50 mL) and the combined organic phases were washed with brine (20 mL), dried (Na2SO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 20-50% ethyl acetate/hexanes to provide the desired product.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][N:5]([CH3:20])[C:6]1[N:11]=[C:10]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[CH:8][CH:7]=1.[C:21](O)(=[O:24])[CH:22]=[CH2:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:21]([NH:2][CH2:3][CH2:4][N:5]([CH3:20])[C:6]1[N:11]=[C:10]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:17])[CH3:18])[CH:9]=[CH:8][CH:7]=1)(=[O:24])[CH:22]=[CH2:23]
Reactant: CN(CCN)c1cccc(NC(=O)OC(C)(C)C)n1
Reactant: C=CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CC(=O)NCCN(C)c1cccc(NC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
A mixture of 110c (1.2 g, 4.5 mmol), acrylic acid (0.37 mL, 5.4 mmol), HATU (2.05 g, 5.4 mmol) and DIPEA (4.6 mL, 10.8 mmol) in DCM (30 mL) was stirred at rt overnight. The mixture was washed with water. The organic layer was separated, dried over Na2SO4, filtered and concentrated to give tert-butyl 6-((2-acrylamidoethyl)(methyl)amino)pyridin-2-ylcarbamate 110d (1.2 g, 75%) as a brown oil. The material was used for the next step directly. ESI-LCMS: m/z=321.3
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([S:12](Cl)(=[O:14])=[O:13])=[C:9]([CH3:16])[C:8]=2[CH:17]=1)([CH3:3])[CH3:2].[NH2:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([OH:24])=[O:23]>>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([S:12]([NH:18][C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=3)[C:22]([OH:24])=[O:23])(=[O:14])=[O:13])=[C:9]([CH3:16])[C:8]=2[CH:17]=1)([CH3:3])[CH3:2]
Reactant: Nc1cccc(C(=O)O)c1
Reactant: Cc1c(S(=O)(=O)Cl)oc2ccc(C(C)C)cc12
Product: Cc1c(S(=O)(=O)Nc2cccc(C(=O)O)c2)oc2ccc(C(C)C)cc12
Yield: 18.7 %

Procedure:
The product was prepared according to General Procedure 1, described in Example 1, starting from 5-isopropyl-3-methylbenzofuran-2-sulfonyl chloride (Intermediate 16) (24 mg, 0.09 mmol) and 3-aminobenzoic acid (24 mg, 0.18 mmol) giving 6.3 mg (19%) of the title compound. MS (ESI+) calcd for C19H19NO5S 373.098393, found 373.098603.